glycogen and Hyperglycemia

As the burden of type 2 diabetes mellitus (T2DM) grows in the 21st century, the need to understand glucose metabolism heightens. Increased gluconeogenesis is a major contributor to the hyperglycemia seen in T2DM. Isotope tracer experiments in humans and animals over several decades have offered insights into gluconeogenesis under euglycemic and diabetic conditions. This review focuses on the current understanding of carbon flux in gluconeogenesis, including substrate contribution of various gluconeogenic precursors to glucose production. Alterations of gluconeogenic metabolites and fluxes in T2DM are discussed. We also highlight ongoing knowledge gaps in the literature that require further investigation. A comprehensive analysis of gluconeogenesis may enable a better understanding of T2DM pathophysiology and identification of novel targets for treating hyperglycemia.

Topics: Animals; Carbon; Carbon Isotopes; Diabetes Mellitus, Type 2; Gluconeogenesis; Glucose; Glycogen; Humans; Hyperglycemia; Metabolomics

Proinsulin C-peptide, released in equimolar amounts with insulin by pancreatic β cells, since its discovery in 1967 has been thought to be devoid of biological functions apart from correct insulin processing and formation of disulfide bonds between A and B chains. However, in the last two decades research has brought a substantial amount of data indicating a crucial role of C-peptide in regulating various processes in different types of cells and organs. C-peptide acts presumably via either G-protein-coupled receptor or directly inside the cell, after being internalized. However, a receptor binding this peptide has not been identified yet. This peptide ameliorates pathological changes induced by type 1 diabetes mellitus, including glomerular hyperfiltration, vessel endothelium inflammation and neuron demyelinization. In diabetic patients and diabetic animal models, C-peptide substitution in physiological doses improves the functional and structural properties of peripheral neurons and protects against hyperglycemia-induced apoptosis, promoting neuronal development, regeneration and cell survival. Moreover, it affects glycogen synthesis in skeletal muscles. In vitro C-peptide promotes disaggregation of insulin oligomers, thus enhancing its bioavailability and effects on metabolism. There are controversies concerning the biological action of C-peptide, particularly with respect to its effect on Na⁺/K⁺-ATPase activity. Surprisingly, the excess of circulating peptide associated with diabetes type 2 contributes to atherosclerosis development. In view of these observations, long-term, large-scale clinical investigations using C-peptide physiological doses need to be conducted in order to determine safety and health outcomes of long-term administration of C-peptide to diabetic patients.

Topics: Animals; Apoptosis; Atherosclerosis; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Neuropathies; Disease Models, Animal; Glycogen; Humans; Hyperglycemia; Muscle, Skeletal; Peripheral Nervous System

This review deals with the role of glycogen storage in skeletal muscle for the development of insulin resistance and type 2 diabetes. Specifically, the role of the enzyme glycogen synthase, which seems to be locked in its hyperphosphorylated and inactivated state, is discussed. This defect seems to be secondary to ectopic lipid disposition in the muscle cells. These molecular defects are discussed in the context of the overall pathophysiology of hyperglycemia in type 2 diabetic subjects.

Topics: Diabetes Mellitus, Type 2; Glucose; Glycated Hemoglobin; Glycogen; Glycogen Synthase; Humans; Hyperglycemia; Insulin; Insulin Resistance; Lipid Metabolism; Muscle, Skeletal; Phosphorylation

Type 2 diabetes is a complex metabolic disease with hyperglycemia as its recognizable hallmark. Hepatic glucose output is elevated in Type 2 diabetic patients, and evidence suggests drugs which lower hepatic glucose production are effective antihyperglycemic agents. Glycogenolysis, which is the release of monomeric glucose from its polymeric storage form called glycogen, is a key contributor to hepatic glucose output. Glycogen phosphorylase is the enzyme that catalyzes this process. This review covers advances in the design of small molecule inhibitors of this enzyme, their biological activity, and their potential as effective antihyperglycemic agents for the treatment of Type 2 diabetes.

Topics: Diabetes Mellitus, Type 2; Enzyme Inhibitors; Glucose; Glycogen; Glycogen Phosphorylase; Humans; Hyperglycemia; Hypoglycemic Agents; Liver

Nuclear magnetic resonance (NMR) spectroscopy has made noninvasive and repetitive measurements of human hepatic glycogen concentrations possible. Monitoring of liver glycogen in real-time mode has demonstrated that glycogen concentrations decrease linearly and that net hepatic glycogenolysis contributes only about 50 percent to glucose production during the early period of a fast. Following a mixed meal, hepatic glycogen represents approximately 20 percent of the ingested carbohydrates, while only about 10 percent of an intravenous glucose load is retained by the liver as glycogen. During mixed-meal ingestion, poorly controlled type 1 diabetic patients synthesize only about 30 percent of the glycogen stored in livers of nondiabetic humans studied under similar conditions. Reduced net glycogen synthesis can be improved but not normalized by short-term, intensified insulin treatment. A decreased increment in liver glycogen content following meals was also found in patients with maturity-onset diabetes of the young due to glucokinase mutations (MODY-2). In patients with poorly controlled type 2 diabetes, fasting hyperglycemia can be attributed mainly to increased rates of endogenous glucose production, which was found by 13C NMR to be due to increased rates of gluconeogenesis. Metformin treatment improved fasting hyperglycemia in these patients through a reduction in hepatic glucose production, which could be attributed to a decrease in gluconeogenesis. In conclusion, NMR spectroscopy has provided new insights into the pathogenesis of hyperglycemia in type 1, type 2, and MODY diabetes and offers the potential of providing new insights into the mechanism of action of novel antidabetic therapies.

Topics: Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Fasting; Glucose; Glycogen; Humans; Hyperglycemia; Liver; Liver Glycogen; Magnetic Resonance Spectroscopy; Metformin; Time Factors

Insulin resistance is defined as a clinical state in which a normal or elevated insulin level produces an attenuated biologic response. Specifically, the biologic response most studied is insulin-stimulated glucose disposal, yet the precise cellular mechanism responsible is not yet known. However, the presence of insulin resistance is observed many years before the onset of clinical hyperglycemia and the diagnosis of Type 2 diabetes. Insulin resistance at this stage appears to be significantly associated with a clustering of cardiovascular risk factors predisposing the individual to accelerated cardiovascular disease. An overview of insulin resistance and the associated clinical insulin resistant state will be discussed.

Topics: Animals; Biological Transport; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucose; Glycogen; Humans; Hyperglycemia; Insulin; Insulin Resistance; Models, Chemical; Signal Transduction; Syndrome

In vitro evidence indicates that the liver responds directly to changes in circulating glucose concentrations with reciprocal changes in glucose production and that this autoregulation plays a role in maintenance of normoglycemia. Under in vivo conditions it is difficult to separate the effects of glucose on neural regulation mediated by the central nervous system from its direct effect on the liver. Nevertheless, it is clear that nonhormonal mechanisms can cause significant changes in net hepatic glucose balance. In response to hyperglycemia, net hepatic glucose output can be decreased by as much as 60-90% by nonhormonal mechanisms. Under conditions in which hepatic glycogen stores are high (i.e. the overnight-fasted state), a decrease in the glycogenolytic rate and an increase in the rate of glucose cycling within the liver appear to be the explanation for the decrease in hepatic glucose output seen in response to hyperglycemia. During more prolonged fasting, when glycogen levels are reduced, a decrease in gluconeogenesis may occur as a part of the nonhormonal response to hyperglycemia. A substantial role for hepatic autoregulation in the response to insulin-induced hypoglycemia is most clearly evident in severe hypoglycemia (< or = 2.8 mmol/l). The nonhormonal response to hypoglycemia apparently involves enhancement of both gluconeogenesis and glycogenolysis and is capable of supplying enough glucose to meet at least half of the requirement of the brain. The nonhormonal response can include neural signaling, as well as autoregulation. However, even in the absence of the ability to secrete counterregulatory hormones (glucocorticoids, catecholamines, and glucagon), dogs with denervated livers (to interrupt neural pathways between the liver and brain) were able to respond to hypoglycemia with increases in net hepatic glucose output. Thus, even though the endocrine system provides the primary response to changes in glycemia, autoregulation plays an important adjunctive role.

Topics: Animals; Blood Glucose; Dogs; Gluconeogenesis; Glucose; Glycogen; Homeostasis; Humans; Hyperglycemia; Liver; Rats

Topics: Adenosine Triphosphate; Blood Glucose; Diabetes Mellitus, Type 2; Diet Therapy; Exercise Therapy; Female; Glycogen; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Secretion; Male; Sulfonylurea Compounds

Insulin plays a key role in the maintenance of normal glucose tolerance by suppressing endogenous glucose production during a meal. Insulin is not, however, involved in the regulation of splanchnic glucose uptake. The latter process appears, based on studies performed in dogs, to be regulated primarily by the arterial-portal glucose gradient and to a smaller extent by glucose mass-action. Regarding peripheral glucose utilization, insulin is not needed to maintain a normal rate of glucose utilization since this can also be achieved by hyperglycaemia and glucose mass-action. Insulin is, however, necessary for the maintenance of normal rates of glucose oxidation and storage in insulin-sensitive tissues, and for the prevention of excessive gluconeogenic substrate production.

Topics: Animals; Carbohydrate Metabolism; Dogs; Gluconeogenesis; Glucose; Glycogen; Humans; Hyperglycemia; Insulin; Liver; Muscles; Myocardium; Viscera

By the term "insulin resistance" we understand the attenuation of insulin-stimulated glucose uptake, which is mainly due to attenuated glycogen synthesis in skeletal muscle and is partially compensated with regard to plasma glucose homeostasis by hyperinsulinemia. Other mechanisms of insulin are either not attenuated or are less so and may contribute via hyperinsulinemia to the prevalence of hypertension, obesity, dyslipoproteinemia and type-II diabetes. At the level of insulin receptors, resistance can be due to muscle-specific, preferential expression of the low-affinity B-isoform of the insulin receptors. In rare cases of extreme resistance, it can also be due to several mutations at the insulin receptor gene or due to insulin-receptor autoantibodies. At the postreceptor level, the translocation and or expression of the insulin-responsive glucose carrier GluT-4 can be down-regulated via the hexosamine pathway by hyperglycemia plus hyperinsulinemia. Furthermore, Glut-4 can be inhibited and/or down-regulated by sustained insulin deficiency, partially via c-AMP-dependent pathways. Additionally, the insulin-induced glycogen synthesis in skeletal muscle can be attenuated by the endogenous peptides amylin and calcitonin-gene-related peptide, and by modulations of endothelial function, perfusion and capillary recruitment in the microcirculation of skeletal muscle. Epidemiological data indicate a genetic predisposition for insulin resistance. However, among the many mechanisms potentially contributing to the complex syndrome of insulin resistance, no specific localization of that predisposition can be proposed at present.

Topics: Amyloid; beta-N-Acetylhexosaminidases; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glycogen; Humans; Hyperglycemia; Hyperinsulinism; Insulin Resistance; Islet Amyloid Polypeptide; Monosaccharide Transport Proteins; Receptor, Insulin

Altered glucose homeostasis in the neonate often results from antecedent events during fetal life. This article describes the normal and altered development of glucoregulatory capabilities during perinatal life and relates it to problems of hypo- and hyperglycemia in the neonate.

Topics: Diabetes Mellitus; Embryonic and Fetal Development; Female; Fetus; Gluconeogenesis; Glucose; Glycogen; Homeostasis; Humans; Hyperglycemia; Hyperinsulinism; Hypoglycemia; Infant, Newborn; Infant, Premature; Mass Screening; Maternal-Fetal Exchange; Pregnancy; Pregnancy in Diabetics; Risk

This paper reviews experimental work bearing on the feasibility of using the analog of glucose, 5-thio-D-glucose, to control human male fertility. The initial experiments in mice indicated that suitable oral doses of thioglucose caused reversible infertility unaccompanied by loss of libido or evidence of extratesticular toxicity. Subsequent work in mice and rats showed that treatment of 7 or 8 weeks appeared to cause irreversible sterility in many of the animals. In both species the smallest doses causing infertility also caused transient hyperglycemia. In rats a large dose of thioglucose was found to raise the concentration of nonesterified fatty acids in the blood and repeated smaller doses increased the excretion of catecholamines. These reports, suggesting that it can cause sterility and has extratesticular effects on metabolism, do not augur well for the acceptibility of thioglucose as a suitable chemical with which to control fertility in the human male.

Topics: Amino Acids; Animals; Antispermatogenic Agents; Blood Glucose; Cricetinae; Deoxyglucose; Female; Fertility; Gerbillinae; Glucose; Glycogen; Haplorhini; Hyperglycemia; Male; Mice; Protein Biosynthesis; Rats; Testis

Topics: Adrenal Glands; Animals; Blood Glucose; Carbohydrate Metabolism; Carbon Isotopes; Gluconeogenesis; Glucose; Glucose Tolerance Test; Glycogen; Humans; Hyperglycemia; Insulin; Insulin Resistance; Insulin Secretion; Liver; Myocardium; Wounds and Injuries

Topics: Adenosine Triphosphate; Animals; Blood Glucose; Citrates; Glucose; Glucosephosphates; Glutamates; Glycogen; Hexokinase; Hexosediphosphates; Hexosephosphates; Hyperglycemia; Islets of Langerhans; Lactates; Methods; Mice; NAD; NADP; Obesity; Organophosphorus Compounds; Pyruvates; Spectrometry, Fluorescence; Uridine Diphosphate Sugars

Topics: Amino Acids; Cyclic AMP; Diabetes Mellitus; Digestive System; Fatty Acids, Nonesterified; Glucagon; Gluconeogenesis; Glucose; Glycogen; Humans; Hyperglycemia; Insulin; Insulin Secretion; Liver Glycogen; Pancreas; Pancreatic Diseases; Pancreatic Neoplasms

Topics: Adipose Tissue; Blood Glucose; Cell Membrane Permeability; Cytoplasm; Diabetes Mellitus; Diabetic Coma; Gluconeogenesis; Glucose; Glycogen; Glycolysis; Glycosuria, Renal; Humans; Hyperglycemia; Insulin; Lipid Metabolism; Liver; Mitochondria; Muscles; Pancreas; Pancreatectomy; Proteins; Time Factors

Topics: Acid Phosphatase; Adult; Animals; Citric Acid Cycle; Diabetes Mellitus; Erythroblastosis, Fetal; Female; Glycogen; Glycolysis; Histocytochemistry; Humans; Hyperglycemia; Infant, Newborn; Insulin; Islets of Langerhans; Lysosomes; Mice; Obesity; Pentosephosphates; Pregnancy; Transaminases

Topics: Acidosis; Adipose Tissue; Animals; Animals, Laboratory; Blood Glucose; Diabetes Mellitus; Disease Models, Animal; Feeding Behavior; Glycogen; Guinea Pigs; Haplorhini; Hyperglycemia; Hyperinsulinism; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Ketone Bodies; Mice; Muscles; Obesity; Pancreas; Prediabetic State; Rats

Topics: Animals; Carbohydrate Metabolism; Diazoxide; Glucocorticoids; Glycogen; Glycolysis; Humans; Hyperglycemia; Insulin; Insulin Secretion; Potassium; Potassium Deficiency; Rats; Sodium; Sulfonamides; Water-Electrolyte Balance

The effect of hyperglycaemia on exercise with low and elevated muscle glycogen on glucose utilization (GUR), carbohydrate and fat oxidation, hormonal and metabolite responses, as well as rating of perceived exertion (RPE) were explored.. Five healthy trained males were exercised for 90 min at 70% V̇O. The CHO-L and CHO-D conditions resulted in muscle glycogen concentrations of 377 and 159 mmol/g dw, respectively. Hyperglycaemia elevated plasma insulin concentrations with higher levels for CHO-L than for CHO-D (P < 0.01). Conversely, CHO-D elevated plasma adrenaline and noradrenaline higher than CHO-L (P < 0.05). Plasma fat metabolites (NEFA, β-hydroxybutyrate, and glycerol) were higher under CHO-D than CHO-L (P < 0.01). The resultant was that the rates of total carbohydrate and fat oxidation were elevated and depressed for loaded CHO-L vs CHO-D respectively (P < 0.01), although no difference was found for GUR (P > 0.05). The RPE over the exercise period was higher for CHO-D than CHO-L (P < 0.05).. Hyperglycaemia during exercise, when muscle glycogen is reduced, attenuates insulin but promotes catecholamines and fat metabolites. The effect is a subsequent elevation of fat oxidation, a reduction in CHO oxidation without a concomitant increase in GUR, and an increase in RPE.

Topics: Adolescent; Adult; Carbohydrate Metabolism; Cross-Over Studies; Diet, Carbohydrate Loading; Exercise; Glycogen; Healthy Volunteers; Hormones; Humans; Hyperglycemia; Lipid Metabolism; Male; Muscle, Skeletal; Oxidation-Reduction; Physical Exertion; Young Adult

Mitochondrial dysfunction has been implicated in the pathogenesis of type 2 diabetes. We hypothesized that any impairment in insulin-stimulated muscle ATP production could merely reflect the lower rates of muscle glucose uptake and glycogen synthesis, rather than cause it. If this is correct, muscle ATP turnover rates in type 2 diabetes could be increased if glycogen synthesis rates were normalized by the mass-action effect of hyperglycemia. Isoglycemic- and hyperglycemic-hyperinsulinemic clamps were performed on type 2 diabetic subjects and matched controls, with muscle ATP turnover and glycogen synthesis rates measured using (31)P- and (13)C-magnetic resonance spectroscopy, respectively. In diabetic subjects, hyperglycemia increased muscle glycogen synthesis rates to the level observed in controls at isoglycemia [from 19 ± 9 to 41 ± 12 μmol·l(-1)·min(-1) (P = 0.012) vs. 40 ± 7 μmol·l(-1)·min(-1) in controls]. This was accompanied by a modest increase in muscle ATP turnover rates (7.1 ± 0.5 vs. 8.6 ± 0.7 μmol·l(-1)·min(-1), P = 0.04). In controls, hyperglycemia brought about a 2.5-fold increase in glycogen synthesis rates (100 ± 24 vs. 40 ± 7 μmol·l(-1)·min(-1), P = 0.028) and a 23% increase in ATP turnover rates (8.1 ± 0.9 vs. 10.0 ± 0.9 μmol·l(-1)·min(-1), P = 0.025) from basal state. Muscle ATP turnover rates correlated positively with glycogen synthesis rates (r(s) = 0.46, P = 0.005). Changing the rate of muscle glucose metabolism in type 2 diabetic subjects alters demand for ATP synthesis at rest. In type 2 diabetes, skeletal muscle ATP turnover rates reflect the rate of glucose uptake and glycogen synthesis, rather than any primary mitochondrial defect.

Topics: Adenosine Triphosphate; Algorithms; Blood Glucose; Breath Tests; Diabetes Mellitus, Type 2; Energy Metabolism; Female; Glucose Clamp Technique; Glycogen; Humans; Hyperglycemia; Insulin; Male; Middle Aged; Muscle, Skeletal; Up-Regulation

Muscle contains the largest reservoir of glycogen (Glyc), a depot that is closely regulated and with influence on insulin sensitivity. The current study examines muscle Glyc in type 2 diabetes mellitus (T2DM) and obesity and with respect to muscle fiber type, intramyocellular lipid content (IMCL), and mitochondrial function (oxidative enzyme activity; OX-Enz). There is increasing interest in the relation of IMCL and mitochondrial dysfunction with insulin resistance (IR), yet the association with muscle Glyc has not been examined with regard to these parameters. Using a quantitative histological approach specific to muscle fiber types, we assessed muscle Glyc, IMCL, and OX-Enz in vastus lateralis obtained by percutaneous biopsy in lean nondiabetic (L; n = 16), obese nondiabetic (Ob; n = 15), and T2DM volunteers (n = 14). Insulin sensitivity was estimated using homeostasis model assessment (HOMA)-IR. Muscle Glyc was reduced in T2DM, a deficit evident for type IIa fibers, yet minor in types I and IIb fibers. Low Glyc in T2DM correlated with fasting hyperglycemia. Also, in T2DM and Ob, there was significantly higher IMCL and lower OX-Enz in all fiber types. The IMCL-to-OX-Enz ratio, especially for type I fibers, correlated strongly with IR. Similarly, a Glyc-to-OX-Enz ratio correlated with IR, particularly for type IIb fibers. This ratio tended to be higher in Ob and T2DM. In summary, there is decreased muscle Glyc in T2DM yet a disproportional Glyc-to-OX-Enz relationship that is related to IR, although not as robustly as the IMCL-to-OX-Enz ratio.

Topics: Diabetes Mellitus, Type 2; Fasting; Female; Glycogen; Homeostasis; Humans; Hyperglycemia; Insulin Resistance; Lipid Metabolism; Male; Middle Aged; Mitochondria, Muscle; Muscle Fibers, Skeletal; Muscle, Skeletal; Obesity; Reference Values

To determine the effect of a single bout of exercise and increased substrate availability after exercise on gene expression and content of the glucose transporter-4 (GLUT-4) protein in equine skeletal muscle.. 6 healthy adult Thoroughbreds.. The study was designed in a balanced, randomized, 3-way crossover fashion. During 2 trials, horses were exercised at 45% of their maximal rate of oxygen consumption for 60 minutes after which 1 group received water (10 mL/kg), and the other group received glucose (2 g/kg, 20% solution) by nasogastric intubation. During 1 trial, horses stood on the treadmill (sham exercise) and then received water (10 mL/kg) by nasogastric intubation. Muscle glycogen concentration and muscle GLUT-4 protein and mRNA content were determined before exercise and at 5 minutes and 4, 8, and 24 hours after exercise.. Although exercise resulted in a 30% reduction in muscle glycogen concentration, no significant difference was detected in muscle GLUT-4 protein or mRNA content before and after exercise. Glycogen replenishment was similar in both exercised groups and was not complete at 24 hours after exercise. Horses that received glucose had significantly higher plasma glucose and insulin concentrations for 3 hours after exercise, but no effect of hyperglycemia was detected on muscle GLUT-4 protein or mRNA content.. Under the conditions of this study, neither exercise nor the combination of exercise followed by hyperglycemia induced translation or transcription of the GLUT-4 protein in horses.

Topics: Animals; Blood Glucose; Exercise Test; Female; Glucose; Glucose Transporter Type 4; Glycogen; Horses; Hyperglycemia; Intubation, Gastrointestinal; Lactates; Male; Monosaccharide Transport Proteins; Muscle Proteins; Muscle, Skeletal; Oxygen Consumption; Physical Conditioning, Animal

The purpose of this study was to determine whether pre-exercise ingestion of meals with moderate and high glycemic indexes (GI) affects glucose availability during exercise and exercise performance time. Six male volunteers (22 +/- 1 years; 80.4 +/- 3.7 kg; VO(2peak), 54.3 +/- 1.2 ml. kg(-1). min(-1)) ingested 75 g of carbohydrate in the form of 2 different breakfast cereals, rolled oats (moderate GI, approximately 61; MOD-GI) or puffed rice (high GI, approximately 82; HI-GI), combined with 300 mL of water; or water alone (control). The trials were randomized, and the meals were ingested 45 minutes before the subjects performed cycling exercise (60% VO(2peak)) to exhaustion. Venous blood samples were drawn to measure glucose, free fatty acids (FFAs), glycerol, insulin (INS), epinephrine (EPI) and norepinephrine (NE) concentrations. A muscle biopsy specimen was obtained from the vastus lateralis before the meal and immediately after exercise for glycogen determination. Before exercise, both test meals elicited significant (P <.05) hyperglycemia and hyperinsulinemia compared with control. The glycemic response was higher (P <.05) at the start of exercise after the HI-GI meal than after the control. During exercise, plasma glucose levels were higher (P <.05) at 60 (5.2 +/- 0.1, 4.2 +/- 0.2, and 4.6 +/- 0.1 mmol. L(-1)) and 90 (4.8 +/- 0.1, 4.1 +/- 0.1, and 4.3 +/- 0.1 mmol. L(-1)) minutes after the MOD-GI meal than after either the HI-GI or control. Total carbohydrate oxidation was greater (P <.05) during the MOD-GI trial than in control and was directly correlated with exercise performance time (r =.95, P <.0001). Pre-exercise plasma FFA levels were suppressed (P <.05) 30 and 45 minutes after ingestion of the HI-GI meal and 45 minutes after the MOD-GI meal compared with control. At 30, 60, and 120 minutes of exercise, FFAs remained suppressed (P <.05) for both test meals compared with control. At exhaustion, plasma glucose, INS, FFA, glycerol, EPI, and NE levels and muscle glycogen use were not different for all trials. Exercise time was prolonged (P <.05) after the MOD-GI meal compared with control, but the HI-GI trial was not different from control (MOD-GI, 165 +/- 11; HI-GI, 141 +/- 8; control, 134 +/- 13 minutes). Thus, in contrast to the HI-GI meal or control, the MOD-GI breakfast cereal ingested 45 minutes before exercise enhanced performance time, maintained euglycemia for a longer period during exercise, and resulted in greater total carbohydrate ox

Topics: Adult; Blood Glucose; Body Mass Index; Catecholamines; Dietary Carbohydrates; Edible Grain; Energy Metabolism; Exercise; Glycogen; Humans; Hyperglycemia; Insulin; Male; Muscle, Skeletal; Oxygen Consumption; Physical Endurance; Time Factors

The effects of fasting on the pathways of insulin-stimulated glucose disposal were explored in three groups of seven normal subjects. Group 1 was submitted to a euglycemic hyperinsulinemic clamp ( approximately 100 microU/ml) after both a 12-h and a 4-day fast. The combined use of [3-(3)H]- and [U-(14)C]glucose allowed us to demonstrate that fasting inhibits, by approximately 50%, glucose disposal, glycolysis, glucose oxidation, and glycogen synthesis via the direct pathway. In group 2, in which the clamp glucose disposal during fasting was restored by hyperglycemia (155 +/- 15 mg/dl), fasting stimulated glycogen synthesis (+29 +/- 2%) and inhibited glycolysis (-32 +/- 3%) but only in its oxidative component (-40 +/- 3%). Results were similar in group 3 in which the clamp glucose disposal was restored by a pharmacological elevation of insulin ( approximately 2,800 microU/ml), but in this case, both glycogen synthesis and nonoxidative glycolysis participated in the rise in nonoxidative glucose disposal. In all groups, the reduction in total carbohydrate oxidation (indirect calorimetry) induced by fasting markedly exceeded the reduction in circulating glucose oxidation, suggesting that fasting also inhibits intracellular glycogen oxidation. Thus prior fasting favors glycogen retention by three mechanisms: 1) stimulation of glycogen synthesis via the direct pathway; 2) preferential inhibition of oxidative rather than nonoxidative glycolysis, thus allowing carbon conservation for glycogen synthesis via the indirect pathway; and 3) suppression of intracellular glycogen oxidation.

Topics: Adult; Blood Glucose; Calorimetry; Carbohydrate Metabolism; Carbon Dioxide; Carbon Radioisotopes; Cell Respiration; Energy Metabolism; Fasting; Female; Glucose; Glycogen; Glycolysis; Humans; Hyperglycemia; Hyperinsulinism; Injections, Intravenous; Lipid Metabolism; Male; Oxidation-Reduction

To determine the respective roles of insulin and glucagon for hepatic glycogen synthesis and turnover, hyperglycemic clamps were performed with somatostatin [0.1 micrograms/(kg.min)] in healthy young men under conditions of: (I) basal fasting) portal vein insulinemia-hypoglucagonemia, (II) basal portal vein insulinemia-basal glucagonemia, and (III) basal peripheral insulinemia-hypoglucagonemia. Synthetic rates, pathway (direct versus indirect) contributions, and percent turnover of hepatic glycogen were assessed by in vivo 13C nuclear magnetic resonance spectroscopy during [1-13C]glucose infusion followed by a natural abundance glucose chase in conjunction with acetaminophen to noninvasively sample the hepatic UDP-glucose pool. In the presence of hyperglycemia (10.4 +/- 0.1 mM) and basal portal vein insulinemia (192 +/- 6 pM), suppression of glucagon secretion (plasma glucagon, I:31 +/- 4, II: 63 +/- 8 pg/ml) doubled the hepatic accumulation of glycogen (Vsyn) compared with conditions of basal glucagonemia [I: 0.40 +/- 0.06, II: 0.19 +/- 0.03 mumol/(liter.min): P < 0.0025]. Glycogen turnover was markedly reduced (I: 19 +/- 7%, II: 69 +/- 12%; P < 0.005), so that net rate of glycogen synthesis increased approximately fivefold (P < 0.001) by inhibition of glucagon secretion. The relative contribution of gluconeogenesis (indirect pathway) to glycogen synthesis was lower during hypoglucagonemia (42 +/- 6%) than during basal glucagonemia (54 +/- 5%; P < 0.005). Under conditions of basal peripheral insulinemia (54 +/- 2 pM) and hypoglucagonemia (III) there was negligible hepatic glycogen synthesis and turnover. In conclusion, small changes in portal vein concentrations of insulin and glucagon independently affect hepatic glycogen synthesis and turnover. Inhibition of glucagon secretion under conditions of hyperglycemia and basal concentrations of insulin results in: (a) twofold increase in rate of hepatic glycogen synthesis, (b) reduction of glycogen turnover by approximately 73%, and (c) augmented percent contribution of the direct pathway to glycogen synthesis compared with conditions of basal glucagonemia.

Topics: Adult; Amino Acids; C-Peptide; Fatty Acids, Nonesterified; Gastrointestinal Agents; Glucagon; Glucose; Glucose Clamp Technique; Glycogen; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Lactates; Lactic Acid; Liver; Male; Models, Biological

Two study protocols to examine the effects of chronic (72-96 h) physiologic euglycaemic hyperinsulinaemia (+ 72 pmol/l) and chronic hyperglycaemic (+ 1.4 mmol/l) hyperinsulinaemia (+ 78 pmol/l) on insulin sensitivity and insulin secretion were performed in 15 healthy young subjects. Subjects received a three-step euglycaemic insulin (insulin infusion rates = 1.5, 3, and 6 nmol.kg-1.min-1) clamp and a hyperglycaemia (6.9 mmol/l) clamp before and after chronic insulin or glucose infusion. Following 4 days of sustained euglycaemic hyperinsulinaemia whole body glucose disposal decreased by 20-40%. During each insulin clamp step, the defect in insulin action was accounted for by impaired non-oxidative glucose disposal (p < 0.01). Chronic euglycaemic hyperinsulinaemia did not alter insulin-mediated suppression of hepatic glucose production. Following insulin infusion the ability of hyperglycaemia to stimulate insulin secretion was significantly diminished. Following 72 h of chronic glucose infusion (combined hyperglycaemic hyperinsulinaemia), there was no change in whole body glucose disposal. However, glucose oxidation during each insulin clamp step was significantly increased and there was a reciprocal decline in non-oxidative glucose disposal by 25-39% (p < 0.01); suppression of hepatic glucose production by insulin was unaltered by chronic hyperglycaemic hyperinsulinaemia. Chronic glucose infusion increased the plasma insulin response to acute hyperglycaemia more than twofold. These results demonstrate that chronic, physiologic hyperinsulinaemia, whether created by exogenous insulin infusion or by stimulation of endogenous insulin secretion, leads to the development of insulin resistance, which is characterized by a specific defect in the non-oxidative (glycogen synthetic) pathway. These findings indicate that hyperinsulinaemia should be considered, not only as a compensatory response to insulin resistance, but also as a self-perpetuating cause of the defect in insulin action.

Topics: Adult; Blood Glucose; Cholesterol; Female; Glucose; Glucose Clamp Technique; Glycogen; Humans; Hyperglycemia; Hyperinsulinism; Insulin; Insulin Resistance; Insulin Secretion; Liver; Male; Triglycerides

Treatment with tyrosine kinase inhibitors (TKIs), especially nilotinib, often results in hyperglycemia, which may further increase cardiovascular disease risk in patients with chronic myeloid leukemia (CML). The mechanism underlying the TKI-induced glucose dysregulation is not clear. TKIs are suggested to affect insulin secretion but also insulin sensitivity of peripheral tissue has been proposed to play a role in the pathogenesis of TKI-induced hyperglycemia. Here, we aimed to assess whether skeletal muscle glucose uptake and insulin responses are altered in nondiabetic patients with CML receiving TKI treatment. After a glycogen-depleted exercise bout, an intravenous glucose bolus (0.3 g/kg body weight) was administered to monitor 2-h glucose tolerance and insulin response in 14 patients with CML receiving nilotinib, 14 patients with CML receiving imatinib, and 14 non-CML age- and gender-matched controls. A dynamic [

Topics: Blood Glucose; Cardiovascular Diseases; Fluorodeoxyglucose F18; Glucose; Glycogen; Humans; Hyperglycemia; Imatinib Mesylate; Insulin; Insulin Resistance; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Pyrimidines; Tyrosine Kinase Inhibitors

Dysfunction of glucokinase (GCK) caused by mutations in the GCK gene is the main cause of maturity-onset diabetes of the young type-2 (MODY2, also known as GCK-MODY), which is usually present in adolescence or young adulthood. MODY2 is characterized by mild, stable fasting hyperglycemia that presents at birth, usually 5.4-8.3 mmol L

Topics: Adolescent; Child, Preschool; Diabetes Mellitus, Type 2; Female; Glucokinase; Glycogen; Humans; Hyperglycemia; Kinetics; Male; Mutation; Young Adult

Diabetic cardiomyopathy (DCM) is linked to disturbance in cardiac glucose handling and increased cardiac glycogen storage. This study tested the potential role of sacubitril/valsartan on the progression of DCM in high fat diet (HFD)/streptozotocin (STZ)-induced type 2 diabetic rats compared to valsartan alone, including their effects on the cardiac glycophagy process.. Rats were fed on HFD for 6 weeks followed by single low-dose STZ (35 mg/kg). After confirming hyperglycemia, diabetic rats were continued on HFD and divided into three subgroups: Untreated-diabetic, Valsartan-treated diabetic and Sacubitril/valsartan-treated diabetic groups; in addition to a control group. Changes in ECG, blood glucose, serum insulin, lipid profile, and Homeostasis model of assessment of insulin resistance (HOMA-IR) were assessed and the degree of cardiac fibrosis was examined. Cardiac glycogen content and glycophagy process were evaluated.. Sacubitril/valsartan administration to diabetic rats resulted in improvement of metabolic changes more than valsartan alone. Also, sacubitril/valsartan effectively prevented diabetes-associated cardiac hypertrophy, QTc prolongation, and fibrosis. Finally, cardiac glycogen concentrations in diabetic rats were decreased by sacubitril/valsartan combination, coupled with significant induction of glycophagy process in the diabetic rats' heart.. Sacubitril/valsartan therapy provides a more favorable metabolic and cardioprotective response compared to valsartan alone in a rat model of DCM. These findings may be due to a direct cardioprotective impact of sacubitril/valsartan and secondary beneficial effects of improved hyperglycemia and dyslipidemia. In addition, these beneficial cardiac effects could be attributed to the induction of the glycophagy process and alleviating cardiac glycogen overload.

Topics: Aminobutyrates; Animals; Biphenyl Compounds; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Drug Combinations; Glycogen; Heart Failure; Hyperglycemia; Mice; Rats; Stroke Volume; Tetrazoles; Valsartan

Glycerol-3-phosphate (Gro3P) phosphatase (G3PP) hydrolyzes Gro3P to glycerol that exits the cell, thereby operating a "glycerol shunt", a metabolic pathway that we identified recently in mammalian cells. We have investigated the role of G3PP and the glycerol shunt in the regulation of glucose metabolism and lipogenesis in mouse liver.. We generated hepatocyte-specific G3PP-KO mice (LKO), by injecting AAV8-TBG-iCre to male G3PP. LKO mice showed no change in body weight, food intake, fed and fasted glycemia but had increased fed plasma triglycerides. Hepatic glucose production from glycerol was increased in fasted LKO mice. LKO mouse hepatocytes displayed reduced glycerol production, elevated triglyceride and lactate production at high glucose concentration. Hyperglycemia in LKO mice led to increased liver weight and accumulation of triglycerides, glycogen and cholesterol together with elevated levels of Gro3P, dihydroxyacetone phosphate, acetyl-CoA and some Krebs cycle intermediates in liver. Hyperglycemic LKO mouse liver showed elevated expression of proinflammatory cytokines and M1-macrophage markers accompanied by increased plasma triglycerides, LDL/VLDL, urea and uric acid and myocardial triglycerides.. The glycerol shunt orchestrated by G3PP acts as a glucose excess detoxification pathway in hepatocytes by preventing metabolic disturbances that contribute to enhanced liver fat, glycogen storage, inflammation and lipid build-up in the heart. We propose G3PP as a novel therapeutic target for hepatic disorders linked to nutrient excess.

Topics: Animals; Glucose; Glycerol; Glycogen; Hyperglycemia; Liver; Male; Mice; Phosphoric Monoester Hydrolases; Triglycerides

To unveil the adaptation of Litopenaeus vannamei to elevated ambient ammonia-N, crustacean hyperglycaemic hormone (CHH) was knocked down to investigate its function in glucose metabolism pathway under ammonia-N exposure. When CHH was silenced, haemolymph glucose increased significantly during 3-6 h, decreased significantly during 12-48 h and recovered to the control groups' level at 72 h. After CHH knock-down, dopamine (DA) contents reduced significantly during 3-24 h, which recovered after 48 h. Besides, the expressions of guanylyl cyclase (GC) and DA1R in the hepatopancreas decreased significantly, while DA4R increased significantly. Correspondingly, the contents of cyclic AMP (cAMP), cyclic GMP (cGMP) and diacylglycerol (DAG) and the expressions of protein kinase A (PKA), protein kinase G (PKG), AMP active protein kinase α (AMPKα) and AMPKγ were significantly down-regulated, while the levels of protein kinase C (PKC) and AMPKβ were significantly up-regulated. The expressions of cyclic AMP response element-binding protein (CREB) and GLUT2 decreased significantly, while GLUT1 increased significantly. Moreover, glycogen content, glycogen synthase and glycogen phosphorylase activities in hepatopancreas and muscle were significantly increased. Furthermore, the levels of key enzymes hexokinase, pyruvate kinase and phosphofructokinase in glycolysis (GLY), rate-limiting enzymes citrate synthase in tricarboxylic acid and critical enzymes phosphoenolpyruvate carboxykinase, fructose diphosphate and glucose-6-phosphatase in gluconeogenesis (GNG) were significantly decreased in hepatopancreas. These results suggest that CHH affects DA and then they affect their receptors to transmit glucose metabolism signals into the hepatopancreas of L. vannamei under ammonia-N stress. CHH acts on the cGMP-PKG-AMPKα-CREB pathway through GC, and CHH affects DA to influence cAMP-PKA-AMPKγ-CREB and DAG-PKC-AMPKβ-CREB pathways, thereby regulating GLUT, inhibiting glycogen metabolism and promoting GLY and GNG. This study contributes to further understand glucose metabolism mechanism of crustacean in response to environmental stress.

Topics: Ammonia; Animals; Arthropod Proteins; Glucose; Glycogen; Hyperglycemia; Invertebrate Hormones; Nerve Tissue Proteins; Nitrogen; Penaeidae; RNA Interference

Maytenus ilicifolia Mart. ex Reissek, Celastraceae, is popularly known as "espinheira-santa" and used to treat pathologies related to the stomach. However, in popular culture, this species has also been used to treat other disorders such as diabetes, but without scientific evidence, requiring more phytochemical and pharmacological studies on the plant.. This work aims to investigate the anti-hyperglycemic potential of ethanolic extracts obtained from leaves from two different accessions of Maytenus ilicifolia (MIA and MIB) in normal hyperglycemic rats.. The animals were divided into different experimental groups: normal hyperglycemic (negative control); MIA (treatment of Maytenus ilicifolia extract from access 116); MIB (treatment with Maytenus ilicifolia extract from access 122; and glipizide (positive control). At 30 min after treatment, all animals received glucose overload orally. Blood collection occurred at different periods for the assessment of blood glucose (0, 60, 90 and 210 min after treatment) and at the end of the experiment blood was collected through cardiac puncture and the liver, muscle, pancreas and intestine were dissected for further analysis.. Chromatographic analysis identified oleic and palmitic acid as the most common constituents, and both extracts of Maytenus ilicifolia caused a reduction in blood glucose levels within 60 min after administration of glucose overload when compared to the normal hyperglycemic group. No significant changes were observed in hepatic and muscular glycogen levels, plasma insulin concentration and disaccharidases activity with none of the extracts in the model employed. However, hyperglycemic rats treated with the extracts showed a marked increase in triglyceride and HDL cholesterol levels.. Our data suggest that Maytenus ilicifolia extracts from different locations showed differences in chemical composition which did not reflect significant differences in the results of biological tests. In addition, it was possible to conclude that the treatment with Maytenus ilicifolia had a discreet anti-hyperglycemic effect; however, it was not possible to identify the responsible mechanism, being necessary, therefore, new studies using different technologies in order to determine the possible mechanisms of action of the extract.

Topics: Alanine Transaminase; Animals; Blood Glucose; Disaccharides; Ethanol; Glipizide; Glucose; Glycogen; Hyperglycemia; Insulin; Lipids; Male; Maytenus; Oxidative Stress; Plant Extracts; Plant Leaves; Rats, Wistar; Urea

The hypoglycemic effects and potential mechanism of sweet potato leaf polyphenols (SPLP) on type 2 diabetes mellitus (T2DM) were investigated. Results showed that oral administration of SPLP to mice could alleviate body weight loss, decrease fasting blood glucose levels (by 64.78%) and improve oral glucose tolerance compared with those of untreated diabetic mice. Furthermore, increased fasting serum insulin levels (by 100.11%), ameliorated insulin resistance and improved hepatic glycogen (by 126.78%) and muscle glycogen (increased by 135.85%) were observed in the SPLP treatment group. SPLP also could reverse dyslipidemia, as indicated by decreased total cholesterol, triglycerides, low density lipoprotein-cholesterol and promoted high density lipoprotein-cholesterol. Histopathological analysis revealed that SPLP could relieve liver inflammation and maintain the islet structure to inhibit β-cell apoptosis. A quantitative real-time polymerase chain reaction confirmed that SPLP could up-regulate the phosphatidylinositol 3-kinase/protein kinase B/glycogen synthase kinase-3β signaling pathway to improve glucose metabolism and up-regulate the phosphatidylinositol 3-kinase/protein kinase B/glucose transporter 4 signaling pathway in the skeletal muscle to enhance glucose transport. This study provides useful information to support the application of SPLP as a natural product for the treatment of T2DM.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Eating; Glucose Transporter Type 4; Glycogen; Glycogen Synthase Kinase 3 beta; Hyperglycemia; Hypoglycemic Agents; Insulin; Ipomoea batatas; Islets of Langerhans; Lipids; Liver; Liver Glycogen; Male; Mice; Pancreas; Phosphatidylinositol 3-Kinase; Plant Leaves; Polyphenols; Proto-Oncogene Proteins c-akt; Signal Transduction

Topics: Adolescent; Biopsy; Chronic Disease; Diabetes Mellitus, Type 1; Female; Glycogen; Humans; Hyperglycemia; Hyperlactatemia; Ketosis; Liver; Liver Diseases; Magnetic Resonance Imaging; Recurrence; Transaminases

Structural and physiological changes in sperm and semen parameters reduce fertility in diabetic patients. Securigera Securidaca (S. Securidaca) seed is a herbal medicine with hypoglycemic, antioxidant, and anti-hypertensive effects. The question now is whether this herbal medicine improves fertility in diabetic males. The study aimed to evaluate the effects of hydroalcoholic extract of S. Securidaca seeds (HESS), glibenclamide and a combination of both on fertility in hyperglycemic rats by comparing histological and some biochemical changes in testicular tissue and sperm parameters. The treatment protocol included administration of three doses of HESS and one dose of glibenclamide, as well as treatment with both in diabetic Wistar diabetic rats and comparison of the results with untrated groups. The quality of the testicular tissue as well as histometric parameters and spermatogenesis indices were evaluated during histopathological examination. Epididymal sperm analysis including sperm motility, viability, abnormalities, maturity, and chromatin structure were studied. The effect of HESS on the expression of LDH and FGF21 genes and tissue levels of glycogen, lactate, and total antioxidant capacity in testicular tissue was investigated and compared with glibenclamide. HESS improved sperm parameters in diabetic rats but showed little restorative effect on damaged testicular tissue. In this regard, glibenclamide was more effective than the highest dose of HESS and its combination with HESS enhanced its effectiveness so that histological tissue characteristics and sperm parameters were were comparable to those of healthy rats. The expression level of testicular FGF21 gene increased in diabetic rats, which intensified after treatment with HESS as well as glibenclamide. The combination of HESS and glibenclamide restored the expression level of testicular LDH gene, as well as tissue storage of glycogen, lactate and LDH activity, and serum testosterone to the levels near healthy control. S. Securidaca seeds can be considered as an effective supplement in combination with hypoglycemic drugs to prevent infertility complications in diabetes.

Topics: Animals; Blood Glucose; Drug Therapy, Combination; Ethanol; Fibroblast Growth Factors; Gene Expression; Glyburide; Glycogen; Hyperglycemia; L-Lactate Dehydrogenase; Male; Plant Extracts; Rats; Rats, Wistar; Securidaca; Seeds; Spermatozoa; Testis; Water

Flowering tops of Trifolium pratense L. (Fabaceae) are known for its traditional medicinal values. In present study, our aim was to investigate effect of standardized aqueous extract of flowering tops of Trifolium pratense L. on insulin resistance and SIRT1 expression in type 2 diabetic rats. Type 2 diabetes was induced by feeding high fat diet and administering low dose of streptozotocin. Diabetic animals were treated with standardized aqueous extract at three different doses. Parameters such as blood glucose, lipid profile, glycohemoglobin, insulin sensitivity, HOMA-IR and liver glycogen content were measured. Changes in morphology and expression of SIRT1 in pancreatic tissue were measured in histopathological and immunohistological studies. Aqueous extract treatment showed reduction in hyperglycemia and improved insulin sensitivity. Extract treatment also showed reduction in formation of glycated hemoglobin and improved liver glycogen level. Histopathological study revealed protecting effect of extract in pancreatic tissue against hyperglycemia induced damage. Treatment increased expression of SIRT1 in rat pancreatic tissue. Results indicate that the aqueous extract of Trifolium pratense had beneficial role in improving insulin sensitivity and SIRT1 expression.

Topics: Animals; Blood Glucose; Body Weight; Chromatography, High Pressure Liquid; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Flowers; Glycogen; Hyperglycemia; Isoflavones; Male; Pancreas; Plant Extracts; Protective Agents; Rats; Rats, Sprague-Dawley; Sirtuin 1; Streptozocin; Trifolium

Most glucose is processed in muscle, for energy or glycogen stores. Malignant Hyperthermia Susceptibility (MHS) exemplifies muscle conditions that increase [Ca. Animals and humans move by contracting the skeletal muscles attached to their bones. These muscles take up a type of sugar called glucose from food and use it to fuel contractions or store it for later in the form of glycogen. If muscles fail to use glucose it can lead to excessive sugar levels in the blood and a condition called diabetes. Within muscle cells are stores of calcium that signal the muscle to contract. Changes in calcium levels enhance the uptake of glucose that fuel these contractions. However, variations in calcium have also been linked to diabetes, and it remained unclear when and how these ‘signals’ become harmful. People with a condition called malignant hyperthermia susceptibility (MHS for short) have genetic mutations that allow calcium to leak out from these stores. This condition may result in excessive contractions causing the muscle to over-heat, become rigid and break down, which can lead to death if left untreated. A clinical study in 2019 found that out of hundreds of patients who had MHS, nearly half had high blood sugar and were likely to develop diabetes. Now, Tammineni et al. – including some of the researchers involved in the 2019 study – have set out to find why calcium leaks lead to elevated blood sugar levels. The experiments showed that enzymes that help convert glycogen to glucose are more active in patients with MHS, and found in different locations inside muscle cells. Whereas the enzymes that change glucose into glycogen are less active. This slows down the conversion of glucose into glycogen for storage and speeds up the breakdown of glycogen into glucose. Patients with MHS also had fewer molecules that transport glucose into muscle cells and stored less glycogen. These changes imply that less glucose is being removed from the blood. Next, Tammineni et al. used a microscopy technique that is able to distinguish finely separated objects with a precision not reached before in living muscle. This revealed that when the activity of the enzyme that breaks down glycogen increased, it moved next to the calcium store. This effect was also observed in the muscle cells of MHS patients that leaked calcium from their stores. Taken together, these observations may explain why patients with MHS have high levels of sugar in their blood. These findings suggest that MHS may start decades before developing diabetes and blood sugar levels in these patients should be regularly monitored. Future studies should investigate whether drug

Topics: Adult; Aged; Animals; Blood Glucose; Calcium; Diabetes Mellitus; Glucose; Glucose Transporter Type 4; Glycogen; Glycogen Phosphorylase, Muscle Form; Humans; Hyperglycemia; Malignant Hyperthermia; Mice; Middle Aged; Muscle, Skeletal; Phosphorylase Kinase; Phosphorylation

Citrus aurantifolia leaf essential oil was extracted via hydrodistillation, chemical composition of the oil was analyzed using gas chromatography-mass spectrometry and its antidiabetic potentials was assessed in alloxan-induced hyperglycaemic rats using metformin as the reference drug for comparison. Chemical analysis showed that D-limonene (57.84%) was the major constituent of the oil. Other notable compounds identified were neral (7.81%), linalool (4.75%), sulcatone (3.48%) and isogeraniol (3.48%). Intraperitoneal administration of C. aurantifolia oil (100 mg/Kg b.wt.) to hyperglycaemic rats for 14 days caused significant reduction in fasting blood and hepatic glucose, whereas hepatic concentration of glycogen was significantly increased. Also, improvement in dyslipidaemia was observed in C. aurantifolia essential oil-treated hyperglycaemic rats; serum concentration of total cholesterol, triacylglycerol and low density lipoprotein-cholesterol were significantly reduced and high density lipoprotein-cholesterol was increased, resulting in decreased predisposition of rats to cardiac risks. Antihyperglycaemic potential of administration of the oil was lower but compared favourably with the oral antihyperglycaemic agent used as reference antidiabetic drug. Overall, data from this study showed that essential oil from the leaf of C. aurantifolia grown in North-Central Nigeria is a D-limonene chemotype. The oil showed considerable glucose lowering effect as well as the potential to ameliorate hyperglycaemia-induced dyslipidaemic complications in alloxanized rats.

