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

Non-insulin-dependent diabetes mellitus is frequently associated with premature atherosclerosis. Abnormalities in lipid and lipoprotein metabolism contribute to the increased risk of coronary heart disease. One of the most common lipid abnormalities in non-insulin-dependent diabetes mellitus is hypertriglyceridaemia. In the present paper, the authors review the metabolism of triglyceride-rich lipoproteins, with special emphasis on the post-prandial state. Several studies have demonstrated that levels of atherogenic post-prandial lipoproteins are increased in patients with non-insulin-dependent diabetes mellitus. An increased supply of glucose and free fatty acids contributes to overproduction of very low-density lipoproteins, increasing the burden of triglyceride-rich lipoproteins on the common lipolytic pathway at the level of lipoprotein lipase. Low lipoprotein lipase activity and increased amounts of lipolysis-inhibiting free fatty acids further impair lipolysis of post-prandial lipoproteins. The clearance of atherogenic remnants is also delayed in non-insulin-dependent diabetes mellitus. There is evidence that a relative hepatic removal defect exists, secondary to impaired remnant-receptor interaction and increased competition with very low density lipoprotein remnants. Correction of the increased post-prandial lipaemia in non-insulin-dependent diabetes mellitus is advisable, as it may contribute to attenuation of the risk on premature atherosclerosis. When dietary measures and hypoglycaemic agents have failed to achieve acceptable lipid levels, lipid-lowering drugs should be advised. Fibric acids and hydroxymethyl-glutaryl coenzyme A (HMG CoA) reductase inhibitors are the drugs of choice.
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PMID:Triglyceride-rich lipoproteins in non-insulin-dependent diabetes mellitus: post-prandial metabolism and relation to premature atherosclerosis. 890 18

N-Myristoyltransferase (NMT) catalyses the transfer of myristate from myristoyl-CoA to the NH2-terminal glycine residue of several proteins and are important in signal transduction. STZ-induced diabetes (an animal model for insulin-dependent diabetes mellitus, IDDM) resulted in a 2-fold increase in rat liver NMT activity as compared with control animals. In obese Zucker (fa/fa) rats (an animal model for non-insulin dependent diabetes mellitus, NIDDM) there was a approximately 4.7-fold lower liver particulate NMT activity as compared with the control lean rat livers. Administration of sodium orthovanadate to the diabetic rats normalised liver NMT activity. These results would indicate that the rat liver particulate N-myristoyltransferase activity appears to be inversely proportional to the level of plasma insulin, implicating insulin in the control of N-myristoylation.
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PMID:In vivo modulation of N-myristoyltransferase activity by orthovanadate. 892 31

The mechanism of inhibition of gluconeogenesis by phenylalkanoic acids was studied in vitro and in vivo. In vitro production of 14CO2 from labeled glucose or palmitate was not inhibited at 4 mM, a concentration of phenylacetic acid that inhibited gluconeogenesis from lactate/pyruvate. In vitro studies with isolated mitochondria showed that the CoA ester of phenylacetic acid was formed. The parent phenylalkanoic acid had no effect on purified pyruvate carboxylase activity, but phenylacetyl CoA ester decreased pyruvate carboxylation in a concentration-dependent manner. Phenylacetic acid inhibited gluconeogenesis in isolated rat liver cells from 10 mM lactate/1 mM pyruvate (decreased 39%, P < 0.05), but not 10 mM L-glutamine or [14C]aspartate, showing that the inhibition of gluconeogenesis occurred at the level of pyruvate carboxylase. A 20 mg bolus with infusion of 1 mg/min of phenylpropionic acid decreased blood glucose levels of normal [110 +/- 12 to 66 +/- 11 mg/dL, N = 7, P < 0.05 (unpaired Student's t-test vs control)] and streptozocin diabetic rats [295 +/- 14 to 225 +/- 12 mg/dL, N = 7, P < 0.01 (paired t-test vs basal)]. Hepatic glucose production in control and diabetic rats was suppressed under conditions where liver glycogen was depleted, indicating that gluconeogenesis had been inhibited in vivo. The results suggest the possibility that the inappropriate overproduction of glucose can be controlled by inhibitors of pyruvate carboxylase. This class of inhibitors may be useful in the treatment of non-insulin-dependent diabetes mellitus.
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PMID:In vitro and in vivo suppression of gluconeogenesis by inhibition of pyruvate carboxylase. 896 65

