glycogen and Diabetes-Mellitus--Type-1

Glycogenic hepatopathy (GH) in type 1 diabetes-mellitus (T1DM) is characterized by hepatomegaly and perturbations of liver chemistries (LC) that have not been well studied. Furthermore, misdiagnosis with other hepatic complications of T1DM, such as nonalcoholic fatty liver disease, has been described. We perform a systematic review of biopsy-proven GH reports in T1DM patients to identify LC patterns.. A systematic review identified reports of biopsy-proven GH in patients with T1DM. We excluded GH with other liver diseases, Mauriac syndrome, or GH without T1DM. Two reviewers screened and extracted studies and assessed their methodological quality. LC elevation magnitude, AST-to-ALT ratio, R-ratio to designate hepatocellular, cholestatic or mixed pattern of hepatic injury, and evolution of transaminases after glycemic control were analyzed.. GH tends to have AST-predominant elevation with a median of 13 times the upper normal limit and R-ratio >2, which may distinguish it from other etiologies of AST-predominant LC elevation, and in the appropriate clinical context, may obviate invasive tests.

Topics: Adult; Diabetes Mellitus, Type 1; Female; Glycogen; Hepatomegaly; Humans; Liver Diseases; Male; Young Adult

Glycogenic hepatopathy (GH) is a disorder associated with uncontrolled diabetes mellitus, most commonly type 1, expressed as right upper quadrant abdominal pain, hepatomegaly and increased liver enzymes. The diagnosis may be difficult, because laboratory and imaging tests are not pathognomonic. Although GH may be suggested based on clinical presentation and imaging studies, the gold standard for diagnosis is a liver biopsy, showing a significant accumulation of glycogen within the hepatocytes. GH may be diagnosed also after elevated liver enzymes in routine blood tests. GH usually regresses after tight glycemic control. Progression to end-stage liver disease has never been reported. This review aims to increase the awareness to this disease, to suggest a pathway for investigation that may reduce the use of unnecessary tests, especially invasive ones.. A PubMed database search (up to July 1, 2017) was done with the words "glycogenic hepatopathy", "hepatic glycogenosis", "liver glycogenosis" and "diabetes mellitus-associated glycogen storage hepatopathy". Articles in which diabetes mellitus-associated liver glycogen accumulation was described were included in this review.. A total of 47 articles were found, describing 126 patients with GH. Hepatocellular disturbance was more profound than cholestatic disturbance. No synthetic failure was reported.. GH may be diagnosed conservatively, based on corroborating medical history, physical examination, laboratory tests, imaging studies and response to treatment, even without liver biopsy. In case of doubt about the diagnosis or lack of clinical response to treatment, a liver biopsy may be considered. There is no role for noninvasive tests like fibroscan or fibrotest for the diagnosis of GH or for differentiation of this situation from nonalcoholic fatty liver disease.

Topics: Abdominal Pain; Adolescent; Adult; Biomarkers; Biopsy; Child; Diabetes Mellitus, Type 1; Diagnosis, Differential; Female; Glycogen; Hepatomegaly; Humans; Hypoglycemic Agents; Liver; Liver Function Tests; Male; Pancreas Transplantation; Predictive Value of Tests; Prognosis; Risk Factors; Young Adult

Exercise in diabetes patients has many benefits but also several risks, of which hypoglycemia is most often discussed. We present a case with recurrent keto-acidosis post-exercise, in which we hypothesize that glycogen replacement strategies were insufficient. Our experience in this case and review of the literature emphasize the importance of discussing glycogen replacement strategies with your diabetic athletes.

Topics: Adolescent; Athletes; Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Exercise; Glycogen; Humans; Male; Physical Exertion; Recurrence

While it has long been known that zinc (Zn) is crucial for the proper growth and maintenance of normal biological functions, Zn has also been shown to exert insulin-mimetic and anti-diabetic effects. These insulin-like properties have been demonstrated in isolated cells, tissues, and different animal models of type 1 and type 2 diabetes. Zn treatment has been found to improve carbohydrate and lipid metabolism in rodent models of diabetes. In isolated cells, it enhances glucose transport, glycogen and lipid synthesis, and inhibits gluconeogenesis and lipolysis. The molecular mechanism responsible for the insulin-like effects of Zn compounds involves the activation of several key components of the insulin signaling pathways, which include the extracellular signal-regulated kinase 1/2 (ERK1/2) and phosphatidylinositol 3-kinase (PI3-K)/protein kinase B/Akt (PKB/Akt) pathways. However, the precise molecular mechanisms by which Zn triggers the activation of these pathways remain to be clarified. In this review, we provide a brief history of zinc, and an overview of its insulin-mimetic and anti-diabetic effects, as well as the potential mechanisms by which zinc exerts these effects.

Topics: Animals; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Disease Models, Animal; ErbB Receptors; Glycogen; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Lipogenesis; Receptor, IGF Type 1; Signal Transduction; Zinc; Zinc Compounds

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

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

This short review outlines the physiology of glucagon in vivo, with an emphasis on its neural control, the author's area of interest. Glucagon is secreted from alpha cells, which are a minority of the pancreatic islet. Anatomically, they are down stream from the majority islet beta cells. Beta-cell secretory products restrain glucagon secretion. Activation of the autonomic nerves, which innervate the islet, increases glucagon secretion. Glucagon is secreted into the portal vein and thus has its major physiologic action at the liver to break down glycogen. Glucagon thereby maintains hepatic glucose production during fasting and increases hepatic glucose production during stress, including the clinically important stress of hypoglycemia. Three different mechanisms proposed to stimulate glucagon secreted during hypoglycemia are discussed: (1) a stimulatory effect of low glucose directly on the alpha cell, (2) withdrawal of an inhibitory effect of adjacent beta cells, and (3) a stimulatory effect of autonomic activation. In type 1 diabetes (T1DM), increased glucagon secretion contributes to the elevated ketones and acidosis present in diabetic ketoacidosis (DKA). It also contributes to the hyperglycemia seen with or without DKA. The glucagon response to insulin-induced hypoglycemia is impaired soon after the development of T1DM. The mediators of this impairment include loss of beta cells and loss of sympathetic nerves from the autoimmune diabetic islet.

Topics: Animals; Autonomic Nervous System; Blood Glucose; Diabetes Mellitus, Type 1; Glucagon; Glucagon-Secreting Cells; Glycogen; Homeostasis; Humans; Hypoglycemia; Insulin; Islets of Langerhans; Liver

The purpose of this work is to present the main interactions promoted by exercise and synthesize them into mathematical equations. It is intended to extend the ability of the compartmental glucose-insulin model introduced by Sorensen [1985. A physiologic model of glucose metabolism in man and its use to design and assess improved insulin therapies for diabetes. Ph.D. Dissertation, Chemical Engineering Department, MIT, Cambridge] to reproduce variations in the blood glucose concentration induced by exercise in diabetic patients and to complement the previous work by Lenart and Parker [2002. Modeling exercise effects in type I diabetic patients. In: Proceedings of the 15th Triennial World Congress, Barcelona, Spain] and Lenart, DiMascio and Parker [2002. Modeling glycogen-exercise interactions in type I diabetic patients. In: Proceedings of the A.I.Ch.E. Annual Meeting, Indianapolis, IN]. The immediate consequences of exercise are incorporated in this research: redistribution of blood flows, increments in peripheral glucose and insulin uptakes, and increment in hepatic glucose production. The extended model was verified with experimental data for light and moderate intensity exercise. In addition, data extrapolation was introduced to simulate heavy intensity exercise. The hepatic glycogen reservoir limits the peripheral glucose uptake for prolonged exercise. Therefore, the depletion and replenishment of hepatic glycogen were modeled, looking to reproduce the blood glucose levels for a type 1 diabetic patient during a normal day, with meal intakes, insulin infusions and/or boluses, and a predefined exercise regime. From the extensive simulation evaluation, it is found that the new exercise model provides a good approximation to the available experimental data from literature.

Topics: Computer Simulation; Diabetes Mellitus, Type 1; Exercise; Gluconeogenesis; Glucose; Glycogen; Humans; Insulin; Models, Cardiovascular

The brain uses glucose as a primary fuel for energy generation. Glucose gains entry into the brain by facilitated diffusion across the blood-brain barrier. Glucose transport may adapt during changes in cerebral glucose metabolism, neural activation and changes in plasma glucose levels. Within the brain, glucose is either oxidized to produce ATP or used to synthesize glycogen. To ensure the delivery of a continuous supply of glucose to maintain normal cellular function, the brain has developed a complex regulatory system to preserve its supply. Gluco-sensing neurons have been demonstrated in various regions of the brain and they appear to play an important role in not only detecting changes in brain glucose levels but also in initiating responses to maintain constant brain glucose levels. In this review, we will discuss the regulation of brain glucose metabolism (CMR(gluc)) and how it adapts to chronic changes in glycemia, like that seen in hyperglycemic patients with diabetes mellitus or patients with type 1 diabetes, recurrent hypoglycemia, and hypoglycemia unawareness. We will also consider the role of brain glycogen in providing fuel for energy under conditions of stress.

Topics: Blood-Brain Barrier; Brain; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucose; Glucose Transporter Type 1; Glucose Transporter Type 3; Glycogen; Humans; Insulin; Neuroglia; Neurons

The etiology of type I and type II diabetes differs and so do the nutritional challenges during and after exercise. For type I diabetics, exercise may cause hypoglycemia. To avoid hypoglycemia, a carbohydrate-rich meal should be eaten 1 to 3 hours prior to exercise and the insulin dose reduced. During exercise, at least 40 g glucose per hour should be ingested; more if the insulin dose is not reduced. After exercise, it is important to rebuild the glycogen stores to reduce the risk for hypoglycemia. Carbohydrates should always be available during training and in the recovery period. Despite these difficulties, exercise is recommended for type I diabetics and competition at high level is possible. Exercise prevents development of type II diabetes and improves metabolic regulation. For type II diabetics, exercise is normally performed to improve insulin sensitivity and to reduce body weight. Carbohydrates should only be supplied to prevent hypoglycemia.

Topics: Blood Glucose; Body Weight; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Exercise; Glycemic Index; Glycogen; Homeostasis; Humans; Hypoglycemia; Muscle, Skeletal; Nutritional Physiological Phenomena; Physical Endurance

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

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

Prior to the advent of nuclear magnetic resonance (NMR) spectroscopy, human glucose metabolism was studied through tracer and tissue biopsy methodology. NMR spectroscopy now provides a noninvasive means to monitor metabolic flux and intracellular metabolite concentrations continuously. 13C NMR spectroscopy has shown that muscle glycogen synthesis accounts for the majority of insulin-stimulated muscle glucose uptake in normal volunteers and that defects in this process are chiefly responsible for insulin resistance in type 1 and type 2 diabetes mellitus, as well as in other insulin resistant states (obesity, insulin-resistant offspring of type 2 diabetic parents, elevation of plasma FFA concentrations). Furthermore, using 31P NMR spectroscopy to measure intracellular glucose-6-phosphate, it has been shown that defects in insulin-stimulated glucose transport/phosphorylation activity are primarily responsible for the insulin resistance in these states.

Topics: Carbon Isotopes; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Glucose; Glucose-6-Phosphate; Glycogen; Humans; Insulin; Insulin Resistance; Magnetic Resonance Spectroscopy; Muscle, Skeletal; Obesity; Phosphorus Isotopes; Phosphorylation

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Glucose; Glycogen; Homeostasis; Humans; Hypoglycemia; Insulin Resistance; Kidney; Kidney Failure, Chronic; Lactates; Lactic Acid; Male

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

Topics: Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Exercise; Glucagon; Glucose; Glycogen; Hormones; Humans; Insulin; Muscles; Time Factors

Topics: Autonomic Nervous System Diseases; Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Energy Intake; Energy Metabolism; Glucose; Glycogen; Humans; Hypoglycemia; Hypotension, Orthostatic; Insulin; Liver; Muscles; Oxygen Consumption; Physical Exertion

In conclusion, a large body of available evidence indicates that the degree of physical conditioning is an important determinant of insulin sensitivity and overall glucose tolerance. Both acute exercise and chronic physical training are associated with enhanced disposal of a glucose load. Conversely, physical inactivity leads to a deterioration in glucose tolerance. The primary tissue responsible for accelerated glucose disposal following exercise is muscle. After an acute bout of exercise, enhanced glucose transport and augmented glycogen synthesis are largely responsible for the improvement in glucose tolerance. The beneficial effects of chronic physical training on glucose metabolism appear to be explained by multiple factors, including increased muscle mass, augmented muscle blood flow and capillary area, enhanced mitochondrial oxidative enzyme capacity, and activation of the glucose transport system. Despite these well-documented effects of training on glucose metabolism, the precise role of exercise in the treatment of diabetic patients remains to be established. In insulin-dependent (type I) diabetic individuals, acute exercise has been shown to be a helpful adjunct in establishing good glycemic control. However, the role of acute exercise in helping to smooth out glycemic control in non-insulin-dependent (type II) diabetic patients has received little attention. The role of chronic physical training in the treatment of both insulin-dependent (type I) and non-insulin-dependent (type II) diabetic individuals remains to be established.

Topics: Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Exercise Therapy; Glucose; Glycogen; Humans; Insulin; Insulin Resistance; Obesity; Physical Education and Training

Topics: Adipose Tissue; Animals; Blood Glucose; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Energy Metabolism; Exercise Therapy; Fatty Acids, Nonesterified; Food; Glucose; Glucose Tolerance Test; Glycogen; Homeostasis; Humans; Insulin; Insulin Resistance; Lipids; Liver; Muscles; Physical Exertion; Quality of Life

Topics: Adrenergic beta-Antagonists; Blood Glucose; Diabetes Mellitus, Type 1; Epinephrine; Fatty Acids; Gluconeogenesis; Glycogen; Growth Hormone; Homeostasis; Humans; Hydrocortisone; Hypoglycemia; Insulin; Insulin Resistance; Insulin, Regular, Pork; Kinetics; Lipolysis; Liver; Norepinephrine; Phentolamine; Propranolol; Receptors, Adrenergic, alpha; Receptors, Adrenergic, beta

The use of beta-blockers in diabetes mellitus has largely been restricted because of the reported adverse effects. Clinical investigations aimed at elucidating the possible reactions associated with the use of beta-blockers have disclosed no evidence of masking or signs or insulin-induced hypoglycaemia or potentiation of the insulin effect. Prolonged hypoglycaemia may develop, however, as a result of physical effort. There is no proof that during insulin-induced hypoglycaemia the concentrations of counter-regulatory hormones are depressed, but that of glycerol, a gluconeogenic precursor, is slightly diminished. Intensification of the hypertensive reaction during hypoglycaemia is less likely to occur during treatment with beta-selective blockers. In insulin-dependent diabetics receiving beta 1-blockers there is no evidence of any change - either deterioration or improvement - in metabolic control. In one small controlled trial there was no sign of impairment of the peripheral arterial circulation over a short period of administration of a non-selective beta-blocker. In general, for patients suffering from insulin-dependent diabetes, cardioselective agents are preferable. Since cardioselectivity is a dose-dependent property, reasonable caution should also be observed when using this type of drug in diabetes.

