glycogen and Hyperinsulinism

Hypoglycaemia is frequent in children and prompt management is required to prevent brain injury. In this article we will consider hypoglycaemia in children after the neonatal period. The most common causes are diabetes mellitus and idiopathic ketotic hypoglycaemia (IKH) but a number of endocrine disorders and inborn errors of metabolism (IEMs) need to be excluded. Elucidation of the diagnosis relies primarily on investigations during a hypoglycaemic episode but may also involve biochemical tests between episodes, dynamic endocrine tests and molecular genetics. Specific treatment such as cortisol replacement and pancreatic surgery may be required for endocrine causes of hypoglycaemia, such as adrenal insufficiency and congenital hyperinsulinism. In contrast, in IKH and most IEMs, hypoglycaemia is prevented by limiting the duration of fasting and maintaining a high glucose intake during illnesses.

Topics: Blood Glucose; Clinical Laboratory Techniques; Diagnosis, Differential; Early Diagnosis; Emergency Treatment; Fatty Acids; Glucose; Glycogen; Homeostasis; Humans; Hyperinsulinism; Hypoglycemia; Infections; Ketone Bodies; Liver Failure; Medical History Taking; Physical Examination

Most of the literature related to high altitude medicine is devoted to the short-term effects of high-altitude exposure on human physiology. However, long-term effects of living at high altitudes may be more important in relation to human disease because more than 400 million people worldwide reside above 1500 m. Interestingly, individuals living at higher altitudes have a lower fasting glycemia and better glucose tolerance compared with those who live near sea level. There is also emerging evidence of the lower prevalence of both obesity and diabetes at higher altitudes. The mechanisms underlying improved glucose control at higher altitudes remain unclear. In this review, we present the most current evidence about glucose homeostasis in residents living above 1500 m and discuss possible mechanisms that could explain the lower fasting glycemia and lower prevalence of obesity and diabetes in this population. Understanding the mechanisms that regulate and maintain the lower fasting glycemia in individuals who live at higher altitudes could lead to new therapeutics for impaired glucose homeostasis.

Topics: Adipose Tissue; Altitude; Diabetes Mellitus; Glucagon; Glucose; Glycogen; Homeostasis; Humans; Hyperinsulinism; Hypoglycemia; Hypoxia; Liver; Muscle, Skeletal; Obesity; Time Factors

The edematogenic properties of insulin have long been documented, although they have been underestimated despite current trends toward intensive insulin therapy. Insulin treatment has been associated with weight gain, mild or moderate edema, and, rarely, generalized edema and cardiopulmonary congestion. In addition, the use in recent years of thiazolidinediones, which improve insulin sensitivity, has been associated with weight gain and peripheral edema, which can progress to pulmonary edema, particularly when thiazolidinediones are used in combination with insulin. This article attempts to raise awareness about the overlooked edematogenic action of insulin. In addition, the potential role of edema-provoking properties of insulin in the development of vascular complications in patients with diabetes is discussed.

Topics: Capillary Permeability; Diabetic Angiopathies; Drug Interactions; Edema; Glycogen; Humans; Hyperinsulinism; Hypoglycemic Agents; Insulin; Mitochondria; Sodium; Thiazolidinediones; Water-Electrolyte Balance; Weight Gain

In vivo nuclear magnetic resonance (NMR) spectroscopy is a powerful tool for noninvasive metabolic research. NMR studies of tissue glycogen metabolism and glucose utilization have generated results with major implications for normal glucose homeostasis and the pathophysiology of type 2 diabetes mellitus. A key question for clinicians and physiologists reading these highly technical studies is: How accurate for whole-body carbohydrate metabolism is NMR spectroscopy? We review this topic and discuss technical, metabolic, and interpretive factors that may limit quantitative accuracy of this modality. We conclude that seeing is not yet believing regarding in vivo NMR spectroscopy; there are still important limitations to quantification of whole-body carbohydrate metabolism.

Topics: Carbohydrate Metabolism; Energy Metabolism; Evaluation Studies as Topic; Glycogen; Humans; Hyperinsulinism; Liver; Magnetic Resonance Spectroscopy; Muscles; Reproducibility of Results

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

Several types of experimental obesities are characterized by the occurrence of an early hypersecretion of insulin that produces an increase in both triglyceride secretion by the liver and fat deposition in adipose tissue. This hypersecretion of insulin, together with other ill-defined factors, is subsequently responsible for a state of insulin resistance. The early oversecretion of insulin in hypothalamic and genetic (e.g. fa/fa rats) obesities can be experimentally demonstrated. Thus, within 20 min of acute lesion of the ventromedial hypothalamus (VMH), glucose-induced insulin secretion is greater in lesioned than in non-lesioned control rats; this increase can be blocked by superimposed, acute vagotomy. Moreover, an infusion of glucose to 17-day-old, pre-weaned control and genetically pre-obese rats (i.e. animals genetically-determined to become obese but with a normal body weight at this age) elicits much greater insulinaemia in the pre-obese than in the controls, despite similar basal, pre-infusion values in both. This increased insulin secretion in the pre-obese rats can be restored to normal by pre-treating them acutely with the cholinergic inhibitor, atropine. Thus, in these two types of obesity, an increased vagal tone appears to be of importance for the early occurrence of insulin over-secretion. Hyperinsulinaemia produced by increased tone of the vagus nerve appears to be reinforced by the decreased activity of the sympathetic system observed in obese rodents. In many obese rodents, plasma growth hormone levels are abnormally low. The inadequate secretion of this hyperglycaemic hormone may explain why, in some types of obesity syndrome, hyperglycaemia is not necessarily present, despite insulin resistance. Insulin resistance in experimental obesities has been shown to occur at the level of the adipose tissue, the muscles and more recently, the liver. The latter has been demonstrated using the in vivo euglycaemic clamp technique; thus, glycogenolysis of genetically obese (fa/fa) rats could not be shut off, as in controls, by either basal or increased plasma insulin levels. This particular pathway is therefore insulin resistant. The precise etiology of the early over-secretion of insulin in VMH-lesioned rats is, however, unknown: with VMH lesions, the origin is clearly the central nervous system (CNS), but the pathways actually interrupted by the lesions and those responsible for the hyperactivity of the vagus, remain to be determined.(ABSTRACT TR

Topics: Adipose Tissue; Animals; Energy Metabolism; Glucose; Glycogen; Hyperinsulinism; Hypothalamus, Middle; Insulin; Insulin Resistance; Insulin Secretion; Liver; Models, Biological; Muscles; Obesity; Rats; Vagus Nerve

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

Glycogen synthesis is a critical metabolic function of the endometrium to prepare for successful implantation and sustain embryo development. Yet, regulation of endometrial carbohydrate metabolism is poorly characterized. Whereas glycogen synthesis is attributed to progesterone, we previously found that the metabolic B isoform of the insulin receptor is maximally expressed in secretory-phase endometrium, indicating a potential role of insulin in glucose metabolism.. We sought to determine whether insulin or progesterone regulates glycogen synthesis in human endometrium.. Endometrial epithelial cells were isolated from 28 healthy women and treated with insulin, medroxyprogesterone (MPA), or vehicle. Intracellular glycogen and the activation of key enzymes were quantified.. In epithelia, insulin induced a 4.4-fold increase in glycogen, whereas MPA did not alter glycogen content. Insulin inactivated glycogen synthase (GS) kinase 3α/β (GSK3α/β), relieving inhibition of GS. In a regulatory mechanism, distinct from liver and muscle, insulin also increased GS by 3.7-fold through increased GS 2 (GYS2) gene expression.. We demonstrate that insulin, not progesterone, directly regulates glycogen synthesis through canonical acute inactivation of GSK3α/β and noncanonical stimulation of GYS2 transcription. Persistently elevated GS enables endometrium to synthesize glycogen constitutively, independent of short-term nutrient flux, during implantation and early pregnancy. This suggests that insulin plays a key, physiological role in endometrial glucose metabolism and underlines the need to delineate the effect of maternal obesity and hyperinsulinemia on fertility and fetal development.

Topics: Adult; Cells, Cultured; Endometrium; Female; Gene Expression Regulation, Enzymologic; Glucose; Glycogen; Glycogen Synthase; Glycogenolysis; Humans; Hyperinsulinism; Insulin; Medroxyprogesterone; Muscle, Skeletal

We tested the hypotheses that human brain glycogen is mobilized during hypoglycemia and its content increases above normal levels ("supercompensates") after hypoglycemia.. We utilized in vivo (13)C nuclear magnetic resonance spectroscopy in conjunction with intravenous infusions of [(13)C]glucose in healthy volunteers to measure brain glycogen metabolism during and after euglycemic and hypoglycemic clamps.. After an overnight intravenous infusion of 99% enriched [1-(13)C]glucose to prelabel glycogen, the rate of label wash-out from [1-(13)C]glycogen was higher (0.12 +/- 0.05 vs. 0.03 +/- 0.06 micromol x g(-1) x h(-1), means +/- SD, P < 0.02, n = 5) during a 2-h hyperinsulinemic-hypoglycemic clamp (glucose concentration 57.2 +/- 9.7 mg/dl) than during a hyperinsulinemic-euglycemic clamp (95.3 +/- 3.3 mg/dl), indicating mobilization of glucose units from glycogen during moderate hypoglycemia. Five additional healthy volunteers received intravenous 25-50% enriched [1-(13)C]glucose over 22-54 h after undergoing hyperinsulinemic-euglycemic (glucose concentration 92.4 +/- 2.3 mg/dl) and hyperinsulinemic-hypoglycemic (52.9 +/- 4.8 mg/dl) clamps separated by at least 1 month. Levels of newly synthesized glycogen measured from 4 to 80 h were higher after hypoglycemia than after euglycemia (P

Topics: Adaptation, Physiological; Adult; Blood Glucose; Brain; Carbon Isotopes; Energy Metabolism; Female; Glucose; Glucose Clamp Technique; Glycogen; Humans; Hyperinsulinism; Hypoglycemia; Infusions, Intravenous; Magnetic Resonance Spectroscopy; Male; Models, Biological; Young Adult

Although data suggest that physical activity is associated with decreased insulin resistance, recommendations for exercise training are not specific for age or level of obesity. Therefore, we examined the influence of moderate-intensity (50% of VO2max) exercise training (MI) versus high-intensity (75% of VO2max) exercise training (HI) on insulin-stimulated glucose disposal (ISGD) in elderly individuals.. Following medical examinations, 21 overweight (body mass index = 29 +/- 1 kg x m(-2)) elderly (74 +/- 1 yr) subjects were randomized to 1) HI, 2) MI, or a 3) nonexercising control group. Subjects enrolled in HI or MI completed a 12-wk exercise training regimen designed to expend 1000 kcal x wk. ISGD was assessed using a hyperinsulinemic, euglycemic clamp pre- and postintervention. ISGD was corrected for hepatic glucose production (glucose Ra) using a constant rate infusion of [6,6-H2]glucose and determined during the last 30 min of the clamp by subtracting glucose Ra from the exogenous glucose infusion rate. Nonoxidative glucose disposal was calculated using indirect calorimetry. Body composition testing was completed using dual energy x-ray absorptiometry.. ISGD increased by approximately 20% with HI (Delta of 1.4 +/- 0.5 mg x kg(-1) FFM.min(-1)). However, ISGD did not change (Delta of -0.4 +/- 0.1 mg x kg(-1) FFM.min(-1)) with MI and was not different (Delta of -0.2 +/- 0.1 mg x kg(-1) FFM.min(-1)) in the control group. Nonoxidative glucose disposal increased with HI (Delta of 1.4 +/- 0.5 mg x kg(-1) FFM.min(-1)), but there was no change in nonoxidative glucose disposal with MI or in the control group. No change in body weight or percentage of body fat was observed in any group.. In weight-stable subjects, MI resulted in no change in ISGD, and the improvement in ISGD with HI was completely reliant on improvements in nonoxidative glucose disposal.

Topics: Aged; Arkansas; Exercise; Female; Glycogen; Humans; Hyperinsulinism; Male

The hypermetabolic response to burn increases protein catabolism. Euglycemic hyperinsu-linemia with exogenous insulin maintains muscle protein by continued stimulation of net protein synthesis. Our aim was to determine the effect of euglycemic hyperinsulinemia over the entire hospitalization on muscle anabolism by investigating lean body mass (LBM) as the primary endpoint.. Eighteen subjects between the ages of 2 and 18 with burns of more than 40% were prospectively randomized into 2 groups, a control (n = 9) and a treatment group (n = 9). The treatment group was given continuous intravenous insulin at a rate of at least 1.5 microU/kg/min to maintain serum glucose levels between 100 to 140 mg/dL. Treatment was instituted 24 to 48 hours after arrival and continued until the patient's injury was 95% healed. All patients received continuous enteral feeding. Patients underwent body composition studies by dual-energy x-ray absorptiometry (DEXA) scan on postoperative day 6 after initial burn excision and when 95% healed.. Nutritional intakes were not different between groups. In the control, subjects continued catabolism resulted in peripheral muscle wasting and centripetal obesity with diminished truncal LBM. The treatment group had improvement in lean body mass (P =.004) and bone mass (P =.025). The treatment group also had less peripheral muscle wasting with overall increases in upper/lower extremity LBM (P =.005). Hospital length of stay in days per percent of total body surface area burned was decreased in the insulin group (control = 1.03 +/- 0.1 vs 0.7 +/- 0.9 for insulin patients; P <.05).. Euglycemic hyperinsulinemia throughout the hospital course mitigates muscle catabolism and preserves lean body mass.

Topics: Adult; Blood Glucose; Body Composition; Body Weight; Burns; Calorimetry, Indirect; Child; Child, Preschool; Electrolytes; Energy Metabolism; Female; Follow-Up Studies; Glucose Clamp Technique; Glycogen; Humans; Hyperinsulinism; Hypoglycemic Agents; Insulin; Male; Muscle, Skeletal; Nutrition Assessment; Prospective Studies

To investigate the effect of thalidomide on glucose turnover (glucose production and uptake), on intracellular pathways of glucose utilization (glycogen synthesis [GS], glycolysis [GLS], carbohydrate oxidation, and nonoxidative GLS), and on free fatty acid (FFA) turnover (lipolysis, FFA oxidation, and FFA reesterification).. A total of 6 patients with type 2 diabetes were studied with 4-h isoglycemic-hyperinsulinemic clamps (approximately 8 mmol/l and 500-600 pmol/l, respectively) before treatment (Prestudy), after 3 weeks of thalidomide (150 mg orally at bedtime), and after 3 weeks of placebo.. Thalidomide reduced insulin-stimulated glucose uptake by 31% (from 27.7 to 19.2 pmol x kg(-1) x min(-1), P < 0.05) compared with the prestudy and by 21% (from 24.2 to 19.2 pmol x kg(-1) x min(-1), P < 0.05) compared with placebo. Thalidomide also reduced insulin-stimulated GS by 48% (from 14.1 to 8.2 micromol x kg(-1) x min(-1), P < 0.05) compared with the prestudy and by 40% (from 13.6 to 8.2 micromol x kg(-1) x min(-1), P < 0.5) compared with placebo. Thalidomide had no effect on rates of GLS, carbohydrate oxidation, nonoxidative GLS, lipolysis, FFA oxidation, and reesterification.. We conclude that thalidomide increased insulin resistance in obese patients with type 2 diabetes by inhibiting insulin-stimulated GS and that patients taking thalidomide should be monitored for possible deterioration in their glucose tolerance.