Topics: Alloxan; Animals; Citrus; Gas Chromatography-Mass Spectrometry; Glucose; Glycogen; Hyperglycemia; Hypoglycemic Agents; Limonene; Male; Nigeria; Oils, Volatile; Plant Leaves; Rats; Rats, Wistar

The main physiological consequence of diabetes mellitus is chronic hyperglycemia. This condition is related to the formation of free radicals including advanced glycation end products (AGES) and to an increase in inflammatory processes. Cochlospermum regium (Schrank) Pilg., part of the Bixaceae family, is a cerrado plant known for its anti-inflammatory effects. The objectives of this study were to analyze the constituent compounds of C. regium roots and to evaluate the antioxidant, antiglycation, antidiabetic, and anticholinergic effects of its hydromethanolic extract through in vitro and in vivo experimental models. The presence of phenols, flavonoids, condensed tannins, and flavonols was analyzed by liquid chromatography - photodiode array (LC/PDA) analysis. Whereas antioxidant activity was investigated via DPPH, ABTS, β-carotene/linoleic acid, and malondialdehyde colorimetric assays. Inhibition of AGEs was examined via a bovine serum albumin system whose glycosylating agent was glucose. Antidiabetic potential was examined in normoglycemic Wistar rats that received glucose overload, in alloxan-induced diabetic rats, and in rats that received a hyperglycemic diet. Disaccharidase inhibition was assessed using in vitro and in vivo methods, as was acetylcholinesterase (AChE) inhibition in brain structures. The hydromethanolic extract (CRHE) possessed a high concentration of phenolic compounds and showed antioxidant effects. The LC-DAD results revealed that CRHE contained a high concentration of phenolic acids and the majority was gallic acid. Treatment with CRHE caused significant inhibition of AGE formation. The oral glucose tolerance test (OGTT) in normoglycemic animals showed a reduction in blood glucose levels after treatment with 100 mg/kg CHRE, accompanied by an increase in hepatic glycogen content. There was also a significant reduction in the fasting glucose levels of alloxan-induced diabetic animals after 7 days of treatment with daily doses of 100 mg/kg. After 14 weeks of hyperglycemic diet, the last four or which were combined with 100 mg/kg CRHE treatment, there was a decrease in blood triglyceride levels. There was also a statistically significant decrease in the enzymatic activity of maltase, lactase and sucrase. The results demonstrate that oral administration of 30 and 100 mg/kg CRHE inhibited AChE activity in different brain structures. Thus, the extract of C. regium showed promising antioxidant, antiglycation, and antidiabetic effects that

Topics: Alloxan; Animals; Antioxidants; Bixaceae; Blood Glucose; Cholinesterase Inhibitors; Diabetes Mellitus, Experimental; Flavonoids; Glucose Tolerance Test; Glycogen; Hyperglycemia; Hypoglycemic Agents; Male; Phenols; Plant Extracts; Plant Roots; Rats; Rats, Wistar

Skeletal muscle plays a central role in the control of metabolism and exercise tolerance. Analysis of muscle enhancers activated after exercise in mice revealed the orphan nuclear receptor NURR1/NR4A2 as a prominent component of exercise-responsive enhancers. We show that exercise enhances the expression of NURR1, and transgenic overexpression of NURR1 in skeletal muscle enhances physical performance in mice. NURR1 expression in skeletal muscle is also sufficient to prevent hyperglycemia and hepatic steatosis, by enhancing muscle glucose uptake and storage as glycogen. Furthermore, treatment of obese mice with putative NURR1 agonists increases energy expenditure, improves glucose tolerance, and confers a lean phenotype, mimicking the effects of exercise. These findings identify a key role for NURR1 in governance of skeletal muscle glucose metabolism, and reveal a transcriptional link between exercise and metabolism. Our findings also identify NURR1 agonists as possible exercise mimetics with the potential to ameliorate obesity and other metabolic abnormalities.

Topics: Animals; Carbohydrate Metabolism; Energy Metabolism; Fatty Liver; Glucose; Glycogen; Homeostasis; Humans; Hyperglycemia; Liver; Male; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Nuclear Receptor Subfamily 4, Group A, Member 2; Obesity; Physical Conditioning, Animal; Transcription, Genetic; Up-Regulation

Momordica charantia (M. charantia) has antidiabetic effects, and cucurbitane-type triterpenoid is one of the compounds of M. charantia. This study aims to investigate whether the new cucurbitane-type triterpenoids affect insulin sensitivity both in vitro and in vivo, and the underlying mechanisms.. Four compounds (C1-C4) isolated from the ethanol extract of M. charantia enhance glucose uptake in C2C12 myotubes via insulin receptor substrate-1 (IRS-1) rather than via adenosine monophosphate-activated protein kinase. The most potent, compound 2 (C2), significantly increases the activation of IRS-1 and downstream signaling pathways, resulting in glucose transporter 4 translocation. Furthermore, these C2-induced in vitro effects are blocked by specific signal inhibitors. We further evaluate the antidiabetic effect of C2 using a streptozotocin (STZ)-induced diabetic mouse model. Consistent with in vitro data, treatment with C2 (1.68 mg kg. Our findings demonstrate that the new cucurbitane-type triterpenoids have potential for prevention and management of diabetes by improving insulin sensitivity and glucose homeostasis.

Topics: Absorption, Physiological; Animals; Cell Line; Diabetes Mellitus, Experimental; Drug Discovery; Ethnopharmacology; Fruit; Glucose; Glycogen; Hyperglycemia; Hypoglycemic Agents; Insulin Resistance; Male; Mice; Mice, Inbred ICR; Molecular Structure; Momordica charantia; Muscle Fibers, Skeletal; Muscle, Skeletal; Organ Specificity; Republic of Korea; Streptozocin; Triterpenes

Hyperglycemia induced oxidative stress inside the cells. Myricitrin, as an antioxidant plant-derived component, may be useful in hyperglycemia. Hence, the aim of this study was conducted to evaluate the antioxidant effects of myricitrin on hyperglycemia-induced oxidative damage in myotubes (C2C12 cells). In this experimental study, mouse myoblast cell line (C2C12) was obtained and divided into five groups: control, hyperglycemia, hyperglycemia + myricitrin 1, 3, and 10 μM. After treatment period for 48 h, cells were collected, homogenized, and centrifuged at 2000 rpm for 10 min. All samples were kept at - 80 °C until experimental and real-time PCR assessments were performed. Hyperglycemia increased malondialdehyde (MDA) (p < 0.05), total antioxidant capacity (TAC) (p < 0.001), and cellular apoptosis, and decreased levels of superoxide dismutase (SOD), catalase (CAT) (p < 0.01), myotube glycogen content (p < 0.05), glucose transporter type 4 (Glut-4), and cellular viability (p < 0.001). Myricitrin administration improved SOD (p < 0.05), CAT (p < 0.01), muscle cell's glycogen content (p < 0.01), Glut-4 gene expression (p < 0.001), Thiazolyl blue tetrazolium bromide (MTT) (p < 0.05), and Bax to Bcl-2 ratio (p < 0.001), and reduced MDA (p < 0.05) compared to hyperglycemia group. In conclusion, hyperglycemic condition induced oxidative stress along with cellular apoptosis, and myricitrin improved these disorders. Also, low and moderate doses of myricitrin are more efficient on skeletal muscle cells exposed to hyperglycemic statues than a high concentration of this antioxidant agent.

Topics: Animals; Antioxidants; Apoptosis; Cell Line; Cell Survival; Culture Media; Flavonoids; Gene Expression Regulation; Glucose; Glucose Transporter Type 4; Glycogen; Hyperglycemia; Lipid Peroxidation; Mice; Muscle Fibers, Skeletal; Oxidative Stress

Among the foremost common flavonoids within the human diet, quercetin glycosides possess neuroprotective, cardioprotective, anti-oxidative, chemopreventive, and anti-allergic properties. Isoquercetin is one such promising candidate with anti-diabetic potential. However, complete studies of its molecular action on insulin signaling pathway and carbohydrate metabolizing enzymes remain unclear. Hence, we have designed this study to accumulate the experimental evidence in support of anti-diabetic effects of isoquercetin. Male albino Wistar rats were divided into seven groups. Rats (Groups 3-7) were administered a single intraperitoneal injection of streptozotocin (STZ; 40 mg/kg b.w) to induce diabetes mellitus. As an extension, STZ rats received isoquercetin at three different doses (20, 40 and 80 mg/kg b.w), and Group 7 rats received glibenclamide (standard drug) (600 μg/kg b.w). The results showed that STZ exaggerated blood sugar, decreased insulin, altered metabolizing enzymes, and impaired the mRNA expression of insulin signaling genes and carbohydrate metabolizing enzyme genes. Supplementation with isoquercetin significantly normalized blood sugar levels, insulin and regulated the mRNA expression of insulin signaling genes and carbohydrate metabolizing enzyme genes. The results achieved with isoquercetin are similar to that of standard drug glibenclamide. The findings suggest isoquercetin could be a possible therapeutic agent for treating diabetes mellitus in the near future.

Topics: Animals; Biomarkers; Blood Glucose; Diabetes Mellitus, Experimental; Gene Expression Regulation, Enzymologic; Glycated Hemoglobin; Glycogen; Hyperglycemia; Hypoglycemic Agents; Insulin; Liver; Male; Quercetin; Rats; Rats, Wistar; RNA, Messenger; Signal Transduction

In the present study, the hybrid grouper (Epinephelus fuscoguttatus ♀ × E. lanceolatus ♂), a typical carnivorous fish, was chosen as a model to investigate the regulation of glycogen metabolism owning to its characteristic of glucose intolerance. The variation of plasma glucose concentration, glycogen content, and expressions of glycogen metabolism-related genes under acute hyperglycemia stress were measured. Following glucose administration, plasma glucose concentration increased immediately, and the glucose level remained elevated for at least 12 h. The prolonged glucose clearance and hyperglycemia revealed glucose intolerance of this fish species. Meanwhile, the glycogen content in both liver and muscle changed significantly during the clearance of plasma glucose. However, the peak value of hepatic glycogen (1 and 12 h post injection) appeared much earlier than muscle (3 and 24 h post injection). To investigate the regulation of glycogen metabolism from molecular aspect, the complete coding sequence (CDS) of glycogen synthase (GS) and glycogen phosphorylase (GP) in both liver and muscle types were obtained, encoding a polypeptide of 704, 711, 853, and 842 amino acid residues, respectively. The results of gene expression analysis revealed that the expression of liver type and muscle type GS was significantly higher than other time points at 12 and 24 h post glucose injection, respectively. Meanwhile, the highest expressions of GP in both liver and muscle types occurred at 24 h post glucose injection. The response of GS and GP to glucose load may account for the variation of glycogen content at the transcriptional level to some extent.

Topics: Animals; Bass; Blood Glucose; Fish Diseases; Glycogen; Glycogen Synthase; Hyperglycemia; Phosphorylases; Stress, Physiological

Obesity-associated insulin resistance (IR) is a major risk factor for developing type 2 diabetes and an array of other metabolic disorders. In particular, hepatic IR contributes to the increase in hepatic glucose production and consequently the development of fasting hyperglycemia. In this study, we explored whether kaempferol, a flavonoid isolated from Gink go biloba, is able to regulate hepatic gluconeogenesis and blood glucose homeostasis in high-fat diet-fed obese mice and further explored the underlying mechanism by which it elicits such effects. Oral administration of kaempferol (50 mg/kg/day), which is the human equivalent dose of 240 mg/day for an average 60 kg human, significantly improved blood glucose control in obese mice, which was associated with reduced hepatic glucose production and improved whole-body insulin sensitivity without altering body weight gain, food consumption or adiposity. In addition, kaempferol treatment increased Akt and hexokinase activity, but decreased pyruvate carboxylase (PC) and glucose-6 phosphatase activity in the liver without altering their protein expression. Consistently, kaempferol decreased PC activity and suppressed gluconeogenesis in HepG2 cells as well as primary hepatocytes isolated from the livers of obese mice. Furthermore, we found that kaempferol is a direct inhibitor of PC. These findings suggest that kaempferol may be a naturally occurring antidiabetic compound that acts by suppressing glucose production and improving insulin sensitivity. Kaempferol suppression of hepatic gluconeogenesis is due to its direct inhibitory action on the enzymatic activity of PC.

Topics: Animals; Blood Glucose; Body Composition; Diet, High-Fat; Eating; Gluconeogenesis; Glycogen; Hyperglycemia; Hypoglycemic Agents; Kaempferols; Liver; Male; Mice, Inbred C57BL; Obesity; Proto-Oncogene Proteins c-akt; Pyruvic Acid; Triglycerides

Background Iodine is a nonpareil constituent of thyroid hormones (THs) and a prime regulator of thyroid gland functioning. Although essential at recommended levels for the prevention of iodine deficiency disorders (IDDs), exposure to excess iodine reportedly causes hypothyroidism, hyperthyroidism, and several other emerging deleterious impacts. The objective of the present study is to explore the influence of excess iodide exposure on carbohydrate and lipid metabolism along with the histoarchitecture of certain associated organs such as the pancreas, liver, kidney, and skeletal and cardiac muscle because information on those aspects was found to be scanty. Methods Twelve rats were taken, six were fed with iodine through gavage at a dose of 3.5 mg potassium iodide (KI)/100-g body weight, which corresponded to 500 times of the physiological daily dosage of iodide for a period of 60 days, while the other six formed the control group. Results KI-treated rats presented high body weight and urinary iodine with low TH levels, suggesting a primary thyroid dysfunction. There was an increase in blood glucose, cholesterol, triglycerides, low density lipoprotein (LDL), and very low density lipoprotein (VLDL), while high density lipoprotein (HDL) levels decreased. Tissue glycogen content in the liver and skeletal muscle was decreased and was increased in the heart and kidney. Histological sections of the pancreas showed a complete disruption with hardly recognizable histoarchistructure. Treated liver sections displayed the broadened central vein with degenerated hepatocytes, while skeletal muscle sections showed dissolution of muscle fibre cells linked with loss of glycogen from these organs. Histological changes in the heart include features similar to those of a fatty heart with cardiac muscles mutilation, while that of the kidney shows an increase in glomerular tuft size and Bowman's space expansion with general deterioration. Conclusions It may thus be concluded that excess iodine exposure for a long duration causes the development of a biochemical state of hypothyroidism. The developed hypothyroidism was found responsible for the hyperglycaemic and hypercholestromic status evident by high blood glucose and cholesterol levels and the depletion of glycogen at its storage sites in the liver and skeletal muscle but the extra deposition in the cardiac muscle and kidney; histomicrophotographs showed severe destruction of the pancreatic structure. All these alterations

Topics: Animals; Blood Glucose; Body Weight; Carbohydrate Metabolism; Drug Overdose; Glycogen; Hypercholesterolemia; Hyperglycemia; Hypothyroidism; Lipid Metabolism; Male; Potassium Iodide; Rats; Rats, Wistar; Thyroid Hormones; Time Factors

Available data showed that the intestine increases it glucose uptake in response to hyperglycemia induced by anycause. However, what the intestine does with the glucose is not known. This study investigated the metabolic fate of theglucose taken up by the intestine during hyperglycaemia in dogs. Experiments were carried out on fasted, male, anaesthetizedmongrel dogs divided into 4 groups. The control (group 1, n=5) received normal saline (0.2 ml/kg) while groups 2-4(subdivided into two as low or high dose, n=5 each) received adrenaline (1 μg/kg or 5 μg/kg), glucagon (3 ng/kg or 8 ng/kg)and glucose (10 mg/kg/min or 20 mg/kg/min). Through a midline laparatomy, the upper jejunum was cannulated for IntestinalBlood Flow (IBF) measurement. Blood glucose and lactate levels were determined using glucose oxidase and lactatedehydrogenase methods, respectively. Intestinal Glucose/Lactate Uptake (IGU/ILU) was calculated as the product of IBFand arterio-venous glucose /lactate difference [(A-V) glucose/lactate]. Jejunal tissue samples were obtained for the determinationof Glycogen Content (GC) and activities of Glycogen Synthase (GS), Glycogen Phosphorylase 'a' (GPa), hexokinase andglucose-6-phosphatase. Anthrone method was used to determine GC while activities of GS, GPa, hexokinase and glucose-6-phosphatase were determined spectrophotometrically. Data were subjected to descriptive statistics and analyzed usingstudent's t-test and ANOVA at α0.05. Arterial and venous blood glucose and lactate were increased by adrenaline, glucagonand glucose. Venous lactate was higher than arterial lactate in all groups. Intestinal blood flow, (A-V) glucose and (A-V)lactate were increased in all the experimental groups. Intestinal glucose uptake increased by 624% (adrenaline), 705%(glucagon) and 589% (glucose) while intestinal lactate release increased by 422%, 459% and 272% respectively. IntestinalGC increased from 138.72 ± 4.58 mg/100 g to 167.17 ± 4.20 mg/100 g (adrenaline), 229.21 ± 6.25 mg/100 g (glucagon) and165.17 ± 4.20 mg/100 g (glucose). Adrenaline and glucose had no effect on GS activity but it was increased by glucagon;GPa was decreased while hexokinase activity was increased by adrenaline, glucagon, and glucose. Glucose-6-phosphataseactivity was not affected by adrenaline and glucagon but decreased by glucose. The intestine modulates blood glucose levelsthrough lactate formation, glycogen formation and most probably conversion of lactate to glucose through gluconeogenesis

Topics: Animals; Blood Glucose; Dogs; Glucagon; Gluconeogenesis; Glucose; Glycogen; Hyperglycemia; Insulin; Intestinal Mucosa; Male

Fenugreek (Trigonella foenum-graecum) seeds and onion (Allium cepa) are independently known to have antidiabetic effects through different mechanisms. The beeneficial influence of a combination of dietary fenugreek seeds and onion on hyperglycemia and its associated metabolic abnormalities were evaluated in streptozotocin-induced diabetic rats.. Diabetes was experimentally induced with streptozotocin and diabetic rats were fed with 10% fenugreek or 3% onion or their combination for 6 weeks.. These dietary interventions significantly countered hyperglycemia, partially improved peripheral insulin resistance and impaired insulin secretion, reduced β-cell mass and markedly reversed the abnormalities in plasma albumin, urea, creatinine, glycated hemoglobin and advanced glycation end products in diabetic rats. These beneficial effects were highest in the fenugreek+onion group. Diabetic rats with these dietary interventions excreted lesser glucose, albumin, urea and creatinine, which were accompanied by improved body weights compared with the diabetic controls. These dietary interventions produced ameliorative effects on pancreatic pathology as reflected by near-normal islet cells, restored glycogen and collagen fiber deposition in diabetic rats.. This study documented the hypoglycemic and insulinotropic effects of dietary fenugreek and onion, which were associated with countering of metabolic abnormalities and pancreatic pathology. It may be strategic to derive maximum nutraceutical antidiabetic benefits from these functional food ingredients by consuming them together.

Topics: Animals; Blood Glucose; Collagen; Diabetes Mellitus, Experimental; Glycogen; Hyperglycemia; Hypoglycemic Agents; Insulin; Islets of Langerhans; Male; Metabolic Diseases; Onions; Pancreas; Phytotherapy; Plant Extracts; Rats; Rats, Wistar; Seeds; Streptozocin; Trigonella

[6]-Gingerol, a major component of Zingiber officinale, was previously reported to ameliorate hyperglycemia in type 2 diabetic mice. Endocrine signaling is involved in insulin secretion and is perturbed in db/db Type-2 diabetic mice. [6]-Gingerol was reported to restore the disrupted endocrine signaling in rodents. In this current study on Lepr. 4-weeks treatment of [6]-Gingerol dramatically increased glucose-stimulated insulin secretion and improved glucose tolerance. Plasma GLP-1 was found to be significantly elevated in the treated mice. Pharmacological intervention of GLP-1 levels regulated the effect of [6]-Gingerol on insulin secretion. Mechanistically, [6]-Gingerol treatment upregulated and activated cAMP, PKA, and CREB in the pancreatic islets, which are critical components of GLP-1-mediated insulin secretion pathway. [6]-Gingerol upregulated both Rab27a GTPase and its effector protein Slp4-a expression in isolated islets, which regulates the exocytosis of insulin-containing dense-core granules. [6]-Gingerol treatment improved skeletal glycogen storage by increased glycogen synthase 1 activity. Additionally, GLUT4 transporters were highly abundant in the membrane of the skeletal myocytes, which could be explained by the increased expression of Rab8 and Rab10 GTPases that are responsible for GLUT4 vesicle fusion to the membrane.. Collectively, our study reports that GLP-1 mediates the insulinotropic activity of [6]-Gingerol, and [6]-Gingerol treatment facilitates glucose disposal in skeletal muscles through increased activity of glycogen synthase 1 and enhanced cell surface presentation of GLUT4 transporters.

Topics: Animals; Blood Glucose; Catechols; Diabetes Mellitus, Type 2; Fatty Alcohols; Glucagon-Like Peptide 1; Glucose Transporter Type 4; Glycogen; Glycogen Synthase; Hyperglycemia; Insulin; Insulin Secretion; Insulin-Secreting Cells; Membrane Proteins; Mice; Mice, Inbred NOD; Mice, Knockout; Muscle, Skeletal; Phytotherapy; Plant Extracts; rab GTP-Binding Proteins; Secretory Pathway; Vesicular Transport Proteins; Zingiber officinale

Topics: Animal Feed; Animals; Animals, Newborn; Birth Weight; Blood Glucose; Diabetes Mellitus, Type 2; Diet; Female; Fetal Growth Retardation; Glucose-6-Phosphatase; Glycogen; Hyperglycemia; Insulin Resistance; Liver; Male; Methionine; Muscles; Phosphoenolpyruvate Carboxykinase (GTP); Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction; Swine; Weaning

Infusion of mesenchymal stem cells (MSCs) has been identified in the rapid alleviation in hyperglycemia of diabetic individuals, but the mechanism involved has not been adequately explained by these cells' potential role in modulating system insulin sensitivity and islet regeneration. In this study, we demonstrated adipose-derived mesenchymal stem cells (ASCs) produced significantly lower blood glucose via promoting hepatic glycogen synthesis and inhibiting hepatic glucose production within 24 h after infusion in T2DM rats. In vitro, HepG2 cells treated with palmitate (PA) were used as a model of hepatic glucose metabolism disorder to confirm that ASCs stimulates the phosphorylation of hepatic AMP-activated protein kinase (AMPK) to restores hepatic glucose metabolism in type 2 diabetes. In summary, this study indicated that ASCs improve hyperglycemia via regulating hepatic glucose metabolism. Additionally, the effect of ASCs on hepatic glucose metabolism depended on the AMPK signaling pathway. Thus, this is the new research of the molecular mechanisms of MSCs administration to improve glucose metabolism, and it may indicate a new treatment target of MSCs in T2DM.

Topics: Adipose Tissue; Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Enzymes; Glucose; Glycogen; Hep G2 Cells; Humans; Hyperglycemia; Infusions, Intravenous; Liver; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Palmitates; Rats, Sprague-Dawley

Steroid-induced diabetes is the most common form of drug-induced hyperglycemia. Therefore, metabolic and immunological alterations associated with chronic oral corticosterone were investigated using male nonobese diabetic mice. Three weeks after corticosterone delivery, there was reduced sensitivity to insulin action measured by insulin tolerance test. Body composition measurements revealed increased fat mass and decreased lean mass. Overt hyperglycemia (>250 mg/dL) manifested 6 weeks after the start of glucocorticoid administration, whereas 100% of the mice receiving the vehicle control remained normoglycemic. This phenotype was fully reversed during the washout phase and readily reproducible across institutions. Relative to the vehicle control group, mice receiving corticosterone had a significant enhancement in pancreatic insulin-positive area, but a marked decrease in CD3

Topics: Administration, Oral; Animals; Body Composition; CD3 Complex; Citrate (si)-Synthase; Corticosterone; Gene Expression Regulation, Enzymologic; Glycogen; Glycogen Synthase; Hyperglycemia; Insulin; Insulin Resistance; Islets of Langerhans; Male; Mice, Inbred NOD; Models, Biological; Phenotype; Rats; Thinness

Cinnamon has a history of use for medicinal purposes and its major benefits have been linked to cinnamaldehyde. The present study aimed to investigate the hypoglycemic action of cinnamaldehyde against fatty-sucrosed diet/streptozotocin (FSD/STZ)-rat model of gestational diabetes. Female albino rats were divided into three groups. Group I fed with normal diet (ND) while group II and III were fed with FSD for eight weeks (five weeks pre-gestational and three weeks gestational). Rats of group III were administered with a daily oral dose of 20mg/kg cinnamaldehyde one week before mating onward. At the 7th day of gestation, FSD-fed rats were injected intraperitoneally with STZ (25mg/kg b.wt.) to induce gestational diabetes. Pre-mating treatment of cinnamaldehyde controls hyperphagia and glucose intolerance during the gestational period than in diabetic rats. It also reduced levels of fructosamine, total cholesterols, triglycerides, leptin, tumor necrosis factor-alpha (TNF-α), malondialdehyde (MDA) and nitric oxide (NO), while it significantly increased levels of high-density lipoprotein (HDL)-cholesterol, adiponectin, liver glycogen, reduced glutathione (GSH) and catalase activity at term pregnancy. In addition, cinnamaldehyde administration up-regulated the mRNA expression of peroxisome proliferated activated receptor-gamma (PPARγ) and also ameliorated the number of viable fetuses, implantation loss sites, fetal glucose and insulin levels. In conclusion, cinnamaldehyde has safe hypoglycemic action on gestational diabetes by potentiating insulin secretion and sensitivity through activating the antioxidant defense system, suppressing pro-inflammatory cytokines production, upregulating PPARγ gene expression and alleviating the reproductive performance.

Topics: Acrolein; Adipose Tissue; Animals; Antioxidants; Biomarkers; Blood Glucose; Body Weight; Cholesterol; Cytokines; Diabetes, Gestational; Feeding Behavior; Female; Fetus; Fructosamine; Glucose Tolerance Test; Glycogen; Hyperglycemia; Inflammation Mediators; Insulin; Leptin; Liver; Oxidative Stress; PPAR gamma; Pregnancy; Pregnancy Outcome; Rats; RNA, Messenger; Triglycerides

Pancreatic beta cells maintain glucose homeostasis and beta cell dysfunction is a major risk factor in developing diabetes. Therefore, understanding the developmental regulatory networks that define a fully functional beta cell is important for elucidating the genetic origins of the disease. Aldehyde dehydrogenase activity has been associated with stem/progenitor cells and we have previously shown that Aldh1b1 is specifically expressed in pancreas progenitor pools. Here we address the hypothesis that Aldh1b1 may regulate the timing of the appearance and eventual functionality of beta cells.. We generated an Aldh1b1-knockout mouse line (Aldh1b1 (tm1lacZ)) and used this to study pancreatic development, beta cell functionality and glucose homeostasis in the absence of Aldh1b1 function.. Differentiation in the developing pancreas of Aldh1b1 (tm1lacZ) null mice was accelerated. Transcriptome analyses of newborn and adult islets showed misregulation of key beta cell transcription factors and genes crucial for beta cell function. Functional analyses showed that glucose-stimulated insulin secretion was severely compromised in islets isolated from null mice. Several key features of beta cell functionality were affected, including control of oxidative stress, glucose sensing, stimulus-coupling secretion and secretory granule biogenesis. As a result of beta cell dysfunction, homozygous mice developed glucose intolerance and age-dependent hyperglycaemia.. These findings show that Aldh1b1 influences the timing of the transition from the pancreas endocrine progenitor to the committed beta cell and demonstrate that changes in the timing of this transition lead to beta cell dysfunction and thus constitute a diabetes risk factor later in life. Gene Expression Omnibus (GEO) accession: GSE58025.

Topics: Aldehyde Dehydrogenase; Aldehyde Dehydrogenase 1 Family; Aldehyde Dehydrogenase, Mitochondrial; Alleles; Animals; Blood Glucose; Cell Differentiation; Glucose; Glucose Tolerance Test; Glycogen; Homeostasis; Hyperglycemia; Insulin-Secreting Cells; Islets of Langerhans; Liver; Male; Mice; Mice, Knockout; Oxidative Stress; Real-Time Polymerase Chain Reaction; Risk Factors; Stem Cells; Transcriptome

This study examines how chronically hyperglycemic rainbow trout modulate glucose kinetics in response to graded exercise up to critical swimming speed (Ucrit), with or without exogenous glucose supply. Our goals were 1) to quantify the rates of hepatic glucose production (Ra glucose) and disposal (Rd glucose) during graded swimming, 2) to determine how exogenous glucose affects the changes in glucose fluxes caused by exercise, and 3) to establish whether exogenous glucose modifies Ucrit or the cost of transport. Results show that graded swimming causes no change in Ra and Rd glucose at speeds below 2.5 body lengths per second (BL/s), but that glucose fluxes may be stimulated at the highest speeds. Excellent glucoregulation is also achieved at all exercise intensities. When exogenous glucose is supplied during exercise, trout suppress hepatic production from 16.4 ± 1.6 to 4.1 ± 1.7 μmol·kg(-1)·min(-1) and boost glucose disposal to 40.1 ± 13 μmol·kg(-1)·min(-1). These responses limit the effects of exogenous glucose to a 2.5-fold increase in glycemia, whereas fish showing no modulation of fluxes would reach dangerous levels of 114 mM of blood glucose. Exogenous glucose reduces metabolic rate by 16% and, therefore, causes total cost of transport to decrease accordingly. High glucose availability does not improve Ucrit because the fish are unable to take advantage of this extra fuel during maximal exercise and rely on tissue glycogen instead. In conclusion, trout have a remarkable ability to adjust glucose fluxes that allows them to cope with the cumulative stresses of a glucose overload and graded exercise.

Topics: Animals; Blood Glucose; Carbohydrate Metabolism; Female; Glucagon; Glucose; Glycogen; Hyperglycemia; Liver; Male; Oncorhynchus mykiss; Oxidation-Reduction; Oxygen Consumption; Physical Exertion; Swimming

Four isolipidic and isoenergetic diets with different protein:carbohydrate (CH) contents (48:38, 52:34, 56:30, 60:26) were fed to juvenile Senegalese sole (22·01 (sem 0·01) g) during 104 d. Oral glucose tolerance tests were performed at the beginning (4 d) and at the end (104 d) of the experiment to assess the effect of the dietary treatment on glucose tolerance. Samples of blood, liver and muscle of all dietary groups were also obtained at the initial and final phases of the trial at different postprandial times (0, 1, 5 and 10 h after feeding) in order to analyse glucose and NEFA in plasma, and metabolites and enzyme activities involved in glycogen metabolism, glycolysis, gluconeogenesis and lipogenesis pathways in liver and muscle. The results obtained in this study suggest a good glucose tolerance in Senegalese sole. This species tolerated important amounts of CH in the diet without showing any deleterious signs in terms of growth or any metabolic disorders. After 104 d of feeding diets with an important amount of CH (48:38 and 52:34), the control of glycaemia was maintained and even postprandial glucose levels in plasma were (in general) lower than at the beginning of the experiment. This reasonable tolerance to glucose is also reflected by an increased use of glucose through glycolysis in liver (indicated by glucokinase activity), and the absence of changes in lipogenic potential in the same tissue (indicated by ATP citrate lyase activity). No clear changes were induced in the muscle by the dietary treatments.

Topics: Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Aquaculture; ATP Citrate (pro-S)-Lyase; Blood Glucose; Diet; Dietary Carbohydrates; Dietary Proteins; Energy Intake; Fatty Acids, Nonesterified; Flatfishes; Glucokinase; Glucose; Glycogen; Glycolysis; Hyperglycemia; Lipid Metabolism; Liver; Muscles; Postprandial Period

New potential drugs based on vanadium are being developed as possible treatments for diabetes mellitus (DM) and its complications. In this regard, our working group developed metforminium decavanadate (MetfDeca), a compound with hypoglycemic and hypolipidemic properties. MetfDeca was evaluated in models of type 1 and type 2 diabetes mellitus, on male Wistar rats. Alloxan-induction was employed to produce DM1 model, while a hypercaloric-diet was employed to generate DM2 model. Two-month treatments with 3.7 μg (2.5 μM)/300 g/twice a week for DM2 and 7.18 μg (4.8 μM)/300 g/twice a week for DM1 of MetfDeca, respectively, were administered. The resulting pharmacological data showed nontoxicological effects on liver and kidney. At the same time, MetfDeca showed an improvement of carbohydrates and lipids in tissues and serum. MetfDeca treatment was better than the monotherapies with metformin for DM2 and insulin for DM1. Additionally, MetfDeca showed a protective effect on pancreatic beta cells of DM1 rats, suggesting a possible regeneration of these cells, since they recovered their insulin levels. Therefore, MetfDeca could be considered not only as an insulin-mimetic agent, but also as an insulin-enhancing agent. Efforts to elucidate the mechanism of action of this compound are now in progress.

Topics: Animals; Diabetes Mellitus, Experimental; Glucose Tolerance Test; Glycated Hemoglobin; Glycogen; Hyperglycemia; Insulin; Male; Metformin; Rats, Wistar; Triglycerides; Vanadates

A low carbohydrate diet (LCHD) as well as sodium glucose cotransporter 2 inhibitors (SGLT2i) may reduce glucose utilization and improve metabolic disorders. However, it is not clear how different or similar the effects of LCHD and SGLT2i are on metabolic parameters such as insulin sensitivity, fat accumulation, and especially gluconeogenesis in the kidney and the liver. We conducted an 8-week study using non-diabetic mice, which were fed ad-libitum with LCHD or a normal carbohydrate diet (NCHD) and treated with/without the SGLT-2 inhibitor, ipragliflozin. We compared metabolic parameters, gene expression for transcripts related to glucose and fat metabolism, and glycogen content in the kidney and the liver among the groups. SGLT2i but not LCHD improved glucose excursion after an oral glucose load compared to NCHD, although all groups presented comparable non-fasted glycemia. Both the LCHD and SGLT2i treatments increased calorie-intake, whereas only the LCHD increased body weight compared to the NCHD, epididimal fat mass and developed insulin resistance. Gene expression of certain gluconeogenic enzymes was simultaneously upregulated in the kidney of SGLT2i treated group, as well as in the liver of the LCHD treated group. The SGLT2i treated groups showed markedly lower glycogen content in the liver, but induced glycogen accumulation in the kidney. We conclude that LCHD induces deleterious metabolic changes in the non-diabetic mice. Our results suggest that SGLT2i induced gluconeogenesis mainly in the kidney, whereas for LCHD it was predominantly in the liver.

Topics: Animals; Body Weight; Cyclic AMP Response Element-Binding Protein; Diabetes Mellitus, Experimental; Diet, Carbohydrate-Restricted; Energy Intake; Fatty Acid Synthases; Forkhead Box Protein O1; Gluconeogenesis; Glucose Tolerance Test; Glucosides; Glycogen; Hyperglycemia; Insulin Resistance; Kidney; Lipid Metabolism; Liver; Male; Mice, Inbred C57BL; Obesity; RNA, Messenger; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Thiophenes; Triglycerides; Up-Regulation

The effect of germinated Superhongmi, a reddish brown pigmented rice cultivar, on the glucose profile and bone turnover in the postmenopausal-like model of ovariectomized rats was determined. The ovariectomized Sprague-Dawley rats were randomly divided into three dietary groups (

Topics: Adipokines; Animals; Biomarkers; Blood Glucose; Body Weight; Bone and Bones; Bone Resorption; Dietary Supplements; Estradiol; Female; Germination; Glycogen; Hyperglycemia; Hypoglycemic Agents; Insulin; Oryza; Ovariectomy; Postmenopause; Random Allocation; Rats, Sprague-Dawley

Medicinal plants have long been used against life-threatening diseases including diabetes, with more or less success. Some of these plants have been shown to possess antioxidant activities, which could help improving diabetes inconveniences. In that context, we investigated the effects of spirulina supplementation on alloxan-induced diabetic rats, hypothesizing that co-administration of spirulina with rat diet could ameliorate diabetes complications and provide as benefits as the common antidiabetic insulin. Following alloxan treatment, male Wistar rats were fed daily with 5% spirulina-enriched diet or treated with insulin (0.5 IU/rat) for 21 days. Both spirulina and insulin treatments of diabetic rats resulted in a significant reduction in fasting blood glucose and an increase of glycogen level. Spirulina supplementation also impeded loss of body weight and ameliorated hepatic toxicity indices, i.e. alkaline phosphatases and transaminases activities, bilirubin levels and lipid peroxidation. Besides, triglycerides, total cholesterol, and low-density lipoprotein cholesterol levels decreased in the serum. Moreover, diabetic rats fed with spirulina exhibited sig changes in antioxidant enzyme activities in the liver (ie, decrease in superoxide dismutase and increase in catalase and glutathione peroxidase activities). The beneficial effects of spirulina or insulin were confirmed by histological study of the liver of diabetic rats. Overall, this study indicates that treatment with spirulina decreased hyperglycemia and oxidative stress in diabetic rats, this amelioration being even more pronounced than that provided by insulin injection. Therefore, administration of this alga would be very helpful in the prevention of diabetic complications.

Topics: Alloxan; Animals; Anthocyanins; Blood Glucose; Catalase; Cholesterol; Diabetes Mellitus, Experimental; Diet; Flavonoids; Glycogen; Hyperglycemia; Hypoglycemic Agents; Insulin; Lipid Peroxidation; Liver; Male; Oxidative Stress; Rats; Rats, Wistar; Spirulina; Superoxide Dismutase; Tannins; Thiobarbituric Acid Reactive Substances; Triglycerides

Insulin secretion from pancreatic β-cells is impaired in all forms of diabetes. The resultant hyperglycaemia has deleterious effects on many tissues, including β-cells. Here we show that chronic hyperglycaemia impairs glucose metabolism and alters expression of metabolic genes in pancreatic islets. In a mouse model of human neonatal diabetes, hyperglycaemia results in marked glycogen accumulation, and increased apoptosis in β-cells. Sulphonylurea therapy rapidly normalizes blood glucose levels, dissipates glycogen stores, increases autophagy and restores β-cell metabolism. Insulin therapy has the same effect but with slower kinetics. Similar changes are observed in mice expressing an activating glucokinase mutation, in in vitro models of hyperglycaemia, and in islets from type-2 diabetic patients. Altered β-cell metabolism may underlie both the progressive impairment of insulin secretion and reduced β-cell mass in diabetes.

Topics: Animals; Apoptosis; Autophagy; Blood Glucose; Cell Line; Diabetes Mellitus, Type 2; Disease Models, Animal; Glucokinase; Glycogen; Humans; Hyperglycemia; Hypoglycemic Agents; In Vitro Techniques; Infant, Newborn; Infant, Newborn, Diseases; Insulin; Insulin-Secreting Cells; Mice; Mutation; Rats; Sulfonylurea Compounds

Salvianolic acid B (Sal B), a major polyphenolic compound of Salvia miltiorrhiza Bunge, has been shown to possess potential antidiabetic activities. However, the action mechanism of SalB in type 2 diabetes has not been investigated extensively. The present study was designed to investigate the effects of Sal B on diabetes-related metabolic changes in a spontaneous model of type 2 diabetes, as well as its potential molecular mechanism.. Male C57BL/KsJ-db/db mice were orally treated with Sal B (50 and 100 mg/kg) or metformin (positive drug, 300 mg/kg) for 6 weeks.. Both doses of Sal B significantly decreased fasting blood glucose, serum insulin, triglyceride and free fatty acid levels, reduced hepatic gluconeogenic gene expression and improved insulin intolerance in db/db mice. High dose Sal B also significantly improved glucose intolerance, increased hepatic glycolytic gene expression and muscle glycogen content, and ameliorated histopathological alterations of pancreas, similar to metformin. Sal B treatment resulted in increased phosphorylated AMP-activated protein kinase (p-AMPK) protein expression in skeletal muscle and liver, increased glucose transporter 4 (GLUT4) and glycogen synthase protein expressions in skeletal muscle, and increased peroxisome proliferator-activated receptor alpha (PPARα) and phosphorylated acetyl CoA carboxylase (p-ACC) protein expressions in liver.. Our data suggest that Sal B displays beneficial effects in the prevention and treatment of type 2 diabetes at least in part via modulation of the AMPK pathway.

Topics: AMP-Activated Protein Kinases; Animals; Benzofurans; Body Weight; Dyslipidemias; Gene Expression Regulation; Gluconeogenesis; Glucose; Glucose Intolerance; Glucose Transporter Type 4; Glycogen; Glycogen Synthase; Glycolysis; Hyperglycemia; Hyperinsulinism; Lipids; Liver; Male; Mice, Inbred C57BL; Muscle, Skeletal; Pancreas; Phosphorylation; PPAR alpha; RNA, Messenger; Signal Transduction

Some studies refer that the entire plant of Anoda cristata is consumed as food and medicine; in particular for treating diabetes, inflammation, fever, cough, and wounds. The aim of this study was to establish the preclinical efficacy of Anoda cristata as hypoglycemic and/or antihyperglycemic agent using well-known animal models.. The acute toxicity was analyzed by the Lorke method. Acute hypoglycemic as well as oral glucose and sucrose tolerance tests were used to determine the hypoglycemic and antihyperglycemic action of Anoda cristata. Several preparations of the plant, including a mucilage (M), an aqueous (T-AE), a free mucilage aqueous (FM-AE), and an organic (OE) extracts, were tested in healthy and NA-STZ-hyperglycemic mice. Glibenclamide (15mg/kg), acarbose (5mg/kg ) and metformin (200mg/kg) were used as positive controls. The major compounds acacetin (1) and diosmetin (2), isolated from an infusion of the plant applying chromatographic methods, were evaluated as hypoglycemic agents using the same assays. The FM-AE was tested also in rats with metabolic syndrome induced by a high-fructose fed. Finally some assays were performed to determine the antioxidant capacity of the FM-AE in vitro.. The results demonstrated that the extracts and compounds from Anoda cristata were effective for reducing blood glucose levels in healthy and NA-STZ-hyperglycemic mice when compared with vehicle groups (p<0.05). The FM-AE exerted also positive effect over different biochemical parameters altered in rats with metabolic syndrome induced by a fructose diet. FM-AE has also antioxidant action effectively trapping ONOO(-) and ROO(•) radicals. The major flavonoids isolated from the plant, namely acacetin (1) and diosmetin (2), caused significant hypoglycemic effect and possessed antioxidant activity.. Anoda cristata is effective to diminish glucose levels in vivo and to ameliorate different disorders related with the metabolic syndrome in rats. According to the results, the efficacy of Anoda cristata preparations could be due to the presence of active principles with different mode of actions at the molecular level, including α-glycosidases inhibitors, insulin secretagogues, glucose entrapment and radical trapping agents.

Topics: Animals; Antioxidants; Blood Glucose; Diabetes Mellitus, Experimental; Flavones; Flavonoids; Free Radicals; Glycogen; Hyperglycemia; Hypoglycemic Agents; Insulin; Lipid Metabolism; Liver; Male; Malvaceae; Metabolic Syndrome; Mice, Inbred ICR; Phytotherapy; Plant Components, Aerial; Plant Preparations; Plants, Edible; Rats; Rats, Sprague-Dawley; Uric Acid

The present study was designed to evaluate the potential hypoglycemic and hypolipidemic effects of Angelica sinensis polysaccharide (ASP), purified from the fresh roots of Angelica sinensis (AS), in prediabetic and streptozotocin (STZ)-induced diabetic BALB/c mice. It was observed that fasting blood glucose (FBG) levels in both models were reduced after a 4-week oral administration of ASP or metformin, and abnormal fasting serum insulin (FINS) concentrations were ameliorated as well. Moreover, the homeostasis model assessment-insulin resistance (HOMA-IR) index was decreased strikingly and body weight (BW) was reduced significantly in prediabetic mice after treatment with ASP. In addition, ASP also contributed to improving the dyslipidemia conditions. Elevated serum total cholesterol (TC) or triglyceride (TG) concentrations were reduced after treatment with ASP in prediabetic mice or STZ-induced diabetic mice. Meanwhile, hepatic glycogen (HG) and muscle glycogen (MG) concentrations were increased while insulin resistance (IR)-related inflammatory factors IL-6 and TNF-α in serum were reduced in STZ-induced diabetic mice. Histopathological examination indicated that the impaired pancreatic/hepatic tissues or adipose tissues were effectively restored in STZ-induced diabetic mice or prediabetic mice after the ASP treatment. Taken together, these results revealed that ASP efficiently exerted hypoglycemic and hypolipidemic benefits, and its potential effect was associated with the amelioration of IR. ASP can be applied in the prevention and treatment of diabetes.

Topics: Adipose Tissue, White; Angelica sinensis; Animals; Anti-Inflammatory Agents, Non-Steroidal; Diabetes Mellitus, Type 2; Glycogen; Hyperglycemia; Hyperinsulinism; Hyperlipidemias; Hypoglycemic Agents; Hypolipidemic Agents; Insulin Resistance; Lipid Metabolism Disorders; Liver; Male; Mice, Inbred BALB C; Muscle, Skeletal; Pancreas; Plant Roots; Polysaccharides; Prediabetic State; Random Allocation

The study was designed to investigate the probable mechanisms of anti-hyperglycemic activity of B. Vulgaris.. Aqueous fraction of B. Vulgaris extract was the only active fraction (50mg/kg). Plasma insulin level was found to be the highest at 30 mins after B. Vulgaris administration at a dose of 200mg/kg. B. Vulgaris treated mice were also assayed for plasma Acetylcholine, Glucagon Like Peptide-1 (GLP-1), Gastric Inhibitory Peptide (GIP), Vasoactive Intestinal Peptide, Pituitary Adenylate Cyclase-Activating Peptide (PACAP), Insulin Like Growth Factor-1 (IGF-1), Pancreatic Polypeptides (PP), and Somatostatin, along with the corresponding insulin levels. Plasma Acetylcholine and GLP-1 significantly increased in B. Vulgaris treated animals and were further studied. Pharmacological enhancers, inhibitors, and antagonists of Acetylcholine and GLP-1 were also administered to the test animals, and corresponding insulin levels were measured. These studies confirmed the role of acetylcholine and GLP-1 in enhanced insulin secretion (p<0.05). Principal signaling molecules were quantified in isolated mice islets for the respective pathways to elucidate their activities. Elevated concentrations of Acetylcholine and GLP-1 in B. Vulgaris treated mice were found to be sufficient to activate the respective pathways for insulin secretion (p<0.05). The amount of membrane bound GLUT1 and GLUT4 transporters were quantified and the subsequent glucose uptake and glycogen synthesis were assayed. We showed that levels of membrane bound GLUT4 transporters, glucose-6-phosphate in skeletal myocytes, activity of glycogen synthase, and level of glycogen deposited in the skeletal muscles all increased (p<0.05).. Findings of the present study clearly prove the role of Acetylcholine and GLP-1 in the Insulin secreting activity of B. Vulgaris. Increased glucose uptake in the skeletal muscles and subsequent glycogen synthesis may also play a part in the anti-hyperglycemic activity of B. Vulgaris.

Topics: Acetylcholine; Animals; Beta vulgaris; Biological Transport; Cell Membrane; Diabetes Mellitus, Experimental; Glucagon-Like Peptide 1; Glucose; Glucose Transporter Type 4; Glucose-6-Phosphate; Glycogen; Glycogen Synthase; Hexokinase; Homeostasis; Hyperglycemia; Insulin; Insulin Secretion; Mice; Muscle Cells; Muscle, Skeletal; Plant Extracts; Water

Trans-anethole (TA), a terpenoid and a principle constituent of many essential oils from medicinal plants possess hypoglycemic and antioxidant activities. This study was undertaken to explore beneficial effects of TA on key enzymes of carbohydrate metabolism in streptozotocin (STZ)-induced type 2 diabetic rats. Diabetes was induced in male albino Wistar rats by intraperitoneal administration of STZ (40 mg/kg BW). TA was administered to diabetic rats at a dose of 20, 40 and 80 mg/kg BW for 45 days. However, the dose at 80 mg/kg BW, resulted in a significant reduction in the levels of plasma glucose, glycosylated haemoglobin (HbA1c) and increase in the levels of insulin and haemoglobin (Hb). Upon administration of TA, the altered levels of liver glycolytic enzyme (hexokinase), hepatic shunt enzyme (glucose-6-phosphate dehydrogenase) and gluconeogenic enzymes (glucose-6-phosphatase and fructose-1,6-bisphosphatase) in the liver and kidney of diabetic rats significantly reverted to near normal levels. In addition to this, TA also improved the hepatic and muscle glycogen content in diabetic rats. The histological studies showed the ameliorative effect of TA on the β-cells of pancreas in diabetic rats. The results were compared with glibenclamide, a standard oral hypoglycemic drug. These encouraging findings suggest that TA may be used as a propitious bioactive compound in the development of therapeutic agents against type 2 diabetes mellitus.

Topics: Allylbenzene Derivatives; Animals; Anisoles; Diabetes Mellitus, Experimental; Flavoring Agents; Gluconeogenesis; Glycogen; Glycolysis; Hyperglycemia; Male; Rats; Rats, Wistar

Major aims were to determine whether exposure to the commonly used food additive carrageenan could induce fasting hyperglycemia and could increase the effects of a high fat diet on glucose intolerance and dyslipidemia.. C57BL/6J mice were exposed to either carrageenan, high fat diet, or the combination of high fat diet and carrageenan, or untreated, for one year. Effects on fasting blood glucose, glucose tolerance, lipid parameters, weight, glycogen stores, and inflammation were compared.. Exposure to carrageenan led to glucose intolerance by six days and produced elevated fasting blood glucose by 23 weeks. Effects of carrageenan on glucose tolerance were more severe than from high fat alone. Carrageenan in combination with high fat produced earlier onset of fasting hyperglycemia and higher glucose levels in glucose tolerance tests and exacerbated dyslipidemia. In contrast to high fat, carrageenan did not lead to weight gain. In hyperinsulinemic, euglycemic clamp studies, the carrageenan-exposed mice had higher early glucose levels and lower glucose infusion rate and longer interval to achieve the steady-state.. Carrageenan in the Western diet may contribute to the development of diabetes and the effects of high fat consumption. Carrageenan may be useful as a nonobese model of diabetes in the mouse.

Topics: Animals; Blood Glucose; Body Weight; Carrageenan; Diet; Diet, High-Fat; Disease Models, Animal; Dyslipidemias; Food Additives; Food Deprivation; Glucose; Glucose Tolerance Test; Glycated Hemoglobin; Glycogen; Hyperglycemia; Hyperlipidemias; Inflammation; Lipids; Male; Mice; Mice, Inbred C57BL; Risk Factors

The liver maintains glucose and lipid homeostasis by adapting its metabolic activity to the energy needs of the organism. Communication between hepatocytes and extracellular environment via endocytosis is key to such homeostasis. Here, we addressed the question of whether endosomes are required for gluconeogenic gene expression. We took advantage of the loss of endosomes in the mouse liver upon Rab5 silencing. Strikingly, we found hepatomegaly and severe metabolic defects such as hypoglycemia, hypercholesterolemia, hyperlipidemia, and glycogen accumulation that phenocopied those found in von Gierke's disease, a glucose-6-phosphatase (G6Pase) deficiency. G6Pase deficiency alone can account for the reduction in hepatic glucose output and glycogen accumulation as determined by mathematical modeling. Interestingly, we uncovered functional alterations in the transcription factors, which regulate G6Pase expression. Our data highlight a requirement of Rab5 and the endosomal system for the regulation of gluconeogenic gene expression that has important implications for metabolic diseases.

Topics: Animals; Computer Simulation; Diabetes Mellitus, Experimental; Endosomes; Gene Knockdown Techniques; Gluconeogenesis; Glucose; Glucose-6-Phosphatase; Glycogen; Glycogen Storage Disease Type I; Hepatomegaly; Hyperglycemia; Hypoglycemia; Insulin; Lipid Metabolism; Liver; Mice, Knockout; Models, Biological; Proteomics; rab5 GTP-Binding Proteins; Signal Transduction

The art of Ayurveda and the traditional healing system in India have reflected the ethnomedicinal importance of the plant Woodfordia fruticosa Kurtz, which demonstrates its vast usage in the Ayurvedic preparations as well as in the management of diabetes by the traditional healers.. The study aimed to ascertain the antidiabetic potential of W. fruticosa flower methanolic extract (WF) on Streptozotocin (STZ)-nicotinamide-induced diabetic rat model.. Diabetes was induced in Sprague Dawley (SD) rats by STZ-nicotinamide and thereafter diabetic rats were treated with three different doses of WF (100, 200 and 400mg/kg body weight) respectively and glibenclamide as a positive control. Biochemical parameters such as blood glucose, serum insulin and C-peptide levels were measured with oxidative stress markers. Furthermore, histology of liver and pancreas was carried out to evaluate glycogen content and β-cell structures. Moreover, immunohistochemistry and western blot analysis were performed on kidney and pancreas tissues to determine renal Bcl-2, pancreatic insulin and glucose transporter (GLUT-2, 4) protein expression in all the experimental groups.. The acute toxicity study showed non-toxic nature of all the three doses of WF. Further, studies on diabetic rats exhibited anti-hyperglycemic effects by upregulating serum insulin and C-peptide levels. Similarly, WF shown to ameliorate oxidative stress by downregulating LPO levels and augmenting the antioxidant enzyme (ABTS). Furthermore, histopathological analysis demonstrate recovery in the structural degeneration of β-cells mass of pancreas tissue with increase in the liver glycogen content of the diabetic rats. Interestingly, protective nature of the extract was further revealed by the immunohistochemical study result which displayed upregulation in the insulin and renal Bcl-2 expression, the anti apoptosis protein. Moreover, western blot result have shown slight alteration in the GLUT-2 and GLUT-4 protein expression with the highest dose of WFc treatment, that might have stimulated glucose uptake in the pancreas and played an important role in attenuating the blood glucose levels.. The overall study result have demonstrated the potential of WF in the management of diabetes and its related complications, thus warrants further investigation on its major compounds with in depth mechanistic studies at molecular level.