Topics: Adrenergic beta-Antagonists; Alprenolol; Blood Glucose; Catecholamines; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Drug Synergism; Fatty Acids, Nonesterified; Gluconeogenesis; Glucose Tolerance Test; Glycerol; Glycogen; Humans; Hypertension; Hypoglycemia; Insulin; Lactates; Lactic Acid; Metoprolol; Oxprenolol; Propranolol

Topics: Adipose Tissue; Aging; Animals; Antibody Formation; Cattle; Diabetes Mellitus; Diabetes Mellitus, Type 1; Fatty Acids; Glucose; Glycogen; Humans; Hypoglycemic Agents; Insulin; Islets of Langerhans; Ketone Bodies; Lipid Metabolism; Liver; Muscles; Rabbits; Triglycerides

The aim of this study was to examine the effects of a high carbohydrate diet on glycaemic control, resting muscle glycogen levels and exercise performance in athletes with insulin dependent diabetes (IDDM). Seven trained (mean +/- S.D., VO2max 50.3 +/- 7.4 ml/kg/min) IDDM males consumed a high carbohydrate diet (HCD) or a normal mixed diet (NMD) for 3 week periods in a randomised crossover trial with a one week wash-out. Carbohydrate provided 59% or 50% of total energy intake, respectively, on the two diets. Fasting plasma lipids, mean blood glucose (over 96 h), fructosamine and muscle glycogen were measured and insulin use recorded. Exercise performance was evaluated by a 15 min time trial following a 50 min pre-loading block. Statistical significance was assessed using two tailed paired Student t-tests. Mean blood glucose was 10% higher on HCD than NMD (p = 0.005), fructosamine levels were 375 +/- 54 and 353 +/- 51 (mol/L on HCD and NMD, resp., p = 0.04) and daily insulin requirements were 15% higher on HCD than NMD (p = 0.02). Fasting blood lipids were similar on the two diets. Muscle glycogen was significantly lower on HCD than NMD (88.2 +/- 19.2 and 95.6 +/- 14.6 mmol/kg ww, respectively, p = 0.02). Exercise completed during the time trial was 6% less on HCD than on NMD (p = 0.007). An increased carbohydrate intake for three weeks, in IDDM athletes, is associated with a deterioration in glycaemic control, increased insulin requirements, decreased muscle glycogen and reduced exercise performance. These data do not support recommendations for IDDM athletes to consume a high carbohydrate diet, at least not when glycaemic control worsens upon following this advice, as was observed in this short-term study.

Topics: Adolescent; Adult; Blood Glucose; Diabetes Mellitus, Type 1; Dietary Carbohydrates; Exercise; Glycogen; Humans; Insulin; Male; Muscle, Skeletal; Random Allocation

Glycogen neutrophils level was evaluated in 54 patients with non-insulin dependent diabetes mellitus (NIDDM) and 10 patients with insulin dependent diabetes mellitus (IDDM). Glycogen concentration estimated by histochemical method was lower in diabetics than in control group. Patients with NIDDM were divided in the groups according to: sex, duration of disease, a kind of complications and a way of treatment. The glycogen contents in neutrophils, defined in "score"-unit was not different in isolated groups. There was found significant correlation between glycogen contents in neutrophils and the metabolic control in patients with IDDM (r = 0.72) and less significant in patients with NIDDM (r = 0.29).

Topics: Adult; Aged; Aged, 80 and over; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glycogen; Humans; Middle Aged; Neutrophils

This study examines the clinical-pathological profiles of patients with glycogenic hepatopathy in a contemporary cohort of patients at an adult acute care hospital.. Liver biopsies with glycogenic hepatopathy were retrieved from the departmental surgical pathology database, the histological findings were studied, and the clinical findings were reviewed.. Five cases of glycogenic hepatopathy were found, including cases associated with type 1 diabetes mellitus (n = 1), type 2 diabetes mellitus (n = 1), corticosteroids (n = 2), and anorexia (n = 2, including the patient with type 1 diabetes). AST and ALT were normal to mildly elevated (13-115 U/L and 7-126 U/L, respectively). Trace ascites was present in two patients. Hepatomegaly was only present in the patient with type 1 diabetes at the time of diagnosis.. Four of five cases were associated with etiologies other than type 1 diabetes, which is widely reported as the most common etiology of glycogenic hepatopathy. This study suggests that etiologies currently only rarely recognized may actually be more common causes of glycogenic hepatopathy than type 1 diabetes in a contemporary adult population. It is important not only to recognize that these rarely reported causes of glycogenic hepatopathy may be underrecognized, but that the clinical presentation may also be mild.

Topics: Adult; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glycogen; Hepatomegaly; Humans; Liver Diseases

We report a case of severe glycogenic hepatopathy in a 17-year-old boy with poorly controlled type 1 diabetes. On presentation, major findings included unexplained pronounced hepatomegaly and increased liver enzymes, ferritin, and triglycerides. Histology and electron microscopy evaluation showed severe glycogen storage, steatosis, and signs of fibrosis, resembling the histomorphological findings of Mauriac syndrome. After information about the nature of the disease and intensification of insulin therapy with insulin pump, liver enzymes, ferritin, and triglycerides normalized within 1 month.. Glycogenic hepatopathy is a rare but important potential complication in poorly controlled juvenile diabetic patients. With improved metabolic control, it is fully reversible.

Topics: Adolescent; Diabetes Mellitus, Type 1; Glycogen; Hepatomegaly; Humans; Liver Diseases; Male

Topics: Diabetes Mellitus, Type 1; Glycogen; Humans; Liver Diseases; Liver Function Tests; Tomography, X-Ray Computed

Green tea, traditionally used as antidiabetic medicine, positively affects the diabetic nephropathy. It was assumed that these beneficial effects were due to the hypoglycemiant capacity of the tea, wich reduces the glycemic overload and, consequently, the advanced glycation end products rate and oxidative damage. However, these results are still controversial, since tea is not always able to exert a hypoglycemic action, as demonstrated by previous studies.. Investigate if green tea infusion can generate positive outcomes for the kidney independently of glycemic control, using a model of severe type 1 diabetes.. We treated streptozotocin type 1 diabetic young rats with 100 mg/kg of green tea, daily, for 42 days, and evaluated the serum and tissue markers for stress and function. We also analyzed the ion dynamics in the organ and the morphological alterations promoted by diabetes and green tea treatment. Besides, we analyzed, by an in silico approach, the interactions of the green tea main catechins with the proteins expressed in the kidney.. Our findings reveal that the components of green tea can interact with the proteins participating in cell signaling pathways that regulate energy metabolism, including glucose and glycogen synthesis, glucose reabsorption, hypoxia management, and cell death by apoptosis. Such interaction reduces glycogen accumulation in the organ, and protects the DNA. These results also reflect in a preserved glomerulus morphology, with improvement in pathological features, and suggesting a prevention of kidney function impairment.. Our results show that such benefits are achieved regardless of the blood glucose status, and are not dependent on the reduction of hyperglycemia.

Topics: Animals; Camellia sinensis; Catalase; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Nephropathies; DNA Damage; Glycemic Control; Glycogen; Kidney; Male; Nitric Oxide; Rats, Wistar; Superoxide Dismutase; Tea

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

Topics: Adolescent; Alanine; Alanine Transaminase; Aspartate Aminotransferases; Diabetes Mellitus, Type 1; Female; Glycogen; Growth Disorders; Hepatomegaly; Humans; Liver; Syndrome

Glycogen is a complex branched glucose polymer. Liver glycogen in db/db mouse, a type-2 diabetic mouse model, has been found to be more molecularly fragile than in healthy mice. Size-exclusion chromatography was employed in this study to investigate the molecular structure of liver glycogen in two types of type 1 diabetic mouse models (NOD and C57BL/6J mice), sacrificed at various times throughout the diurnal cycle, and the fragility of liver glycogen after exposure to a hydrogen-bond disruptor were tested. Type 1 diabetic mice exhibit a similar glycogen fragility with that observed for db/db mice. This eliminates many of the potential causes for glycogen molecular fragility; the most likely explanation is that it is caused by high blood-glucose level and/or insulin deficiency, both phenotypes being common to both type 1 and type 2 diabetic mice. This result suggests ways towards new drug targets for the management of diabetes.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Glycogen; Liver; Male; Mice; Mice, Inbred C57BL

Glycogenic hepatopathy (GH) is a rare complication of poorly controlled type 1 diabetes mellitus (T1DM). We present a 19-year-old woman with T1DM and autoimmune thyroiditis who admitted to our department because of abrupt onset intermittent abdominal pain in the right upper quadrant accompanied by laboratory evidence of acute anicteric hepatitis. Physical examination revealed significant hepatomegaly but the common imagining studies were negative. Following exclusion of common causes of acute hepatitis and because of the presence of smooth muscle antibodies in a young female patient with already established two autoimmune diseases, a liver biopsy was performed in order to exclude the potential presence of autoimmune hepatitis. However, liver histology showed typical findings of GH. Intense treatment targeting strict glycemic control resulted in normalisation of liver biochemistry. This case underlines that GH should be considered as a rare cause of acute hepatitis in T1DM patients with poor glycemic control.

Topics: Diabetes Mellitus, Type 1; Female; Glycogen; Hepatomegaly; Humans; Hypoglycemic Agents; Infusions, Subcutaneous; Insulin; Liver Function Tests; Young Adult

Topics: Adolescent; Aspartate Aminotransferases; Diabetes Mellitus, Type 1; Female; Fibrosis; gamma-Glutamyltransferase; Glycogen; Hepatocytes; Hepatomegaly; Humans; Liver; Liver Diseases; Portal System; Syndrome

To detect the changes in the liver function in both male and female OVE26 mice from young to adults for better understanding of type 1 diabetes-induced hepatic changes, OVE26 mice and wild-type FVB mice were raised in the same environment without any intervention, and then killed at 4, 12, 24 and 36 weeks for examining liver's general properties, including pathogenic and molecular changes. The influence of diabetes on the bodyweight of male and female mice was different. Both male and female OVE26 mice did not obtain serious liver injury or non-alcoholic fatty liver disease, manifested by mild elevation of plasma alanine transaminase, and less liver lipid content along with significantly suppressed lipid synthesis. Uncontrolled diabetes also did not cause hepatic glycogen accumulation in OVE26 mice after 4 weeks. Oxidative stress test showed no change in lipid peroxidation, but increased protein oxidation. Changed endoplasmic reticulum stress and apoptosis along with increased antioxidant capacity was observed in OVE26 mice. In conclusion, uncontrolled type 1 diabetes did not cause hepatic lipid deposition most likely because of reduced lipids synthesis in response to insulin deficiency. Enhanced antioxidant capacity might not only prevent the occurrence of severe acute liver injury but also the self-renewal, leading to liver dysfunction.

Topics: Animals; Antioxidants; Autophagy; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Endoplasmic Reticulum Stress; Glycogen; Inflammation; Insulin; Lipids; Liver; Mice; Oxidative Stress

The aim of the present study was to determine the effects of curcumin on antioxidants using a rat model of type 1 diabetes. Seven‑week‑old male Sprague‑Dawley rats were injected with Streptozotocin (STZ) intraperitoneally to induce this model, and then treated with 1.0% curcumin (weight ratio) mixed in their diet for 21 days. The present study included three groups: Control group (NC), diabetic rat model group (DC) and a curcumin treated group (Diab‑Cur). The results demonstrated that curcumin treatment markedly decreased the blood glucose levels, plasma malondialdehyde concentration and plasma activity of glutathione peroxidase (GSH‑Px) and catalase (CAT); however, it increased the plasma superoxide dismutase (SOD) and insulin levels. Curcumin treatment increased the expression of the CAT, GSH‑Px, HO‑1 and norvegicus NAD(P)H quinone dehydrogenase 1, and decreased the SOD1 expression, which, led to a diminished oxidative stress status. In addition, curcumin treatment significantly increased the protein expression of Keap1 in the Diab‑Cur group when compared with the DC group, decreased cytosolic concentrations of Nrf2 while increasing nuclear accumulation of Nrf2. The results provide evidence that oxidative stress in the STZ‑induced diabetic rat model may be attenuated by curcumin via the activation of the Keap1‑Nrf2‑ARE signaling pathway, as evidenced by a decrease in the blood glucose concentration and an increase in the transcription of several antioxidant genes.

Topics: Animals; Antioxidants; Biomarkers; Catalase; Curcumin; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Disease Models, Animal; Glutathione Peroxidase; Glycogen; Liver; Male; Malondialdehyde; Oxidative Stress; Rats; Superoxide Dismutase

Topics: Diabetes Mellitus, Type 1; Gastrointestinal Diseases; Glycogen; Humans; Liver Diseases

Glycogenic hepatopathy (GH) is a rare complication of poorly controlled type 1 diabetes mellitus (T1DM), and is characterized by elevated liver enzymes, hepatomegaly, and glycogen accumulation. We herein present the case of a 23-year-old man with poorly controlled T1DM who had liver dysfunction. Imaging studies showed severe hepatomegaly and fatty liver. The examination of a liver biopsy specimen revealed fatty droplets, ballooning, inflammation, and mild fibrosis. Subsequent periodic acid-Schiff (PAS) staining after diastase digestion confirmed GH. In this case, the improvement of hyperglycemia, not HbA1c, resulted in the improvement of the patient's liver function. This is the first report on the use of continuous glucose monitoring in patients with GH to show that continuous hyperglycemia may worsen GH.

Topics: Diabetes Mellitus, Type 1; Glycogen; Hepatomegaly; Humans; Liver Diseases; Liver Function Tests; Male; Young Adult

The objective of the study was to evaluate the efficacy of garcinol as an antidiabetic candidate in streptozotocin-induced diabetic Wistar rats. Diabetic rats showed a significant increase in the biochemical parameters such as fasting blood glucose, glycated haemoglobin, urea, alanine aminotransferase and aspartate aminotransferase, malondialdehyde, total cholesterol, triglycerides, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, atherogenic index and a significant decrease in plasma insulin, HOMA-β-cell functioning index, glycogen, high-density lipoprotein cholesterol, body weight and antioxidant enzyme activities, viz. superoxide dismutase, catalase and reduced glutathione. Oral administration of garcinol (10 and 20 mg/kg body weight/day) for 30 days improved the above-mentioned alterations. The effect produced by the drug was compared with that of glibenclamide, a standard hypoglycaemic drug. These findings reveal that garcinol can be a promising antidiabetic candidate in the future.

Topics: Animals; Antioxidants; Blood Glucose; Body Weight; Catalase; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Fasting; Glutathione; Glycated Hemoglobin; Glycogen; Homeostasis; Hypoglycemic Agents; Hypolipidemic Agents; Insulin; Insulin-Secreting Cells; Kidney; Liver; Male; Malondialdehyde; Rats; Rats, Wistar; Superoxide Dismutase; Terpenes; Urea

Glycogenic hepatopathy is a rare condition that causes significant hepatomegaly and elevated liver enzyme levels in uncontrolled type 1 diabetic patients. It develops due to excessive accumulation of glycogen in the hepatocytes. It is typically reversible with good glycemic control and rarely progresses to mild fibrosis, but not cirrhosis.