Topics: Blood Glucose; Cross-Over Studies; Diabetes Mellitus, Type 2; Female; Glucose; Glucose Clamp Technique; Glycogen; Humans; Hyperinsulinism; Infusions, Intravenous; Insulin; Lipolysis; Male; Middle Aged; Placebos; Radioisotope Dilution Technique; Single-Blind Method; Thalidomide; Tritium

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

Carbohydrate metabolism was assessed in 20 glucose-intolerant subjects before and after 12 wk on a high-carbohydrate diet (HC) or the diet combined with exercise training (HC-EX). The diet provided 60% of energy as carbohydrate and 20% as fat. Neither treatment altered fasting glucose or insulin concentrations or their response to a meal. During a glucose clamp (216 pmol insulin/L) glucose disposal increased from 13.2 +/- 0.83 to 14.6 +/- 0.83 mumol.kg fat-free mass-1.min-1 (P < 0.05) in both groups. During more pronounced hyperinsulinemia (654 pmol/L) glucose disposal did not change significantly (49.9 +/- 3.8 to 50.7 +/- 3.8 mumol.kg fat-free mass-1.min-1). Muscle glycogen increased in the HC-EX group (78.5 +/- 8.1 to 161.1 +/- 15.7 mmol glucose/kg muscle), with no changes in the HC group. These results do not support the recommendation to increase the dietary carbohydrate content for improving postprandial glucose metabolism or insulin action in glucose-intolerant adults unless combined with exercise training, which promotes muscle glycogen storage.

Topics: Aged; Aging; Blood Glucose; Body Composition; Dietary Carbohydrates; Dose-Response Relationship, Drug; Energy Metabolism; Exercise; Female; Glucose Clamp Technique; Glucose Tolerance Test; Glycogen; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Male; Middle Aged; Muscle, Skeletal; Time Factors

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

This study investigated the role of GABA in attenuating liver insulin resistance (IR) in type 2 diabetes parents and reducing its risk in their descendants' liver. Both sexes' rats were divided into four groups of non-diabetic control, diabetic control (DC), GABA-treated (GABA), and insulin-treated (Ins). The study duration lasted for six months and the young animals followed for four months. Consequently, hyperinsulinemic-euglycemic clamp was performed for all animals. Apart from insulin tolerance test (ITT), serum and liver lipid profile were measured in all groups. Glycogen levels, expression of Foxo1, Irs2, Akt2, and Pepck genes in the liver were assessed for all groups. Overall, GABA improved ITT, increased liver glycogen levels and decreased lipid profile, blood glucose level, and HbA1c in parents and their offspring in compared to the DC group. GIR also increased in both parents and their offspring by GABA. Moreover, the expression of Foxo1, Irs2, Akt2, and Pepck genes improved in GABA-treated parents and their descendants in compared to DC group. Results indicated that GABA reduced liver IR in both parents and their offspring via affecting their liver insulin signaling and gluconeogenesis pathways.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Endocrinology; Female; gamma-Aminobutyric Acid; Gluconeogenesis; Glucose; Glucose Clamp Technique; Glucose Tolerance Test; Glycogen; Hyperinsulinism; Insulin; Insulin Resistance; Liver; Male; Rats; Rats, Wistar; Signal Transduction

During the development of type 2 diabetes mellitus (T2DM), hyperinsulinemia is the earliest symptom. It is believed that long-term high insulin stimulation might facilitate insulin resistance in the liver, but the underlying mechanism remains unknown. Herein, we report that hyperinsulinemia could induce persistent early growth response gene-1 (Egr-1) activation in hepatocytes, which provides negative feedback inhibition of insulin sensitivity by inducing the expression of protein tyrosine phosphatase-1B (PTP1B). Deletion of Egr-1 in the liver remarkably decreases glucose production, thus improving systemic glucose tolerance and insulin sensitivity. Mechanistic analysis indicates that Egr-1 inhibits insulin receptor phosphorylation by directly activating PTP1B transcription in the liver. Our results reveal the molecular mechanism by which hyperinsulinemia accelerates insulin resistance in hepatocytes during the progression of T2DM.

Topics: Animals; Cells, Cultured; Diabetes Mellitus, Type 2; Disease Models, Animal; Early Growth Response Protein 1; Gene Knockout Techniques; Glucose; Glycogen; Hyperinsulinism; Insulin; Insulin Resistance; Liver; Male; Mice; Phosphorylation; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Receptor, Insulin; Transcriptional Activation

The present study investigated the effects of oral ethinylestradiol-levonorgestrel (EEL) on hepatic lipid and glycogen contents during high fructose (HF) intake, and determined whether pyruvate dehydrogenase kinase-4 (PDK-4) and glucose-6-phosphate dehydrogenase (G6PD) activity were involved in HF and (or) EEL-induced hepatic dysmetabolism. Female Wistar rats weighing 140-160 g were divided into groups. The control, EEL, HF, and EEL+HF groups received water (vehicle, p.o.), 1.0 μg ethinylestradiol plus 5.0 μg levonorgestrel (p.o.), fructose (10%

Topics: Administration, Oral; Animals; Antioxidants; Blood Glucose; Dose-Response Relationship, Drug; Drug Combinations; Ethinyl Estradiol; Female; Fructose; Glucosephosphate Dehydrogenase; Glycogen; Hyperinsulinism; Insulin Resistance; Levonorgestrel; Lipid Metabolism; Lipid Peroxidation; Liver; Protein Kinases; Rats; Rats, Wistar; Uric Acid

Topics: Animals; Carbohydrate Metabolism; Circadian Rhythm; Dogs; Female; Glucose; Glycogen; Hyperinsulinism; Insulin; Liver; Liver Glycogen; Male; Time Factors

In humans, low levels of growth hormone (GH) and its mediator, IGF-1, associate with hepatic lipid accumulation. In mice, congenital liver-specific ablation of the GH receptor (GHR) results in reductions in circulating IGF-1 and hepatic steatosis, associated with systemic insulin resistance. Due to the intricate relationship between GH and IGF-1, the relative contribution of each hormone to the development of hepatic steatosis is unclear. Our goal was to dissect the mechanisms by which hepatic GH resistance leads to steatosis and overall insulin resistance, independent of IGF-1. We have generated a combined mouse model with liver-specific ablation of GHR in which we restored liver IGF-1 expression via the hepatic IGF-1 transgene. We found that liver GHR ablation leads to increases in lipid uptake, de novo lipogenesis, hyperinsulinemia, and hyperglycemia accompanied with severe insulin resistance and increased body adiposity and serum lipids. Restoration of IGF-1 improved overall insulin sensitivity and lipid profile in serum and reduced body adiposity, but was insufficient to protect against steatosis-induced hepatic inflammation or oxidative stress. We conclude that the impaired metabolism in states of GH resistance results from direct actions of GH on lipid uptake and de novo lipogenesis, whereas its actions on extrahepatic tissues are mediated by IGF-1.

Topics: Animals; Blotting, Western; Fatty Acids; Fatty Acids, Nonesterified; Fatty Liver; Glycogen; Growth Hormone; Hyperinsulinism; Insulin Resistance; Insulin-Like Growth Factor I; Lipid Metabolism; Lipid Peroxidation; Liver; Male; Mice; Mice, Knockout; Oxidative Stress; Receptors, Somatotropin

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

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 effect of a long-term high-fat, high-caloric diet on the dysfunction of pancreas has not been clarified. We investigated the pancreatic histopathology and β-cell apoptosis in Bama minipigs after 23 months on a high-fat high-sucrose diet (HFHSD).. Bama minipigs were randomly assigned to control (n = 6) and HFHSD groups (n = 6) for 23 months, and biochemical parameters were measured. Pancreata were subjected to histological analysis, followed by assessment with transmission electron microscopy. Lipid peroxidation was determined by the malondialdehyde concentration and antioxidant enzyme activity. Β-cell apoptosis was measured by an immunohistochemical method.. In the HFHSD group, the islets were enlarged, and the pancreatic tissue had observed significant fatty infiltration. Moreover, the feeding program damaged the normal pancreatic tissue structure. The level of lipid peroxidation was increased, and the activities of pancreatic antioxidant enzymes were significantly decreased. The expression levels of caspase-3, Bax, and insulin were significantly increased (P < 0.05), and the expression levels of proliferating cell nuclear antigen and Bcl-2 were decreased (P < 0.05).. The long-term HFHSD promotes pancreatic steatosis and oxidative stress, which increases β-cell apoptosis as indicated by the activation of caspase-3 through the mitochondrial pathway (Bcl-2/Bax).

Topics: Animals; Antioxidants; Apoptosis; bcl-2-Associated X Protein; Biomarkers; Blood Glucose; Caspase 3; Cell Proliferation; Diet, High-Fat; Dietary Sucrose; Disease Models, Animal; Glycogen; Hyperinsulinism; Insulin; Insulin-Secreting Cells; Islets of Langerhans; Lipid Peroxidation; Malondialdehyde; Obesity; Oxidative Stress; Pancreatic Diseases; Proto-Oncogene Proteins c-bcl-2; Swine; Swine, Miniature; Time Factors

The pyruvate dehydrogenase complex (PDH) has been hypothesized to link lipid exposure to skeletal muscle insulin resistance through a glucose-fatty acid cycle in which increased fatty acid oxidation increases acetyl-CoA concentrations, thereby inactivating PDH and decreasing glucose oxidation. However, whether fatty acids induce insulin resistance by decreasing PDH flux remains unknown. To genetically examine this hypothesis we assessed relative rates of pyruvate dehydrogenase flux/mitochondrial oxidative flux and insulin-stimulated rates of muscle glucose metabolism in awake mice lacking pyruvate dehydrogenase kinase 2 and 4 [double knockout (DKO)], which results in constitutively activated PDH. Surprisingly, increased glucose oxidation in DKO muscle was accompanied by reduced insulin-stimulated muscle glucose uptake. Preferential myocellular glucose utilization in DKO mice decreased fatty acid oxidation, resulting in increased reesterification of acyl-CoAs into diacylglycerol and triacylglycerol, with subsequent activation of PKC-θ and inhibition of insulin signaling in muscle. In contrast, other putative mediators of muscle insulin resistance, including muscle acylcarnitines, ceramides, reactive oxygen species production, and oxidative stress markers, were not increased. These findings demonstrate that modulation of oxidative substrate selection to increase muscle glucose utilization surprisingly results in muscle insulin resistance, offering genetic evidence against the glucose-fatty acid cycle hypothesis of muscle insulin resistance.

Topics: Animals; Carnitine; Citric Acid Cycle; Dietary Fats; Enzyme Activation; Fatty Acids; Glucose; Glycogen; Hyperinsulinism; Insulin Resistance; Isoenzymes; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Biological; Muscle, Skeletal; Nuclear Magnetic Resonance, Biomolecular; Oxidation-Reduction; Oxidative Stress; Phosphorylation; Protein Kinase C; Protein Kinase C-theta; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Pyruvate Dehydrogenase Acetyl-Transferring Kinase; Pyruvate Dehydrogenase Complex; Reactive Oxygen Species; RNA, Messenger; Substrate Specificity

Insulin rapidly suppresses hepatic glucose production and slowly decreases expression of genes encoding gluconeogenic proteins. In this study, we show that an immediate effect of insulin is to redirect newly synthesized glucose-6-phosphate to glycogen without changing the rate of gluconeogenesis. This process requires hepatic Akt2, as revealed by blunted insulin-mediated suppression of glycogenolysis in the perfused mouse liver, elevated hepatic glucose production during a euglycemic-hyperinsulinemic clamp, or diminished glycogen accumulation during clamp or refeeding in mice without hepatic Akt2. Surprisingly, the absence of Akt2 disrupted glycogen metabolism independent of GSK3α and GSK3β phosphorylation, which is thought to be an essential step in the pathway by which insulin regulates glycogen synthesis through Akt. These data show that (1) the immediate action of insulin to suppress hepatic glucose production functions via an Akt2-dependent redirection of glucose-6-phosphate to glycogen, and (2) insulin increases glucose phosphorylation and conversion to glycogen independent of GSK3.

Topics: Animals; Disease Models, Animal; Glucose Clamp Technique; Glucose-6-Phosphate; Glycogen; Glycogen Synthase Kinase 3; Glycogenolysis; Hyperinsulinism; Insulin; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Postprandial Period; Proto-Oncogene Proteins c-akt; Signal Transduction

Profound hypoglycemia occurs rarely as a late complication after Roux-en-Y gastric bypass (RYGB). We investigated the role of glucagon-like-peptide-1 (GLP-1) in four subjects who developed recurrent neuro-glycopenia 2 to 3 y after RYGB.. A standardized test meal (STM) was administered to all four subjects. A 2 h hyperglycemic clamp with GLP-1 infusion during the second hour was performed in one subject, before, during a 4 wk trial of octreotide (Oc), and after 85% distal pancreatectomy. After cessation of both glucose and GLP-1 infusion at the end of the 2 h clamp, blood glucose levels were monitored for 30 min. Responses were compared with a control group (five subjects 12 mo status post-RYGB without hypoglycemic symptoms).. During STM, both GLP-1 and insulin levels were elevated 3- to 4-fold in all subjects, and plasma glucose-dependent insulinotropic peptide (GIP) levels were elevated 2-fold. Insulin responses to hyperglycemia ± GLP-1 infusion in one subject were comparable to controls, but after cessation of glucose infusion, glucose levels fell to 40 mg/dL. During Oc, the GLP-1 and insulin responses to STM were reduced (>50%). During the clamp, insulin response to hyperglycemia alone was reduced, but remained unchanged during GLP-1. Glucagon levels during hyperglycemia alone were suppressed and further suppressed after the addition of GLP-1. With the substantial drop in glucose during the 30 min follow-up, glucagon levels failed to rise. Due to persistent symptoms, one subject underwent 85% distal pancreatectomy; postoperatively, the subject remained asymptomatic (blood glucose: 119-220 mg/dL), but a repeat STM showed persistence of elevated levels of GLP-1. Histologically enlarged islets, and β-cell clusters scattered throughout the acinar parenchyma were seen, as well as β-cells present within pancreatic duct epithelium. An increase in pancreatic and duodenal homeobox-1 protein (PDX-1) expression was observed in the subject compared with control pancreatic tissue.. A persistent exaggerated hypersecretion of GLP-1, which has been shown to be insulinotropic, insulinomimetic, and glucagonostatic, is the likely cause of post-RYGB hypoglycemia. The hypertrophy and ectopic location of β-cells is likely due to overexpression of the islet cell transcription factor, PDX-1, caused by prolonged hypersecretion of GLP-1.