Topics: Animals; Diabetes Mellitus, Experimental; Flowers; Glucose Transporter Type 2; Glucose Transporter Type 4; Glycogen; Hyperglycemia; Hypoglycemic Agents; Insulin; Kidney; Liver; Male; Niacinamide; Oxidative Stress; Pancreas; Phytochemicals; Plant Extracts; Proto-Oncogene Proteins c-bcl-2; Rats, Sprague-Dawley; Streptozocin; Woodfordia

Gluconeogenesis is critical for maintenance of euglycemia during fasting. Elevated gluconeogenesis during type 2 diabetes (T2D) contributes to chronic hyperglycemia. Pyruvate is a major gluconeogenic substrate and requires import into the mitochondrial matrix for channeling into gluconeogenesis. Here, we demonstrate that the mitochondrial pyruvate carrier (MPC) comprising the Mpc1 and Mpc2 proteins is required for efficient regulation of hepatic gluconeogenesis. Liver-specific deletion of Mpc1 abolished hepatic MPC activity and markedly decreased pyruvate-driven gluconeogenesis and TCA cycle flux. Loss of MPC activity induced adaptive utilization of glutamine and increased urea cycle activity. Diet-induced obesity increased hepatic MPC expression and activity. Constitutive Mpc1 deletion attenuated the development of hyperglycemia induced by a high-fat diet. Acute, virally mediated Mpc1 deletion after diet-induced obesity decreased hyperglycemia and improved glucose tolerance. We conclude that the MPC is required for efficient regulation of gluconeogenesis and that the MPC contributes to the elevated gluconeogenesis and hyperglycemia in T2D.

Topics: Acrylates; Animals; Cells, Cultured; Citric Acid Cycle; Diet, High-Fat; Gluconeogenesis; Glucose; Glutamine; Glycogen; Hepatocytes; Hyperglycemia; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria, Liver; Obesity; Proprotein Convertase 1; Proprotein Convertase 2; Pyruvic Acid; Triglycerides

Pyruvate transport across the inner mitochondrial membrane is believed to be a prerequisite for gluconeogenesis in hepatocytes, which is important for the maintenance of normoglycemia during prolonged food deprivation but also contributes to hyperglycemia in diabetes. To determine the requirement for mitochondrial pyruvate import in gluconeogenesis, mice with liver-specific deletion of mitochondrial pyruvate carrier 2 (LS-Mpc2(-/-)) were generated. Loss of MPC2 impaired, but did not completely abolish, hepatocyte conversion of labeled pyruvate to TCA cycle intermediates and glucose. Unbiased metabolomic analyses of livers from fasted LS-Mpc2(-/-) mice suggested that alterations in amino acid metabolism, including pyruvate-alanine cycling, might compensate for the loss of MPC2. Indeed, inhibition of pyruvate-alanine transamination further reduced mitochondrial pyruvate metabolism and glucose production by LS-Mpc2(-/-) hepatocytes. These data demonstrate an important role for MPC2 in controlling hepatic gluconeogenesis and illuminate a compensatory mechanism for circumventing a block in mitochondrial pyruvate import.

Topics: Alanine; Animals; Blood Glucose; Cell Line; Citric Acid Cycle; Diabetes Mellitus, Experimental; Gluconeogenesis; Glycogen; Hepatocytes; Hyperglycemia; Intestinal Mucosa; Liver; Male; Metabolome; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria, Liver; Proprotein Convertase 1; Proprotein Convertase 2; Pyruvic Acid

Recently, there has been a growing interest in alternative therapies and in the therapeutic use of natural products for the treatment of diabetes. Therefore, in this study, we investigated the hypoglycemic and hypolipidemic effects of brown algae, Padina arborescens, in an animal model of type 2 diabetes. For 6 weeks, male C57BL/KsJ-db/db mice were administrated either control diet with no treatment or were treated with rosiglitazone (RG; 0.005%, w/w) or P. arborescens extract (PAE; 0.5%, w/w). At the end of the experimental period, the blood glucose levels, glycosylated hemoglobin levels, and plasma insulin levels were significantly lower in the RG and PAE groups compared with the control group. In addition, glucose tolerance was significantly improved in the RG and PAE groups. The homeostatic index of insulin resistance was lower in the RG and PAE groups than the diabetic control group. Also, the total cholesterol, LDL-cholesterol, triglyceride, and free fatty acid levels were lower in the PAE group than in the control group, whereas the HDL-C level was higher in the PAE group. Supplementation with PAE significantly lowered hepatic glucose-6-phosphatase and phosphoenolpyruvate carboxykinase activities, and increased glucokinase activity in the liver. Consequently, these results suggest that PAE may be beneficial in improving insulin resistance, hyperglycemia, and dyslipidemia in type 2 diabetics.

Topics: Adiponectin; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Diet; Disease Models, Animal; Dyslipidemias; Fasting; Glucose Tolerance Test; Glycated Hemoglobin; Glycogen; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Lipids; Male; Mice; Mice, Inbred C57BL; Phaeophyceae; Rosiglitazone; Thiazolidinediones

The study was designed to investigate the anti-hyperglycemic activity of selenium nanoparticles (SeNPs) in streptozotocin-induced diabetic rats. Fifty-five mg/kg of streptozotocin was injected in rats to induce diabetes. Animals either treated with SeNPs alone or with insulin (6 U/kg) showed significantly decreased fasting blood glucose levels after 28 days of treatment. The serum insulin concentration in untreated diabetic animals was also enhanced by SeNPs. The results demonstrated that SeNPs could significantly decrease hepatic and renal function markers, total lipid, total cholesterol, triglyceride and low-density lipoprotein cholesterol levels, and glucose-6-phosphatase activity. At the same time, SeNPs increased malic enzyme, hexokinase and glucose-6-phosphate dehydrogenase activity, liver and kidney glycogen contents, and high-density lipoprotein cholesterol levels. In addition, SeNPs were able to prevent the histological injury in the hepatic and renal tissues of rats. However, insulin injection also exhibited a significant improvement in diabetic animals after 28 days of treatment. This study suggests that SeNPs can alleviate hyperglycemia and hyperlipidemia in streptozotocin-induced diabetic rats, possibly by eliciting insulin-mimetic activity.

Topics: Animals; Biomarkers; Blood Glucose; Body Weight; Carbohydrate Metabolism; Diabetes Mellitus, Experimental; Dynamic Light Scattering; Fasting; Gene Expression Regulation; Glutathione Peroxidase; Glycogen; Hyperglycemia; Hypoglycemic Agents; Insulin; Kidney; Lipids; Liver; Male; Nanoparticles; Rats, Wistar; Selenium; Streptozocin

Epidemiological studies have demonstrated that diabetes mellitus is a serious health burden for both governments and healthcare providers. This study was hypothesized to evaluate the antihyperglycemic potential of eugenol by determine the activities of key enzymes of glucose metabolism in streptozotocin (STZ)-induced diabetic rats. Diabetes was induced into male albino Wistar rats by intraperitoneal administration of STZ (40 mg/kg body weight (b.w.)). Eugenol was administered to diabetic rats intragastrically at 2.5, 5, and 10 mg/kg b.w. for 30 days. The dose 10 mg/kg b.w. significantly reduced the levels of blood glucose and glycosylated hemoglobin (HbA1c) and increased plasma insulin level. The altered activities of the key enzymes of carbohydrate metabolism such as hexokinase, pyruvate kinase, glucose-6-phosphate dehydrogenase, glucose-6-phosphatase, fructose-1,6-bisphosphatase, and liver marker enzymes (AST, ALT, and ALP), creatine kinase and blood urea nitrogen in serum and blood of diabetic rats were significantly reverted to near normal levels by the administration of eugenol. Further, eugenol administration to diabetic rats improved body weight and hepatic glycogen content demonstrated the antihyperglycemic potential of eugenol in diabetic rats. The present findings suggest that eugenol can potentially ameliorate key enzymes of glucose metabolism in experimental diabetes, and it is sensible to broaden the scale of use of eugenol in a trial to alleviate the adverse effects of diabetes.

Topics: Animals; Blood Glucose; Blood Urea Nitrogen; Body Weight; Carbohydrates; Diabetes Mellitus, Experimental; Drinking Behavior; Eugenol; Feeding Behavior; Fructose-Bisphosphatase; Glucose; Glucose Tolerance Test; Glucose-6-Phosphatase; Glucosephosphate Dehydrogenase; Glycated Hemoglobin; Glycogen; Hexokinase; Hyperglycemia; Insulin; Kidney; Liver; Male; Pancreas; Pyruvate Kinase; Rats; Streptozocin

Eicosapentaenoic acid-enriched phosphatidylcholine was isolated from the sea cucumber Cucumaria frondosa (Cucumaria-PC) and its effects on streptozotocin (STZ)-induced hyperglycemic rats were investigated. Male Sprague-Dawley rats were randomly divided into normal control, model control (STZ), low- and high-dose Cucumaria-PC groups (STZ + Cucumaria-PC at 25 and 75 mg/Kg·b·wt, intragastrically, respectively). Blood glucose, insulin, glycogen in liver and gastrocnemius were determined over 60 days. Insulin signaling in the rats' gastrocnemius was determined by reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blotting. The results showed that Cucumaria-PC significantly decreased blood glucose level, increased insulin secretion and glycogen synthesis in diabetic rats. RT-PCR analysis revealed that Cucumaria-PC significantly promoted the expressions of glycometabolism-related genes of insulin receptor (IR), insulin receptor substrate-1 (IRS-1), phosphoinositide 3-kinase (PI3K), protein kinase B (PKB), and glucose transporter 4 (GLUT4) in gastrocnemius. Western blotting assay demonstrated that Cucumaria-PC remarkably enhanced the proteins abundance of IR-β, PI3K, PKB, GLUT4, as well as phosphorylation of Tyr-IR-β, p85-PI3K, Ser473-PKB (P < 0.05 and P < 0.01). These findings suggested that Cucumaria-PC exhibited significant anti-hyperglycemic activities through up-regulating PI3K/PKB signal pathway mediated by insulin. Nutritional supplementation with Cucumaria-PC, if validated for human studies, may offer an adjunctive therapy for diabetes mellitus.

Topics: Animals; Blood Glucose; Cucumaria; Diabetes Mellitus, Experimental; Eicosapentaenoic Acid; Enzyme Activation; Glucose Transporter Type 4; Glycogen; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Receptor Substrate Proteins; Insulin Secretion; Male; Muscle, Skeletal; Phosphatidylcholines; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Receptor, Insulin; Signal Transduction; Up-Regulation

The effect of betulinic acid on glycemia and its mechanism of action compared with 1,25(OH)2 vitamin D3 in rat muscle were investigated. Betulinic acid improved glycemia, induced insulin secretion and increased the glycogen content and glucose uptake in muscle tissue. Additionally, the integrity of both PI3K and the cytoskeleton is necessary for the stimulatory action of betulinic acid in glucose uptake. The genomic effect was apparent, since cycloheximide and PD98059 nullified the stimulatory effect of betulinic acid on glucose uptake. Therefore, although this compound did not modify the DNA transcription, the protein translation was significantly improved. Also, betulinic acid increased the GLUT4 immunocontent and its translocation was corroborated by GLUT4 localization at the plasma membrane (after 180 min). On the other hand, the effect of 1,25(OH)2 vitamin D3 on glucose uptake is not mediated by PI3K and microtubule activity. In contrast, the nuclear activity of 1,25(OH)2 vitamin D3 is necessary to trigger glucose uptake. In addition, the increased DNA transcription and GLUT4 immunocontent provide evidence of a mechanism by which 1,25(OH)2 vitamin D3 contributes to glycemia. In conclusion, betulinic acid acts as an insulin secretagogue and insulinomimetic agent via PI3K, MAPK and mRNA translation and partially shares the genomic pathway with 1,25(OH)2 vitamin D3 to upregulate the GLUT4. In summary, betulinic acid regulates glycemia through classical insulin signaling by stimulating GLUT4 synthesis and translocation. In addition, it does not cause hypercalcemia, which is highly significant from the drug discovery perspective.

Topics: Animals; Betulinic Acid; Biological Transport; Blood Glucose; Calcium; Glucose; Glucose Transporter Type 4; Glycogen; Homeostasis; Hyperglycemia; Insulin; L-Lactate Dehydrogenase; Male; Muscle, Skeletal; Pentacyclic Triterpenes; Protein Transport; Rats; Rats, Wistar; Signal Transduction; Triterpenes; Vitamin D

The present study was aimed to evaluate the effect of morin on blood glucose, insulin level, hepatic glucose regulating enzyme activities and glycogen level in experimental diabetes. Diabetes mellitus was induced by a single intraperitoneal injection of streptozotocin (STZ) (50 mg/kg b.w.). Five days after STZ injection, diabetic rats received morin (25 and 50 mg/kg b.w.) orally for 30 days. Glibenclamide was used as reference drug. Morin treatment significantly reduced the blood glucose and improved the serum insulin levels. Further, a dose-dependent reduction in glucose-6-phosphatase and fructose-1,6-bisphosphatase was observed along with the increase in liver hexokinase and glucose-6-phosphate dehydrogenase activities. Morin supplement were found to be effective in preserving the normal histological appearance of pancreatic islets as well as to preserve insulin-positive β-cells in STZ-rats. Therefore, these findings suggest that morin displays beneficial effects in the treatment of diabetes, mediated through the regulation of carbohydrate metabolic enzyme activities.

Topics: Animals; Blood Glucose; Carbohydrate Metabolism; Diabetes Mellitus, Experimental; Flavonoids; Glycogen; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Liver; Male; Pancreas; Rats; Rats, Wistar

This study aimed at assessing the effects of Kefir, a probiotic fermented milk, on oxidative stress in diabetic animals. The induction of diabetes was achieved in adult male Wistar rats using streptozotocin (STZ). The animals were distributed into four groups as follows: control (CTL); control Kefir (CTLK); diabetic (DM) and diabetic Kefir (DMK). Starting on the 5th day of diabetes, Kefir was administered by daily gavage at a dose of 1.8 mL/day for 8 weeks. Before and after Kefir treatment, the rats were placed in individual metabolic cages to obtain blood and urine samples to evaluate urea, creatinine, proteinuria, nitric oxide (NO), thiobarbituric acid reactive substances (TBARS) and C-reactive protein (CRP). After sacrificing the animals, the renal cortex was removed for histology, oxidative stress and NOS evaluation. When compared to CTL rats, DM rats showed increased levels of glycemia, plasmatic urea, proteinuria, renal NO, superoxide anion, TBARS, and plasmatic CRP; also demonstrated a reduction in urinary urea, creatinine, and NO. However, DMK rats showed a significant improvement in most of these parameters. Despite the lack of differences observed in the expression of endothelial NO synthase (eNOS), the expression of inducible NO synthase (iNOS) was significantly lower in the DMK group when compared to DM rats, as assessed by Western blot analysis. Moreover, the DMK group presented a significant reduction of glycogen accumulation within the renal tubules when compared to the DM group. These results indicate that Kefir treatment may contribute to better control of glycemia and oxidative stress, which is associated with the amelioration of renal function, suggesting its use as a non-pharmacological adjuvant to delay the progression of diabetic complications.

Topics: Animals; Cultured Milk Products; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Disease Progression; Glucose Tolerance Test; Glycogen; Hyperglycemia; Kidney Diseases; Kidney Tubules; Male; Nitric Oxide; Oxidative Stress; Probiotics; Rats; Rats, Wistar; Streptozocin

Diabetes mellitus is the most common endocrine disorder that affects more than 285 million people worldwide. The purpose of this study was to investigate the effect of mesenchymal stem cells (MSCs) from the bone marrow of albino rats, on hyperglycemia, hyperlipidemia, and oxidative stress induced by intraperitoneal injection (i.p.) of alloxan at a dose of 150 mg/kg in rats. Injection of alloxan into rats resulted in a significant increase in serum glucose, total cholesterol, triglyceride, low density lipoprotein cholesterol, and sialic acid level and a significant decrease in serum insulin, high density lipoprotein-cholesterol, vitamin E, and liver glycogen as compared to their corresponding controls. Also, oxidative stress was noticed in pancreatic tissue as evidenced by a significant decrease in glutathione level, superoxide dismutase, glutathione-S-transferase activities, also a significant increase in malondialdehyde and nitric oxide levels when compared to control group. Treatment of diabetic rats with MSCs stem cells significantly prevented these alterations and attenuated alloxan-induced oxidative stress. In conclusion, rat bone marrow harbors cells that have the capacity to differentiate into functional insulin-producing cells capable of controlling hyperglycemia, hyperlipidemia, and oxidative stress in diabetic rats. This may be helpful in the prevention of diabetic complications associated with oxidative stress.

Topics: Alloxan; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Female; Flow Cytometry; Glutathione; Glycogen; Hyperglycemia; Hyperlipidemias; Insulin; Lipids; Liver; Male; Malondialdehyde; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; N-Acetylneuraminic Acid; Nitric Oxide; Oxidative Stress; Pancreas; Rats, Wistar; Vitamin E

Based on previous studies we hypothesize that under stress conditions catecholamine-induced hyperglycemia contributes to enhance cortisol production in head kidney of rainbow trout. Therefore, treatment with propranolol (β-adrenoceptor blocker) should reduce the hyperglycemia elicited by stress and, therefore, we expected reduced glucosensing response and cortisol production in head kidney. Propranolol treatment was effective in blocking most of the effects of catecholamines in liver energy metabolism resulting in a lower glycemia in stressed fish. The decreased glycemia of stressed fish treated with propranolol was observed along with reduced transcription of genes involved in the cortisol synthetic pathway, which supports our hypothesis. However, changes in putative glucosensing parameters assessed in head kidney were scarce and in general did not follow changes noted in glucose levels in plasma. Furthermore, circulating cortisol levels did not change in parallel with changes in glycemia. As a whole, the present results suggest that glycemia could participate in the regulation of cortisol synthetic pathways but other factors are also likely involved. Propranolol effects on trout stress response were different depending on time passed after stress onset; the direct or indirect involvement of catecholaminergic response in the regulation of cortisol production and release deserves further investigation.

Topics: Animals; Blood Glucose; Catecholamines; Glycogen; Head Kidney; Hydrocortisone; Hyperglycemia; Lactates; Liver; Oncorhynchus mykiss; Stress, Physiological

Transient carotid artery occlusion causes ischemia/reperfusion (I/R) injury resulting in neuron and pancreatic β-cell death with consequential post-stroke hyperglycemia, which can lead to diabetes and may accelerate the development of Alzheimer's disease. Antioxidants have been shown to protect against the I/R injury and destruction of neurons. However, it is unknown whether the protection against I/R injury extends to the pancreatic β-cells. Therefore, we investigated whether treatment with ebselen, a glutathione peroxidase mimic, prevents neuronal and β-cell death following I/R in gerbils susceptible to stroke. After 28 days post artery occlusion, there was widespread neuronal cell death in the CA1 of the hippocampus and elevated IL-1β and TNF-α levels. Pretreatment with ebselen prevented the death by 56% and attenuated neurological damage (abnormal eyelid drooping, hair bristling, muscle tone, flexor reflex, posture, and walking patterns). Ischemic gerbils also exhibited impaired glucose tolerance and insulin sensitivity which induced post-stroke hyperglycemia associated with decreased β-cell mass due to increased β-cell apoptosis. Ebselen prevented the increased β-cell apoptosis, possibly by decreasing IL-1β and TNF-α in islets. Ischemia also attenuated hepatic insulin signaling, and expression of GLUT2 and glucokinase, whereas ebselen prevented the attenuation and suppressed gluconeogenesis by decreasing PEPCK expression. In conclusion, antioxidant protection by ebselen attenuated I/R injury of neurons and pancreatic β-cells and prevented subsequent impairment of glucose regulation that could lead to diabetes and Alzheimer's disease.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Azoles; Brain Ischemia; Cell Survival; Cytokines; Gerbillinae; Glycogen; Hyperglycemia; Insulin; Insulin-Secreting Cells; Isoindoles; Liver; Male; Organoselenium Compounds; Random Allocation; Reperfusion Injury; Signal Transduction

Ursolic acid (UA) is a pentacyclic triterpenoid compound that naturally occurs in fruits, leaves and flowers of medicinal herbs. This study investigated the dose-response efficacy of UA (0.01 and 0.05%) on glucose metabolism, the polyol pathway and dyslipidemia in streptozotocin/nicotinamide-induced diabetic mice. Supplement with both UA doses reduced fasting blood glucose and plasma triglyceride levels in non-obese type 2 diabetic mice. High-dose UA significantly lowered plasma free fatty acid, total cholesterol and VLDL-cholesterol levels compared with the diabetic control mice, while LDL-cholesterol levels were reduced with both doses. UA supplement effectively decreased hepatic glucose-6-phosphatase activity and increased glucokinase activity, the glucokinase/glucose-6-phosphatase ratio, GLUT2 mRNA levels and glycogen content compared with the diabetic control mice. UA supplement attenuated hyperglycemia-induced renal hypertrophy and histological changes. Renal aldose reductase activity was higher, whereas sorbitol dehydrogenase activity was lower in the diabetic control group than in the non-diabetic group. However, UA supplement reversed the biochemical changes in polyol pathway to normal values. These results demonstrated that low-dose UA had preventive potency for diabetic renal complications, which could be mediated by changes in hepatic glucose metabolism and the renal polyol pathway. High-dose UA was more effective anti-dyslipidemia therapy in non-obese type 2 diabetic mice.

Topics: Animals; Antineoplastic Agents, Phytogenic; Blotting, Western; Diabetes Complications; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dyslipidemias; Glucokinase; Glucose; Glucose Transporter Type 2; Glucose-6-Phosphatase; Glycogen; Hyperglycemia; Kidney Diseases; Male; Mice; Mice, Inbred ICR; Mice, Inbred NOD; Polymers; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Triterpenes; Ursolic Acid

The objective of this study was to investigate the mode of action of dopamine in regulating hemolymph sugar level in the fresh water edible crab, Oziothelphusa senex senex. Injection of dopamine produced hyperglycemia in a dose-dependent manner in intact crabs but not in eyestalkless crabs. Administration of dopamine resulted in a significant decrease in total carbohydrates and glycogen levels with a significant increase in glycogen phosphorylase activity levels in hepatopancreas and muscle of intact crabs, indicating dopamine-induced glycogenolysis resulting in hyperglycemia. Bilateral eyestalk ablation resulted in significant increase in the total carbohydrates and glycogen levels with a significant decrease in the activity levels of phosphorylase in the hepatopancreas and muscle of the crabs. Eyestalk ablation resulted in significant decrease in hemolymph hyperglycemic hormone levels. The levels of hyperglycemic hormone in the hemolymph of dopamine injected crabs were significantly higher than in control crabs. However, no significant changes in the levels of hemolymph hyperglycemic hormone and sugar and tissue carbohydrate and phosphorylase activity were observed in dopamine injected eyestalk ablated crabs when compared with eyestalk ablated crabs. These results support an earlier hypothesis in crustaceans that dopamine acts as a neurotransmitter and induces hyperglycemia by triggering the release of hyperglycemic hormone in the crab, O. senex senex.

Topics: Animals; Brachyura; Carbohydrate Metabolism; Dopamine; Freshwater Biology; Glycogen; Hemolymph; Hyperglycemia; Neurotransmitter Agents

This study assessed the effect of gas stunning which has not been conducted until now in comparison with slaughter without stunning on the welfare and meat quality of rabbits. Eighty male New Zealand White rabbits were divided into two groups of 40 animals and subjected to either halal slaughter without stunning (HS) or gas stunning using 61.4% CO2, 20.3% oxygen and 18.3 % nitrogen (GS). Analysis of the sticking blood revealed that both slaughter procedures caused a substantial increase in the levels of catecholamines, hypercalcemia, hyperglycemia, lactic acidemia and an increase in enzyme activities. The ultimate pH of the Longissimus lumborum muscle did not differ between treatments. GS exhibited higher lightness and cooking loss, and lower glycogen and MFI than HS. This indicates that both GS and HS can be significant stressors although the amount of stress may be below the threshold to negatively affect rabbit meat quality.

Topics: Abattoirs; Animal Welfare; Animals; Carbon Dioxide; Catecholamines; Food Quality; Gases; Glycogen; Hydrogen-Ion Concentration; Hypercalcemia; Hyperglycemia; Lactic Acid; Male; Meat; Nitrogen; Oxygen; Rabbits; Stress, Physiological

To investigate whether alpha-lipoic acid (ALA) could attenuate the insulin resistance and metabolic disorders in high fat diet-fed mice.. Male mice were fed a high fat diet (HFD) plus ALA (100 and 200 mg·kg(-1)·d(-1)) or HFD plus a positive control drug metformin (300 mg·kg(-1)·d(-1)) for 24 weeks. During the treatments, the relevant physiological and metabolic parameters of the mice were measured. After the mice were euthanized, blood samples and livers were collected. The expression of proteins and genes related to glucose metabolism in livers were analyzed by immunoblotting and real time-PCR.. HFD induced non-alcoholic fatty liver disease (NAFLD) and abnormal physiological and metabolic parameters in the mice, which were dose-dependently attenuated by ALA. ALA also significantly reduced HFD-induced hyperglycemia and insulin resistance in HFD-fed mice. Furthermore, ALA significantly upregulated the glycolytic enzymes GCK, HK-1 and PK, and the glycogen synthesis enzyme GS, and downregulated the gluconeogenic enzymes PEPCK and G6Pase, thus decreased glucose production, and promoted glycogen synthesis and glucose utilization in livers. Moreover, ALA markedly increased PKB/Akt and GSK3β phosphorylation, and nuclear carbohydrate response element binding protein (ChREBP) expression in livers. Metformin produced similar effects as ALA in HFD-fed mice.. ALA is able to sustain glucose homeostasis and prevent the development of NAFLD in HFD-fed mice.

Topics: Animals; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Diet, High-Fat; Down-Regulation; Gluconeogenesis; Glucose; Glycogen; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Glycolysis; Hyperglycemia; Insulin Resistance; Liver; Male; Metabolic Diseases; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Nuclear Proteins; Proto-Oncogene Proteins c-akt; Thioctic Acid; Transcription Factors; Up-Regulation

Benzopyrones are proven antidiabetic drug candidate in diabetic drug discovery. In this view novel synthetic benzopyrone analogues were selected for testing in experimental diabetes. Type 2 diabetes (T2D) was induced in Wistar rats by streptozotocin (60 mg/kg, i.p.) followed by nicotinamide (120 mg/kg i.p.). Rats having fasting blood glucose (FBG)>200 mg/dL, 7 days after T2D-induction, are selected for the study. Test compounds and standard treatment were continued for 15 days. FBG, oral glucose tolerance test (OGTT), and insulin tolerance test (ITT) were determined on 21st day after induction of T2D. Plasma lipids and serum insulin were estimated. Homeostatic model assessment (HOMA-IR) was then calculated from serum insulin. Rats were sacrificed and pancreas was isolated for histopathological observations. Oxidative stress markers were estimated in liver homogenate. Quercetin, a natural product with benzopyrone ring, showed significant hypoglycemic activity comparable to glibenclamide. Treatment with test compounds lowered the FBG and insulin resistance was significant alleviated as determined by OGTT, HOMA-IR, and ITT. There was significant normalisation of liver antioxidant enzymes compared to diabetic rats indicating that all the synthesised benzopyrone analogues are beneficial in reducing oxidative stress and are on par with the standard quercetin and glibenclamide in experimental T2D.

Topics: Animals; Biomarkers; Blood Glucose; Coumarins; Creatinine; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Fasting; Glucose Tolerance Test; Glycation End Products, Advanced; Glycogen; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Lipids; Liver; Male; Niacinamide; Oxidative Stress; Pancreas; Rats, Wistar; Streptozocin

The present study investigated the effect of diphenyl diselenide [(PhSe)2 ] on metabolic disorders induced by acephate acute exposure in rats. We also investigated a possible mechanism of action of (PhSe)2 against hyperglycemia induced by acephate. (PhSe)2 was administered to rats at a dose of 10 or 30 mg/kg by oral gavage (p.o.) 1 hour prior to acephate administration (140 mg/kg; p.o.). Glucose and corticosterone levels as well as the lipid status were determined in plasma of rats. Cardiovascular risk factors and the atherogenic index were calculated. Glycogen levels as well as tyrosine aminotransferase (TAT) and glucose-6-phosphatase (G6Pase) activities were determined in livers of rats. Cerebral acetylcholinesterase (AChE) activity was assayed. Acephate induced an increase in glucose and corticosterone levels as well as in TAT and G6Pase activities. AChE activity was inhibited by acephate. Triglyceride (TG) levels and the cardiovascular risk factor TG/high-density lipoprotein-cholesterol (HDL) were increased by acephate. (PhSe)2 was effective against the metabolic disorders induced by acephate acute exposure in rats.

Topics: Acetylcholinesterase; Animals; Benzene Derivatives; Blood Glucose; Cholesterol, HDL; Corticosterone; Glucose-6-Phosphatase; Glycogen; Hyperglycemia; Liver; Male; Metabolic Diseases; Organoselenium Compounds; Organothiophosphorus Compounds; Phosphoramides; Protective Agents; Rats; Rats, Wistar; Triglycerides; Tyrosine Transaminase

The contribution of liver glycogen catabolism to hyperglycemia and glucose intolerance induced by pharmacological hypercortisolism were investigated.. For this purpose, adult male Wistar rats that received 1.0 mg/kg dexamethasone (DEX) ip at 8:00 a.m. (DEX group) or saline (CON group) once a day for 5 consecutive days were compared.. Experimental hypercortisolism was confirmed by higher (p<0.05) glycemia, lower (p<0.05) body weight and glucose intolerance. In the fed state, the basal glycogen catabolism and the glucagon (1 nM) and epinephrine (2 μM) induced glycogen catabolism were similar between the groups. The activation of glycogen catabolism induced by phenylephrine (2 μM) and isoproterenol (20 μM) were increased (p<0.05) and decreased (p<0.05), respectively, in DEX rats. Furthermore, DEX rats exhibited higher (p<0.05) glycogen catabolism during the infusion of cAMP (3 μM). However, during the infusion of cAMP (15 μM), 6MB-cAMP (3 μM) or cyanide (0.5 mM), the intensification of glycogen breakdown was similar. Thus, in general, hypercortisolism does not influence the basal glycogen catabolism and the liver responsiveness to glycogenolytic agents in the fed state. In contrast with fed state, fasted rats (DEX group) showed a more intense (p<0.05) basal glycogen catabolism.. The contribution of glycogen catabolism to hyperglycemia during hypercortisolism depends of the nutritional status, starting from a negligible participation in the fed state up to a significant contribution in the fasted state.

Topics: Animals; Body Weight; Cushing Syndrome; Cyclic AMP; Dexamethasone; Epinephrine; Fasting; Glucagon; Glucose Intolerance; Glycogen; Hyperglycemia; Liver; Male; Rats; Rats, Wistar

Impaired glucose tolerance (IGT) is characterized by decreased oxidative capacity and reduced carbohydrate utilization during exercise. However, it is unclear if the presence of impaired fasting glucose (IFG) affects fuel utilization during exercise in adults with IGT. We tested the hypothesis that the presence of IFG in adults with IGT decreases reliance on carbohydrate during exercise. Middle-aged, obese, sedentary individuals (n = 6, IGT and n = 6, IFG+IGT) were compared during exercise at 60% peak O2 consumption for 45 min on a cycle ergometer. Glucose rates of appearance and disposal and muscle glycogen were assessed by stable isotope dilution methods, and fat utilization was estimated via indirect calorimetry. A 75-g oral glucose tolerance test was used to determine fasting and 2-h glucose concentrations. A glucose intolerance severity z-score was calculated from the oral glucose tolerance test. Glucose flux (i.e., rates of appearance and disposal) was not different between groups. However, individuals with IFG+IGT had lower muscle glycogen use (P < 0.05) and elevated fat oxidation (P < 0.01) during exercise compared with those with isolated IGT. Plasma nonesterified fatty acids and glucose were significantly higher during exercise in subjects with IFG+IGT vs. IGT alone (P < 0.05). Fat utilization during exercise correlated with fasting glucose (r = 0.57, P = 0.05), glucose intolerance severity z-score (r = 0.66, P = 0.01), and nonesterified fatty acids (trend; r = 0.55, P = 0.08). The presence of IFG shifts fuel selection toward increased fat oxidation and decreased muscle glycogen utilization during exercise in adults with IGT. Whether these differences in substrate use contribute to, or are the result of, movement along the continuum from prediabetes to type 2 diabetes awaits further work.

Topics: Adult; Anaerobic Threshold; Anthropometry; Blood Chemical Analysis; Blood Glucose; Calorimetry, Indirect; Exercise; Fasting; Fatty Acids, Nonesterified; Female; Glucose; Glucose Intolerance; Glucose Tolerance Test; Glycogen; Humans; Hyperglycemia; Insulin; Insulin Resistance; Lipid Metabolism; Male; Middle Aged; Oxygen Consumption

This study tested whether the glycogen-accumulating effect of chronic in vivo pharmacological 5'AMP-activated protein kinase (AMPK) activation could improve glycemic control under conditions of insulin deficiency. Male Wistar rats were rendered diabetic through the administration of streptozotocin (STZ) and then treated for 7 consecutive days with the AMPK activator 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR). Subsequently, glycogen content and synthesis, glucose oxidation, and fatty acid oxidation (FAO) were determined in oxidative and glycolytic skeletal muscles. Glycemia, insulinemia, glucagonemia, and circulating triglycerides (TG) and non-esterified fatty acids (NEFAs) were measured after AICAR treatment. Insulin was almost undetectable in STZ rats and these animals were severely hyperglycemic. Glycogen content was markedly low mainly in glycolytic muscles of STZ rats and AICAR treatment restored it to control values. No differences were found among all muscles studied with regards to the content and phosphorylation of Akt/protein kinase B and glycogen synthase kinase 3. Even though glycogen synthase content was reduced in all muscles from STZ rats, insulin-induced dephosphorylation/activation of this enzyme was preserved and unaffected by AICAR treatment. Glucagon and NEFAS were 2- and 7.4-fold fold higher in STZ rats than controls, respectively. AICAR did not affect hyperglycemia and hyperglucagonemia in STZ rats; however, it normalized circulating NEFAs and significantly increased FAO in glycolytic muscles. In conclusion, even though AICAR-induced AMPK activation enhanced glycogen accumulation in glycolytic muscles and normalized circulating NEFAs and TG levels, the hyperglycemic effects of glucagon likely offset the potentially glucose-lowering effects of AICAR, resulting in no improvement of glycemic control in insulin-deficient rats.

Topics: Adenylate Kinase; Adiposity; Aminoimidazole Carboxamide; Animals; Blood Glucose; Epididymis; Fatty Acids; Glucagon; Glycogen; Glycogen Synthase; Glycogen Synthase Kinase 3; Hyperglycemia; Insulin; Male; Muscle, Skeletal; Oxidation-Reduction; Palmitates; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Ribonucleotides; Triglycerides

The glucokinase activators improve the fasting as well as postprandial glucose control and are important investigational drugs for the treatment of diabetes. However, recent studies have implicated that continuous activation of glucokinase with a small molecule activator can increase hepatic triglycerides and the long term glucose control is not achieved. In this study, we investigated the effect of combination of glucokinase activator (GKA, Piragliatin) with GLP-1 receptor agonist exendin-4 (Ex-4) in male db/db mice. Twelve weeks combination treatment in the db/db mice resulted in a significant decrease in body weight gain, food consumption, random glucose and %HbA1c. The decrease in serum glucose and %HbA1c in combination group was more profound and significantly different than that of individual treatment (GKA or Ex-4) group. GKA treatment increased hepatic triglycerides, whereas combination of Ex-4 with GKA attenuated hepatic steatosis. The combination of GKA with Ex-4 reduced the hepatic lipid accumulation, improved the insulin sensitivity, and reduced hepatic glucose production in db/db mice. Overall, our data indicate that combination of GKA and GLP-1 receptor agonist Ex-4 improves glucose homeostasis, shows antiobesity activity, without causing harmful side effects like fatty liver.

Topics: Animals; Benzeneacetamides; Body Weight; Drug Synergism; Eating; Enzyme Activation; Exenatide; Fatty Liver; Glucokinase; Glucose; Glycogen; Homeostasis; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Liver; Male; Mice; Mice, Inbred C57BL; Peptides; Venoms

The goal of this study was to examine the effect of Virgin Argan Oil (VAO) obtained from the fruit of Argania spinosa in a model of type 2 diabetes and hypertensive rats. Neonatal diabetes was induced by a single i.p. injection of streptozotocin (90 mg/kg) 2 days after birth. To induce NO-deficient hypertension, the adult diabetic animals were treated with l-nitroarginine methylester (l-NAME) (30 mg/kg/day) given orally for 21 days.. Following treatment with VAO (21 days), the hyperglycemia decreased to 1.3 ± 0.07 g/l compared with 1.92 ± 0.09 g/l (p < 0.01) in the untreated diabetic-hypertensive rats. The simultaneous administration of VAO with l-NAME prevented the increase in blood pressure during the 3 weeks of treatment. Blood pressure remained constant at 131 ± 1 mm Hg after 21 days - vs 157 ± 0.64 mm Hg in untreated animals (p < 0.001).. The treatment with VAO to diabetic-hypertensive rats caused a significant increase of hepatic glycogen levels (13.3 ± 1.8 vs 6.34 ± 0.75 mg/g tissue in untreated diabetic-hypertensive control group; p < 0.01).. In conclusion, the overall findings indicate that VAO possesses antidiabetic and antihypertensive activity in n-stz/l-NAME rats. This effect may be related to its high content of tocopherols, phenolic compounds, and unsaturated fatty acids.

Topics: Animals; Animals, Newborn; Antihypertensive Agents; Blood Glucose; Blood Pressure; Diabetes Mellitus, Experimental; Glycogen; Hyperglycemia; Hypertension; Hypoglycemic Agents; Liver; NG-Nitroarginine Methyl Ester; Phytotherapy; Plant Oils; Rats; Rats, Wistar; Sapotaceae

Diabetic nephropathy is strongly associated with both increased oxidative stress and kidney tissue hypoxia. The increased oxidative stress causes increased kidney oxygen consumption resulting in kidney tissue hypoxia. To date, it has been difficult to determine the role of kidney hypoxia, per se, for the development of nephropathy. We tested the hypothesis that kidney hypoxia, without confounding factors such as hyperglycemia or elevated oxidative stress, results in nephropathy. To induce kidney hypoxia, dinitrophenol (30 mg per day per kg bodyweight by gavage), a mitochondrial uncoupler that increases oxygen consumption and causes kidney hypoxia, was administered for 30 consecutive days to rats. Thereafter, glomerular filtration rate, renal blood flow, kidney oxygen consumption, kidney oxygen tension, kidney concentrations of glucose and glycogen, markers of oxidative stress, urinary protein excretion, and histological findings were determined and compared with vehicle-treated controls. Dinitrophenol did not affect arterial blood pressure, renal blood flow, glomerular filtration rate, blood glucose, or markers of oxidative stress but increased kidney oxygen consumption, and reduced cortical and medullary concentrations of glucose and glycogen, and resulted in intrarenal tissue hypoxia. Furthermore, dinitrophenol treatment increased urinary protein excretion, kidney vimentin expression, and infiltration of inflammatory cells. In conclusion, increased mitochondrial oxygen consumption results in kidney hypoxia and subsequent nephropathy. Importantly, these results demonstrate that kidney tissue hypoxia, per se, without confounding hyperglycemia or oxidative stress, may be sufficient to initiate the development of nephropathy and therefore demonstrate a new interventional target for treating kidney disease.

Topics: Animals; Dinitrophenols; Glucose; Glycogen; Hyperglycemia; Hypoxia; Kidney; Kidney Diseases; Male; Mitochondria; Oxidative Stress; Oxygen Consumption; Rats; Rats, Sprague-Dawley; Renal Circulation; Uncoupling Agents; Vimentin

This study investigated the effects of a combination of fucosylated chondroitin sulfate (CHS) and rosiglitazone (RSG) on glucose metabolism in the liver of insulin-resistant C57BL/6J mice fed a high-fat high-sucrose diet for 19 weeks. The results showed that the combination (CHS/RSG) synergistically improved body weight gain, liver weight, fasting blood glucose levels, glucose tolerance on an oral glucose tolerance test, serum insulin levels, homeostasis model assessment indexes, and hepatic glycogen content. In liver tissue, CHS/RSG significantly normalized the activities of hexokinase, pyruvate kinase, and glucose-6-phosphatase. In additionally, it increased the mRNA expression of insulin receptors, insulin receptor substrate 2, phosphatidylinositol 3 kinase (PI3K), protein kinase B (PKB), and glycogen synthase, and inhibited glycogen synthase kinase 3β(GSK-3β) mRNA expression in the liver. This suggests that CHS/RSG treatment improves glucose metabolism by modulating metabolic enzymes and strengthening the PI3K/PKB/GSK-3β signal pathway mediated by insulin at the transcriptional level.

Topics: Animals; Blood Glucose; Body Weight; Chondroitin Sulfates; Diet, High-Fat; Drug Synergism; Drug Therapy, Combination; Gene Expression Regulation; Glucose Tolerance Test; Glucose-6-Phosphatase; Glycogen; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hexokinase; Hyperglycemia; Hypoglycemic Agents; Insulin Resistance; Liver; Male; Mice; Mice, Inbred C57BL; Organ Size; Phosphatidylinositol 3-Kinase; Proto-Oncogene Proteins c-akt; Pyruvate Kinase; Receptor, Insulin; Rosiglitazone; Sea Cucumbers; Signal Transduction; Thiazolidinediones

We studied the effects of Russian preparation of porcine calcitonin (Calcitrinum, 1 U/100 g) on the level of glucose and total calcium, glycogen concentration in the liver, and glucose consumption by the muscle and adipose tissues in vivo and in vitro. The basal level of insulin and secretion of insulin in the dynamics of glucose tolerance test were studied after treatment with calcitonin. In addition to hypocalcemic effect, this substance produced significant hyperglycemic effects, decreased glycogen amount in the liver, inhibited insulin-induced glucose consumption by muscular and adipose tissues in vivo and in vitro, slowed down insulin secretion during glucose load, and impaired glucose tolerance. Thus, calcitonin had contra-insular effects on glucose metabolism.

Topics: Adipose Tissue; Animals; Blood Glucose; Bone Density Conservation Agents; Calcitonin; Calcium; Glucose; Glucose Tolerance Test; Glycogen; Glycogenolysis; Hyperglycemia; Hypocalcemia; Insulin; Insulin Secretion; Liver; Male; Muscles; Rats; Rats, Wistar

Insulin resistance in Type 2 diabetes leads to hepatic steatosis that can accompanied by progressive inflammation of the liver. Citrus unshiu peel is a rich source of citrus flavonoids that possess anti-inflammatory, anti-diabetic and lipid-lowering effects. However, the ability of citrus unshiu peel ethanol extract (CPE) to improve hyperglycemia, adiposity and hepatic steatosis in Type 2 diabetes is unknown. Thus, we evaluated the effects of CPE on markers for glucose, lipid metabolism and inflammation in Type 2 diabetic mice. Male C57BL/KsJ-db/db mice were fed a normal diet with CPE (2 g/100 g diet) or rosiglitazone (0.001 g/100 g diet) for 6 weeks. Mice supplemented with the CPE showed a significant decrease in body weight gain, body fat mass and blood glucose level. The antihyperglycemic effect of CPE appeared to be partially mediated through the inhibition of hepatic gluconeogenic phosphoenolpyruvate carboxykinase mRNA expression and its activity and through the induction of insulin/glucagon secretion. CPE also ameliorated hepatic steatosis and hypertriglyceridemia via the inhibition of gene expression and activities of the lipogenic enzymes and the activation of fatty acid oxidation in the liver. These beneficial effects of CPE may be related to increased levels of anti-inflammatory adiponectin and interleukin (IL)-10, and decreased levels of pro-inflammatory markers (IL-6, monocyte chemotactic protein-1, interferon-γ and tumor necrosis factor-α) in the plasma or liver. Taken together, we suggest that CPE has the potential to improve both hyperglycemia and hepatic steatosis in Type 2 diabetes.

Topics: Adipose Tissue; Animals; Blood Glucose; Citrus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Enzymes; Fatty Liver; Gene Expression Regulation; Glycogen; Hyperglycemia; Inflammation; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Phosphoenolpyruvate Carboxykinase (ATP); Plant Extracts; Weight Gain

Muscle contractile activity functions as a potent stimulus for acute interleukin (IL)-6 expression in working skeletal muscles. Recently, we established an "in vitro contraction model" using highly-developed contractile C2C12 myotubes by applying electric pulse stimulation (EPS). Herein, we characterize the effects of EPS-evoked contraction on IL-6 expression in contractile C2C12 myotubes. Both secretion and mRNA expression of IL-6 were significantly up-regulated by EPS in a frequency-dependent manner in contracting myotubes during a 24-h period, and the response was blunted by cyclosporine A, a calcineurin inhibitor. Longer time (~12h) was required for the induction of IL-6 after the initiation of EPS as compared to that of other contraction-inducible CXC chemokines such as CXCL1/KC, which were induced in less than 3 hours. Furthermore, these acute inducible CXC chemokines exhibited no autocrine effect on IL-6 expression. Importantly, contraction-dependent IL-6 up-regulation was markedly suppressed in the presence of high levels of glucose along with increased glycogen accumulations. Experimental manipulation of intracellular glycogen contents by modulating available glucose or pyruvate during a certain EPS period further established the suppressive effect of glycogen accumulations on contraction-induced IL-6 up-regulation, which appeared to be independent of calcineurin activity. We also document that EPS-evoked contractile activity improved insulin-responsiveness in terms of intracellular glycogen accumulations. Taken together, these data provide important insights into the regulation of IL-6 expression in response to contractile activity of muscle cells, which is difficult to examine using in vivo experimental techniques. Our present results thus expand the usefulness of our "in vitro contraction model".

Topics: Animals; Calcineurin; Calcineurin Inhibitors; Calcium Signaling; Cell Line; Chemokines, CXC; Electric Stimulation; Glucose; Glycogen; Hyperglycemia; Hypoglycemic Agents; Immunosuppressive Agents; Insulin; Insulin Resistance; Interleukin-6; Kinetics; Mice; Muscle Contraction; Muscle Fibers, Skeletal; RNA, Messenger; Up-Regulation

The current work aimed to investigate the different toxic effects of chlorpyrifos (CPF) in subchronic exposure. Two groups of Sprague-Dawley male rats were exposed to CPF alone in a dose of 30 mg/kg body weight, or CPF dose as previous plus glutathione (GSH) in a dose of 100 mg/kg body weight, for 90 days, twice weekly, orally. Another two groups of rat were given corn oil (control) or GSH. There is a significant decrease in hemoglobin concentration, haematocrit percentage, thrombocytic indices, total protein and albumin levels in CPF-exposed group. CPF induced hyperglycemia and significant increase in total cholesterol, but a significant decrease in triglyceride levels was obtained. A significant increase in the levels of lipid peroxidation was obtained while a significant decrease of the total antioxidant was recorded. The decrease in glycogen content and some histopathological changes were observed in liver after CPF exposure. Furthermore, co-administration of GSH can restore some of these alterations.

Topics: Animals; Antioxidants; Blood; Chlorpyrifos; Cholesterol; Dose-Response Relationship, Drug; Glutathione; Glycogen; Hyperglycemia; Lipid Peroxidation; Liver; Oxidative Stress; Protective Agents; Rats; Rats, Sprague-Dawley; Toxicity Tests, Subchronic; Triglycerides

Diabetes mellitus is one of the three most common modem diseases. A number of animal models is used in investigations of the mechanisms of development of the disease. Most of these models replicate the symptoms of type 1 diabetes mellitus. The development of type 2 diabetes is caused by the insulin resistance, hyperglycemia, structural and functional disorders of the pancreatic cells. Investigation of pathogenesis of type 2 diabetes is complicated by the lack of adequate models of this disease. In this work, based on existing hyperglycemia model, we propose the model of metabolic syndrome as a precursor of type 2 diabetes. The development of metabolic syndrome symptoms was caused by 28 days long intramuscular injection of protamine sulfate to guinea pigs at a dose of 15 mg/kg along with keeping of animals on a high glucose diet. Increased blood glucose and cholesterol levels, reduction of glycogen in liver, the structural and functional damage and reduce in the number of functionally active beta-cells in the pancreas of the experimental animals were observed. The results confirm the development of the metabolic syndrome symptoms in experimental animals, which makes it possible to use such methodical approach in creation of promising type 2 diabetes model.

Topics: Animals; Diabetes Mellitus, Type 2; Diet; Disease Models, Animal; Glucose; Glycogen; Guinea Pigs; Hyperglycemia; Injections, Intramuscular; Insulin Resistance; Insulin-Secreting Cells; Liver; Male; Metabolic Syndrome; Protamines

The purpose of this study was to investigate the involvement of acetylcholinesterase (AChE) inhibition in hyperglycemic and stressogenic effects of monocrotophos in rats. Oral administration of monocrotophos (1.8 mg/kg b.w., 1/10 LD(50)) caused reversible hyperglycemia in rats with peak increase occurring at 2 h following administration. The hyperglycemic outcome at 2 h was accompanied by significant inhibition of acetylcholinesterase (AChE) activity in brain (84%), adrenal (68%) and liver (53%) and stressogenic effects as revealed by marked increase in plasma corticosterone (102%) and liver tyrosine aminotransferase (TAT) (104%) activity. At 4 h following administration, there was normalization of hyperglycemia and hypercorticosteronemia, marginal attenuation of liver TAT activity and marked increase in liver glycogen content, without spontaneous reactivation of AChE activity in the organs studied. Interestingly, pre-treatment of rats with acetylcholine (ACh) receptor antagonists-atropine sulfate and methyl atropine nitrate offered significant protection against hyperglycemia, hypercorticosteronemia and increased liver TAT activity induced by monocrotophos. Our results clearly demonstrate the involvement of AChE inhibition in hyperglycemia and stressogenic effects of monocrotophos in rats following acute exposure. Protection offered by both, general and peripheral ACh antagonists provide further evidence for the involvement of peripheral AChE inhibition in the monocrotophos-induced effects.

Topics: Acetylcholinesterase; Adrenal Glands; Animals; Atropine; Atropine Derivatives; Blood Glucose; Brain; Cholinergic Antagonists; Cholinesterase Inhibitors; Corticosterone; Glycogen; Hyperglycemia; Liver; Male; Monocrotophos; Rats; Rats, Inbred Strains; Receptors, Cholinergic; Stress, Psychological; Tyrosine Transaminase

Studies were carried out on conscious female non-pregnant (NP) and pregnant (P; third-trimester) dogs (n 16; eight animals per group) to define the role of the liver in mixed meal disposition with arteriovenous difference and tracer techniques. Hepatic and hindlimb substrate disposal was assessed for 390 min during and after an intragastric mixed meal infusion labelled with [¹⁴C]glucose. The P dogs exhibited postprandial hyperglycaemia compared with NP dogs (area under the curve (AUC; change from basal over 390 min) of arterial plasma glucose: 86 680 (sem 12 140) and 187 990 (sem 33 990) mg/l in NP and P dogs, respectively; P < 0·05). Plasma insulin concentrations did not differ significantly between the groups (AUC: 88 230 (sem 16 314) and 69 750 (sem 19 512) pmol/l in NP and P dogs, respectively). Net hepatic glucose uptake totalled 3691 (sem 508) v. 5081 (sem 1145) mg/100 g liver in NP and P dogs, respectively (P = 0·38). The AUC of glucose oxidation by the gut and hindlimb were not different in NP and P dogs, but hepatic glucose oxidation (84 (sem 13) v. 206 (sem 30) mg/100 g liver) and glycogen synthesis (0·4 (sem 0·5) v. 26 (sem 0·7) g/100 g liver) were greater in P dogs (P < 0·05). The proportion of hepatic glycogen deposited via the direct pathway did not differ between the groups. Hindlimb glucose uptake and skeletal muscle glycogen synthesis was similar between the groups, although final glycogen concentrations were higher in NP dogs (9·6 (sem 0·6) v. 70 (sem 0·6) mg/g muscle; P < 0·05). Thus, hepatic glucose oxidation and glycogen storage were augmented in late pregnancy. Enhanced hepatic glycogen storage following a meal probably facilitates the maintenance of an adequate glucose supply to maternal and fetal tissues during the post-absorptive period.

