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

The aim of our research was to uncover perturbations in in-utero fetal cerebral metabolism resulting from hyperglycemia and hyperketonemia, which occur during maternal diabetes. Therefore, we examined the effects of glucose overload and hyperketonemia on glucose metabolism in the diabetic fetal brain; more specifically, the effect of diabetes on the glucose flux via pyruvate dehydrogenase (PDH) and pyruvate carboxylase (PC) and subsequent metabolism in the fetal cerebral tricarboxylic acid (TCA) cycle were examined, as well as the effect of diabetes on energy fuel utilization in the neurons and glia. Diabetes was induced in pregnant rabbits, and towards term, [U-(13)C(6)]glucose was infused into maternal circulation, and [(13)C]glucose metabolites were subsequently studied in fetal brain extracts by (13)C MRS isotopomer analysis. Significantly elevated maternal and fetal plasma glucose levels (three- and up to fivefold, respectively) and fetal brain glucose levels (up to eightfold) accompanied by an increase of beta-hydroxybutyrate (beta-HBA) levels (approximately 20-fold) were found in the hyperketonemic diabetic animals, whereas fetal cerebral lactate levels were decreased. Alterations in the (13)C labeling patterns, mainly of glutamine, led us to suggest that the entry of beta-HBA-derived acetyl-CoA inhibits formation and entry of labeled glucose-derived acetyl-CoA into the TCA cycle, mainly in glia. Accumulation of glucose and the decrease in lactate levels in the fetal brain are most likely the result of an inhibitory effect of beta-HBA on glycolysis. In addition, loss of (13)C enrichment of TCA cycle intermediates and products, glutamate and glutamine, in the hyperketonemic diabetic fetal brain may be attributed to the effect of beta-HBA fuel utilization by the fetal brain.
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PMID:Effect of endogenous beta-hydroxybutyrate on brain glucose metabolism in fetuses of diabetic rabbits, studied by (13)C magnetic resonance spectroscopy. 1197 97

Summary. Many studies have shown that experimental type 1 diabetes causes morphological, functional, and metabolic alterations in the small intestine. The more frequent form of the disease, type 2 diabetes, however, has been less studied. Here the influence of diabetes on the functionality of the small intestine was studied in an experimental diabetes model, with a certain degree of residual insulin secretion, specifically in the n0-STZ model. - The diabetic rats in this model were found to have glycaemia levels higher than in the controls (8.82 +/- 0.27 and 6.18 +/- 0.18 mmol/L; p < 0.01), while their plasma insulin levels were lower than in the control rats (2.65 +/- 0.32 and 3.60 +/- 0.25 ng/ml; p < 0.05). Although there were no significant variations in body weight between the two groups, both the weight and the length of the intestine were significantly greater (p < 0.05) in the diabetic rats than in the controls. The sucrase and maltase activities were greater (p < 0.01) in the proximal intestine of the diabetic rats (94 +/- 8 and 234 +/- 12 mU/mg protein, respectively) than in the control rats (50 +/- 2 and 149 +/- 20 mU/mg protein, respectively). The 6-phosphofructo-1-kinase activity (mU/mg proteins) was less (p < 0.05) in the proximal and distal intestine of the diabetic rats (160 +/- 40 and 80 +/- 20, respectively) than in the controls (280 +/- 30 and 230 +/- 30, respectively). No significant differences were observed in the lactate dehydrogenase or active and total pyruvate dehydrogenase measured in the distal and proximal intestine of control and diabetic rats. In conclusion, our results show that experimental diabetes (n0-STZ model) similar to human type 2 diabetes produces certain morphological and enzymatic alterations which affect the digestion and absorption of carbohydrates and the intestinal metabolism of glucose. These alterations may contribute to producing the post-prandial hyperglycaemia which characterizes diabetes.
Exp Clin Endocrinol Diabetes 2002 May
PMID:Morphological and enzymatic changes of the small intestine in an n0-STZ diabetes rat model. 1201 71