Topics: Blood Glucose; Endocrine System; Female; Gastric Bypass; Gastric Inhibitory Polypeptide; Gastrointestinal Tract; Glucagon-Like Peptide 1; Glycogen; Homeodomain Proteins; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Middle Aged; Obesity; Pancreas; Trans-Activators

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

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

In rodents, acute brain insulin action reduces blood glucose levels by suppressing the expression of enzymes in the hepatic gluconeogenic pathway, thereby reducing gluconeogenesis and endogenous glucose production (EGP). Whether a similar mechanism is functional in large animals, including humans, is unknown. Here, we demonstrated that in canines, physiologic brain hyperinsulinemia brought about by infusion of insulin into the head arteries (during a pancreatic clamp to maintain basal hepatic insulin and glucagon levels) activated hypothalamic Akt, altered STAT3 signaling in the liver, and suppressed hepatic gluconeogenic gene expression without altering EGP or gluconeogenesis. Rather, brain hyperinsulinemia slowly caused a modest reduction in net hepatic glucose output (NHGO) that was attributable to increased net hepatic glucose uptake and glycogen synthesis. This was associated with decreased levels of glycogen synthase kinase 3β (GSK3β) protein and mRNA and with decreased glycogen synthase phosphorylation, changes that were blocked by hypothalamic PI3K inhibition. Therefore, we conclude that the canine brain senses physiologic elevations in plasma insulin, and that this in turn regulates genetic events in the liver. In the context of basal insulin and glucagon levels at the liver, this input augments hepatic glucose uptake and glycogen synthesis, reducing NHGO without altering EGP.

Topics: Animals; Brain; Dogs; Fatty Acids, Nonesterified; Glucagon; Gluconeogenesis; Glucose; Glycogen; Humans; Hyperinsulinism; Insulin; Liver

This study investigated whether exercise training could prevent the negative side effects of dexamethasone. Rats underwent a training period and were either submitted to a running protocol (60% physical capacity, 5 days/week for 8 weeks) or kept sedentary. After this training period, the animals underwent dexamethasone treatment (1 mg/kg per day, i.p., 10 days). Glycemia, insulinemia, muscular weight and muscular glycogen were measured from blood and skeletal muscle. Vascular endothelial growth factor (VEGF) protein was analyzed in skeletal muscles. Dexamethasone treatment evoked body weight loss (-24%), followed by muscular atrophy in the tibialis anterior (-25%) and the extensor digitorum longus (EDL, -15%). Dexamethasone also increased serum insulin levels by 5.7-fold and glucose levels by 2.5-fold compared to control. The exercise protocol prevented atrophy of the EDL and insulin resistance. Also, dexamethasone-treated rats showed decreased muscular glycogen (-41%), which was further attenuated by the exercise protocol. The VEGF protein expression decreased in the skeletal muscles of dexamethasone-treated rats and was unaltered by the exercise protocol. These data suggest that exercise attenuates hyperglycemia and may also prevent insulin resistance, muscular glycogen loss and muscular atrophy, thus suggesting that exercise may have some benefits during glucocorticoid treatment.

Topics: Animals; Blood Glucose; Body Weight; Dexamethasone; Exercise Test; Glucocorticoids; Glycogen; Hyperinsulinism; Insulin; Insulin Resistance; Male; Muscle, Skeletal; Muscular Atrophy; Physical Conditioning, Animal; Rats; Rats, Wistar; Time Factors

Sinigrin (SIN) and allyl isothiocyanate (AITC) are compounds found in high concentrations in Brassica family vegetables, especially in Brussels sprouts. Recently, they have been used as a nutrition supplement for their preventive and medicinal effect on some types of cancer and other diseases. In this research, nutritional significance of parent glucosinolate sinigrin 50 μmol/kg b. w./day and its degradation product allyl isothiocyanate 25 μmol/kg b. w./day and 50 μmol/kg b. w./day was studied by the evaluation of their influence on some parameters of carbohydrate and lipid metabolism in an animal rat model in vivo after their single (4 h) and 2 weeks oral administration. Additionally, the aim of this trial was to evaluate the direct action of AITC on basal and epinephrine-induced lipolysis in isolated rat adipocytes at concentration 1 μM, 10 μM and 100 μM in vitro. Sole AITC after 4 h of its ingestion caused liver triacylglycerols increment at both doses and glycaemia only at the higher dose. Multiple SIN treatment showed its putative bioconversion into AITC. It was found that SIN and AITC multiple administration in the same way strongly disturbed lipid and carbohydrate homeostasis, increasing esterified and total cholesterol, free fatty acids and lowering tracylglycerols in the blood serum. Additionally, AITC at both doses elevated insulinaemia and liver glycogen enhancement. The in vitro experiment revealed that AITC potentiated basal lipolysis process at 10 μM, and had stimulatory effect on epinephrine action at 1 μM and 10 μM. The results of this study demonstrated that the effect of SIN and AITC is multidirectional, indicating its impact on many organs like liver as well as pancreas, intestine in vivo action and rat adipocytes in vitro. Whilst consumption of cruciferous vegetables at levels currently considered "normal" seems to be beneficial to human health, this data suggest that any large increase in intake could conceivably lead to undesirable effect. This effect is potentiated with time of action of the examined compounds, whose influence is rather adverse for the majority of metabolic pathways (liver steatosis at short duration and insulinaemia, cholesterolaemia at long time treatment). Beneficial action of AITC concerned intensified hydrolysis of TG in the blood serum with a simultaneous lipolysis in adipocytes.

Topics: Adipocytes; Animals; Brassica; Carbohydrate Metabolism; Cholesterol; Dose-Response Relationship, Drug; Epinephrine; Esterification; Fatty Acids, Nonesterified; Fatty Liver; Glucosinolates; Glycogen; Homeostasis; Hydrolysis; Hyperinsulinism; Isothiocyanates; Lipid Metabolism; Lipolysis; Liver; Male; Models, Animal; Pancreas; Rats; Rats, Wistar; Time Factors; Triglycerides

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

To examine whether escitalopram enhances net hepatic glucose uptake during a hyperinsulinemic hyperglycemic clamp, studies were performed in conscious 42-h-fasted dogs. The experimental period was divided into P1 (0-90 min) and P2 (90-270 min). During P1 and P2 somatostatin (to inhibit insulin and glucagon secretion), 4x basal intraportal insulin, basal intraportal glucagon, and peripheral glucose (2x hepatic glucose load) were infused. Saline was infused intraportally during P1 in all groups. In one group saline infusion was continued in P2 (SAL, n = 11), while escitalopram was infused intraportally at 2 microg/kg/min (L-ESC, n = 6) or 8 microg/kg/min (H-ESC, n = 7) during P2 in two other groups. The arterial insulin concentrations rose approximately four fold (to 123 +/- 8, 146 +/- 13 and 148 +/- 15 pmol/L) while glucagon concentrations remained basal (41 +/- 3, 44 +/- 9 and 40 +/- 3 ng/L) in all groups. The hepatic glucose load averaged 216 +/- 13, 223 +/- 19 and 202 +/- 12 micromol/kg/min during the entire experimental period (P1 and P2) in the SAL, L-ESC and H-ESC groups, respectively. Net hepatic glucose uptake was 11.6 +/- 1.4, 10.1 +/- 0.9 and 10.4 +/- 2.3 micromol/kg/min in P1 and averaged 16.9 +/- 1.5, 15.7 +/- 1.3 and 22.6 +/- 3.7 (P < 0.05) in the SAL, L-ESC and H-ESC groups, respectively during the last hour of P2 (210-270 min). Net hepatic carbon retention (glycogen storage) was 15.4 +/- 1.3, 14.9 +/- 0.6 and 20.9 +/- 2.6 (P < 0.05) micromol/kg/min in SAL, L-ESC and H-ESC respectively during the last hour of P2. Escitalopram enhanced net hepatic glucose uptake and hepatic glycogen deposition, showing that it can improve hepatic glucose clearance under hyperinsulinemic hyperglycemic conditions. Its use in individuals with diabetes may, therefore, result in improved glycemic control.

Topics: Animals; Antidepressive Agents, Second-Generation; Carbon; Citalopram; Diabetes Mellitus, Type 2; Dogs; Glucose; Glucose Clamp Technique; Glycogen; Hyperinsulinism; Infusions, Intravenous; Liver; Portal Vein; Somatostatin; Time Factors

Obesity is an important risk factor for the development of type 2 diabetes, but not all obese individuals develop this complication. The clinical signs of type 2 diabetes can often be reversed with weight loss; however, it is unknown whether the skeletal muscle oxidative stress associated with type 2 diabetes remains after weight loss. We hypothesised that chronic exposure to high glucose and insulin would re-elicit impaired metabolism in primary myotubes from patients with a history of type 2 diabetes.. Obese participants with or without type 2 diabetes completed a standardised weight loss protocol, following which all participants were euglycaemic and had similar indices of insulin sensitivity. Satellite cells were isolated from muscle biopsies and differentiated under low or high glucose and insulin conditions (HGI).. Cells from participants with no history of type 2 diabetes showed robust increases in mitochondrial content, citrate synthase and cytochrome c oxidase activities when exposed to HGI. This increase in oxidative capacity was absent in cells from patients with a history of type 2 diabetes. High glucose and insulin caused increased oxidative damage in cells from the latter, despite higher superoxide dismutase expression. Cells from patients with a history of type 2 diabetes were unable to decrease mitochondrial membrane potential in response to HGI, potentially due to lower levels of uncoupling protein-3.. This is the first report to note that primary myotubes from patients with a history of type 2 diabetes are unable to adapt to a hyperglycaemic-hyperinsulinaemic challenge. We have demonstrated that impaired mitochondrial biogenesis and an inability to manage oxidative stress define a muscle phenotype at risk of obesity-associated type 2 diabetes.

Topics: Adult; Body Composition; Body Mass Index; Diabetes Complications; Diabetes Mellitus, Type 2; Female; Glucose Clamp Technique; Glycated Hemoglobin; Glycogen; Humans; Hyperinsulinism; Hypoglycemic Agents; Insulin; Ion Channels; Male; Middle Aged; Mitochondrial Proteins; Muscle Fibers, Skeletal; Muscle, Skeletal; Obesity; Oxidative Stress; Triglycerides; Uncoupling Protein 3; Weight Loss

Measurement of plasma C2 glucose enrichment is cumbersome. Therefore, the plasma C5 glucose-to-(2)H(2)O rather than the plasma C5-to-C2 glucose ratio commonly has been used to measure gluconeogenesis and glycogenolysis during hyperinsulinemic-euglycemic clamps. The validity of this approach is unknown.. Ten nondiabetic and 10 diabetic subjects ingested (2)H(2)O the evening before study. The following morning, insulin was infused at a rate of 0.6 mU . kg(-1) . min(-1) and glucose was clamped at approximately 5.3 mmol/l for 5 h. Plasma C5 glucose, C2 glucose, and (2)H(2)O enrichments were measured hourly from 2 h onward.. Plasma C2 glucose and plasma (2)H(2)O enrichment were equal in both groups before the clamp, resulting in equivalent estimates of gluconeogenesis and glycogenolysis. In contrast, plasma C2 glucose and plasma C5 glucose enrichments fell throughout the clamp, whereas plasma (2)H(2)O enrichment remained unchanged. Since the C5 glucose concentration and, hence, the C5 glucose-to-(2)H(2)O ratio is influenced by both gluconeogenesis and glucose clearance, whereas the C5-to-C2 glucose ratio is only influenced by gluconeogenesis, the C5 glucose-to-(2)H(2)O ratio overestimated (P < 0.01) gluconeogenesis during the clamp. This resulted in biologically implausible negative (i.e., calculated rates of gluconeogenesis exceeding total endogenous glucose production) rates of glycogenolysis in both the nondiabetic and diabetic subjects.. Plasma C5 glucose-to-(2)H(2)O ratio does not provide an accurate assessment of gluconeogenesis in nondiabetic or diabetic subjects during a traditional (i.e., 2-3 h) hyperinsulinemic-euglycemic clamp. The conclusions of studies that have used this approach need to be reevaluated.

Topics: Blood Glucose; Deuterium Oxide; Diabetes Mellitus; Glucagon; Gluconeogenesis; Glucose Clamp Technique; Glycogen; Human Growth Hormone; Humans; Hyperinsulinism; Infusions, Intravenous; Insulin; Kinetics; Reference Values; Reproducibility of Results; Somatostatin; Water

Sutherlandia frutescens has been marked as a potential hypoglycaemic agent for the treatment of type 2 diabetes. We investigated the effects of Sutherlandia frutescens in bringing about hypoglycaemia and promoting glucose uptake in pre-diabetic rats. Crushed Sutherlandia frutescens leaves in drinking water were administered to rats fed a high fat diet. Positive control rats received only metformin. Glucose uptake experiments were undertaken using [(3)H] deoxy-glucose. Various physiological parameters were also measured. Rats receiving Sutherlandia frutescens displayed normoinsulinaemic levels, after 8 weeks medicational compliance, compared to the fatty controls. There was a significant increase in glucose uptake into muscle and adipose tissue, and a significant decrease in intestinal glucose uptake (p<0.001 at 60min) in rats receiving the plant extract. The Sutherlandia frutescens plant extract shows promise as a type 2 anti-diabetes medication because of its ability to normalize insulin levels and glucose uptake in peripheral tissues and suppress intestinal glucose uptake, with no weight gain noted. The exact mechanism of action and the extract's efficacy in humans need further confirmation.