Topics: Animals; Biological Transport; Blood Glucose; Dogs; Female; Glucose; Glycogen; Glycolysis; Hindlimb; Hyperglycemia; Hypoglycemia; Insulin; Intestinal Absorption; Kinetics; Liver; Liver Glycogen; Models, Animal; Muscle, Skeletal; Oxidation-Reduction; Postprandial Period; Pregnancy

Zingiber officinale (ZO), commonly known as ginger, has been traditionally used in the treatment of diabetes mellitus. Several studies have reported the hypoglycaemic properties of ginger in animal models. The present study evaluated the antihyperglycaemic effect of its aqueous extract administered orally (daily) in three different doses (100, 300, 500 mg/kg body weight) for a period of 30 d to streptozotocin (STZ)-induced diabetic rats. A dose-dependent antihyperglycaemic effect revealed a decrease of plasma glucose levels by 38 and 68 % on the 15th and 30th day, respectively, after the rats were given 500 mg/kg. The 500 mg/kg ZO significantly (P<0·05) decreased kidney weight (% body weight) in ZO-treated diabetic rats v. control rats, although the decrease in liver weight (% body weight) was not statistically significant. Kidney glycogen content increased significantly (P<0·05) while liver and skeletal muscle glycogen content decreased significantly (P<0·05) in diabetic controls v. normal controls. ZO (500 mg/kg) also significantly decreased kidney glycogen (P<0·05) and increased liver and skeletal muscle glycogen in STZ-diabetic rats when compared to diabetic controls. Activities of glucokinase, phosphofructokinase and pyruvate kinase in diabetic controls were decreased by 94, 53 and 61 %, respectively, when compared to normal controls; and ZO significantly increased (P<0·05) those enzymes' activities in STZ-diabetic rats. Therefore, the present study showed that ginger is a potential phytomedicine for the treatment of diabetes through its effects on the activities of glycolytic enzymes.

Topics: Animals; Body Weight; Carbohydrate Metabolism; Diabetes Mellitus, Type 1; Gluconeogenesis; Glycogen; Glycolysis; Hyperglycemia; Hypoglycemic Agents; Kidney; Lethal Dose 50; Liver; Male; Muscle, Skeletal; Organ Size; Phytotherapy; Plant Extracts; Rats; Rats, Sprague-Dawley; Rhizome; Streptozocin; Zingiber officinale

Exendin-4 is a stable peptide agonist of GLP-1 receptor that exhibits insulinotropic actions. Some in vivo studies indicated insulin-independent glucoregulatory actions of exendin-4. That finding prompted us to evaluate effects of exendin-4 on liver glucose metabolism. Acute and chronic treatment of exendin-4 resulted in increased hepatic glucokinase activity in db/db mice but not in lean C57 mice. The stimulatory effect of exendin-4 on glucokinase activity was abrogated by exendin 9-39, a GLP-1 antagonist. Exposure of hepatocytes isolated from db/db mice to exendin-4 elicited a rapid increase in cAMP, which was synergized by IBMX, an inhibitor of cAMP degradation. The GLP-1 antagonist, exendin 9-39, has abolished the cAMP generating effects of exendin-4 as well. Furthermore, chronic treatment of exendin-4 in streptozotocin-treated C57 mice resulted in restoration of hepatic glycogen, an indicator of improved glucose metabolism, without apparent changes in serum insulin levels. In conclusion, exendin-4 increased glucokinase enzyme protein and activity in liver via a mechanism parallel to and independent of insulin. Exendin-4-induced increase in hepatic glucokinase activity is more pronounced in the presence of hepatic insulin resistance. This beneficial effect of exendin-4 on liver glucokinase activity may be mediated by GLP-1 receptor.

Topics: Animals; Cyclic AMP; Diabetes Mellitus, Experimental; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucokinase; Glucose; Glycogen; Hepatocytes; Hyperglycemia; Insulin; Insulin Resistance; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Peptides; Receptors, Glucagon; Venoms

A stimulatory effect of apigenin-6-C-β-fucopyranoside (1) on glucose uptake was observed when rat soleus muscle was incubated with 1, 10 and 100 μM of this flavonoid glycoside. The presence of specific insulin signaling inhibitors, such as wortmannin, an inhibitor of phosphoinositide 3-kinase (PI3K), RO318220, an inhibitor of protein kinase C (PKC), PD98059, an inhibitor of mitogen-activated protein kinase (MEK), and HNMPA(AM)₃, an insulin receptor tyrosine kinase activity inhibitor showed that apigenin-6-C-β-fucopyranoside triggers different metabolic pathways in skeletal muscle. The oral administration of crude extract, fractions and isolated flavonoids (apigenin-6-C-β-fucopyranoside (1) and apigenin-6-C-(2″-O-α-rhamnopyranosyl)-β-fucopyranoside (2)) from Averrhoa carambola leaves exhibited a potential hypoglycemic activity in hyperglycemic normal rats. Additionally, both flavonoids significantly increased the muscle and liver glycogen content after an acute treatment. The results indicate that A. carambola can be regarded as a potent antihyperglycemic agent with insulin secretagogue and insulin mimetic properties.

Topics: Administration, Oral; Animals; Apigenin; Glucose; Glycogen; Glycosides; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Secretion; Liver; Magnoliopsida; Male; Metabolic Networks and Pathways; Mitogen-Activated Protein Kinases; Muscle, Skeletal; Phosphoinositide-3 Kinase Inhibitors; Phytotherapy; Plant Extracts; Plant Leaves; Protein Kinase C; Protein-Tyrosine Kinases; Rats; Rats, Wistar; Signal Transduction

In this study we evaluated the hyperglycemic and hyperlipidemic effects of chlorpyrifos (CPF) after an acute exposure in rats. The mechanisms involved in hyperglycemia induced by CPF were studied. A single dose of CPF (50 mg kg(-1), subcutaneous, s.c.) was administered to overnight-fasted rats. Glucose and corticosterone levels, lipid status and paraoxonase (PON1) activity were determined in plasma of rats. Cardiovascular risk factors and the atherogenic index were calculated. Glycogen levels, tyrosine aminotransferase (TAT) and glucose-6-phosphatase (G6Pase) activities were determined in livers of rats. Cerebral acetylcholinesterase (AChE) activity was also determined. CPF caused an increase in glucose and glycogen levels as well as in TAT and G6Pase activities. The CPF exposure caused an increase in corticosterone levels, an inhibition of AChE activity and a reduction of PON1 activity. Regarding the lipid status, CPF induced an increase in triglycerides (TG) and low-density lipoprotein-cholesterol (LDL) levels and a decrease in high-density lipoprotein (HDL) levels associated with an increase of cardiovascular risk factors and the atherogenic index. The present study demonstrated that a single CPF administration caused hyperglycemia and hyperlipidemia in rats. The activation of the gluconeogenesis pathway, probably elicited by hypercorticosteronemia, is involved in the hyperglycemic effect of CPF in rats.

Topics: Acetylcholinesterase; Animals; Aryldialkylphosphatase; Blood Glucose; Chlorpyrifos; Corticosterone; Environmental Pollutants; Glucose-6-Phosphatase; Glycogen; GPI-Linked Proteins; Hyperglycemia; Hyperlipidemias; Lipids; Male; Rats; Rats, Wistar; Toxicity Tests, Acute; Tyrosine Transaminase

Glucose-6-phosphatase (G6PC) plays an important role in glucose homeostasis because it catalyzes the final steps of gluconeogenesis and glycogenolysis. Maternal malnutrition during pregnancy affects G6PC activity, yet it is unknown whether epigenetic regulations of the G6PC gene are also affected. In this study, we fed primiparous, purebred Meishan sows either standard-protein (SP; 12% crude protein) or low-protein (LP; 6% crude protein) diets throughout gestation and analyzed hepatic G6PC expression in both male and female newborn piglets. The epigenetic regulation of G6PC, including DNA methylation, histone modifications, and micro RNA (miRNA), was determined to reveal potential mechanisms. Male, but not female, LP piglets had a significantly lower serum glucose concentration and greater hepatic G6PC mRNA expression and enzyme activity. Also, in LP males, glucocorticoid receptor binding to the G6PC promoter was lower compared with SP males, which was accompanied by hypomethylation of the G6PC promoter. Modifications in histones also were gender dependent; LP males had less histone H3 and histone H3 lysine 9 trimethylation and more histone H3 acetylation and histone H3 lysine 4 trimethylation on the G6PC promoter compared with the SP males, whereas LP females had more H3 and greater H3 methylation compared with their SP counterparts. Moreover, two miRNA, ssc-miR-339-5p and ssc-miR-532-3p, targeting the G6PC 3' untranslated region were significantly upregulated by the LP diet only in females. These results suggest that a maternal LP diet during pregnancy causes hepatic activation of G6PC gene expression in male piglets, which possibly contributes to adult-onset hyperglycemia.

Topics: Age Factors; Animals; Animals, Newborn; Blood Glucose; Diet, Protein-Restricted; DNA Methylation; Epigenesis, Genetic; Female; Glucose-6-Phosphatase; Glycogen; Hyperglycemia; Liver; Male; Metabolic Syndrome; MicroRNAs; Pregnancy; Prenatal Exposure Delayed Effects; Random Allocation; Sex Characteristics; Sus scrofa

Acute hyperglycaemia rapidly suppresses endogenous glucose production (EGP) in non-diabetic individuals, mainly by inhibiting glycogenolysis. Loss of this 'glucose effectiveness' contributes to fasting hyperglycaemia in type 2 diabetes. Elevated NEFA levels characteristic of type 2 diabetes impair glucose effectiveness, although the mechanism is not fully understood. Therefore we examined the impact of increasing NEFA levels on the ability of hyperglycaemia to regulate pathways of EGP.. We performed 4 h 'pancreatic clamp' studies (somatostatin; basal glucagon/growth hormone/insulin) in seven non-diabetic individuals. Glucose fluxes (D-[6,6-(2)H(2)]glucose) and hepatic glycogen concentrations ((13)C magnetic resonance spectroscopy) were quantified under three conditions: euglycaemia, hyperglycaemia and hyperglycaemia with elevated NEFA (HY-NEFA).. EGP was suppressed by hyperglycaemia, but not by HY-NEFA. Hepatic glycogen concentration decreased ~14% with prolonged fasting during euglycaemia and increased by ~12% with hyperglycaemia. In contrast, raising NEFA levels in HY-NEFA caused a substantial ~23% reduction in hepatic glycogen concentration. Moreover, rates of gluconeogenesis were decreased with hyperglycaemia, but increased with HY-NEFA.. Increased NEFA appear to profoundly blunt the ability of hyperglycaemia to inhibit net glycogenolysis under basal hormonal conditions.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 2; Fasting; Fatty Acids, Nonesterified; Glucagon; Glucose Clamp Technique; Glycogen; Glycogenolysis; Human Growth Hormone; Humans; Hyperglycemia; Insulin; Liver; Male; Somatostatin

Atypical antipsychotic drugs such as Olanzapine induce weight gain and metabolic changes associated with the development of type 2 diabetes. The mechanisms underlying the metabolic side-effects of these centrally acting drugs are still unknown to a large extent. We compared the effects of peripheral (intragastric; 3 mg/kg/h) versus central (intracerebroventricular; 30 µg/kg/h) administration of Olanzapine on glucose metabolism using the stable isotope dilution technique (Experiment 1) in combination with low and high hyperinsulinemic-euglycemic clamps (Experiments 2 and 3), in order to evaluate hepatic and extra-hepatic insulin sensitivity, in adult male Wistar rats. Blood glucose, plasma corticosterone and insulin levels were measured alongside endogenous glucose production and glucose disappearance. Livers were harvested to determine glycogen content. Under basal conditions peripheral administration of Olanzapine induced pronounced hyperglycemia without a significant increase in hepatic glucose production (Experiment 1). The clamp experiments revealed a clear insulin resistance both at hepatic (Experiment 2) and extra-hepatic levels (Experiment 3). The induction of insulin resistance in Experiments 2 and 3 was supported by decreased hepatic glycogen stores in Olanzapine-treated rats. Central administration of Olanzapine, however, did not result in any significant changes in blood glucose, plasma insulin or corticosterone concentrations nor in glucose production. In conclusion, acute intragastric administration of Olanzapine leads to hyperglycemia and insulin resistance in male rats. The metabolic side-effects of Olanzapine appear to be mediated primarily via a peripheral mechanism, and not to have a central origin.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Glucose; Glucose Clamp Technique; Glycogen; Hyperglycemia; Insulin; Insulin Resistance; Liver; Male; Olanzapine; Rats; Rats, Wistar

Glucagon like peptide-1 (GLP-1) stimulates insulin secretion from the pancreas but also has extra-pancreatic effects. GLP-1 may stimulate glucose uptake in cultured muscle cells but the mechanism is not clearly defined. Furthermore, while the pancreatic effects of GLP-1 are glucose-dependent, the glucose-dependency of its extra-pancreatic effects has not been examined.. Skeletal muscle satellite cells isolated from young (22.5 ± 0.97 yr), lean (BMI 22.5 ± 0.6 kg/m(2)), healthy males were differentiated in media containing either 22.5 mM (high) or 5 mM (normal) glucose for 7 days in the absence or presence of insulin and/or various GLP-1 concentrations. Myocellular effects of GLP-1, insulin and glucose were assessed by western-blot, glucose uptake and glycogen synthesis.. We firstly show that the GLP-1 receptor protein is expressed in differentiated human muscle satellite cells (myocytes). Secondly, we show that in 5 mM glucose media, exposure of myocytes to GLP-1 results in a dose dependent increase in glucose uptake, GLUT4 amount and subsequently glycogen synthesis in a PI3K dependent manner, independent of the insulin signaling cascade. Importantly, we provide evidence that differentiation of human satellite cells in hyperglycemic (22.5 mM glucose) conditions increases GLUT1 expression, and renders the cells insulin resistant and interestingly GLP-1 resistant in terms of glucose uptake and glycogen synthesis. Hyperglycemic conditions did not affect the ability of insulin to phosphorylate downstream targets, PKB or GSK3. Interestingly we show that at 5 mM glucose, GLP-1 increases GLUT4 protein levels and that this effect is abolished by hyperglycemia.. GLP-1 increases glucose uptake and glycogen synthesis into fully-differentiated human satellite cells in a PI3-K dependent mechanism potentially through increased GLUT4 protein levels. The latter occurs independently of the insulin signaling pathway. Attenuation of both GLP-1 and insulin-induced glucose metabolism by hyperglycemia is likely to occur downstream of PI3K.

Topics: Cell Differentiation; Cell Proliferation; Cells, Cultured; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Glycogen; Humans; Hyperglycemia; Insulin; Male; Receptors, Glucagon; Satellite Cells, Skeletal Muscle; Signal Transduction; Young Adult

Persimmon Leaf (PL), commonly consumed as herbal tea and traditional medicines, contains a variety of compounds that exert antioxidant, α-amylase and α-glucosidase inhibitory activity. However, little is known about the in vivo effects and underlying mechanisms of PL on hyperglycemia, hyperlipidemia and hepatic steatosis in type 2 diabetes. Powered PL (5%, w/w) was supplemented with a normal diet to C57BL/KsJ-db/db mice for 5 weeks. PL decreased blood glucose, HOMA-IR, plasma triglyceride and total cholesterol levels, as well as liver weight, hepatic lipid droplets, triglycerides and cholesterol contents, while increasing plasma HDL-cholesterol and adiponectin levels. The anti-hyperglycemic effect was linked to decreased activity of gluconeogenic enzymes as well as increased glycogen content, glucokinase activity and its mRNA level in the liver. PL also led to a decrease in lipogenic transcriptional factor PPARγ as well as gene expression and activity of enzymes involved in lipogenesis, with a simultaneous increase in fecal lipids, which are seemingly attributable to the improved hyperlipidemia and hepatic steatosis and decreased hepatic fatty acid oxidation. Furthermore, PL ameliorated plasma and hepatic oxidative stress. Supplementation with PL may be an effective dietary strategy to improve type 2 diabetes accompanied by dyslipidemia and hepatic steatosis by partly modulating the activity or gene expression of enzymes related to antioxidant, glucose and lipid homeostasis.

Topics: Adiponectin; Animals; Antioxidants; Blood Glucose; Cholesterol; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dietary Supplements; Diospyros; Dyslipidemias; Fatty Liver; Gene Expression; Glucokinase; Glycogen; Hyperglycemia; Hypoglycemic Agents; Insulin Resistance; Lipid Metabolism; Lipogenesis; Liver; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Phytotherapy; Plant Leaves; Plant Preparations; PPAR gamma; RNA, Messenger; Triglycerides

Type 2 diabetes is caused by relative deficiency of insulin secretion and is associated with dysregulation of glucagon secretion during the late stage of diabetes development. Like insulin secretion from beta cells, glucagon secretion is dependent on calcium signals and a calcium sensing protein, synaptotagmin-7. In this study, we tested the relative contribution of dysregulated glucagon secretion and reduced insulin release in the development of hyperglycaemia and type 2 diabetes by using synaptotagmin-7 knockout (KO) mice, which exhibit glucose intolerance, reduced insulin secretion and nearly abolished Ca(2+)-stimulated glucagon secretion.. We fed the synaptotagmin-7 KO and control mice with a high-fat diet (HFD) for 14 weeks, and compared their body weight, glucose levels, glucose and insulin tolerance, and insulin and glucagon secretion.. On the HFD, synaptotagmin-7 KO mice showed progressive impairment of glucose tolerance and insulin secretion, along with continued maintenance of a low glucagon level. The control mice were less affected in terms of glucose intolerance, and showed enhanced insulin secretion with a concurrent increase in glucagon levels. Unexpectedly, after 14 weeks of HFD feeding, only the control mice displayed resting hyperglycaemia, whereas in synaptotagmin-7 KO mice defective insulin secretion and reduced insulin sensitivity were not sufficient to cause hyperglycaemia in the absence of enhanced glucagon secretion.. Our data uncover a previously overlooked role of dysregulated glucagon secretion in promoting hyperglycaemia and the ensuing diabetes, and strongly suggest maintenance of adequate regulation of glucagon secretion as an important therapeutic target in addition to the preservation of beta cell function and mass in the prevention and treatment of diabetes.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Dietary Fats; Glucagon; Glycogen; Hyperglycemia; Male; Mice; Mice, Knockout; Synaptotagmins

Recent extensive studies have revealed that molecular hydrogen (H(2)) has great potential for improving oxidative stress-related diseases by inhaling H(2) gas, injecting saline with dissolved H(2), or drinking water with dissolved H(2) (H(2)-water); however, little is known about the dynamic movement of H(2) in a body. First, we show that hepatic glycogen accumulates H(2) after oral administration of H(2)-water, explaining why consumption of even a small amount of H(2) over a short span time efficiently improves various disease models. This finding was supported by an in vitro experiment in which glycogen solution maintained H(2). Next, we examined the benefit of ad libitum drinking H(2)-water to type 2 diabetes using db/db obesity model mice lacking the functional leptin receptor. Drinking H(2)-water reduced hepatic oxidative stress, and significantly alleviated fatty liver in db/db mice as well as high fat-diet-induced fatty liver in wild-type mice. Long-term drinking H(2)-water significantly controlled fat and body weights, despite no increase in consumption of diet and water. Moreover, drinking H(2)-water decreased levels of plasma glucose, insulin, and triglyceride, the effect of which on hyperglycemia was similar to diet restriction. To examine how drinking H(2)-water improves obesity and metabolic parameters at the molecular level, we examined gene-expression profiles, and found enhanced expression of a hepatic hormone, fibroblast growth factor 21 (FGF21), which functions to enhance fatty acid and glucose expenditure. Indeed, H(2) stimulated energy metabolism as measured by oxygen consumption. The present results suggest the potential benefit of H(2) in improving obesity, diabetes, and metabolic syndrome.

Topics: Animals; Diabetes Mellitus, Type 2; Energy Metabolism; Fatty Liver; Fibroblast Growth Factors; Glycogen; Hydrogen; Hyperglycemia; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Oxidative Stress; Random Allocation; Rats; Rats, Sprague-Dawley; RNA, Messenger; Water

We investigated the effect of Ishige okamurae extract on blood glucose level and insulin resistance in C57BL/-KsJ-db/db mice. We administered a standard AIN-93G diet with or without IOE to the animals for 6 weeks. After 6 weeks, blood glucose level was improved and blood glycosylated hemoglobin levels were lowered in sample group mice as compared to those in the diabetic control group mice. Hyperinsulinemia was reduced in the I. okamurae extract group mice with type 2 diabetes. With regard to hepatic glucose metabolic enzyme activities, glucokinase activity was enhanced in the IOE group mice, while glucose-6-phosphatase and phosphoenolpyruvate carboxykinase activities in the IOE group mice were significantly lowered than those in the diabetic control group mice. In addition, the hepatic glycogen content was elevated in the IOE group as compared to that in the diabetic control group. The homeostatic index of insulin resistance was lower in the I. okamurae extract group mice than in the diabetic control group mice. These results suggest that a dietary supplement of I. okamurae extract lowers the blood glucose level by altering the hepatic glucose metabolic enzyme activities and improves insulin resistance.

Topics: Animals; Blood Glucose; Body Weight; Eating; Glucose Tolerance Test; Glycated Hemoglobin; Glycogen; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Liver; Liver Function Tests; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Phaeophyceae; Plant Extracts

In this paper, the effect of peroral antidiabetic pioglitazone, a thiazolidinedione derivate, on selected parameters of carbohydrate and lipid metabolism in N-methyl-N-nitrosourea-induced mammary carcinogenesis in female Sprague-Dawley rats was evaluated. Pioglitazone was administered in the diet at two concentrations (10 ppm and 100 ppm), the chemoprevention was initiated 12 days before carcinogenesis induction and lasted until the termination of the experiment. The experiment was terminated 17 weeks after carcinogenesis induction, selected organs and tissues were removed and weighed and basic metabolic and hormonal parameters were determined. Pioglitazone increased glycemia (without exceeding normal values) and glycogen concentration in both liver and heart muscle without altering insulinemia and increased triacylglycerol concentration in liver, these changes were more prominent in group with higher dose. Pioglitazone also reduced corticosterone serum concentration and attenuated lipid peroxidation. Pioglitazone and other glitazones may be useful in alleviation of unfavourable metabolic changes in cancer patients.

Topics: Animals; Corticosterone; Female; Glycogen; Heart; Hyperglycemia; Hyperinsulinism; Lipid Peroxidation; Liver; Mammary Neoplasms, Experimental; Methylnitrosourea; Muscles; Myocardium; Pioglitazone; Rats; Rats, Sprague-Dawley; Thiazolidinediones; Triglycerides

Recently, it is implicated that the abnormality of Akt signaling pathway is involved in the diabetic pathology. Previous studies have demonstrated that berberine could decrease blood glucose by elevating liver glycogen synthesis. However, the underlying mechanism is still unclear. In the present study, we investigated the effects of berberine on fasting blood glucose, liver glycogen, Akt, Glycogen synthase kinase-3, glucokinase and insulin receptor substrate (IRS) in alloxan-induced diabetic mice, exploring its possible hypoglycemic mechanism. We found that in alloxan-induced diabetic mice, the high blood glucose was significantly lowered by berberine treatment. Liver glycogen content, the expression and activity of glucokinase and the phosphorylated Akt and IRS were all significantly reduced in diabetic mice whereas berberine blocked these changes. Berberine also depressed the increasing of phosphorylated GSK-3β in diabetic mice. Collectively, Berberine upregulates the activity of Akt possibly via insulin signaling pathway, eventually lowering high blood glucose in alloxan-induced diabetic mice.

Topics: Animals; Berberine; Blood Glucose; Blotting, Western; Diabetes Mellitus, Experimental; Glucokinase; Glycogen; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hyperglycemia; Male; Mice; Mice, Inbred C57BL; Phosphorylation; Proto-Oncogene Proteins c-akt; Random Allocation; Reverse Transcriptase Polymerase Chain Reaction; RNA; Signal Transduction; Specific Pathogen-Free Organisms

Examine whether normalizing net hepatic glycogenesis restores endogenous glucose production and hepatic glucose phosphorylation in response to diabetic levels of plasma glucose and insulin in Zucker diabetic fatty rats (ZDF).. Hepatic glucose and intermediate fluxes (µmol · kg(-1) · min(-1)) were measured with and without a glycogen phosphorylase inhibitor (GPI) using [2-(3)H]glucose, [3-(3)H]glucose, and [U-(14)C]alanine in 20 h-fasted conscious ZDF and their lean littermates (ZCL) under clamp conditions designed to maintain diabetic levels of plasma glucose and insulin.. With infusion of GPI into ZDF (ZDF-GPI+G), compared with vehicle infused ZDF (ZDF-V), high glycogen phosphorylase a activity was decreased and low synthase I activity was increased to that of ZCL. Low net glycogenesis from plasma glucose rose to 75% of ZCL levels (4 ± 1 in ZDF-V, 18 ± 1 in ZDF-GPI+G, and 24 ± 2 in ZCL) and phosphoenolpyruvate 260% (4 ± 2 in ZDF-V, 16 ± 1 in ZDF+GPI-G, and 6 ± 2 in ZCL). High endogenous glucose production was suppressed with GPI infusion but not to that of ZCL (46 ± 4 in ZDF-V, 18 ± 4 in ZDF-GPI+G, and -8 ± 3 in ZCL). This was accompanied by reduction of the higher glucose-6-phosphatase flux (75 ± 4 in ZDF-V, 41 ± 4 in ZDF-GPI+G, and 86 ± 12 in ZCL) and no change in low glucose phosphorylation or total gluconeogenesis.. In the presence of hyperglycemic-hyperinsulinemia in ZDF, reduced glycogenic flux partially contributes to a lack of suppression of hepatic glucose production by failing to redirect glucose-6-phosphate flux from production of glucose to glycogen but is not responsible for a lower rate of glucose phosphorylation.

Topics: Animals; Body Weight; Gluconeogenesis; Glucose; Glucose-6-Phosphatase; Glycogen; Hyperglycemia; Hyperinsulinism; Insulin; Liver; Male; Obesity; Rats; Rats, Zucker

Maslinic acid (MA), a natural triterpene from Olea europaea L., is a well-known inhibitor of glycogen phosphorylase and elicits multiple biological activities. The purpose of this study was to evaluate the effects of MA on focal cerebral ischemia in hyperglycemic rats. Adult rats were made hyperglycemic by intraperitoneal injection of streptozotocin and were given MA (50 mg/kg or 5 mg/kg) intragastrically for 14 consecutive days. Transient middle cerebral artery occlusion/reperfusion was then induced by a suture insertion technique. Results showed that diabetic rats pretreated with high-dose MA had lower blood glucose levels, but both doses reduced infarct volumes and improved neurological scores. Less glutamate overflow was also observed in MA-treated rats after 2 hr of ischemia followed by 24 hr and 72 hr reperfusion. In addition, MA treatment enhanced the glial glutamate transporter GLT-1 expression at the protein and mRNA levels. However, the injection of dihydrokainate, a GLT-1 glutamate transporter inhibitor, reversed the effect of MA. Previous studies have shown that suppression of glutamate uptake via nuclear factor-κB (NF-κB) activation is an important contributory factor in ischemia-triggered glutamate excitotoxicity, and inhibition of NF-κB could prevent ischemic suppression of glutamate uptake and GLT-1 expression. In the present study, we showed that MA pretreatment attenuated ischemia-induced translocation of NF-κB p65 subunit to the nucleus. In conclusion, these findings demonstrate that, in addition to showing promising antidiabetic properties, MA has a direct beneficial effect in cerebral ischemic injury, which may be correlated with the promotion of glutamate clearance by NF-κB-mediated GLT-1 up-regulation.

Topics: Animals; Blood Glucose; Brain; Brain Ischemia; Diabetes Mellitus, Experimental; Enzyme Inhibitors; Excitatory Amino Acid Transporter 2; Glycogen; Glycogen Phosphorylase; Hyperglycemia; Liver; Male; Neuroglia; Rats; Rats, Sprague-Dawley; Streptozocin; Triterpenes; Up-Regulation

Fisetin (3, 7, 3', 4'-tetrahydroxyflavone) is a bioflavonoid found in fruits and vegetables. It exhibits a wide variety of pharmacological properties, including antioxidant, antiinflammatory and anticarcinogenic effects. Recently we have reported the hypoglycemic actions of fisetin. Oral administration of fisetin (10mg/kg body weight) to diabetic rats for 30 days established a significant (P<0.05) decline in blood glucose and glycosylated hemoglobin levels and a significant (P<0.05) increase in plasma insulin level. In the present study the activities of key enzymes of carbohydrate metabolism were assayed to establish the modulatory actions of fisetin in maintaining the glucose homeostasis. The altered activities of key enzymes of carbohydrate metabolism such as hexokinase, pyruvate kinase, lactate dehydrogenase, glucose-6-phosphatase, fructose-1,6-bisphosphatase, glucose-6-phosphate dehydrogenase, glycogen synthase and glycogen phosphorylase in liver and kidney tissues of diabetic rats were significantly (P<0.05) reverted to near normalcy by the administration of fisetin. Thus, fisetin regulates carbohydrate metabolism by modulating the key regulatory enzymes in the hepatic and renal tissues of diabetic rats.

Topics: Animals; Carbohydrate Metabolism; Diabetes Mellitus, Experimental; Flavonoids; Flavonols; Glycogen; Hyperglycemia; Kidney; Liver; Male; Rats; Rats, Wistar

To compare the effect of fluctuating glucose with sustained hyperglycaemia on systemic oxidative stress during 72 h of glucose infusion.. Catheterised male Sprague-Dawley rats were given either a continuous high (CHG), low (CLG) or pulsatile (FLU) infusion of glucose or saline (VEH) for 72 h. Plasma ascorbate oxidation ratio (AOR) and malondialdehyde (MDA) were used as biomarkers of oxidative stress and damage.. The FLU group showed significant increases in both plasma AOR and MDA at 48 and 72 h (p < 0.05 all cases), whereas the CHG group, despite being infused with three times the amount of glucose, only showed increased MDA levels at 72 h time point (p < 0.05).. Our data suggests that fluctuating glucose levels lead to oxidative stress similar to that of sustained hyperglycaemia despite a much lower total glycaemic exposure. Thus, our data supports the notion that fluctuating glucose may be relatively more deleterious than sustained hyperglycaemia.

Topics: Animals; Biomarkers; Blood Glucose; Disease Models, Animal; Glucose; Glycogen; Hyperglycemia; Infusions, Intravenous; Insulin; Liver; Male; Malondialdehyde; Oxidative Stress; Rats; Rats, Sprague-Dawley; Time Factors; Triglycerides

Malnutrition in utero can "program" the fetal tissues, making them more vulnerable to metabolic disturbances. Also there is association between excessive consumption of fructose and the development of metabolic syndrome. However, there is little information regarding the acute effect of physical exercise on subjects recovered from malnutrition and/or fed with a fructose-rich diet. The objective of this study was to evaluate the metabolic aspects and the response to acute physical exercise in rats recovered from fetal protein malnutrition with a fructose-rich diet.. Pregnant Wistar rats were fed with a balanced (B) diet or a low-protein (L) diet. After birth and until 60 days of age, the offspring were distributed into four groups according to the diet received: B: B diet during the whole experiment; balanced/fructose (BF): B diet until birth and fructose-rich (F) diet afterwards; low protein/balanced (LB): L diet until birth and B diet afterwards; low protein/fructose (LF): L diet until birth and F diet afterwards.. The excess fructose intake reduced the body weight gain, especially in the BF group. Furthermore, the serum total cholesterol and the LDL cholesterol were elevated in this group. In the LF group, the serum total cholesterol and the muscle glycogen increased. Acute physical exercise increased the serum concentrations of glucose, triglycerides, HDL cholesterol and liver lipids and reduced the concentrations of muscle glycogen in all groups.. An excess fructose intake induced some signs of metabolic syndrome. However, protein malnutrition appeared to protect against the short term effects of fructose. In other hand, most responses to acute physical exercise were not influenced by early malnutrition and/or by the fructose overload.

Topics: Animals; Animals, Newborn; Female; Fructose; Glycogen; Hyperglycemia; Hyperlipidemias; Lactation; Lipid Metabolism; Liver; Male; Maternal Nutritional Physiological Phenomena; Metabolic Syndrome; Motor Activity; Muscle, Skeletal; Pregnancy; Protein Deficiency; Rats; Rats, Wistar; Weight Gain

In this study, the hyperglycemic effect of melatonin in the freshwater edible crab, Oziotelphusa senex senex, is investigated. Injection of melatonin induced hyperglycemia in a dose-dependent manner. Administration of melatonin produced hyperglycemia in both intact and eyestalk-ablated crabs. Bilateral eyestalk ablation resulted in significant increase in the total carbohydrates and glycogen levels with a significant decrease in phosphorylase activity in the hepatopancreas and muscle of the crabs. Injection of melatonin resulted in significant decrease in the total carbohydrate and glycogen levels, with an increase in phosphorylase activity in hepatopancreas and muscle of both intact and eyestalk-ablated crabs. From the results, it is hypothesized that melatonin-induced hyperglycemia in the crab, O. senex senex, is not mediated by eyestalk hyperglycemic hormone.

Topics: Animals; Brachyura; Carbohydrate Metabolism; Carbohydrates; Glycogen; Hemolymph; Homeostasis; Hyperglycemia; Melatonin

The present study was aimed to investigate the possible effects of beta-casomorphin-7, against hyperglycemia and free radical-mediated oxidative stress in streptozotocin-induced diabetic rats by assaying the blood glucose level and the activity of plasma enzymatic antioxidants, such as superoxide dismutase (SOD), catalase and glutathione peroxidase (GSH-Px). A significant increase in the levels of both blood glucose and oxidative stress with a predominant decrease in antioxidant status was observed in the diabetic rats when compared to control rats. After 15 days oral administration of beta-casomorphin-7 (7.5 x 10(-8) mol/day), the elevated blood glucose level was reduced. Oral administration of beta-CM-7 to diabetic rats showed an increase in the level of plasma insulin, the elevated plasma glucagon level was markedly reduced by the oral administration of beta-CM-7. Oral administration of beta-CM-7 to the diabetic group of rats also showed a significant elevation in the activity of SOD and catalase. Thus, the results of the present study suggest that beta-casomorphin-7 can protect rats from hyperglycemia and free radical-mediated oxidative stress in diabetic rats.

Topics: Animals; Antioxidants; Blood Glucose; Diabetes Mellitus, Type 1; Endorphins; Glucagon; Glycogen; Hyperglycemia; Hypoglycemic Agents; Insulin; Male; Malondialdehyde; Oxidative Stress; Oxidoreductases; Peptide Fragments; Random Allocation; Rats; Rats, Sprague-Dawley; Streptozocin; Time Factors; Weight Gain

We evaluated the effects of stress as mimicked by corticosterone (CORT) administration on the uptake of glucose by skeletal muscles (M. fibularis longus) in broiler chickens (Gallus gallus domesticus). The results showed that both chronic (7 d) and short-term (3 h) CORT administration resulted in hyperglycemia and hyperinsulinemia. Plasma level of nitric oxide (NO) and the activity of NO synthase (NOS) were both suppressed by either chronic or acute stress. In vivo CORT treatment could stimulate the in vitro uptake of 2-deoxy-D-[1,2-3H]-glucose (2-DG). Sodium nitroprusside (SNP) administration improved the in vitro uptake of 2-DG in both CORT and control groups. In CORT treatment, however, the stimulating effect of NO on 2-DG uptake was relatively lower compared to control group, whereas it was restored by insulin. Insulin stimulated muscle in vitro 2-DG uptake in either control or CORT group, with the improvement being significantly higher in control chickens. The results indicated that the reduced circulating and muscle level of NO level via the suppression of NOS by corticosterone treatment was involved in the stress-induced insulin resistance. It appears that CORT could suppress the insulin stimulated glucose uptake in skeletal muscle, inducing insulin resistance in broiler chickens. We conclude that NO could stimulate glucose transport in chicken skeletal muscle and that the reduced circulating and muscle level of NO is involved in the insulin resistance induced by corticosterone treatment.

Topics: Animals; Biological Transport; Blood Glucose; Chickens; Corticosterone; Deoxyglucose; Diet; Enzyme Inhibitors; Glycogen; Hyperglycemia; Hyperinsulinism; Insulin; Insulin Resistance; Male; Muscle, Skeletal; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Nitroprusside; Time Factors

The present study was undertaken to investigate the hyperglycemic potential of acute exposure to acephate and its etiology employing rat model system. Oral administration of acephate (140mg/kg b.w.) caused reversible hyperglycemia as evidenced by peak increase in blood glucose at 2h after the administration (87% over control) followed by trend of normalization. In further experiment carried out to understand the etiology of the induced hyperglycemia, we observed that 2h exposure to acephate caused significant increase in blood glucose, plasma corticosterone (78%) and activities of two gluconeogenesis enzymes in liver viz., glucose-6-phosphatase (91%) and tyrosine aminotransferase (84%) compared to that in control. When rats were exposed to acephate for 6h, decrement was observed in elevated levels of blood glucose, plasma corticosterone and the gluconeogenesis enzymes of the liver. Adrenal cholesterol levels in acephate-exposed rats were significantly depleted. While the glycogen content in liver of 2-h exposure group was comparable to control, a tremendous increase in liver glycogen content ( approximately 3.5 folds) was observed in rats of the 6-h exposure group. Our results demonstrate that acephate causes reversible hyperglycemia in rats probably by enhancing hepatic glucose output via gluconeogenesis. A role for hyperactivity of adrenal cortex is suggested in increased gluconeogenesis while significant attenuation in elevated levels of blood glucose and the activity the gluconeogenesis enzyme, glucose-6-phosphatase in liver with concomitant increase in liver glycogen are indicative of the onset of counter-regulatory responses such as hyperinsulinemia, to overcome the induced hyperglycemia.

Topics: Adrenal Cortex; Animals; Blood Glucose; Cholesterol; Corticosterone; Fasting; Gluconeogenesis; Glucose-6-Phosphatase; Glycogen; Hyperglycemia; Insecticides; Liver; Male; Organothiophosphorus Compounds; Phosphoramides; Rats; Rats, Wistar; Time Factors; Tyrosine Transaminase

We examined the intracellular metabolic fate of plasma glucose during a hyperglycemic clamp in impaired glucose-tolerant (IGT; n = 21) and normal glucose-tolerant subjects (n = 10) using a combination of [3-(3)H]glucose infusion with measurement of [(3)H]water formation and indirect calorimetry. IGT was associated with approximately 35% reduced first-phase insulin responses, normal second-phase insulin response, and 25-30% reduced insulin sensitivity, resulting in approximately 35% reduced plasma glucose disposal. This was coupled with approximately 55% reduced storage of plasma glucose (P < 0.01) and approximately 15-20% reduced glycolysis of plasma glucose (P < 0.03), accounting for approximately 75 and 25% of the reduction in glucose disposal, respectively. Decreased glucose oxidation accounted for virtually all the decrease in glycolysis. Therefore, nonoxidative glycolysis of plasma glucose in IGT was similar to that in NGT (P > 0.9) and accounted for an increased proportion of systemic glucose disposal (P < 0.05). We conclude that, in IGT, decreased disposal of plasma glucose involves mainly decreased glycogen synthesis and to a lesser extent decreased glycolysis, which is accounted for by decreased glucose oxidation. An increased proportion of plasma glucose hence undergoes nonoxidative glycolysis, representing a novel early abnormality in the pathogenesis of T2DM.

Topics: Alanine; Blood Glucose; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Glucagon; Glucose Clamp Technique; Glucose Intolerance; Glycogen; Glycolysis; Humans; Hyperglycemia; Lactic Acid; Male; Middle Aged; Oxidation-Reduction

To evaluate the possible role of glucose in the control of food intake (FI) in fish and the involvement of glucosensing system in that role, we have subjected rainbow trout (via intraperitoneal injections) to control, hyperglycemic (500 mg kg(-1) glucose body mass) or hypoglycemic (4 mg kg(-1) bovine insulin) conditions for 10 days. The experimental design was appropriate since hypoglycemia and hyperglycemia were observed the first 5 days after treatment and changes observed in metabolic parameters in liver were similar to those of fish literature. Hyperglycemic conditions elicited small changes in FI accompanied by increased glucose and glycogen levels, glucokinase (GK) activity and glycolytic potential in hypothalamus and hindbrain. In contrast, hypoglycemic conditions elicited a marked increase in FI accompanied by decreased glucose and glycogen levels and GK activity in the same brain regions whereas both regions displayed different responses in glycolytic potential. These results allow us to hypothesize that, despite the relative intolerance to glucose of carnivorous fish, changes in plasma glucose levels in rainbow trout detected by glucosensing areas in brain regions (hypothalamus and hindbrain) are integrated in those or near areas eliciting a response in FI, which was more important under hypoglycemic than under hyperglycemic conditions.

Topics: Animals; Appetite Regulation; Blood Glucose; Chemoreceptor Cells; Energy Metabolism; Glucokinase; Glucose; Glycogen; Glycolysis; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Hypothalamus; Nerve Net; Oncorhynchus mykiss; Rhombencephalon; Sensory Receptor Cells; Species Specificity; Time Factors

Matricaria chamomilla L., known as "chamomile", has been used as an herbal tea or supplementary food all over the world. We investigated the effects of chamomile hot water extract and its major components on the prevention of hyperglycemia and the protection or improvement of diabetic complications in diabetes mellitus. Hot water extract, esculetin (3) and quercetin (7) have been found to show moderate inhibition of sucrase with IC50 values of 0.9 mg/mL and 72 and 71 microM, respectively. In a sucrose-loading test, the administration of esculetin (50 mg/kg body weight) fully suppressed hyperglycemia after 15 and 30 min, but the extract (500 mg/kg body weight) and quercetin (50 mg/kg body weight) were less effective. On the other hand, a long-term feed test (21 days) using a streptozotocin-induced rat diabetes model revealed that the same doses of extract and quercetin showed significant suppression of blood glucose levels. It was also found that these samples increased the liver glycogen levels. Moreover, chamomile extract showed potent inhibition against aldose reductase (ALR2), with an IC50 value of 16.9 microg/mL, and its components, umbelliferone (1), esculetin (3), luteolin (6), and quercetin (7), could significantly inhibit the accumulation of sorbitol in human erythrocytes. These results clearly suggested that daily consumption of chamomile tea with meals could contribute to the prevention of the progress of hyperglycemia and diabetic complications.

Topics: Aldehyde Reductase; alpha-Amylases; Animals; Beverages; Blood Glucose; Diabetes Complications; Diabetes Mellitus, Experimental; Diet; Enzyme Inhibitors; Erythrocytes; Female; Glycogen; Glycoside Hydrolase Inhibitors; Humans; Hyperglycemia; Liver; Male; Matricaria; Mice; Plant Extracts; Rats; Rats, Wistar; Sorbitol; Sucrase

The effect of fermented mushroom of Coprinus comatus rich in vanadium (CCRV) on glycaemic metabolism was studied in this paper. Alloxan-induced hyperglycemic mice were used in this study. The insulin secretion and glycogen synthesis of the mice were analyzed. At the same time, the gluconeogenesis of the normal mice was also determined. The alloxan-damaged pancreatic beta-cells of the mice were also studied in this paper. After the mice were administered (i.g.) with CCRV, the level of insulin secretion and glycogen synthesis of alloxan-induced hyperglycemic mice elevated (p<0.05, p<0.01) and the gluconeogenesis of the normal mice was inhibited (p<0.01). Also, the alloxan-damaged pancreatic beta-cells of the mice were partly recovered gradually after the mice were administered (i.g.) with CCRV 15 days later. These may account for the causes of CCRV-induced significant decreases of the blood glucose in hyperglycemic mice.

Topics: Agaricales; Animals; Cell Death; Female; Fermentation; Gluconeogenesis; Glucose; Glycogen; Hyperglycemia; Insulin; Insulin-Secreting Cells; Liver; Mice; Vanadium

Studies have revealed that high-fat (HF) diets promote hyperglycaemia, whole-body insulin resistance and non-alcoholic fatty liver disease (NAFLD). Recently, hepatic glucagon resistance has been shown to occur in rats fed a HF diet. More precisely, diet-induced obesity (DIO) reduces the number of hepatic plasma membrane glucagon receptors (GR), which results in a diminished response to glucagon during a hyperglucagonaemic clamp. The present study was undertaken to test the hypothesis that a HF-DIO is associated with a desensitization and destruction of the hepatic GR. We also hypothesized that a single bout of endurance exercise would modify the GR cellular distribution under our DIO model. Male rats were either fed a standard (SD) or a HF diet for two weeks. Each group was subdivided into a non-exercised (Rest) and an acute exercised (EX) group. The HF diet resulted in a reduction of total hepatic GR (55%) and hepatic plasma membrane GR protein content (20%). These changes were accompanied by a significant increase in endosomal and lysosomal GR content with the feeding of a HF diet. The reduction of GR plasma membrane as well as the increase in endosomal GR was strongly correlated with an increase of PKC-alpha, suggesting a role of PKC-alpha in GR desensitization. EX increased significantly PKC-alpha protein content in both diets, suggesting a role of PKC-alpha in EX-induced GR desensitization. The present results suggest that liver lipid infiltration plays a role in reducing glucagon action in the liver through a reduction in total cellular and plasma membrane GR content. Furthermore, the GR desensitization observed in our in vivo model of HF diet-induced hepatic steatosis and in EX individuals may be regulated by PKC-alpha.

Topics: Animals; beta-Adrenergic Receptor Kinases; Cell Membrane; Dietary Fats; Endosomes; Fatty Liver; G-Protein-Coupled Receptor Kinase 2; Glycogen; Hepatocytes; Hyperglycemia; Lysosomes; Male; Obesity; Physical Exertion; Protein Kinase C-alpha; Rats; Rats, Sprague-Dawley; Receptors, Glucagon; Triglycerides

The aim of this study was to evaluate the existence of a glucosensor in different regions of the brain and in the Brockmann bodies (BB) of the rainbow trout, Oncorhynchus mykiss. Five groups (n = 12) of trout were injected intraperitoneally with saline alone (control) or saline-containing bovine glucagon (100 mug/kg), bovine insulin (4 mg/kg), 2-deoxy-d-glucose (100 mg/kg), or d-glucose (500 mg/kg) to promote hyperglycemia (glucagon, d-glucose, 2-deoxy-d-glucose) or hypoglycemia (insulin). Six hours after injection, samples from four brain regions (hypothalamus, telencephalon, hindbrain, and midbrain) and the entire BB were taken. Our results demonstrate within the BB and both the hypothalamus and hindbrain a metabolic response different to that observed in other tissues (midbrain, telencephalon) but similar to that described in tissues known to be glucosensors in mammals. The metabolic responses of these areas to changes in plasma glycemia were characterized by parallel changes in GLUT-2 expression, hexokinase-IV, or glucokinase activity and expression, glycolytic potential, and levels of glycogen and glucose. These changes are similar to those reported in mammalian pancreatic beta-cells and glucose-excited (GE) neurons, two cell types containing glucosensors. This study provides evidence for the presence of glucosensors responsive to hyper- and hypoglycemia in rainbow trout BB, hypothalamus, and hindbrain.

Topics: Animals; Blood Glucose; Cattle; Deoxyglucose; Glucagon; Glucokinase; Glucose; Glucose Transporter Type 2; Glycogen; Hexokinase; Hormones; Hyperglycemia; Hypoglycemic Agents; Hypothalamus; Insulin; Islets of Langerhans; Mesencephalon; Oncorhynchus mykiss; Rhombencephalon; Telencephalon; Time Factors

High-fat diets and oxidative damage may contribute to the development of type 2 diabetes. Hypolipidaemic drugs and antioxidants were supposed to prevent the development of the disease. In this study, we investigated preventive effects of fenofibrate (200 mg kg(-1)), vitamin C (30 mg kg(-1)), combination of both in mice induced by streptozotocin (35 mg kg(-1)) and soluble lard (15 ml kg(-1)). The results showed the mice demonstrated hyperglycaemia and hypercholesterolaemia, visceral fat accumulation, and a slight increase in liver glycogen/triglyceride and oxidative stress within 60 days of treatment. Fenofibrate enhanced insulin sensitivity, improved glycaemic control, lowered serum triglycerides, reduced body and visceral fat weights, and decreased liver glycogen/lipid levels but showed hepatotoxicity in the mice. Vitamin C neither itself prevented nor enhanced preventive effects of fenofibrate on glucose and lipid metabolism but partly attenuated the hepatotoxicity of fenofibrate. These results suggest that fenofibrate inhibit development of type 2 diabetes induced by high-fat diets and oxidative stress. However, here, vitamin C just can serve as an adjunct to fenofibrate therapy against its hepatotoxicity. In the future study, we should investigate if higher dosage of vitamin C or other antioxidants would enhance preventive effects of fenofibrate in type 2 diabetes.

Topics: Animals; Antioxidants; Ascorbic Acid; Blood Glucose; Chemical and Drug Induced Liver Injury; Cholesterol; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dietary Fats; Drug Therapy, Combination; Fenofibrate; Glycogen; Hypercholesterolemia; Hyperglycemia; Hypoglycemic Agents; Hypolipidemic Agents; Insulin Resistance; Intra-Abdominal Fat; Liver; Liver Diseases; Male; Matrix Metalloproteinase 9; Mice; Oxidative Stress; Streptozocin; Triglycerides

Hypersecretion of glucagon contributes to abnormally increased hepatic glucose output in type 2 diabetes. Somatostatin (SST) inhibits murine glucagon secretion from isolated pancreatic islets via somatostatin receptor subtype-2 (sst2). Here, we characterize the role of sst2 in controlling glucose homeostasis in mice with diet-induced obesity. Sst2-deficient (sst2(-/-)) and control mice were fed high-fat diet for 14 wk, and the parameters of glucose homeostasis were monitored. Hepatic glycogen and lipid contents were quantified enzymatically and visualized histomorphologically. Enzymes regulating glycogen and lipid synthesis and breakdown were measured by real-time PCR and/or Western blot. Gluconeogenesis and glycogenolysis were determined from isolated primary hepatocytes and glucagon or insulin secretion from isolated pancreatic islets. Nonfasting glucose, glucagon, and fasting nonesterified fatty acids of sst2(-/-) mice were increased. Inhibition of glucagon secretion from sst2-deficient pancreatic islets by glucose or somatostatin was impaired. Insulin less potently reduced blood glucose concentration in sst2-deficient mice as compared with wild-type mice. Sst2-deficient mice had decreased nonfasting hepatic glycogen and lipid content. The activity/expression of enzymes controlling hepatic glycogen synthesis of sst2(-/-) mice was decreased, whereas enzymes facilitating glycogenolysis and lipolysis were increased. Somatostatin and an sst2-selective agonist decreased glucagon-induced glycogenolysis, without influencing de novo glucose production using cultured primary hepatocytes. This study demonstrates that ablation of sst2 leads to hyperglucagonemia. Increased glucagon concentration is associated with impaired glucose control in sst2(-/-) mice, resulting from decreased hepatic glucose storage, increased glycogen breakdown, and reduced lipid accumulation. Sst2 may constitute a therapeutic target to lower hyperglucagonemia in type 2 diabetes.

