Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Non-insulin-dependent diabetes mellitus (NIDDM) results from an imbalance between insulin sensitivity and insulin secretion. Both longitudinal and cross-sectional studies have demonstrated that the earliest detectable abnormality in NIDDM is an impairment in the body's ability to respond to insulin. Because the pancreas is able to appropriately augment its secretion of insulin to offset the insulin resistance, glucose tolerance remains normal. With time, however, the beta-cell fails to maintain its high rate of insulin secretion and the relative insulinopenia (i.e., relative to the degree of insulin resistance) leads to the development of impaired glucose tolerance and eventually overt diabetes mellitus. The cause of pancreatic "exhaustion" remains unknown but may be related to the effect of glucose toxicity in a genetically predisposed beta-cell. Information concerning the loss of first-phase insulin secretion, altered pulsatility of insulin release, and enhanced proinsulin-insulin secretory ratio is discussed as it pertains to altered beta-cell function in NIDDM. Insulin resistance in NIDDM involves both hepatic and peripheral, muscle, tissues. In the postabsorptive state hepatic glucose output is normal or increased, despite the presence of fasting hyperinsulinemia, whereas the efficiency of tissue glucose uptake is reduced. In response to both endogenously secreted or exogenously administered insulin, hepatic glucose production fails to suppress normally and muscle glucose uptake is diminished. The accelerated rate of hepatic glucose output is due entirely to augmented gluconeogenesis. In muscle many cellular defects in insulin action have been described including impaired insulin-receptor tyrosine kinase activity, diminished glucose transport, and reduced glycogen synthase and pyruvate dehydrogenase. The abnormalities account for disturbances in the two major intracellular pathways of glucose disposal, glycogen synthesis, and glucose oxidation. In the earliest stages of NIDDM, the major defect involves the inability of insulin to promote glucose uptake and storage as glycogen. Other potential mechanisms that have been put forward to explain the insulin resistance, include increased lipid oxidation, altered skeletal muscle capillary density/fiber type/blood flow, impaired insulin transport across the vascular endothelium, increased amylin, calcitonin gene-related peptide levels, and glucose toxicity.
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PMID:Pathogenesis of NIDDM. A balanced overview. 153 77

To investigate the effects of carnitine on insulin sensitivity in non-insulin-dependent diabetes, insulin-mediated glucose disposal was measured in nine diabetic patients (age 54 +/- 3 years, BMI 27 +/- 1 kg/mq) during a primed (3 mmol) constant (1.7 mumol/min) intravenous infusion of carnitine. In control experiments, the same patients received saline instead of carnitine. Plasma glucose concentration was maintained constant at the level of 100 mg/dl during both studies while plasma insulin was raised to a plateau of 60 microU/ml. Despite similar insulin levels, whole-body glucose utilization was higher with carnitine (4.05 +/- 0.37 mg/kg/min) than saline infusion (3.52 +/- 0.36). Blood lactate concentrations were similar in the basal state and decreased significantly during carnitine infusion (P less than 0.05-0.005), whereas it remained substantially unchanged during saline infusion. Plasma FFA decreased to a similar level (0.1 mmol/l) in both studies. We conclude that an acute carnitine administration is able to improve insulin sensitivity in NIDDM patients. The lactate data suggest that this effect may at least in part be mediated by carnitine activation of pyruvate dehydrogenase.
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PMID:Carnitine improves peripheral glucose disposal in non-insulin-dependent diabetic patients. 177 12

The therapeutic potential of sodium dichloroacetate (DCA) formerly called vitamin B 15, has already been under investigation for the past few years. The predominant property of DCA underlying its therapeutic action is activation of pyruvate dehydrogenase. The potential therapeutic use of DCA in the treatment of lactic acidosis and type II diabetes mellitus related directly to its stimulatory effect on this enzyme. Additional favourable effects of DCA on cardiac performance in states such as ischaemia, where glucose becomes a major energy-yielding substrate, have also been demonstrated. Treatment of lipid disorders might become further indications for the implementation of this substance. DCA inhibits hydroxy-methyl-glutaryl CoA reductase, thus lowering cholesterol and triglyceride levels. Earlier suggestions that DCA produced a major degree of acute toxicity were not confirmed in recent studies using DCA of established purity and homogeneity. These findings and recent evidence suggesting a potentially important role of DCA in the treatment of lactic acidosis are the reason and basis for a review of the established actions of this substance.
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PMID:[Sodium dichloroacetate--a substance with manifold therapeutic potential]. 218 Feb 10