Topics: Anesthesia; Animals; Blood Glucose; Body Weight; Diet; Dietary Fats; Glucose; Glycogen; Hyperinsulinism; Hypoglycemic Agents; Insulin; Intestinal Mucosa; Male; Metformin; Plant Extracts; Plants, Medicinal; Prediabetic State; Rats; Rats, Wistar

We examined whole-body and muscle metabolism in patients with type 1 diabetes during moderate exercise at differing circulating insulin concentrations.. Eight men (mean +/- SEM age 36.4 +/- 1.5 years; diabetes duration 11.3 +/- 1.4 years; BMI 24.6 +/- 0.7 kg/m(2); HbA(1c) 7.9 +/- 0.2% and VO(2) peak 44.5 +/- 1.2 ml kg(-1) min(-1)) with type 1 diabetes were studied on two occasions at rest (2 h) and during 45 min of cycling at 60% maximum VO(2) with insulin infused at the rate of either 15 (LO study) or 50 (HI) mU m(-2) min(-1) and blood glucose clamped at 8 mmol/l. Indirect calorimetry, insulin-glucose clamps and thigh muscle biopsies were employed to measure whole-body energy and muscle metabolism.. Fat oxidation contributed 15 and 23% to total energy expenditure during exercise in the HI and LO studies, respectively. The respective carbohydrate (CHO) oxidation rates were 31.7 +/- 2.7 and 27.8 +/- 1.9 mg kg(-1) min(-1) (p < 0.05). Exogenous glucose utilisation rate during exercise was substantially greater (p < 0.001) in the HI study (18.4 +/- 2.1 mg kg(-1) min(-1)) than in the LO study (6.9 +/- 1.2 mg kg(-1) min(-1)). Muscle glycogen content fell by approximately 40% during exercise in both trials. Muscle glycogen utilisation, muscle intermediary metabolism, and phosphorylation of protein kinase B/Akt, glycogen synthase kinase 3alpha/beta and extracellular signal-regulated protein kinase 1 and 2 proteins were no different between interventions.. In patients with type 1 diabetes, exercise under peak therapeutic insulin concentrations increases exogenous glucose utilisation but does not spare muscle glycogen utilisation. A disproportionate increase in exogenous glucose utilisation relative to the increase in CHO oxidation suggests an increase in glucose flux through non-oxidative pathways.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 1; Energy Metabolism; Exercise; Glucose; Glycogen; Humans; Hyperinsulinism; Insulin; Male; Middle Aged; Muscle, Skeletal; Oxygen Consumption

The liver is inaccessible to organ balance measurements in humans. To validate [(18)F]fluorodeoxyglucose ([(18)F]FDG) positron emission tomography (PET) in the quantification of hepatic glucose uptake (HGU), we determined [(18)F]FDG modeling parameters, lumped constant (LC), and input functions (single arterial versus dual).. Anesthetized pigs were studied during fasting (n = 6), physiologic (n = 4), and supraphysiologic (n = 4) hyperinsulinemia. PET was performed with C(15)O (blood pool) and [(18)F]FDG (glucose uptake). 6,6-Deuterated glucose ([(2)H]G) was coinjected with [(18)F]FDG and blood collected from the carotid artery and portal and hepatic veins to compute LC as ratio between tracers fractional extraction. HGU was estimated from PET images and ex vivo from high-performance liquid chromatography measurements of liver [(18)F]FDG versus [(18)F]FDG-6-phosphate and [(18)F]-glycogen. Endogenous glucose production was measured with [(2)H]G and hepatic blood flow by flowmeters.. HGU was increased in hyperinsulinemia versus fasting (P < .05). Fractional extraction of [(18)F]FDG and [(2)H]G was similar (not significant), intercorrelated (r = 0.98, P < .0001), and equally higher during hyperinsulinemia than fasting (P 0.95, P < .0001), with a modest underestimation of HGU by the former.. [(18)F]FDG-PET-derived parameters provide accurate quantification of HGU and estimates of liver perfusion and glucose production. In the liver, LC of [(18)F]FDG is nearly unitary. Using a single arterial input introduces only a small error in estimation of HGU.

Topics: Animals; Blood Flow Velocity; Blood Glucose; Chromatography, High Pressure Liquid; Fasting; Fluorodeoxyglucose F18; Glucose; Glucose-6-Phosphate; Glycogen; Hepatic Artery; Hyperinsulinism; Insulin; Liver; Liver Circulation; Models, Biological; Portal Vein; Positron-Emission Tomography; Radiopharmaceuticals; Swine

Obesity and type 2 diabetes are worldwide health issues. The present paper investigates prenatal and postnatal pathways to obesity, identifying different metabolic outcomes with different effects on insulin sensitivity and different underlying mechanisms involving key components of insulin receptor signaling pathways. Pregnant Wistar rats either were fed chow ad libitum or were undernourished throughout pregnancy, generating either control or intrauterine growth restricted (IUGR) offspring. Male offspring were fed either standard chow or a high-fat diet from weaning. At 260 d of age, whole-body insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp, and other metabolic parameters were measured. As expected, high-fat feeding caused diet-induced obesity (DIO) and insulin resistance. Importantly, the insulin sensitivity of IUGR offspring was similar to that of control offspring, despite fasting insulin hypersecretion and increased adiposity, irrespective of postnatal nutrition. Real-time PCR and Western blot analyses of key markers of insulin sensitivity and metabolic regulation showed that IUGR offspring had increased hepatic levels of atypical protein kinase C zeta (PKC zeta) and increased expression of fatty acid synthase mRNA. In contrast, DIO led to decreased expression of fatty acid synthase mRNA and hepatic steatosis. The decrease in hepatic PKC zeta with DIO may explain, at least in part, the insulin resistance. Our data suggest that the mechanisms of obesity induced by prenatal events are fundamentally different from those of obesity induced by postnatal high-fat nutrition. The origin of insulin hypersecretion in IUGR offspring may be independent of the mechanistic events that trigger the insulin resistance commonly observed in DIO.

Topics: Animal Feed; Animals; Blood Glucose; C-Peptide; Caloric Restriction; Diabetes, Gestational; Dietary Fats; Female; Fetal Growth Retardation; Fetal Nutrition Disorders; Glucose Clamp Technique; Glycogen; Hyperinsulinism; Insulin; Insulin Resistance; Insulin Secretion; Lipid Metabolism; Liver; Male; Muscle, Skeletal; Obesity; Phosphoenolpyruvate Carboxykinase (GTP); Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar

Mice with liver-specific overexpression of dominant negative phosphorylation-defective S503A-CEACAM1 mutant (L-SACC1) developed chronic hyperinsulinemia resulting from blunted hepatic clearance of insulin, visceral obesity, and glucose intolerance. To determine the underlying mechanism of altered glucose homeostasis, a 2-h hyperinsulinemic euglycemic clamp was performed, and tissue-specific glucose and lipid metabolism was assessed in awake L-SACC1 and wild-type mice. Inactivation of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) caused insulin resistance in liver that was mostly due to increased expression of fatty acid synthase and lipid metabolism, resulting in elevated intrahepatic levels of triglyceride and long-chain acyl-CoAs. Whole body insulin resistance in the L-SACC1 mice was further attributed to defects in insulin-stimulated glucose uptake in skeletal muscle and adipose tissue. Insulin resistance in peripheral tissues was associated with significantly elevated intramuscular fat contents that may be secondary to increased whole body adiposity (assessed by (1)H-MRS) in the L-SACC1 mice. Overall, these results demonstrate that L-SACC1 is a mouse model in which chronic hyperinsulinemia acts as a cause, and not a consequence, of insulin resistance. Our findings further indicate the important role of CEACAM1 and hepatic insulin clearance in the pathogenesis of obesity and insulin resistance.

Topics: Acyl Coenzyme A; Animals; Blood Glucose; Carcinoembryonic Antigen; Disease Models, Animal; Fatty Acid Synthases; Fatty Acid Transport Proteins; Glucose; Glucose Clamp Technique; Glucose Intolerance; Glucose-6-Phosphate; Glycogen; Hyperinsulinism; Insulin; Insulin Resistance; Lipoprotein Lipase; Liver; Mice; Mice, Knockout; Muscle, Skeletal; Triglycerides

The introduction of 13C magnetic resonance spectroscopy (MRS) has enabled noninvasive measurement of muscle glycogen synthesis in humans. Conclusions based on measurements by the MRS technique assume that glucose metabolism in gastrocnemius muscle is representative for all skeletal muscles and thus can be extrapolated to whole-body muscle glucose metabolism. An alternative method to assess whole-body muscle glycogen synthesis is the use of [3-(3)H]glucose. In the present study, we compared this method to the MRS technique, which is a well-validated technique for measuring muscle glycogen synthesis. Muscle glycogen synthesis was measured in the gastrocnemius muscle of six lean healthy subjects by MRS and by the isotope method during a hyperinsulinemic-euglycemic clamp. Mean muscle glycogen synthesis as measured by the isotope method was 115 +/- 26 micromol x kg(-1) muscle x min(-1) vs. 178 +/- 72 micromol x kg(-1) muscle x min(-1) (P = 0.03) measured by MRS. Glycogen synthesis rates measured by MRS exceeded 100% of glucose uptake in three of the six subjects. We conclude that glycogen synthesis rates measured in gastrocnemius muscle cannot be extrapolated to whole-body muscle glycogen synthesis.

Topics: Adult; Female; Glucose; Glucose Clamp Technique; Glycogen; Humans; Hyperinsulinism; Insulin; Isotope Labeling; Magnetic Resonance Spectroscopy; Male; Muscle, Skeletal; Organ Specificity; Tritium

To determine whether the hepatic insulin resistance of obesity and type 2 diabetes is due to impaired insulin-induced suppression of glycogenolysis as well as gluconeogenesis, 10 lean nondiabetic, 10 obese nondiabetic, and 11 obese type 2 diabetic subjects were studied after an overnight fast and during a hyperinsulinemic-euglycemic clamp. Gluconeogenesis and glycogenolysis were measured using the deuterated water method. Before the clamp, when glucose and insulin concentrations differed among the three groups, gluconeogenesis was higher in the diabetic than in the obese nondiabetic subjects (P < 0.05) and glycogenolysis was higher in the diabetic than in the lean nondiabetic subjects (P < 0.05). During the clamp, when glucose and insulin concentrations were matched and glucagon concentrations were suppressed, both glycogenolysis and gluconeogenesis were higher (P < 0.01) in the diabetic versus the obese and lean nondiabetic subjects. Furthermore, glycogenolysis and gluconeogenesis were higher (P < 0.01) in the obese than in the lean nondiabetic subjects. Plasma free fatty acid concentrations correlated (P < 0.001) with glucose production and gluconeogenesis both before and during the clamp and with glycogenolysis during the clamp (P < 0.01). We concluded that defects in the regulation of glycogenolysis as well as gluconeogenesis cause hepatic insulin resistance in obese nondiabetic and type 2 diabetic humans.

Topics: Blood Glucose; Body Mass Index; Body Weight; Diabetes Mellitus, Type 2; Female; Gluconeogenesis; Glucose Clamp Technique; Glycogen; Humans; Hyperinsulinism; Insulin; Male; Middle Aged; Obesity

Insulin activates several processes potentially dangerous for the arterial wall and hyperinsulinemia might be atherogenic. However, other insulin effects are protective for the vessel wall and thus anti-atherogenic. Aim of this study was to investigate whether insulin effects on potentially pro-atherogenic and anti-atherogenic processes were differently affected in cells from insulin-resistant individuals.. We determined insulin effect on nitric oxide (NO) production and plasminogen activator inhibitor (PAI)-1 synthesis in 12 fibroblast strains obtained from skin biopsy samples of 6 insulin-sensitive (IS) (clamp M >7 mg/kg body weight per minute) and 6 insulin-resistant (IR) (clamp M <5 mg/kg body weight per minute) healthy volunteers. Insulin effects on NO release and Akt phosphorylation were significantly impaired in fibroblasts from IR as compared with IS individuals. Conversely, there was not any difference between IR and IS strains in insulin ability to increase PAI-1 antigen levels and, after 24-hour insulin incubation, PAI-1 mRNA increase in IR strains was only slightly less than in IS strains. Insulin ability to induce MAPK activation was also comparable in IR and IS cells.. We conclude that in cells from IR individuals, insulin action on anti-atherogenic processes, such as NO release, is impaired, whereas the hormone ability to stimulate atherogenic processes, such as PAI-1 release, is preserved.

Topics: Adult; Atherosclerosis; Cells, Cultured; Culture Media; Female; Fibroblasts; Glucose; Glycogen; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Male; MAP Kinase Signaling System; Nitric Oxide; Nitric Oxide Synthase Type III; Phosphorylation; Plasminogen Activator Inhibitor 1; Proto-Oncogene Proteins c-akt; RNA, Messenger; Serine

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

To assess the role of the alpha1b-adrenergic receptor (AR) in glucose homeostasis, we investigated glucose metabolism in knockout mice deficient of this receptor subtype (alpha1b-AR-/-). Mutant mice had normal blood glucose and insulin levels, but elevated leptin concentrations in the fed state. During the transition to fasting, glucose and insulin blood concentrations remained markedly elevated for at least 6 h and returned to control levels after 24 h whereas leptin levels remained high at all times. Hyperinsulinemia in the post-absorptive phase was normalized by atropine or methylatropine indicating an elevated parasympathetic activity on the pancreatic beta cells, which was associated with increased levels of hypothalamic NPY mRNA. Euglycemic clamps at both low and high insulin infusion rates revealed whole body insulin resistance with reduced muscle glycogen synthesis and impaired suppression of endogenous glucose production at the low insulin infusion rate. The liver glycogen stores were 2-fold higher in the fed state in the alpha1b-AR-/- compared with control mice, but were mobilized at the same rate during the fed to fast transition or following glucagon injections. Finally, high fat feeding for one month increased glucose intolerance and body weight in the alpha1b-AR-/-, but not in control mice. Altogether, our results indicate that in the absence of the alpha1b-AR the expression of hypotalamic NPY and the parasympathetic nervous activity are both increased resulting in hyperinsulinemia and insulin resistance as well as favoring obesity and glucose intolerance development during high fat feeding.

Topics: Animals; Blood Glucose; Body Weight; Glucagon; Glucose; Glycogen; Homeostasis; Hyperinsulinism; Insulin Resistance; Leptin; Liver; Male; Mice; Mice, Mutant Strains; Mice, Obese; Receptors, Adrenergic; Receptors, Adrenergic, alpha-1; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Time Factors

Topics: Biological Transport; Erythrocyte Membrane; Glucose; Glycogen; Humans; Hyperinsulinism; Hypertension; Insulin; Insulin Resistance; Membrane Fluidity; Muscle, Skeletal

The AMP-activated kinase has been proposed to be an important intracellular energy sensor because the enzyme controls lipid and glucose oxidation. In the corresponding knockout mice, insulin-stimulated muscle glycogen synthesis and glucose tolerance are reduced. In addition, these mice excrete catecholamines in excess, suggesting that the central and autonomic nervous systems are impaired. Indeed, in the brain, fuel sensor mechanisms have been described, and recently, evidence has shown that the AMP-activated kinase could control food intake. We show in this study that the intracerebroventricular infusion of 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR), a pharmacological AMP-activated kinase activator, increased insulin-stimulated muscle glycogen synthesis and insulin sensitivity during a hyperinsulinemic clamp. Similarly, we infused AICAR in the brain of fasted mice, i.e. when insulinemia was low, and showed that muscle glycogen synthesis was also increased. We then studied the effect of a cerebral infusion of the peripheral signals, i.e. insulin and glucose, known to be detected by the brain. The cerebral infusion of insulin increased muscle glycogen synthesis. This effect was blunted by the coinfusion of glucose, which induced insulin resistance. Importantly, the cerebral injections of AICAR, insulin, and glucose were associated with variations in the phosphorylation state of the AMP-activated kinase in the hypothalamus. In conclusion, our data showed for the first time that 1) the brain is sensitive to insulin and glucose for the regulation of muscle glycogen synthesis; and 2) the cerebral infusion of AICAR enhances insulin sensitivity. Although the above mechanisms are correlated with the regulation of AMP-activated kinase, the direct involvement of the enzyme in the mechanism remains to be demonstrated.