Topics: Child; Diabetes Mellitus, Type 1; Female; Glycogen; Hepatitis; Humans; Recurrence

Glycogenic hepatopathy (GH) is an underdiagnosed complication of uncontrolled type 1 diabetes mellitus (T1DM). It appears as an acute relapsing hepatitis with reversible transaminase elevations secondary to excessive hepatic glycogen accumulation. Patients are often asymptomatic but can present with abdominal pain, nausea and vomiting. Physical examination shows hepatomegaly without splenomegaly. GH is diagnosed by biopsy as it is clinically indistinguishable from non-alcoholic fatty liver disease (NAFLD), a more common cause of hepatic dysfunction in diabetics. Here we describe a case of GH in a patient with uncontrolled type 1 diabetes whose clinical course was complicated by drug-induced liver injury. The patient initially presented with diabetic ketoacidosis and had a mild transaminitis, thought to be due to NAFLD. She developed profound transaminase elevations while receiving treatment with newer antipsychotic medications for her bipolar disorder. Liver biopsy showed evidence of resolving glycogenic hepatopathy with signs of drug-induced liver injury. This case report reviews the pathology and pathogenesis of GH and reminds the clinician to keep GH within the differential diagnosis for severe transaminitis in a patient with type 1 diabetes mellitus.

Topics: Abdominal Pain; Antipsychotic Agents; Biopsy; Bipolar Disorder; Chemical and Drug Induced Liver Injury; Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Diagnosis, Differential; Dibenzocycloheptenes; Female; Glycogen; Hepatomegaly; Heterocyclic Compounds, 4 or More Rings; Humans; Liver; Magnetic Resonance Imaging; Young Adult

Topics: Acidosis, Lactic; Adolescent; Blood Glucose; Diabetes Mellitus, Type 1; Female; Glycogen; Humans; Liver; Liver Diseases; Liver Function Tests; Predictive Value of Tests

Glycogenic hepatopathy is a rare and under-recognized complication in long-standing poorly controlled type 1 diabetes mellitus patients. This is a distinct entity from other causes of hepatomegaly and elevated liver enzymes in diabetics, such as nonalcoholic fatty liver disease. Glycogenic hepatopathy is characterized by the combination of poorly controlled diabetes, acute liver injury with marked elevation in serum aminotransferases, and the characteristic histological features on liver biopsy. It is important to distinguish this entity as it has the potential for resolution following improved glycemic control. In this report, we describe four cases of adult patients presenting elevated serum transaminases and hepatomegaly with a history of poorly controlled type I diabetes mellitus. One of the patients had also elevated amylase and lipase in the serum, without clinical or imagiologic evidence of acute pancreatitis (AP). Liver biopsy was performed in all patients and revealed glycogenic hepatopathy. Clinician's awareness of glycogenic hepatopathy should prevent diagnostic delay or misdiagnosis and will provide better insight and management for this condition.

Topics: Adult; Delayed Diagnosis; Diabetes Mellitus, Type 1; Diagnosis, Differential; Female; Glycogen; Humans; Liver Diseases; Male; Patient Compliance; Young Adult

Increasing studies have shown protective effects of intermittent hypoxia on brain injury and heart ischemia. However, the effect of intermittent hypoxia on blood glucose metabolism, especially in diabetic conditions, is rarely observed. The aim of this study was to investigate whether intermittent hypoxia influences blood glucose metabolism in type 1 diabetic rats. Streptozotocin-induced diabetic adult rats and age-matched control rats were treated with intermittent hypoxia (at an altitude of 3 km, 4 h per day for 3 weeks) or normoxia as control. Fasting blood glucose, body weight, plasma fructosamine, plasma insulin, homeostasis model assessment of insulin resistance (HOMA-IR), pancreas β-cell mass, and hepatic and soleus glycogen were measured. Compared with diabetic rats before treatment, the level of fasting blood glucose in diabetic rats after normoxic treatment was increased (19.88 ± 5.69 mmol/L vs. 14.79 ± 5.84 mmol/L, p < 0.05), while it was not different in diabetic rats after hypoxic treatment (13.14 ± 5.77 mmol/L vs. 14.79 ± 5.84 mmol/L, p > 0.05). Meanwhile, fasting blood glucose in diabetic rats after hypoxic treatment was also lower than that in diabetic rats after normoxic treatment (13.14 ± 5.77 mmol/L vs. 19.88 ± 5.69 mmol/L, p<0.05). Plasma fructosamine in diabetic rats receiving intermittent hypoxia was significantly lower than that in diabetic rats receiving normoxia (1.28 ± 0.11 vs. 1.39 ± 0.11, p < 0.05), while there were no significant changes in body weight, plasma insulin and β-cell mass. HOMA-IR in diabetic rats after hypoxic treatment was also lower compared with diabetic rats after normoxic treatment (3.48 ± 0.48 vs. 3.86 ± 0.42, p < 0.05). Moreover, intermittent hypoxia showed effect on the increase of soleus glycogen but not hepatic glycogen. We conclude that intermittent hypoxia maintains glycemia in streptozotocin-induced diabetic rats and its regulation on muscular glycogenesis may play a role in the underlying mechanism.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Fructosamine; Glycogen; Humans; Hypoxia; Insulin; Insulin Resistance; Insulin-Secreting Cells; Liver; Male; Muscle, Skeletal; Rats

Glycogen is a major substrate in energy metabolism and particularly important to prevent hypoglycemia in pathologies of glucose homeostasis such as type 1 diabetes mellitus (T1DM). (13) C-MRS is increasingly used to determine glycogen in skeletal muscle and liver non-invasively; however, the low signal-to-noise ratio leads to long acquisition times, particularly when glycogen levels are determined before and after interventions. In order to ease the requirements for the subjects and to avoid systematic effects of the lengthy examination, we evaluated if a standardized preparation period would allow us to shift the baseline (pre-intervention) experiments to a preceding day. Based on natural abundance (13) C-MRS on a clinical 3 T MR system the present study investigated the test-retest reliability of glycogen measurements in patients with T1DM and matched controls (n = 10 each group) in quadriceps muscle and liver. Prior to the MR examination, participants followed a standardized diet and avoided strenuous exercise for two days. The average coefficient of variation (CV) of myocellular glycogen levels was 9.7% in patients with T1DM compared with 6.6% in controls after a 2 week period, while hepatic glycogen variability was 13.3% in patients with T1DM and 14.6% in controls. For comparison, a single-session test-retest variability in four healthy volunteers resulted in 9.5% for skeletal muscle and 14.3% for liver. Glycogen levels in muscle and liver were not statistically different between test and retest, except for hepatic glycogen, which decreased in T1DM patients in the retest examination, but without an increase of the group distribution. Since the CVs of glycogen levels determined in a "single session" versus "within weeks" are comparable, we conclude that the major source of uncertainty is the methodological error and that physiological variations can be minimized by a pre-study standardization. For hepatic glycogen examinations, familiarization sessions (MR and potentially strenuous interventions) are recommended. Copyright © 2016 John Wiley & Sons, Ltd.

Topics: Adult; Algorithms; Carbon-13 Magnetic Resonance Spectroscopy; Diabetes Mellitus, Type 1; Glycogen; Humans; Liver; Male; Muscle, Skeletal; Reproducibility of Results; Sensitivity and Specificity

An acute bout of exercise elicits a rapid, potentially deleterious, reduction in blood glucose in patients with type 1 diabetes mellitus (T1DM). In the current study, we examined whether a 10-week aerobic training program could alleviate the rapid exercise-associated reduction in blood glucose through changes in the glucoregulatory hormonal response or increased hepatic glycogen storage in an insulin-treated rat model of T1DM. Thirty-two male Sprague-Dawley rats were divided evenly into 4 groups: non-T1DM sedentary (C) (n = 8), non-T1DM exercised (CX) (n = 8), T1DM sedentary (D) (n = 8), and T1DM exercised (DX) (n = 8). Exercise training consisted of treadmill running for 5 days/week (1 h, 27 m/min, 6% grade) for 10 weeks. T1DM was induced by multiple streptozotocin injections (20 mg/kg) followed by implantation of subcutaneous insulin pellets. At week 1, an acute exercise bout led to a significant reduction in blood glucose in DX (p < 0.05), whereas CX exhibited an increase in blood glucose (p < 0.05). During acute exercise, serum epinephrine was increased in both DX and CX (p < 0.05), whereas serum glucagon was increased during recovery only in CX (p < 0.01). Following aerobic training in DX, the exercise-mediated reduction in blood glucose remained; however, serum glucagon increased to the same extent as in CX (p < 0.05). DX exhibited significantly less hepatic glycogen (p < 0.001) despite elevations in glycogenic proteins in the liver (p < 0.05). Elevated serum epinephrine and decreased hepatic adrenergic receptor expression were also evident in DX (p < 0.05). In summary, despite aerobic training in DX, abrupt blood glucose reductions and hepatic glycogen deficiencies were evident. These data suggest that sympathetic overactivity may contribute to deficiencies in hepatic glycogen storage.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Epinephrine; Glucagon; Glycogen; Insulin; Liver; Male; Physical Conditioning, Animal; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic; Sedentary Behavior

A mechanistic cause for Mauriac syndrome, a syndrome of growth failure and delayed puberty associated with massive liver enlargement from glycogen deposition in children with poorly controlled type 1 diabetes, is unknown. We discovered a mutation in the catalytic subunit of liver glycogen phosphorylase kinase in a patient with Mauriac syndrome whose liver extended into his pelvis. Glycogen phosphorylase kinase activates glycogen phosphorylase, the enzyme that catalyzes the first step in glycogen breakdown. We show that the mutant subunit acts in a dominant manner to completely inhibit glycogen phosphorylase kinase enzyme activity and that this interferes with glycogenolysis causing increased levels of glycogen in human liver cells. It is known that even normal blood glucose levels physiologically inhibit glycogen phosphorylase to diminish glucose release from the liver when glycogenolysis is not needed. The patient's mother possessed the same mutant glycogen phosphorylase kinase subunit, but did not have diabetes or hepatomegaly. His father had childhood type 1 diabetes in poor glycemic control, but lacked the mutation and had neither hepatomegaly nor growth failure. This case proves that the effect of a mutant enzyme of glycogen metabolism can combine with hyperglycemia to directly hyperinhibit glycogen phosphorylase, in turn blocking glycogenolysis causing the massive liver in Mauriac disease.

Topics: Adolescent; Diabetes Mellitus, Type 1; Glycogen; Glycogen Phosphorylase, Liver Form; Growth Disorders; Hepatomegaly; Humans; Male; Mutation; Phosphorylase Kinase; Puberty, Delayed; Syndrome

There are several claims about the beneficial effects of supplementing L-glutamine to both type 1 and type 2 diabetes. The purpose of the present study was to provide detailed knowledge about the fate of this amino acid in the liver, the first organ that receives the compound when ingested orally. The study was done using the isolated perfused rat liver, an experimental system that preserves the microcirculation of the organ and that allows to measured several parameters during steady-state and pre steady-state conditions. L-Glutamine was infused in the portal vein (5 mM) and several parameters were monitored. Livers from type 1 diabetic rats showed an accelerated response to L-glutamine infusion. In consequence of this accelerated response livers from type 1 diabetic rats presented higher rates of ammonia, urea, glucose and lactate output during the first 25-30 minutes following L-glutamine infusion. As steady-state conditions approached, however, the difference between type 1 diabetes and control livers tended to disappear. Measurement of the glycogen content over a period of 100 minutes revealed that, excepting the initial phase of the L-glutamine infusion, the increased glucose output in livers from type 1 diabetic rats was mainly due to accelerated glycogenolysis. Livers from type 2 diabetic rats behaved similarly to control livers with no accelerated glucose output but with increased L-alanine production. L-Alanine is important for the pancreatic β-cells and from this point of view the oral intake of L-glutamine can be regarded as beneficial. Furthermore, the lack of increased glucose output in livers from type 2 diabetic rats is consistent with observations that even daily L-glutamine doses of 30 g do not increase the glycemic levels in well controlled type 2 diabetes patients.

Topics: Alanine; Ammonia; Animals; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Gluconeogenesis; Glucose; Glutamine; Glycogen; Lactic Acid; Liver; Male; Oxygen; Rats; Rats, Wistar; Urea

Nerium oleander L. (syn. Nerium indicum Mill. and Nerium odorum Aiton.) is used for its anti-diabetic properties in Pakistan, Algeria, Morocco and is also recognized in Ayurveda. The present study was undertaken to investigate the anti-diabetic capacity of a standardized hydromethanolic extract of Nerium oleander in alloxan induced diabetes in mice.. Nerium oleander leaf extract (NOLE) was orally administered at 50 and 200mg/kg body weight (BW) dose to alloxanized mice (blood glucose >200mg/dl). After 20 consecutive days of treatment, various diabetic parameters were studied and compared with untreated mice. Furthermore, gas chromatography-mass spectrometry (GC-MS) and high performance liquid chromatography (HPLC) analysis was employed to reveal the phytochemical composition of the plant extract.. NOLE demonstrated antihyperglycaemic activity by reducing 73.79% blood glucose level after 20 days of treatment. Oral glucose tolerance test (OGTT) revealed increase in glucose tolerance as evident by 65.72% decrease in blood glucose in 3h post treatment. Percentage decrease in different liver marker enzymes were significant along with decrease in triglyceride and cholesterol levels, displaying potent antihyperlipidemic activity. Peroxidase and catalase activity in liver, kidney and skeletal muscle were significantly restored besides marked reduction in lipid peroxidation and normalization of hepatic glycogen level in the NOLE treated alloxanized mice. Different bioactive phytocompounds with potent anti-diabetic activity were identified by GC-MS and HPLC analysis.. The present investigation revealed that Nerium oleander possess potent anti-diabetic activity as claimed in different ethnopharmacological practices.

