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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study we examine the hypothesis that an inositol glycan phosphate can act similarly to insulin on intact cells. The inositol glycan phosphate used in this study (glycan alpha) was isolated previously from the glycoinositol phospholipid anchor of human erythrocyte acetylcholinesterase and was shown to have the structure glycine-ethanolamine-PO4-Man-Man-(N,N-dimethylethanolamine-PO4)Man- (N,N-dimethyl)GlcN-inositol-PO4. The cellular response investigated was the glucagon-stimulated activation of glycogen phosphorylase in rat hepatocytes. When hepatocytes were incubated with 20 nM glucagon for 4 min, the ratio of phosphorylase a activity to total phosphorylase increased from a basal value of 0.49 +/- 0.02 to 0.82 +/- 0.03 (mean +/- SE, n = 15). Inclusion of either 100 nM insulin or 3-10 microM glycan alpha during the glucagon incubation significantly decreased the glucagon-stimulated activity ratio to 0.74 +/- 0.03 for either agent. Furthermore, hepatocyte preparations differed in their response to insulin and were divided into insulin-responsive and -resistant groups. Glycan alpha had a significant effect only in the insulin-responsive group for which the observed activity ratio for 10 microM glycan alpha plus glucagon (0.68 +/- 0.05) compared closely with that for insulin plus glucagon (0.70 +/- 0.04). For the insulin-resistant group, the activity ratio in the presence of 10 microM glycan alpha was 0.81 +/- 0.03, unchanged from the control with glucagon alone. Because glycan alpha contains an inositol phosphate group, the effect of inositol cyclic 1,2-phosphate on the glucagon-stimulated activity ratio was determined.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1993 Sep
PMID:Inositol glycan phosphate derived from human erythrocyte acetylcholinesterase glycolipid anchor and inositol cyclic 1,2-phosphate antagonize glucagon activation of glycogen phosphorylase. 834 43

Maintenance of plasma glucose concentrations within a narrow range despite wide fluctuations in the demand (e.g. vigorous exercise) and supply (e.g. large carbohydrate meals) of glucose results from coordination of factors that regulate glucose release into and removal from the circulation. On a moment-to-moment basis these processes are controlled mainly by insulin and glucagon, whose secretion is reciprocally influenced by the plasma glucose concentration. In the resting postabsorptive state, release of glucose from the liver (equally via glycogenolysis and gluconeogenesis) is the key regulated process. Glycogenolysis depends on the relative activities of glycogen synthase and phosphorylase, the latter being the more important. The activities of fructose-1,6-diphosphatase, phosphoenolpyruvate carboxylkinase and pyruvate dehydrogenase regulate gluconeogenesis, whose main precursors are lactate, glutamine and alanine. In the postprandial state, suppression of liver glucose output and stimulation of skeletal muscle glucose uptake are the most important factors. Glucose disposal by insulin-sensitive tissues is regulated initially at the transport step and the mainly by glycogen synthase, phosphofructokinase and pyruvate dehydrogenase. Hormonally induced changes in intracellular fructose 2,6-bisphosphate concentrations play a key role in muscle glycolytic flux and both glycolytic and gluconeogenic flux in the liver. Under stressful conditions (e.g. hypoglycaemia, trauma, vigorous exercise), increased secretion of other hormones such as adrenaline, cortisol and growth hormone, and increased activity of the sympathetic nervous system, come into play; their actions to increase hepatic glucose output and to suppress tissue glucose uptake are partly mediated by increases in tissue fatty acid oxidation. In diabetes, the most common disorder of glucose homeostasis, fasting hyperglycaemia, results primarily from excessive release of glucose by the liver due to increased gluconeogenesis; postprandial hyperglycaemia results from both impaired suppression of hepatic glucose release and impaired skeletal muscle glucose uptake. These abnormalities are usually due to the combination of impaired insulin secretion and tissue resistance to insulin, the causes of which remain to be determined.
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PMID:Control of glycaemia. 837 4