Topics: Aminoimidazole Carboxamide; AMP-Activated Protein Kinases; Animals; Fasting; Glucose; Glycogen; Hyperinsulinism; Hypoglycemic Agents; Hypothalamus; Injections, Intraventricular; Insulin; Male; Mice; Mice, Inbred C57BL; Multienzyme Complexes; Muscle, Skeletal; Phosphorylation; Protein Serine-Threonine Kinases; Ribonucleosides

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

Albuterol overdose can lead to tachycardia, hypotension, tremor, hypokalemia, and hyperglycemia in children. Hypoglycemia had been previously reported in only one child. We describe a 3-year-old boy who ingested high-dose albuterol in this report. On arrival to the emergency department, the child was agitated and had noticeable restlessness, sinus tachycardia, mild hypokalemia (3.2 mEq/L), and hyperglycemia (187 mg/dL). Activated charcoal and intravenous hydration were given, and electrocardiogram monitoring was performed. Sinus tachycardia resolved within 4 to 6 hours. Hypoglycemia (45 mg/dL) was identified 4 hours after admission. The child recovered uneventfully within 24 hours with glucose replacement. This case suggests that hypoglycemia could be a late complication of acute albuterol overdose; thus, the period of observation should be extended in these cases.

Topics: Adrenergic beta-Agonists; Albuterol; Charcoal; Child, Preschool; Diseases in Twins; Drug Overdose; Fluid Therapy; Glucose; Glycogen; Humans; Hyperinsulinism; Hypoglycemia; Hypokalemia; Male; Psychomotor Agitation; Tachycardia, Sinus; Time Factors; Tremor

To study effects of sex on free fatty acid (FFA)-induced insulin resistance, we have examined the effects of acute elevations of plasma FFA levels on insulin-stimulated total body glucose uptake in nine healthy young women. Euglycemic-hyperinsulinemic (approximately 500 pmol/l) clamps were performed for 4 h with coinfusion of either lipid/heparin (L/H) to acutely raise plasma FFA levels (from approximately 600 to approximately 1,200 micro mol/l) or saline/glycerol to lower fatty acids (from approximately 600 to approximately 50 micro mol/l). L/H infusion inhibited insulin-stimulated glucose uptake (determined with [3-(3)H]glucose) and glycogen synthesis by 31 and 40%, respectively (P < 0.01), almost completely abolished insulin suppression of endogenous glucose production (EGP) (13.6 vs. 10.0 micro mol x kg(-1) x min(-1), NS), prevented the insulin induced increase in carbohydrate oxidation (8.1 vs. 7.4 micro mol x kg(-1) x min(-1), NS), and stimulated fat oxidation (from 3.6 to 5.1 micro mol x kg(-1) x min(-1), P < 0.01). These data showed that acute increases in plasma FFA levels inhibited the actions of insulin on glucose uptake, glycogen synthesis, and EGP in women to a degree similar to that previously reported in men. We conclude that at insulin and FFA levels in the postprandial range, women and men were susceptible to FFA-induced peripheral and hepatic insulin resistance.

Topics: Adipose Tissue; Adult; Black People; Blood Glucose; Body Constitution; Body Mass Index; Body Weight; Calorimetry, Indirect; Emulsions; Fat Emulsions, Intravenous; Fatty Acids, Nonesterified; Female; Glucose; Glucose Clamp Technique; Glycogen; Glycolysis; Heparin; Humans; Hyperinsulinism; Insulin; Lecithins; Philadelphia; Reference Values; Safflower Oil; Soybean Oil; White People

In healthy individuals, peripheral insulin resistance evoked by dietary saturated lipid can be accompanied by increased insulin secretion such that glucose tolerance is maintained. Substitution of long-chain omega-3 fatty acids for a small percentage of dietary saturated fat prevents insulin resistance in response to high-saturated fat feeding. We substituted a small amount (7%) of dietary lipid with long-chain omega-3 fatty acids during 4 wk of high-saturated fat feeding to investigate the relationship between amelioration of insulin resistance and glucose-stimulated insulin secretion (GSIS). We demonstrate that, despite dietary delivery of saturated fat throughout, this manipulation prevents high-saturated fat feeding-induced insulin resistance with respect to peripheral glucose disposal and reverses insulin hypersecretion in response to glucose in vivo. Effects of long-chain omega-3 fatty acid enrichment to lower GSIS were also observed in perifused islets suggesting a direct effect on islet function. However, long-chain omega-3 fatty acid enrichment led to hepatic insulin resistance with respect to suppression of glucose output and impaired glucose tolerance in vivo. Our data demonstrate that the insulin response to glucose is suppressed to a greater extent than whole-body insulin sensitivity is enhanced by enrichment of a high-saturated fat diet with long-chain omega-3 fatty acids. Additionally, reduced GSIS despite glucose intolerance suggests that either long-chain omega-3 fatty acids directly impair the beta-cell response to saturated fat such that insulin secretion cannot be augmented to normalize glucose tolerance or beta-cell compensatory hypersecretion represents a response to insulin resistance at the level of peripheral glucose disposal but not endogenous glucose production.

Topics: Animals; Dietary Fats; Fatty Acids, Omega-3; Female; Fish Oils; Glucose; Glucose Clamp Technique; Glucose Intolerance; Glycogen; Hyperinsulinism; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Leptin; Liver; Phenotype; Rats; Rats, Wistar; Triglycerides

Norepinephrine (NE) and epinephrine (Epi) help maintain normal blood glucose levels by stimulating glucagon release, glycogenolysis, and food consumption, and by inhibiting insulin release. The absence of NE and Epi in dopamine beta-hydroxylase-null (Dbh-/-) mice results in chronically low blood glucose levels, an impaired glucagon response to hypoglycemia, and elevated insulin levels. Nevertheless, Dbh-/- mice have normal glycogen levels and degrade it normally during a fast. Dbh-/- mice defend blood glucose levels better than controls in an insulin tolerance test but have increased sensitivity to glucose-stimulated insulin secretion and respond normally in a glucose tolerance test. Pharmacological evidence indicates that the hyperinsulinemia results from lack of alpha2-adrenoreceptor stimulation and increased parasympathetic tone. Dbh-/- mice eat normally after challenges with modest levels of insulin or 2-deoxyglucose but fail to eat under more extreme conditions when control mice still do. We suggest that the primary difference in Dbh-/- mice is chronic hyperinsulinemia associated with an altered glucose set point. However, these animals compensate for NE/Epi-mediated glycogenolysis and feeding.

Topics: Adrenergic alpha-Agonists; Animals; Atropine Derivatives; Blood Glucose; Clonidine; Deoxyglucose; Eating; Epinephrine; Female; Glucagon; Glucose Tolerance Test; Glycogen; Hyperinsulinism; Insulin; Male; Mice; Mice, Inbred Strains; Mice, Knockout; Muscarinic Antagonists; Norepinephrine

In vivo effects of milrinone, a selective phosphodiesterase 3 (PDE-3) inhibitor, on plasma free fatty acids (FFA), glucose, and insulin levels were examined in alert rats. In dose response studies, intravenous injection of 1, 5 or 25 micromol/kg of milrinone provoked an immediate increase in plasma concentrations of FFA and insulin, while glucose levels rose only in response to the 5- and 25-micromol/kg doses. During euglycemic-hyperinsulinemic (approximately 450 pmol/L) clamps, intravenous injection of milrinone (25 micromol/kg) completely inhibited insulin suppression of lipolysis and of endogenous glucose production, while having no effect on insulin-stimulated glucose uptake (ISGU). To explore the reason why ISGU was not affected, we performed reverse-transcriptase polymerase chain reaction (RT-PCR) with RNA from skeletal muscle, fat, and liver. The results showed that PDE-3B mRNA was expressed in adipose tissue and liver, but it was not detected in skeletal muscle. We conclude that PDE-3 plays a major role in the inhibitory action of insulin on lipolysis in fat and on glucose production in liver and, in addition, seems to be involved in insulin secretion in pancreatic beta cells.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Actins; Adipose Tissue; Animals; Cyclic Nucleotide Phosphodiesterases, Type 3; Dose-Response Relationship, Drug; Fatty Acids, Nonesterified; Glucose; Glucose Clamp Technique; Glycogen; Hyperinsulinism; Hypoglycemic Agents; Insulin; Lipolysis; Liver; Male; Milrinone; Muscle, Skeletal; Phosphodiesterase Inhibitors; Rats; Rats, Sprague-Dawley; RNA, Messenger

High-fat (HFD) and high-sucrose diets (HSD) reduce insulin suppression of glucose production in vivo, increase the capacity for gluconeogenesis in vitro, and increase glucose-6-phosphatase (G-6-Pase) activity in whole cell homogenates. The present study examined the effects of HSD and HFD on in vivo gluconeogenesis, the catalytic and glucose-6-phosphate translocase subunits of G-6-Pase, glucokinase (GK) translocation, and glucose cycling. Rats were fed a high-starch control diet (STD; 68% cornstarch), HSD (68% sucrose), or HFD (45% fat) for 7-13 days. The ratio of 3H in C6:C2 of glucose after 3H2O injection into 6- to 8-h-fasted rats was significantly increased in HSD (0.68 +/- 0.07) and HFD (0.71 +/- 0.08) vs. STD (0.40 +/- 0.10). G-6-Pase activity was significantly higher in HSD and HFD vs. STD in both intact and disrupted liver microsomes. HSD and HFD significantly increased the amount of the p36 catalytic subunit protein, whereas the p46 glucose-6-phosphate translocase protein was increased in HSD only. Despite increased nonglycerol gluconeogenesis and increased G-6-Pase, basal glucose and insulin levels as well as glucose production were not significantly different among groups. Hepatocyte cell suspensions were used to ascertain whether diet-induced adaptations in glucose phosphorylation and GK might serve to compensate for upregulation of G-6-Pase. Tracer-estimated glucose phosphorylation and glucose cycling (glucose <--> glucose 6-phosphate) were significantly higher in cells isolated from HSD only. After incubation with either 5 or 20 mM glucose and no insulin, GK activity (nmol. mg protein(-1). min(-1)) in digitonin-treated eluates (translocated GK) was significantly higher in HSD (32 +/- 4 and 146 +/- 6) vs. HFD (4 +/- 1 and 83 +/- 10) and STD (9 +/- 2 and 87 +/- 9). Thus short-term, chronic exposure to HSD and HFD increase in vivo gluconeogenesis and the G-6-Pase catalytic subunit. Exposure to HSD diet also leads to adaptations in glucose phosphorylation and GK translocation.

Topics: Animals; Biological Transport; Dietary Fats; Dietary Sucrose; Glucokinase; Gluconeogenesis; Glucose; Glucose-6-Phosphatase; Glycogen; Hepatocytes; Hyperinsulinism; Male; Phosphorylation; Rats; Rats, Sprague-Dawley

Chronic attenuation of hyperinsulinemia by diazoxide (DZ), an inhibitor of glucose-mediated insulin secretion, improved insulin sensitivity and glucose tolerance and caused down-regulation of lipid metabolizing enzymes in adipose tissue and decreased the rate of weight gain in mildly hyperglycemic obese Zucker rats. Since the liver plays a central role in glucose homeostasis, we studied the effect of chronic insulin suppression on key insulin-sensitive enzymes regulating hepatic gluconeogenesis.. DZ (150 mg/kg per day) or vehicle (control) was administered to 7-week-old female obese and lean Zucker rats for a period of 4 weeks.. DZ-treated animals showed lower fasting plasma insulin levels (P<0.001) than their controls. Plasma glucose levels were lower in DZ obese rats than in controls (P<0.001), without a significant change in DZ lean animals. DZ had no effect on glucose transporter 2 protein expression in either strain. DZ treatment resulted in lower hepatic glucokinase (P<0.001) and glucose-6-phosphatase (P<0.0001) and phosphoenolpyruvate carboxykinase (PEPCK) activities only in obese rats compared with controls (P<0.001). However, DZ-treated lean rats demonstrated higher PEPCK activity than controls (P<0.002). DZ-treated animals demonstrated enhanced hepatic glucose-6-phosphate content (P<0.01), glycogen synthase activity (P<0.0001) and glycogen content (P<0.02) compared with their controls despite increased hepatic glycogen phosphorylase a activity in these animals (P<0.02).. Chronic suppression of hyperinsulinemia in obese Zucker rats by DZ decreased the activities of key enzymes regulating hepatic gluconeogenesis, implying that attenuation of the hyperinsulinemic state by DZ may be therapeutically beneficial.

Topics: Animals; Blood Glucose; Body Weight; Diazoxide; Eating; Female; Glucokinase; Gluconeogenesis; Glucose Transporter Type 2; Glucose-6-Phosphatase; Glycogen; Glycogen Phosphorylase; Glycogen Synthase; Hyperinsulinism; Insulin; Lipids; Liver; Monosaccharide Transport Proteins; Obesity; Protein Serine-Threonine Kinases; Rats; Rats, Zucker; Thinness

In addition to suppressing appetite, leptin may also modulate insulin secretion and action. Leptin was administered here to insulin-resistant rats to determine its effects on secretagogue-stimulated insulin release, whole body glucose disposal, and insulin-stimulated skeletal muscle glucose uptake and transport. Male Wistar rats were fed either a normal (Con) or a high-fat (HF) diet for 3 or 6 mo. HF rats were then treated with either vehicle (HF), leptin (HF-Lep, 10 mg. kg(-1). day(-1) sc), or food restriction (HF-FR) for 12-15 days. Glucose tolerance and skeletal muscle glucose uptake and transport were significantly impaired in HF compared with Con. Whole body glucose tolerance and rates of insulin-stimulated skeletal muscle glucose uptake and transport in HF-Lep were similar to those of Con and greater than those of HF and HF-FR. The insulin secretory response to either glucose or tolbutamide (a pancreatic beta-cell secretagogue) was not significantly diminished in HF-Lep. Total and plasma membrane skeletal muscle GLUT-4 protein concentrations were similar in Con and HF-Lep and greater than those in HF and HF-FR. The findings suggest that chronic leptin administration reversed a high-fat diet-induced insulin-resistant state, without compromising insulin secretion.