Topics: Algeria; alpha-Amylases; Animals; Blood Glucose; Catalase; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Female; Glycated Hemoglobin; Glycogen; Hypoglycemic Agents; Insulin; Liver; Male; Medicine, Traditional; Mice; Morocco; Nerium; Pakistan; Peroxidase; Phytotherapy; Plant Extracts; Plant Leaves; Thiobarbituric Acid Reactive Substances

Topics: Adult; Biomarkers; Diabetes Mellitus, Type 1; Female; Glycogen; Humans; Liver Diseases; Transaminases

Rehmannia glutinosa (Gaertn.) DC. (RG) has been widely used as traditional Chinese herbal medicine for treatment of diabetes and its complications. The polysaccharide fraction of RG has been proposed to possess hypoglycemic effect by intraperitoneal administration, however, the mechanisms responsible for the hypoglycemic effect of RG polysaccharide (RGP) remain poorly understood. Here we studied the anti-hyperglycemic and anti-hyperlipidemic effect of oral administration of a purified RGP and its underlying mechanisms in streptozotocin (STZ)-induced diabetic mice.. The preliminary structure of RGP was determined by GC and FT-IR. Mice were injected with STZ to induce type 1 diabetes. RGP at doses of 20, 40 and 80 mg/kg/day was orally administered to mice for 4 weeks, and metformin was used as positive control. After 4 weeks, the blood biochemical parameters, the pancreatic insulin contents, in vitro insulin secretion, the hepatic glycogen contents and mRNA expression of phosphoenolpyruvate carboxyl kinase (PEPCK) were assayed.. RGP was composed of rhamnose, arabinose, mannose, glucose and galactose in the molar ratio of 1.00:1.26:0.73:16.45:30.40 with the average molecular weight of 63.5 kDa. RGP administration significantly decreased the blood levels of glucose, total cholesterol, triglycerides, low density lipoprotein-cholesterol, and increased the blood levels of high density lipoprotein-cholesterol and insulin in diabetic mice, concurrent with increases in body weights and pancreatic insulin contents. The in vitro study revealed that RGP significantly enhanced both basal and glucose-stimulated insulin secretions, as well as islet insulin contents in the pancreatic islets of diabetic mice. Moreover, RGP reversed the increased mRNA expression of PEPCK and the reduced glycogen contents in the liver of diabetic mice. Furthermore, RGP exhibited potent anti-inflammatory and anti-oxidative activities, as evidenced by the decreased blood levels of TNF-α, IL-6, monocyte chemoattractant protein-1, MDA, and also the elevated blood levels of SOD and GPx activities in diabetic mice.. Taken together, RGP can effectively ameliorate hyperglycemia, hyperlipemia, vascular inflammation and oxidative stress in STZ-induced diabetic mice, and thus may be a potential therapeutic option for type 1 diabetes.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Cholesterol; Cytokines; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Glutathione Peroxidase; Glycogen; Hypoglycemic Agents; Hypolipidemic Agents; Insulin; Liver; Male; Mice; Molecular Structure; Pancreas; Polysaccharides; Rehmannia; Streptozocin; Superoxide Dismutase; Triglycerides

The sampling included 23 children with glycogen disease. All patients were examined using system of continuous monitoring of content of glucose applied during 72 hours. It was established that hypoglycemia was detected in 19 (82.6%) children. At that, in 7 (30.4%) children the level of glucose was below detected range (< 2.2 mmol/l). In patients ignoring proposed recommendations (lack of compliance) expression of hypoglycemia was reliably higher than in children being on a diet and following recommendations of physician. In primary patients as compared with secondary patients rate and duration of hypoglycemia in blood serum activity of aspartate aminotransferase also was reliably higher. Independently of all that, the more frequently hypoglycemia developed the more expressed hypoglycemia was. Therefore, continuous monitoring of content of glucose in intercellular fluid is an effective instrument for detecting degree of compensation of carbohydrate metabolism in patients with glycogen disease. The day continuous monitoring of level of glucose permits to provide the most complete picture of fluctuations of glycaemia during a day. The obtained data can be used as a basis for composing an optimal algorithm of diet therapy.

Topics: Adolescent; Blood Glucose; Blood Glucose Self-Monitoring; Child; Child, Preschool; Diabetes Mellitus, Type 1; Glycogen; Humans; Hypoglycemia; Infant; Male

Glycogen levels in liver and skeletal muscle assessed non-invasively using magnetic resonance spectroscopy after a 48-h pre-study period including a standardized diet and withdrawal from exercise did not differ between individuals with well-controlled Type 1 DM and matched healthy controls.

Topics: Adult; Case-Control Studies; Diabetes Mellitus, Type 1; Diet; Exercise; Glycogen; Humans; Liver; Liver Glycogen; Magnetic Resonance Spectroscopy; Male; Muscle Fibers, Skeletal; Muscle, Skeletal; Young Adult

Antidesma bunius L (Phyllanthaceae) is commonly known to local people in North-east Thailand as a medicinal plant.. To investigate hypoglycaemic activities of methanolic extract of A. bunius in type 1 diabetes.. A daily dose of A. bunius extract (250 mg/kg body weight) was given orally to alloxan-induced diabetic rats for 28 days. Blood glucose, insulin, TC, TG, amylase, lipase, liver glycogen were analysed.. Extract revealed a significant reduction in blood glucose level (80.5%) along with an increase in serum insulin (134%), lipase (90.7%) and liver glycogen level (160%). Also amylase (28.2%) activity, TC (40.2%), and TG (28.8%) levels were significantly decreased when compared with diabetic control rats. A. bunius extract improved the histo-architectural of the β-cells.. The results suggested that A. bunius extract possess anti-diabetic activity, through the enhancement of hepatic glycogen storage and regeneration of the islet of Langerhans.

Topics: Alloxan; Amylases; Animals; Blood Glucose; Cholesterol; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Female; Glycogen; Humans; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Lethal Dose 50; Lipase; Liver; Male; Malpighiaceae; Mice; Phytotherapy; Plant Extracts; Plants, Medicinal; Rats

Sterol regulatory element-binding protein-1 (SREBP-1) is a key transcription factor that regulates genes in the de novo lipogenesis and glycolysis pathways. The levels of SREBP-1 are significantly elevated in obese patients and in animal models of obesity and type 2 diabetes, and a vast number of studies have implicated this transcription factor as a contributor to hepatic lipid accumulation and insulin resistance. However, its role in regulating carbohydrate metabolism is poorly understood. Here we have addressed whether SREBP-1 is needed for regulating glucose homeostasis. Using RNAi and a new generation of adenoviral vector, we have silenced hepatic SREBP-1 in normal and obese mice. In normal animals, SREBP-1 deficiency increased Pck1 and reduced glycogen deposition during fed conditions, providing evidence that SREBP-1 is necessary to regulate carbohydrate metabolism during the fed state. Knocking SREBP-1 down in db/db mice resulted in a significant reduction in triglyceride accumulation, as anticipated. However, mice remained hyperglycemic, which was associated with up-regulation of gluconeogenesis gene expression as well as decreased glycolysis and glycogen synthesis gene expression. Furthermore, glycogen synthase activity and glycogen accumulation were significantly reduced. In conclusion, silencing both isoforms of SREBP-1 leads to significant changes in carbohydrate metabolism and does not improve insulin resistance despite reducing steatosis in an animal model of obesity and type 2 diabetes.

Topics: Animals; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Gene Expression Regulation; Gene Knockdown Techniques; Gluconeogenesis; Glycogen; Liver; Male; Mice; Obesity; Sterol Regulatory Element Binding Protein 1

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

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

Mauriac syndrome is characterised by growth failure, cushingoid appearance and hepatomegaly which occurs in patients with insulin dependent diabetes and was first described shortly after the introduction of insulin as a treatment for the condition.. To describe the clinical features, histological findings and outcome of young people with glycogenic hepatopathy, the hepatic manifestation of Mauriac syndrome (MS).. Retrospective cohort study.. Young people with glycogenic hepatopathy.. Tertiary paediatric hepatology unit.. Thirty-one young people (16 M), median age of 15.1 years (IQR 14-16.2) presented within the study period. Median age of diagnosis of diabetes was 10 years (IQR 8-11). Median insulin requirement was 1.33 units/kg/day; median HbA1c was 96.7 mmol/mol (IQR 84.7-112.0). Growth was impaired: median height z-score was -1.01 (-1.73 to 0.4) and median body mass index (BMI) z-score was 0.28 (-0.12 to 0.67). Hepatomegaly was universal with splenomegaly in 16%. Transaminases were abnormal with a median aspartate aminotransferase (AST) of 76 IU/L and gamma glutamyltransferase of 71 IU/L. Liver biopsy was undertaken in 19 (61%). All showed enlarged hepatocytes with clear cytoplasm with glycogenated nuclei in 17. Steatosis was present in the majority. Inflammation was present in 8 (42%). Fibrosis was seen in 14 (73%) and was generally mild though 2 had bridging fibrosis. Megamitochondria were described in 7. Presence of megamitochondria correlated with AST elevation (p=0.026) and fibrosis on biopsy (p=0.007). At follow-up 17 children had normal or improved transaminases, in 13 there was no change. Transaminases followed the trend of the child's HbA1c.. Despite modern insulin regimens and monitoring in children with type 1 diabetes, MS still exists. Significant steatosis, inflammation and fibrosis were all seen in liver biopsies.

Topics: Adolescent; Biopsy; Diabetes Mellitus, Type 1; Fatty Liver; Female; Glycogen; Growth Disorders; Hepatitis; Hepatomegaly; Humans; Liver; Liver Cirrhosis; Male; Retrospective Studies; Syndrome

We present the case of a 13-year-old male with poorly controlled type 1 diabetes mellitus who developed significantly deranged liver transaminases following an episode of diabetic ketoacidosis. A liver biopsy diagnosed glycogenic hepatopathy (GH). We believe the combination of GH and ischaemic hepatitis led to his presentation.

Topics: Adolescent; Biopsy; Blood Glucose; Diabetes Mellitus, Type 1; Disease Progression; Dose-Response Relationship, Drug; Fluid Therapy; Glycated Hemoglobin; Glycogen; Humans; Hypoglycemic Agents; Insulin; Liver; Liver Diseases; Male; Transaminases

Finding alternatives for insulin therapy and making advances in etiology of type 1 diabetes benefits from a full structural and functional insight into Islets of Langerhans. Electron microscopy (EM) can visualize Islet morphology at the highest possible resolution, however, conventional EM only provides biased snapshots and lacks context. We developed and employed large scale EM and compiled a resource of complete cross sections of rat Islets during immuno-destruction to provide unbiased structural insight of thousands of cells at macromolecular resolution. The resource includes six datasets, totalling 25.000 micrographs, annotated for cellular and ultrastructural changes during autoimmune diabetes. Granulocytes are attracted to the endocrine tissue, followed by extravasation of a pleiotrophy of leukocytes. Subcellullar changes in beta cells include endoplasmic reticulum stress, insulin degranulation and glycogen accumulation. Rare findings include erythrocyte extravasation and nuclear actin-like fibers. While we focus on a rat model of autoimmune diabetes, our approach is general applicable.

Topics: Animals; Cell Nucleolus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Disease Progression; Endocrine Cells; Endoplasmic Reticulum Stress; Erythrocytes; Glycogen; Granulocytes; Insulin; Insulin-Secreting Cells; Islets of Langerhans; Leukocytes; Microscopy, Electron; Rats

Topics: Adolescent; Child; Diabetes Mellitus, Type 1; Female; Glycogen; Humans; Liver Diseases; Male; Non-alcoholic Fatty Liver Disease; Tomography, X-Ray Computed

Topics: Adult; Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Female; Glycogen; Hepatomegaly; Humans; Liver Diseases; Magnetic Resonance Imaging; Young Adult

Exercise is essential into the therapeutic management of diabetic patients, but their level of exercise tolerance is lowered due to alterations of glucose metabolism. As soy isoflavones have been shown to improve glucose metabolism, this study aimed to assess the effects of a dietary supplement containing soy isoflavones and alpha-galactooligosaccharides on muscular glucose, glycogen synthase (GSase), and glycogen content in a type 1 diabetic animal model. The dietary supplement tested was a patented compound, Fermented Soy Permeate (FSP), developed by the French Company Sojasun Technologies. Forty male Wistar rats were randomly assigned to control or diabetic groups (streptozotocin, 45 mg/kg). Each group was then divided into placebo or FSP-supplemented groups. Both groups received by oral gavage, respectively, water or diluted FSP (0.1 g/day), daily for a period of 3 weeks. At the end of the protocol, glycemia was noticed after a 24-h fasting period. Glucose, total GSase, and the glycogen content were determined in the skeletal muscle (gastrocnemius). Diabetic animals showed a higher blood glucose concentration, but a lower glucose and glycogen muscle content than controls. Three weeks of FSP consumption allowed to restore the muscle glucose concentration, but failed to reduce glycemia and to normalize the glycogen content in diabetic rats. Furthermore, the glycogen content was increased in FSP-supplemented controls compared to placebo controls. Our results demonstrated that diabetic rats exhibited a depleted muscle glycogen content (-25%). FSP-supplementation normalized the muscle glucose level without restoring the glycogen content in diabetic rats. However, it succeeded to increase it in the control group (+20%).

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Dietary Supplements; Fermentation; Glucose; Glycine max; Glycogen; Humans; Isoflavones; Male; Muscle, Skeletal; Plant Extracts; Rats; Rats, Wistar; Trisaccharides

The present study was designed to systematically investigate the antidiabetic potential of Amaranthus spinosus leaves which are traditionally known to have various medicinal properties and used for the treatment of diabetes mellitus. The ethanolic extract of leaves of Amaranthus spinosus was administered (150, 300 and 450 mg/kg bw) to type-1 and type-2 diabetic rats. Standard drugs, glibenclamide and metformin were used as a positive control for comparison. Changes in carbohydrate and lipid metabolism and antioxidants were assessed and compared with control and standard drug treated animals. Among the standardized extract doses tested (150, 300 and 450 mg/kg bw), higher doses significantly decreased plasma glucose levels (p<0.01 and p<0.001), hepatic glucose-6-phophatase activity (p<0.01 and p<0.001) and increased the hepatic glycogen content (p<0.01) with a concurrent increase in hexokinase activity in both type 1 and 2 diabetic rats (p<0.01 and p<0.001). Besides, the higher doses also significantly lowered the plasma and hepatic lipids, urea, creatinine levels (p<0.001) and lipid peroxidation with an improvement in the antioxidant profiles (p<0.001) of both type-1 and type-2 diabetic rats. It is concluded that Amaranthus spinosus has potential antidiabetic activity and significantly improves disrupted metabolisms and antioxidant defense in type-1 and type-2 diabetic rats.

Topics: Amaranthus; Animals; Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucose-6-Phosphatase; Glycogen; Hypoglycemic Agents; Lipid Metabolism; Liver; Male; Plant Leaves; Plant Preparations; Rats

Supercompensated brain glycogen may contribute to the development of hypoglycemia unawareness in patients with type 1 diabetes by providing energy for the brain during periods of hypoglycemia. Our goal was to determine if brain glycogen content is elevated in patients with type 1 diabetes and hypoglycemia unawareness. We used in vivo (13)C nuclear magnetic resonance spectroscopy in conjunction with [1-(13)C]glucose administration in five patients with type 1 diabetes and hypoglycemia unawareness and five age-, gender-, and body mass index-matched healthy volunteers to measure brain glycogen content and metabolism. Glucose and insulin were administered intravenously over ∼51 hours at a rate titrated to maintain a blood glucose concentration of 7 mmol/L. (13)C-glycogen levels in the occipital lobe were measured at ∼5, 8, 13, 23, 32, 37, and 50 hours, during label wash-in and wash-out. Newly synthesized glycogen levels were higher in controls than in patients (P<0.0001) for matched average blood glucose and insulin levels, which may be due to higher brain glycogen content or faster turnover in controls. Metabolic modeling indicated lower brain glycogen content in patients than in controls (P=0.07), implying that glycogen supercompensation does not contribute to the development of hypoglycemia unawareness in humans with type 1 diabetes.