Topics: Animal Feed; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Disease Models, Animal; Fasting; Fatty Acids, Nonesterified; Female; Glucagon; Gluconeogenesis; Glycogen; Glycogen Synthase; Glycogenolysis; Homeostasis; Hyperglycemia; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mice, Obese; Obesity; Receptors, Somatostatin; Triglycerides

Parasympathetic (cholinergic) innervation is implicated in the stimulation of hepatic glucose uptake by portal vein hyperglycaemia. We determined the direct effects of acetylcholine on hepatocytes. Acute exposure to acetylcholine mimicked insulin action on inactivation of phosphorylase, stimulation of glycogen synthesis and suppression of phosphoenolpyruvate carboxykinase mRNA levels but with lower efficacy and without synergy. Pre-exposure to acetylcholine had a permissive effect on insulin action similar to glucocorticoids and associated with increased glucokinase activity. It is concluded that acetylcholine has a permissive effect on insulin action but cannot fully account for the rapid stimulation of glucose uptake by the portal signal.

Topics: Acetylcholine; Animals; Carboxy-Lyases; Cells, Cultured; Cholinergic Agents; Drug Synergism; Glucocorticoids; Glucokinase; Glucose; Glycogen; Hepatocytes; Hyperglycemia; Hypoglycemic Agents; Insulin; Male; Parasympathetic Nervous System; Portal Vein; Rats; Rats, Wistar; RNA, Messenger; Signal Transduction

Hyperglycemia is a defining feature of Type 1 and 2 diabetes. Hyperglycemia also causes insulin resistance, and our group (Kraegen EW, Saha AK, Preston E, Wilks D, Hoy AJ, Cooney GJ, Ruderman NB. Am J Physiol Endocrinol Metab Endocrinol Metab 290: E471-E479, 2006) has recently demonstrated that hyperglycemia generated by glucose infusion results in insulin resistance after 5 h but not after 3 h. The aim of this study was to investigate possible mechanism(s) by which glucose infusion causes insulin resistance in skeletal muscle and in particular to examine whether this was associated with changes in insulin signaling. Hyperglycemia (~10 mM) was produced in cannulated male Wistar rats for up to 5 h. The glucose infusion rate required to maintain this hyperglycemia progressively lessened over 5 h (by 25%, P < 0.0001 at 5 h) without any alteration in plasma insulin levels consistent with the development of insulin resistance. Muscle glucose uptake in vivo (44%; P < 0.05) and glycogen synthesis rate (52%; P < 0.001) were reduced after 5 h compared with after 3 h of infusion. Despite these changes, there was no decrease in the phosphorylation state of multiple insulin signaling intermediates [insulin receptor, Akt, AS160 (Akt substrate of 160 kDa), glycogen synthase kinase-3beta] over the same time course. In isolated soleus strips taken from control or 1- or 5-h glucose-infused animals, insulin-stimulated 2-deoxyglucose transport was similar, but glycogen synthesis was significantly reduced in the 5-h muscle sample (68% vs. 1-h sample; P < 0.001). These results suggest that the reduced muscle glucose uptake in rats after 5 h of acute hyperglycemia is due more to the metabolic effects of excess glycogen storage than to a defect in insulin signaling or glucose transport.

Topics: Animals; Blood Glucose; Glucose; Glycogen; GTPase-Activating Proteins; Hyperglycemia; In Vitro Techniques; Infusions, Intravenous; Insulin; Insulin Resistance; Male; Muscle, Skeletal; Oncogene Protein v-akt; Phosphorylation; Random Allocation; Rats; Rats, Wistar; Signal Transduction

In the present study, the polyherbal preparation diabegon, containing 18 plant extracts with hypoglycemic activity, was evaluated for its preventive effect during progression of type 2 diabetes in high-fructose-diet-fed rats. Oral administration of diabegon (100 mg/kg body weight) delayed development of glucose intolerance for 4 weeks in comparison with the diabetic control group, and the effect of diabegon was compared to that of the standard insulin sensitizer drug rosiglitazone. Diabegon treatment also ameliorated the elevation of glycosylated haemoglobin, liver glycogen content, plasma insulin, homeostasis model assessment, free fatty acids, triglycerides, total cholesterol, LDL-cholesterol, and VLDL-cholesterol, whereas it increased HDL-cholesterol after 56 days of treatment (P<0.05). The mechanism of action by which diabegon attenuates insulin resistance and dyslipidemia may be through induction of peroxisome proliferator-activated receptor-gamma and lipoprotein lipase activity in peripheral tissues (muscles). Moreover, diabegon administration for 56 days also produced no alteration in liver and kidney function tests, which seems to indicate its non-toxicity during treatment. Our present results suggest that diabegon may be included in diabetes mellitus treatment regimens, as a drug with good antidiabetic actions but no toxic manifestations.

Topics: Administration, Oral; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Fructose; Glucose Tolerance Test; Glycated Hemoglobin; Glycogen; Homeostasis; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Kidney; Lipids; Lipoprotein Lipase; Liver; Male; Plant Extracts; PPAR gamma; Rats; Rats, Wistar

In this study we determined body weight-specific fetal (umbilical) glucose uptake (UGU), utilization (GUR), and production rates (GPR) and insulin action in intrauterine growth-restricted (IUGR) fetal sheep. During basal conditions, UGU from the placenta was 33% lower in IUGR fetuses, but GUR was not different between IUGR and control fetuses. The difference between glucose utilization and UGU rates in the IUGR fetuses demonstrated the presence and rate of fetal GPR (41% of GUR). The mRNA concentrations of the gluconeogenic enzymes glucose-6-phophatase and PEPCK were higher in the livers of IUGR fetuses, perhaps in response to CREB activation, as phosphorylated CREB/total CREB was increased 4.2-fold. A hyperglycemic clamp resulted in similar rates of glucose uptake and utilization in IUGR and control fetuses. The nearly identical GURs in IUGR and control fetuses at both basal and high glucose concentrations occurred at mean plasma insulin concentrations in the IUGR fetuses that were approximately 70% lower than controls, indicating increased insulin sensitivity. Furthermore, under basal conditions, hepatic glycogen content was similar, skeletal muscle glycogen was increased 2.2-fold, the fraction of fetal GUR that was oxidized was 32% lower, and GLUT1 and GLUT4 concentrations in liver and skeletal muscle were the same in IUGR fetuses compared with controls. These results indicate that insulin-responsive fetal tissues (liver and skeletal muscle) adapt to the hypoglycemic-hypoinsulinemic IUGR environment with mechanisms that promote glucose utilization, particularly for glucose storage, including increased insulin action, glucose production, shunting of glucose utilization to glycogen production, and maintenance of glucose transporter concentrations.

Topics: Animals; Blood Glucose; Cyclic AMP Response Element-Binding Protein; Female; Fetal Growth Retardation; Gene Expression; Glucose; Glucose Transport Proteins, Facilitative; Glucose-6-Phosphatase; Glycogen; Hyperglycemia; Insulin; Insulin Resistance; Lactic Acid; Liver; Male; Oxygen; Phosphoenolpyruvate Carboxykinase (GTP); Placental Insufficiency; Pregnancy; Pregnancy Complications; Regional Blood Flow; RNA, Messenger; Sheep, Domestic; Umbilical Cord

The aqueous extract of the fruits of Terminalia chebula Retz. has been evaluated for its antidiabetic activity in streptozotocin (STZ) induced mild diabetic rats and compared with a known drug, tolbutamide. The oral effective dose (ED) of the extract was observed to be 200 mg/kg body weight, which produced a fall of 55.6% (p<0.01) in the oral glucose tolerance test. Oral administration of ED of aqueous extract of T.chebula (AETC) daily once for two months reduced the elevated blood glucose by 43.2% (p<0.01) and significantly reduced the increase in glycosylated hemoglobin (HbA1c) (p<0.01). The same dose also showed a marked improvement in controlling the elevated blood lipids as well as decreased serum insulin levels in contrast to the untreated diabetic animals. Hepatic and skeletal muscle glycogen content decreased by 75% and 62.9% respectively in diabetic controls, these alterations were partly prevented (34.9% and 21.17%) in AETC treated group when compared to the healthy controls. The in vitro studies with pancreatic islets showed that the insulin release was nearly two times more than that in untreated diabetic animals. The treatment did not have any unfavorable effect on other blood parameters of liver and kidney function tests. LD 50 was found to be above 3 g/kg bw i.e. 15 times of ED, because there were no deaths of animals even at this dose indicating high margin of safety. These findings suggest further investigations for the possible use of the aqueous extract of fruits of T.chebula for the treatment of diabetes.

Topics: Administration, Oral; Animals; Diabetes Mellitus, Experimental; Fruit; Glucose Tolerance Test; Glycated Hemoglobin; Glycogen; Hyperglycemia; Hypoglycemic Agents; Insulin; Islets of Langerhans; Kidney; Lipids; Liver; Male; Muscle, Skeletal; Phytotherapy; Plant Extracts; Rats; Rats, Wistar; Terminalia; Time Factors; Tolbutamide

Farnesoid X receptor (FXR) plays an important role in maintaining bile acid and cholesterol homeostasis. Here we demonstrate that FXR also regulates glucose metabolism. Activation of FXR by the synthetic agonist GW4064 or hepatic overexpression of constitutively active FXR by adenovirus-mediated gene transfer significantly lowered blood glucose levels in both diabetic db/db and wild-type mice. Consistent with these data, FXR null mice exhibited glucose intolerance and insulin insensitivity. We further demonstrate that activation of FXR in db/db mice repressed hepatic gluconeogenic genes and increased hepatic glycogen synthesis and glycogen content by a mechanism that involves enhanced insulin sensitivity. In view of its central roles in coordinating regulation of both glucose and lipid metabolism, we propose that FXR agonists are promising therapeutic agents for treatment of diabetes mellitus.

Topics: 3-Hydroxybutyric Acid; Adenoviridae; Animals; Blood Glucose; Blotting, Northern; Blotting, Western; Cholesterol; Diabetes Mellitus, Experimental; DNA-Binding Proteins; Etoposide; Gluconeogenesis; Glucose; Glycogen; Hepatocytes; Hyperglycemia; Hyperlipidemias; Insulin; Insulin Resistance; Isoxazoles; Lipids; Liver; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Models, Statistical; Receptors, Cytoplasmic and Nuclear; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Time Factors; Transcription Factors; Triglycerides

Aberrant energy metabolism is one characteristic of diabetes mellitus (DM). Two types of DM have been identified, type 1 and type 2. Most of type 2 DM patients eventually become insulin dependent because insulin secretion by the islets of Langerhans becomes exhausted. In the present study, we show that resveratrol (3,5,4'-trihydroxylstilbene) possesses hypoglycemic and hypolipidemic effects in streptozotocin-induced DM (STZ-DM) rats. In resveratrol-treated STZ-DM rats, the plasma glucose concentration on day 14 was reduced by 25.3 +/- 4.2%, and the triglyceride concentration was reduced by 50.2 +/- 3.2% compared with the vehicle-treated rats. In STZ-nicotinamide DM rats, the plasma glucose concentration on day 14 was reduced by 20.3 +/- 4.2%, and the triglyceride concentration was reduced by 33.3 +/- 2.2% compared with the vehicle-treated rats. Resveratrol administration ameliorates common DM symptoms, such as body weight loss, polyphagia, and polydipsia. In STZ-nicotinamide DM rats, resveratrol administration significantly decreased insulin secretion and delayed the onset of insulin resistance. Further studies showed that glucose uptake by hepatocytes, adipocytes, and skeletal muscle and hepatic glycogen synthesis were all stimulated by resveratrol treatment. Because the stimulation of glucose uptake was not attenuated in the presence of an optimal amount of insulin in insulin-responsive cells, the antihyperglycemic effect of resveratrol appeared to act through a mechanism(s) different from that of insulin.

Topics: Animals; Antioxidants; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Drug Synergism; Glucose; Glycogen; Hepatocytes; Hyperglycemia; Insulin; Male; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Time Factors; Wine

The effect of restoration of normoglycemia by a novel sodium-dependent glucose transporter inhibitor (T-1095) on impaired hepatic glucose uptake was examined in 14-week-old Zucker diabetic fatty (ZDF) rats. The nontreated group exhibited persistent endogenous glucose production (EGP) despite marked hyperglycemia. Gluconeogenesis and glucose cycling (GC) were responsible for 46 and 51% of glucose-6-phosphatase (G6Pase) flux, respectively. Net incorporation of plasma glucose into hepatic glycogen was negligible. Glucokinase (GK) and its inhibitory protein, GK regulatory protein (GKRP), were colocalized in the cytoplasm of hepatocytes. At day 7 of drug administration, EGP was slightly reduced, but G6Pase flux and GC were markedly lower compared with the nontreated group. In this case, GK and GKRP were colocalized in the nuclei of hepatocytes. When plasma glucose and insulin levels were raised during a clamp, EGP was completely suppressed and GC, glycogen synthesis from plasma glucose, and the fractional contribution of plasma glucose to uridine diphosphoglucose flux were markedly increased. GK, but not GKRP, was translocated from the nucleus to the cytoplasm. Glucotoxicity may result in the blunted response of hepatic glucose flux to elevated plasma glucose and/or insulin associated with impaired regulation of GK by GKRP in ZDF rats.

Topics: Animals; Blood Glucose; Carbonates; Carrier Proteins; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Glucagon; Glucokinase; Glucose; Glucose-6-Phosphatase; Glucosides; Glycogen; Glycogen Synthase; Hyperglycemia; Insulin; Liver; Liver Glycogen; Male; Muscle, Skeletal; Phosphorylases; Rats; Rats, Zucker

An investigation was made to reveal the possible involvement of thyroid hormones, if any, in terazosin (an alfa-1 adrenergic receptor blocker) induced alterations in tissue lipid peroxidation (LPO) and in the concentration of different serum lipids. We determined the impact of terazosin on the changes in hypercholesterolemic (CCT) diet induced thyroid dysfunction; cardiac, renal and hepatic LPO and on serum glucose concentration in female Wister rats. Simultaneously levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), creatinine, alkaline phosphatase (ALP) activity, hepatic glycogen synthesis and total daily food consumption were studied as supporting parameters. While a decrease in the level of serum thyroid hormones, HDL-C and in hepatic glycogen content, was observed in CCT diet fed animals; it increased the concentration of other serum lipids, glucose and creatinine; ALP activity; tissue and serum LPO. However, following terazosin administration for 15 days to CCT diet fed animals, status of thyroid hormones and all other thyroid dependent parameters were reversed suggesting that the drug might be acting through an alteration in the thyroid functions.

Topics: Adrenergic alpha-Antagonists; Animals; Blood Glucose; Cholesterol, Dietary; Disease Models, Animal; Eating; Female; Glycogen; Heart; Hypercholesterolemia; Hyperglycemia; Hypoglycemic Agents; Hypolipidemic Agents; Kidney; Lipid Peroxidation; Lipids; Lipoproteins; Liver; Prazosin; Rats; Rats, Wistar; Thyroid Gland; Thyroxine; Triiodothyronine

The present study tested the hypothesis that the phosphorylation and regulation of metabolic proteins implicated in glucose homeostasis were impaired in the heart of the type 2 diabetic Zucker-diabetic-fatty (ZDF) rat model. The onset of hyperglycaemia in ZDF rats was not uniform, instead it either progressed rapidly (3-4 weeks) or was delayed (6-8 weeks). In both the early and late onset hyperglycaemic ZDF rats, AMPKalpha Thr172 phosphorylation in the heart was significantly decreased. In the early onset hyperglycaemic ZDF rats, PKB Ser473 phosphorylation was reduced, whereas Thr308 phosphorylation was significantly increased. In the late onset hyperglycaemic ZDF rats, PKB Ser473 phosphorylation was unchanged, but Thr308 phosphorylation remained elevated. Cardiac GLUT4 protein and mRNA expression were significantly reduced in the early onset hyperglycaemic ZDF rats, whereas increased protein expression was observed in the late onset hyperglycaemic ZDF rats. In conclusion, the present study has demonstrated that following a more rapid onset of hyperglycaemia, the type 2 diabetic heart is more prone to alterations in the signaling proteins implicated in glucose metabolism.

Topics: AMP-Activated Protein Kinases; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Disease Models, Animal; Disease Progression; Glucose; Glucose Transporter Type 4; Glycogen; Glycogen Synthase Kinase 3; Hyperglycemia; Insulin; Male; Multienzyme Complexes; Myocardium; Phosphorylation; Protein Kinases; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Rats; Rats, Zucker; RNA, Messenger; Time Factors

Insulin modulates glucose homeostasis, but the role of insulin-responsive transcription factors in such actions is not well understood. Recently, we have identified the insulin-response element-binding protein-1 (IRE-BP1) as a transcription factor that appears to mediate insulin action on multiple target genes. To examine the possibility that IRE-BP1 is an insulin-responsive glucoregulatory factor involved in the metabolic actions of insulin, we investigated the effect of adenoviral overexpression of hepatic IRE-BP1 on the glycemic control of insulin-resistant diabetic rats. Adenoviral IRE-BP1 lowered both fasting and postprandial glucose levels, and microarray of hepatic RNA revealed modulation of the expression of genes involved in gluconeogenesis, lipogenesis, and fatty acid oxidation. The insulin mimetic effects of IRE-BP1 were also confirmed in L6 myocytes; stable constitutive expressions of IRE-BP1 enhanced glucose transporter expression, glucose uptake, and glycogen accumulation in these cells. These findings showed physiologic sufficiency of IRE-BP1 as the transcriptional mediator of the metabolic action of insulin. Understanding IRE-BP1 action should constitute a useful probe into the mechanisms of metabolic regulation and an important target to develop therapeutic agents that mimic or enhance insulin action.

Topics: Animals; Base Sequence; Blood Glucose; Cell Line; Diabetes Mellitus, Experimental; DNA, Complementary; Gene Expression Profiling; Glucose; Glycogen; Hyperglycemia; Insulin Resistance; Iron Regulatory Protein 1; Liver; Male; Models, Biological; Monosaccharide Transport Proteins; Rats; Rats, Sprague-Dawley; Rats, Zucker; Transfection

Phosphorylase is regulated by a number of small-molecular-weight effectors that bind to three sites on the enzyme. Recently, a fourth site referred to as the indole-inhibitor site has been identified. Synthetic compounds bind to the site and inhibit activity. However, the effects of these compounds in the presence of other endogenous effectors are unknown. We have determined the effects of four indole derivative glycogen phosphorylase inhibitors (GPI) on recombinant human liver glycogen phosphorylase a activity. The GPIs tested were all potent inhibitors. However, the endogenous inhibitors (glucose, ADP, ATP, fructose 1-phosphate, glucose 6-phosphate, UDP-glucose) and the activator (AMP) markedly reduced the inhibitory effect of GPIs. Consistent with these in vitro findings, the IC50 for the inhibition of glycogenolysis in cells and the liver drug concentration associated with glucose-lowering activity in diabetic ob/ob mice in vivo were also significantly higher than those determined in in vitro enzyme assays. The inhibitory effect of indole-site effectors is modulated by endogenous small-molecular-weight effectors of phosphorylase a activity. However, at higher concentrations (10-30 microM), the GPI effect was dominant and resulted in inhibition of phosphorylase a activity irrespective of the presence or absence of the other modulators of the enzyme.

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Amides; Animals; Blood Glucose; Cell Line; Dose-Response Relationship, Drug; Enzyme Activation; Fructosephosphates; Glucosephosphates; Glycogen; Humans; Hyperglycemia; Hypoglycemia; Indoles; Liver; Male; Phosphorylase a; Phosphorylase b; Rats; Rats, Sprague-Dawley; Uridine Diphosphate Glucose

The insulin-like effects of peroxovanate (POV) and peroxovanadyl (PSV) on rates of lactate formation and glycogen synthesis were measured in isolated incubated soleus muscle preparations. In another experiment rats were made insulin deficient by streptozotocin injection and treated with POV and PSV (0.25 mM) administered in the drinking water and in the course of 7 days glycemia were determined. Also, signal transduction proteins ERK 1 and ERK 2 involved in the insulin signaling were measured in soleus muscle of diabetic rats treated with POV and PSV. Peroxides of vanadate and vanadyl significantly stimulated glucose utilization in soleus muscle preparations in vitro. The stimulation of glycogen synthesis and lactate formation by POV and PSV was similar to insulin stimuli. Rats treated with POV or PSV presented reduction of glycemia, food and fluid intake with amelioration of the diabetic state during the short period of treatment (7 days). POV and PSV modulated ERK1/2 phosphorilation and the insulin administration in these rats caused an addictive effect on phosphorilation state of these proteins.

Topics: Animals; Diabetes Mellitus, Experimental; Glucose; Glycogen; Hyperglycemia; Hypoglycemic Agents; Insulin; Lactic Acid; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Muscle, Skeletal; Phosphorylation; Rats; Rats, Wistar; Signal Transduction; Vanadates; Vanadium Compounds

Activation of inflammatory pathways may contribute to the beginning and the progression of both atherosclerosis and type 2 diabetes. Here we report a novel interaction between insulin action and control of inflammation, resulting in glucose intolerance and vascular inflammation and amenable to therapeutic modulation. In insulin receptor heterozygous (Insr+/-) mice, we identified the deficiency of tissue inhibitor of metalloproteinase 3 (Timp3, an inhibitor of both TNF-alpha-converting enzyme [TACE] and MMPs) as a common bond between glucose intolerance and vascular inflammation. Among Insr+/- mice, those that develop diabetes have reduced Timp3 and increased TACE activity. Unchecked TACE activity causes an increase in levels of soluble TNF-alpha, which subsequently promotes diabetes and vascular inflammation. Double heterozygous Insr+/-Timp3+/- mice develop mild hyperglycemia and hyperinsulinemia at 3 months and overt glucose intolerance and hyperinsulinemia at 6 months. A therapeutic role for Timp3/TACE modulation is supported by the observation that pharmacological inhibition of TACE led to marked reduction of hyperglycemia and vascular inflammation in Insr+/- diabetic mice, as well as by the observation of increased insulin sensitivity in Tace+/- mice compared with WT mice. Our results suggest that an interplay between reduced insulin action and unchecked TACE activity promotes diabetes and vascular inflammation.

Topics: Analysis of Variance; Animals; Deoxyglucose; Diabetes Mellitus; Electrophoresis, Polyacrylamide Gel; Gene Expression Profiling; Genetic Vectors; Glucose; Glucose Tolerance Test; Glycogen; Heterozygote; Homeostasis; Hyperglycemia; Hyperinsulinism; Inflammation; Insulin; Liver; Mice; Mice, Inbred C57BL; Mice, Transgenic; Muscle, Skeletal; Muscles; Phosphorylation; Promoter Regions, Genetic; Protein Binding; Receptor, Insulin; Reverse Transcriptase Polymerase Chain Reaction; RNA; RNA, Messenger; RNA, Small Interfering; Signal Transduction; Time Factors; Tissue Inhibitor of Metalloproteinase-3; Tumor Necrosis Factor-alpha

Intestinal glucagon-like peptide-1 (GLP-1) is a hormone released into the hepatoportal circulation that stimulates pancreatic insulin secretion. GLP-1 also acts as a neuropeptide to control food intake and cardiovascular functions, but its neural role in glucose homeostasis is unknown. We show that brain GLP-1 controlled whole-body glucose fate during hyperglycemic conditions. In mice undergoing a hyperglycemic hyperinsulinemic clamp, icv administration of the specific GLP-1 receptor antagonist exendin 9-39 (Ex9) increased muscle glucose utilization and glycogen content. This effect did not require muscle insulin action, as it also occurred in muscle insulin receptor KO mice. Conversely, icv infusion of the GLP-1 receptor agonist exendin 4 (Ex4) reduced insulin-stimulated muscle glucose utilization. In hyperglycemia achieved by i.v. infusion of glucose, icv Ex4, but not Ex9, caused a 4-fold increase in insulin secretion and enhanced liver glycogen storage. However, when glucose was infused intragastrically, icv Ex9 infusion lowered insulin secretion and hepatic glycogen levels, whereas no effects of icv Ex4 were observed. In diabetic mice fed a high-fat diet, a 1-month chronic i.p. Ex9 treatment improved glucose tolerance and fasting glycemia. Our data show that during hyperglycemia, brain GLP-1 inhibited muscle glucose utilization and increased insulin secretion to favor hepatic glycogen stores, preparing efficiently for the next fasting state.

Topics: Adipose Tissue; Animals; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Blood Glucose; Brain; Dose-Response Relationship, Drug; Glucagon-Like Peptide 1; Glucose; Glucose Clamp Technique; Glucose Tolerance Test; Glycogen; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hyperglycemia; Hyperinsulinism; Insulin; Insulin Resistance; Insulin Secretion; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscles; Nuclear Proteins; Osmosis; Peptide Fragments; Phosphatidylinositol 3-Kinases; Phosphorylation; Receptor, Insulin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Time Factors; Transcription Factors

The purpose of this study was to investigate the role of insulin on skeletal muscle GLUT-4 protein expression and glycogen storage after postexercise carbohydrate supplementation. Male Sprague-Dawley rats were randomly assigned to one of six treatment groups: sedentary control (Con), Con with streptozocin (Stz/C), immediately postexercise (Ex0), Ex0 with Stz (Stz/Ex0), 5-h postexercise (Ex5), and Ex5 with Stz (Stz/Ex5). Rats were exercised by swimming (2 bouts of 3 h) and carbohydrate supplemented immediately after each exercise session by glucose intubation (1 ml of a 50% wt/vol). Stz was administered 72-h before exercise, which resulted in hyperglycemia and elimination of the insulin response to the carbohydrate supplement. GLUT-4 protein of Ex0 rats was 30% above Con in fast-twitch (FT) red and 21% above Con in FT white muscle. In Ex5, GLUT-4 protein was 52% above Con in FT red and 47% above Con in FT white muscle. Muscle glycogen in FT red and white muscle was also increased above Con in Ex5 rats. Neither GLUT-4 protein nor muscle glycogen was increased above Con in Stz/Ex0 or Stz/Ex5 rats. GLUT-4 mRNA in FT red muscle of Ex0 rats was 61% above Con but only 33% above Con in Ex5 rats. GLUT-4 mRNA in FT red muscle of Stz/C and Stz/Ex0 rats was similar but significantly elevated in Ex5/Stz rats. These results suggest that insulin is essential for the increase in GLUT-4 protein expression following postexercise carbohydrate supplementation.

Topics: Animals; Antibiotics, Antineoplastic; Gene Expression; Glucose Transporter Type 4; Glycogen; Hyperglycemia; Hypoglycemic Agents; Insulin; Male; Monosaccharide Transport Proteins; Muscle Fibers, Fast-Twitch; Muscle Fibers, Slow-Twitch; Muscle Proteins; Muscle, Skeletal; Physical Exertion; Rats; Rats, Sprague-Dawley; RNA, Messenger; Streptozocin

Cardiac dysfunction is a severe secondary effect of Type 2 diabetes. Recruitment of the protein kinase B/glycogen synthase kinase-3 pathway represents an integral event in glucose homeostasis, albeit its regulation in the diabetic heart remains undefined. Thus the following study tested the hypothesis that the regulation of protein kinase B/glycogen synthase kinase-3 was altered in the myocardium of the Zucker diabetic fatty rat. Second, exercise has been shown to improve glucose homeostasis, and, in this regard, the effect of swimming training on the regulation of protein kinase B/glycogen synthase kinase-3 in the diabetic rat heart was examined. In the sedentary Zucker diabetic fatty rats, glucose levels were elevated, and cardiac glycogen content increased, compared with wild type. A 13-wk swimming regimen significantly reduced plasma glucose levels and cardiac glycogen content and partially normalized protein kinase B-serine473, protein kinase B-threonine308, and glycogen synthase kinase-3alpha phosphorylation in Zucker diabetic fatty rats. In conclusion, hyperglycemia and increased cardiac glycogen content in the Zucker diabetic fatty rats were associated with dysregulation of protein kinase B/glycogen synthase kinase-3 phosphorylation. These anomalies in the Zucker diabetic fatty rat were partially normalized with swimming. These data support the premise that exercise training may protect the heart against the deleterious consequences of diabetes.

Topics: Animals; Blood Glucose; Diabetes Mellitus; Glycogen; Glycogen Synthase Kinase 3; Heart Ventricles; Heat-Shock Proteins; HSP72 Heat-Shock Proteins; Hyperglycemia; Insulin; Male; Muscle, Skeletal; Myocardium; Phosphofructokinases; Phosphorylation; Physical Conditioning, Animal; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Rats; Rats, Zucker; Swimming

Insulin resistance is one of the primary characteristics of type 2 diabetes. Mice overexpressing a dominant-negative IGF-I receptor specifically in muscle (MKR mice) demonstrate severe insulin resistance with high levels of serum and tissue lipids and eventually develop type 2 diabetes at 5-6 wk of age. To determine whether lipotoxicity plays a role in the progression of the disease, we crossed MKR mice with mice overexpressing a fatty acid translocase, CD36, in skeletal muscle. The double-transgenic MKR/CD36 mice showed normalization of the hyperglycemia and the hyperinsulinemia as well as a marked improvement in liver insulin sensitivity. The MKR/CD36 mice also exhibited normal rates of fatty acid oxidation in skeletal muscle when compared with the decreased rate of fatty acid oxidation in MKR. With the reduction in insulin resistance, beta-cell function returned to normal. These and other results suggest that the insulin resistance in the MKR mice is associated with increased muscle triglycerides levels and that whole-body insulin resistance can be, at least partially, reversed in association with a reduction in muscle triglycerides levels, although the mechanisms are yet to be determined.

Topics: Animals; CD36 Antigens; Diabetes Mellitus, Type 2; Fatty Acids; Glucose; Glucose Clamp Technique; Glycogen; Hyperglycemia; Hyperinsulinism; In Vitro Techniques; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Liver; Male; Mice; Mice, Transgenic; Muscle, Skeletal; Oxidation-Reduction; Triglycerides

The mechanism of cytotoxic effects of hyperglycaemia on the brain has not yet been explained and the proposed hypotheses are not fully convincing. In the present study, we aimed to assess the effect of high doses of glucose on the ultrastructure of the mice brain. The results, which are in agreement with the literature data, show that the administration of a single high dose of glucose, as well as its chronic application, leads to accumulation of glycogen granules in the cytoplasm of astrocytes. A new observation is the detection of glycogen granules in the ultrastructurally changed mitochondria of astrocytes as well as in the mitochondria of some synapses. Our hypothesis assumes that excess of glucose may cause an increase in the vulnerability of the brain mitochondria. This in turn may enable glucose and cytoplasmic enzymes to penetrate into the mitochondria and they therein synthesise glycogen. Mitochondrial dysfunction may in turn lead to neurodegeneration by apoptotic process.

Topics: Animals; Brain; Glucose; Glycogen; Hyperglycemia; Male; Mice; Mitochondria; Submitochondrial Particles

To study the hypoglycemic activity of ginseng glycopeptide (GGP).. Normal mice or rabbits and alloxan or streptozotocin-induced hyperglycemic rats or mice were used in the study. Blood glucose and liver glycogen levels of the experimental animals during the trial period were analyzed by spectrophotometry with O-toluidine and iodine reagents, respectively.. Significant decreases in blood glucose and liver glycogen levels were induced in a dose-dependent manner after administration of GGP 50, 100, or 200 mg/kg injected ip or sc to normal mice and injected im 30 or 60 mg/kg to normal rabbits. The hypoglycemic activity of GGP lasted for about 16 h, and were examined in both normal animals and hyperglycemic animals.. GGP injection induced the pronounced decreases in blood glucose and liver glycogen levels in both normal and hyperglycemic animals.

Topics: Alloxan; Animals; Blood Glucose; Glycogen; Glycopeptides; Hyperglycemia; Hypoglycemic Agents; Liver; Male; Mice; Panax; Plants, Medicinal; Rabbits; Random Allocation; Rats; Rats, Wistar; Streptozocin

Metabolic interventions improve performance during demand-induced ischemia by reducing myocardial lactate production and improving regional systolic function. We tested the hypotheses that 1) stimulation of glycolysis would increase lactate production and improve ventricular wall motion, and 2) the addition of fatty acid oxidation inhibition would reduce lactate production and further improve contractile function. Measurements were made in anesthetized open-chest swine hearts. Three groups, hyperglycemia (HG), HG + oxfenicine (HG + Oxf), and control (CTRL), were treated under aerobic conditions and during demand-induced ischemia. During demand-induced ischemia, HG resulted in greater lactate production and tissue lactate content but had no significant effect on glucose oxidation. HG + Oxf significantly lowered lactate production and increased glucose oxidation compared with both the CTRL and HG groups. Myocardial energy efficiency was greater in the HG and HG + Oxf groups under aerobic conditions but did not change during demand-induced ischemia. Thus enhanced glycolysis resulted in increased energy efficiency under aerobic conditions but significantly enhanced lactate production with no further improvement in function during demand-induced ischemia. Partial inhibition of free fatty acid oxidation in the presence of accelerated glycolysis increased energy efficiency under aerobic conditions and significantly reduced lactate production and enhanced glucose oxidation during demand-induced ischemia.

Topics: Animals; Coronary Circulation; Disease Models, Animal; Fatty Acids, Nonesterified; Glycogen; Glycolysis; Hyperglycemia; Lactic Acid; Myocardial Ischemia; Myocardium; Oxidation-Reduction; Physical Conditioning, Animal; Sus scrofa; Ventricular Function, Left

Insulin-independent effects of a physiological increase in free fatty acid (FFA) levels on fasting glucose production, gluconeogenesis, and glycogenolysis were assessed by administering [6,6-(2)H(2)]-glucose and deuteriated water ((2)H(2)O) in 12 type 1 diabetic patients, during 6-h infusions of either saline or a lipid emulsion. Insulin was either fully replaced (euglycemic group, n = 6), or underreplaced (hyperglycemic group, n = 6). During saline infusions, plasma FFA levels remained unchanged. Glucose concentrations decreased from 6.7 +/- 0.4 to 5.3 +/- 0.4 mmol/l and 11.9 +/- 1.0 to 10.5 +/- 1.0 mmol/l in the euglycemic and hyperglycemic group, respectively. Accordingly, glucose production declined from 84 +/- 5 to 63 +/- 5 mg x m(-2) x min(-1) and from 84 +/- 5 to 68 +/- 4 mg x m(-2) x min(-1), due to declining rates of glycogenolysis but unaltered rates of gluconeogenesis. During lipid infusions, plasma FFA levels increased twofold. In the euglycemic group, plasma glucose increased from 6.8 +/- 0.3 to 7.8 +/- 0.8 mmol/l. Glucose production declined less in the lipid study than in the saline study due to a stimulation of gluconeogenesis by 6 +/- 1 mg x m(-2) x min(-1) and a decline in glycogenolysis that was 6 +/- 2 mg x m(-2) x min(-1) less in the lipid study than in the saline study. In contrast, in the hyperglycemic group, there were no significant effects of elevated FFA on glucose production, gluconeogenesis, or glycogenolysis. In conclusion, a physiological elevation of plasma FFA levels stimulates glycogenolysis as well as gluconeogenesis and causes mild fasting hyperglycemia. These effects of FFA appear attenuated in the presence of hyperglycemia.

Topics: Adult; Blood Glucose; C-Peptide; Deuterium Oxide; Diabetes Mellitus, Type 1; Fatty Acids, Nonesterified; Gluconeogenesis; Glucose Clamp Technique; Glycogen; Humans; Hyperglycemia; Insulin; Kinetics; Male; Reference Values

In utero overexposure to glucocorticoids may explain the association between low birth weight and subsequent development of the metabolic syndrome. We previously showed that prenatal dexamethasone (dex) exposure in the rat lowers birth weight and programs adult fasting and postprandial hyperglycemia, associated with increased hepatic gluconeogenesis driven by elevated liver glucocorticoid receptor (GR) expression. This study aimed to determine whether prenatal dex (100 microg/kg per day from embryonic d 15 to embryonic d 21) programs adult GR expression in skeletal muscle and/or adipose tissue and whether this contributes to altered peripheral glucose uptake or metabolism. In utero dex-exposed rats remained lighter until 6 months of age, despite some early catch-up growth. Adults had smaller epididymal fat pads, with a relative increase in muscle size. Although glycogen storage was reduced in quadriceps, 2-deoxyglucose uptake into extensor digitorum longus muscle was increased by 32% (P < 0.05), whereas uptake in other muscles and adipose beds was unaffected by prenatal dex. GR mRNA was not different in most muscles but selectively reduced in soleus (by 23%, P < 0.05). However, GR mRNA was markedly increased specifically in retroperitoneal fat (by 50%, P < 0.02). This was accompanied by a shift from peroxisomal proliferator-activated receptor gamma 1 to gamma 2 expression and a reduction in lipoprotein lipase mRNA (by 28%, P < 0.02). Adipose leptin, uncoupling protein-3 and resistin mRNAs, muscle GLUT-4, and circulating lipids were not affected by prenatal dex. These data suggest that hyperglycemia in 6-month-old rats exposed to dexamethasone in utero is not due to attenuated peripheral glucose disposal. However, increased GR and attenuated fatty acid uptake specifically in visceral adipose are consistent with insulin resistance in this crucial metabolic depot and could indirectly contribute to increased hepatic glucose output.

Topics: Adipose Tissue; Animals; Birth Weight; Blood Glucose; Body Weight; Deoxyglucose; Dexamethasone; Epididymis; Fatty Acids; Female; Glucocorticoids; Glucose Transporter Type 4; Glycogen; Hyperglycemia; Insulin Resistance; Male; Monosaccharide Transport Proteins; Muscle Proteins; Muscle, Skeletal; Organ Size; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; Receptors, Glucocorticoid; RNA, Messenger; Transcription Factors

The purpose of the present study was to assess the effects of exogenously increasing the circulating levels of glucagon on the metabolic responses to exercise in rats. A total of six groups of rats were infused (iv) either with glucagon (20 or 50 ng x kg(-1) x min(-1)) or saline (0.9% NaCl), either in the resting state or during a bout of running exercise (45 min, 26 m x min(-1), 0% grade). Blood samples were taken at the end of the 45-min experiment. Animals infused with glucagon at 50 ng x kg(-1) x min(-1) showed significantly (P<0.01) higher mean plasma glucagon concentrations than animals infused with saline or glucagon at 20 ng x kg(-1) x min(-1). In addition, exercise resulted in significantly (P<0.05) higher mean plasma glucagon concentrations, compared to rest, in all groups. In spite of these differences in glucagon concentrations, there were no significant (P>0.05) effects of exercise and glucagon infusion on mean hepatic glycogen, plasma glucose, insulin, C-peptide, beta-hydroxybutyrate, or catecholamine concentrations. Although exercise resulted in a significant (P<0.01) increase in plasma glycerol and free fatty acid concentrations and a significant (P<0.05) decrease in glycogen in the soleus muscle, these responses were not affected by the glucagon infusion. These results suggest that the liver is non-responsive to physiological hyperglucagonemia in a short-term (45 min) exercise situation.

Topics: 3-Hydroxybutyric Acid; Animals; Ankle; Blood Glucose; C-Peptide; Dose-Response Relationship, Drug; Epinephrine; Fatty Acids, Nonesterified; Glucagon; Glycerol; Glycogen; Hyperglycemia; Infusions, Intravenous; Insulin; Liver Glycogen; Male; Muscle, Skeletal; Norepinephrine; Physical Conditioning, Animal; Rats; Rats, Sprague-Dawley; Reference Values

Glycogen-targeting subunits of protein phosphatase-1 (PP-1) are scaffolding proteins that facilitate the regulation of key enzymes of glycogen metabolism by PP-1. In the current study, we have tested the effects of hepatic expression of GMDeltaC, a truncated version of the muscle-targeting subunit isoform, in rats rendered insulin-deficient via injection of a single moderate dose of streptozotocin (STZ). Three key findings emerged. First, GMDeltaC expression in liver was sufficient to fully normalize blood glucose levels (from 335 +/- 31 mg/dl prior to viral injection to 109 +/- 28 mg/dl 6 days after injection) and liver glycogen content in STZ-injected rats. Second, this normalization occurred despite very low levels of liver glucokinase expression in the insulin-deficient STZ-injected rats. Finally, the hyperphagia induced by STZ injection was completely reversed by GMDeltaC expression in liver. In contrast to these findings with GMDeltaC, overexpression of another targeting subunit, GL, in STZ-injected rats caused a large increase in liver glycogen stores but only a transient decrease in food intake and blood glucose levels. The surprising demonstration of a glucose-lowering effect of GMDeltaC in the background of depressed hepatic glucokinase expression suggests that controlled stimulation of liver glycogen storage may be an effective mechanism for improving glucose homeostasis, even when normal pathways of glucose disposal are impaired.

Topics: Adenoviridae; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Genetic Therapy; Glucokinase; Glycogen; Hyperglycemia; Hyperphagia; Liver; Male; Phosphoprotein Phosphatases; Protein Phosphatase 1; Protein Subunits; Rats; Rats, Wistar; Streptozocin

To investigate in glycolytic and oxidative muscles of trained (nine weeks) and untrained hyperglycaemic female rats the effect of hyperandrogenicity and/or endurance training on energy metabolic properties.. Glycogen content and activity of muscle enzymes with regulatory functions in glycogen synthesis were examined.. Testosterone treatment increased glycogen content of extensor digitorum longus (EDL) and soleus muscles of hyperglycaemic sedentary (18% and 84% respectively) and hyperglycaemic trained (7% and 16% respectively) rats. In both types of muscle of the hyperglycaemic testosterone treated exercised subgroup, less depletion of glycogen was found than in the untreated group (38% and 87% for EDL and soleus respectively).. The mechanisms by which training and/or hyperandrogenism alone or in combination elicits their specific effects are complex. Differences in sex, surgery, levels of hormones administered, and exercise model used may be the main reasons for the observed discrepancies. Conclusions from the results: (a) hyperandrogenism is not a primary cause of the development of insulin resistance; (b) glycogen content of slow and fast twitch muscle is increased by training through increased glycogen synthase activity. The most plausible explanation for differences between different muscle fibre types is the different levels of expression of androgen receptors in these fibres. Hyperandrogenicity therefore acts on energy metabolic variables of hyperglycaemic animals by different mechanisms in glycolytic and oxidative muscle fibres.

Topics: Animals; Chronic Disease; Female; Glycogen; Glycogen Phosphorylase; Glycogen Synthase; Hyperglycemia; Muscle, Skeletal; Physical Conditioning, Animal; Physical Endurance; Rats; Rats, Inbred BN; Testosterone

The present study was designed to investigate the antihyperglycemic effects of aqueous and ethanolic extracts from Gongronema latifolium leaves on glucose and glycogen metabolism in livers of non-diabetic and streptozotocin-induced diabetic rats. To investigate the effects of aqueous or ethanolic leaf extracts of G. latifolium, non-diabetic and STZ diabetic rats were treated twice daily (100 mg/Kg) for two weeks. Diabetic rats showed a significant decrease in the activities of hepatic hexokinase (HK), phosphofructokinase (PFK) and glucose-6-phosphate dehydrogenase (G6PDH) and an increase in glucokinase (GK) activity. The levels of hepatic glycogen and glucose were also increased in diabetic rats. However, there were no significant differences in the activities of glucose-6-phosphatase (G6Pase) in treated and untreated diabetic rats. The ethanolic extract significantly increased the activities of HK (p<0.01), PFK (p<0.001) and G6PDH (p<0.01) in diabetic rats, decreased the activity of GK (p<0.05) and the levels of hepatic glycogen (p<0.01) and both hepatic (p<0.001) and blood glucose (40%). The aqueous extract of G. latifolium was only able to significantly increase the activities of HK and decrease the activities of GK but did not produce any significant change in the hepatic glycogen and both hepatic and blood glucose content of diabetic rats. Our data show that the ethanolic extract from G. latifolium leaves has antihyperglycemic potency, which is thought to be mediated through the activation of HK, PFK, G6PDH and inhibition of GK in the liver. The ethanolic extract is under further investigation to determine the chemical structure of the active compound(s) and its/their mechanism of action.

Topics: Animals; Apocynaceae; Diabetes Mellitus, Experimental; Ethanol; Glucose; Glycogen; Hyperglycemia; Hypoglycemic Agents; Liver; Male; Phosphotransferases (Carboxyl Group Acceptor); Plant Extracts; Plant Leaves; Rats; Rats, Wistar; Streptozocin; Water

A considerable amount of clinical and experimental evidence now exists suggesting the involvement of free radical-mediated oxidative processes in the pathogenesis of diabetic complications. If the diabetic state is associated with a generalized increase in oxidative stress, it might well be reflected in the alterations in embryonic and fetal development during pregnancy. In the present study, incidence of the malformed fetuses, biochemical parameters and antioxidant system activity of streptozotocin (STZ)-induced diabetic pregnant rats was investigated and the results obtained were compared with those of the control group (non-diabetic). Virgin female Wistar rats were injected with 40 mg/kg streptozotocin (STZ) before mating. All the females were killed on Day 21 of pregnancy and the fetuses were analyzed. A maternal blood sample was collected by venous puncture and the maternal liver was removed for biochemical measurement. The diabetic dams presented hyperglycemia, hyperlipemia, hypertriglyceridemia, hypercholesterolemia, hyperuricemia, decreased reduced glutathione (GSH), hepatic glycogen and superoxide dismutase (SOD) determinations. There was an increased incidence of skeletal and visceral malformation in fetuses from diabetic rats. Our findings suggest that oxidative stress occurs in the diabetic pregnant state, which might promote maternal homeostasis alterations. These diabetic complications might be a contributory factor to conceptus damage causing embryonic death (abortion/miscarriage) or the appearance of malformations in the fetuses of diabetic dams. Antioxidant treatment of women with diabetes may be important in future attempts to prevent congenital malformations.

Topics: Animals; Antioxidants; Congenital Abnormalities; Diabetes Mellitus, Experimental; Female; Gestational Age; Glutathione; Glycogen; Hypercholesterolemia; Hyperglycemia; Hyperlipidemias; Hypertriglyceridemia; Liver; Male; Oxidative Stress; Pregnancy; Pregnancy in Diabetics; Rats; Rats, Wistar; Superoxide Dismutase; Uric Acid

The Indian traditional system of medicine prescribed traditional plant therapies. Two such plants, i.e. Momordica charantia (MC) and Mucuna pruriens (MP), earlier shown to reduce hyperglycaemia, were assessed for their anti hyperglycaemic effect on varying degrees of hyperglycaemia and diabetic complications. Alcohol and aqueous extracts of MC (50, 100 and 200 mg/kg/day) and only an alcohol extract of MP (100, 200 and 400 mg/kg/day) were evaluated in a pilot study (plasma glucose >180 mg/dL, 21 days), a chronic study in alloxanized rats (plasma glucose >280mg/dL, 120 days) and streptozotocin (STZ) mice (plasma glucose >400 mg/dL, 60 days). In the pilot study, the maximum antihyperglycaemic effect occurred with an aqueous extract of MC at week 3 and an alcohol extract of MP at week 6 at a dose of 200 mg/kg/day. In chronic alloxanized rats, the selected dose of MC led to a significant fall of 64.33%, 66.96%, 69.7% and 70.53% in plasma glucose levels at 1, 2, 3 and 4 months, respectively. MP showed a decrease of 40.71%, 45.63%, 50.33% and 51.01% at the same time period. In chronic STZ diabetic mice, MC led to a mean reduction of 15.37%, 18.68% and 22.86% in plasma glucose levels on days 40, 50 and 60 of sampling while MP had no significant effect. The alteration in hepatic and skeletal muscle glycogen content and hepatic glucokinase, hexokinase, glucose-6-phosphate and phosphofructokinase levels in diabetic mice were partially restored by MC but not by MP. The mechanism of action of MC and MP is discussed.

Topics: Animals; Blood Glucose; Brain; Carbohydrate Metabolism; Carbohydrates; Diabetes Mellitus, Experimental; Female; Glucokinase; Glucose-6-Phosphate; Glycogen; Heart; Hexokinase; Hyperglycemia; India; Kidney; Liver; Male; Mice; Momordica charantia; Mucuna; Muscles; Phosphofructokinases; Phytotherapy; Plant Extracts; Rats; Toxicity Tests, Acute

Fetal macrosomia may occur even in adequately controlled diabetic mothers. This may reflect the problem of using maternal glycemia as an indicator of fetal glycemia, because the placenta interposed between both compartments has its own glucose metabolism. Here, we propose a model by which the placenta protects the fetus at moderate levels of maternal hyperglycemia. One characteristic feature of the human placenta in diabetes is the increased deposition of glycogen. Neither hyperglycemia nor hyperinsulinemia increase the glycogen content in the trophoblast. Since the glycogen increments in diabetes are predominantly located around fetoplacental vessels, it is tempting to assume a fetal origin of glucose making up the glycogen deposits. In fact, glucose can be transported back from the fetus into the placenta and this reflux is increased in diabetes. Therefore, in conditions of fetal glucose levels exceeding the demand for sustaining fetal growth and metabolism, glucose can be stored in the liver and other fetal tissues. Once these stores are saturated, glucose is extracted from the fetal circulation by the glucose transporters GLUT1 and GLUT3 on cells surrounding the fetoplacental vasculature and stored therein, again in the form of glycogen. These processes might be under the control of fetal insulin, because insulin injected into the fetal circulation increases placental glycogen stores. Fetal macrosomia would then occur only when fetal hyperglycemia exceeds the placental capacity to store excess fetal glucose. Thus, the placental failure to protect the fetus would cause the 'unexplained' phenotypic changes occasionally found in fetuses born to well-controlled diabetic women.

Topics: Female; Fetal Macrosomia; Glucose; Glucose Transporter Type 1; Glucose Transporter Type 3; Glycogen; Humans; Hyperglycemia; Models, Biological; Monosaccharide Transport Proteins; Nerve Tissue Proteins; Placenta; Placenta Diseases; Pregnancy; Pregnancy in Diabetics

Tungstate was orally administered to 7.5-week-old male Zucker diabetic fatty (ZDF) rats that already showed moderate hyperglycemia (180 +/- 16 mg/dl). The animals became normoglycemic for approximately 10 days. Then, glycemia started to rise again, although it did not reach the initial values until day 24, when levels stabilized at approximately 200 mg/dl for the duration of the experiment. Untreated ZDF rats showed steadily increased blood glucose levels between 7.5 and 10 weeks of age, when they reached a maximum value of 450 +/- 19 mg/dl, which was maintained throughout the experiment. In addition, tolerance to intraperitoneal glucose load improved in treated diabetic rats. Serum levels of triglycerides were elevated in untreated diabetic rats compared with their lean counterparts (ZLC). In the liver of diabetic animals, glucokinase (GK), glycogen phosphorylase a (GPa), liver-pyruvate kinase (L-PK), and fatty acid synthase (FAS) activities decreased by 81, 30, 54, and 35%, respectively, whereas phosphoenolpyruvate carboxykinase (PEPCK) levels increased by 240%. Intracellular glucose-6-phosphate (G6P) decreased by 40%, whereas glycogen levels remained unaffected. Tungstate treatment of these rats induced a 42% decrease in serum levels of triglycerides and normalized hepatic G6P concentrations, GPa activity, and PEPCK levels. GK activity in treated diabetic rats increased to 50% of the values of untreated ZLC rats. L-PK and FAS activity increased to higher values than those in untreated lean rats (1.7-fold L-PK and 2.4-fold FAS). Hepatic glycogen levels were 55% higher than those in untreated diabetic and healthy rats. Tungstate treatment did not significantly change the phosphotyrosine protein profile of primary cultured hepatocytes from diabetic animals. These data suggest that tungstate administration to ZDF rats causes a considerable reduction of glycemia, mainly through a partial restoration of hepatic glucose metabolism and a decrease in lipotoxicity.