Myoblasts from human skeletal muscle were isolated from needle biopsy samples of vastus lateralis and fused to differentiated multinucleated myotubes. Specific high-affinity insulin and insulin-like growth factor I (IGF-I) binding, glucose transporter proteins GLUT1 and GLUT4, glycogen synthase and pyruvate dehydrogenase proteins, and their specific mRNAs were identified in fused myotubes. Insulin and IGF-I stimulated 2-deoxyglucose uptake twofold with half-maximal stimulation by insulin at 0.98 +/- 0.12 nmol/l and maximal stimulation at 17.5 nmol/l. Acute insulin treatment (33 nmol/l) doubled glycogen synthase activity and glucose incorporation into glycogen while increasing pyruvate dehydrogenase approximately 30%. In cells cultured from NIDDM subjects, both basal (6.9 +/- 1.0 vs. 13.0 +/- 1.7 pmol.mg protein-1.min-1) and acute insulin-stimulated transport (13.5 +/- 2.0 vs. 22.4 +/- 1.3 pmol.mg protein-1.min-1) were significantly reduced compared with nondiabetic control subjects (both P < or = 0.005). GLUT1 protein content of total membranes from NIDDM subjects was decreased compared with control subjects, while GLUT4 levels were similar between groups. A significant correlation (r = 0.65, P < or = 0.05) was present when maximal rates of insulin-stimulated glucose transport in cell culture from subjects were compared with their corresponding in vivo glucose disposal determined by hyperinsulinemic glucose clamp. In summary, differentiated human skeletal muscle cultures exhibit biochemical and molecular features of insulin-stimulated glucose transport and intracellular enzyme activity comparable with the in vivo situation. Defective insulin-stimulated glucose transport persists in muscle cultures from NIDDM subjects and resembles the reduced insulin-mediated glucose uptake present in vivo. We conclude that this technique provides a relevant cellular model to study insulin action and glucose metabolism in normal subjects and determine the mechanisms of insulin resistance in NIDDM.
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PMID:Insulin action and glucose metabolism in nondiabetic control and NIDDM subjects. Comparison using human skeletal muscle cell cultures. 762

We previously demonstrated in the rat that long term exposure to fatty acids inhibits B-cell function in vivo and in vitro. To further assess the clinical significance of these findings, we tested in human islets the effects of fatty acids on glucose-induced insulin release and biosynthesis and on pyruvate dehydrogenase (PDH) activity. Human islets were obtained from the beta-Cell Transplant Unit (Brussels, Belgium). Exposure to 0.125 mmol/L palmitate or oleate for 48 h during tissue culture (RPMI-1640 and 5.5 mmol/L glucose) inhibited the postculture insulin response to 27 mmol/L glucose by 40% and 42% (P < 0.01 for difference). Inhibition was partly prevented by coculture with 1 mumol/L etomoxir, a carnitine-palmitoyl-transferase-I inhibitor (P < 0.05 for effect of etomoxir). Inhibitory effects on glucose-induced insulin secretion by previous palmitate were additive to the inhibitory effects exerted by previous high glucose (11 and 27 mmol/L). Palmitate-induced inhibition of insulin secretion was evident after exposure to 25 mumol/L added fatty acid. The insulin content of islets exposed to fatty acids was significantly reduced, and glucose-induced proinsulin biosynthesis was inhibited by 59% after palmitate addition and by 51% after oleate exposure (P < 0.01). These effects were partly prevented by etomoxir (P < 0.05). The activity of PDH in mitochondrial extracts of islets preexposed for 48 h to palmitate was decreased by 35% (P < 0.05) vs. that in control islets, whereas the activity of PDH kinase (which inactivates PDH) was significantly increased in the same preparations (P < 0.05). The effects of ketones were tested by 48-h exposure to beta-hydroxybutyrate (beta-D-OHB). Ten millimoles of D-beta-OHB per L inhibited the subsequently tested insulin response to 27 mmol/L glucose by 56% (P < 0.001). Half-maximal inhibitory effects of D-beta-OHB on insulin secretion and insulin content were seen at concentrations between 0.5-2.5 mmol/L. Inhibition by D-beta-OHB was partially reversed by etomoxir, whereas exposure to D-beta-OHB failed to affect PDH and PDH kinase activities. We conclude that fatty acids as well as ketone bodies diminish B-cell responsiveness to glucose in human islets by way of a glucose-fatty acid cycle. Increased plasma concentrations of fatty acids and ketones are likely to be important factors behind the negative influences on B-cell function exerted by a diabetic state in both type 1 and type 2 diabetes.
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PMID:Long term exposure to fatty acids and ketones inhibits B-cell functions in human pancreatic islets of Langerhans. 774 4