Topics: Blood Glucose; Brain; Diabetes Mellitus, Type 1; Female; Glycogen; Humans; Hypoglycemia; Insulin; Magnetic Resonance Spectroscopy; Male; Middle Aged

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

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

Type 1 diabetes subjects are characterized by impaired direct pathway synthesis of hepatic glycogen that is unresponsive to insulin therapy. Since it is not known whether this is an irreversible defect of insulin-dependent diabetes, direct and indirect pathway glycogen fluxes were quantified in streptozotocin (STZ)-induced diabetic rats and compared with STZ rats that received subcutaneous or intraperitoneal insulin (I-SC or I-IP). Three groups of STZ rats were studied at 18 days post-STZ treatment. One group was administered I-SC and another I-IP as two daily injections of short-acting insulin at the start of each light and dark period for days 9-18. A third group did not receive any insulin, and a fourth group of nondiabetic rats was used as control. Glycogen synthesis via direct and indirect pathways, de novo lipogenesis, and gluconeogenesis were determined over the nocturnal feeding period using deuterated water. Direct pathway was residual in STZ rats, and glucokinase activity was also reduced significantly from control levels. Insulin administration restored both net glycogen synthesis via the direct pathway and glucokinase activity to nondiabetic control levels and improved the lipogenic pathway despite an inefficient normalization of the gluconeogenic pathway. We conclude that the reduced direct pathway flux is not an irreversible defect of insulin-dependent diabetes.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Glucokinase; Gluconeogenesis; Glycogen; Insulin; Lipogenesis; Male; Rats; Rats, Wistar

Topics: Blood Glucose; Diabetes Mellitus, Type 1; Glycogen; Humans; Hypoglycemia; Muscle, Skeletal; Physical Endurance; Reference Values

Topics: Abdominal Pain; Adult; Diabetes Mellitus, Type 1; Diagnosis, Differential; Epilepsy; Female; Glycated Hemoglobin; Glycogen; Humans; Hypoglycemic Agents; Insulin; Liver; Liver Diseases; Liver Function Tests; Ultrasonography

Intravenous insulin infusion partly improves liver glucose fluxes in type 1 diabetes (T1D). This study tests the hypothesis that continuous subcutaneous insulin infusion (CSII) normalizes hepatic glycogen metabolism.. T1D with poor glycemic control (T1Dp; HbA(1c): 8.5 ± 0.4%), T1D with improved glycemic control on CSII (T1Di; 7.0 ± 0.3%), and healthy humans (control subjects [CON]; 5.2 ± 0.4%) were studied. Net hepatic glycogen synthesis and glycogenolysis were measured with in vivo (13)C magnetic resonance spectroscopy. Endogenous glucose production (EGP) and gluconeogenesis (GNG) were assessed with [6,6-(2)H(2)]glucose, glycogen phosphorylase (GP) flux, and gluconeogenic fluxes with (2)H(2)O/paracetamol.. When compared with CON, net glycogen synthesis was 70% lower in T1Dp (P = 0.038) but not different in T1Di. During fasting, T1Dp had 25 and 42% higher EGP than T1Di (P = 0.004) and CON (P < 0.001; T1Di vs. CON: P = NS). GNG was 74 and 67% higher in T1Dp than in T1Di (P = 0.002) and CON (P = 0.001). In T1Dp, GP flux (7.0 ± 1.6 μmol ⋅ kg(-1) ⋅ min(-1)) was twofold higher than net glycogenolysis, but comparable in T1Di and CON (3.7 ± 0.8 and 4.9 ± 1.0 μmol ⋅ kg(-1) ⋅ min(-1)). Thus T1Dp exhibited glycogen cycling (3.5 ± 2.0 μmol ⋅ kg(-1) ⋅ min(-1)), which accounted for 47% of GP flux.. Poorly controlled T1D not only exhibits augmented fasting gluconeogenesis but also increased glycogen cycling. Intensified subcutaneous insulin treatment restores these abnormalities, indicating that hepatic glucose metabolism is not irreversibly altered even in long-standing T1D.

Topics: Adult; Diabetes Mellitus, Type 1; Fasting; Female; Glucose; Glycogen; Humans; Liver; Magnetic Resonance Imaging; Male; Postprandial Period; Young Adult

The inedible bottom part of asparagus (Asparagus officinalis L.) spears, around one-third to one-half of the total length, is always discarded as by-product. Since it still contains various bioactive substances, this by-product might have potential usage in food supplements for its therapeutic effects. In this study the hypoglycaemic effect of the aqueous extract of asparagus by-product (AEA) was evaluated in a streptozotocin (STZ)-induced diabetic rat model.. Continuous administration of AEA for 21 days significantly decreased fasting serum glucose and triglyceride levels but markedly increased body weight and hepatic glycogen level in diabetic rats. In an oral glucose tolerance test, both the blood glucose level measured at 30, 60 and 120 min after glucose loading and the area under the glucose curve showed a significant decrease after AEA treatment.. The results of this study demonstrate that AEA has hypoglycaemic and hypotriglyceridaemic functions, suggesting that it might be useful in preventing diabetic complications associated with hyperglycaemia and hyperlipidaemia.

Topics: Animals; Asparagus Plant; Diabetes Mellitus, Type 1; Dietary Supplements; Food-Processing Industry; Glucose Intolerance; Glycogen; Hypertriglyceridemia; Hypoglycemia; Hypoglycemic Agents; Industrial Waste; Liver; Male; Plant Extracts; Plant Stems; Random Allocation; Rats; Rats, Sprague-Dawley; Streptozocin; Weight Loss

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

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

Hepatic glycogen synthesis from intact hexose (direct pathway) relative to that from gluconeogenic precursors (indirect pathway) was quantified in ad libitum-fed rats. Following (2)H(2)O administration and overnight feeding, the livers were removed and glycogen (2)H-enrichment was measured by (2)H NMR. Six controls and six rats rendered hyperglycemic by streptozotocin (STZ; fasting blood glucose = 385 +/- 31 mg/dl) were studied. The indirect pathway contribution, estimated as glycogen hydrogen 5 relative to hydrogen 2 enrichment, was 54% +/- 4% for control rats-similar to values from healthy, meal-fed humans. In STZ-treated rats, the indirect pathway contribution was significantly higher (68% +/- 4%, P < 0.05 vs. controls), similar to that of Type 1 diabetic (T1D) patients. In conclusion, sources of hepatic glycogen synthesis in rats during ad libitum nocturnal feeding were quantified by analysis of glycogen enrichment from (2)H(2)O. STZ caused alterations resembling the pathophysiology of hepatic glycogen synthesis in T1D patients.

Topics: Animals; Deuterium; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Feeding Behavior; Glycogen; Humans; Liver; Magnetic Resonance Spectroscopy; Male; Rats; Rats, Wistar; Signal Transduction; Streptozocin; Water

Taurine had the hypoglycemic effect during experimental insulin-dependent diabetes mellitus and decreased the concentrations of glucose and fructosamine, and increased the contents of insulin, C-peptide, and glycogen in the liver. Studying the dynamics of structural changes in pancreatic tissue confirmed a positive effect of taurine on beta-cell function. The protective effect of taurine manifested in the absence of morphological signs for alloxan-induced diabetes: decrease in the number and size of pancreatic islets, change in their distribution, reduction of beta-cell count, and accumulation of homogeneous deposits in islets.

Topics: Animals; Body Weight; C-Peptide; Cell Count; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diuresis; Drinking; Fructosamine; Glucose; Glycogen; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Liver; Male; Pancreas; Rats; Taurine

The purpose of the research was to study influence of first diagnosed type 1 diabetes mellitus (FDDM-1), including metabolic consequences of diabetic ketoacidosis, on utilization of main nutritious substrates under conditions of aerobic exercise. 48 patients with FDDM-1 (15females and 33 males) and 36 healthy volunteers, composing the control group, had a protocol of bicycle ergometry test with slowly growing load. Patients with FDDM-1 were divided into 2 subgroups in line with clinical characteristic of endocrinopathy debut. Subgroup 1 consisted of 15 patients, who had diabetic precoma, subgroup 2 was composed of 33 patients who did not have diabetic ketoacidosis in onset of disease. Aerobic load in patients with FDDM-1 was realized in stable condition of the main disease subcompensation, and in 1 month under condition of FDDM-1 compensation. Lipid and carbohydrate consumption percentage was estimated by the method of indirect colorimetry. Patients with FDDM-1 in stage of subcompensation did not have metabolism transformation with dominating consumption of lipids, which was noticed in healthy persons. When increase intensity of physical exercise, the reliably higher rate of carbohydrate sources consumption for supply of muscular contractions was noticed in patients with FDDM-1, especially in subgroup 2. After FDDM-1 compensation the structure of metabolic substrates consumption in warm-up period in both subgroups of patients with FDDM-1 did not have reliable differences in comparison with control group, but all further levels of aerobic exercise were characterized by significant increase of carbohydrate sources oxidation in comparison with such oxidation in healthy persons. Patients with FDDM-1 had decreased muscular tissue ability to utilize lipids in the aerobic stage of physical exercise, which can cause decrease of tolerance to physical work as a result of disorder lipid and carbohydrate participation in motion activity.

Topics: Adult; Carbohydrates; Diabetes Mellitus, Type 1; Exercise; Female; Glycogen; Health Status; Humans; Male; Oxygen Consumption

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

Substrate oxidation and the respective contributions of exogenous glucose, glucose released from the liver, and muscle glycogen oxidation were measured by indirect respiratory calorimetry combined with tracer technique in eight control subjects and eight diabetic patients (5 men and 3 women in both groups) of similar age, height, body mass, and maximal oxygen uptake, over a 60-min exercise period on cycle ergometer at 50.8% (SD 4.0) maximal oxygen uptake [131.0 W (SD 38.2)]. The subjects and patients ingested a breakfast (containing approximately 80 g of carbohydrates) 3 h before and 30 g of glucose (labeled with 13C) 15 min before the beginning of exercise. The diabetic patients also received their usual insulin dose [Humalog = 9.1 U (SD 0.9); Humulin N = 13.9 U (SD 4.4)] immediately before the breakfast. Over the last 30 min of exercise, the oxidation of carbohydrate [1.32 g/min (SD 0.48) and 1.42 g/min (SD 0.63)] and fat [0.33 g/min (SD 0.10) and 0.30 g/min (SD 0.10)] and their contribution to the energy yield were not significantly different in the control subjects and diabetic patients. Exogenous glucose oxidation was also not significantly different in the control subjects and diabetic patients [6.3 g/30 min (SD 1.3) and 5.2 g/30 min (SD 1.6), respectively]. In contrast, the oxidation of plasma glucose and oxidation of glucose released from the liver were significantly lower in the diabetic patients than in control subjects [14.5 g/30 min (SD 4.3) and 9.3 g/30 min (SD 2.8) vs. 27.9 g/30 min (SD 13.3) and 21.6 g/30 min (SD 12.8), respectively], whereas that of muscle glycogen was significantly higher [28.1 g/30 min (SD 15.5) vs. 11.6 g/30 min (SD 8.1)]. These data indicate that, compared with control subjects, in diabetic patients fed glucose before exercise, substrate oxidation and exogenous glucose oxidation overall are similar but plasma glucose oxidation is lower; this is associated with a compensatory higher utilization of muscle glycogen.

Topics: Adult; Blood Glucose; Breath Tests; Calorimetry, Indirect; Carbon Dioxide; Carbon Isotopes; Case-Control Studies; Diabetes Mellitus, Type 1; Energy Metabolism; Exercise; Female; Glucose; Glycogen; Humans; Hypoglycemic Agents; Insulin; Lipid Metabolism; Liver; Male; Muscle, Skeletal; Oxidation-Reduction; Oxygen Consumption; Time Factors

Genetically-engineered cells offer a solution to the cell availability problem in tissue engineering a pancreatic substitute for the treatment of insulin-dependent diabetes. These cells can be non-beta cells, such as hepatocytes or myoblasts, retrieved as a biopsy from the same patient and genetically engineered to secrete recombinant insulin constitutively or under transcriptional regulation. However, the continuous or slowly responsive insulin secretion dynamics from these cells cannot provide physiologic glucose regulation in patients. Our objective consists of using such cells as an insulin source and of regulating insulin release by incorporating a glucose-responsive material, which acts as a control barrier for insulin in a cell-material hybrid device. Experiments were performed with insulinoma betaTC3 cells, HepG2 hepatomas, and C2C12 myoblasts, the latter two genetically-modified to constitutively secrete insulin. The control barrier consisted of concanavalin A (con A)-based glucose-responsive material, which forms a gel at low and a sol at high glucose concentrations. Results demonstrated that the device released insulin at a higher rate in response to glucose challenges. In contrast, a device containing an inert hydrogel instead of glucose-responsive material released insulin at an essentially constant rate, irrespective of the surrounding glucose concentration. Necessary material improvements include increased sensitivity to glucose, so that the material responds to physiologically relevant glucose concentrations, and increased stability. The prospects of developing a properly functional, implantable substitute based on engineered non-beta cells and glucose-responsive material, and the material and device improvements that need to be made prior to in vivo experiments, are discussed.

Topics: Alginates; Animals; Cell Line; Cell Line, Tumor; Cell Survival; Concanavalin A; Diabetes Mellitus, Type 1; Glucose; Glucuronic Acid; Glycogen; Hexuronic Acids; Humans; Hydrogels; Insulin; Insulin Secretion; Membranes, Artificial; Pancreas, Artificial; Phase Transition; Polycarboxylate Cement; Tissue Engineering; Transfection

The contributions of hepatic glycogenolysis to fasting glucose production and direct pathway to hepatic glycogen synthesis were quantified in eight type 1 diabetic patients and nine healthy control subjects by ingestion of (2)H(2)O and acetaminophen before breakfast followed by analysis of urinary water and acetaminophen glucuronide. After overnight fasting, enrichment of glucuronide position 5 relative to body water (G5/body water) was significantly higher in type 1 diabetic patients compared with control subjects, indicating a reduced contribution of glycogenolysis to glucose production (38 +/- 3 vs. 46 +/- 2%). Following breakfast, G5/body water was significantly higher in type 1 diabetic patients, indicating a smaller direct pathway contribution to glycogen synthesis (47 +/- 2 vs. 59 +/- 2%). Glucuronide hydrogen 2 enrichment (G2) was equivalent to body water during fasting (G2/body water 0.94 +/- 0.03 and 1.02 +/- 0.06 for control and type 1 diabetic subjects, respectively) but was significantly lower after breakfast (G2/body water 0.78 +/- 0.03 and 0.82 +/- 0.05 for control and type 1 diabetic subjects, respectively). The reduced postprandial G2 levels reflect incomplete glucose-6-phosphate-fructose-6-phosphate exchange or glycogen synthesis from dietary galactose. Unlike current measurements of human hepatic glycogen metabolism, the (2)H(2)O/acetaminophen assay does not require specialized on-site clinical equipment or personnel.