In rat pancreatic islets chronically exposed to high glucose or high free fatty acid (FFA) levels, glucose-induced insulin release and mitochondrial glucose oxidation are impaired. These abnormalities are associated with high basal ATP levels but a decreased glucose-induced ATP production (Delta of increment over baseline 0.7 +/- 0.5 or 0.5 +/- 0.3 pmol/islet in islets exposed to glucose or FFA vs. 12.0 +/- 0.6 in control islets, n = 3; P < 0.01) and, as a consequence, with an altered ATP/ADP ratio. To investigate further the mechanism of the impaired ATP formation, we measured in rat pancreatic islets glucose-stimulated pyruvate dehydrogenase (PDH) activity, a key enzyme for pyruvate metabolism and for the subsequent glucose oxidation through the Krebs cycle, and also the uncoupling protein-2 (UCP-2) content by Western blot. In islets exposed to high glucose or FFA, glucose-stimulated PDH activity was impaired and UCP-2 was overexpressed. Because UCP-2 expression is modulated by a peroxisome proliferator- activated receptor (PPAR)-dependent pathway, we measured PPAR-gamma contents by Western blot and the effects of a PPAR-gamma antagonist. PPAR-gamma levels were overexpressed in islets cultured with high FFA levels but unaffected in islets exposed to high glucose. In islets exposed to high FFA concentration, a PPAR-gamma antagonist was able to prevent UCP-2 overexpression and to restore insulin secretion and the ATP/ADP ratio. These data indicate that in rat pancreatic islets chronically exposed to high glucose or FFA, glucose-induced impairment of insulin secretion is associated with (and might be due to) altered mitochondrial function, which results in impaired glucose oxidation, overexpression of the UCP-2 protein, and a consequent decrease of ATP production. This alteration in FFA cultured islets is mediated by the PPAR-gamma pathway.
Diabetes 2002 Sep
PMID:Role of ATP production and uncoupling protein-2 in the insulin secretory defect induced by chronic exposure to high glucose or free fatty acids and effects of peroxisome proliferator-activated receptor-gamma inhibition. 1219 68

Two classes of inositol phosphoglycans have been implicated as second messengers of insulin, one that activates pyruvate dehydrogenase and contains D-chiroinositol, and one that inhibits cyclic AMP-dependent protein kinase and contains myoinositol. We examined the effects of a 3-day fast on muscle contents of inositols in healthy humans. An oral glucose tolerance test was performed and a biopsy was obtained from the quadriceps femoris muscle after an overnight fast and after a 72-hour fast. The 72-hour fast significantly increased plasma glucose (1.5- to 2-fold) and insulin (2- to 4-fold) after glucose ingestion versus the values after the overnight fast, indicating the manifestation of peripheral insulin resistance. The 72-hour fast resulted in an approximately 20% decrease in the muscle content of D-chiroinositol (P < 0.02), but no change in the myoinositol content. These data demonstrate that fasting specifically decreases the muscle content of D-chiroinositol in human muscle and this may contribute to the finding that insulin-mediated activation of pyruvate dehydrogenase is attenuated after short-term starvation.
Int J Exp Diabetes Res
PMID:Fasting decreases the content of D-chiroinositol in human skeletal muscle. 1245 57

The effects of diabetes and exercise training on the activity of pyruvate dehydrogenase (PDH) complex in skeletal muscle were examined in rats. Male Sprague-Dawley rats were divided into four groups as follows: non-diabetic sedentary, non-diabetic trained, diabetic sedentary, and diabetic trained groups. Diabetic rats were prepared by a bolus injection of intravenous streptozotocin (50 mg/kg body weight). Exercise training was performed by having rats run on a treadmill at a speed of 25 m/min for 45 min/day, 6 days/wk for 4 wks. Exercise training decreased serum concentrations of glucose and non-esterified fatty acid in diabetic rats. GLUT4 content in skeletal muscle in sedentary rats was significantly decreased by diabetes; however, exercise training significantly increased the GLUT4 content in diabetic rats. The total and actual activities and the proportion of actual activity of the PDH complex were decreased in diabetic sedentary rats. Exercise training did not affect the total activity of the PDH complex in non-diabetic rats, whereas it increased the total activity in diabetic rats to the same level as that in non-diabetic rats. In diabetic rats, exercise training tended to increase the proportion of actual activity of the PDH complex from 2.7 +/- 0.4% to 4.7 +/- 0.8%, although the proportion of actual activity in non-diabetic rats was decreased by exercise training. The present study suggests that exercise training may improve glucose metabolism in the skeletal muscle of streptozotocin-induced diabetic rats probably through the mechanisms of increasing both GLUT4 content and the activity of the PDH complex.
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PMID:Exercise training increases the activity of pyruvate dehydrogenase complex in skeletal muscle of diabetic rats. 1250 73