In skeletal muscle, a defect in the covalent activation of glycogen synthase by insulin has been identified in insulin resistance and in Type 2 (non-insulin-dependent) diabetes mellitus, but a similar defect in insulin action at the adipose tissue has not been demonstrated. We sought to determine whether this defect in insulin action in muscle was also present in the same pathway in adipose tissue. We examined the effect of in vivo insulin on adipose tissue glycogen synthase and phosphorylase activity in normal (n = 11), hyperinsulinaemic (n = 8), and impaired glucose tolerant and Type 2 diabetic (n = 8) rhesus monkeys. Adipose tissue samples were obtained before and during a euglycaemic hyperinsulinaemic clamp. Glycogen synthase fractional velocity, independent and total activities were significantly higher in the insulin-stimulated samples compared to the basal samples in the normal group (p < 0.05, respectively). In the hyperinsulinaemic group, however, insulin had no effect on glycogen synthase fractional velocity or independent activity, but did increase the total activity of glycogen synthase and phosphorylase (p < 0.05, respectively). Furthermore, both the basal and the insulin-stimulated total activities of these two enzymes were significantly greater in the hyperinsulinaemic group as compared to both the normal and the diabetic groups (p < 0.05, respectively). In the diabetic group, insulin was without effect on glycogen synthase fractional velocity, independent activity or total activity. We conclude that the covalent activation of adipose tissue glycogen synthase by insulin is absent in both obese hyperinsulinaemic and in spontaneously diabetic monkeys.
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PMID:Adipose tissue glycogen synthase activation by in vivo insulin in spontaneously insulin-resistant and type 2 (non-insulin-dependent) diabetic rhesus monkeys. 846 68

The potential role of nitric oxide in the diabetes-induced hypersensitive activation of glycogen phosphorylase by epinephrine was investigated in adult rat ventricular cardiomyocytes. Pretreatment of normal and diabetic-derived cells with 1 mM sodium nitroprusside significantly diminished the phosphorylase activation response by nearly 20% in both normal and diabetic myocytes but failed to alter the hypersensitivity of the diabetic cells. Nitroprusside increased cGMP levels in both normal and diabetic myocytes although the effect was more pronounced in the diabetic cells. Epinephrine did not alter cellular cGMP content and cGMP levels were consistently lower in diabetic myocytes when compared with normal myocytes. Preincubation of ventricular myocytes with the nitric oxide synthase inhibitor L-iminoethyl ornithine did not affect phosphorylase activation. These data indicate that nitric oxide plays a minor role in phosphorylase activation by epinephrine in rat cardiomyocytes and suggest that signal transduction via nitric oxide is not affected by the onset of diabetes.
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PMID:Cyclic GMP accumulation in normal and diabetic primary culture adult rat ventricular cardiomyocytes: a minor role for nitric oxide in phosphorylase activation. 858 75

The frequent development of Type 2 diabetes in the obese suggests a relationship between obesity and diabetes. This study presents evidence for a continuum form obesity to diabetes via glucose intolerance and hyperinsulinemic diabetes. The defect which seems to be at the origin of this development resides in the increase in lipid oxidation already present in the early stages of obesity. It reflects the increased utilisation of fatty acids for energy purpose in the obese, at the expenses of glucose. In non-diabetic obese subjects, insulin resistance can be demonstrated by the inhibition of glucose storage during a euglycemic, hyperinsulinemic, clamp. This defect in glucose storage is not observed during a oral glucose tolerance test (OGTT), as it is compensated by hyperinsulinemia and hyperglycemia during glucose tolerance. Glucose tolerance appears with the inhibition of glucose oxidation by the augmented lipid oxidation. This decreased glucose utilization causes a slowdown of the utilization of glycogen stores which leads, as a consequence, to the inhibition of glycogen synthase by its product, glycogen. Diabetes appears when the increase in glycemia and insulinemia does not compensate any more for the inhibition of glucose storage. The rise in basal glycemia simultaneously with the fall in glucose storage corresponds to the transition to diabetes. The decreased glucose mobilization together with the inhibition of glycogen phosphorylase are such in the diabetic patient that glycogen stores tend to remain full and glycogen synthase is inhibited by negative feedback. The retrograde inhibition of glycogen stores on glycogen synthase activity brings up incapacity to store glucose and leads to a rise in glycemia. Finally, the evolution of obesity to diabetes leads to a decrease in insulin secretion with increase in hepatic glucose production through gluconeogenesis and decreased capacity to store glucose. Therapeutic implications are discussed in this review.
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PMID:[From obesity to diabetes]. 859 98

