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

Hyperinsulinemia accompanies obesity in human patients and experimental rodent models and exacerbates insulin resistance, but the causes of increased insulin secretion remain obscure. This review examines progress in defining biochemical and molecular beta-cell defects that have elucidated in the past 5 years. Some defects, such as decreased glucose transport, decreased mitochondrial FAD-linked glycerophosphate dehydrogenase activity, and altered anomeric specificity for glucose, become evident only after onset of non-insulin-dependent diabetes mellitus. Thus, these defects are unlikely to play a role in the pathogenesis of hyperinsulinemia in obesity. Other biochemical changes, including increased glucokinase and (or) hexokinase function, increased glucose cycling, and altered regulation of intracellular Ca2+ are present in obese nondiabetic animals and may therefore contribute to development of hyperinsulinemia. Few developmental studies have been performed to correlate onset of defects with environmentally and genetically mediated control mechanisms of beta-cell function. However, the availability of new molecular biology techniques should facilitate identification of factors causing hyperinsulinemia in obesity.
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PMID:beta-cell stimulus - secretion coupling defects in rodent models of obesity. 874 32

The activities of FAD-linked glycerophosphate dehydrogenase (m-GDH), glutamate dehydrogenase (GlDH), glutamate-pyruvate transaminase (GPT) and glutamate-oxalacetate transaminase (GOT) were measured in purified populations of CD3+ lymphocytes from 55 control subjects, 62 type-2 diabetics and 50 non-diabetic relatives of the latter patients. The activity of m-GDH was measured by both a radioisotopic procedure and colourimetric technique. As judged from these measurements and relative to the paired value for GlDH, the incidence of abnormally low m-GDH activity was significantly higher in type-2 diabetics than in control subjects. Moreover, the paired ratio in reaction velocity between the colourimetric and radioisotopic assay of m-GDH was abnormally high in patients with low m-GDH activity. Low m-GDH activity often coincided with increased GPT activity in plasma or high GPT/GOT ratio in lymphocytes. No obvious clustering of these anomalies was found in relatives of diabetic patients. These findings suggest that an inherited or acquired genomic defect of m-GDH in lymphocytes, and possibly in pancreatic B-cells, may participate to the pathogenesis of non-insulin-dependent diabetes mellitus.
Diabetes Res Clin Pract 1996 Mar
PMID:FAD-glycerophosphate dehydrogenase activity in lymphocytes of type-2 diabetic patients and their relatives. 879 98

The activities of the mitochondrial FAD-linked glycerophosphate dehydrogenase (m-GDH), glutamate dehydrogenase, alpha-ketoglutarate dehydrogenase, glutamate-pyruvate transaminase (GPT) and glutamate-oxaloacetate transaminase were measured in islet and liver homogenates from fetal, neonatal, adult male, adult female, pregnant and lactating rats. Either parallel or dissociated ontogenic changes were observed in islet and liver homogenates. The activity of islet m-GDH was slightly, albeit not significantly, lower in neonates than in adult rats, comparable in male and female adult animals, unaffected by pregnancy, and increased during lactation. It was much higher in fetal or adult islets cultured for 7 days than in freshly isolated islets from adult rats. In cultured islets from adult rats, the increase in m-GDH activity coincided with a dramatic decrease of GPT activity, a situation the mirror image of that found in several animal models of non-insulin-dependent diabetes mellitus. The intrinsic properties of m-GDH, as judged by comparison of measurements made by either a radioisotopic or a colorimetric procedure, were not identical in islet and liver homogenates and differed between fetal and adult islets, suggesting the existence of distinct iso-enzymes. These findings illustrate adaptive changes of islet enzymes, with exclusive or partial mitochondrial location, in ontogenic situations characterized by a remodelling of fuel homeostasis.
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PMID:Ontogeny of FAD-linked glycerophosphate dehydrogenase in rat pancreatic islets. 879 9