Adrenalectomy (ADX) lowers circulating glucose levels in animal models of non-insulin dependent diabetes (NIDDM) and obesity. To investigate the role of hepatic glucose production (HGP) and tissue glucose oxidation in the improvement in glucose tolerance, hepatocyte gluconeogenesis and the activity of pyruvate dehydrogenase (PDH) were examined in different tissues of gold thioglucose (GTG) obese mice 2 weeks after ADX or sham ADX. GTG-obese mice which had undergone ADX weighed significantly less than their adrenal intact counterparts (GTG ADX: 37.5 +/- 0.7 g; GTG: 44.1 +/- 0.4; p < 0.05), and demonstrated lower serum glucose (GTG ADX: 22.5 +/- 1.6 mmol/L; GTG: 29.4 +/- 1.9 mmol/L; p < 0.05) and serum insulin levels (GTG ADX: 76 +/- 10 microU/mL; GTG: 470 +/- 63 microU/mL; p < 0.05). Lactate conversion to glucose by hepatocytes isolated from ADX GTG mice was significantly reduced compared with that of hepatocytes from GTG mice (GTG ADX: 125 +/- 10 nmol glucose/10(6) cells; GTG: 403 +/- 65 nmol glucose/10(6) cells; p < 0.05). ADX also significantly reduced both the glycogen (GTG ADX: 165 +/- 27 mumol/liver; GTG: 614 +/- 60 mumol/liver; p < 0.05) and fatty acid content (GTG ADX: 101 +/- 9 mg fatty acid/g liver; GTG: 404 +/- 40 mg fatty acid/g liver; p < 0.05) of the liver of GTG-obese mice. ADX of GTG-obese mice reduced PDH activity by varying degrees in all tissues, except quadriceps muscle. These observations are consistent with an ADX induced decrease in hepatic lipid stores removing fatty acid-induced increases in gluconeogenesis and increased peripheral availability of fatty acids inhibiting PDH activity via the glucose/fatty acid cycle. It is also evident that the improvement in glucose tolerance which accompanies ADX of GTG-obese mice is not due to increased PDH activity resulting in enhanced peripheral glucose oxidation. Instead, it is more likely that reduced blood glucose levels after ADX of GTG-obese mice are the result of decreased gluconeogenesis in the liver.
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PMID:Hepatic gluconeogenesis and the activity of PDH in individual tissues of GTG-obese mice following adrenalectomy. 882 61

The sand rat (Psammomys obesus) is an animal model for non-insulin dependent diabetes mellitus, which is induced by a regular chow diet. The total activity of liver pyruvate dehydrogenase complex in the sand rats under normoglycemic and normoinsulinemic conditions was one half as high as that in the albino rats, but the activity of liver 3-hydroxyacyl-CoA dehydrogenase was more than 4 times greater in the former than in the latter, suggesting a low capacity for glucose oxidation and a high capacity for fatty acid oxidation in the sand rats. These metabolic conditions may be related to the predisposition of the animals towards diabetes. Diet-induced diabetes in the sand rats resulted in decreasing the active form of liver pyruvate dehydrogenase complex and in increasing the activity of liver 3-hydroxyacyl-CoA dehydrogenase, suggesting that the diabetic conditions further suppress glucose oxidation and promote fatty acid oxidation.
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PMID:Activities of liver pyruvate dehydrogenase complex and 3-hydroxyacyl-CoA dehydrogenase in sand rat (Psammomys obesus). 899 32

The mechanisms responsible for the competition between glucose and fatty acids as oxidative fuels are not yet completely understood in humans. Maintenance of plasma fatty acid concentrations by means of lipid and heparin infusion during hyperinsulinemic, euglycemic clamps in humans first suppresses glucose oxidation and only later decreases nonoxidative glucose disposal; muscle pyruvate dehydrogenase activity is inhibited when plasma fatty acid concentrations are maintained during hyperinsulinemic, euglycemic clamps. The maintenance of plasma fatty acid concentrations impairs insulin-stimulated muscle glucose uptake only if fatty acid uptake by skeletal muscles is increased. The role of hyperglycemia in glucose-fatty acid competition has recently been emphasized. Fatty acid utilization by muscle is impaired in patients with type 2 diabetes mellitus during fasting hyperglycemia: both lipid oxidation and uptake of plasma fatty acids by skeletal muscle are impaired during postabsorptive conditions. Hyperglycemia indirectly activates pyruvate dehydrogenase, the rate-limiting enzyme for glucose oxidation. The ability of increased glucose availability to stimulate glucose oxidation and reduce lipid oxidation by skeletal muscle can be considered a corollary of the Randle glucose-fatty acid cycle. It can be concluded that within a reasonable range of carbohydrate-to-fat ratios, the addition of fat to a meal does not decrease postprandial carbohydrate oxidation. Furthermore, high-fat meals do not promote fat oxidation leading to fat storage in adipose tissue.
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PMID:Effect of lipid oxidation on glucose utilization in humans. 949 64