We tested the hypothesis that diabetes impairs myocardial glucose uptake and pyruvate oxidation under normal conditions and during a dobutamine-induced increase in work. We also tested the hypothesis that an increase in work would result in a decrease in the levels of malonyl CoA, a potent inhibitor of carnitine palmitoyltransferase I (CPT I). Streptozotocin-diabetic micropigs were compared with a nondiabetic control group (n = 8 per group). Triglyceride emulsion, glucose, and somatostatin were infused into the nondiabetic group to create an acute diabetic-like state. In accord with our hypothesis, malonyl CoA decreased significantly with dobutamine in both groups, providing a possible mechanism for increased fatty acid oxidation through relieved inhibition on CPT I. In the absence of dobutamine, glucose uptake and tracer-measured lactate uptake were decreased by 57 and 80%, respectively, in the diabetic group. Dobutamine infusion resulted in similar increases in cardiac contractility, oxygen consumption, and glucose uptake in both groups despite reductions of 50-65% in GLUT-4 and GLUT-1 protein in the diabetic group. Diabetic animals possessed a defect in myocardial pyruvate oxidation, as reflected in increased lactate production, and depressed lactate uptake and pyruvate dehydrogenase activity under control and dobutamine conditions. In conclusion, the major derangement in carbohydrate metabolism in diabetic myocardium was not in glycolysis but, rather, in pyruvate oxidation.
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PMID:Impaired pyruvate oxidation but normal glucose uptake in diabetic pig heart during dobutamine-induced work. 899 89

The onset of NIDDM in obese Zucker diabetic fatty (fa/fa) rats is preceded by a striking increase in the plasma levels of free fatty acids (FFAs) and by a sixfold rise in triglyceride content in the pancreatic islets. The latter finding provides clear evidence of elevated tissue levels of long-chain fatty acyl CoA, which can impair beta-cell cell function. To determine if the triglyceride accumulation is entirely the passive consequence of high plasma FFA levels or if prediabetic islets have an increased lipogenic capacity that might predispose to NIDDM, the metabolism of long-chain fatty acids was compared in islets of obese prediabetic and nonprediabetic Zucker diabetic fatty (ZDF) rats and of lean Wistar and lean ZDF rats. When cultured in 1 or 2 mmol/l FFA, islets of both female and male obese rats accumulated, respectively, 7 and 15 times as much triglyceride as islets from lean rats exposed to identical FFA concentrations. The esterification of [14C]palmitate and 9,10-[3H]palmitate was increased in islets of male obese rats and could not be accounted for by defective oxidation of 9,10-[3H]-palmitate. Glycerol-3-PO4 acyl-transferase (GPAT) activity was 12 times that of controls. The mRNA of GPAT was increased in islets of obese rats. We conclude that, in the presence of comparable elevations in FFA concentrations, the islets of obese prediabetic rats have a higher lipogenic capacity than controls. This could be a factor in their high risk of diabetes.
Diabetes 1997 Mar
PMID:Increased lipogenic capacity of the islets of obese rats: a role in the pathogenesis of NIDDM. 903 96

The effects of diabetes on myocardial metabolism are complex in that they are tied to the systemic metabolic abnormalities of the disease (hyperglycemia and elevated levels of free fatty acid and ketone bodies), and changes in cardiomyocyte phenotype (e.g., down-regulation of glucose transporters and PDH activity). The cardiac adaptations appear to be driven by the severity of the systemic abnormalities of the disease. The diabetes-induced changes in the plasma milieu and cardiac phenotype both cause impaired glycolysis, pyruvate oxidation, and lactate uptake, and a greater dependency on fatty acids as a source of acetyl CoA. Studies in isolated hearts suggest that therapies aimed at decreasing fatty acid oxidation, or directly stimulating pyruvate oxidation would be of benefit to the diabetic heart during and following myocardial ischemia.
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PMID:Regulation of energy substrate metabolism in the diabetic heart. 921 69

The knowledge of the mechanism whereby glucose and other fuel stimuli promote the release of insulin by the pancreatic beta cell remains fragmentary. The closure of metabolically sensitive K+ channels and a rise in cytosolic free Ca2+ are key features of beta-cell metabolic signal transduction. However, these two signalling events do not account for the dose dependence of glucose-induced insulin secretion. In fact, recent evidence indicates that there are KATP channel and Ca2+ independent pathway(s) of beta-cell activation which remain to be defined. In this review, we have limited our attention to the recent developments in our understanding of the mode of action of nutrient secretagogues. A particular emphasis is placed in summarising the evidence in support of two new concepts: 1) oscillations in the glycolytic pathway and beta-cell metabolism contribute to the oscillatory nature of beta-cell ionic events and insulin secretion; 2) malonyl-CoA and long chain acyl-CoA esters may act as metabolic coupling factors in beta-cell signalling. Finally, we propose that the altered expression of genes encoding enzymes in the pathway of malonyl-CoA formation and fatty acid oxidation contributes to the beta-cell insensitivity to glucose in some patients with non-insulin-dependent diabetes mellitus.
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PMID:Signal transduction mechanisms in nutrient-induced insulin secretion. 924 99