The enzyme activities of mitochondrial glycerol phosphate dehydrogenase (mGPD) (EC 1.1.99.5) and pyruvate carboxylase (PC) (EC 6.4.1.1) have been reported to be low in the pancreatic islet of several rodent models of NIDDM. The present study was undertaken to discern whether mGPD is abnormal in the Zucker diabetic fatty (ZDF) rat (ZDF/Gmi-fa/fa), an animal model of NIDDM in which insulin secretion is unable to counteract the insulin resistance associated with the obesity that characterizes this model. Experiments were performed in prediabetic 6-week-old ZDF rats in comparison with 12-week-old overtly hyperglycemic animals and, as controls, Zucker lean (ZL) rats (ZDF/Gmi-+/fa or -+/+) and Wistar rats (+/+) of the same ages. The enzyme activity of mGPD was 32 and 18% of normal in islets of 6- and 12-week-old ZDF rats, respectively (P < 0.001 by analysis of variance). The activity of PC, which like mGPD is relatively abundant in the pancreatic islet, was 17 and 10% of normal in the islets of 6- and 12-week-old ZDF rats, respectively (P < 0.001). The activity of mGPD was normal in islets from ZL rats. However, PC activity was slightly lower in islets of 6- (51% of normal, P = 0.007) and 12-week-old (67% of normal, P = 0.01) ZL rats. The amounts of mGPD protein, as judged from Western analysis, and of PC protein, as judged from probing transblots with streptavidin that binds to biotin-containing enzymes, roughly correlated with the enzyme activities. This indicates that the decreased enzyme activities are caused by the decreased net synthesis of these enzymes rather than by the decreased activity of a normal amount of enzyme. The enzyme activity of succinate dehydrogenase, a control for mGPD, was normal in the ZL and ZDF rats. An incidental finding of the current study was the discovery of beta-methylcrotonyl-CoA carboxylase and propionyl-CoA carboxylase in the islet. Levels of these enzymes were also normal. Although reductions in mGPD and PC may contribute to the abnormal insulin secretion present in overt diabetes, they are modest compared with the severe reductions seen in inherited inborn errors of metabolism. Because of this and because more than a single enzyme is affected and the enzymes in the islet are diminished in more than one rodent model of NIDDM, these reductions are unlikely to represent the primary genetic defect in the ZDF rat. Since ZDF rats are euglycemic at 6 weeks of age and ZL animals are euglycemic throughout life and since these animals demonstrate low enzyme activities, this evidence suggests that it is not hyperglycemia but rather some other component of the diabetic syndrome that is responsible for the reductions in these enzymes.
Diabetes 1996 Nov
PMID:Low mitochondrial glycerol phosphate dehydrogenase and pyruvate carboxylase in pancreatic islets of Zucker diabetic fatty rats. 886 70

Obese subjects with excess intra-abdominal fat deposition suffer greater adverse metabolic consequences than do similarly overweight subjects with a predominantly subcutaneous distribution of adiposity. Little is known about the factors regulating the regional distribution of body fat. Leptin is a recently characterized protein secreted by adipocytes that appears to provide a long-term hormonal feedback signal regulating fat mass. No systematic evaluation of site-related differences in human adipocyte leptin expression has been reported to date. Levels of leptin mRNA were examined by quantitative reverse transcription-polymerase chain reaction in adipocytes isolated from omental and subcutaneous adipose depots of nonobese and mildly obese individuals undergoing elective surgery. In all individuals studied (n = 24), leptin mRNA levels were higher in subcutaneous than in omental adipocytes (P < 0.0001). In contrast, there were no consistent site-specific differences in the expression of glycerol-3-phosphate dehydrogenase mRNA. The subcutaneous-to-omental ratio of leptin mRNA expression was markedly higher in women (5.5 +/- 1.1-fold) than in men (1.9 +/- 0.2-fold) (P < 0.02). A significant relationship between BMI and leptin mRNA expression was demonstrable in the subcutaneous adipocytes of women (P < 0.006). Thus, leptin mRNA appears to be expressed predominantly by subcutaneous adipocytes, particularly in women. These findings suggest a possible role for leptin in the control of adipose tissue distribution and mass.
Diabetes 1997 Mar
PMID:Depot- and sex-specific differences in human leptin mRNA expression: implications for the control of regional fat distribution. 903 87

The Ca(2+)-sensitive and mitochondrial enzyme FAD-linked glycerophosphate dehydrogenase (m-GDH) represents an essential component of the pancreatic B-cell glucose-sensing device. This report deals with the first identified case of mutation in the calcium-binding domain of the m-GDH gene in a patient with type-2 diabetes and his glucose-intolerant half sister. Single strand conformation polymorphism analysis indeed revealed an abnormal mobility of the 32P-labelled polymerase chain reaction product in these two subjects. The corresponding base pair mutations and amino acid changes were documented. In the diabetic proband, the relative extent of the Ca(2+)-induced activation of m-GDH in CD3+ T-lymphocytes was lower than in his brother with a normal m-GDH gene sequence.
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PMID:Mutation in the calcium-binding domain of the mitochondrial glycerophosphate dehydrogenase gene in a family of diabetic subjects. 907 Aug 47