Topics: 3-O-Methylglucose; Animals; Blood Glucose; Body Mass Index; Diet; Dietary Fats; Energy Intake; Glucose Clamp Technique; Glucose Tolerance Test; Glucose Transporter Type 4; Glycogen; Hyperinsulinism; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Male; Monosaccharide Transport Proteins; Muscle Proteins; Muscle, Skeletal; Rats; Rats, Wistar; Tolbutamide

Although chronic hyperinsulinemia has been shown to induce insulin resistance, the basic cellular mechanisms responsible for this phenomenon are unknown. The present study was performed 1) to determine the time-related effect of physiological hyperinsulinemia on glycogen synthase (GS) activity, hexokinase II (HKII) activity and mRNA content, and GLUT-4 protein in muscle from healthy subjects, and 2) to relate hyperinsulinemia-induced alterations in these parameters to changes in glucose metabolism in vivo. Twenty healthy subjects had a 240-min euglycemic insulin clamp study with muscle biopsies and then received a low-dose insulin infusion for 24 (n = 6) or 72 h (n = 14) (plasma insulin concentration = 121 +/- 9 or 143 +/- 25 pmol/l, respectively). During the baseline insulin clamp, GS fractional velocity (0.075 +/- 0.008 to 0.229 +/- 0.02, P < 0.01), HKII mRNA content (0.179 +/- 0.034 to 0.354 +/- 0.087, P < 0.05), and HKII activity (2.41 +/- 0.63 to 3.35 +/- 0.54 pmol x min(-1) x ng(-1), P < 0.05), as well as whole body glucose disposal and nonoxidative glucose disposal, increased. During the insulin clamp performed after 24 and 72 h of sustained physiological hyperinsulinemia, the ability of insulin to increase muscle GS fractional velocity, total body glucose disposal, and nonoxidative glucose disposal was impaired (all P < 0.01), whereas the effect of insulin on muscle HKII mRNA, HKII activity, GLUT-4 protein content, and whole body rates of glucose oxidation and glycolysis remained unchanged. Muscle glycogen concentration did not change [116 +/- 28 vs. 126 +/- 29 micromol/kg muscle, P = nonsignificant (NS)] and was not correlated with the change in nonoxidative glucose disposal (r = 0.074, P = NS). In summary, modest chronic hyperinsulinemia may contribute directly (independent of change in muscle glycogen concentration) to the development of insulin resistance by its impact on the GS pathway.

Topics: Adult; Female; Glucose; Glucose Transporter Type 4; Glycogen; Glycogen Synthase; Hexokinase; Humans; Hyperinsulinism; Insulin; Isoenzymes; Male; Monosaccharide Transport Proteins; Muscle Proteins; Muscle, Skeletal; Oxidation-Reduction; Reference Values; RNA, Messenger; Time Factors

Gluconeogenesis (GNG) is enhanced in type 2 diabetes. In experimental animals, insulin at high doses decreases the incorporation of labeled GNG precursors into plasma glucose. Whether physiological hyperinsulinemia has any effect on total GNG in humans has not been determined. We combined the insulin clamp with the (2)H(2)O technique to measure total GNG in 33 subjects with type 2 diabetes (BMI 29.0 +/- 0.6 kg/m(2), fasting plasma glucose 8.1 +/- 0.3 mmol/l) and in 9 nondiabetic BMI-matched subjects after 16 h of fasting and after euglycemic hyperinsulinemia. A primed-constant infusion of 6,6-(2)H-glucose was used to monitor endogenous glucose output (EGO); insulin (40 mU. min(-1). m(-2)) was then infused while clamping plasma glucose for 2 h (at 5.8 +/- 0.1 and 4.9 +/- 0.2 mmol/l for diabetic and control subjects, respectively). In the fasting state, EGO averaged 15.2 +/- 0.4 micromol. min(-1). kg(-1)(ffm) (62% from GNG) in diabetic subjects and 12.2 +/- 0.7 micromol. min(-1). kg(-1)(ffm) (55% from GNG) in control subjects (P < 0.05 or less for both fluxes). Glycogenolysis (EGO - GNG) was similar in the two groups (P = NS). During the last 40 min of the clamp, both EGO and GNG were significantly (P < 0.01 or less, compared with fasting) inhibited (EGO 7.1 +/- 0.9 and 3.6 +/- 0.5 and GNG 7.9 +/- 0.5 and 4.5 +/- 1.0 respectively) but remained significantly (P < 0.05) higher in diabetic subjects, whereas glycogenolysis was suppressed completely and equally in both groups. During hyperinsulinemia, GNG micromol. min(-1). kg(-1)(ffm) in diabetic and control subjects, was reciprocally related to plasma glucose clearance. In conclusion, physiological hyperinsulinemia suppresses GNG by approximately 20%, while completely blocking glycogenolysis. Resistance of GNG (to insulin suppression) and resistance of glucose uptake (to insulin stimulation) are coupled phenomena. In type 2 diabetes, the excess GNG of the fasting state is carried over to the insulinized state, thereby contributing to glucose overproduction under both conditions.

Topics: Adult; Blood Glucose; Blood Pressure; Body Constitution; Body Mass Index; Deuterium Oxide; Diabetes Mellitus, Type 2; Fasting; Female; Gluconeogenesis; Glucose Clamp Technique; Glycated Hemoglobin; Glycogen; Humans; Hyperinsulinism; Insulin; Kinetics; Male; Middle Aged; Reference Values; Regression Analysis; Time Factors

Insulin resistance of skeletal muscle has been associated with increased lipid availability. This study aimed to estimate volume fractions of intramyocellular triglyceride droplets and glycogen granules in skeletal muscle using electron microscopy and furthermore, relate these findings to insulin sensitivity and the level of circulating lipids.. We compared 11 obese patients with Type II (non-insulin-dependent) diabetes mellitus and 11 obese normoglycaemic subjects matched for age and sex. Glucose metabolism was determined using the euglycaemic hyperinsulinaemic clamp technique (40 mU.m(-2).min(-1)) coupled with indirect calorimetry and tritiated glucose. On the second day, using an automatic procedure, a fasting muscle biopsy was carried out and processed for electron microscopy. Volume fractions of intramyocellular structures were estimated by pointcounting on photographic pictures in a blinded manner.. Insulin-stimulated total glucose disposal rate was lower in the Type II diabetic subjects compared with the obese normoglycaemic subjects (4.96 +/- 049 vs 10.35 +/- 0.89 mg.min(-1).kg ffm(-1), p < 0.001) as was glucose storage (2.03 +/- 0.50 vs 6.59 +/- 0.83, p < 0.001). The electron microscopy study revealed that the diabetic subjects had higher intramyocellular amounts of triglyceride (1.43 +/- 0.21 vs 0.39 +/- 0.07%, p < 0.001) and lower amounts of glycogen (3.53 +/- 0.33 vs 6.94 +/- 0.54%, p < 0.001). Mitochondrial volume was identical indicating equal aerobic capacity. The fractional intramyocellular lipid volume was found to be positively associated with fasting NEFA (r = 0.63, p = < 0.05 and r = 0.79, p = < 0.05) and triglyceride (r = 0.74, p = 0.01 and r = 0.62, p < 0.05) in the obese diabetic and normoglycaemic cohorts respectively. Intramyocellular lipid content was negatively correlated to insulin sensitivity (r = -0.71, p < 0.02) in the obese diabetic group whereas no significant association was found in the obese normoglycaemic group.. This study shows that fat accumulates intramyocellulary while glycogen stores are simultaneously reduced in obese subjects with Type II (non-insulin-dependent) diabetes mellitus. Quantitatively, a major component of the excessive lipid accumulation could be secondary in origin, related to the diabetic state in itself, although a contribution from the altered insulin action cascade of obesity and diabetes cannot be excluded. In both groups significant positive relations were found between circulating and intramyocellular lipid.

Topics: Adipocytes; Blood Glucose; Calorimetry, Indirect; Cholesterol; Cholesterol, HDL; Diabetes Mellitus; Fatty Acids, Nonesterified; Glucose Clamp Technique; Glucose Tolerance Test; Glycogen; Humans; Hyperinsulinism; Insulin Resistance; Lipid Metabolism; Middle Aged; Muscle, Skeletal; Obesity; Triglycerides; White People

Obesity and insulin resistance in skeletal muscle are two major factors in the pathogenesis of type 2 diabetes. Mice with muscle-specific inactivation of the insulin receptor gene (MIRKO) are normoglycemic but have increased fat mass. To identify the potential mechanism for this important association, we examined insulin action in specific tissues of MIRKO and control mice under hyperinsulinemic-euglycemic conditions. We found that insulin-stimulated muscle glucose transport and glycogen synthesis were decreased by about 80% in MIRKO mice, whereas insulin-stimulated fat glucose transport was increased threefold in MIRKO mice. These data demonstrate that selective insulin resistance in muscle promotes redistribution of substrates to adipose tissue thereby contributing to increased adiposity and development of the prediabetic syndrome.

Topics: Adipose Tissue; Animals; Blood Glucose; Glucose; Glucose Clamp Technique; Glycogen; Glycolysis; Hyperinsulinism; Insulin; Insulin Resistance; Male; Mice; Mice, Knockout; Muscle, Skeletal; Obesity; Receptor, Insulin; Reference Values

To examine the mechanism by which free fatty acids (FFA) induce insulin resistance in human skeletal muscle, glycogen, glucose-6-phosphate, and intracellular glucose concentrations were measured using carbon-13 and phosphorous-31 nuclear magnetic resonance spectroscopy in seven healthy subjects before and after a hyperinsulinemic-euglycemic clamp following a five-hour infusion of either lipid/heparin or glycerol/heparin. IRS-1-associated phosphatidylinositol 3-kinase (PI 3-kinase) activity was also measured in muscle biopsy samples obtained from seven additional subjects before and after an identical protocol. Rates of insulin stimulated whole-body glucose uptake. Glucose oxidation and muscle glycogen synthesis were 50%-60% lower following the lipid infusion compared with the glycerol infusion and were associated with a approximately 90% decrease in the increment in intramuscular glucose-6-phosphate concentration, implying diminished glucose transport or phosphorylation activity. To distinguish between these two possibilities, intracellular glucose concentration was measured and found to be significantly lower in the lipid infusion studies, implying that glucose transport is the rate-controlling step. Insulin stimulation, during the glycerol infusion, resulted in a fourfold increase in PI 3-kinase activity over basal that was abolished during the lipid infusion. Taken together, these data suggest that increased concentrations of plasma FFA induce insulin resistance in humans through inhibition of glucose transport activity; this may be a consequence of decreased IRS-1-associated PI 3-kinase activity.

Topics: Adolescent; Adult; Fatty Acids, Nonesterified; Female; Glucose; Glucose Clamp Technique; Glucose-6-Phosphate; Glycerol; Glycogen; Humans; Hyperinsulinism; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Lipid Metabolism; Magnetic Resonance Spectroscopy; Male; Muscle, Skeletal; Phosphatidylinositol 3-Kinases; Phosphoproteins

Type 2 diabetes mellitus and obesity are characterized by fasting hyperinsulinemia, insulin resistance with respect to glucose metabolism, elevated plasma free fatty acid (FFA) levels, hypertriglyceridemia, and decreased high-density lipoprotein (HDL) cholesterol. An association between hyperinsulinemia and dyslipidemia has been suggested, but the causality of the relationship remains uncertain. Therefore, we infused eight 12-week-old male catheterized conscious normal rats with insulin (1 mU/min) for 7 days while maintaining euglycemia using a modification of the glucose clamp technique. Control rats (n = 8) received vehicle infusion. Baseline FFAs were 1.07+/-0.13 mmol/L, decreased to 0.57+/-0.10 (P < .05) upon initiation of the insulin infusion, and gradually increased to 0.95+/-0.12 by day 7 (P = NS vbaseline). On day 7 after a 6-hour fast, plasma insulin, glucose, and FFA levels in control and chronically hyperinsulinemic rats were 32+/-5 versus 116+/-21 mU/L (P < .005), 122+/-4 versus 129+/-8 mg/dL (P = NS), and 1.13+/-0.18 versus 0.95+/-0.12 mmol/L (P = NS); total plasma triglyceride and cholesterol levels were 78+/-7 versus 66+/-9 mg/dL (P = NS) and 50+/-3 versus 47+/-2 mg/dL (P = NS), respectively. Very-low-density lipoprotein (VLDL) + intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), and HDL2 and HDL3 subfractions of plasma triglyceride and cholesterol were similar in control and hyperinsulinemic rats. Plasma FFA correlated positively with total (r = .61, P < .005) triglycerides. On day 7 after an 8-hour fast, hyperinsulinemic-euglycemic clamps with 3-3H-glucose infusion were performed in all rats. Chronically hyperinsulinemic rats showed peripheral insulin resistance (glucose uptake, 15.8+/-0.8 v 19.3+/-1.4 mg/kg x min, P < .02) but normal suppression of hepatic glucose production (HGP) compared with control rats (4.3+/-1.0 v 5.6+/-1.4 mg/kg x min, P = NS). De novo tissue lipogenesis (3-3H-glucose incorporation into lipids) was increased in chronically hyperinsulinemic versus control rats (0.90+/-0.10 v 0.44+/-0.08 mg/kg x min, P < .005). In conclusion, chronic physiologic hyperinsulinemia (1) causes insulin resistance with regard to the suppression of plasma FFA levels and increases lipogenesis; (2) induces peripheral but not hepatic insulin resistance with respect to glucose metabolism; and (3) does not cause an elevation in VLDL-triglyceride or a reduction in HDL-cholesterol.

Topics: Animals; Blood Glucose; Chronic Disease; Energy Metabolism; Fatty Acids, Nonesterified; Glucose Clamp Technique; Glycogen; Glycolysis; Hyperinsulinism; Hyperlipidemias; Hypoglycemic Agents; Insulin; Insulin Resistance; Lipids; Lipoproteins; Liver; Male; Rats; Rats, Sprague-Dawley; Triglycerides

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

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

The effects of increased plasma free fatty acids (FFA) on insulin-dependent whole body glucose disposal, skeletal muscle glycolysis, glycogen synthesis, pyruvate versus FFA/ketone oxidation, and glucose 6-phosphate (Glu-6-P) were investigated in the awake rat. A control group (glycerol-infused) and high plasma FFA group (Liposyn-infused) were clamped at euglycemia (approximately 6 mM)-hyperinsulinemia (10 milliunits/kg/min) throughout the experiment (180-240 min). In the initial experiment, 13C NMR was used to observe [1-13C]glucose incorporation into [1-13C]glycogen in the rat hindlimb for glycogen synthesis calculations and into [3-13C]lactate and [3-13C]alanine for glycolytic flux calculations. These experiments were followed by 31P NMR measurements of Glu-6-P changes under identical conditions of the initial experiment. Plasma FFA concentrations were 2.25 +/- 0.36 and 0.20 +/- 0.03 mM in the high plasma FFA and control groups respectively (p < 0.0005). Glucose infusion rates (Ginf) decreased significantly in the Liposyn-infused rats (29.5 +/- 0.7 and 27.2 +/- 1.2 mg/kg/min for control and high plasma FFA group, respectively, at 15 min to 30.7 +/- 2.3 and 17.7 +/- 1.3 mg/kg/min, respectively, at the end of the experiment, p < 0.002). Glycogen synthesis rates were 163 +/- 32 and 104 +/- 17 nmol/g/min, and glycolytic rates were 57.9 +/- 8.0 and 19. 5 +/- 3.6 nmol/g/min (p < 0.002) in the control and high plasma FFA groups, respectively. The relative flux of pyruvate versus free fatty acids and ketones entering the tricarboxylic acid cycle was greater in the control (57 +/- 9%) versus high plasma FFA group (25 +/- 4%) (p < 0.005) as assessed by [4-13C]glutamate/[3-13C]lactate steady state isotopic enrichment measurements. Finally, Glu-6-P concentrations increased by 29.8 +/- 7.0 and 52.8 +/- 12.3% (p < 0. 05) in the control and high plasma FFA groups, respectively, above their basal concentrations by 180 min. In conclusion, we have demonstrated the ability to use in vivo NMR to elucidate the metabolic fate of glucose within skeletal muscle of an awake rat during a euglycemic-hyperinsulinemic clamp and increased levels of plasma FFA. These data suggest that increased concentrations of plasma FFA inhibit insulin-stimulated muscle glucose metabolism in the rat through inhibition of glycolysis.