Topics: Acetaminophen; Adult; Body Water; Deuterium; Diabetes Mellitus, Type 1; Fasting; Female; Food; Fructosephosphates; Glucose-6-Phosphate; Glycogen; Humans; Kinetics; Liver; Magnetic Resonance Spectroscopy; Male

To develop and evaluate the efficacy of diabetes-targeted cell therapies in humans, a reliable model in larger animals is highly desirable. This article reports the surgical technique of total pancreatectomy in pigs and the biochemical analysis of the characteristics of totally pancreatectomized pigs.. Surgical total pancreatectomy was conducted in 23 pigs. Blood glucose, insulin, biochemistries, activity index, and intravenous glucose tolerance test (IVGTT) were examined to assess the pathophysiological profiles of diabetic pigs.. A total of 14 pigs successfully underwent total pancreatectomy without requiring biliary reconstruction and were analyzed in the present study. Activity index was decreased from day 5 on and the mean survival of totally pancreatectomized pigs was 7.6 +/- 2.7 days. No endogenous insulin secretion was confirmed in these pigs. Pigs which received total pancreatectomy demonstrated significantly higher levels of ketone bodies. IVGTT performed within 4 days after total pancreatectomy showed a spontaneous decrease in blood glucose levels despite an absence of endogenous insulin secretion. IVGTT on day 5 or later showed continued hyperglycemia in pigs with total pancreatectomy. Histological examination showed atrophy of hepatocytes and decreased glycogen storage in the liver and decreased mucus production of the small intestine.. This article describes a porcine model of diabetes created by total pancreatectomy and it analyzes the pathophysiological profiles in the animals. The present study has suggested that IVGTT on day 5 or later after total pancreatectomy is a reliable method to evaluate the efficacy of cell therapies.

Topics: Alanine Transaminase; Animals; Area Under Curve; Aspartate Aminotransferases; Atrophy; Blood Glucose; Blood Urea Nitrogen; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diarrhea; Disease Models, Animal; Glucose Tolerance Test; Glycogen; Hepatocytes; Intestinal Mucosa; Ketone Bodies; L-Lactate Dehydrogenase; Liver; Pancreatectomy; Potassium; Swine

Caesalpinia bonducella, widely distributed throughout the coastal region of India and used ethnically by the tribal people of India for controlling blood sugar was earlier reported by us to possess hypoglycemic activity in animal model. This prompted us to undertake a detail study with the aqueous and ethanolic extracts of the seeds of this plant in both type 1 and 2 diabetes mellitus in Long Evans rats. Significant blood sugar lowering effect (P < 0.05) of C. bonducella was observed in type 2 diabetic model. Special emphasis was given on the mechanistic study by gut absorption of glucose and liver glycogen.

Topics: Animals; Blood Glucose; Body Weight; Caesalpinia; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Glycogen; Hypoglycemic Agents; Intestinal Absorption; Lipids; Liver; Male; Plant Extracts; Rats; Rats, Long-Evans

To determine whether insulin induces acute changes in endogenous glucose production (EGP) via changes in gluconeogenesis (GNG), glycogenolysis (GL), or both, we measured GNG (with (2)H(2)O) and GL (EGP-GNG) in nine patients with type 1 diabetes during acute insulin excess produced by subcutaneous injection of insulin and during insulin deficiency which developed between 5 and 8 h after insulin injection. During insulin excess, free insulin concentration rose fivefold (from 36 to 180 pmol/l). Plasma glucose was maintained between 6.2 and 6.7 mmol/l for approximately 4 h with IV glucose. EGP (with 6,6-(2)H glucose) decreased from 17.1 to 9.8 micro mol. kg(-1). min(-1) after 1 h. This decrease was almost completely accounted for by a decrease in GL (from 10.7 to 4.6 micro mol. kg(-1). min(-1)). During insulin deficiency, plasma glucose rose from 6.2 to 10.5 mmol/l and EGP from 9.5 to 14.3 micro mol/kg min. The increase in EGP again was accounted for by an increase in GL. We conclude that in type 1 diabetes acute regulation of EGP by insulin is mainly via changes in GL while GNG changes little during the early hours of acute insulin excess or deficiency.

Topics: Adult; Blood Glucose; Carbohydrate Metabolism; Diabetes Mellitus, Type 1; Dose-Response Relationship, Drug; Fatty Acids, Nonesterified; Female; Gluconeogenesis; Glucose; Glycogen; Hormones; Humans; Insulin; Ketone Bodies; Lipids; Male; Oxidation-Reduction

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

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

We have recently shown, in studies with patients with Type 1 (insulin dependent) diabetes, that alcohol intake at 21:00 h significantly reduced blood glucose values after 10-12 h, compared with control studies with no alcohol.. We hypothesised that this was due to the following effects of alcohol: (1) alcohol metabolism increases NADH, leading to a reduction in hepatic gluconeogenesis; (2) increased glycogen phosphorylase activity depletes hepatic glycogen stores; (3) after the alcohol is metabolised, hepatic insulin sensitivity is increased, leading to the restoration of glycogen stores and reduction in blood glucose levels; and (4) consequently, after several hours, glycogen stores and insulin sensitivity return to normal.. A model describing these changes (DiasNet-Alcohol) was implemented into the DiasNet model of human glucose metabolism. Our study suggests that the DiasNet-Alcohol model gives a reasonable approximation of these effects of alcohol on blood glucose concentration observed in our study and supports our hypothesis for the mechanism behind these effects in Type 1 diabetes.

Topics: Bayes Theorem; Blood Glucose; Central Nervous System Depressants; Decision Making, Computer-Assisted; Decision Support Systems, Clinical; Diabetes Mellitus, Type 1; Ethanol; Glycogen; Glycogen Phosphorylase; Humans; Hypoglycemia; Models, Theoretical; NAD

Glucokinase (GK) plays a crucial role in hepatic glucose disposal. Its activity is decreased in patients with maturity-onset diabetes of the young and in some animal models of diabetes. We investigated the feasibility of manipulating GK expression as an adjuvant treatment for type 1 diabetes, using an E1/E3-deleted adenoviral vector (Ad.EF1(alpha)GK) delivered to the liver of streptozotocin-induced type 1 diabetic rats. First, we studied the metabolic impact of constitutive glucokinase expression in the absence of insulin. Normal blood glucose levels were observed after gene transfer, and glucose tolerance was substantially enhanced compared with diabetic control animals, suggesting that hepatic GK expression is a feasible mechanism to enhance glucose disposal. In a second study we administered Ad.EF1(alpha)GK together with subcutaneous insulin injections to determine whether the combined action of insulin plus GK activity would provide better glucose homeostasis than insulin treatment alone. This combination approach resulted in constant, near-normal glucose values under fed conditions. Furthermore, the animals stayed in the normoglycemic range after an overnight fast, indicating that the risk to develop hypoglycemia is not increased by expression of GK. Alterations of other metabolic routes were observed, suggesting that insulin-regulated expression of GK may be necessary to use the strategy as a treatment of type 1 diabetes.

Topics: Adenoviridae; Diabetes Mellitus, Type 1; Genetic Therapy; Genetic Vectors; Glucokinase; Glucose; Glycogen; Hypoglycemic Agents; Insulin; Lipid Metabolism; Liver; Triglycerides

In a family with agenesis of the dorsal pancreas only the mother presents with insulin-dependent diabetes mellitus, whereas her sons are glucose tolerant. We examined whether metabolic defects can be detected early in this disease. Plasma glucose profiles were obtained from patients with dorsal pancreas agenesis and from matched healthy subjects. Hepatic glycogen synthesis and breakdown were determined from the time course of glycogen concentrations using noninvasive (13)C nuclear magnetic resonance spectroscopy. Gluconeogenesis was calculated from the difference between glucose production (measured with D-[6,6-(2)H(2)]glucose) and glycogen breakdown. Frequently sampled iv glucose tolerance tests were performed to assess insulin secretion and sensitivity. The mean plasma glucose level was higher (12.9 +/- 0.4 vs. 5.9 +/- 0.1 mmol/liter), whereas the peak plasma insulin level was lower (236 vs. 397 +/- 23 pmol/liter) in the diabetic mother than in her nondiabetic sons and healthy subjects. In all patients, however, glycogen synthesis and breakdown were reduced by approximately 55% (P < 0.05) and 40% (P < 0.02), respectively. Gluconeogenesis (6.8 +/- 0.8 vs. 4.2 +/- 0.3 micro mol/kg.min; P < 0.05) and hepatic insulin clearance (6.8 +/- 1.3 vs. 2.8 +/- 1.0 ml/kg.min) were increased in all patients. In conclusion, patients with complete agenesis of the dorsal pancreas exhibit marked defects in hepatic glycogen metabolism, which are present even in the nondiabetic offspring.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Fatty Acids, Nonesterified; Female; Glucagon; Gluconeogenesis; Glucose Tolerance Test; Glycogen; Human Growth Hormone; Humans; Hydrocortisone; Insulin; Insulin Resistance; Insulin Secretion; Kinetics; Leptin; Liver; Magnetic Resonance Spectroscopy; Male; Middle Aged; Norepinephrine; Pancreas

Insufficiently treated type 1 diabetic patients exhibit inappropriate postprandial hyperglycemia and reduction in liver glycogen stores. To examine the effect of acute improvement of metabolic control on hepatic glycogen metabolism, lean young type 1 diabetic (HbA1c 8.8 +/- 0.3%) and matched nondiabetic subjects (HbA1c 5.4 +/- 0.1%) were studied during the course of a day with three isocaloric mixed meals. Hepatic glycogen concentrations were determined noninvasively using in vivo 13C nuclear magnetic resonance spectroscopy. Rates of net glycogen synthesis and breakdown were calculated from linear regression of the glycogen concentration time curves from 7:30-10:30 P.M. and from 10:30 P.M. to 8:00 A.M., respectively. The mean plasma glucose concentration was approximately 2.4-fold higher in diabetic than in nondiabetic subjects (13.6 +/- 0.4 vs. 5.8 +/- 0.1 mmol/l, P < 0.001). Rates of net glycogen synthesis and net glycogen breakdown were reduced by approximately 74% (0.11 +/- 0.02 vs. 0.43 +/- 0.04 mmol/l liver/min, P < 0.001) and by approximately 47% (0.10 +/- 0.01 vs. 0.19 +/- 0.01 mmol/l liver/min, P < 0.001) in diabetic patients, respectively. During short-term (24-h) intensified insulin treatment, the mean plasma glucose level was not different between diabetic and nondiabetic subjects (6.4 +/- 0.1 mmol/l). Net glycogen synthesis and breakdown increased by approximately 92% (0.23 +/- 0.04 mmol/l liver/min, P = 0.017) and by approximately 40% (0.14 approximately 0.01 mmol/l liver/min, P = 0.011), respectively. In conclusion, poorly controlled type 1 diabetic patients present with marked reduction in both hepatic glycogen synthesis and breakdown. Both defects in glycogen metabolism are improved but not normalized by short-term restoration of insulinemia and glycemia.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Fatty Acids, Nonesterified; Female; Glucagon; Glycogen; Humans; Hypoglycemic Agents; Insulin; Liver; Male; Time Factors

Topics: Adult; Diabetes Mellitus, Type 1; Female; Glycogen; Humans; Hypoglycemia; Liver

Selenium in serum and selenium and glycogen in erythrocytes were determined in diabetic patients divided into noninsulin-dependent (n = 50) and insulin-dependent (n = 31) groups according to the etiopathogenesis of their diabetes. Selenium was determined by the method of atomic absorption spectrometry. Serum level of selenium was statistically significantly different in patients with either noninsulin-dependent (59.23 +/- 12.2 microg/L) or insulin-dependent (58.23 +/- 16.7 microg/L) diabetes mellitus as compared with the control group of 62 subjects (64.2 +/- 11.5 microg/L; p < 0.05). There was no statistically significant difference in the serum levels of selenium between the groups of patients with noninsulin-dependent and insulin-dependent diabetes mellitus. The levels of erythrocyte glycogen were 2.0580 +/- 1.326, 2.0380 +/- 1.735, and 2.0036 +/- 1.3537 microg/g Hb in the control group, noninsulin-dependent group, and insulin-dependent group, respectively, with no statistically significant between-group difference. The decreased levels of selenium in serum and erythrocytes of diabetic patients suggest the possible role of glutathione peroxidase activity.

Topics: Adult; Case-Control Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Erythrocytes; Female; Glycogen; Humans; Male; Selenium

Measurements have been made of the urinary content of inositol phosphoglycans IPG P-type and IPG A-type, putative insulin second messengers, in preeclampsia, in type I insulin-treated diabetic pregnant women and their matched control subjects, and nonpregnant women of child-bearing age. The content of IPG P-type and IPG A-type was also measured in the placenta from preeclamptic patients and from normal pregnancies. Pregnancy was associated with an increase, approximately twofold, in urinary output of IPG-P-type relative to nonpregnant controls (P<0.01). The 24-h output of IPG P-type in urine in preeclamptic women was significantly higher (2- to 3-fold) than in pregnant control subjects matched for age, parity, and stage of gestation (P<0.02). In contrast, insulin-dependent diabetic pregnant women did not show any significant change in urinary output of IPG P-type or IPG A-type relative to pregnant control subjects. Evidence for a possible relationship and correlation between the urinary excretion of IPG P-type and markers of preeclampsia, including proteinuria (r = 0.720, P<0.01), plasma aspartate transaminase (r = 0.658, P<0.05), and platelet counts (r = 0.613, P<0.05) is presented. A high yield of IPG P-type was extracted from human placenta, in preeclampsia some 3-fold higher (P = 0.03) than the normal value, whereas no IPG A-type (with lipogenic-stimulating activity) was found. Low concentrations of placental IPG A-type were detected relative to IPG P-type using assay systems dependent upon the effect of this mediator on cAMP-dependent protein kinase or on a proliferation assay using thymidine incorporation into DNA of EGFR T17 fibroblasts. It is postulated that the high urinary excretion IPG P-type in preeclampsia reflects high placental levels and relates to the accumulation of glycogen in the placenta. The paracrine effects of placental IPG P-type (stimulation off other endocrine glands and/or endothelial cells) could contribute to the pathogenesis of the maternal syndrome. A possible theoretical link between elevated placental IPG P-type and apoptosis is proposed.

Topics: Adult; Animals; Biomarkers; Cell Line; Cyclic AMP-Dependent Protein Kinases; Diabetes Mellitus, Type 1; Enzyme Activation; Female; Fibroblasts; Gestational Age; Glycogen; Glycogen Synthase; Humans; Inositol Phosphates; Male; Placenta; Polysaccharides; Pre-Eclampsia; Pregnancy; Pregnancy in Diabetics; Rats; Rats, Wistar; Signal Transduction

A major function of insulin in target tissues is the activation of glycogen synthase. Phosphatidylinositol 3-kinase (PI3K) has been implicated in the insulin-induced activation of glycogen synthase, although the true function of this enzyme remains unclear. Data presented here demonstrate that the PI3K inhibitors wortmannin and LY-294002 block the insulin-stimulated activation of protein phosphatase 1 (PP1) in rat ventricular cardiomyocytes. This loss of phosphatase activation mimics that seen in diabetic cardiomyocytes, in which insulin stimulation fails to activate both PP1 and glycogen synthase. Interestingly, in diabetic cells, insulin stimulated PI3K activity to 300% of that in untreated controls, whereas this activity was increased by only 77% in normal cells. PI3K protein levels, however, were similar in normal and diabetic cells. Our results indicate that PI3K is involved in the stimulation of glycogen synthase activity by insulin through the regulation of PP1. The inability of insulin to stimulate phosphatase activity in diabetic cells, despite a significant increase in PI3K activity, suggests a defect in the insulin signaling pathway that contributes to the pathology of insulin-dependent diabetes.