Mitochondrial FAD-linked glycerophosphate dehydrogenase (mGPDH) is thought to be an important factor for glucose sensing in pancreatic beta cells. To evaluate the significance of the mGPDH gene in the development of non-insulin-dependent diabetes mellitus (NIDDM), we set up primers and conditions for polymerase chain reaction (PCR) amplification of the coding exons and flanking regions. Screening of 100 Japanese NIDDM patients for mutations using the PCR-single strand conformation polymorphism (SSCP) method revealed four variants (ACA:Thr243-ACG:Thr243, CAT:His264-CGT:Arg264, GCA:Ala305-GCC:Ala305, GCA:Ala 306-TCA:Ser306). The His264-Arg264 variant was found in 36 patients, while the other variants were found in only one patient each. Neither the genotypic (chi 2 = 3.15, p = 0.21) nor the allelic (chi 2 = 2.27, p = 0.13) frequency of the His264-Arg264 mutation differed between 253 Japanese NIDDM patients and 157 non-diabetic subjects. In addition, in NIDDM patients, neither the treatment modality nor body mass index differed between those with and without this mutation. These results suggest that inherited defects at this locus do not make a major contribution to genetic susceptibility to NIDDM in the Japanese population.
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PMID:Detection of variants in the mitochondrial glycerophosphate dehydrogenase gene in Japanese NIDDM patients. 908 74

An abnormally low activity of mitochondrial FAD-linked glycerophosphate dehydrogenase (m-GDH), relative to the paired measurement of glutamate dehydrogenase, was found in CD3+ lymphocytes from 4 out of 14 mothers with gestational diabetes mellitus, but in none of 36 control mothers. The low m-GDH activity coincided with an abnormally high incidence of familial history for non-insulin-dependent diabetes. These findings are compatible with the view that an inherited or acquired defect of m-GDH may participate to the pathogenesis of beta-cell dysfunction in a subgroup of patients with gestational diabetes.
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PMID:Low mitochondrial glycerophosphate dehydrogenase activity in lymphocytes of women with gestational diabetes. 910

As part of an ongoing search for susceptibility loci for NIDDM, we tested 19 genes whose products are implicated in insulin secretion or action for linkage with NIDDM. Loci included the G-protein-coupled inwardly rectifying potassium channels expressed in beta-cells (KCNJ3 and KCNJ7), glucagon (GCG), glucokinase regulatory protein (GCKR), glucagon-like peptide I receptor (GLP1R), LIM/homeodomain islet-1 (ISL1), caudal-type homeodomain 3 (CDX3), proprotein convertase 2 (PCSK2), cholecystokinin B receptor (CCKBR), hexokinase 1 (HK1), hexokinase 2 (HK2), mitochondrial FAD-glycerophosphate dehydrogenase (GPD2), liver and muscle forms of pyruvate kinase (PKL, PKM), fatty acid-binding protein 2 (FABP2), hepatic phosphofructokinase (PFKL), protein serine/threonine phosphatase 1 beta (PPP1CB), and low-density lipoprotein receptor (LDLR). Additionally, we tested the histidine-rich calcium locus (HRC) on chromosome 19q. All regions were tested for linkage with microsatellite markers in 751 individuals from 172 families with at least two patients with overt NIDDM (according to World Health Organization criteria) in the sibship, using nonparametric methods. These 172 families comprise 352 possible affected sib pairs with overt NIDDM or 621 possible affected sib pairs defined as having a fasting plasma glucose value of >6.1 mmol/l or a glucose value of >7.8 mmol/l 2 h after oral glucose load. No evidence for linkage was found with any of the 19 candidate genes and NIDDM in our population by nonparametric methods, suggesting that those genes are not major contributors to the pathogenesis of NIDDM. However, some evidence for suggestive linkage was found between a more severe form of NIDDM, defined as overt NIDDM diagnosed before 45 years of age, and the CCKBR locus (11p15.4; P = 0.004). Analyses of six additional markers spanning 27 cM on chromosome 11p confirmed the suggestive linkage in this region. Whether an NIDDM susceptibility gene lies on chromosome 11p in our population must be determined by further analyses.
Diabetes 1997 Jun
PMID:Genetics of NIDDM in France: studies with 19 candidate genes in affected sib pairs. 916 80

Control rats and diabetic animals injected with streptozotocin during the neonatal period were either maintained on a standard diet or given access to food supplemented with dehydroepiandrosterone (DHEA, 0.2%) for 11 days before sacrifice. In both control and diabetic rats, DHEA feeding augmented the activity of the mitochondrial FAD-linked glycerophosphate dehydrogenase and cytosolic NADP-linked malate dehydrogenase in liver, but not so in either the parotid gland or pancreatic islets. DHEA lowered, in both control and diabetic rats, the ratio between D-glucose oxidation and utilization and the rate of insulin release in pancreatic islets exposed to a high concentration of D-glucose, as well as the insulin concentration and insulin/glucose ratio in plasma. These findings support the view that, in diabetes, DHEA, by increasing sensitivity to insulin, may allow islet B-cells to avoid the otherwise unfavorable consequences of chronic hyperactivity.
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PMID:Effects of dehydroepiandrosterone in rats injected with streptozotocin during the neonatal period. 923


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