Topics: Alanine; Animals; Carbon Isotopes; Fatty Acids, Nonesterified; Glucose; Glucose Clamp Technique; Glucose-6-Phosphate; Glycogen; Glycolysis; Hyperinsulinism; Infusions, Intravenous; Insulin; Ketones; Kinetics; Lactates; Magnetic Resonance Spectroscopy; Models, Biological; Muscle, Skeletal; Phosphorus; Pyruvates; Rats; Rats, Sprague-Dawley; Wakefulness

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

We determined the effect of infusion of glucosamine (GlcN), which bypasses the rate limiting reaction in the hexosamine pathway, on insulin-stimulated rates of glucose uptake and glycogen synthesis in vivo in rat tissues varying with respect to their glutamine:fructose-6-phosphate amidotransferase (GFA) activity. Three groups of conscious fasted rats received 6-h infusions of either saline (BAS), insulin (18 mU/kg x min) and saline (INS), or insulin and GlcN (30 micromol/ kg x min, GLCN). [3-(3)H]glucose was infused to trace whole body glucose kinetics and glycogen synthesis, and rates of tissue glucose uptake were determined using a bolus injection of [1-(14)C]2-deoxyglucose at 315 min. GlcN decreased insulin-stimulated glucose uptake (315-360 min) by 49% (P < 0.001) at the level of the whole body, and by 31-53% (P < 0.05 or less) in the heart, epididymal fat, submandibular gland and in soleus, abdominis and gastrocnemius muscles. GlcN completely abolished glycogen synthesis in the liver. GlcN decreased insulin-stimulated glucose uptake similarly in the submandibular gland (1.3 +/- 0.2 vs. 2.0 +/- 0.3 nmol/mg protein x min, GLCN vs. INS, P < 0.05) and gastrocnemius muscle (1.4 +/- 0.3 vs. 3.1 +/- 0.5 nmol/mg protein x min), although the activity of the hexosamine pathway, as judged from basal GFA activity, was 10-fold higher in the submandibular gland (286 +/- 35 pmol/mg protein x min) than in gastrocnemius muscle (27 +/- 3 pmol/mg protein x min, P < 0.001). These data raise the possibility that overactivity of the hexosamine pathway may contribute to glucose toxicity not only in skeletal muscle but also in other insulin sensitive tissues. They also imply that the magnitude of insulin resistance induced between tissues is determined by factors other than GFA.

Topics: Adipose Tissue; Animals; Blood Glucose; Deoxyglucose; Glucosamine; Glucose; Glucose Clamp Technique; Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing); Glycogen; Hexosamines; Hyperinsulinism; Infusions, Intravenous; Insulin; Insulin Resistance; Male; Muscle, Skeletal; Myocardium; Rats; Rats, Wistar; Submandibular Gland

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

To elucidate cellular mechanisms of insulin resistance induced by excess dietary fat, we studied conscious chronically high-fat-fed (HFF) and control chow diet-fed rats during euglycemic-hyperinsulinemic (560 pmol/l plasma insulin) clamps. Compared with chow diet feeding, fat feeding significantly impaired insulin action (reduced whole body glucose disposal rate, reduced skeletal muscle glucose metabolism, and decreased insulin suppressibility of hepatic glucose production [HGP]). In HFF rats, hyperinsulinemia significantly suppressed circulating free fatty acids but not the intracellular availability of fatty acid in skeletal muscle (long chain fatty acyl-CoA esters remained at 230% above control levels). In HFF animals, acute blockade of beta-oxidation using etomoxir increased insulin-stimulated muscle glucose uptake, via a selective increase in the component directed to glycolysis, but did not reverse the defect in net glycogen synthesis or glycogen synthase. In clamp HFF animals, etomoxir did not significantly alter the reduced ability of insulin to suppress HGP, but induced substantial depletion of hepatic glycogen content. This implied that gluconeogenesis was reduced by inhibition of hepatic fatty acid oxidation and that an alternative mechanism was involved in the elevated HGP in HFF rats. Evidence was then obtained suggesting that this involves a reduction in hepatic glucokinase (GK) activity and an inability of insulin to acutely lower glucose-6-phosphatase (G-6-Pase) activity. Overall, a 76% increase in the activity ratio G-6-Pase/GK was observed, which would favor net hepatic glucose release and elevated HGP in HFF rats. Thus in the insulin-resistant HFF rat 1) acute hyperinsulinemia fails to quench elevated muscle and liver lipid availability, 2) elevated lipid oxidation opposes insulin stimulation of muscle glucose oxidation (perhaps via the glucose-fatty acid cycle) and suppression of hepatic gluconeogenesis, and 3) mechanisms of impaired insulin-stimulated glucose storage and HGP suppressibility are not dependent on concomitant lipid oxidation; in the case of HGP we provide evidence for pivotal involvement of G-6-Pase and GK in the regulation of HGP by insulin, independent of the glucose source.

Topics: Acyl Coenzyme A; Animals; Blood Glucose; Dietary Fats; Glucokinase; Gluconeogenesis; Glucose Clamp Technique; Glucose-6-Phosphatase; Glycogen; Glycogen Synthase; Hyperinsulinism; Insulin; Insulin Resistance; Kinetics; Liver; Liver Glycogen; Muscle, Skeletal; Pyruvate Dehydrogenase Complex; Rats; Rats, Wistar; Reference Values; Triglycerides

We examined whether hyperinsulinemia is associated with changes in the amount of L-carnitine and acetyl-L-carnitine in the muscle and whether the source of acetyl-coenzyme A (CoA) (glucose or free fatty acids [FFAs]) influences its further metabolism to acetyl-L-carnitine or through tricarboxylic acid in the skeletal muscle of man in vivo. Twelve healthy men (aged 45 +/- 2 years; body mass index, 25.2 +/- 1.0 kg/m2) were studied using a 4-hour euglycemic-hyperinsulinemic clamp (1.5 mU/kg/min) and indirect calorimetry. Although the mean muscle free L-carnitine and acetyl-L-carnitine concentrations remained unchanged during hyperinsulinemia in the group as a whole, the individual changes in muscle free L-carnitine and acetyl-L-carnitine concentrations were inversely related (r = -.72, P < .02). The basal level of acetyl-L-carnitine was inversely related to the rate of lipid oxidation (r = -.70, P < .02). In a stepwise linear regression analysis, 77% of the variation in the change of acetyl-L-carnitine concentrations was explained by the basal muscle glycogen level (inversely) and nonoxidative glucose disposal rate (directly) during hyperinsulinemia (P < .001); by adding the final FFA concentration (inverse correlation) to the model, 88% of the variation was explained (P < .001). In conclusion, (1) hyperinsulinemia does not enhance skeletal muscle free L-carnitine or acetyl-L-carnitine concentrations in-man, and (2) the acetyl group of acetyl-L-carnitine in human skeletal muscle in vivo is probably mostly derived from glucose and not through beta-oxidation from fatty acids.

Topics: Acetyl Coenzyme A; Acetylcarnitine; Adult; Calorimetry, Indirect; Fatty Acids, Nonesterified; Glucose; Glycogen; Humans; Hyperinsulinism; Insulin; Linear Models; Lipid Metabolism; Male; Middle Aged; Muscle, Skeletal; Oxidation-Reduction

The role of increased lipid availability in the generation of insulin resistance by growth hormone has not been established. We investigated this in rats infused with saline (controls) or human growth hormone (hGH) (500 micrograms x kg-1 x 24 h-1) for 5 h or 3 days. hGH infusion increased basal plasma insulin at 5 h (335 +/- 33 vs. 197 +/- 15 [controls]; P < 0.005) and at 3 days (396 +/- 34 vs. 218 +/- 14 pmol/l; P < 0.0001). Plasma nonesterified fatty acid (0.26 +/- 0.01 vs. 0.21 +/- 0.01 [controls] g/l) and liver long-chain acyl-CoA (21.2 +/- 1.9 vs. 14.1 +/- 1.1 [controls] nmol/g wet wt) were elevated at 5 h (P < 0.01 for both) but were below control levels after 3 days of hGH infusion (P < 0.01 for both); indirect calorimetry after 3 days demonstrated decreased lipid oxidation. Clamp studies showed similar degrees of peripheral insulin resistance at 5-h and 3-day hGH infusion (glucose disposal reduced by 25% versus controls). Insulin-stimulated glucose metabolic index (Rg') in red gastrocnemius muscle (red muscle) was reduced (P < 0.05 and P < 0.01) at 5 h and 3 days of hGH infusion, respectively (e.g., 5 h, 10.0 +/- 1.8 vs. 24.1 +/- 4.4 [controls] micromol x 100 g-1 x min-1), whereas insulin-mediated muscle glycogen synthesis was reduced (P < 0.03) only in rats infused with hGH for 3 days. We conclude that in the rat, hGH rapidly induces persistent peripheral insulin resistance and basal hyperinsulinemia. However, the transient nature of increased lipid mobilization suggests that it is not an important factor in the manifestation of muscle insulin resistance during prolonged hGH elevation. The persistent insulin resistance is not associated with increased lipid oxidation but is associated with hyperinsulinemia and reduced insulin-mediated muscle glycogen synthesis.

Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Epididymis; Fatty Acids, Nonesterified; Glycogen; Growth Hormone; Humans; Hyperinsulinism; Infusions, Intravenous; Insulin; Insulin Resistance; Kinetics; Male; Muscle, Skeletal; Myocardium; Patch-Clamp Techniques; Rats; Rats, Wistar; Reference Values; Triglycerides

To evaluate the effects of chronic hyperinsulinemia/obesity on the proximal events leading to the activation of glycogen synthase.. 100 d old second generation of chronically hyperinsulinemic/obese rats born to mothers which were artificially reared on a high carbohydrate (HC) milk formula in their infancy were used for this study and compared with mother-fed (MF) controls.. Glycogen, glycogen synthase, protein phosphatase-1 (PP-1), mitogen-activated protein kinase (MAPK), insulin-stimulated protein kinase (ISPK) and protein kinase A (PKA) were measured in liver and muscle of both MF and HC rats.. Glycogen content, glycogen synthase and PP-1 activities were significantly reduced in liver and muscle of HC rats compared to MF controls while trypsin released PP-1 activity was elevated. The activities of both MAPK and ISPK were also decreased in the HC rats. In contrast PKA activity was increased.. Glycogen synthase activity in the basal state may be impaired in the hyperinsulinemic HC rats in two ways: (i) by a decrease in the activities of the kinases that presumably activate PP-1 and (ii) by increased activity of PKA which inactivates glycogen synthase directly by phosphorylation and indirectly by its effects on PP-1.

Topics: Animals; Calcium-Calmodulin-Dependent Protein Kinases; Cyclic AMP-Dependent Protein Kinases; Dietary Carbohydrates; Enzyme Activation; Female; Glycogen; Glycogen Synthase; Hyperinsulinism; Liver; Male; Muscle, Skeletal; Obesity; Phosphoprotein Phosphatases; Pregnancy; Prenatal Exposure Delayed Effects; Protein Phosphatase 1; Protein Serine-Threonine Kinases; Rats; Rats, Sprague-Dawley; Ribosomal Protein S6 Kinases

The effects of long-term exposure (7 wk) to hyperinsulinaemia on insulin sensitivity were studied in female rats. The rats were made hyperinsulinaemic by implantation of osmotic minipumps that were changed once a week. Elevated adrenergic activity and secretion of glucocorticoids were controlled by another minipump with propranolol and adrenalectomy with corticosterone substitution, respectively. This resulted in hyperinsulinaemia and moderate hypoglycaemia, the latter probably counteracted by overeating and increased glucagon secretion, as indicated by increased body weight and lower liver glycogen contents, respectively. Euglycaemic, hyperinsulinaemic clamp measurements showed a significantly higher glucose disposal rate (P < 0.05) in the hyperinsulinaemic rats 18.8 +/- 1.1 mg kg-1 min-1 compared with the control groups 14.6 +/- 0.4 and 15.4 +/- 0.9 mg kg-1 min-1. Insulin stimulation of 2-deoxyglucose as well as glycogen synthesis was measured in the extensor digitorum longus muscle, the red and white part of the gastrocnemius, the soleus muscle, the liver and in parametrial, retroperitoneal, and inguinal adipose tissue. No differences were found between the groups in the insulin response of the 2-deoxyglucose uptake. Glycogen synthesis was significantly elevated in all muscles in the insulin treated compared with the control rats but no differences were found in the liver. Capillary density was significantly elevated per unit muscle surface area in the soleus and extensor digitorum longus muscles of the insulin-exposed rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Glucose; Body Weight; Deoxyglucose; Female; Glycogen; Hyperinsulinism; Insulin; Muscle, Skeletal; Propranolol; Rats; Rats, Sprague-Dawley

Methodology for assessing the glycolytic and oxidative fluxes from plasma glucose, by measuring 3H2O and 14CO2 rates of production during [3-3H]- and [U-14C]glucose infusion, was tested in healthy subjects. In study 1, during staircase 3H2O infusion in six subjects, calculated rates of 3H2O appearance agreed closely with 3H2O infusion rates. In study 2, when [2-3H]glucose and NaH14CO3 were infused in four subjects in the basal state and during a 4-h euglycemic insulin (approximately 70 microU/ml) clamp, accurate estimates of the rates of [2-3H]glucose detritiation were obtained (94-97% of the expected values), and the recovery factor of NaH14CO3 did not change during hyperinsulinemia. In study 3, 11 subjects underwent a 4-h euglycemic insulin (approximately 70 microU/ml) clamp with [3-3H]- and [U-14C]glucose infusion and measurement of gaseous exchanges by indirect calorimetry to estimate the rates of total glycolysis, glycogen synthesis, glucose oxidation, nonoxidative glycolysis, hepatic glucose production, glucose recycling, and glucose conversion to fat. Hyperinsulinemia stimulated glycogen synthesis above baseline more than glycolysis [increment of 4.78 +/- 0.37 vs. 2.0 +/- 0.17 mg.min-1 x kg-1 of lean body mass (LBM), respectively, P < 0.01] and incompletely suppressed (approximately 87%) hepatic glucose production. The major component of nonoxidative glycolysis shifted from glucose recycling in the postabsorptive state (approximately 57% of nonoxidative glycolysis) to glucose conversion to fat during hyperinsulinemia (approximately 59% of nonoxidative glycolysis). Lipid oxidation during the insulin clamp was negatively correlated with both isotopic glucose oxidation (r = -0.822, P < 0.002) and glycolysis (r = -0.582, P < 0.07). In conclusion, in healthy subjects, glycogen synthesis plays a greater role than glycolysis and glucose oxidation in determining insulin-mediated glucose disposal. Part of insulin-mediated increase in glycolysis/oxidation might be secondary to the relief of the competition between fat and glucose for oxidation.