Glycogen phosphorylase regulates the breakdown of glycogen into glucose, but as previous studies have demonstrated, the control of glycogen metabolism becomes deregulated in diabetes mellitus. Messenger RNA levels encoding several different proteins are altered in skeletal muscle biopsies of patients with insulin-dependent and non-insulin-dependent diabetes. The possible alteration of expression of the gene encoding the skeletal muscle isoform of glycogen phosphorylase during diabetes has not previously been investigated. We examined the effect of streptozotocin-induced diabetes and insulin treatment on glycogen phosphorylase mRNA in rat skeletal muscle; glycogen phosphorylase mRNA levels were elevated in diabetic rat muscle tissue, but were partially suppressed in diabetic rat muscle following insulin treatment. To distinguish between the effects of insulin and counter-regulatory hormones on glycogen phosphorylase mRNA levels, we employed differentiating rat L6 myoblasts in culture. Insulin stimulated the accumulation of glycogen phosphorylase mRNA as determined by Northern blot analysis. Moreover, insulin and dibutyryl cAMP stimulated expression of a transiently transfected chloramphenicol acetyl transferase reporter gene under the control of the muscle glycogen phosphorylase promoter in differentiating myotubes in culture, suggesting that the effects of insulin and counter-regulatory hormones on glycogen phosphorylase mRNA are at the level of transcription. These results suggest that insulin and epinephrine may participate in the induction of the glycogen phosphorylase gene during myogenesis; moreover, activation of this gene in muscle tissue may be a contributing factor in impaired glycogen storage during uncontrolled diabetes.
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PMID:Expression of the gene encoding glycogen phosphorylase is elevated in diabetic rat skeletal muscle and is regulated by insulin and cyclic AMP. 863 70

A 64-year-old female with McArdle's disease and non-insulin-dependent diabetes mellitus (NIDDM) is reported. She had none of the characteristic symptoms of McArdle's disease such as muscle cramps but her serum creatine kinase level was elevated. Muscle biopsy with negative muscle phosphorylase staining showed McArdle's disease. Modified forearm ischemic exercise test was done at two conditions; fasting and two hours after a meal. When fasting, the level of lactic acid did not elevate after exercise. After a meal, however, the serum lactic acid level rose with the elevation of plasma glucose and IRI. Thus, we suggested that high plasma glucose and insulin due to NIDDM may induce blood-borne glucose uptake with exercise.
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PMID:McArdle's disease with non-insulin-dependent diabetes mellitus: the beneficial effects of hyperglycemia and hyperinsulinemia for exercise intolerance. 879 56

The enzymatic histochemical and ultrastructural alterations of the rat heart during development of streptozotocin (STZ) induced diabetic cardiomyopathy were studied. Moreover, the response of the isolated diabetic hearts to Ca overload-Ca paradox-was investigated. In the early stage of diabetes (1 week of diabetes), no apparent histochemical changes were observed but gentle alterations of the ultrastructure of the myocytes and particularly capillaries were found. Structural changes of the myocytes and microangiopathy accompanied by decreased activities of some enzymes (phosphorylase, various dehydrogenases, ATPase) progressed with time and were more pronounced late in diabetes (9 weeks). Ca paradox induced severe structural damage of the majority of cardiomyocytes and loss of the cellular integrity, and marked decrease in activities of all enzymes. However, in acute diabetic heart only partial Ca paradox was observed. It was manifested by transmural heterogeneity of structural and enzymatic histochemical changes. Evident preservation of the ultrastructure and enzyme activities of the myocardium was revealed in late stage (9 weeks) of diabetes. It can be concluded that diabetes results in prevention of the Ca overload in rat myocardium in vitro. Disturbances in coronary perfusion associated with microangiopathy as well as altered Ca handling and depressed heart function may account for delayed development of Ca paradox in diabetic heart.
Diabetes Res Clin Pract 1996 Jul
PMID:Resistance of diabetic rat hearts to Ca overload-related injury. Histochemical and ultrastructural study. 886 49