To elucidate cellular mechanisms of insulin resistance induced by excess dietary fat, we studied conscious chronically high-fat-fed (HFF) and control chow diet-fed rats during euglycemic-hyperinsulinemic (560 pmol/l plasma insulin) clamps. Compared with chow diet feeding, fat feeding significantly impaired insulin action (reduced whole body glucose disposal rate, reduced skeletal muscle glucose metabolism, and decreased insulin suppressibility of hepatic glucose production [HGP]). In HFF rats, hyperinsulinemia significantly suppressed circulating free fatty acids but not the intracellular availability of fatty acid in skeletal muscle (long chain fatty acyl-CoA esters remained at 230% above control levels). In HFF animals, acute blockade of beta-oxidation using etomoxir increased insulin-stimulated muscle glucose uptake, via a selective increase in the component directed to glycolysis, but did not reverse the defect in net glycogen synthesis or glycogen synthase. In clamp HFF animals, etomoxir did not significantly alter the reduced ability of insulin to suppress HGP, but induced substantial depletion of hepatic glycogen content. This implied that gluconeogenesis was reduced by inhibition of hepatic fatty acid oxidation and that an alternative mechanism was involved in the elevated HGP in HFF rats. Evidence was then obtained suggesting that this involves a reduction in hepatic glucokinase (GK) activity and an inability of insulin to acutely lower glucose-6-phosphatase (G-6-Pase) activity. Overall, a 76% increase in the activity ratio G-6-Pase/GK was observed, which would favor net hepatic glucose release and elevated HGP in HFF rats. Thus in the insulin-resistant HFF rat 1) acute hyperinsulinemia fails to quench elevated muscle and liver lipid availability, 2) elevated lipid oxidation opposes insulin stimulation of muscle glucose oxidation (perhaps via the glucose-fatty acid cycle) and suppression of hepatic gluconeogenesis, and 3) mechanisms of impaired insulin-stimulated glucose storage and HGP suppressibility are not dependent on concomitant lipid oxidation; in the case of HGP we provide evidence for pivotal involvement of G-6-Pase and GK in the regulation of HGP by insulin, independent of the glucose source.
Diabetes 1997 Nov
PMID:Mechanisms of liver and muscle insulin resistance induced by chronic high-fat feeding. 935 24

The discovery of the clinically important glycohemoglobin adducts and their relation to diabetes mellitus have greatly stimulated the study of other minor post-translational modifications of hemoglobin. Chromatographic and electrophoretic procedures have played an important role in these studies. Today several hemoglobin adducts are known and the formation of adducts with glucose, phosphorylated carbohydrates, urea/cyanate, aspirin, vitamins, acetaldehyde, penicillin and acetyl CoA have been described. Furthermore, new adducts, such as those observed using hemoglobin as a biochemical marker monitoring environmental, occupational and lifestyle exposures to reactive toxic chemicals are constantly being reported. This review deals with chromatographic and electrophoretic separation methods available for the study of non-enzymatic post-translational modifications of hemoglobin. Suitability, perspectives and biomedical applications are discussed.
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PMID:Chromatographic and electrophoretic methods for modified hemoglobins. 939 79

Chronic high-fat feeding in rats induces profound whole-body insulin resistance, mainly due to effects in oxidative skeletal muscle. The mechanisms of this reaction remain unclear, but local lipid availability has been implicated. The aim of this study was to examine the influence of three short-term physiological manipulations intended to lower muscle lipid availability on insulin sensitivity in high-fat-fed rats. Adult male Wistar rats fed a high-fat diet for 3 weeks were divided into four groups the day before the study: one group was fed the normal daily high-fat meal (FM); another group was fed an isocaloric low-fat high-glucose meal (GM); a third group was fasted overnight (NM); and a fourth group underwent a single bout of exercise (2-h swim), then were fed the normal high-fat meal (EX). In vivo insulin action was assessed using the hyperinsulinemic glucose clamp (plasma insulin 745 pmol/l, glucose 7.2 mmol/l). Prior exercise, a single low-fat meal, or fasting all significantly increased insulin-stimulated glucose utilization, estimated at either the whole-body level (P < 0.01 vs. FM) or in red quadriceps muscle (EX 18.2, GM 28.1, and NM 19.3 vs. FM 12.6 +/- 1.1 micromol x 100 g(-1) x min(-1); P < 0.05), as well as increased insulin suppressibility of muscle total long-chain fatty acyl-CoA (LC-CoA), the metabolically available form of fatty acid (EX 24.0, GM 15.5, and NM 30.6 vs. FM 45.4 nmol/g; P < 0.05). There was a strong inverse correlation between glucose uptake and LC-CoA in red quadriceps during the clamp (r = -0.7, P = 0.001). Muscle triglyceride was significantly reduced by short-term dietary lipid withdrawal (GM -22 and NM -24% vs. FM; P < 0.01), but not prior exercise. We concluded that muscle insulin resistance induced by high-fat feeding is readily ameliorated by three independent, short-term physiological manipulations. The data suggest that insulin resistance is an important factor in the elevated muscle lipid availability induced by chronic high-fat feeding.
Diabetes 1997 Dec
PMID:Diet-induced muscle insulin resistance in rats is ameliorated by acute dietary lipid withdrawal or a single bout of exercise: parallel relationship between insulin stimulation of glucose uptake and suppression of long-chain fatty acyl-CoA. 939 90


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