Topics: Androstadienes; Animals; Cells, Cultured; Chromatography, High Pressure Liquid; Diabetes Mellitus, Type 1; Enzyme Activation; Enzyme Inhibitors; Glycogen; Glycogen-Synthase-D Phosphatase; Hypoglycemic Agents; Insulin; Male; Muscle Fibers, Skeletal; Myocardium; Phosphatidylinositol 3-Kinases; Phosphoprotein Phosphatases; Protein Phosphatase 1; Rats; Rats, Sprague-Dawley; Signal Transduction; Wortmannin

Histological and immunohistochemical studies were carried out on the pancreas of twelve cattle of insulin-dependent diabetes mellitus (IDDM). They showed clinical signs such as persistent hyperglycemia, glycosuria and decreased glucose tolerance, and some cases accompanied with or without ketonuria. Histopathologically, eight cattle were diagnosed as chronic IDDM, while others were acute IDDM. The most characteristic lesions of the pancreas in chronic IDDM showed a decrease in the size and number of pancreatic islets, interlobular and interacinar fibrosis, mild lymphocytic insulitis, and vacuolation of a few islets. Almost all cells in the atrophied islets had a small amount of ungranulated cytoplasm. Immunohistochemical examination revealed that the atrophied islet cells did not react to anti-insulin antibody, but occasionally reacted to anti-glucagon or somatostatin antibodies. A few solitary islets with mild lymphocytic infiltration, necrotic islets with occasional calcification, and atrophied islets with mild fibrosis were also observed. A few islets consisted of many islet cells with vacuolated cytoplasm including a small number of insulin-positive granules. Accumulation of glycogen granules was occasionally observed in these islets. Islet fibrosis was due to the proliferation of collagen fibers reactive to both anti-collagen type I and type III antibodies. In acute IDDM, the major islets consisted of the cells with vacuolated cytoplasm indicating the degranulation of islet cells. These islets contained many islet cells with shrunken cytoplasm and karyorrhectic nuclei. Lymphocytic infiltration was frequently observed in the islets which consisted of many islet cells having karyorrhectic nuclei and vacuolated and severely degranulated cytoplasm. Immunohistochemically, islet cells with vacuolated cytoplasm had a small amount of insulin-positive granules, suggesting severe degranulation of beta-cells. An increase in acinar islet-cells and proliferation of ductal epithelial cells showing insulin-immunoreactivity were observed. Bovine IgG-immunoreactive islet cells were frequently seen in the vacuolated islets. In summary, pathological observations suggested that beta-cells were being destroyed by an inflammatory process which selectively affected the pancreatic islets. Lymphocytic insulitis and anti-bovine immunoreactive islet cells were thought to be the most significant changes in determining the etiology and pathogenesis of bovine IDDM, and suggested

Topics: Animals; Atrophy; Calcinosis; Cattle; Cattle Diseases; Diabetes Mellitus, Type 1; Female; Fibrosis; Glycogen; Immunohistochemistry; Islets of Langerhans; Male; Pancreas; Vacuoles

Acute physical exercise usually enhances insulin sensitivity. We examined the effect of a competitive 42 km marathon run on glucose uptake and lipid oxidation in 7 runners with insulin-dependent diabetes mellitus (IDDM), aged 36 +/- 3 yr, BMI 23.9 +/- 0.5 kg m-2, VO2max 46 +/- 1 ml kg-1 min-1, HbA1c 7.7 +/- 0.3%, duration of diabetes 16 +/- 5 yr, runtime 3 h 47 +/- 8 min. On the marathon day, they reduced pre-race insulin doses by 26 +/- 8%, and ingested 130 +/- 33 g carbohydrate before, 91 +/- 26 g during, and 115 +/- 20 g after the race. During the run, blood glucose concentration fell from 14.4 +/- 2.0 to 7.4 +/- 3.0 mmol l-1 (p < 0.05) and serum insulin from 51 +/- 8 to 33 +/- 8 pmol l-1 (p < 0.05). Serum NEFA increased by 4-fold (p < 0.05), but fell to the normal level by next morning. Muscle glycogen content was 56% lower (p < 0.05) and glycogen synthase fractional activity 40% greater (p < 0.05) in the morning after the marathon as compared to the resting control day. In spite of glycogen depletion, whole body glucose disposal (euglycaemic insulin clamp) was unchanged, while glucose oxidation (indirect calorimetry) was decreased by 49% (p < 0.05) and lipid oxidation increased by 41% (p < 0.01). There was an inverse correlation between the rates of lipid oxidation and glucose uptake after the marathon (r = -0.75; p < 0.05).. after successfully managed marathon running in patients with IDDM, insulin sensitivity was not increased in spite of low glycogen content and enhanced glycogen synthase activity after marathon, probably because of increased lipid oxidation.

Topics: Adult; Arteries; Blood Glucose; Creatine Kinase; Diabetes Mellitus, Type 1; Energy Metabolism; Fatty Acids, Nonesterified; Female; Forearm; Glucagon; Glucose Clamp Technique; Glycogen; Glycogen Synthase; Growth Hormone; Humans; Hydrocortisone; Insulin; Insulin Resistance; Lipid Metabolism; Male; Muscles; Myoglobin; Oxidation-Reduction; Running

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

The effects of physiological increments in epinephrine and insulin on glucose production (GP), skeletal muscle glycogen metabolism, and substrate oxidation were studied in eight insulin-dependent diabetes mellitus (IDDM) and nine control subjects. Epinephrine was coinfused for the final 120 min of a 240-min euglycemic, hyperinsulinemic clamp. In both groups, insulin increased glucose uptake, glycogen synthesis, and whole body carbohydrate (CHO) oxidation and inhibited GP (by 70-80%) and lipid oxidation (by approximately 50%), whereas epinephrine antagonized the effect of insulin on glucose uptake and glycogen synthesis. In contrast, GP increased in IDDM subjects (P < 0.02) but remained suppressed by insulin in controls. CHO oxidation fell (1.37 +/- 0.25 vs. 2.08 +/- 0.32 mg.kg-1.min-1) and lipid oxidation increased to baseline in IDDM subjects, with increments in plasma free fatty acids (FFA) and glycerol. In contrast, in controls, plasma FFA and glycerol remained suppressed and lipid oxidation decreased further with epinephrine (P < 0.005). Epinephrine completely reversed insulin's activation of muscle glycogen synthase in both groups. Thus, during hyperinsulinemia, the hepatic response to epinephrine in IDDM subjects may be dependent on activation of lipid oxidation. Skeletal muscle glycogen metabolism is exquisitely sensitive to epinephrine despite the presence of hyperinsulinemia.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Epinephrine; Female; Glycogen; Glycogen Synthase; Hormones; Humans; Insulin; Lipid Metabolism; Male; Middle Aged; Muscle, Skeletal; Oxidation-Reduction; Phosphorylases; Reference Values

The present investigation was conducted to study metabolic and hormonal responses to prolonged exercise to exhaustion in insulin-dependent diabetic subjects. Sixteen healthy subjects (control) and 15 diabetics with no-insulin administration for 12 hours were studied. They were submitted to short-term exercise to exhaustion on a cycle ergometer at 55% to 60% of maximum oxygen consumption (VO2max). Exercise tolerance was significantly lower in diabetic subjects (66 +/- 6.7 v 117 +/- 9.4 minutes), and glucose concentration was significantly higher in these subjects. At exhaustion, only diabetic subjects showed a significant decrease in glycemia (142 +/- 20 v 111 +/- 16 mg/dL). Lactate concentration increased significantly during exercise up to 30 minutes, but at exhaustion only control subjects showed a reduction. No significant difference in free fatty acid (FFA) concentrations was observed between the groups during a 30-minute exercise period; however, at exhaustion levels were significantly higher in control subjects. Prolactin and C-peptide concentrations were significantly lower in diabetic subjects, whereas glucagon concentration was higher. No significant differences between the groups were observed for cortisol and growth hormone (GH) concentrations. We conclude that (1) diabetic subjects show reduced exercise tolerance when no insulin is administered for 12 hours, and (2) exercise to exhaustion reduces serum glucose concentrations in insulin-dependent diabetics.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Exercise Tolerance; Fatty Acids, Nonesterified; Glycogen; Humans; Lactates; Lactic Acid; Male; Muscles; Respiration

Insulin binding to trophoblast plasma membranes and the placental glycogen content were measured in twelve healthy women, in eleven well-controlled gestational diabetic women who were treated either with diet alone (n = 4) or with insulin (n = 7) and in 18 women with well-controlled overt diabetes mellitus (six White B; four White C; eight White D). The competitive binding assay was carried out with 22 concentrations of unlabelled insulin. Binding data were analysed by a non-linear direct model fitting procedure assuming one non-cooperative binding site. Maximum specific binding was unchanged in the total collective of gestational diabetic women, but was decreased by 30% in those treated with diet (6.2 +/- 2.2%) and increased by 90% in insulin-treated women (16.4 +/- 10.2%) as compared to the control subjects (8.7 +/- 2.5%). The diet-treated women had only 40% as many and those treated with insulin had more than twice as many receptors compared to control subjects on a per mg protein basis and if expressed per total placenta. In patients with overt diabetes mellitus maximum specific binding (18.5 +/- 10.6%) was higher (p less than 0.05) due to more receptors compared to control subjects but was similar to the insulin-treated gestational diabetic patients. Maximum specific binding and receptor concentrations did not correlate linearly with maternal plasma insulin levels. Receptor affinities were virtually similar in all groups (1.8 x 10(9) l/mol). The placental glycogen content was reduced (p less than 0.05) to about 80% of that of control subjects in the diet-treated collective, whereas it was unchanged compared to control subjects in the insulin-treated gestational diabetic women despite a 40% increase (p less than 0.001) of the maternal-to-cord serum glucose ratio. In overt diabetic patients the maternal-to-cord serum glucose ratio and the placental glycogen content were higher (p less than 0.05) than in the control subjects. We conclude that trophoblast plasma membranes from gestational diabetic women treated with diet alone express less and those from women treated with insulin express more insulin receptors than those from a healthy control group in vitro. These differences could not have been disclosed without consideration of the mode of treatment. Trophoblast plasma membranes from overt diabetic women have more insulin receptors than those from healthy control subjects.

Topics: Adult; Amniotic Fluid; Binding, Competitive; Birth Weight; Cell Membrane; Diabetes Mellitus, Type 1; Diabetes, Gestational; Diet, Diabetic; Female; Glucose; Glycogen; Humans; Infant, Newborn; Insulin; Kinetics; Placenta; Pregnancy; Pregnancy in Diabetics; Receptor, Insulin; Trophoblasts

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

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

Measurements were made of the levels of metabolic intermediates and activities of enzymes of the glycolytic route, pentose phosphate pathway, and polyol pathway in livers and kidneys of NOD mice. A 34% decrease in UDP-glucose, a 40% decrease in glucose-6-phosphate (G6P) and fructose-6-phosphate, and a 75% decrease in fructose-2,6-bisphosphate (F2,6P) were found in the livers of NOD mice. The fall in the level of F2,6P (the important regulator of glycolysis) is accompanied by a 20% reduction in the activity of phosphofructokinase. These changes are in agreement with previously reported liver depletion of glycogen and reduced synthesis of proteins and nucleic acids in the diabetic state. In the kidney, the increase in hexokinase activity is consistent with increased levels of G6P and glycogen content of kidney in diabetes. The decreased level of phosphoribosyl pyrophosphate was reported to be a regulator of kidney growth in the initial period of diabetes but can still be found in NOD mice 6 wk after development of hyperglycemia. The reported changes are similar to those seen in alloxan- or streptozocin-induced diabetic animals, but certain changes are more marked in NOD mice, especially those directed to increase nucleic acid and protein synthesis in the diabetic kidney.

Topics: Adenosine Triphosphate; Aldehyde Reductase; Animals; Diabetes Mellitus, Type 1; Female; Fructosephosphates; Glucose; Glucosephosphates; Glycogen; Hexokinase; Kidney; L-Lactate Dehydrogenase; Liver; Mice; Mice, Inbred NOD; Phosphofructokinase-1; Pyruvate Kinase

Topics: Animals; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucose; Glycogen; Humans; Insulin; Islets of Langerhans

Topics: Blood Pressure; Diabetes Mellitus, Type 1; Gluconeogenesis; Glycogen; Hepatic Veins; Humans; Liver; Liver Circulation; Pharmaceutical Preparations; Physical Exertion

We searched for metabolic crossover points in muscle glucose metabolite profiles during maintenance of matched glucose fluxes across forearm muscle in insulin-resistant type I (insulin-dependent) diabetic patients and nondiabetic subjects. To classify subjects as insulin sensitive or insulin resistant, whole-body and forearm glucose disposal, oxidative and nonoxidative glucose disposal (indirect calorimetry), and glycogen synthesis (muscle glycogen content in needle biopsies) were measured under euglycemic conditions at two insulin concentrations. Whole-body and forearm muscle glucose disposal were significantly reduced in diabetic patients compared with control subjects. The reduction in total glucose disposal was due to similar relative reductions in oxidative and nonoxidative glucose disposal, pointing toward rate limitation early in glucose metabolism. The defect in nonoxidative glucose disposal was at least partly due to a defect in muscle glycogen synthesis, because muscle glycogen content failed to increase in response to an increase in the plasma insulin concentration in the diabetic patients. The most-insulin-resistant type 1 diabetic patients were restudied under conditions where, by glucose mass action, whole-body glucose disposal was forced to be similar to that in the control subjects. Matching glucose fluxes in the two groups resulted in similar rates of forearm and whole-body oxidative and nonoxidative glucose disposal and muscle glycogen synthesis, but it did not result in accumulation of free intracellular glucose, glucose-6-phosphate, glucose-1-phosphate, fructose-6-phosphate, or lactate in muscle. These data imply that the rate-limiting defect for glucose disposal in skeletal muscle of type I diabetic patients is at the level of glucose transport.