Topics: Administration, Oral; Animals; Diabetes Mellitus; Glucose-6-Phosphate; Glycogen; Hyperglycemia; Hypoglycemic Agents; Islets of Langerhans; Liver; Male; Obesity; Phosphorylation; Rats; Rats, Zucker; Tungsten Compounds; Tyrosine

In situations of sustained hyperglycemia, much larger amounts of glycogen accumulate in islet B-cells than in other pancreatic cells. The labelling of such a glycogen pool could thus conceivably provide a mean for assessing the relative contribution of insulin-producing cells to the total pancreatic mass. In such a perspective, the present study aims at investigating pancreatic glycogen accumulation in hereditarily diabetic Goto-Kakizaki (GK) rats. When cultured at 30 mM D-glucose in the presence of D-[U-14C]glucose, pancreatic islets from GK rats accumulated 14C-labelled glycogen in a manner comparable to that previously documented in islets from normal rats. Likewise, the glycogen content of the pancreatic gland, relative to the plasma D-glucose concentration, was not different in GK and normal rats. The GK rats thus apparently represent a suitable model for further studies on the in vivo labelling of B-cell glycogen in the perspective of the non-invasive imaging and quantification of the endocrine pancreas.

Topics: Animals; Carbon Radioisotopes; Cell Culture Techniques; Diabetes Mellitus, Type 2; Female; Glucose; Glycogen; Hyperglycemia; Islets of Langerhans; Liver; Male; Models, Animal; Organ Size; Pancreas; Rats

The responses of the pancreatic alpha- and beta-cells to small changes in glucose were examined in overnight-fasted conscious dogs. Each study consisted of an equilibration (-140 to -40 min), a control (-40 to 0 min), and a test period (0 to 180 min), during which BAY R3401 (10 mg/kg), a glycogen phosphorylase inhibitor, was administered orally, either alone to create mild hypoglycemia or with peripheral glucose infusion to maintain euglycemia or create mild hyperglycemia. Drug administration in the hypoglycemic group decreased net hepatic glucose output (NHGO) from 8.9 +/- 1.7 (basal) to 6.0 +/- 1.7 and 5.8 +/- 1.0 pmol x kg(-1) x min(-1) by 30 and 90 min. As a result, the arterial plasma glucose level decreased from 5.8 +/- 0.2 (basal) to 5.2 +/- 0.3 and 4.4 +/- 0.3 mmol/l by 30 and 90 min, respectively (P < 0.01). Arterial plasma insulin levels and the hepatic portal-arterial difference in plasma insulin decreased (P < 0.01) from 78 +/- 18 and 90 +/- 24 to 24 +/- 6 and 12 +/- 12 pmol/l over the first 30 min of the test period and decreased to 18 +/- 6 and 0 pmol/l by 90 min, respectively. The arterial glucagon levels and the hepatic portal-arterial difference in plasma glucagon increased from 43 +/- 5 and 4 +/- 2 to 51 +/- 5 and 10 +/- 5 ng/l by 30 min (P < 0.05) and to 79 +/- 16 and 31 +/- 15 ng/l by 90 min (P < 0.05), respectively. In euglycemic dogs, the arterial plasma glucose level remained at 5.9 +/- 0.1 mmol/l, and the NHGO decreased from 10 +/- 0.6 to -3.3 +/- 0.6 pmol x kg(-1) x min(-1) (180 min). The insulin and glucagon levels and the hepatic portal-arterial differences remained constant. In hyperglycemic dogs, the arterial plasma glucose level increased from 5.9 +/- 0.2 to 6.2 +/- 0.2 mmol/l by 30 min, and the NHGO decreased from 10 +/- 1.7 to 0 pmol x kg(-1) x min(-1) by 30 min. The arterial plasma insulin levels and the hepatic portal-arterial difference in plasma insulin increased from 60 +/- 18 and 78 +/- 24 to 126 +/- 30 and 192 +/- 42 pmol/l by 30 min, after which they averaged 138 +/- 24 and 282 +/- 30 pmol/l, respectively. The arterial plasma glucagon levels and the hepatic portal-arterial difference in plasma glucagon decreased slightly from 41 +/- 7 and 4 +/- 3 to 34 +/- 7 and 3 +/- 2 ng/l during the test period. These data show that the alpha- and beta-cells of the pancreas respond as a coupled unit to very small decreases in the plasma glucose level.

Topics: Alanine; Animals; Arteries; Blood Glucose; Dogs; Female; Gluconeogenesis; Glucose; Glycerol; Glycogen; Hormones; Hyperglycemia; Hypoglycemia; Islets of Langerhans; Ketones; Lactic Acid; Liver; Liver Circulation; Male; Reference Values

As judged from morphological criteria, glycogen accumulates to a larger extent in insulin-producing B-cells than in acinar cells of the pancreas in situations of sustained hyperglycemia. In the present study, the glycogen content of the pancreatic gland and liver was measured in either euglycemic or glucose-infused hyperglycemic control rats, as well as in streptozotocin-induced diabetic rats. Whilst the glycogen content of the pancreas was significantly higher in STZ rats than in control euglycemic rats, it was further enhanced in glucose-infused control rats, despite the fact that the latter animals were not more severely hyperglycemic and for a shorter time than STZ rats. From these measurements, it was estimated that, relative to wet weight, the glycogen content was, under the present experimental conditions, about 75 times higher in insulin-producing than other pancreatic cells. Moreover, it is proposed that the intravenous administration of glucagon may help in distinguishing between the glycogen present in the endocrine and exocrine moieties of the pancreatic gland, this hormone being apparently unable to provoke glycogenolysis in the exocrine pancreas, at variance with the situation prevailing in isolated pancreatic islets.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Glycogen; Hyperglycemia; Injections, Intravenous; Insulin; Insulin Secretion; Islets of Langerhans; Liver Glycogen; Organ Size; Pancreas; Rats; Rats, Wistar; Time Factors

Under conditions of sustained hyperglycemia, glycogen accumulates in pancreatic islets, but not so in acinar pancreatic cells. We investigated whether advantage could be taken of such a situation in the perspective of the noninvasive imaging of the endocrine pancreas. Control rats or animals injected with streptozotocin (STZ) were infused with solutions of D-glucose mixed with a tracer amount of D-[U-14C]glucose, and the radioactive glycogen content of both liver and pancreas was then measured. After 48 h of infusion, the radioactive glycogen content of the pancreas was 30 times lower in STZ rats than in control animals, coinciding with a 50 times lower insulin content. In the control rats, a sizable labeling of pancreatic glycogen was also recorded when D-[U-14C]glucose was infused for only the last 4 h of unlabeled D-glucose infusion; such a labeling was not decreased when the animals were further infused for 1 h with only the unlabeled hexose. Moreover, a pronounced difference in the pancreatic gland and blood radioactive content of control rats was still observed when the hyperglycemic animals were killed only 40 min after the i.v. injection of D-[U-14C]glucose. In STZ rats transplanted with islets and later infused with D-[U-14C]glucose, the total radioactive content and radioactive glycogen content were both much higher in the transplanted islets than in the pancreatic gland. These results allow one to define the conditions under which the administration of either 2-deoxy-2-[18F]fluoro-D-glucose or 11C-labeled D-glucose could conceivably be used to favor the selective labeling of the endocrine, as distinct from exocrine, pancreas.

Topics: Animals; Diabetes Mellitus, Experimental; Female; Glucose; Glycogen; Hyperglycemia; Insulin; Islets of Langerhans Transplantation; Liver; Liver Glycogen; Organ Size; Pancreas; Parotid Gland; Rats; Rats, Wistar

High-fat and high-sucrose diets increase the contribution of gluconeogenesis to glucose appearance (glc R(a)) under basal conditions. They also reduce insulin suppression of glc R(a) and insulin-stimulated muscle glycogen synthesis under euglycemic, hyperinsulinemic conditions. The purpose of the present study was to determine whether these impairments influence liver and muscle glycogen synthesis under hyperglycemic, hyperinsulinemic conditions. Male rats were fed a high-sucrose, high-fat, or low-fat, starch control diet for either 1 (n = 5-7/group) or 5 wk (n = 5-6/group). Studies involved two 90-min periods. During the first, a basal period (BP), [6-3H]glucose was infused. In the second, a hyperglycemic period (HP), [6-3H]glucose, [6-14C]glucose, and unlabeled glucose were infused. Plasma glucose (BP: 111.2 +/- 1.5 mg/dl; HP: 172.3 +/- 1.5 mg/dl), insulin (BP: 2.5 +/- 0.2 ng/ml; HP: 4.9 +/- 0.3 ng/ml), and glucagon (BP: 81.8 +/- 1.6 ng/l; HP: 74.0 +/- 1.3 ng/l) concentrations were not significantly different among diet groups or with respect to time on diet. There were no significant differences among groups in the glucose infusion rate (mg x kg(-1) x min(-1)) necessary to maintain arterial glucose concentrations at approximately 170 mg/dl (pooled average: 6.4 +/- 0.8 at 1 wk; 6.4 +/- 0.7 at 5 wk), percent suppression of glc R(a) (44.4 +/- 7.8% at 1 wk; 63.2 +/- 4.3% at 5 wk), tracer-estimated net liver glycogen synthesis (7.8 +/- 1.3 microg x g liver(-1) x min(-1) at 1 wk; 10.5 +/- 2.2 microg x g liver(-1) x min(-1) at 5 wk), indirect pathway glycogen synthesis (3.7 +/- 0.9 microg x g liver(-1) x min(-1) at 1 wk; 3.4 +/- 0.9 microg x g liver(-1) x min(-1) at 5 wk), or tracer-estimated net muscle glycogenesis (1.0 +/- 0.3 microg x g muscle(-1) x min(-1) at 1 wk; 1.6 +/- 0.3 microg x g muscle(-1) x min(-1) at 5 wk). These data suggest that hyperglycemia compensates for diet-induced insulin resistance in both liver and skeletal muscle.

Topics: Analysis of Variance; Animals; Body Weight; Diet; Dietary Fats; Dietary Sucrose; Glucagon; Glucose; Glucose Clamp Technique; Glycogen; Hyperglycemia; Insulin; Insulin Resistance; Liver; Male; Muscle, Skeletal; Rats; Rats, Sprague-Dawley; Starch

The rate of hepatic glucose production (R(a) glucose) of rainbow trout (Oncorhynchus mykiss) was measured in vivo by continuous infusion of [6-(3)H]glucose and in vitro on isolated hepatocytes to examine the role of epinephrine (Epi) in its regulation. By elevating Epi concentration and/or blocking beta-adrenoreceptors with propranolol (Prop), our goals were to investigate the mechanism for Epi-induced hyperglycemia to determine the possible role played by basal Epi concentration in maintaining resting R(a) glucose and to assess indirect effects of Epi in the intact animal. In vivo infusion of Epi caused hyperglycemia (3.75 +/- 0.16 to 8.75 +/- 0.54 mM) and a twofold increase in R(a) glucose (6.57 +/- 0.79 to 13.30 +/- 1.78 micromol. kg(-1). min(-1), n = 7), whereas Prop infusion decreased R(a) from 7.65 +/- 0.92 to 4.10 +/- 0.56 micromol. kg(-1). min(-1) (n = 10). Isolated hepatocytes increased glucose production when treated with Epi, and this response was abolished in the presence of Prop. We conclude that Epi-induced trout hyperglycemia is entirely caused by an increase in R(a) glucose, because the decrease in the rate of glucose disappearance normally seen in mammals does not occur in trout. Basal circulating levels of Epi are involved in maintaining resting R(a) glucose. Epi stimulates in vitro glucose production in a dose-dependent manner, and its effects are mainly mediated by beta-adrenoreceptors. Isolated trout hepatocytes produce glucose at one-half the basal rate measured in vivo, even when diet, temperature, and body size are standardized, and basal circulating Epi is responsible for part of this discrepancy. The relative increase in R(a) glucose after Epi stimulation is similar in vivo and in vitro, suggesting that indirect in vivo effects of Epi, such as changes in hepatic blood flow or in other circulating hormones, do not play an important role in the regulation of glucose production in trout.

Topics: Adrenergic Agonists; Adrenergic beta-Antagonists; Animals; Cell Fractionation; Cells, Cultured; Dose-Response Relationship, Drug; Epinephrine; Female; Glucose; Glycogen; Glycolysis; Hyperglycemia; Kinetics; Liver; Male; Oncorhynchus mykiss; Propranolol; Sodium Chloride

Mantle tissue pieces from adult Otala lactea continuously synthesized glycogen over a 72-h incubation period. Acid-saline extract of the cerebral ganglia inhibited glycogen synthesis by mantle tissue in vitro. This effect was dose-dependent. The glycogen reduction factor from the cerebral ganglia was heat stable, protease sensitive, and relatively hydrophobic. The cerebral ganglia extract also stimulated mantle glycogen phosphorylase in vitro in a dose-dependent manner. The results suggest the presence of a hyperglycemic factor in the cerebral ganglia of Otala. The molecular weight of this factor, estimated by size-exclusion chromatography, was approximately 10,000. Mammalian glucagon had no significant effect on glycogen synthesis by the mantle pieces.

Topics: Animals; Cell Extracts; Culture Techniques; Dose-Response Relationship, Drug; Enzyme Activation; Ganglia, Invertebrate; Glucagon; Glucose; Glycogen; Hyperglycemia; Phosphorylases; Snails

In our previous study, we found that myricetin, a naturally occurring bioflavonoid, was able to stimulate glucose transport in rat adipocytes and enhance insulin-stimulated lipogenesis. We report here that after 2 days of treatment with myricetin (3 mg/12 h), hyperglycemia in diabetic rats was reduced by 50% and the hypertriglyceridemia that is often associated with diabetes was normalised. Treatment with myricetin increased hepatic glycogen and glucose-6-phosphate content. It increased hepatic glycogen synthase I activity without having any effect on total glycogen synthase nor phosphorylase a activity. It lowered phosphorylase a activity in the muscle. Thus, the hypoglycemic effect of myricetin is likely to be due to its effect on glycogen metabolism. There was no indication of serious hepatotoxicity with myricetin treatment and therefore, myricetin could be of therapeutic potential in diabetes.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Eating; Flavonoids; Glucose-6-Phosphate; Glycogen; Glycogen Synthase; Hindlimb; Hyperglycemia; Hypertriglyceridemia; Hypoglycemic Agents; Liver; Liver Glycogen; Male; Muscle, Skeletal; Phosphorylase a; Rats; Rats, Wistar

Sustained hyperglycemia allows the preferential labelling of pancreatic glycogen by D-[U-14C]glucose in control rats, as compared to animals previously injected with streptozotocin (STZ rats). The major aim of the present study was to investigate whether a sizeable difference between control and STZ rats could also be observed in terms of the radioactive content of the pancreatic gland 8 h after the intravenous injection of 2-deoxy-2-[18F]fluoro-D-glucose, both types of animals being examined at the same level of hyperglycemia. Although the radioactive content of muscle, liver and kidney was lower in STZ rats than in control animals, such a difference failed to achieve statistical significance in brain, hypophysis, pancreas and parotid gland. It is proposed, therefore, that 11C-labelled D-glucose, rather than 2-deoxy-2-[18F]fluoro-D-glucose should be used in the perspective of the non-invasive imaging of the endocrine pancreas.

Topics: Animals; Diabetes Mellitus, Experimental; Female; Fluorine Radioisotopes; Fluorodeoxyglucose F18; Glycogen; Hyperglycemia; Pancrelipase; Rats; Rats, Wistar; Tissue Distribution

In the rat model of forebrain ischemia, long-term dexamethasone treatment is reported to cause hyperglycemia and worsen postischemic functional and histologic injury. This effect was assumed to result from glucose enhancement of intraischemic lactic acidosis within the brain. Short-term insulin therapy restored normoglycemia but did not return histologic injury completely to baseline values. Using a nonischemic rat model, the current study attempted to identify a metabolic basis for such outcome data.. Fifty-eight halothane-anesthetized (1.3% inspired) Sprague-Dawley rats were assigned randomly to be administered either no treatment (N = 18) or 2 mg/kg intraperitoneal dexamethasone (N = 40). The latter were administered dexamethasone 3 h before the study only (N = 8) or for 3 h before the study plus daily for 1 day (N = 8), 2 days (N = 8), or 4 days (N = 16). Of the rats treated with dexamethasone for 4 days, one half (N = 8) were administered an insulin-containing saline infusion subsequently to restore normoglycemia short-term. All other rats (N = 50) were administered an infusion of saline without insulin. Plasma glucose was quantified, and brains were excised after in situ freezing. Brain glucose and glycogen concentrations were measured using enzymatic fluorometric analyses.. After 4 days of dexamethasone treatment, plasma glucose was 159% greater than in rats administered placebo (i.e., 22.01 +/- 4.66 vs. 8.51 +/- 1.65 micromol/ml; mean +/- SD; P < 0.0001). Brain glucose concentrations increased parallel to plasma glucose. An insulin infusion for 27 +/- 5 min restored normoglycemia but resulted in a brain-to-plasma glucose ratio that was 32% greater than baseline values (P < 0.01). Neither dexamethasone nor the combination of dexamethasone plus insulin affected brain glycogen concentrations.. In a nonischemic rat model, dexamethasone alone had no independent effect on the brain-to-plasma glucose ratio. However, short-term insulin therapy caused a dysequilibrium between plasma and brain glucose, resulting in an underestimation of brain glucose concentrations when normoglycemia was restored. The dysequilibrium likely was caused by the rapid rate of glucose reduction. The magnitude of the effect may account for the failure of insulin to reverse dexamethasone enhancement of neurologic injury completely in a previous report that used the rat model of forebrain ischemia.

Topics: Animals; Blood Glucose; Brain; Dexamethasone; Glucocorticoids; Glucose; Glycogen; Hyperglycemia; Hypoglycemic Agents; Insulin; Male; Rats; Rats, Sprague-Dawley

Abnormalities in glucose metabolism and insulin action are frequently detected in patients with essential hypertension. Spontaneously hypertensive rats (SHR) have been used as an experimental model to understand this pathological condition. The objective of the present study was to assess glucose metabolism and insulin action in SHR and Wistar rats under fed and fasting conditions. Peripheral glucose utilization was estimated by kinetic studies with [6-(3)H]-glucose and gluconeogenetic activity was measured during continuous [(14)C]-bicarbonate infusion. Plasma glucose levels were higher in the SHR group. Plasma insulin levels in the fed state were higher in the SHR group (99.8 +/- 6.5 microM) than in the control group (70.4 +/- 3.6 microM). Muscle glycogen content was reduced in SHR compared to control under the various experimental conditions. Peripheral glucose utilization was slightly lower in the SHR group in the fed state (8.72 +/- 0.55 vs 9.52 +/- 0.80 mg kg(-1) min(-1) in controls). Serum free fatty acid levels, hepatic glycogen levels, hepatic phosphoenolpyruvate carboxykinase activity and gluconeogenetic activity were similar in the two groups. The presence of hyperglycemia and hyperinsulinemia and the slightly reduced peripheral glucose utilization suggest the presence of resistance to the action of insulin in peripheral tissues of SHR. Hepatic gluconeogenesis does not seem to contribute to the metabolic alterations detected in these animals.

Topics: Animals; Glucose; Glycogen; Hyperglycemia; Hypertension; Male; Phosphoenolpyruvate Carboxykinase (ATP); Rats; Rats, Inbred SHR; Rats, Wistar

Human insulin was glycated under hyperglycemic reducing conditions and a novel diglycated form (M(r) 6135.1 Da) was purified by RP-HPLC. Endoproteinase Glu-C digestion combined with mass spectrometry and automated Edman degradation localized glycation to Gly(1) and Phe(1) of the insulin A- and B-chains, respectively. Intraperitoneal (i.p.) administration of diglycated insulin to mice alone or in combination with glucose (7 nmol/kg) resulted in a 43-61% and 11-34% reduction in glucose lowering activity, respectively, compared with native insulin. Consistent with these findings, diglycated insulin (10(-9) to 10(-7) mol/liter) was 22-38% less effective (P < 0.001) than native insulin in stimulating glucose uptake, glucose oxidation and glycogen production in isolated mouse abdominal muscle.

Topics: Amino Acids; Animals; Biological Transport; Blood Glucose; Chromatography, High Pressure Liquid; Deoxyglucose; Glucose; Glycogen; Glycoproteins; Glycosylation; Humans; Hyperglycemia; Injections, Intraperitoneal; Insulin; Male; Mass Spectrometry; Mice; Mice, Inbred Strains; Muscle, Smooth; Serine Endopeptidases

We tested the hypothesis that a lack of suppression of glucagon causes postprandial hyperglycemia in subjects with type 2 diabetes. Nine diabetic subjects ingested 50 g glucose on two occasions. On both occasions, somatostatin was infused at a rate of 4.3 nmol/kg x min, and insulin was infused in a diabetic insulin profile. On one occasion, glucagon was also infused at a rate of 1.25 ng/kg x min to maintain portal glucagon concentrations constant (nonsuppressed study day). On the other occasion, glucagon infusion was delayed by 2 h to create a transient decrease in glucagon (suppressed study day). Glucagon concentrations on the suppressed study day fell to about 70 ng/L during the first 2 h, rising thereafter to approximately 120 ng/L. In contrast, glucagon concentrations on the nonsuppressed study day remained constant at about 120 ng/L throughout. The decrease in glucagon resulted in substantially lower (P < 0.001) glucose concentrations on the suppressed compared with the nonsuppressed study days (9.2+/-0.7 vs. 10.9+/-0.8 mmol/L) and a lower (P < 0.001) rate of release of [14C]glucose from glycogen (labeled by infusing [1-14C]galactose). On the other hand, flux through the hepatic UDP-glucose pool (and, by implication, glycogen synthesis), measured using the acetaminophen glucuronide method, did not differ on the two occasions. We conclude that lack of suppression of glucagon contributes to postprandial hyperglycemia in subjects with type 2 diabetes at least in part by accelerating glycogenolysis. These data suggest that agents that antagonize glucagon action or secretion are likely to be of value in the treatment of patients with type 2 diabetes.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Galactose; Glucagon; Glycogen; Human Growth Hormone; Humans; Hyperglycemia; Infusions, Intravenous; Insulin; Insulin Secretion; Male; Middle Aged; Postprandial Period

Vacuolization of the renal tubular epithelial cells (the Armanni-Ebstein lesion) associated with diabetic hyperglycemia is usually regarded as an accumulation of glycogen. In a case of death of diabetic coma, the vacuoles were stained strongly for lipids. This observation may have both clinical and therapeutic consequences, and may increase our knowledge of the metabolism in diabetes.

Topics: Diabetic Coma; Fatal Outcome; Female; Glycogen; Humans; Hyperglycemia; Kidney Tubules, Proximal; Lipids; Middle Aged

Cortical metabolites and regional cerebral intracellular pH (pHi) were measured in normoglycemic (NM), acute hyperglycemic (AH), and chronic hyperglycemic (CH, 2 week duration, streptozotocin-induced) Wistar rat brains during cardiac arrest and resuscitation. During total ischemia in AH and CH rats (plasma glucose approximately 30 mM), cortical ATP, PCr, glucose, and glycogen all fell significantly as expected. Lactate levels increased dramatically in association with a concomitant intracellular acidosis. Although lactate reached higher concentrations in AH and CH than NM, pHi was significantly lower only in the AH group. With 5 min of reperfusion, all groups recovered to near baseline in all variables, though lactate remained elevated. In a separate aspect of the study, animals from each experimental group were allowed to recover for 4 days following resuscitation, with outcome being gauged by mortality rate and hippocampal CA1 neuron counts. NM survival rate was significantly better than AH and CH. In particular, no CH rats survived for 4 days despite rapid initial recovery. After 4 days, the AH group had suffered significantly greater CA1 neuron loss than the NM rats. In summary, our research identified differences in intra-ischemic acid-base status in the two hyperglycemic groups, suggesting that chronic hyperglycemia may alter the brain's buffering capacity. These observations may account for differences between acutely and chronically hyperglycemic subjects regarding outcome, and they suggest that factors other than hydrogen ion production during ischemia are responsible for modulating outcome.

Topics: Acidosis, Lactic; Acute Disease; Adenosine Triphosphate; Animals; beta-Galactosidase; Blood Glucose; Cardiopulmonary Resuscitation; Cell Survival; Cerebral Cortex; Chronic Disease; Diabetes Mellitus, Experimental; Energy Metabolism; Glycogen; Heart Arrest; Hippocampus; Hydrogen-Ion Concentration; Hyperglycemia; Image Processing, Computer-Assisted; Ischemic Attack, Transient; Lactase; Male; Neurons; Rats; Rats, Wistar

Sustained hyperglycemia impairs insulin-stimulated glucose utilization in the skeletal muscle of both humans and experimental animals--a phenomenon referred to clinically as glucose toxicity. To study how this occurs, a model was developed in which hyperglycemia produces insulin resistance in vitro. Rat extensor digitorum longus muscles were preincubated for 4 h in Krebs-Henseleit solution containing glucose or glucose + insulin at various concentrations, after which insulin action was studied. Preincubation with 25 mmol/l glucose + insulin (10 mU/ml) led to a 70% decrease in the ability of insulin (10 mU/ml) to stimulate glucose incorporation into glycogen and a 30% decrease in 2-deoxyglucose (2-DG) uptake, compared with muscles incubated with 0 mmol/l glucose. Glucose incorporation into lipid and its oxidation to CO2 were marginally diminished, if at all. The alterations of glycogen synthesis and 2-DG uptake were first evident after 1 h and were maximal after 2 h of preincubation; they were not observed in muscles preincubated with 25 mmol/l glucose + insulin for 5 min. Preincubation for 4 h with 25 mmol/l glucose in the absence of insulin produced a similar although somewhat smaller decrease in insulin-stimulated glycogen synthesis; however, it did not alter 2-DG uptake, glucose oxidation to CO2, or incorporation into lipids. Studies of insulin signaling in the latter muscles revealed that activation of Akt/protein kinase B (PKB) was diminished by 60%, compared with that of muscles preincubated in a glucose-free medium; whereas activation of phosphatidylinositol (PI) 3-kinase, an upstream regulator of Akt/PKB in the insulin-signaling cascade, and of mitogen-activated protein (MAP) kinase, a parallel signal, was unaffected. Immunoblots demonstrated that this was not due to a change in Akt/PKB abundance. The results indicate that hyperglycemia-induced insulin resistance can be studied in rat skeletal muscle in vitro. They suggest that impairment of insulin action in these muscles is related to inhibition of Akt/PKB by events that do not affect PI 3-kinase.

Topics: Animals; Calcium-Calmodulin-Dependent Protein Kinases; Deoxyglucose; Enzyme Activation; Glucose; Glycogen; Hyperglycemia; In Vitro Techniques; Insulin; Kinetics; Male; Mitogen-Activated Protein Kinase 1; Muscle, Skeletal; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley

Insulin resistance, a major factor in the pathogenesis of type 2 diabetes mellitus, is due mostly to decreased stimulation of glycogen synthesis in muscle by insulin. The primary rate-controlling step responsible for the decrease in muscle glycogen synthesis is not known, although hexokinase activity and glucose transport have been implicated.. We used a novel nuclear magnetic resonance approach with carbon-13 and phosphorus-31 to measure intramuscular glucose, glucose-6-phosphate, and glycogen concentrations under hyperglycemic conditions (plasma glucose concentration, approximately 180 mg per deciliter [10 mmol per liter]) and hyperinsulinemic conditions in six patients with type 2 diabetes and seven normal subjects. In vivo microdialysis of muscle tissue was used to determine the gradient between plasma and interstitial-fluid glucose concentrations, and open-flow microperfusion was used to determine the concentrations of insulin in interstitial fluid.. The time course and concentration of insulin in interstitial fluid were similar in the patients with diabetes and the normal subjects. The rates of whole-body glucose metabolism and muscle glycogen synthesis and the glucose-6-phosphate concentrations in muscle were approximately 80 percent lower in the patients with diabetes than in the normal subjects under conditions of matched plasma insulin concentrations. The mean (+/-SD) intracellular glucose concentration was 2.0+/-8.2 mg per deciliter (0.11+/-0.46 mmol per liter) in the normal subjects. In the patients with diabetes, the intracellular glucose concentration was 4.3+/-4.9 mg per deciliter (0.24+/-0.27 mmol per liter), a value that was 1/25 of what it would be if hexokinase were the rate-controlling enzyme in glucose metabolism.. Impaired insulin-stimulated glucose transport is responsible for the reduced rate of insulin-stimulated muscle glycogen synthesis in patients with type 2 diabetes mellitus.

Topics: Adult; Aged; Biological Transport; Blood Glucose; Diabetes Mellitus, Type 2; Extracellular Space; Female; Glucose; Glucose-6-Phosphate; Glycogen; Hexokinase; Humans; Hyperglycemia; Hyperinsulinism; Insulin; Magnetic Resonance Spectroscopy; Male; Middle Aged; Models, Biological; Muscle, Skeletal

Using a specific 13C NMR localization method, 13C label incorporation into the glycogen C1 resonance was measured while infusing [1-(13)C]glucose in intact rats. The maximal concentration of [1-(13)C]glycogen was 5.1 +/- 0.6 micromol g(-1) (mean +/- SE, n = 8). During the first 60 min of acute hyperglycemia, the rate of 13C label incorporation (synthase flux) was 2.3 +/- 0.7 micromol g(-1) h(-1) (mean +/- SE, n = 9 rats), which was higher (p < 0.01) than the rate of 0.49 +/- 0.14 micromol g(-1) h(-1) measured > or = 2 h later. To assess whether the incorporation of 13C label was due to turnover or net synthesis, the infusion was continued in seven rats with unlabeled glucose. The rate of 13C label decline (phosphorylase flux) was lower (0.33 +/- 0.10 micromol g(-1) h(-1)) than the initial rate of label incorporation (p < 0.01) and appeared to be independent of the duration of the preceding infusion of [1-(13)C]glucose (p > 0.05 for correlation). The results implied that net glycogen synthesis of approximately 3 micromol g(-1) had occurred, similar to previous reports. When infusing unlabeled glucose before [1-(13)C]glucose in three studies, the rate of glycogen C1 accumulation was 0.46 +/- 0.08 micromol g(-1) h(-1). The results suggest that steady-state glycogen turnover rates during hyperglycemia are approximately 1% of glucose consumption.

Topics: Animals; Brain; Carbon Isotopes; Glucose; Glycogen; Glycogen Synthase; Hyperglycemia; Magnetic Resonance Spectroscopy; Male; Rats; Rats, Sprague-Dawley; Reproducibility of Results

We investigated the effect of nutrient intake on glucose metabolism in normal Mexican-Americans (n = 6) and European-Americans (n = 6). Subjects were studied after an 18-h fast and after 5-6 h of ingestion of hourly meals that supplied 6.35 or 12.75 micromol glucose. kg(-1). min(-1). Endogenous glucose production (EGP), gluconeogenesis (GNG), and glycogenolysis (GLY) were estimated by mass isotopomer analysis with [U-(13)C]glucose infusions. Fasting EGP, GNG, and GLY did not differ between the groups. Food ingestion lowered the molar rate of GNG by only 31%. However, while consuming the lower quantity of nutrients, Mexican-Americans had higher plasma glucose (P < 0.05), a 39% higher rate of EGP (P < 0.05), and a 68% (P < 0.025) higher rate of GLY than the European-Americans. At the higher intake, EGP and GLY were suppressed completely in both groups. There was a linear relationship between insulin concentrations, EGP, and GLY in both groups, but the slope of the line was significantly (P < 0.05) greater in the European-Americans. We conclude that the sensitivity of GLY to nutrient intake differs between ethnic groups and that this may play a role in the increased predisposition of Mexican-Americans to type II diabetes.

Topics: Adult; Asian People; Blood Glucose; Carbon Isotopes; Diabetes Mellitus, Type 2; Energy Metabolism; Genetic Predisposition to Disease; Gluconeogenesis; Glucose; Glucose Tolerance Test; Glycogen; Humans; Hyperglycemia; Insulin; Kinetics; Lactic Acid; Male; Mexican Americans; Middle Aged; Postprandial Period; White People

The effects of amylin on fiber type-specific muscle glucose metabolism under hyperglycemic (10 mmol/l) and hyperinsulinemic (2.1 nmol/l) conditions were investigated using a rat hindlimb perfusion system. Amylin concentration ranged from 1 to 100 nM. Efficacy for inhibition of glucose uptake traced with 2-deoxyglucose by amylin was demonstrated in all three fiber types. The incorporation of 2-deoxy-[3H]glucose tracer decreased from control values by 41% in fast oxidative (FO), 36% in fast glycolytic (FG), and 37% in slow oxidative (SO) muscle with 100 nM amylin. Amylin increased intracellular glucose 6-phosphate (G-6-P), and G-6-P was negatively correlated with 2-deoxyglucose uptake in both FO (r = -0.65; P < 0.01) and FG (r = -0.53; P < 0.01) muscle. Muscle glycogen concentration increased under control conditions and decreased in the presence of 100 nM amylin. Lactate arteriovenous efflux across the hindlimb increased significantly above control with 100 nM amylin (5.03 +/- 0.81 to 11.28 +/- 0.94 mumol.g-1.h-1). Adenosine 3',5'-cyclic monophosphate (cAMP) increased in FO and FG muscle with amylin. Salmon calcitonin-(8-32), an amylin antagonist, ameliorated the effect of amylin on all responses other than 2-deoxyglucose uptake and G-6-P concentration. These results suggest that amylin may work through at least two independent mechanisms, a cAMP-mediated effect on glycogen metabolism and a non-cAMP-mediated inhibition of glycolysis.

Topics: Amyloid; Animals; Blood Glucose; Cyclic AMP; Deoxyglucose; Glucose; Glycogen; Hindlimb; Hyperglycemia; Insulin; Islet Amyloid Polypeptide; Lactates; Male; Muscle Fibers, Fast-Twitch; Muscle Fibers, Slow-Twitch; Muscle, Skeletal; Perfusion; Rats; Rats, Sprague-Dawley

Euglycemia was maintained in 13 subjects with low muscle glycogen [low glycogen, euglycemic (LGE), n = 8; low glycogen, euglycemic, hyperinsulinemic (LGEI), n = 5] and 6 subjects with normal muscle glycogen (NGE), whereas hyperglycemia was maintained in 8 low muscle glycogen subjects (LGH). All subjects cycled for 145 min at 70% of maximal oxygen uptake during the infusions. Insulin was infused in LGEI at 0.2 mU.kg-1.min-1. During exercise, respiratory exchange ratio (RER) was lower and norepinephrine higher in LGE than in NGE. In LGEI and LGH, RER at the start of exercise was the same as in LGE but did not decrease as in LGE. Free fatty acids (FFA) were higher and plasma insulin concentrations lower in LGE than NGE, LGEI, or LGH over the first 45 min of exercise. Rate of glucose infusion (Ri) and rate of glucose oxidation (Rox) were higher in LGH and LGEI than in NGE or LGE, and Ri matched Rox in all groups except LGH, in which Ri was greater than Rox. Muscle glycogen disappearance was greater in NGE than LGE, LGEI, or LGH, but the latter three groups did not differ. In conclusion, this study showed that low muscle glycogen content results in a decrease in RER, an increase in FFA, fat oxidation, and norepinephrine both at rest and during exercise, and does not affect Rox when euglycemia is maintained by infusion of glucose alone. Rox was increased only during insulin and hyperglycemia.

Topics: Adult; Bicycling; Blood Glucose; Dietary Carbohydrates; Dietary Fats; Energy Intake; Energy Metabolism; Exercise Test; Glucagon; Glucose Clamp Technique; Glycogen; Humans; Hyperglycemia; Infusions, Intravenous; Insulin; Lactates; Male; Muscle Fatigue; Muscle, Skeletal; Oxygen Consumption; Physical Endurance

Trained cyclists with low muscle glycogen (LGH; n = 8) or normal glycogen (NGH; n = 5) exercised for 145 min at 70% of maximal oxygen uptake during a hyperglycemic clamp. Respiratory exchange ratio was higher in NGH than LGH, and free fatty acid concentrations were lower in NGH than LGH. Areas under the curve for insulin and lactate were lower in LGH than NGH. Total glucose infusion and total glucose oxidation were not different between NGH and LGH, and total glucose oxidation amounted to 65 and 66% of total glucose infusion in NGH and LGH, respectively. Rates of glucose oxidation rose during exercise, reaching peaks of 9.2 +/- 1.7 and 8.3 +/- 1.1 mmol/min in NGH and LGH, respectively. Muscle glycogen disappearance was greater in NGH than LGH. Thus 1) low muscle glycogen content does not cause increased glucose oxidation, even during hyperglycemia; instead there is an increase in fat oxidation, 2) there is an upper limit to the rate of glucose oxidation during exercise with hyperglycemia irrespective of muscle glycogen status, and 3) net muscle glycogen utilization is determined by muscle glycogen content at the start of exercise, even during hyperglycemia.

Topics: Adult; Analysis of Variance; Bicycling; Blood Glucose; Fatty Acids, Nonesterified; Glucagon; Glucose Clamp Technique; Glycogen; Humans; Hyperglycemia; Kinetics; Lactates; Male; Muscle Fatigue; Muscle, Skeletal; Oxygen Consumption; Physical Endurance; Physical Exertion

Intracellular glucose concentration in skeletal muscle of awake rats was determined under conditions of hyperglycemic (10.2 +/- 0.6 mM) hyperinsulinemia (approximately 1,200 pM) and hyperglycemic (20.8 +/- 1.5 mM) hypoinsulinemia (< 12 pM) by use of 13C nuclear magnetic resonance (NMR) spectroscopy during a prime-constant infusion of [1-13C]glucose and [1-13C]mannitol with either insulin (10 mU.kg-1.min-1) or somatostatin (1.0 microgram.kg-1.min-1). Intracellular glucose was calculated as the difference between the concentrations of total tissue glucose (calculated from the in vivo 13C NMR spectrum with mannitol as an internal concentration standard) and extracellular glucose, corrected by the ratio of intra- and extracellular water space. Extracellular concentration was corrected for an interstitial fluid-to-plasma glucose concentration gradient of 0.83 +/- 0.07, determined by open-flow microperfusion. The mean ratio of intra- to extracellular glucose space, determined from the relative NMR signal intensities and concentrations of mannitol and total creatine, was 9.2 +/- 1.1 (hyperglycemic hyperinsulinemia, n = 10), and 9.0 +/- 1.7 (hyperglycemic hypoinsulinemia, n = 7). Mean muscle intracellular glucose concentration was < 0.07 mM under hyperglycemic-hyperinsulinemic conditions (n = 10) and 0.32 +/- 0.06 mM under hyperglycemic-hypoinsulinemic conditions (n = 7). This method is noninvasive and should prove useful for resolving the question of whether glucose transport or phosphorylation is responsible for the reduced rate of muscle glycogen synthesis observed in diabetic subjects.

Topics: Animals; Blood Glucose; Carbon Isotopes; Glucose; Glycogen; Hyperglycemia; Insulin; Intracellular Fluid; Magnetic Resonance Spectroscopy; Male; Mannitol; Muscles; Rats; Rats, Sprague-Dawley

13C NMR spectroscopy was used to assess flux rates of hepatic glycogen synthase and phosphorylase in overnight-fasted subjects under one of four hypoglucagonemic conditions: protocol I, hyperglycemic (approximately 10 mM) -hypoinsulinemia (approximately 40 pM); protocol II, euglycemic (approximately 5 mM) -hyperinsulinemia (approximately 400 pM); protocol III, hyperglycemic (approximately 10 mM) -hyperinsulinemia (approximately 400 pM); and protocol IV; euglycemic (approximately 5 mM) -hypoinsulinemia (approximately 40 pM). Inhibition of net hepatic glycogenolysis occurred in both protocols I and II compared to protocol IV but via a different mechanism. Inhibition of net hepatic glycogenolysis occurred in protocol I mostly due to decreased glycogen phosphorylase flux, whereas in protocol II inhibition of net hepatic glycogenolysis occurred exclusively through the activation of glycogen synthase flux. Phosphorylase flux was unaltered, resulting in extensive glycogen cycling. Relatively high rates of net hepatic glycogen synthesis were observed in protocol III due to combined stimulation of glycogen synthase flux and inhibition of glycogen phosphorylase flux. In conclusion, under hypoglucagonemic conditions: (a) hyperglycemia, per se, inhibits net hepatic glycogenolysis primarily through inhibition of glycogen phosphorylase flux; (b) hyperinsulinemia, per se, inhibits net hepatic glycogenolysis primarily through stimulation of glycogen synthase flux; (c) inhibition of glycogen phosphorylase and the activation of glycogen synthase are not necessarily coupled and coordinated in a reciprocal fashion; and (d) promotion of hepatic glycogen cycling may be the principal mechanism by which insulin inhibits net hepatic glycogenolysis and endogenous glucose production in humans under euglycemic conditions.

Topics: Adult; Female; Gas Chromatography-Mass Spectrometry; Glucose; Glycogen; Glycogen Synthase; Humans; Hyperglycemia; Hyperinsulinism; Insulin; Liver; Magnetic Resonance Spectroscopy; Male; Phosphorylases

1. Effect of water soluble fraction of alcoholic extract of G. sylvestre leaves on glycogen content by isolated rat hemidiaphragm was studied in normal and glucose fed hyperglycemic rats. 2. The leaf extract by itself failed to alter the hepatic glycogen content in normal rats. 3. In glucose fed rats, the leaf extract lowered the glycogen content of the tissue significantly (P<0.05) and this was further lowered when both exogenous insulin and leaf extract was administered. 4. The results are discussed.

Topics: Animals; Blood Glucose; Diaphragm; Glycogen; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Secretion; Liver; Plant Extracts; Plants, Medicinal; Rats

We examined the ability of an equivalent increase in circulating glucose concentrations to inhibit endogenous glucose production (EGP) and to stimulate glucose metabolism in patients with Type 2 diabetes mellitus (DM2). Somatostatin was infused in the presence of basal replacements of glucoregulatory hormones and plasma glucose was maintained either at 90 or 180 mg/dl. Overnight low-dose insulin was used to normalize the plasma glucose levels in DM2 before initiation of the study protocol. In the presence of identical and constant plasma insulin, glucagon, and growth hormone concentrations, a doubling of the plasma glucose levels inhibited EGP by 42% and stimulated peripheral glucose uptake by 69% in nondiabetic subjects. However, the same increment in the plasma glucose concentrations failed to lower EGP, and stimulated glucose uptake by only 49% in patients with DM2. The rate of glucose infusion required to maintain the same hyperglycemic plateau was 58% lower in DM2 than in nondiabetic individuals. Despite diminished rates of total glucose uptake during hyperglycemia, the ability of glucose per se (at basal insulin) to stimulate whole body glycogen synthesis (glucose uptake minus glycolysis) was comparable in DM2 and in nondiabetic subjects. To examine the mechanisms responsible for the lack of inhibition of EGP by hyperglycemia in DM2 we also assessed the rates of total glucose output (TGO), i.e., flux through glucose-6-phosphatase, and the rate of glucose cycling in a subgroup of the study subjects. In the nondiabetic group, hyperglycemia inhibited TGO by 35%, while glucose cycling did not change significantly. In DM2, neither TGO or glucose cycling was affected by hyperglycemia. The lack of increase in glucose cycling in the face of a doubling in circulating glucose concentrations suggested that hyperglycemia at basal insulin inhibits glucose-6-phosphatase activity in vivo. Conversely, the lack of increase in glucose cycling in the presence of hyperglycemia and unchanged TGO suggest that the increase in the plasma glucose concentration failed to enhance the flux through glucokinase in DM2. In summary, both lack of inhibition of EGP and diminished stimulation of glucose uptake contribute to impaired glucose effectiveness in DM2. The abilities of glucose at basal insulin to both increase the flux through glucokinase and to inhibit the flux through glucose-6-phosphatase are impaired in DM2. Conversely, glycogen synthesis is exquisitely sensitive to cha

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Glucagon; Glucose Clamp Technique; Glycogen; Glycolysis; Human Growth Hormone; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Middle Aged; Somatostatin; Sulfonylurea Compounds

To determine the mechanism of impaired insulin-stimulated muscle glycogen metabolism in patients with poorly controlled insulin-dependent diabetes mellitus (IDDM), we used 13C-NMR spectroscopy to monitor the peak intensity of the C1 resonance of the glucosyl units in muscle glycogen during a 6-h hyperglycemic-hyperinsulinemic clamp using [1-(13)C]glucose-enriched infusate followed by nonenriched glucose. Under similar steady state (t = 3-6 h) plasma glucose (approximately 9.0 mM) and insulin concentrations (approximately 400 pM), nonoxidative glucose metabolism was significantly less in the IDDM subjects compared with age-weight-matched control subjects (37+/-6 vs. 73+/-11 micromol/kg of body wt per minute, P < 0.05), which could be attributed to an approximately 45% reduction in the net rate of muscle glycogen synthesis in the IDDM subjects compared with the control subjects (108+/-16 vs. 195+/-6 micromol/liter of muscle per minute, P < 0.001). Muscle glycogen turnover in the IDDM subjects was significantly less than that of the controls (16+/-4 vs. 33+/-5%, P < 0.05), indicating that a marked reduction in flux through glycogen synthase was responsible for the reduced rate of net glycogen synthesis in the IDDM subjects. 31P-NMR spectroscopy was used to determine the intramuscular concentration of glucose-6-phosphate (G-6-P) under the same hyperglycemic-hyperinsulinemic conditions. Basal G-6-P concentration was similar between the two groups (approximately 0.10 mmol/kg of muscle) but the increment in G-6-P concentration in response to the glucose-insulin infusion was approximately 50% less in the IDDM subjects compared with the control subjects (0.07+/-0.02 vs. 0.13+/-0.02 mmol/kg of muscle, P < 0.05). When nonoxidative glucose metabolic rates in the control subjects were matched to the IDDM subjects, the increment in the G-6-P concentration (0.06+/-0.02 mmol/kg of muscle) was no different than that in the IDDM subjects. Together, these data indicate that defective glucose transport/phosphorylation is the major factor responsible for the lower rate of muscle glycogen synthesis in the poorly controlled insulin-dependent diabetic subjects.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 1; Female; Glucose; Glucose Clamp Technique; Glucose-6-Phosphate; Glycogen; Glycogen Synthase; Humans; Hyperglycemia; Hyperinsulinism; Insulin; Magnetic Resonance Spectroscopy; Male; Muscles

Human skeletal muscle cultures (HSMCs) from type II diabetic subjects were used to determine whether metabolic abnormalities such as hyperglycemia or hyperinsulinemia contribute to the defective muscle glycogen synthase (GS) activity present in this disorder. Following approximately 6 weeks of growth, diabetic cultures were fused for 4 days in normal, hyperglycemia, or hyperinsulinemia medium. Fusion of diabetic HSMCs in hyperglycemia medium (20 mmol/l vs. 5.5 mmol/l) had no effect on GS fractional velocity (FV) or mRNA levels, but impaired acute insulin-stimulation of glycogen synthesis and GS activity at 0.1 mmol/l glucose-6-phosphate, and reduced GS protein content by approximately 15% (P < 0.05). Fusion of diabetic muscle cultures in hyperinsulinemia medium (30 micromol/l vs. 22 pmol/l) improved basal GS activity, increasing the reduced GS FV by approximately 50% (P < 0.05), and decreasing the elevated Km(0.1) (half-maximal substrate concentration) by approximately 47% (P < 0.05). Hyperinsulinemia also significantly increased (P < 0.05) the reduced GS mRNA and protein levels of diabetic muscle to levels similar to that in nondiabetic subjects. In contrast to the improvements in the basal state, hyperinsulinemia completely abolished acute insulin responsiveness of GS activity and glycogen synthesis in muscle of type II diabetic subjects. The combination of hyperinsulinemia and hyperglycemia produced effects on both basal and insulin-responsive GS FV and mRNA similar to hyperinsulinemia alone, but hyperinsulinemia prevented hyperglycemia's effect of lowering GS protein and glycogen synthesis. We concluded that, in diabetic muscle, hyperinsulinemia may serve to partially compensate for the impaired basal GS activity and for the adverse effects of hyperglycemia on GS protein content, activity, and glycogen formation by both pre- and posttranslational mechanisms. Despite these beneficial effects, hyperinsulinemia also induces severe impairment of insulin-stimulated GS activity and glycogen formation, which may contribute to acquired muscle insulin resistance of type II diabetes.

Topics: Adult; Biopsy; Blotting, Northern; Cells, Cultured; Diabetes Mellitus, Type 2; Glycogen; Glycogen Synthase; Humans; Hyperglycemia; Hyperinsulinism; Immunoblotting; Insulin; Kinetics; Middle Aged; Muscle, Skeletal; Receptor, Insulin; RNA, Messenger

Little is known about the role of the kidney in plasma glucose regulation during hyperglycemia. We studied 12 overnight-fasted conscious dogs after either intrarenal (IR, n = 6) or peripheral (PH, n = 6) dextrose infusion to maintain hyperglycemia without glycosuria. Systemic and renal glucose kinetics were measured with [6-3H]glucose, lactate balance was measured by arteriovenous difference, and glycogen content was assayed in the kidneys. Plasma glucose (approximately 5.5 vs. approximately 6.3 mM), insulin (approximately 70 vs. approximately 110 pM), and glucose appearance (approximately 14 vs. approximately 16 mumol.kg-1.min-1 increased comparably in both groups (P < 0.05). In IR, fractional extraction of glucose (FEGlc) increased from 4.1 +/- 0.2 to 16.1 +/- 0.5% (P < 0.001) and lactate balance reversed to renal output (+1.3 +/- 0.2 vs. -0.9 +/- 0.2 mumol.kg-1.min-1, P < 0.01). Glycogen content was twofold higher in the left (127 +/- 33 micrograms/g tissue) than in the right kidney (56 +/- 11 micrograms/g tissue, P < 0.01). In PH, FEGlc decreased from 4.9 +/- 0.6 to 2.2 +/- 0.3% (P < 0.05), renal glucose utilization did not change (approximately 1.3 mumol.kg-1.min-1); and glycogen content was equal in both kidneys (approximately 45 micrograms/g tissue). We conclude that, although the kidney plays a minor role in plasma glucose disposal in physiological hyperglycemia, increased glucose uptake, glycogen storage, and lactate formation precede glycosuria and may represent important mechanisms by which the kidney contributes to normalization of plasma glucose in diabetes.

Topics: Animals; Arteries; Blood Glucose; Dogs; Glucose; Glycogen; Hyperglycemia; Kidney; Lactic Acid; Male; Renal Circulation

Both hyperglycemia and hyperinsulinemia stimulate whole body and muscle glucose disposal. To define the impact of increased lactate concentration (4-5 mM) on muscle glucose disposal during hyperglycemia, we studied anesthetized normal rats infused with either sodium lactate or sodium bicarbonate as control. Animals were studied under hyperglycemic clamp (13 mM) using [3-3H]glucose (study 1) and 2-deoxy-[1-3H]glucose (study 2) to assess glucose rate of disappearance (Rd), glycolytic flux (GF), glycogen synthesis, and glucose utilization index by different tissues. Moreover, in study 3, the effect of lactate on the pattern of plasma insulin response to hyperglycemia was evaluated. In study 1, lactate infusion resulted in an increased Rd (38.7 +/- 1.7 vs. 32.3 +/- 1.3 mg.min-1.kg-1; P < 0.01), which was explained by an enhanced rate of glycogen synthesis (23.0 +/- 1.7 vs. 14.7 +/- 1.2 mg.min-1.kg-1; P < 0.001), whereas GF was unchanged. In study 2, lactate-infused animals showed an increased 2-deoxy-glucose disposal and a stimulated glycogen synthase activity as well as an increased glycogen accumulation at the end of the study in several skeletal muscles. In study 3, lactate did not induce any change in either early or late insulin response to hyperglycemia. In conclusion, our results show that muscle glycogen deposition may be enhanced by elevated lactate levels under hyperglycemic conditions and support a role for lactate in the regulation of glucose homeostasis.