Topics: Adult; Blood Glucose; Body Mass Index; Body Water; Carbon Radioisotopes; Female; Glucose; Glycogen; Glycolysis; Humans; Hyperinsulinism; Insulin; Kinetics; Male; Models, Biological; Radioisotope Dilution Technique; 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

The experimental evidence supporting a direct role for hyperinsulinemia as a cause of insulin resistance remains equivocal. Amylin, an islet beta-cell peptide cosecreted with insulin in response to nutrient stimuli, causes insulin resistance when infused into intact animals or applied to isolated skeletal muscles. We compared measures of amylin and insulin gene expression between control and genetically obese, insulin-resistant Lister Albany/NIH-(LA/N-cp) rats. Pancreatic amylin messenger RNA levels were increased 7.8 +/- 0.7-fold (mean +/- SEM), and plasma amylin-like immunoreactive material was increased 10.9 +/- 1.1-fold (LA/N-lean, 14 +/- 4 pM; LA/N-cp, 153 +/- 16 pM; p less than 0.0001) in obese rats. Pancreatic insulin I mRNA levels were increased 7.4 +/- 0.5-fold, and plasma insulin levels 20.0 +/- 5.0-fold, in these rats (LA/N-lean, 308 +/- 84 pM; LA/N-cp 6,120 +/- 1,540 pM; p less than 0.0001). The EC50 for insulin-stimulated incorporation of glucose into glycogen was about fourfold higher in muscles isolated from obese rats. The present results, coupled with previous observations, support the hypothesis that hyperamylinemia, rather than hyperinsulinemia per se, could have directly caused the insulin resistance in the obese LA/N-cp rats. Hyperamylinemia needs to be considered in future experimental studies probing the relation between hyperinsulinemia and insulin resistance.

Topics: Amyloid; Animals; Blood Glucose; Glucose Tolerance Test; Glycogen; Hyperinsulinism; Insulin; Insulin Resistance; Islet Amyloid Polypeptide; Muscles; Obesity; Rats; Rats, Inbred Strains; RNA, Messenger

There is a paucity of information on the significance of insulin on neonatal cerebral glucose metabolism. The effect of insulin on neonatal cerebral glucose uptake and cerebral cortical metabolic intermediates was investigated with the euglycemic hyperinsulinemic clamp in unanesthetized beagles during the first day of life. Insulin was infused at various rates to sustain an elevated steady state plasma insulin concentration in individual pups. Furthermore, blood glucose and 2-deoxyglucose levels were also maintained ("clamped") in a steady state by infusion of glucose and 2-deoxy-[14C]-glucose. Mean (+/- SD) plasma insulin levels were 20 +/- 12 and 2971 +/- 3386 (33-14330) microU/ml in control and hyperinsulinemic pups. Blood glucose concentration was 4.43 +/- 2.64 mM during basal periods and 4.54 +/- 2.87 mM during the clamp period in study pups. Basal fasting glucose utilization in study pups was 43.9 +/- 24 mumol/kg/min and increased to 60.9 +/- 35.2 mumol/kg/min (p less than 0.001) during hyperinsulinemia. Immediately after the euglycemic hyperinsulinemic clamp or fasting in control pups, the cerebral cortex was frozen to the temperature of liquid nitrogen. No differences were noted for any cerebral cortical intermediate between the two pup groups. In addition, there was no relationship between the cerebral intermediates concentration when analyzed as a function of plasma insulin levels. The uptake of cerebral 2-deoxyglucose was analyzed as a function of plasma insulin concentration (120-6900 microU/ml). Brain tissue demonstrated a positive linear relationship for 2-deoxyglucose uptake as a function of plasma insulin concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenosine Triphosphate; Animals; Animals, Newborn; Cerebral Cortex; Citric Acid Cycle; Deoxy Sugars; Deoxyglucose; Disease Models, Animal; Dogs; Glycogen; Hyperinsulinism; Insulin; Liver; Muscles

The chronically hyperinsulinemic Zucker fatty rat, with peripheral insulin resistance and glucose intolerance, represents a model of noninsulin dependent diabetes mellitus (NIDDM). These animals have elevated hepatic glycogen levels. Hepatic levels of synthase phosphatase and phosphorylase phosphatase, which are diminished in the IDDM rat, were markedly increased in the obese rats. Glyburide, a sulfonylurea used in treatment of NIDDM, resulted in reduced levels of glycemia and increased insulin levels in Zucker rats. Hepatic glycogen levels were increased, as was the activation of glycogen synthase, although there were no effects of drug administration on synthase phosphatase or phosphorylase phosphatase activities. G6P levels were increased by glyburide in lean rats but not in obese animals. These effects of glyburide on liver glycogen metabolism are accounted for via potentiation of the glycogenic effects of insulin.

Topics: Animals; Endoplasmic Reticulum; Female; Glucose-6-Phosphate; Glucosephosphates; Glyburide; Glycogen; Glycogen-Synthase-D Phosphatase; Hyperinsulinism; Liver; Obesity; Phosphoprotein Phosphatases; Phosphorylase Phosphatase; Rats; Rats, Zucker

To assess a suitable model for the study of the mechanisms of development of insulin resistance in vivo, liver and muscle glycogen levels (as a metabolic index of tissue insulin sensitivity) were investigated in rats with functioning islet cell adenomas induced by streptozotocin and nicotinamide. These rats have basal moderate hyperinsulinemia and hypoglycemia and show a remarkable increase in insulin secretion after glucose administration. Plasma glucagon concentrations are normal. Nevertheless, in tumor-bearing rats, a reduction of tissue glycogen stores occurs, related to plasma glucose concentrations, and liver glycogen fails to increase even after a glucose load. The lack of excess fat in tumor-bearing rats also suggests a certain insulin insensitivity of the adipose tissue and distinguishes this model of chronic hyperinsulinism from other reported models, such as genetically obese animals.

Topics: Adrenal Glands; Animals; Blood Glucose; Chronic Disease; Disease Models, Animal; Glucagon; Glycogen; Hyperinsulinism; Insulin; Insulin Resistance; Liver; Male; Muscles; Organ Size; Rats; Rats, Inbred Strains

The interaction between epinephrine and insulin in modulating in vivo glucose metabolism within individual tissues of the body has not previously been examined. This was investigated using the euglycemic hyperinsulinemic (120 milliunits/liter) clamp combined with administration of [3H]2-deoxyglucose and D-[U-14C]glucose. Epinephrine produced whole body insulin resistance due to increased hepatic glucose output and reduced peripheral glucose disposal. Despite elevated insulin levels liver glycogen content was reduced by 50% during epinephrine infusion (5 nM). However, this effect was transient, occurring predominantly during the initial 60 min of study. These effects were prevented during beta-adrenergic blockade with propranolol and potentiated during alpha 1-adrenergic blockade with prazosin. The most significant effect of epinephrine in peripheral tissues was increased glycogenolysis in both oxidative and glycolytic skeletal muscle. A significant reduction in insulin-mediated [3H]2-deoxyglucose uptake (30%) was evident in 5 of 9 muscles tested during epinephrine infusion. This effect was most pronounced in the more insulin-sensitive oxidative muscles. The latter effect was probably indirectly mediated via increased glycogenolysis--increased accumulation of metabolites--inhibition of hexokinase. In addition, it is evident that insulin-mediated glycogen synthesis occurred during epinephrine infusion. All effects of epinephrine on muscle glucose metabolism were prevented by propranolol but not prazosin. Similar effects to that observed in muscle were not evident in adipose tissue. It is concluded that epinephrine may override many of the actions of insulin in vivo, and most of these effects are mediated via the beta-adrenergic receptor. In the intact rat there may be a complex interaction between alpha- and beta-adrenergic effects in regulating hepatic glucose output.

Topics: Animals; Blood Glucose; Deoxyglucose; Drug Interactions; Epinephrine; Glycogen; Hyperinsulinism; Insulin; Male; Mathematics; Muscles; Prazosin; Propranolol; Rats; Rats, Inbred Strains

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 effects of chronic insulin administration on the metabolism of isolated adipose cells and muscle were studied. Adipose cells from 2 and 6 wk insulin-treated and control rats, fed either chow or chow plus sucrose, were prepared, and insulin binding, 3-O-methylglucose transport, glucose metabolism, and lipolysis were measured at various insulin concentrations. After 2 wk of treatment, adipose cell size and basal glucose transport and metabolism were unaltered, but insulin-stimulated transport and glucose metabolism were increased two- to threefold when cells were incubated in either 0.1 mM glucose (transport rate limiting) or 10 mM glucose (maximum glucose metabolism). Insulin binding was increased by 30%, but no shift in the insulin dose-response curve for transport or metabolism occurred. After 6 wk of treatment, the effects of hyperinsulinemia on insulin binding and glucose metabolism persisted and were superimposed on the changes in cell function that occurred with increasing cell size in aging rats. Hyperinsulinemia for 2 or 6 wk did not alter basal or epinephrine-stimulated lipolysis in adipose cells or the antilipolytic effect of insulin. In incubated soleus muscle strips, insulin-stimulated glucose metabolism was significantly increased after 2 wk of hyperinsulinemia, but these increases were not observed after 6 wk of treatment. We conclude that 2 wk of continuous hyperinsulinemia results in increased insulin-stimulated glucose metabolism in both adipose cells and soleus muscle. Despite increased insulin binding to adipose cells, no changes in insulin sensitivity were observed in adipose cells or muscle. In adipose cells, the increased glucose utilization resulted from both increased transport (2 wk only) and intracellular glucose metabolism (2 and 6 wk). In muscle, after 2 wk of treatment, both glycogen synthesis and total glucose metabolism were increased. These effects of hyperinsulinemia were lost in muscle after 6 wk of treatment, when compared with sucrose-supplemented controls.

Topics: 3-O-Methylglucose; Adipose Tissue; Animals; Body Composition; Epinephrine; Glucose; Glycogen; Hyperinsulinism; Insulin; Lipolysis; Male; Methylglucosides; Muscles; Organ Size; Rats; Time Factors; Triglycerides

The effects of prior high-intensity cycle exercise (85% VO2 max) to muscular exhaustion on basal and insulin-stimulated glucose metabolism were studied in obese, insulin-resistant, and normal subjects. Six obese (30.4% fat) and six lean (14.5% fat) adult males underwent two separate, two-level hyperinsulinemic-euglycemic clamp studies (100-min infusions at 40 and 400 mU/m2/min), with and without exercise 12 h earlier. Carbohydrate oxidation was estimated by indirect calorimetry using a ventilated hood system, and endogenous glucose production by D-(3-3H)-glucose infusion. Glycogen content and glycogen synthase activity (GS %l) were measured in vastus lateralis muscle biopsies before and at the end of each insulin clamp procedure. After exercise, the obese and lean subjects had comparably low muscle glycogen concentrations (0.10 versus 0.08 mg/g protein, respectively), and equal activation of muscle GS activity (54.4 versus 45.3 GS %l, respectively). In the obese subjects, insulin-stimulated glucose disposal was increased significantly, but not totally corrected to normal. In both groups there was a comparable increase in nonoxidative glucose disposal (NOGD), whereas glucose oxidation was decreased and lipid oxidation was increased. Thus, the major effect of prior exercise was to increase insulin-stimulated glucose disposal in the obese subjects and to alter the pathways of glucose metabolism to favor NOGD and decrease glucose oxidation. No correlation was found between the exercise-induced increase in GS %l and NOGD, except in the normal subjects during maximal insulin stimulation. Thus, glycogen synthase activity does not appear to be rate-limiting for NOGD at physiologic insulin concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Blood Glucose; C-Peptide; Glucose; Glucose Tolerance Test; Glycogen; Glycogen Synthase; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Male; Muscles; Obesity; Oxidation-Reduction; Physical Exertion; Urea

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

Topics: Fructose-1,6-Diphosphatase Deficiency; Galactose; Gluconeogenesis; Glucosephosphate Dehydrogenase Deficiency; Glycogen; Glycogen Storage Disease; Glycoside Hydrolases; Humans; Hyperinsulinism; Hypoglycemia; Hypothyroidism; Insulin; Lactates; Leucine; Parathyroid Hormone; Phosphorylases; Pyruvate Carboxylase Deficiency Disease

Topics: Animals; Female; Glucose; Glucosephosphate Dehydrogenase; Glutamate Dehydrogenase; Glycerolphosphate Dehydrogenase; Glycogen; Hexokinase; Hyperinsulinism; Hypothalamus; Insulin; L-Lactate Dehydrogenase; Liver; Liver Glycogen; Muscles; Phosphofructokinase-1; Phosphogluconate Dehydrogenase; Pyruvate Kinase; Rats; Tibia

Topics: Adipose Tissue; Animals; Blood Glucose; Carbon Dioxide; Carbon Isotopes; Diaphragm; Glucose; Glycogen; Hyperinsulinism; In Vitro Techniques; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Male; Obesity; Rats; Rodent Diseases

Topics: Adipose Tissue; Animals; Blood Glucose; Blood Volume; Fatty Acids, Nonesterified; Food Deprivation; Glucose; Glycogen; Hyperinsulinism; Insulin; Liver; Mice; Norepinephrine; Obesity; Pancreas; Radioimmunoassay

Topics: Animals; Caseins; Female; Gluconeogenesis; Glucose; Glucose Tolerance Test; Glycogen; Humans; Hyperinsulinism; Hypoglycemia; In Vitro Techniques; Infant; Leucine; Male; Maple Syrup Urine Disease; Rats

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

Topics: Animals; Carbohydrate Metabolism; Female; Glycogen; Histocytochemistry; Hyperinsulinism; Placenta; Pregnancy; Pregnancy Complications; Rats

1. [U-(14)C]Glucose was injected into mice and the distribution of (14)C in various chemical fractions of the whole body was determined at times from 15min. to 8hr. after injection. 2. At 1hr. after injection 31.8% of the recovered (14)C was found in the expired air and 26.7% was found in the isolated glycogen, lipids, proteins, nucleic acids and in other acid-insoluble carbon compounds (;residual (14)C'). The rest (41.5%) was combined in acid-soluble substances. 3. When insulin was injected 5min. or 1hr. before injection of [U-(14)C]glucose, and the mouse was killed 1hr. later, the (14)C content of expired air, glycogen, protein and ;residual (14)C' was not significantly affected; but the incorporation of (14)C into lipids was increased two- to three-fold. 4. Chromatography of the lipids on silicic acid columns and by thin-layer chromatography showed that the main effect of insulin injection was to increase the incorporation of (14)C into fatty acids. 5. A significant increase of (14)C after insulin injection was also found in a glyceride in which the (14)C was combined in glycerol.

Topics: Animals; Carbon Isotopes; Chemistry Techniques, Analytical; Chromatography, Thin Layer; Glucose; Glycogen; Hyperinsulinism; Hypoglycemia; In Vitro Techniques; Lipids; Mice; Nucleic Acids; Protein Biosynthesis