Altered pyruvate dehydrogenase (PDH) functioning occurs in primary PDH deficiencies and in diabetes, starvation, sepsis, and possibly Alzheimer's disease. Currently, the activity of the enzyme complex is difficult to measure in a rapid high-throughput format. Here we describe the use of a monoclonal antibody raised against the E2 subunit to immunocapture the intact PDH complex still active when bound to 96-well plates. Enzyme turnover was measured by following NADH production spectrophotometrically or by a fluorescence assay on mitochondrial protein preparations in the range of 0.4 to 5.0 micro g per well. Activity is sensitive to known PDH inhibitors and remains regulated by phosphorylation and dephosphorylation after immunopurification because of the presence of bound PDH kinase(s) and phosphatase(s). It is shown that the immunocapture assay can be used to detect PDH deficiency in cell extracts of cultured fibroblasts from patients, making it useful in patient screens, as well as in the high-throughput format for discovery of new modulators of PDH functioning.
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PMID:Immunocapture and microplate-based activity measurement of mammalian pyruvate dehydrogenase complex. 1263 10

Intrauterine growth retardation (IUGR) has been linked to the development of type 2 diabetes in later life. We have developed a model of uteroplacental insufficiency, a common cause of intrauterine growth retardation, in the rat. Early in life, the animals are insulin resistant and by 6 mo of age they develop diabetes. Glycogen content and insulin-stimulated 2-deoxyglucose uptake were significantly decreased in muscle from IUGR rats. IUGR muscle mitochondria exhibited significantly decreased rates of state 3 oxygen consumption with pyruvate, glutamate, alpha-ketoglutarate, and succinate. Decreased pyruvate oxidation in IUGR mitochondria was associated with decreased ATP production, decreased pyruvate dehydrogenase activity, and increased expression of pyruvate dehydrogenase kinase 4. Such a defect in IUGR mitochondria leads to a chronic reduction in the supply of ATP available from oxidative phosphorylation. Impaired ATP synthesis in muscle compromises energy-dependent GLUT4 recruitment to the cell surface, glucose transport, and glycogen synthesis, which contribute to insulin resistance and hyperglycemia of type 2 diabetes.
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PMID:Impaired oxidative phosphorylation in skeletal muscle of intrauterine growth-retarded rats. 1263 57