Topics: Animals; Deoxyglucose; Glucose; Glucose Clamp Technique; Glycogen; Glycogen Synthase; Glycolysis; Hyperglycemia; Infusions, Intravenous; Kinetics; Male; Muscle, Skeletal; Rats; Rats, Sprague-Dawley; Sodium Bicarbonate; Sodium Lactate; Tritium

The purpose of the present study was to determine whether intracerebral interleukin (IL)-1 mediates the endotoxin [lipopolysaccharide (LPS)]-induced increase in glucose flux. To accomplish this goal, a specific receptor antagonist for IL-1 (IL-1ra) or artificial cerebrospinal fluid was infused into the lateral ventricle via an intracerebroventricular cannula before, and for 4 h after, the intravenous injection of LPS. Whole body glucose flux was measured in conscious unrestrained rats using [3-3H]glucose. LPS increased both the plasma glucose concentration and the rate of glucose production (95 and 80%, respectively). In contrast, intracerebroventricular infusion of IL-1ra (2 mg/kg + 2 mg-kg-1.h-1) attenuated by approximately 50% the LPS-induced changes in glucose metabolism. IL-1ra also blunted the increase in plasma catecholamines, but not the elevation in glucagon and corticosterone concentrations, observed after LPS. Intracerebroventricular infusion of IL-1ra greatly reduced the LPS-induced hyperlactacidemia but did not alter the increase in muscle pyruvate dehydrogenase activity. An intravenous infusion of a 10-fold greater dose of IL-1ra, however, did not antagonize the LPS-induced increase in glucose flux. These data indicate that a major portion of the stimulation of glucose flux, as well as the increase in plasma catecholamines in response to LPS, is mediated by IL-1 within the central nervous system.

Topics: Animals; Blood Glucose; Blood Pressure; Brain; Endotoxins; Glycogen; Hormones; Hyperglycemia; Interleukin-1; Lipopolysaccharides; Male; Osmolar Concentration; Pyruvate Dehydrogenase Complex; Rats; Rats, Sprague-Dawley

To investigate the effects of an acute dose of the fatty acid oxidation inhibitor, Etomoxir, on the activity of the pyruvate dehydrogenase complex (PDHC) in different tissues in lean and obese mice.. An acute dose of Etomoxir was given to mice in which obesity had been induced by an injection of gold thioglucose and to age-matched controls. The effects of time, dose and nutritional state were studied.. PDHC activity in heart, quadricaps muscle, liver and white adipose tissue, glycogen content of liver and quadricaps muscle, serum glucose and insulin were measured in fed and fasted animals and in fasted animals after the ingestion of a glucose load.. Etomoxir caused an increase in the activity of the active form of the PDHC (PDHCa) in the heart, liver and WAT of fed lean mice and in the heart and liver of fed obese mice. In fasted mice, increased PDHCa was seen in the heart of lean mice and in the liver of obese mice. Etomoxir increased the PDHC response to an oral glucose challenge in the liver and WAT of lean mice and in the liver of obese mice. Etomoxir had no effect on PDHCa in quadricaps muscle. Serum glucose levels were decreased in fasted mice with no change in the fed mice. Etomoxir decreased liver glycogen content in both fed and fasted animals and inhibited the accumulation of muscle glycogen following the glucose load.. Acute inhibition of fatty acid oxidation results in tissue specific increases in PDHCa. Improvements in glucose oxidation in tissues other than skeletal muscle may contribute to the improved glucose tolerance seen following acute Etomoxir administration.

Topics: Adipose Tissue; Animals; Blood Glucose; Carnitine O-Palmitoyltransferase; Dose-Response Relationship, Drug; Epoxy Compounds; Fatty Acids; Glucose; Glycogen; Homeostasis; Hyperglycemia; Hypoglycemic Agents; Insulin; Liver; Male; Mice; Mice, Inbred CBA; Muscle, Skeletal; Myocardium; Obesity; Oxidation-Reduction; Pyruvate Dehydrogenase Complex; Time Factors

Sepsis and endotoxin (LPS) have been demonstrated to impair insulin-mediated glucose uptake in skeletal muscle. However, the intracellular mechanism responsible for this defect is not fully defined. The purpose of the present study was to determine whether specific elements of the insulin receptor (IR) signaling pathway in skeletal muscle are altered by LPS. In vivo injection of Escherichia coli LPS resulted in a 44% reduction in whole body glucose disposal under euglycemic hyperinsulinemic conditions, which was largely accounted for by a decreased rate of glycogen synthesis. Scatchard analysis indicated that the number and affinity of the high-affinity insulin binding sites in muscle were similar between control and LPS-treated rats. Western blot analysis indicated that under basal conditions, the levels of total and phosphorylated IR, insulin receptor substrate (IRS)-1, and mitogen-activated protein (MAP) kinase were not significantly different between control and endotoxic rats. In control animals, muscle obtained 2 min after intravenous injection of a maximally stimulating dose of insulin demonstrated a marked increase in the amount of phosphorylated IR (approximately 5-fold), IRS-1 (approximately 10-fold), and MAP kinase (approximately 10-fold). Insulin-stimulated phosphorylation of IR, IRS-1, and MAP kinase was markedly diminished (approximately 75%, 90%, and 78%, respectively) in LPS-treated rats. However, there was no concomitant reduction in the total abundance of these proteins under hyperinsulinemic conditions. These data demonstrate that LPS alters multiple steps in the insulin signal transduction pathway, but not insulin binding, in skeletal muscle that may mediate the observed impairment in glucose uptake.

Topics: Adenosine Triphosphate; Animals; Blood Glucose; Calcium-Calmodulin-Dependent Protein Kinases; Endotoxins; Glucose; Glycogen; Hyperglycemia; Insulin; Insulin Receptor Substrate Proteins; Lipopolysaccharides; Male; Muscle, Skeletal; Phosphocreatine; Phosphoproteins; Phosphorylation; Rats; Rats, Sprague-Dawley; Signal Transduction

Early hyperglycaemia induced by streptozocin was studied in fasting rats. It was found that the early hyperglycaemia was attenuated, the hypoglycaemia was prolonged, and the initiation of the permanent hyperglycaemia was delayed. The early hyperglycaemia induced by streptozocin was further attenuated in carbon tetrachloride pretreated fasting rats. It was speculated that the appearance of the early hyperglycaemia was liver related.

Topics: Animals; Blood Glucose; Carbon Tetrachloride; Diabetes Mellitus, Experimental; Diet; Fasting; Gluconeogenesis; Glycogen; Hyperglycemia; Hypoglycemia; Insulin; Liver; Male; Rats; Rats, Sprague-Dawley; Streptozocin

Postabsorptive hepatic glucose output (HGO) was estimated in normal (n = 9) and streptozotocin (STZ) diabetic rats after a 6-h [3-3H]glucose infusion. In diabetic rats, HGO was estimated at ambient (n = 12) or normal (achieved via phlorizin infusion; n = 9) glucose concentrations. HGO was not statistically different between normal and diabetic rats (63 +/- 3 vs. 77 +/- 10 mumol.kg-1.min-1; P > 0.05). HGO was also normal in diabetic rats even when plasma glucose was normalized with phlorizin infusion (71 +/- 5 vs. 63 +/- 3 mumol.kg-1.min-1; P > 0.05). In contrast, peripheral glucose uptake, when estimated at matched euglycemia, was lower by approximately 25% in diabetic than in normal rate (46 +/- 6 vs. 62 +/- 3 mumol.kg-1.min-1; P < 0.01). In addition, acute changes in plasma glucose concentrations did not have significant effects on HGO or peripheral glucose uptake in diabetic rats (P > 0.05), resulting in markedly decreased glucose clearance at ambient hyperglycemia (P < 0.001). In conclusion, postabsorptive HGO was not elevated in a majority (17 of 21) of STZ diabetic rats with severe hyperglycemia and therefore was not responsible for postabsorptive hyperglycemia. Our data suggest that an impairment in the ability of glucose to regulate peripheral glucose uptake or HGO develops in STZ diabetes and contributes to postabsorptive hyperglycemia.

Topics: Absorption; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Glucagon; Glucose; Glycogen; Glycosuria; Hyperglycemia; Insulin; Liver; Male; Phlorhizin; Rats; Rats, Wistar; Time Factors

The hypoglycemic effect of the rhizomes of Ophiopogonis Tuber (Liliaceae) was investigated in normal and streptozotocin-induced diabetic mice. The n-butanol extract of rhizomes of Ophiopogonis Tuber (BM) (100 mg/kg) reduced the blood glucose of normal mice from 201 +/- 13 to 151 +/- 7 mg/100 ml 4h after intraperitoneal administration (p < 0.054), and also significantly lowered the blood glucose of streptozotocin-induced diabetic mice from 590 +/- 28 to 470 +/- 37 mg/100 ml under similar conditions (p < 0.05). BM also tended to suppress epinephrine-induced hyperglycemia in mice. We concluded that the hypoglycemic effect of BM does not alter the insulin concentration.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Drugs, Chinese Herbal; Epinephrine; Glucose Tolerance Test; Glycogen; Hyperglycemia; Hypoglycemic Agents; Insulin; Male; Mice; Mice, Inbred Strains; Plant Roots

To test the hypothesis that increased flux through the hexosamine biosynthetic pathway can induce insulin resistance in skeletal muscle in vivo, we monitored glucose uptake, glycolysis, and glycogen synthesis during insulin clamp studies in 6-h fasted conscious rats in the presence of a sustained (7-h) increase in glucosamine (GlcN) availability. Euglycemic (approximately 7 mM) insulin (approximately 2,500 pM) clamps with saline or GlcN infusions were performed in control (CON; plasma glucose [PG] = 7.4 +/- 0.2 mM), diabetic (D; PG = 19.7 +/- 1.1), and phlorizin-treated (3-wk) diabetic rats (D + PHL; PG = 7.6 +/- 0.9). 7-h euglycemic hyperinsulinemia with saline did not significantly decrease Rd (360-420 min = 39.2 +/- 3.6 vs. 60-120 min = 42.2 +/- 3.7 mg/kg.min; P = NS). GlcN infusion raised plasma GlcN concentrations to approximately 1.2 mM and increased muscle and liver UDP-GlcNAc levels by 4-5-fold in all groups. GlcN markedly decreased Rd in CON (360-420 min = 30.4 +/- 1.3 vs. 60-120 min = 44.1 +/- 3.5 mg/kg.min; P < 0.01) and D + PHL (360-420 min = 29.4 +/- 2.5 vs. 60-120 min = 43.8 +/- 2.9 mg/kg.min; P < 0.01), but not in D (5-7 h = 21.5 +/- 0.8 vs. 0-2 h = 24.3 +/- 1.1 mg/kg.min; P = NS). Thus, increased GlcN availability induces severe skeletal muscle insulin resistance in normoglycemic but not in chronically hyperglycemic rats. The lack of additive effects of GlcN and chronic hyperglycemia (experimental diabetes) provides support for the hypothesis that increased flux through the GlcN pathway in skeletal muscle may play an important role in glucose-induced insulin resistance in vivo.

Topics: Animals; Blood Glucose; Glucosamine; Glucose; Glycogen; Glycolysis; Hexokinase; Hyperglycemia; Insulin Resistance; Male; Muscles; Rats; Rats, Sprague-Dawley

Glucose production and utilization and activities of key enzymes involved in liver and muscle glucose metabolism were studied in post-absorptive streptozotocin-diabetic rats after 12 h of severe hyperglycaemia (17.5 +/- 0.5 mmol/l) and insulinopenia (5 +/- 1 microU/ml). Basal glucose production was increased: 36.6 +/- 3.0 mg.kg.min-1, vs 24.4 +/- 2.5 in controls (p < 0.05); liver glycogen concentration was decreased by 40% (p < 0.05); liver phosphoenolpyruvate carboxykinase and glucose-6-phosphatase activities were increased by 375 and 156%, respectively (p < 0.001 and < 0.01). During a euglycaemic clamp at a plasma insulin level of 200 microU/ml, glucose production was totally suppressed in controls, but persisted at 20% of basal in diabetic rats. In these rats, glucose production was suppressed at a plasma insulin level of 2500 microU/ml. Basal whole body glucose utilization rate, 2-deoxy-1-[3H]-D-glucose ([3H]-2DG) uptake by muscles and muscle glycogen concentrations were similar in both groups, as well as total and active forms of pyruvate dehydrogenase and glycogen synthase activities. During the euglycaemic clamp, the total body glucose utilization rates and [3H]-2DG uptake by muscles were similar in control and diabetic rats at a plasma insulin level of 200 microU/ml, but lower in diabetic rats at a plasma insulin level of 2500 microU/ml. We conclude 1) in recent-onset severely insulinopenic rats, an excessive glucose production via gluconeogenesis prevailed, mainly accounting for the concomitant hyperglycaemia. This excess glucose output cannot be attributed to liver insulin resistance: the gluconeogenic pathway is physiologically less sensitive than glycogenolysis to the inhibition by insulin.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adipose Tissue; Adipose Tissue, Brown; Animals; Blood Glucose; Deoxyglucose; Diabetes Mellitus, Experimental; Fatty Acids, Nonesterified; Glucagon; Glucose; Glucose Clamp Technique; Glycogen; Glycolysis; Hyperglycemia; Insulin; Insulin Resistance; Liver; Liver Glycogen; Male; Muscle, Skeletal; Myocardium; Organ Specificity; Rats; Rats, Wistar; Reference Values

We determined the impact of variable insulinemia and glycemia on the in vivo partitioning of glucose effectiveness (GE) and insulin sensitivity (SI) and the in vitro intracellular processing of glucose metabolism. Six somatostatin- and [3-3H]glucose-infused dogs underwent euglycemic and hyperglycemic clamps at four physiological insulin (Ins) levels before a muscle biopsy. From the rates of glucose infusion (GINF), total glucose disposal (Rd), total glycolysis (GF), and glucose storage (GS), plots of delta GINF, delta Rd, delta GS vs. delta log Ins concentration were found to be linear for each dog, allowing calculation of the partitioning of GE and SI into their major in vivo sites (periphery vs. liver) and intracellular metabolic pathways (GS vs. GF). Insulinopenia induced a significant reduction in total GE. From insulinopenia to high insulinemia, the 2.3-fold increase in total GE was due to the increased peripheral glucose responsiveness of the GS pathway. Hyperglycemia induced a significant reduction in total SI, with approximately one-half of this reduction due to the decreased peripheral insulin responsiveness of the GF pathway. In skeletal muscle, both glycogen content and glycogen synthase fractional activity were positively correlated with log Ins concentration, Rd, and GS but negatively correlated with glucose 6-phosphate concentration. Moreover, both Rd and GS were negatively correlated with lactate concentration. We conclude that 1) the inhibition of GE and SI induced by insulinopenia and hyperglycemia, respectively, is due mainly to the reduced peripheral responsiveness of contrasting intracellular metabolic pathways; and 2) hyperinsulinemia and/or hyperglycemia stimulates glycogen synthesis and GF but not nonoxidative glycolysis.

Topics: Animals; Blood Glucose; Dogs; Fatty Acids, Nonesterified; Glucagon; Glucose; Glucose Clamp Technique; Glycogen; Glycogen Synthase; Hyperglycemia; Insulin; Lactates; Lactic Acid; Male; Muscle, Skeletal; Somatostatin

Mice were studied with the euglycemic hyperinsulinemic and the hyperglycemic clamp techniques after a 6-h fast: 1) euglycemic (6.7 +/- 0.2 mM) hyperinsulinemia (approximately 800 microU/ml); 2) hyperglycemic (15.3 +/- 0.4 mM) hyperinsulinemia (approximately 800 microU/ml). All mice received an infusion of [3-3H]glucose and [U-14C]lactate. Basal hepatic glucose production (HGP) averaged approximately 170 mumol.kg-1.min-1 in both groups. During euglycemic and hyperglycemic hyperinsulinemia, HGP decreased by 53% (to 76.7 +/- 11.1 mumol.kg-1.min-1; P < 0.01) and 74% (to 43.3 +/- 7.2 mumol.kg-1.min-1; P < 0.01), respectively. Hyperglycemia increased glucose cycling (by 2.1-fold; P < 0.01) and the contribution of gluconeogenesis to HGP (88 vs. 43%; P < 0.01) while decreasing that of glycogenolysis (12 vs. 57%; P < 0.01). The percentage of neosynthetized hepatic glycogen formed via the direct pathway was markedly increased during hyperglycemia (53 +/- 2% vs. 23 +/- 3%; P < 0.01): These data indicate that the assessment of hepatic glucose fluxes can be accomplished in conscious unrestrained mice and that, in the presence of hyperinsulinemia, hyperglycemia causes 1) a further inhibition of HGP mainly via inhibition of glycogenolysis and increase in hepatic glucose cycling; and 2) about a fivefold stimulation in the direct pathway of hepatic glycogen formation.

Topics: Animals; Feasibility Studies; Glucose; Glucose Clamp Technique; Glycogen; Hyperglycemia; Insulin; Liver; Male; Mice; Mice, Inbred C57BL

Human recombinant insulin-like growth factor-I (IGF-I) exerts insulin-like antidiabetic properties in vitro and in vivo. To determine the effects of IGF-I infusion on insulin and amylin release, plasma glucose of freely moving undisturbed rats was constantly maintained at 13.9 mmol/liter by variable glucose infusion for 120 min in three groups of fasted Sprague-Dawley rats (hyperglycemic clamp technique). Group A, vehicle infusion (control group); group B, bolus 0.39 nmol plus 0.39 nmol/h IGF-I continously; and group C, bolus 1.96 nmol plus 1.96 nmol/h IGF-I continuously. During the steady-state phase of the experiment, IGF-I dose dependently reduced plasma insulin (pmol/liter: A, 718 +/- 58; B, 613 +/- 35, NS vs. A; C, 408 +/- 21, P < 0.01 vs. A; dose-response effect: P < 0.0001), plasma amylin (pmol/liter: A, 10.2 +/- 0.6; B, 8.8 +/- 0.5, NS vs. A; C, 5.8 +/- 0.4, P < 0.01 vs. A; dose-response effect: P < 0.0001), and net glucose uptake (mumol/kg.min: A, 188 +/- 12; B, 160 +/- 12, NS vs. A; C, 134 +/- 7, P < 0.01 vs. A; dose-response effect: P < 0.0025). At the same time, the ratio of plasma insulin/plasma amylin (mol/mol: A, 72 +/- 6; B, 71 +/- 5; C, 74 +/- 9; NS), the ratio of net glucose uptake/plasma insulin (mumol/kg.min per pmol/liter: A, 0.28 +/- 0.03; B, 0.27 +/- 0.02; C, 0.36 +/- 0.04; NS), and glycogen content of liver, heart, and various hindlimb muscles remained unaffected. The results demonstrate that IGF-I is a potent inhibitor of insulin and amylin release in healthy rats exposed to hyperglycemia and suggest that IGF-I infusion inhibits hormone secretion from pancreatic beta cells at infusion rates that do not affect insulin-stimulated glucose uptake by peripheral tissues.

Topics: Amyloid; Animals; Consciousness; Dose-Response Relationship, Drug; Glucose; Glycogen; Homeostasis; Hyperglycemia; Insulin; Insulin-Like Growth Factor I; Islet Amyloid Polypeptide; Liver; Male; Muscle, Skeletal; Radioimmunoassay; Rats; Rats, Sprague-Dawley

Increases in brain glucose will worsen outcome after global cerebral ischemia, and some experimental evidence suggests that the duration of hyperglycemia also may influence outcome. Different types of hyperglycemia were studied to identify metabolic differences that might account for alterations in postischemic outcome.. Ninety pentobarbital-anesthetized Sprague-Dawley rats were divided into three groups: normoglycemic nondiabetic rats (N) (n = 30), chronically hyperglycemic diabetic rats (HD) (n = 30), and acutely hyperglycemic, glucose-infused nondiabetic rats (HN) (n = 30). These groups were further subdivided into groups of six rats each that received 0, 2.5, 5, 10, or 15 min of complete cerebral ischemia (potassium chloride--induced cardiac arrest). Brains were excised after 10-kW focused microwave radiation and metabolites were measured using enzymatic fluorometric techniques.. At all study intervals, plasma glucose concentrations in HD and HN were fourfold greater than in N. Before ischemia, brain glucose concentrations in all groups were proportional to plasma glucose concentrations; however, brain glycogen concentrations did not differ among groups. After the onset of ischemia, there was an immediate diminution of brain glucose, glycogen, adenosine triphosphate (ATP), and phosphocreatine that in all cases was most pronounced during the initial 2.5 min of ischemia. Consumption of carbohydrate stores and lactate production were greater in HD and HN than in N. HD had lesser preischemic ATP concentrations and energy charges relative to N and HN (P < 0.05), perhaps reflecting their disease state; however, at 2.5 min of ischemia, the relationship of ATP concentrations and energy charges was HN > HD > N (P < 0.05 among all). In all groups, ATP and phosphocreatine were more than 96% depleted by 10 min of ischemia. With few exceptions (ATP concentrations and energy charges before ischemia and at 2.5 min, and lactate concentration in HD < HN at 15 min), there were no measured metabolic differences between HD and HN.. In these studies, the duration of hyperglycemia did not affect intraischemic carbohydrate consumption. At short durations of ischemia (2.5 min), both HD and HN groups had greater intraischemic ATP concentrations and energy charges than N; however, at longer durations of ischemia (> 5.0 min), high-energy phosphate depletion was similarly severe in all groups. These studies suggest that energy failure is not the origin of worse postischemic neurologic injury in hyperglycemic subjects, nor does energy failure readily explain reported differences between acutely and chronically hyperglycemic subjects exposed to global cerebral ischemia.

Topics: Adenine Nucleotides; Animals; Blood Glucose; Blood Pressure; Brain; Brain Ischemia; Diabetes Mellitus, Experimental; Energy Metabolism; Glucose; Glycogen; Hyperglycemia; Lactates; Rats; Rats, Sprague-Dawley

The effect of age and streptozocin concentration on the induction by streptozocin of hyperglycaemia in fasting rats is investigated. The data show that there is a dose dependent effect of streptozocin on the hyperglycaemia induced by streptozocin, and 60 mg/kg streptozocin is significantly more effective than 20 or 40 mg/kg streptozocin in inducing hyperglycaemia. Moreover, the hyperglycaemia induced by 60 mg/kg streptozocin is greater in 8 week old rats than in 4 or 6 week old rats, suggesting an influence of age on streptozocin-induced hyperglycaemia.

Topics: Aging; Animals; Blood Glucose; Body Weight; Fasting; Glycogen; Hyperglycemia; Injections, Intravenous; Liver; Male; Rats; Rats, Sprague-Dawley; Streptozocin

1. Red blood cells can store glucose and may thus participate in blood glucose homeostasis. We investigated if a defect in this process exists in non-insulin dependent diabetes (NIDD). 2. Blood was obtained in fasting conditions from 10 normal and 10 newly diagnosed NIDD patients (before and after 4 weeks Metformin therapy). Washed erythrocytes were resuspended in media containing various glucose concentrations (4.4, 6.6, 8.8 and 13.2 mmol/L). Total glucose uptake was calculated as the sum of the measurements of lactate as well as free glucose, the latter being determined before and after addition of amyloglucosidase to the pellet. 3. Cells from diabetics showed a pronounced reduction in glucose uptake, particularly in their capacity to store glucose as glycogen (reactive to amyloglucosidase). Metformin treatment almost normalized glycogen levels, whereas lactate declined concomitantly in the pellet. 4. Our data demonstrate that a defect in glucose uptake exists in erythrocytes from NIDD patients, affecting both free and stored glucose, and that this defect is reversed by Metformin treatment, indicating that this drug can increase glycogen levels even in insulin-insensitive cells. 5. Thus, in view of their total mass, erythrocytes may be important in the impaired glucose homeostasis in NIDD, in particular in marked hyperglycaemia such as after a meal.

Topics: Adult; Diabetes Mellitus, Type 2; Erythrocytes; Glucose; Glycogen; Humans; Hyperglycemia; Lactates; Lactic Acid; Metformin; Middle Aged

The effect of moderate hyperglycemia on renal ATP production and ATPase activity of rat fetus was investigated using the experimental procedure of maternal continuous infusion of glucose during the last 5 days of gestation. Glucose-infused mothers and their fetuses showed a high level of glycemia (8.8 and 5.5 mM, respectively) and a high level of insulinemia (3 times higher than in controls). No change in either ATP or ADP concentration was detectable but an increase in NaK ATPase activity occurred without any change in Mg ATPase activity. These modifications should be the result of an enhanced Na/glucose cotransport leading to an enhanced extrusion of Na at the basolateral membrane. These results indicate that immature kidney is able to increase NaK ATPase activity to maintain Na homeostasis.

Topics: Adenosine Triphosphatases; Animals; Body Weight; Female; Fetus; Glucose; Glycogen; Hyperglycemia; Infusions, Intravenous; Insulin; Kidney; Nucleotides; Osmolar Concentration; Pregnancy; Pregnancy Complications; Rats; Rats, Wistar; Sodium-Potassium-Exchanging ATPase

The effects of an exhaustive bout of eccentric exercise on insulin secretion and action were determined using the hyperglycemic clamp technique. Clamps were performed on eight healthy men after 7 days of inactivity and approximately 36 h after a bout of eccentric exercise. Eccentric exercise consisted of 10 sets of 10 repetitions of combined knee extensions and flexions for each leg at a mean torque 84 +/- 5% of peak concentric torque. During the hyperglycemic clamp procedure, plasma glucose concentration was acutely raised to 10 mmol/l and was maintained near this level for 120 min. Arterialized blood samples were obtained from a heated hand vein to determine plasma glucose and insulin concentrations. Eccentric exercise appeared to produce marked muscle damage, as indicated by a 50-fold increase in plasma creatine phosphokinase (100 +/- 17 vs. 5,209 +/- 3,811 U/l, P < 0.001) and subjective reports of muscle soreness. Peak insulin response during the early phase (0-10 min) of the hyperglycemic clamp was higher after eccentric exercise (183 +/- 38 microU/ml) than after the control clamp (100 +/- 23 microU/ml, P < 0.005). Late-phase (10- to 120-min) insulin response was not altered after eccentric exercise. Peak plasma C-peptide concentrations were higher during the early phase (5.0 +/- 0.7 vs. 4.3 +/- 0.8 ng/ml, P < 0.05) and the late phase (7.5 +/- 0.9 vs. 5.4 +/- 0.6 ng/ml, P < 0.05). Prior eccentric exercise had no significant effect on whole body glucose disposal or glucose disposal rate adjusted for prevailing plasma insulin concentration. These data provide evidence that a single bout of eccentric exercise causes an increase in pancreatic beta-cell insulin secretion in response to hyperglycemia.

Topics: Adult; Blood Glucose; Body Composition; C-Peptide; Creatine Kinase; Diet; Exercise; Glycogen; Humans; Hyperglycemia; Insulin; Insulin Secretion; Male; Muscles; Oxygen Consumption; Running

The hypoglycemic effect of different dose of Polygonati Rhizoma, i.e., "Ousei", was investigated in both normal and streptozotocin-induced diabetic mice. The methanol extract of Polygonati Rhizoma (OM) (800 mg/kg) reduced the blood glucose of normal mice from 202 +/- 7 to 144 +/- 13 mg/100 ml 4 h after intraperitoneal administration (p < 0.01), and also lowered significantly the blood glucose of streptozotocin-induced diabetic mice from 589 +/- 34 to 396 +/- 15 mg/100 ml under similar conditions (p < 0.001). However, the hypoglycemic effects were not accompanied by any alteration in the serum insulin in these mice. OM also suppressed epinephrine-induced hyperglycemia in mice. These results support, therefore, the use of Polygonati Rhizoma in patients with diabetes and confirm its role as a traditional medicine. In addition, one of the active components of OM was identified as a spirostanol glycoside (PO-2).

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Epinephrine; Glucose Tolerance Test; Glycogen; Hyperglycemia; Injections, Intraperitoneal; Insulin; Male; Mice; Plant Extracts; Plants, Medicinal; Tolbutamide

To evaluate the long-held concept that acidic guanidines lack glycemic effects, guanidinoalkanoic acids and the biguanide metformin (positive control) were administered to KKAy mice, a model of noninsulin-dependent diabetes. Two acidic guanidines, 3-guanidinopropionic acid (3-GPA) and guanidinoacetic acid, decreased the plasma glucose level; other compounds were ineffective. 3-GPA was more potent than even metformin. Insulin suppression tests in KKAy mice indicated that improved insulin sensitivity was the mode of action for 3-GPA. Glycemic effects in KKAy mice resulted from increased glucose disposal whereas gluconeogenesis, hepatic glycogen content and intestinal glucose absorption were unchanged. 3-GPA's glycemic effect was corroborated in two other models of noninsulin-dependent diabetes. In ob/ob mice, the compound reduced hyperglycemia, polyuria, glycosuria and hyperinsulinemia. In insulin-resistant rhesus monkeys, it increased the disappearance of i.v. glucose. The glycemic action of 3-GPA required the presence of some circulating insulin as well as hyperglycemia because the compound was ineffective in normoglycemic mice, insulinopenic Chinese hamsters and streptozotocin-diabetic rats. These data indicate that acidic guanidine derivatives can ameliorate hyperglycemia in animal models of noninsulin-dependent diabetes. Because acidic derivatives uniquely lack the propensity of guanidine compounds for inducing lactic acidosis, our finding suggests a new approach for developing improved antidiabetes compounds from this chemical class.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Gluconeogenesis; Glucose; Glycogen; Guanidines; Hyperglycemia; Insulin; Insulin Resistance; Intestinal Absorption; Liver Glycogen; Macaca mulatta; Male; Metformin; Mice; Mice, Inbred C57BL; Mice, Obese; Muscles; Propionates; Structure-Activity Relationship

Both hyperinsulinemia and hyperglycemia stimulate skeletal muscle glucose uptake. However, the intracellular metabolic fate of the phosphorylated glucose may be different when the prevalent stimulus for glucose uptake is hyperinsulinemia or hyperglycemia. To define the impact of hyperglycemia on the intracellular glucose disposal, we studied control and diabetic conscious rats under four experimental conditions: 1) basal insulin and basal glucose; 2) basal insulin and high glucose; 3) high insulin and basal glucose; and 4) high insulin and high glucose. Under both basal insulin (130 pM) and high insulin (2500 pM), hyperglycemia (15 mM) increased glucose uptake and muscle and liver glycogen synthesis similarly in control and diabetic rats. Hyperglycemia resulted in a more significant decline in the muscle G-6-P concentration in diabetic rats than in control rats, suggesting activation of intracellular glucose metabolism. The diabetic skeletal muscle glycogen synthase was severely resistant to insulin stimulation compared with control (FV0.1 = 0.31 +/- 0.04 vs. 0.49 +/- 0.03; Km = 0.19 +/- 0.05 vs. 0.10 +/- 0.01 mM; P < 0.01), but it was markedly responsive to glucose stimulation under both basal (FV0.1 = 0.38 +/- 0.03 vs. 0.21 +/- 0.03; Km = 0.10 +/- 0.01 vs. 0.35 +/- 0.08 mM) and high insulin (FV0.1 = 0.65 +/- 0.07 vs. 0.31 +/- 0.04; Km = 0.11 +/- 0.02 vs. 0.19 +/- 0.05 mM). By contrast, in control rats, hyperglycemia did not exert any stimulatory effect on skeletal muscle glycogen synthase. Thus, some metabolic alteration associated with the diabetic state renders the skeletal muscle glycogen synthase selectively responsive to glucose stimulation. This may represent a compensatory mechanism for the severe impairment in insulin's activation of this enzyme in diabetes.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Glucose; Glucose Clamp Technique; Glycogen; Glycogen Synthase; Glycolysis; Hyperglycemia; Kinetics; Liver Glycogen; Male; Muscles; Pancreatectomy; Rats; Rats, Sprague-Dawley; Reference Values

Studies were conducted in extracorporeally perfused, intact, working pig hearts to determine whether, in heart muscle, trace-labeled deoxyglucose serves as an accurate marker of glycolytic flux in reperfusion after exposures to mild to moderate regional ischemia. In the main study, two groups of hearts were compared, as distinguished by levels of glucose in the whole-blood perfusate (euglycemic hearts [group I], blood glucose of 7.4 +/- 0.2 mumol/ml, n = 7; hyperglycemic hearts [group II], blood glucose of 12.9 +/- 0.5 mumol/ml, n = 8). Both groups were subjected to a 60% reduction in anterior descending coronary flow for 30 minutes followed by reperfusion for 40 minutes. Modest and comparable regional mechanical stunning during reflow was noted in both groups. Glucose utilization, as estimated from the release of 3H2O from the steady-state infusion of [5-3H]glucose during aerobic perfusion, was modest but during reperfusion was noted to increase significantly above aerobic values in each of the two groups, with a doubling of rates in group II hearts compared with group I hearts (p less than 0.041 or p less than 0.090). Net lactate extraction was comparable in reflow in both groups, suggesting in this specific instance a preferential enhancement of glucose oxidation in hyperglycemic group II hearts. Shifts in accumulation of tissue radioactivity of [U-14C]2-deoxyglucose in reperfused myocardium were not able to track these trends. The variability of 14C-labeled radioactivity among animals was marked and essentially masked any ability to discern trends in glycolysis as described by tritiated glucose between the aerobic and reperfusion intervals. When the data were arrayed by linear regression analysis, the slopes derived from 14C-labeled deoxyglucose were either discordant or insensitive to those described by 3H-labeled glucose. Tissue glycogen levels were slow to recover in early reflow and at end reperfusion were still significantly depressed from aerobic levels. The present data indicate that coronary reperfusion and hyperglycemia have influence in determining glycolytic flux in myocardium. Labeled deoxyglucose, considered solely as a marker of exogenous glucose utilization, appears to be an insensitive agent in describing these events at conditions of relatively low glucose flux.

Topics: Animals; Carbon Radioisotopes; Deoxyglucose; Glucose; Glycogen; Glycolysis; Hyperglycemia; Myocardial Reperfusion; Myocardium; Swine; Tritium

Liver glycogen formation can occur via the direct (glucose----glucose-6-phosphate----glycogen) or indirect (glucose----C3 compounds----glucose-6-phosphate----glycogen) pathways. In the present study we have examined the effect of hyperglycemia on the pathways of hepatic glycogenesis, estimated from liver uridine diphosphoglucose (UDPglucose) specific activities, and on peripheral (muscle) glucose metabolism in awake, unstressed control and 90% pancreatectomized, diabetic rats. Under identical conditions of hyperinsulinemia (approximately 550 microU/ml), 2-h euglycemic (6 mM) and hyperglycemic (+5.5 mM and +11 mM) clamp studies were performed in combination with [3-3H,U-14C]glucose, [6-3H,U-14C]glucose, or [3-3H]glucose and [U-14C]lactate infusions under postabsorptive conditions. Total body glucose uptake and muscle glycogen synthesis were decreased in diabetic vs. control rats during all the clamp studies, whereas glycolytic rates were similar. By contrast, hyperglycemia determined similar rates of liver glycogen synthesis in both groups. Nevertheless, in diabetic rats, the contribution of the direct pathway to hepatic glycogen repletion was severely decreased, whereas the indirect pathway was markedly increased. After hyperglycemia, hepatic glucose-6-phosphate concentrations were increased in both groups, whereas UDPglucose concentrations were reduced only in the control group. These results indicate that in the diabetic state, under hyperinsulinemic conditions, hyperglycemia normally stimulates liver glycogen synthesis through a marked increase in the indirect pathway, which in turn may compensate for the reduction in the direct pathway. The increase in the hepatic concentrations of both glucose-6-phosphate and UDPglucose suggests the presence, in this diabetic rat model, of a compensatory "push" mechanism for liver glycogen repletion.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Gluconeogenesis; Glucose Clamp Technique; Glucosyltransferases; Glycogen; Hyperglycemia; Hyperinsulinism; Insulin; Lactates; Liver Glycogen; Male; Muscles; Pancreas; Rats

Insulin resistance and a defective insulin activation of the enzyme glycogen synthase in skeletal muscle during euglycaemia may have important pathophysiological implications in Type 2 (non-insulin-dependent) diabetes mellitus. Hyperglycaemia may serve to compensate for these defects in Type 2 diabetes by increasing glucose disposal through a mass action effect. In the present study, rates of whole-body glucose oxidation and glucose storage were measured during fasting hyperglycaemia and isoglycaemic insulin infusion (40 mU.m-2.min-1, 3 h) in 12 patients with Type 2 diabetes. Eleven control subjects were studied during euglycaemia. Biopsies were taken from the vastus lateralis muscle. Fasting and insulin-stimulated glucose oxidation, glucose storage and muscle glycogen synthase activation were all fully compensated (normalized) during hyperglycaemia in the diabetic patients. The insulin-stimulated increase in muscle glycogen content was the same in the diabetic patients and in the control subjects. Besides hyperglycaemia, the diabetic patients had elevated muscle free glucose and glucose 6-phosphate concentrations. A positive correlation was demonstrated between intracellular free glucose concentration and muscle glycogen synthase fractional velocity insulin activation (0.1 mmol/l glucose 6-phosphate: r = 0.65, p less than 0.02 and 0.0 mmol/l glucose 6-phosphate: r = 0.91, p less than 0.0001). In conclusion, this study indicates an important role for hyperglycaemia and elevated muscle free glucose and glucose 6-phosphate concentrations in compensating (normalizing) intracellular glucose metabolism and skeletal muscle glycogen synthase activation in Type 2 diabetes.

Topics: Blood Glucose; C-Peptide; Calorimetry; Diabetes Mellitus, Type 2; Enzyme Activation; Fasting; Female; Glucose; Glucose Clamp Technique; Glycated Hemoglobin; Glycogen; Glycogen Synthase; Humans; Hyperglycemia; Insulin; Male; Middle Aged; Muscles; Reference Values

To examine the mechanisms of hyperglycemia-induced insulin resistance, eight insulin-dependent (type I) diabetic men were studied twice, after 24 h of hyperglycemia (mean blood glucose 20.0 +/- 0.3 mM, i.v. glucose) and after 24 h of normoglycemia (7.1 +/- 0.4 mM, saline) while receiving identical diets and insulin doses. Whole-body and forearm glucose uptake were determined during a 300-min insulin infusion (serum free insulin 359 +/- 22 and 373 +/- 29 pM, after hyper- and normoglycemia, respectively). Muscle biopsies were taken before and at the end of the 300-min insulin infusion. Plasma glucose levels were maintained constant during the 300-min period by keeping glucose for 150 min at 16.7 +/- 0.1 mM after 24-h hyperglycemia and increasing it to 16.5 +/- 0.1 mM after normoglycemia and by allowing it thereafter to decrease in both studies to normoglycemia. During the normoglycemic period (240-300 min), total glucose uptake (25.0 +/- 2.8 vs. 33.8 +/- 3.9 mumol.kg-1 body wt.min-1, P less than 0.05) was 26% lower, forearm glucose uptake (11 +/- 4 vs. 18 +/- 3 mumol.kg-1 forearm.min-1, P less than 0.05) was 35% lower, and nonoxidative glucose disposal (8.9 +/- 2.2 vs. 19.4 +/- 3.3 mumol.kg-1 body wt-1min-1, P less than 0.01) was 54% lower after 24 h of hyper- and normoglycemia, respectively. Glucose oxidation rates were similar. Basal muscle glycogen content was similar after 24 h of hyperglycemia (234 +/- 23 mmol/kg dry muscle) and normoglycemia (238 +/- 22 mmol/kg dry muscle). Insulin increased muscle glycogen to 273 +/- 22 mmol/kg dry muscle after 24 h of hyperglycemia and to 296 +/- 33 mmol/kg dry muscle after normoglycemia (P less than 0.05 vs. 0 min for both). Muscle ATP, free glucose, glucose-6-phosphate, and fructose-6-phosphate concentrations were similar after both 24-h treatment periods and did not change in response to insulin. We conclude that a marked decrease in whole-body, muscle, and nonoxidative glucose disposal can be induced by hyperglycemia alone.

Topics: Adenosine Triphosphate; Adult; Biopsy; Blood Glucose; Circadian Rhythm; Diabetes Mellitus, Type 1; Energy Metabolism; Fatty Acids, Nonesterified; Fructosephosphates; Glucose-6-Phosphate; Glucosephosphates; Glycogen; Growth Hormone; Humans; Hydrocortisone; Hyperglycemia; Insulin; Insulin Resistance; Lactates; Male; Muscles; Osmolar Concentration; Oxidation-Reduction; Potassium; Serum Albumin

Glucagon and insulin changes were measured in acute nickel-treated rats. Also, several parameters related to glucose homeostasis were evaluated. Nickel treatment caused an important and transitory rise in plasma glucose levels. These changes occurred simultaneously to hyperglucagonemia and hypoinsulinemia, leading to a drastic drop in the insulin/glucagon plasma ratio. In such a catabolic situation, hepatic and muscular glycogen levels remained almost unaltered. Hepatic fructose-2,6-bisphosphate (an indicator of gluconeogenic/glycolytic state) was drastically reduced a short time after nickel injection. Such events suggested that it was mainly gluconeogenesis and not glycogenolysis, which contributes to enhanced plasma glucose. Animals treated with large doses of glucagon did not mimic the hyperglycaemic responses induced by nickel, due to counteracting effects of insulin on plasma glucose. When diabetic rats were treated with nickel, the hyperglucagonemic response still remained, but plasma glucose levels did not increase at the same extent as when nickel was applied to control animals. Overall results suggest that both, glucagon and insulin changes are essential in the development of nickel-induced hyperglycaemia. Also, the lack of glycogenolytic response insinuates a direct or indirect inhibition of this process mediated by nickel and will need further investigation.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Female; Glucagon; Glycogen; Homeostasis; Hyperglycemia; Injections, Intraperitoneal; Insulin; Liver; Nickel; Radioimmunoassay; Rats; Rats, Inbred Strains

This study examined the effect of maternal hyperglycemia during pregnancy due to streptozotocin-induced diabetes on the synthesis of glycogen in the brain and liver of embryonic and newborn rats. Maternal hyperglycemia (serum glucose 25.3 +/- 0.9 mM) during gestation had no effect compared to controls (5.7 +/- 0.2 mM) on embryonic and newborn glycogen content in liver. In contrast, embryos experiencing hyperglycemia in utero had a two-fold higher brain glycogen content than controls at term; 1.6 mg/g vs. 0.84 mg/g, respectively. Interestingly there was a significant delay in the mobilization of brain glycogen during the immediate postnatal period in the offspring of diabetic mothers and control animals. These results suggest that uncontrolled maternal diabetes during pregnancy may significantly increase the availability of a potentially important local fuel source for the newborn brain: glycogen.

Topics: Animals; Animals, Newborn; Blood Glucose; Brain; Diabetes Mellitus, Experimental; Embryo, Mammalian; Female; Glycogen; Hyperglycemia; Liver; Liver Glycogen; Pregnancy; Pregnancy in Diabetics; Rats; Rats, Inbred Strains

The effects of hyperglycemia on muscle glycogen use and carbohydrate metabolism were evaluated in eight well-trained cyclists (average maximal O2 consumption 4.5 +/- 0.1 l/min) during 2 h of exercise at 73 +/- 2% of maximal O2 consumption. During the control trial (CT), plasma glucose concentration averaged 4.2 +/- 0.2 mM and plasma insulin remained between 6 and 9 microU/ml. During the hyperglycemic trial (HT), 20 g of glucose were infused intravenously after 8 min of exercise, after which a variable-rate infusion of 18% glucose was used to maintain plasma glucose at 10.8 +/- 0.4 mM throughout exercise. Plasma insulin remained low during the 1st h of HT, yet it increased significantly (to 16-24 microU/ml; P less than 0.05) during the 2nd h. The amount of muscle glycogen utilized in the vastus lateralis during exercise was similar during HT and CT (75 +/- 8 and 76 +/- 7 mmol/kg, respectively). As exercise duration increased, carbohydrate oxidation declined during CT but increased during HT. Consequently, after 2 h of exercise, carbohydrate oxidation was 40% higher during HT than during CT (P less than 0.01). The rate of glucose infusion required to maintain hyperglycemia (10 mM) remained very stable at 1.6 +/- 0.1 g/min during the 1st h. However, during the 2nd h of exercise, the rate of glucose infusion increased (P less than 0.01) to 2.6 +/- 0.1 g/min (37 mg.kg body wt-1.min-1) during the final 20 min of exercise. We conclude that hyperglycemia (i.e., 10 mM) in humans does not alter muscle glycogen use during 2 h of intense cycling.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Blood Glucose; Carbohydrate Metabolism; Exercise; Fatty Acids, Nonesterified; Glucose; Glycogen; Humans; Hyperglycemia; Insulin; Lactates; Lactic Acid; Male; Muscles; Pulmonary Gas Exchange

In the rat, muscle glycogen is mobilized during the first stage of exercise, despite normoglycaemia. The aim of the present study was to examine if this process could be prevented or reduced by hyperglycaemia. Three experiments were carried out: in the first, rats were forced to run on a treadmill; in the second the gastrocnemius muscle group was made to contract by stimulation of the sciatic nerve and in the third adrenaline was administered subcutaneously. Each group was divided into two subgroups: control and enriched with glucose (hyperglycaemic). It was shown that hyperglycaemia has no effect on running-induced glycogen mobilization in hind-limb muscles of different fibre composition but prevented it totally in diaphragm muscle. Hyperglycaemia also did not affect the glycogen mobilization induced by stimulation of the sciatic nerve. However, it delayed and reduced markedly the glycogenolytic effect of adrenaline. It is concluded that increased glycogenolysis in muscles at the beginning of exercise may be a consequence of a delay in the activation of glucose transporting mechanisms in muscle cells.

Topics: Animals; Blood Glucose; Electric Stimulation; Epinephrine; Glycogen; Hyperglycemia; Injections, Subcutaneous; Male; Muscle Contraction; Muscles; Physical Exertion; Rats; Rats, Inbred Strains; Sciatic Nerve

Treatment of rats with diazinon (40 mg/kg, i.p.) resulted in hyperglycaemia and depletion of glycogen from the brain and peripheral tissues two hours after administration. The activities of glycogen phosphorylase and phosphoglucomutase were significantly higher in the brain and liver; that of glucose-6-phosphatase was not altered. The activities of the glycolytic enzymes hexokinase and lactate dehydrogenase were increased only in the brain. The cholinesterase activity in the brain was reduced by treatment with diazinon. The activities of the hepatic gluconeogenic enzymes fructose 1,6-diphosphatase and phosphoenolpyruvate carboxykinase were significantly increased. The lactate level was increased in the brain and blood, whereas that of pyruvate was not changed. The activity of glucose-6-phosphate dehydrogenase was not changed to any major extent. Cholesterol and ascorbic acid contents of adrenals were depleted in diazinon-treated animals. The changes were pronounced after intraperitoneal administration of 40 mg/kg diazinon, they were slight but significant after 20 mg/kg, and absent after 10 mg/kg. Hyperglycaemia and changes in carbohydrate metabolism were abolished by adrenalectomy suggesting possible involvement of adrenals.

Topics: Adrenal Glands; Animals; Blood Glucose; Brain; Cholinesterases; Diazinon; Female; Glycogen; Hyperglycemia; Liver Glycogen; Rats

Cytoplasmic and nuclear accumulation of glycogen granules in the kidney cells of 72 male WBN/Kob rats with a long-term diabetic condition was studied histologically and by electron microscopy. The incidence and degree of the accumulation showed good correlation with the blood glucose concentration. In the kidneys, there was evidence of two types of lesion, cytoplasmic glycogen accumulation in the distal convoluted tubules and nuclear accumulation in the ascending thick segment of Henle's loops. Electron microscopically, the cytoplasmic glycogen accumulation was often associated with an increased number of lysosomal bodies containing lamellar bodies. Glycogen bodies, the halo of which was thought to be identical with that of nuclear bodies, were frequently observed in the nuclei containing the glycogen granules. These morphological and topographical differences between the two types of lesion were considered suggestive of different pathogenetic mechanisms for glycogen accumulation in the kidney cells.

Topics: Animals; Blood Glucose; Cell Nucleus; Cytoplasm; Diabetic Nephropathies; Glycogen; Hyperglycemia; Kidney Tubules; Kidney Tubules, Distal; Male; Microscopy, Electron; Rats

The protective effects of atropine, diacetylmonoxime (DAM), and diazepam separately and in combination were investigated in rats exposed to malathion. Malathion (500 mg/kg, ip) inhibited acetylcholinesterase (AchE) activity in RBC and brain and produced hyperglycemia and hyperlactacidemia with depletion of glycogen in liver, triceps, and brain of animals 2 hr after its administration. Atropine (20 mg/kg, ip) given immediately after malathion abolished hyperglycemia and glycogenolytic effect but exhibited no effect on the recovery of inhibited AchE activity. DAM (100 mg/kg ip) given immediately after malathion significantly reactivated the inhibited AchE activity both in RBC and brain. It also partially modified hyperglycemia and glycogenolytic effect. Diazepam (50 mg/kg, ip) slightly modified AchE and abolished hyperglycemia, hyperlactacidemia, and glycogenolytic effects. A combination of these drugs protected the animals from the acute toxic effects of malathion.

Topics: Acidosis, Lactic; Animals; Atropine; Brain; Butanones; Cholinesterase Inhibitors; Cholinesterase Reactivators; Diacetyl; Diazepam; Drug Therapy, Combination; Erythrocytes; Glycogen; Hyperglycemia; Liver Glycogen; Malathion; Male; Rats

Vanadate has insulin-like activity in vitro and in vivo. To characterize the in vivo mechanism of action of vanadate, we examined meal tolerance, insulin-mediated glucose disposal, in vivo liver and muscle glycogen synthesis, and in vitro glycogen synthase activity in 90% partially pancreatectomized rats. Four groups were studied: group I, sham-operated controls; group II, diabetic rats; group III, diabetic rats treated with vanadate; and group IV, diabetic rats treated with phlorizin. Insulin sensitivity, assessed with the euglycemic hyperinsulinemic clamp technique in awake, unstressed rats, was reduced by approximately 28% in diabetic rats. Both vanadate and phlorizin treatment completely normalized meal tolerance and insulin-mediated glucose disposal. Muscle glycogen synthesis was reduced by approximately 80% in diabetic rats (P less than 0.01) and was completely restored to normal by vanadate, but not by phlorizin treatment. Glycogen synthase activity was reduced in skeletal muscle of diabetic rats (P less than 0.05) compared with controls and was increased to supranormal levels by vanadate treatment (P less than 0.01). Phlorizin therapy did not reverse the defect in muscle glycogen synthase. These results suggest that (a) the defect in muscle glycogen synthesis is the major determinant of insulin resistance in diabetic rats; (b) both vanadate and phlorizin treatment normalize meal tolerance and insulin sensitivity in diabetic rats; (c) vanadate treatment specifically reverses the defect in muscle glycogen synthesis in diabetic rats. This effect cannot be attributed to the correction of hyperglycemia because phlorizin therapy had no direct influence on the glycogenic pathway.

Topics: Animals; Chronic Disease; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Glucose Clamp Technique; Glycogen; Glycogen Synthase; Hyperglycemia; Insulin; Liver; Male; Muscles; Phlorhizin; Rats; Rats, Inbred Strains; Vanadates

The influence of brain cholinergic activation on hepatic glycogenolysis and gluconeogenesis was studied in fed and 48-hour fasted rats. Neostigmine was injected into the third cerebral ventricle and hepatic venous plasma glucose, glucagon, insulin, and epinephrine were measured. The activity of hepatic phosphorylase-a and phosphoenolpyruvate-carboxykinase (PEP-CK) was also measured. Experimental groups: 1, intact rats; 2, rats infused with somatostatin through the femoral vein; 3, bilateral adrenodemedullated (ADMX) rats; 4, somatostatin infused ADMX rats; 5, 5-methoxyindole-2-carboxylic acid (MICA) was injected intraperitoneally 30 minutes before injection of neostigmine into the third cerebral ventricle of intact rats. MICA treatment completely suppressed the increase in hepatic glucose in fasted rats, but had no effect in fed rats. Phosphorylase-a activity was not changed in fasted rats, but increased in fed rats, intact rats, somatostatin-infused rats, somatostatin-infused ADMX rats, and ADMX rats in that order. PEP-CK was not changed in fed rats, but increased at 60 and 120 minutes after neostigmine injection into the third cerebral ventricle in fasted rats. We conclude that, in fed states, brain cholinergic activation causes glycogenolysis by epinephrine, glucagon, and direct neural innervation. In fasted states, on the other hand, gluconeogenesis is dependent on epinephrine alone to increase hepatic glucose output.