Topics: Adult; Biological Transport; Diabetes Mellitus, Type 1; Glucose; Glycogen; Glycogen Synthase; Humans; Insulin; Insulin Resistance; Metabolic Clearance Rate; Muscles; Oxidation-Reduction

Topics: Adolescent; Adult; Aged; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glycogen; Humans; Hypoglycemic Agents; Middle Aged; Neutrophils; Peroxidase

Topics: Adolescent; Adult; Diabetes Mellitus, Type 1; Female; Gastric Mucosa; Glycogen; Humans; Male; Triglycerides

The mechanisms of insulin insensitivity in diabetes are poorly understood. We have therefore assessed the relationship between glucose disposal during a euglycaemic clamp, muscle glycogen formation, and the activities of insulin regulated enzymes within skeletal muscle in five Type 1 (insulin-dependent) diabetic patients, both on conventional injection therapy (HbA1 11.0 +/- 1.0 (SD) %) and after 6 weeks continuous subcutaneous insulin infusion (HbA1 7.6 +/- 1.4%, p less than 0.01). On both regimens, overnight euglycaemia before the clamp was maintained with an intravenous insulin infusion. The increase in clamp glucose requirements (insulin 0.1 U X kg-1 X h-1) between injection therapy and continuous subcutaneous insulin infusion was significant (6.2 +/- 0.9 (SE) to 7.0 +/- 0.9 mg X kg-1 X min-1, p less than 0.05), but small compared to differences between subjects. Glucose requirement remained lower than in control subjects (10.4 +/- 0.7 mg X kg-1 X min-1, p less than 0.05). The increase in muscle glycogen with the clamp was slightly higher on continuous subcutaneous insulin infusion (9.5 +/- 2.5 mg/g protein) than on injection therapy (8.5 +/- 2.4 mg/g, p less than 0.05), but less than in control subjects (17.9 +/- 2.1 mg/g, p less than 0.05). The expressed activity of glycogen synthase and pyruvate dehydrogenase increased significantly between fasting and the end of the clamps in the patients (p less than 0.001 and less than 0.005), but was not significantly different between the two treatment regimens. Expressed glycogen synthase activity at the end of the clamp was lower on both treatments than in control subjects (p less than 0.05). Both enzyme activities were, however, highly correlated with glucose requirement between patients, (r = 0.89-0.94, p less than 0.05-0.02), and glycogen synthase was similarly correlated in the control subjects (r = 0.84, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Blood Glucose; Diabetes Mellitus, Type 1; Glycogen; Glycogen Synthase; Humans; Insulin; Insulin Infusion Systems; Muscles; Pyruvate Dehydrogenase Complex

Topics: Amino Acids; Diabetes Mellitus, Type 1; Energy Metabolism; Fatty Acids, Nonesterified; Glucose; Glycogen; Humans; Ketone Bodies; Liver; Liver Glycogen; Muscles; Physical Exertion; Triglycerides

Six men and three women with insulin-dependent diabetes (without complications) participated in physical training three times a week for 20 weeks. Physical training did not change the concentration of fasting blood-glucose, glucose excretion in urine or glucosylated haemoglobin (HbA1). However, the glucose disposal rate during euglycaemic clamp increased after training. In two patients a minor reduction of insulin dosage was necessary to alleviate slight hypoglycaemic episodes. The training resulted in significant increases in quadriceps isometric and dynamic strength and endurance. Maximal oxygen uptake increased by 8%, the activity of glycolytic enzymes in vastus lateralis muscle by 47% for hexokinase, and 30% for tri-osephosphate dehydrogenase and 25% for lactic dehydrogenase, the activity of oxidative enzymes by 42% for citrate synthase and 46% for 3-hydroxy-acyl-CoA-dehydrogenase. The glycogen concentration in the vastus lateralis muscle did not change significantly. Lipoprotein lipase activity did not change in muscle, nor in adipose tissue. The mean muscle fibre area increased by 25% and the area of FTa fibres by 30%. The new formation of capillaries around different muscle fibres was significant for FTb fibres (26%). The proliferation of capillaries, however, appeared to be insufficient to cope with the increased area of muscle fibres. As a result, the mean area of muscle fibre supplied by one capillary (a measure of diffusion distance) significantly increased after training for FTa fibres. It is concluded that with the exception of deficient proliferation of capillaries, patients with insulin-dependent diabetes mellitus show a normal central and peripheral adaptation to physical training. Physical training does not apparently improve blood glucose control in most cases, despite an increased insulin sensitivity.

Topics: Adaptation, Physiological; Adult; Blood Glucose; Capillaries; Diabetes Mellitus, Type 1; Female; Glycogen; Heart Rate; Humans; Male; Middle Aged; Muscles; Oxygen Consumption; Physical Education and Training; Physical Endurance; Physical Exertion; Respiration

The metabolic effects of beta-adrenoceptor blocking agents during hypoglycaemia in patients prone to hypoglycaemia are of interest as diabetics are often treated with these drugs because of hypertension or angina pectoris. Compared with non-diabetics these patients also have impaired glucose compensation after hypoglycaemia, partly secondary to deficient release of glucagon. This makes the diabetics more dependent on adrenergic mechanisms to recover from low blood glucose concentrations. Non-selective beta-adrenoceptor blockade (propranolol) significantly impairs the glucose recovery rate after hypoglycaemia in insulin dependent diabetics, whereas selective beta-adrenoceptor blockade (metoprolol) does not have this side effect. The mechanism of the effect of propranolol is probably an attenuation of the gluconeogenesis secondary to deficient release of the important gluconeogenic substrates lactate and glycerol.

Topics: Adrenergic beta-Antagonists; Blood Glucose; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Glucagon; Gluconeogenesis; Glycerol; Glycogen; Humans; Hypertension; Hypoglycemia; Insulin; Lactates; Lactic Acid; Liver; Metoprolol; Propranolol

The relationship between metabolic control and glycogen lymphocyte content in diabetes mellitus, was studied. 30 insulin-treated and 30 type II diabetic subjects were evaluated with 40 age and sex matched normal controls. Glycaemic control was evaluated by a fasting and 2 h post-prandial plasma glucose and by glycosylated hemoglobin (GHb). Glycogen lymphocyte content was determined by calculation of the PAS-positive Index of the lymphocytes (PIL) according to Skrabalo. While fasting and post-prandial plasma glucose values were significantly higher in insulin-treated than in type II diabetes (p less than 0.001), no differences in GHb values were observed between the two groups (10.31 +/- 0.23% vs 9.80 +/- 0.36%). The mean PIL values were not different in these two groups (0.11 +/- 0.01 vs 0.12 +/- 0.02), but they were significantly higher when compared with control values (0.03 +/- 0.004, p less than 0.001), PIL was positively correlated with GHb in both insulin-treated (r = 0.76, p less than 0.001) and type II diabetes (r = 0.55, p less than 0.001). A correlation between PIL and plasma glucose values was observed only in the insulin-treated group and was weaker (p less than 0.005). No correlation was observed between glycogen lymphocyte content and glucose tolerance in the control group. These data confirm that diabetes mellitus is characterized by a significant increase of PAS-positive lymphocyte content and that it correlates well with glycaemic control.

Topics: Adolescent; Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Glycogen; Humans; Lymphocytes; Male; Middle Aged; Periodic Acid-Schiff Reaction

Topics: Diabetes Mellitus, Type 1; Glycogen; Humans; Insulin; Muscles; Physical Exertion

The effects of diabetes on hepatic carbohydrate metabolism were investigated in spontaneously diabetic Bio-Breeding Worcester (BB/W) rats. The juvenile-onset-type syndrome displayed by these animals is characterized by beta-cell destruction with subsequent ketosis-prone insulinopenia. Livers from diabetic animals demonstrated increased adenosine 3',5'-cyclic monophosphate levels but subnormal total protein and glycogen content. Isolated perfused livers of diabetic BB/W rats demonstrated an increased rate of glucose production from [14C]lactate and an impaired rate of glycogen synthesis. These data were consonant with hepatic enzyme studies demonstrating markedly increased activities of component gluconeogenic (glucose-6-phosphatase, fructose-1,6-diphosphatase, phosphoenolpyruvate carboxykinase) and glycogenolytic (glycogen phosphorylase) enzymes with decreased activities of glycolytic (hexokinase, pyruvate kinase) and glycogenic (glycogen synthase) enzymes. These findings agree with previous studies using alloxan- and streptozotocin-induced diabetic animals and suggest that accelerated hepatic gluconeogenesis and impaired glucose utilization are pathognomonic of all insulin-deficient diabetic syndromes.

Topics: Animals; Cyclic AMP; Diabetes Mellitus, Type 1; Glucose; Glycogen; In Vitro Techniques; Liver; Male; Perfusion; Proteins; Rats

Histologic findings are presented of 28 biopsies taken from 19 insulin-dependent children of either sex with long-standing diabetes who developed the Mauriac syndrome or forms frustes of it. Using this comprehensive material, probably the largest series of biopsies related to this problem, a detailed survey is given on morphologic liver findings associated with this rare type of chronic-diabetic decompensation of metabolism. Behaviour and extent of fat and glycogen deposits, including nuclear liver glycogen, showed marked variations. Not in all cases hepatomegaly, the main clinical symptom, was reflected by corresponding histologic findings. Liver glycogenosis alone is not pathognomonic of the Mauriac syndrome. In the decompensation phase of the disease however, liver glycogenosis is found fairly frequently, whereas in the recompensation phase hepatocytic lipid deposits are a common finding.

Topics: Adolescent; Biopsy; Cell Nucleus; Child; Diabetes Mellitus, Type 1; Female; Glycogen; Growth Disorders; Hepatomegaly; Humans; Lipids; Liver; Male; Syndrome

Six male juvenile diabetics were compared with six non-diabetic male subjects regarding the rate of muscle glycogen resynthesis during recovery after prolonged exercise. The glycogen synthesis were similar in the two groups, which indicates that diabetics can participate in strenuous daily physical activity just as non-diabetics.

Topics: Diabetes Mellitus, Type 1; Glucosephosphates; Glycogen; Glycogen Synthase; Humans; Insulin; Lactates; Male; Muscles; Physical Exertion

Topics: Adolescent; Carbohydrates; Child; Child, Preschool; Diabetes Mellitus, Type 1; Erythrocytes; Glycogen; Histocytochemistry; Humans; Insulin; Lipids; Neutrophils

Topics: Adenosine Triphosphatases; Adult; Creatine Kinase; Diabetes Mellitus, Type 1; Glycogen; Humans; Lactates; Male; Middle Aged; Muscle Contraction; Muscles; Phosphofructokinase-1; Physical Exertion; Succinate Dehydrogenase

Topics: Blood Glucose; Diabetes Mellitus, Type 1; Glycogen; Humans; Insulin; Lactates; Muscles; Oxygen Consumption; Physical Exertion; Time Factors

Glycogen synthesis rate in skeletal muscle studied in six juvenile diabetic and six non-diabetic males ingesting a carbohydrate rich diet during 12 h of resting recovery after exhaustive bicycle exercise. The diabetic subjects took their regular insulin. Blood samples and muscle biopsies were obtained at rest prior to exercise, immediately after cessation of exercise and after 2,4,6.9 and 12 h of recovery. A marked decrease in muscle glycogn content was observed in response to exercise in both groups of subjects. Mean glycogen utilization rate was the same in the two groups. Glycogen synthesis rate during the first 4 h or recovery was 6.4 +/- 0.6 mmol glucosyl units/kg w.w./h in the diabetic subjects and 7.2 +/- 0.7 mmol glycosyl units/kg w.w./h in the non-diabetic subjects. During the next 8 h glycogen synthesis rate was approximately 1/3 of that being 2.0 +/- 0.3 and 2.4 +/- 0.5 mmol glucosyl units/kg w.w./h in the two groups respectively. Glycogen synthetase I-activity increased markedly in response to exercise in both groups of subjects. However, no differences were observed between the groups. No significant differences in muscle glucose 6-phosphate concentrations were observed between the two groups. Plasma glucose levels were significantly higher in the diabetic than in the non-diabetic subjects. It is concluded that glycogen synthesis during recovery following prolonged severe exercise can proceed at the same rate in diabetic subjects taking their regular insulin as in non-diabetic subjects.

Topics: Adolescent; Adult; Blood Glucose; Diabetes Mellitus, Type 1; Dietary Carbohydrates; Glucosephosphates; Glycogen; Glycogen Synthase; Humans; Insulin; Lactates; Male; Muscles; Oxygen Consumption; Physical Exertion

Topics: Adolescent; Biopsy; Child; Child, Preschool; Diabetes Mellitus, Type 1; Female; Glycogen; Hepatomegaly; Humans; Inflammation; Liver; Male

Topics: Carbohydrate Metabolism; Carbohydrate Metabolism, Inborn Errors; Diabetes Mellitus, Type 1; Female; Fructose Intolerance; Galactose; Glucose; Glycogen; Homeostasis; Humans; Hydrocortisone; Hypoglycemia; Infant; Infant, Newborn; Malabsorption Syndromes; Male; Metabolic Diseases; Pregnancy; Pregnancy in Diabetics; Syndrome

Topics: Adult; Blood Cell Count; Blood Glucose; Child; Diabetes Mellitus; Diabetes Mellitus, Type 1; Glucose Tolerance Test; Glucosephosphate Dehydrogenase; Glucosephosphates; Glycogen; Humans; Lymphocytes; Middle Aged; Periodic Acid; Phosphogluconate Dehydrogenase; Staining and Labeling

Topics: Adult; Biguanides; Blood Glucose; Child; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diet, Diabetic; Female; Glucosyltransferases; Glycogen; Glycogen Synthase; Glycosuria; Humans; Insulin; Male; Methods; Middle Aged; Muscles; Physical Exertion; Sulfonylurea Compounds; Time Factors

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

Topics: Adolescent; Adult; Aged; Biopsy; Child; Child, Preschool; Diabetes Mellitus; Diabetes Mellitus, Type 1; Female; Glycogen; Humans; Insulin; Male; Middle Aged; Muscles

Topics: Acute Kidney Injury; Adult; Biopsy; Child; Chronic Disease; Diabetes Mellitus; Diabetes Mellitus, Type 1; Female; Glucose; Glycogen; Humans; Insulin; Male; Methods; Muscles; Peritoneal Dialysis; Shock, Surgical; Uremia; Water

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

Topics: Adipose Tissue; Adolescent; Age Factors; Animals; Biological Assay; Blood Glucose; Carbon Dioxide; Carbon Isotopes; Child; Child, Preschool; Diabetes Mellitus, Type 1; Epididymis; Female; Glucose Tolerance Test; Glycogen; Guinea Pigs; Humans; Infusions, Parenteral; Insulin; Male; Rats

Topics: Adult; Biopsy; Diabetes Mellitus, Type 1; Dwarfism; Female; Glycogen; Hepatomegaly; Humans; Insulin; Obesity

Topics: Adolescent; Adrenal Glands; Blood Glucose; Carbohydrate Metabolism; Child; Diabetes Mellitus; Diabetes Mellitus, Type 1; Female; Glucose; Glycogen; Humans; Hypoglycemia; Infant; Insulin; Insulin Antagonists; Maternal-Fetal Exchange; Pituitary Gland; Pregnancy

Topics: Adipose Tissue; Animals; Calcium; Carbohydrate Metabolism; Carbon Dioxide; Diabetes Mellitus; Diabetes Mellitus, Type 1; Dwarfism; Dwarfism, Pituitary; Fatty Acids; Glycerides; Glycogen; Growth Hormone; Hypopituitarism; Kidney Function Tests; Leucine; Lipid Metabolism; Metabolism; Pharmacology; Primates; Prolactin; Research; Sheep

Topics: Adolescent; Diabetes Mellitus, Type 1; Glycogen; Humans; Insulin; Muscles