The syndrome of insulin resistance comprises the following H-phenomena: 1. Hyperinsulinism compensating the inborn postreceptor insulin resistance, 2. Hyperglycaemia-non-insulin-dependent diabetes mellitus, 3. Hyperlipoproteinaemia with android obesity, 4. Hypertension, 5. Hirsutism with the syndrome of polycystic ovaries as a manifestation of a hyperandrogenic situation in the female organism. Molecular syndromes of this syndrome of insulin resistance are obscure. They are the subject of intensive studies because H-phenomena are an aggregation of the main risk factors of atherogenesis. Recently attention is focused also on amylin--a 37 amino acid peptide with a 50% homologous amino acid sequence with a calcitonin-gene--related peptide (CGRP), which is the product of a gene made up of three introns on the 12th chromosome. Amylin acts in the beta-cells of the pancreas as a co-secretion of insulin. If in excess, it is deposited in the form of an amyloid in the beta-cells. In the early stage of NIDDM it alters the physiological response of the beta-cell to glycaemic stimuli and food, in later stages of the disease, after accumulation, it causes apoptosis of the beta-cell and reduces thus the secretory capacity of the Langerhans islets. It is excreted in the urine and thus, if the glomerular filtration is reduced, it cumulates in the blood stream and thus enhances insulin resistance already in the early stages of chronic renal insufficiency, or in diabetic nephropathy. In type II diabetes similarly as insulin levels also amylin levels are elevated, while in type I diabetes with early autoimmune destruction of the beta-cells the insulin and amylin levels are reduced or even zero. Amylin reduces in the muscle, probably by inhibition of glycogen synthase, the insulin stimulated non-oxidative utilization of glucose into muscle glycogen and conversely by stimulation of phosphorylase it stimulates glycogenolysis and thus also lactate production and gluconeogenesis in the liver which all are anti-insulin effects which intensify the insulin resistance of the main target tissues. Amylin, similarly as CGRP or calcitonin, reduces Ca blood levels and has a vasodilatating effect; it reduces the BP but in different minimal and maximal doses and by a different mechanism and via special receptors because the link of amylin to calcitonin receptors is 100 times lower and does not produce a rise of cAMP in the target cell. The effect on the enhancement of insulin resistance in muscle was proved also by direct measurements using an hyperinsulinaemic euglycaemic clamp. After prolongation of the clamp to more than two hours the effect on insulin resistance disappeared, although the hypocalcinaemic effect persisted. Amylin is able by its biological action to modify the secretion as well as the effectiveness of insulin to pathological values. These two characteristics are typical for impaired glucose tolerance in type II diabetes. Studies are under way to find out whether the effect of amylin is involved directly also in the pathogenesis of the other H-phenomena or only via accentuation of hyperinsulinism. In any case amylin is a new link the role of which in the pathogenesis of NIDDM and the syndrome of insulin resistance awaits evaluation. Due to its effect on gastric evacuation it participates also in the postprandial glycaemic control in particular in type I diabetes where it it begins to be used in therapy. Perhaps it will be possible to administer it in these patients along with insulin to improve diabetes compensation.
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PMID:[Amylin as an additional possible pathogenic factor in NIDDM and the insulin resistance syndrome]. 896 27

The effects of oral administration of tungstate to an animal model of non-insulin-dependent diabetes mellitus (NIDDM), the neonatally streptozotocin-induced diabetic rat was studied. Islet insulin content and beta-cell mass were lowered in these animals. Furthermore, the islets lost their ability to release insulin in response to an increase in glucose concentration. However, the hepatic glucose metabolism in these diabetic animals before the treatment was not significantly altered with regard to glycogen content, or glucokinase or glycogen phosphorylase activities compared with healthy animals. On the other hand, the activation state of glycogen synthase was higher although the total activity was unchanged. Moreover, a 20% increase in the concentrations of liver glucose 6-phosphate compared to their healthy siblings was observed. Oral administration of tungstate for 15 days normalized glycaemia in these diabetic animals (4.6 vs 7.8 mmol/l). Tungstate administration was also able to normalize beta-cell insulin secretion in response to 16.7 mmol/l glucose stimulus, reaching values similar to those observed in healthy animals. Concomitantly, a partial recovery in the insulin content and in preproinsulin mRNA levels was found in the islets of treated animals, which was associated with an increase in the number of beta-cells in the pancreas (1.73 vs 0.86%). The treatment did not change the liver parameters studied, except that it restored glucose 6-phosphate concentrations to healthy values. These data suggest that tungstate administration causes a normalization of glycaemia through the restoration of islet function.
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PMID:Effects of tungstate in neonatally streptozotocin-induced diabetic rats: mechanism leading to normalization of glycaemia. 904 73


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