Topics: Adrenal Medulla; Animals; Blood Glucose; Cerebral Ventricles; Epinephrine; Fasting; Glucagon; Gluconeogenesis; Glycogen; Hyperglycemia; Insulin; Liver; Male; Neostigmine; Phosphoenolpyruvate Carboxykinase (GTP); Phosphorylases; Rats; Rats, Inbred Strains; Somatostatin; Time Factors

Diazinon, an organophosphorous compound, produced hyperglycemia and reduced the glycogen content of the brain 2 h after its administration to rats (40 mg/kg, i.p.). The activities of the glycogenolytic enzymes, glycogen phosphorylase and phosphoglucomutase, were significantly increased, while that of glucose-6-phosphatase was not altered. Atropine (20 mg/kg, i.p.) given immediately after diazinon abolished the changes; tolazoline or propranolol (each at 10 mg/kg, i.p.) injected 30 min before the administration of diazinon significantly reduced the hyperglycemia and the increase in brain glycogenolysis. A combination of tolazoline and propranolol was more effective than either of them alone and completely abolished the hyperglycemia and the changes in brain glycogenolysis. It may be concluded that diazinon initially activates central cholinergic processes leading to hyperglycemia and increased cerebral glycogenolysis in animals.

Topics: Animals; Atropine; Brain; Diazinon; Female; Glucose-6-Phosphatase; Glycogen; Hyperglycemia; Insecticides; Phosphoglucomutase; Phosphorylases; Propranolol; Rats; Rats, Inbred Strains; Tolazoline

An initial transient hyperglycemia was seen in mice injected with asparagine, fluoroacetate, hydroxylamine, or malonate plus methionine, whereas an initial triphasic blood glucose response and a transient "secondary" hyperglycemia were exhibited in those injected with hydroxylamine plus arsenite, and a delayed hypoglycemia was observed in those treated with fluoroacetate or arsenite. The glucose-induced insulin secretion was significantly decreased in isolated pancreatic islets incubated with hydroxylamine plus arsenite. Light and electron microscopy, pyroantimonate technique, and X-ray microanalysis disclosed mitochondrial damage, degeneration, and necrosis among the beta-cells in the islets of mice injected with hydroxylamine plus arsenite. Glycogen depletion and microvesicular fatty change were seen in the liver of mice treated with fluoroacetate, arsenite, or hydroxylamine plus arsenite. These observations support the view that inhibition of the activity of citric acid cycle enzymes and associated reactions in the beta-cells play a role in the induction of diabetic features.

Topics: Animals; Arsenic; Arsenites; Blood Glucose; Citric Acid Cycle; Female; Fluoroacetates; Glucose; Glycogen; Hydroxylamine; Hydroxylamines; Hyperglycemia; Insulin; Insulin Secretion; Islets of Langerhans; Male; Malonates; Methionine; Mice; Mice, Inbred C57BL; Microscopy, Electron; Mitochondria

We have presented evidence suggesting that the suprachiasmatic nucleus (SCN) is involved in central regulation of glucose homeostasis. To elucidate this role of the SCN, we examined the effects of its electrical stimulation on glucose metabolism in male Wistar rats. During and shortly after this stimulation, we observed hyperglycemia associated with enhanced hyperglucagonemia but no immediate hyperinsulinemia. In addition, we detected significant increase in liver glycogen phosphorylase alpha activity and significant decrease in the liver glycogen content. These findings suggest that the SCN is important in control of glucose homeostasis through effects on glucagon and insulin secretions and liver glycogen metabolism.

Topics: Animals; Electric Stimulation; Electrodes; Glucose; Glycogen; Homeostasis; Hyperglycemia; Insulin; Liver; Male; Phosphorylases; Rats; Rats, Inbred Strains; Suprachiasmatic Nucleus

Treatment with malathion resulted in an increase in the level of blood glucose and lactate and reduced cerebral glycogen, 2 hr after its administration. The blood pyruvate level was not changed. The activities of glycogenolytic enzymes (glycogen phosphorylase and phosphoglucomutase) were increased significantly in the brain, whereas that of glucose-6-phosphatase remained unchanged. The activity of the glycolytic enzyme-hexokinase was increased significantly in malathion-treated animals, whereas those of the glucose-6-phosphate and lactate dehydrogenases were not significantly changed. The changes in enzyme activities may be a compensatory mechanism to provide energy in the form of glucose to cerebral tissue on account of stimulatory effects in malathion-treated animals.

Topics: Animals; Blood Glucose; Brain; Female; Glycogen; Glycolysis; Hyperglycemia; Lactates; Malathion; Pyruvates; Rats

Topics: Acute Disease; Animals; Dogs; Glycogen; Heart Atria; Hyperglycemia; Liver Glycogen; Myocarditis; Myocardium; Scorpion Venoms

Effect of diazinon (10,20 and 40 mg/kg, i.p.) on the level of blood glucose in rats was investigated. Hyperglycaemia peaked 2 h after i.p. treatment with 40 mg/kg diazinon. The cerebral acetylcholinesterase activity was significantly reduced. The blood level of pyruvic acid was unchanged while that of lactic acid was significantly increased. Convulsions and biochemical changes caused by diazinon (40 mg/kg) were prevented by diazepam injected immediately after diazinon. In diazinon-treated hyperglycaemic animals, the glycogen content of the brain was depleted, the activities of glycogen phosphorylase, phosphoglucomutase and hexokinase were significantly increased and the activity of glucose-6-phosphatase remained unchanged. Lactate dehydrogenase activity was also increased by treatment with diazinon. The induced changes may compensate for the energy requirement of stimulatory effects caused by diazinon.

Topics: Animals; Blood Glucose; Brain; Brain Chemistry; Cholinesterases; Diazinon; Female; Glycogen; Hyperglycemia; Insecticides; Lactates; Lactic Acid; Pyruvates; Pyruvic Acid; Rats

In conscious fasted rabbits an intravenous infusion of phenylephrine (20 micrograms kg-1 min-1) induced hyperglycaemia. The increase in blood glucose was accompanied by a modest increase in insulin secretion and a reduction of liver glycogen. Muscle glycogen and blood lactate levels were not altered by treatment with phenylephrine. Prazosin, 1 mg kg-1 s.c., partially attenuated phenylephrine-induced hyperglycaemia. Phenoxybenzamine infusion (16.6 micrograms kg-1 min-1) for 15 min suppressed the increase in blood glucose and the reduction in liver glycogen evoked by phenylephrine. This alpha-adrenoceptor blocker also clearly attenuated the blood glucose elevation observed on infusing adrenaline at 0.3 microgram kg-1 min-1. Blockade by phenoxybenzamine of phenylephrine- and adrenaline-induced hyperglycaemia was not accompanied by a significant increase in immunoreactive insulin plasma levels. Yohimbine infused at a rate of 20 micrograms kg-1 min-1, also completely blocked phenylephrine-induced hyperglycaemia. This suppressor effect was accompanied by a marked rebound in insulin secretion. It is concluded that in normal fasted rabbits stimulation of alpha-adrenoceptors induces hyperglycaemia. The increase in blood glucose depends mainly on liver glycogenolysis and inhibition of insulin secretion. Separate blockade of each component suffices to reduce alpha-adrenoceptor-mediated hyperglycaemia.

Topics: Adrenergic alpha-Antagonists; Animals; Blood Glucose; Catecholamines; Fasting; Glycogen; Hyperglycemia; Insulin; Lactates; Male; Phenylephrine; Prazosin; Rabbits; Receptors, Adrenergic, alpha; Time Factors

The effect of maternal hyperglycaemia on glycogen and triglyceride accumulation in the feto-placental unit of non-diabetic rats was studied. Hyperglycaemia was induced by continuous infusion of a 400 g/l glucose solution at the rate of 2-4 g/hr/kg, from day 18.5-20.5 of gestation. Hyperglycaemic mothers were hyperinsulinaemic; their fetuses were hyperglycaemic but their insulin levels were comparable with those of control pregnant rats (infused with a 50 g/l glucose solution at the same rate). Fetal pancreas insulin content in the hyperglycaemic fetuses was pronouncedly reduced. The hyperglycaemia produced an approximately 2-fold increase in placental glycogen content in association with increased activities of placental glycogen synthase and phosphorylase. Maternal serum triglycerides fell concomitant with the hyperglycaemia. Placental triglyceride content of hyperglycaemic rats did not change significantly, whereas up to a 2-fold increase in maternal and fetal liver triglyceride concentration was observed. There was no change in fetal and placental weight. Since we have shown previously an increase in both placental glycogen and triglycerides in diabetic rats with hyperglycaemia, concomitant with elevation of plasma triglycerides and free fatty acids, the present experiments demonstrate that these 2 factors causing placental glycogen and triglyceride accumulation can be dissociated. On the other hand, maternal and fetal liver triglycerides accumulate in the hyperglycaemic rats probably as a result of local de vovo lipogenesis.

Topics: Animals; Blood Glucose; Fatty Acids, Nonesterified; Female; Fetal Blood; Fetus; Glucose-6-Phosphate; Glucosephosphates; Glycogen; Hyperglycemia; Placenta; Pregnancy; Pregnancy Complications; Rats; Rats, Inbred Strains; Triglycerides

In order to delineate the sequence of development of the metabolic changes in the obese-hyperglycaemic syndrome in the NZO mouse, the uptake of 2-deoxyglucose, glucose utilization and glycogen synthesis by isolated soleus muscle in the absence and presence of graded doses of insulin was measured, and related to the gain in body weight and development of hyperinsulinaemia and hyperglycaemia. It was found that the NZO mice were hyperglycaemic and hyperinsulinaemic compared to an unrelated control strain (Balb c) from the earliest age studied (4 weeks). At 4-6 weeks, 2-deoxyglucose uptake and glucose utilization in the absence of insulin were decreased but the sensitivity and responsiveness to added insulin were comparable to those in the control strain. By 11 weeks, the responsiveness to added insulin was markedly impaired, an abnormality also seen at 52 weeks. Abnormal binding of insulin to its receptors was insufficient explanation for the observed changes. It is concluded that hyperinsulinaemia and hyperglycaemia develop early in NZO mice. Basal glucose transport and glucose utilization by isolated soleus muscle are also decreased from an early age, but decreased responsiveness to insulin in the soleus muscle is secondary and to insulin in the soleus muscle is secondary and relatively late manifestations of the syndrome.

Topics: Animals; Biological Transport, Active; Deoxyglucose; Female; Glucose; Glycogen; Hyperglycemia; Hyperinsulinism; In Vitro Techniques; Insulin Resistance; Mice; Mice, Inbred BALB C; Mice, Obese; Muscles; Obesity

The significance of ketosis in this syndrome has been evaluated from several viewpoints. With respect to acid-base considerations (pH, anion gap), ketosis was not very significant. However, with respect to sustained hyperglycemia, the combustion of less glucose than normal by the brain is critical and it is likely that ketone body metabolism plays an important role in this regard. This point can be underscored by a quantitative example. First, assume that the maximum rate of new glucose production in a fasted subject is less than 100 g of glucose per day. Second, since the brain will burn 100 g of glucose per day in a non-ketotic subject, it follows that, even in the absence of glucosuria, there will be a net daily consumption of glucose. Since the hyperglycemic individual has only an extra 100 or so g of glucose, it follows that the blood glucose concentration would approach the renal threshold in several days in the absence of ketosis. Recall that this is a minimum estimate because glucose oxidation in other organs and glucosuria will remove an additional quantity of glucose. Hyperglycemia can only be maintained in the absence of glucose intake if there is a reduced rate of glucose metabolism in the brain. The brain can diminish its rate of glucose catabolism by several mechanisms, including a diminished metabolic rate in the brain and/or the consumption of non-glucose fuels (free fatty acids or beta-hydroxybutyrate) by this organ.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acetone; Acidosis; Brain; Diabetic Coma; Glucose; Glycerides; Glycerol; Glycogen; Humans; Hyperglycemia; Hyperglycemic Hyperosmolar Nonketotic Coma; Ketosis; Proteins; Syndrome

Topics: Acetylcholine; Animals; Brain; Glycogen; Hyperglycemia; Malathion; Male; Rats; Rats, Inbred Strains

The effect of hydralazine in the alteration of blood sugar, tissue glycogen and blood cAMP levels in rats were investigated. Hydralazine was found to increase blood sugar level in intact rats when administered i.p. On the other hand, this hyperglycemia was partially blocked either by the treatment of intact rats with propranolol, beta-adrenergic blocker, or by adrenalectomy. Hydralazine treatment increased blood cAMP level, leading to the hyperglycemia, because pretreatment with phentolamine partially blocked the hydralazine-induced hyperglycemia.

Topics: Adrenal Glands; Animals; Cyclic AMP; Female; Glycogen; Hydralazine; Hyperglycemia; Male; Phentolamine; Propranolol; Rats

Topics: Animals; Arvicolinae; Carbon Dioxide; Energy Intake; Glucose; Glycogen; Hyperglycemia; In Vitro Techniques; Insulin; Lactates; Muscles; Triglycerides

Topics: Animals; Blood Glucose; Carbohydrate Metabolism; Gluconeogenesis; Glucose; Glycogen; Humans; Hyperglycemia; Liver; Rats

Some metabolic changes induced by the intraventricular administration of 6-aminonicotinamide (6-AN) were studied in mice. Five or ten microgram/animal of 6-AN produced a marked hyperglycemia, lowered glycogen content in the brain and liver, and reduced the adrenal epinephrine content. Adrenalectomy or hexamethonium prevented 6-AN-induced hyperglycemia and decrease of glycogen content in the liver but not in the brain. Decrease of adrenal epinephrine content induced by 6-AN was overcome by hexamethonium. Pretreatment with 6-AN (10 microgram/animal) markedly lowered the toxic action, but not the hypoglycemic action, of a large dose of insulin.

Topics: 6-Aminonicotinamide; Adrenalectomy; Animals; Blood Glucose; Brain; Glycogen; Hyperglycemia; Hypoglycemia; Insulin; Liver; Liver Glycogen; Male; Mice; Niacinamide

Experiments were carried out to explain the hypoglycemic effect of dicyclohexylamine (DCH) and related compounds. The agents antagonized blood glucose increase in intact and hepatectomized rats infused with glucose, but not in intact rats receiving epinephrine, and induced liver glycogen rise in normal fasted but not in adrenalectomized rats. No effect on blood glucose of pancreatectomized dogs was found. DCH lowered blood triglycerides without influencing the concentration of plasma fatty acids. Intestinal absorption of glucose was not influenced by low concentrations of the amines. Hypoglycemia may result, at least in part, from stimulated glucose transformation in the muscle tissue without an enhancement of anaerobic glycolysis.

Topics: Adipose Tissue; Adrenalectomy; Amines; Animals; Blood Glucose; Dogs; Female; Glucose; Glycogen; Hyperglycemia; Hypoglycemic Agents; Intestinal Absorption; Lipid Metabolism; Male; Muscles; Pancreatectomy; Rats

Topics: Animals; Brain; Glucose; Glucosephosphates; Glycogen; Hyperglycemia; Insulin; Lactates; Male; Rats

Topics: Animals; Epinephrine; Ganglia; Glycogen; Hyperglycemia; Liver; Pancreas; Phosphorylases; Scorpions

Topics: Adrenalectomy; Animals; Blood Glucose; Epinephrine; Fluorides; Glycogen; Hyperglycemia; Liver; Liver Glycogen; Male; Muscles; Myocardium; Norepinephrine; Phosphorylases; Rats; Time Factors

Topics: Animals; Disease Models, Animal; Glycogen; Hyperglycemia; Hyperinsulinism; Liver Glycogen; Male; Muscles; Myocardium; Phenformin; Rats

Topics: Animals; Diabetes Mellitus; Diabetes Mellitus, Experimental; Dogs; Fatty Liver; Female; Glycogen; Humans; Hyperglycemia; Insulin; Insulin Secretion; Islets of Langerhans; Lipid Metabolism; Liver; Liver Cirrhosis; Liver Diseases; Male; Rabbits; Rats

Hydrocortisone treatment caused a hyperglycaemic state in Clarias batrachus within an hour. The blood glucose values remained significantly increased for 6 days. An initial increase in liver glycogen was followed by a decrease below the normal value. The muscle and brain glycogen levels remained unaffected. A mild degranulation of B cells was seen in the early hours and a conspicuous vacuolation and necrosis of both A and B cells appeared 72-96 h after treatment. Administration of thyroxine resulted in hyperglycaemia within 15 h but a distinct hypoglycaemic condition was seen 4 days after the treatment. Considerable drain in the liver glycogen deposits was noticed between 24 and 72 h while the muscle glycogen showed an increase. The brain glycogen did not change noticeably. Islets of the fishes autopsied between 72 and 96 h contained severely damaged B cells. The A cells remained unaffected. It is suggested that, in addition to several other hormones, hydrocortisone and thyroxine play an important role in carbohydrate metabolism and blood sugar homoeostasis in C. batrachus.

Topics: Animals; B-Lymphocytes; Blood Glucose; Brain; Fish Diseases; Fishes; Glycogen; Hydrocortisone; Hyperglycemia; Islets of Langerhans; Liver Glycogen; Muscles; Thyroxine

Two concepts are advanced to explain some fo the puzzling biochemical features found in nonketotic hyperosmolar diabetic coma. It is firstly suggested that an insulinised liver (reflecting residual beta-cell secretory activity) coexists with a diabetic periphery, thereby inactivating intrahepatic oxidation of incoming free fatty acids, which are directed largly along nonketogenic metabolic pathways such as triglyceride synthesis. This could account for the lack of hyperketonaemia. Secondly, it is hypothesised that within the liver enhanced neoglucogenesis occurs, due to the prevailing portal-vein into ratio of glucagon to insulin, and is mainly responsible for the development of massive hyperglycaemia.

Topics: Animals; Diabetes Mellitus; Diabetic Coma; Fatty Acids, Nonesterified; Glucagon; Glycogen; Humans; Hyperglycemia; Insulin; Islets of Langerhans; Liver; Metabolic Clearance Rate; Osmolar Concentration; Oxidation-Reduction; Rats; Triglycerides

In diabetes mellitus abnormal quantiites of glycoprotein may be formed in the basement membrane of the glomerulus and both renal function and size may increase. It is suggested that these changes, of quite different potential significance, have a common origin an increased rate of uridine-triphosphate synthesis resulting from hyperglycemia.

Topics: Animals; Basement Membrane; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Glycogen; Glycoproteins; Humans; Hyperglycemia; Hypertrophy; Kidney; Kidney Diseases; Kidney Glomerulus; Rats; RNA; Sclerosis; Uracil Nucleotides

An agent extracted from calf bone marrow has a potent hyperglycemic effect when injected into rabbits and causes a very high glycosuric release. This high glucose release come from generalized glycogenolysis, particularly in muscles, contrary to glucagon effect. This agent has glycoprotein characteristics. It might be named, according to its origin: "erthromyelin".

Topics: Animals; Bone Marrow; Cattle; Female; Globulins; Glycogen; Glycoproteins; Glycosuria; Hyperglycemia; Liver; Liver Glycogen; Male; Molecular Weight; Muscles; Rabbits; Sex Factors; Temperature

Intramuscular administration of epinephrine in 2 mg/kg and 5 mg/kg body weight doses to Clarias batrachus caused significant hyperglycemia between 12 and 18 h after treatment. The hormone produced a small decrease in the liver glycogen, but induced a notable fall in the glycogen of muscles and a transient increase in the brain glycogen. Light-microscopical examination of the pancreatic islets revealed degranulation and vacuolization of the beta-cells accompanied by acute necrosis. Damage to the alpha-cells was also noticed in hyperglycemic fish. The changes in the cellular configuration of the islets, blood glucose and on the tissue glycogen contents were dose-dependent. It is suggested that epinephrine alters the carbohydrate metabolism through the alpha-cells of the islets.

Topics: Animals; Blood Glucose; Brain; Epinephrine; Female; Fishes; Fresh Water; Glycogen; Hyperglycemia; Islets of Langerhans; Liver Glycogen; Male; Muscles

Gluconeogenesis, when sharply stimulated by exhaustion of the liver glycogen reserves, is one of the factors maintaining the normal blood sugar level in mice with tumors. Hyperglycemia induce by glucose leads to an increase in the liver glycogen content and a decrease in the intensity of gluconeogenesis in control mice with tumors. Only in the latter, however, does glycogen synthesis from noncarbohydrate compounds rise again steadily after the injections of glucose are discontinued.

Topics: Animals; Gluconeogenesis; Glucose; Glycogen; Hyperglycemia; Liver; Male; Mice; Neoplasm Transplantation; Neoplasms, Experimental; Tyrosine

1. The entry of glucose into the pectoralis major muscle of living rats was measured over a wide range of plasma glucose concentrations. A technique was used by which steady concentrations of substances are maintained in the circulation throughout the experiments. 2. Raising the concentration of glucose in the plasma caused saturation of the mechanism by which it is transported into muscle. Estimates of the values of the kinetic constants for this transport system were: Kt, 34 mumole ml-1 and V, 1-2 mumole min-1-g-1 muscle. 3. When the plasma glucose concentration was raised up to at least twelve times normal, there was no sign of saturation of the transport system in insulin-treated animals. This finding could be explained if insulin increased greatly both V and Kt for glucose transport. 4. Insulin increased the rate of entry of glucose into muscle over the entire range of plasma glucose concentrations studied (4-8 mumole ml.-1). There was evidence that endogenous insulin produced a similar increase in entry rate some 10 min after the injection of glucose. Fasting, which is associated with a decrease in insulin level, depressed the rate of entry. In hyperglycaemia insulin caused a rise in the concentration of glucose within the muscle cells. 5. The insulin-induced increase in the rate of glucose entry into muscle ensured that approximately 25% of an I.V. dose of glucose entered the muscle cells of insulin-treated animals within one minute. This illustrates the quantitatively important regulatory role that skeletal muscle plays in these circumstances in limiting the extent of a rise in circulating glucose.

Topics: Animals; Biological Transport; Blood Glucose; Extracellular Space; Fasting; Female; Glucose; Glucosephosphates; Glycogen; Hyperglycemia; Injections, Intravenous; Insulin; Male; Mannitol; Muscles; Rats

Metabolic effects of vasopressin, glucagan and adrenalin were compared, in intact rats, especially in regard to time courses of effects. Hyperglycaemia was transient in response to vasopressin, prolonged following adrenalin, and, suprisingly, was not discernible after glucagon, except in response to a very large dose. Vasopressin decreased and adrenalin increased, the plasma free fatty acid concentration; both hormones decreased the triacylglycerol level. Muscle glycogen concentrations, measured in heart, diaphragm and skeletal muscle, exhibited small changes, with complex time courses, following hormone administration. Vasopressin brought about a rapid but transient activation of heaptic glycogen phosphorylase which resembled that due to adrenalin. The activation by glucagon of phosphorylase was greater and more prolonged, despite the absence of hyperglycaemia. In response to vasopressin, there was in increase in plasma insulin. Incorporation of 14C from [14C]glucose into glycogen or fatty acids was not influenced by vasopressin. Taken together, these results may be explained by rapid metabolic action of vasopressin on hepatic glycogenolysis, whereas adrenalin has multiple prolonged actions.

Topics: Adipose Tissue; Animals; Blood Glucose; Epinephrine; Fatty Acids; Female; Glucagon; Glycogen; Hyperglycemia; Insulin; Liver; Male; Muscles; Phosphorylases; Rats; Vasopressins

Topics: Animals; Cell Movement; Diabetes Mellitus; Epithelial Cells; Epithelium; Female; Glycogen; Hyperglycemia; Insulin; Male; Mouth Mucosa; Rats; Streptozocin; Wound Healing

Topics: Animals; Antigens; Basement Membrane; Body Weight; Capillaries; Diabetic Retinopathy; Disease Models, Animal; Endothelium; Eye; Glycogen; Hyperglycemia; Inclusion Bodies; Injections, Intravenous; Insulin; Microscopy, Electron; Mitochondria; Plasma Cells; Polyuria; Rats; Retina; Retinal Vessels; Streptozocin; Time Factors; Trypsin

Topics: Adenosine Triphosphate; Anaerobiosis; Brain; Carbohydrate Metabolism; Cyclic AMP; Dietary Carbohydrates; Epinephrine; Glucagon; Gluconeogenesis; Glucose; Glycogen; Glycogen Synthase; Humans; Hyperglycemia; Hypoxia; Insulin; Ketone Bodies; Lactates; Liver; Muscles; Oxidative Phosphorylation; Physical Exertion; Postoperative Complications; Pyruvates; Starvation; Wounds and Injuries

Topics: Animals; Blood Glucose; Epinephrine; Fasting; Female; Glycogen; Hyperglycemia; Injections, Intraperitoneal; Liver Glycogen; Muscles; Propranolol; Rats; Sotalol

Topics: Androgens; Animals; Blood Glucose; Carbohydrate Metabolism; Castration; Glucose; Glycogen; Hyperglycemia; Male; Rats; Testis

Topics: Animals; Blood Glucose; Carbon Radioisotopes; Carboxylic Acids; Eating; Epinephrine; Fasting; Gluconeogenesis; Glucose; Glutamates; Glycogen; Hydrazines; Hydrocortisone; Hyperglycemia; Indoles; Lactates; Liver; Liver Glycogen; Male; Muscles; Phenformin; Rats; Tryptophan

Topics: Acidosis; Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Blood Glucose; Blood Pressure; Body Temperature; Brain; Creatine; Energy Metabolism; Glucosephosphates; Glycogen; Hydrogen-Ion Concentration; Hyperglycemia; Hypoglycemia; Ischemia; Lactates; Phosphocreatine; Pyruvates; Rats

Topics: Animals; Dogs; Glucagon; Glycogen; Hyperglycemia; In Vitro Techniques; Intestine, Small; Liver; Peptides; Rabbits; Vasodilator Agents

Topics: Adipose Tissue; Animals; Diabetes Mellitus, Experimental; Enzyme Induction; Epididymis; Fasting; Glucose; Glucosephosphate Dehydrogenase; Glycerol; Glycerolphosphate Dehydrogenase; Glycogen; Hyperglycemia; L-Lactate Dehydrogenase; Malate Dehydrogenase; Male; Mice; Mice, Inbred Strains; Obesity; Organ Size; Spectrophotometry, Ultraviolet; Time Factors

Topics: Alanine; Animals; Blood Glucose; Brain Chemistry; Diabetes Mellitus; Gluconeogenesis; Glutamates; Glycine; Glycogen; Hyperglycemia; Injections, Intravenous; Ketones; Male; Rats; Starvation; Streptozocin

Topics: Animals; Blood Glucose; Cell Nucleus; Cricetinae; Cytoplasm; Diabetes Mellitus; Disease Models, Animal; Endoplasmic Reticulum; Glycogen; Golgi Apparatus; Hyperglycemia; Insulin; Insulin Secretion; Islets of Langerhans; Microscopy, Electron; Mitochondria

Topics: Age Factors; Animals; Blood Glucose; Child; Diabetes Mellitus, Type 1; Fats; Female; Glucose Tolerance Test; Glycogen; Humans; Hyperglycemia; Hypoglycemia; Male; Rabbits

Topics: Age Factors; Animals; Animals, Newborn; Blood Glucose; Body Temperature; Brain; Brain Chemistry; Cerebellum; Chickens; Circadian Rhythm; Diencephalon; Female; Glycogen; Hyperglycemia; Hypoglycemia; Ischemia; Male; Medulla Oblongata; Motor Activity; Temperature; Time Factors

Topics: Alloxan; Animals; Diaphragm; Glycogen; Hyperglycemia; Larva; Male; Muscles; Rats; Trichinella; Trichinellosis

Topics: Animals; Blood Glucose; Glucose; Glycogen; Hyperglycemia; Iontophoresis; Liver; Liver Glycogen; Muscles; Phospholipases; Rabbits; Snakes; Venoms

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Epinephrine; Fasting; Glycogen; Hyperglycemia; Insulin; Isoproterenol; Male; Rabbits

Topics: Animals; Diabetes Mellitus, Experimental; Fructose; Glucose; Glycogen; Hyperglycemia; Rats; Sorbitol

Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Carbon Dioxide; Carbon Isotopes; Diaphragm; Diet; Epididymis; Glucose; Glycogen; Hyperglycemia; In Vitro Techniques; Insulin; Insulin Resistance; Male; Mice; Mice, Inbred Strains; Muscles; Obesity; Parabiosis; Triglycerides

Topics: Acclimatization; Animals; Blood Glucose; Carbohydrate Metabolism; Cold Climate; Fishes; Freezing; Glycogen; Hematocrit; Hyperglycemia; Hypophysectomy; Liver Glycogen; Male; Muscles; Pituitary Gland

Topics: Adipose Tissue; Animals; Bicarbonates; Diaphragm; Epididymis; Fatty Acids, Nonesterified; Female; Gluconeogenesis; Glucose; Glycogen; Hyperglycemia; Isotonic Solutions; Liver Glycogen; Male; Monoamine Oxidase; Muscles; Phospholipases; Rats; Scorpions; Serotonin Antagonists; Venoms

Topics: Adenine Nucleotides; Animals; Cyclic AMP; Epinephrine; Female; Glucagon; Glucose; Glycogen; Hyperglycemia; In Vitro Techniques; Islets of Langerhans; Mice; Obesity; Theophylline

Topics: Animals; Blood Glucose; Epinephrine; Glycogen; Hyperglycemia; Insulin; Insulin Secretion; Islets of Langerhans; Rabbits; Stress, Physiological; Time Factors; Tolbutamide

Topics: Alcohols; Animals; Benzyl Compounds; Blood Glucose; Carbon Isotopes; Fasting; Gluconeogenesis; Glucose; Glycogen; Hyperglycemia; Liver; Mice; Movement; Pharmaceutic Aids; Time Factors

Topics: Age Factors; Animals; Animals, Newborn; Cytoplasm; Diabetic Nephropathies; Glycogen; Glycogen Storage Disease; Histocytochemistry; Hyperglycemia; Kidney Tubules; Lysosomes; Mice; Microscopy, Electron; Rats; Time Factors

Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Carbon Dioxide; Carbon Isotopes; Diaphragm; Diet Therapy; Glucose; Glycogen; Hyperglycemia; In Vitro Techniques; Insulin; Insulin Resistance; Mice; Muscles; Obesity

Topics: Animals; Blood Glucose; Carbamates; Carbohydrate Metabolism; Diabetes Mellitus; Diabetes Mellitus, Experimental; Disease Models, Animal; Fasting; Glucosamine; Glycogen; Glycosuria; Guinea Pigs; Hyperglycemia; Hypoglycemia; Lactates; Liver Glycogen; Male; Mice; Nitroso Compounds; Obesity; Oxazoles; Phenformin; Pyridinium Compounds; Rats

Topics: Adrenal Glands; Adrenalectomy; Animals; Blood Glucose; Catecholamines; Diet; Glycogen; Hydrocortisone; Hyperglycemia; Niacinamide; Rabbits; Reserpine

Topics: Adenine Nucleotides; Animals; Blood Glucose; Cell-Free System; Cyclic AMP; Esterases; Glycogen; Glycolysis; Guanine Nucleotides; Hyperglycemia; In Vitro Techniques; Liver; Liver Glycogen; Nucleosides; Perfusion; Rats

Topics: Adenine Nucleotides; Adrenal Cortex Hormones; Adrenalectomy; Alloxan; Aminophylline; Animals; Antigens; Asthma; Blood Glucose; Carbohydrate Metabolism; Diazoxide; Drug Hypersensitivity; Epinephrine; Glycogen; Gold; Histamine; Humans; Hydrocortisone; Hyperglycemia; Liver; Mice; Muscles; Obesity; Sympatholytics

1. The effect of the method of killing on the concentration of glycogen in mouse brain was determined. The cerebral glycogen content of mice killed by immersion in liquid nitrogen did not differe significantly from that of animals decapitated and the heads immediately frozen. A delay before freezing led to the rapid loss of brain glycogen, with a 17% fall at 10 s and an 82% loss after 5 min.2. Hyperglycaemia, induced by the administration of D-glucose, resulted in an 8.3% loss of brain glycogen after 120 min. Insulin hypoglycaemia produced a 10.7% fall in glycogen at 60 min followed by an 11.2% increase at 120 min.3. Exposure to either high (32 degrees C) or low (10 degrees C) ambient temperatures caused a depletion of brain glycogen.4. A circadian rhythm of brain glycogen concentration was found, with a nadir which was coincident with the peak of locomotor activity and body temperature.5. Drugs from several pharmacological classes were studied for their in vivo effect on the concentration of glycogen in mouse brain.6. Brain glycogen was increased by all the depressant drugs tested, and by some drugs which had little effect on behaviour (diphenhydramine, phenytoin and propranolol), or which caused excitation (caffeine and nialamide).7. Glycogen was depleted only by amphetamine-like compounds or by bemegride-induced convulsions.8. The results are discussed with particular reference to the possible relation between catecholamines and glycogen metabolism in the brain.

Topics: Amphetamine; Animals; Bemegride; Body Temperature; Brain Chemistry; Caffeine; Catecholamines; Circadian Rhythm; Diphenhydramine; Glucose; Glycogen; Hyperglycemia; Insulin; Male; Mice; Motor Activity; Nialamide; Phenytoin; Propranolol; Seizures; Temperature

Topics: Adipose Tissue; Animals; Enzyme Activation; Glucosyltransferases; Glycogen; Hyperglycemia; Insecta; Male; Neurosecretory Systems; Starvation

Topics: Animals; Blood Glucose; Cold Temperature; Fishes; Glycogen; Hyperglycemia; Liver; Liver Glycogen; Muscle Proteins; Muscles; Proteins

Topics: Acetates; Animals; Bicarbonates; Blood Glucose; Butyrates; Carbon Dioxide; Carbon Isotopes; Cattle; Fatty Acids; Female; Gluconeogenesis; Glucose; Glycogen; Goats; Hyperglycemia; Lactation; Pregnancy; Propionates; Sodium; Species Specificity; Stimulation, Chemical; Time Factors; Valerates

Topics: Adipose Tissue; Animals; Antigen-Antibody Reactions; Antigens; Carbon Isotopes; Diaphragm; Epididymis; Glucose; Glycogen; Guinea Pigs; Hyperglycemia; Immune Sera; Insulin; Insulin Antibodies; Kinetics; Lipid Metabolism; Liver Glycogen; Male; Muscles; Oxidation-Reduction; Radioimmunoassay; Rats

Topics: Adrenal Cortex Hormones; Adrenalectomy; Animals; Atrophy; Blood Glucose; Diabetes Mellitus; Glycogen; Hyperglycemia; Hypoglycemia; Hypophysectomy; Insulin; Insulin Secretion; Islets of Langerhans; Liver Glycogen; Muscles; Myocardium; Necrosis; Rats; Staining and Labeling; Thyroidectomy; Thyroxine

Topics: Adenine Nucleotides; Adipose Tissue; Adrenal Glands; Adrenocorticotropic Hormone; Animals; Corticosterone; Cyclic AMP; Diabetes Mellitus, Experimental; Fatty Acids, Nonesterified; Glycerol; Glycogen; Hyperglycemia; In Vitro Techniques; Lipid Metabolism; Male; Norepinephrine; Rats; Stimulation, Chemical; Theophylline

Topics: Animals; Cyclic AMP; Fluorometry; Glucagon; Glucosephosphate Dehydrogenase; Glucosyltransferases; Glycogen; Hexokinase; Hyperglycemia; Ischemia; Islets of Langerhans; Mice; NADP; Obesity; Phosphoglucomutase

Topics: Adenosine Triphosphate; Animals; Diazoxide; Female; Fluorometry; Glucose; Glycogen; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Secretion; Islets of Langerhans; Liver; Mice

Topics: Animals; Blood Glucose; Butyrates; Epinephrine; Fatty Acids; Glucagon; Glycogen; Hyperglycemia; Liver; Pancreas; Sheep

Topics: Animals; Blood Glucose; Body Weight; Corticosterone; Diabetes Mellitus, Experimental; Fatty Acids; Gluconeogenesis; Glucose; Glycogen; Glycolysis; Hyperglycemia; Liver; Male; Mice; Obesity; Oxidation-Reduction; Pyruvates; Radioactivity; Time Factors

Topics: Animals; Biotin; Blood Glucose; Electroshock; Fasting; Gluconeogenesis; Glycogen; Hyperglycemia; Hypoglycemia; Male; Rats; Stress, Physiological; Vitamin B Deficiency

Topics: Adipose Tissue; Animals; Basal Metabolism; Blood Glucose; Body Weight; Carbon Isotopes; Diet, Reducing; Female; Glucose; Glycogen; Hyperglycemia; Injections, Intravenous; Insulin; Mice; Muscles; Obesity

Topics: Animals; Blood Glucose; Erythrocytes; Glucose; Glycogen; Hyperglycemia; Hypoglycemia; In Vitro Techniques; Lactates; Liver; Male; Methods; Perfusion; Rats

Topics: Animals; Blood Glucose; Gluconeogenesis; Glycogen; Hepatectomy; Hyperglycemia; Hypoglycemia; Liver; Pancreas; Pancreatectomy; Rats

Topics: Animals; Antihypertensive Agents; Carbon Dioxide; Carbon Isotopes; Epinephrine; Fatty Acids, Nonesterified; Glucose; Glycogen; Hyperglycemia; Imidazoles; Lactates; Lipid Metabolism; Liver Glycogen; Male; Muscles; Nicotinic Acids; Norepinephrine; Phentolamine; Rats; Reserpine; Sensory Receptor Cells; Stimulation, Chemical; Sympathetic Nervous System; Sympatholytics; Tolazoline

Topics: Adenine Nucleotides; Animals; Cyclic AMP; Drug Hypersensitivity; Female; Glucosyltransferases; Glycogen; Histamine; Hyperglycemia; Mice; Muscles; Pharmacogenetics

Topics: Adrenal Medulla; Age Factors; Animals; Blood Glucose; Brain; Epinephrine; Glycogen; Hyperglycemia; Liver Glycogen; Mecamylamine; Muscles; NAD; Pyridines; Rats

Topics: Benzothiadiazines; Cyclic AMP; Diazoxide; Glycogen; Glycolysis; Humans; Hyperglycemia; Phosphoric Monoester Hydrolases

Topics: Adenoma, Islet Cell; Adult; Aged; Blood Glucose; Child; Coloring Agents; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diazoxide; Glycogen; Glycolysis; Humans; Hyperglycemia; Injections, Intravenous; Insulin; Liver; Male; Middle Aged

Topics: Acetone; Adenosine Triphosphate; Animals; Blood Glucose; Fluorometry; Glucose; Glycogen; Hexosephosphates; Hyperglycemia; Islets of Langerhans; Mice; Nucleotides; Obesity; Pancreas; Sorbitol; Time Factors

Topics: Adrenal Glands; Animals; Carbohydrate Metabolism; Diaphragm; Drug Antagonism; Glucose; Glycogen; Histamine; Hyperglycemia; Hypoglycemia; In Vitro Techniques; Insulin; Liver Glycogen; Male; Muscles; Oxygen Consumption; Rats; Starvation

Topics: Amylases; Animals; Dogs; Glycogen; Hyperglycemia; Iodine Isotopes; Liver; Liver Glycogen; Mononuclear Phagocyte System; Muscles; Thorium Dioxide

Topics: Adrenal Medulla; Alkaloids; Animals; Brain; Brain Chemistry; Catatonia; Female; Glucose; Glucose Oxidase; Glycogen; Humans; Hyperglycemia; Lactates; Muscles; Rats; Seizures; Sound

Topics: Animals; Electrocardiography; Female; Glucose; Glycogen; Heart; Heart Rate; Histocytochemistry; Hyperglycemia; Hypoxia; Infusions, Parenteral; Myocardium; Pregnancy; Rabbits

Topics: Animals; Butylamines; Catecholamines; Epinephrine; Fasting; Glycogen; Hyperglycemia; Isoproterenol; Lactates; Male; Methoxamine; Norepinephrine; Propranolol; Rats; Sympatholytics

Topics: Adipose Tissue; Animals; Blood Glucose; Carbon Isotopes; Diazoxide; Epididymis; Fatty Acids; Glucose; Glycogen; Hyperglycemia; Injections, Subcutaneous; Insulin; Liver; Liver Glycogen; Male; Mice

Topics: Animals; Blood Glucose; Diabetes Mellitus; Glucose; Glycogen; Histological Techniques; Hyperglycemia; Hypoglycemia; Injections, Intraperitoneal; Pancreas; Rats; Staining and Labeling

Topics: Adrenal Glands; Adrenal Medulla; Adrenocorticotropic Hormone; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Glucose; Glycogen; Hyperglycemia; Insulin; Male; Microchemistry; Pituitary Gland; Pituitary Gland, Posterior; Rats

Topics: Adrenalectomy; Animals; Blood Glucose; Chlorpromazine; Ergotamine; Female; Glucose Tolerance Test; Glycogen; Glycolysis; Hyperglycemia; Hypoglycemia; Injections, Intraperitoneal; Isoproterenol; Male; Propranolol; Rats; Reserpine; Sex Factors; Solanine

Topics: Adipose Tissue; Animals; Blood Glucose; Glucagon; Glycogen; Hyperglycemia; In Vitro Techniques; Insulin; Insulin Secretion; Islets of Langerhans; Liver Glycogen; Manometry; Muscles; Seasons; Turtles

Topics: Glucose; Glycogen; Glycolysis; Humans; Hyperglycemia; Hyperinsulinism; In Vitro Techniques; Insulin; Lactates; Leukocytes

Topics: Acute Disease; Carbohydrate Metabolism; Diabetes Complications; Glycogen; Humans; Hyperglycemia; Metabolic Diseases; Pancreatitis

Topics: Animals; Carbon Isotopes; Fasting; Female; Fetus; Gluconeogenesis; Glucose; Glycogen; Hyperglycemia; Liver; Liver Glycogen; Maternal-Fetal Exchange; Organ Size; Pregnancy; Rats

Topics: Adrenal Glands; Adrenalectomy; Animals; Catecholamines; Curare; Glycogen; Hyperglycemia; Oxygen Consumption; Rats; Stimulation, Chemical; Swine; Tubocurarine

Topics: Animals; Aspergillosis; Dexamethasone; Diabetes Mellitus, Experimental; Glycogen; Hyperglycemia; Keratitis; Rabbits

Topics: Antihypertensive Agents; Child; Diazoxide; Drug Eruptions; Drug Hypersensitivity; Glucose Tolerance Test; Glycerides; Glycogen; Glycogen Storage Disease Type I; Humans; Hyperglycemia; Hyperlipidemias; Hypoglycemia; Insulin; Lipids; Male; Triglycerides; Xanthomatosis

Topics: Adrenal Glands; Adrenalectomy; Animals; Blood; Corticosterone; Epinephrine; Ergotamine; Glucose; Glycogen; Hyperglycemia; Insulin; Niacinamide; Rats

Topics: Adrenal Glands; Adrenalectomy; Animals; Antihypertensive Agents; Diazoxide; Epinephrine; Ergotamine; Glucosyltransferases; Glycogen; Hyperglycemia; Liver; Muscles; Rats

Topics: Adenosine Triphosphate; Adrenal Glands; Animals; Antihypertensive Agents; Diabetes Mellitus, Experimental; Diazoxide; Enzymes; Epinephrine; Esterases; Glucose; Glucosyltransferases; Glycogen; Humans; Hyperglycemia; Insulin; Rats

Topics: Adrenocorticotropic Hormone; Animals; Fatty Acids; Glycogen; Growth Hormone; Haplorhini; Hyperglycemia; Hyperlipidemias; Hypophysectomy; Muscles; Placental Extracts; Proteins; Rabbits; Rats; Triglycerides

Topics: Adipose Tissue; Aging; Animals; Carbon Isotopes; Diaphragm; Epididymis; Glucose; Glycogen; Hyperglycemia; In Vitro Techniques; Injections, Intraperitoneal; Insulin; Male; Mice; Muscles; Obesity; Protein Binding

Topics: Adrenal Medulla; Animals; Blood Glucose; Chlordiazepoxide; Chlorpromazine; Electroconvulsive Therapy; Glucose Tolerance Test; Glycogen; Hyperglycemia; Imipramine; Lactates; Liver Glycogen; Muscles; Myocardium; Phenobarbital; Rats; Serotonin

Topics: Amylases; Animals; Blood Glucose; Dogs; Glucose Tolerance Test; Glycogen; Hyperglycemia; Hypoglycemia; Intestine, Small; Kidney; Liver Glycogen; Pancreatectomy

Topics: Animals; Blood Glucose; Diabetes Mellitus; Diabetes Mellitus, Experimental; Glucagon; Glycogen; Humans; Hyperglycemia; Insulin; Liver; Liver Glycogen; Pharmacology; Rabbits

Topics: Acetone; Adenosine Triphosphate; Animals; Brain Chemistry; Creatine; Female; Fructose; Glucose; Glycogen; Glycolysis; Hyperglycemia; Lactates; Mice; Phosphates; Pyruvates; Spectrophotometry

Topics: Adult; Blood Chemical Analysis; Blood Glucose; Cholesterol; Diagnosis, Differential; Erythrocytes; Galactose; Glucose; Glycerides; Glycogen; Glycogen Storage Disease; Histocytochemistry; Humans; Hyperglycemia; L-Lactate Dehydrogenase; Lactates; Leukocytes; Lipids; Liver Glycogen; Phosphorylase Kinase; Pyruvates

Topics: Anura; Blood Glucose; Body Weight; Glucagon; Glycogen; Hepatectomy; Hyperglycemia; Hypophysectomy; Liver Glycogen; Metabolism; Muscles; Myocardium; Pancreas; Pancreatectomy; Pharmacology; Physiology; Research

The relative activities of adrenaline, noradrenaline and isoprenaline in producing hyperglycaemia and glycogenolysis in skeletal muscle have been studied in both fed and fasted rats, 1 hr after subcutaneous injection of the catechol amines. The relative hyperglycaemic activities of the three catechol amines depended greatly upon the prandial state of the rats and on the dose range used. In fed rats the relative potencies were in the descending order of potency, adrenaline-noradrenaline-isoprenaline, irrespective of the dose range. Isoprenaline had no hyperglycaemic activity in fed rats even at doses as high as 2 mg/kg. In fasted rats the order of potency depended on the dose. At low doses (0.005 to 0.02 mg/kg) the descending order was isoprenaline-adrenaline-noradrenaline. At higher doses (0.1 to 1 mg/kg) the descending order was adrenaline-isoprenaline-noradrenaline. The relative activities of the three catechol amines in causing glycogenolysis in muscle was independent of the dose range or the prandial state of the rats. Under all conditions the descending order of potency was isoprenaline-adrenaline-noradrenaline. The results are discussed with reference to Ahlquist's (1948) hypothesis of alpha- and beta- receptors and were consistent with the concept that, in the rat, liver glycogenolysis is mediated predominantly by alpha-receptors and muscle glycogenolysis mainly by beta-receptors. In general the hyperglycaemic response in the fed rat is mediated predominantly by alpha-receptors and in the fasted rat the response is mainly due to the activation of beta-receptors. A drug possessing both alpha- and beta-receptor activity elicits an exception to this rule in the fasted rat. Several perturbing problems in the literature, particularly with regard to the hyperglycaemic activity of isoprenaline and to the difficulty in blocking the hyperglycaemic response, can now be explained in the light of these findings.

Topics: Amines; Carbohydrate Metabolism; Catecholamines; Catechols; Epinephrine; Fasting; Glycogen; Hyperglycemia; Isoproterenol; Muscles; Norepinephrine; Pharmacology; Rats; Research; Sensory Receptor Cells

Topics: Adolescent; Body Weight; Child; Dehydration; Diabetic Coma; Diabetic Ketoacidosis; Drug Therapy; Fluid Therapy; Glycogen; Glycosuria; Humans; Hyperglycemia; Infant; Infant, Newborn; Insulin; Metabolism; Parenteral Nutrition; Water-Electrolyte Balance

Topics: Animals; Ascorbic Acid; Glycogen; Guinea Pigs; Hyperglycemia; Liver Glycogen; Muscles; Rats; Research; Vitamins

Topics: Adrenal Glands; Blood; Blood Chemical Analysis; Body Weight; Brain; Brain Chemistry; Carbohydrate Metabolism; Chemical Phenomena; Chemistry; Chlorides; Cold Temperature; Electroshock; Glucose; Glycogen; Hyperglycemia; Hyperplasia; Hypertrophy; Liver; Muscles; Neurochemistry; Physiology; Potassium; Rats; Research; Seizures; Sodium; Thymus Gland; Water

Topics: Adrenal Glands; Animals; Diabetes Mellitus; Diabetes Mellitus, Experimental; Glycogen; Hyperglycemia; Hypoglycemia; Pituitary Gland; Rats

Topics: Animals; Glycogen; Glycogenolysis; Hyperglycemia; Liver; Liver Glycogen; Mice; Mice, Obese; Obesity

Topics: Animals; Glycogen; Glycogenolysis; Hyperglycemia; Liver; Liver Glycogen; Rats; X-Rays

Topics: Glycogen; Glycogenolysis; Growth Hormone; Human Growth Hormone; Hyperglycemia

Topics: Glucagon; Glycogen; Glycogenolysis; Hormones; Hyperglycemia; Pancreas; Pancreatic Hormones; Skin

Topics: Body Fluids; Glucagon; Glycogen; Hyperglycemia; Urine

Topics: Animals; Dogs; Glucose; Glycogen; Humans; Hyperglycemia; Liver

Topics: Animals; Biomedical Research; Diabetes Mellitus; Diabetes Mellitus, Experimental; Glycogen; Humans; Hyperglycemia; Pancreas; Rabbits

Topics: Glycogen; Glycogenolysis; Humans; Hyperglycemia; Insulin

Topics: Glycogen; Glycogenolysis; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Insulin

Topics: Glycogen; Humans; Hyperglycemia; Liver; Liver Function Tests; Liver Glycogen; Streptomycin

Two hundred and seven albino rats were injected subcutaneously with alloxan in doses varying from 140 to 200 mg. per cent per kilo of body weight. Fifty-nine animals which developed hyperglycemia (blood sugar levels above 150 mg. per cent) were observed for periods from 5 days to 32 weeks. Postmortem examination of the kidneys of these diabetic animals revealed glycogen deposition in the loops of Henle and convoluted tubules in 26 rats or 44 per cent. Glycogen could not be demonstrated in the glomeruli. Within the time limits of this experiment (32 weeks) no intercapillary glomerulosclerosis was observed. The following facts were revealed regarding glycogen nephrosis in alloxan diabetes: (a) Its appearance in the kidneys of the diabetic rats depended solely upon the terminal blood sugar levels of these animals. A value of 350 mg. per cent was the critical level, above which glycogen nephrosis was almost invariably demonstrable. With terminal levels below 300 mg. per cent no glycogen nephrosis was found. (b) No relationship existed between the postmortem finding of glycogen nephrosis and the initial blood sugar level, or the maximum height of the hyperglycemia attained by individual rats. (c) The results suggest that glycogen nephrosis is a reversible lesion.

Topics: Alloxan; Animals; Body Weight; Diabetes Mellitus; Diabetes Mellitus, Experimental; Glycogen; Hyperglycemia; Kidney; Kidney Diseases; Kidney Tubules; Nephrosis