The number of subjects with Type 2 diabetes (DM2) has risen significantly in the last ten years. Obtaining sufficient human tissue to study this disease process as well as many other diseases is generally difficult. T lymphocytes offer a unique opportunity for these studies. Although resting human peripheral T-lymphocytes are devoid of insulin receptors, these receptors emerge upon activation of cells by specific antigens or mitogens. Concomitant with the insulin receptors, two other growth factor receptors (IGF-1 and IL-2) also emerge on the T lymphocyte cell surface along with intracellular signal transduction mechanisms and insulin degrading enzyme (IDE). After binding to its receptor, insulin has been shown to exert its classical effects on carbohydrate metabolism in the stimulated T- cell; thereby, validating the use of activated T-lymphocytes for studying the pathogenesis of metabolic and immune disorders and the mechanism(s) by which insulin exerts its effects. In activated T-lymphocytes, insulin stimulates glucose uptake, glucose oxidation, pyruvate flux and pyruvate dehydrogenase activity, amino acid transport, lipid metabolism and protein synthesis. Through its ability to enhance nutrient uptake and raise the levels of intermediary cellular metabolism, insulin is believed to maintain the allo-activated state of lymphocytes, enhance T-Lymphocyte responsiveness, and support or possibly promote the actions of immuno-derived regulatory growth and differential factors. Since insulin enhances energy requirements and protein synthesis necessary for appropriate T-cell functions, defects in insulin action may lead to inappropriate immunoresponses in various metabolic states such as in diabetes. Studies from our lab have found insulin binding, processing, and responsiveness in phytohemagglutinin(PHA)-activated T-cells are reflective of the donor's glycemic status and ambient insulin levels in subjects with Type 1 and Type 2 diabetes (DM2) and other insulin resistant states. Our studies show that patients with diabetic ketoacidosis and hyperglycemia have increased proinflammatory cytokines and activated CD4+ and CD8+ T lymphocytes. The diabetic state, where effective insulin concentrations are low and both glucose and free fatty acids are high, provides an environment of oxidative stress and activation of the inflammatory pathways. The mechanisms underlying insulin action, in general, or in the CD4+ and CD8+ T-lymphocytes, in particular, have not been clearly elucidated. Due to the accessibility of obtaining these cells from patients, activated T-lymphocytes offer the potential of studying diabetes and other disease in human subjects.
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PMID:Activated T lymphocytes in Type 2 diabetes: implications from in vitro studies. 1286 64

In Type 2 diabetes, glucose homeostasis is impaired due to either a decrease in insulin secretion or insulin action. In this symposium, molecular targets that could have an impact on either or both of these defects were discussed and data related to specific compounds were presented. Protein tyrosine phosphatase 1B inhibitors that relieve the negative control on insulin action and are active in cell assays, dipeptidyl peptidase IV inhibitors that raise postprandial glucagon-like peptide 1 levels in animals and humans, and pyruvate dehydrogenase kinase inhibitors that increase the levels of pyruvate dehydrogenase, which in turn improve insulin sensitivity, were all discussed. Roche presented for the first time their novel glucokinase activators and discussed both the in vitro and in vivo activity profiles of representative glucokinase activators as potential therapy for Type 2 diabetes. Second generation retinoid X receptor modulators that retain the desirable effects of full agonists, while devoid of their negative attributes, such as triglyceride accumulation, were discussed. Also, clinical efficacy results of synthetic exendin-4, Exenatide trade mark, a glucagon-like peptide 1 analogue, were presented. In the area of obesity, agonists of several central (melanocortin type 4, serotonin subtype 2C and cannabinoid receptor 1) receptors and one peripheral G-protein-coupled receptor, cholecystokinin receptor-A, all of which lead to reduced food intake in animals, were discussed.
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PMID:Metabolic diseases drug discovery world summit. July 28-29, 2003, San Diego, CA, USA. 1451 91

Blood platelets take up glucose through insulin-independent GLUT-3 transporter. It is, however, unclear how diabetes affects further steps of glucose and glucose-derived acetyl-coenzyme A (CoA) metabolism in platelets. There is no evidence to explain whether these changes are linked to the disease-induced disturbances in platelet function. We found that activities of some key enzymes of glucose and acetyl-CoA metabolism in platelets were elevated in diabetes. Activities of hexokinase, pyruvate dehydrogenase and ATP-citrate lyase in diabetic platelets were found to be increased by 53, 56 and 88%, respectively. Accordingly, diabetes brought about 86% increase of platelet acetyl-CoA and activation of malonyl dialdehyde synthesis as well as spontaneous and thrombin-induced platelet aggregation by about 56, 50 and 15%, respectively. Significant correlations have been observed between some parameters of acetyl-CoA metabolism, platelet function and serum fructosamine in diabetic patients but not in healthy individuals. Our findings indicate that increased platelet activity in diabetic subjects may, at least in part, result from chronic hyperglycaemia-induced changes in acetyl-CoA metabolism, yielding an increase in its concentration in platelets.
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PMID:Platelet function and acetyl-coenzyme A metabolism in type 1 diabetes mellitus. 1459 62


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