To test whether gluconeogenesis is increased in non-insulin-dependent diabetic (NIDDM) patients we infused (post-absorptive state) healthy subjects and NIDDM patients with [6,6-2H2]glucose (150 min) and [3-13C]lactate (6 h). Liver glutamine was sampled with phenylacetate and its labelling pattern determined (mass spectrometry) after purification of the glutamine moiety of urinary phenylacetylglutamine. After correction for 13CO2 re-incorporation (control test with NaH13CO3 infusion) this pattern was used to calculate the dilution factor (F) in the hepatic oxaloacetate pool and fluxes through liver Krebs cycle. NIDDM patients had increased lactate turnover rates (16.18+/-0.92 vs 12.14+/-0.60 micromol x kg(-1) x min(-1), p < 0.01) and a moderate rise in glucose production (EGP) (15.39+/-0.87 vs 12.52+/-0.28 micromol x kg(-1) x min(-1) , p = 0.047). Uncorrected contributions of gluconeogenesis to EGP were 31+/-3 % (control subjects) and 17+/-2 % (NIDDM patients). F was comparable (1.34+/-0.02 and 1.39 0.09, respectively) and the corrected percent and absolute contributions of gluconeogenesis were not increased in NIDDM (25+/-3 % and 3.8+/-O.5 micromol x kg(1) x min[-1]) compared to control subjects (41+/-3 % and 5.1+/-0.4 micromol x kg(-1) x min(-1]). The calculated pyruvate carboxylase over pyruvate dehydrogenase activity ratio was comparable (12.1+/-2.6 vs 11.2+/-1.4). Lastly hepatic fatty oxidation, as estimated by the model, was not increased in NIDDM (1.8+/-0.4 vs 1.6+/-0.1 micromol x kg(-1) x min[-1]). In conclusion, in the patients studied we found no evidence of increased hepatic fatty oxidation, or, despite the increased lactate turnover rate, an increased gluconeogenesis.
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PMID:Non-invasive tracing of liver intermediary metabolism in normal subjects and in moderately hyperglycaemic NIDDM subjects. Evidence against increased gluconeogenesis and hepatic fatty acid oxidation in NIDDM. 949 56

Noninsulin-dependent diabetes mellitus (NIDDM), a major health care problem in the Western world, is a disease typified by a relative deficiency of insulin, leading to vast derangements in glucose and lipid homeostasis with disastrous vascular complications. Despite immense research efforts aimed at a clear understanding of the etiology of this complex disease, the molecular mechanisms causing the disorder still remain elusive. This article reviews extant data from recent publications implicating novel signal transduction pathways as important regulators of the insulin stimulus-secretion coupling in the pancreatic beta-cell. The significance of nitric oxide and serine/threonine protein phosphatases, and their inactivation by insulin secretagogues, glucose metabolites, ATP, GTP, glutamate, and inositol hexaphosphate in this arena is scrutinized. Additionally, also presented is the growing concept that an important signal for insulin secretion may reside in the inextricable interplay between glucose and lipid metabolism, specifically the generation of malonyl-CoA, which inhibits carnitine palmitoyltransferase 1 with the attendant accumulation of long-chain acyl CoA esters. Moreover, attention is directed towards novel intracellular actions of hypoglycemic sulfonylureas in the beta-cell. Finally, the importance of "lipotoxicity" and aberrations in glucose uptake and metabolism in beta-cell dysfunction is given consideration. Future research efforts should aim at further characterization of effects of second messengers on protein phosphorylation elements in beta-cells. Additionally, long-term regulation by glucose and the diabetic state (e.g., fatty acids and ketones) on beta-cell protein phosphatases, pyruvate dehydrogenase, and carnitine palmitoyltransferase 1 needs to be explored in greater depth. Clearly, the detrimental impact of diabetic hyperlipidemia on beta-cell function has been a relatively neglected area, but futu re pharmacological approaches directed at preventing lipotoxicity may prove beneficial in the treatment of diabetes.
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PMID:Aspects of novel sites of regulation of the insulin stimulus-secretion coupling in normal and diabetic pancreatic islets. 979 25


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