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

Inappropriately elevated insulin secretion is the hallmark of persistent hyperinsulinemic hypoglycemia of infancy (PHHI), also denoted congenital hyperinsulinism. Causal mutations have been uncovered in genes coding for the beta-cell's ATP-sensitive potassium channel and the metabolic enzymes glucokinase and glutamate dehydrogenase. In addition, one hyperinsulinemic infant was recently found to have a mutation in the gene encoding short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD), an enzyme participating in mitochondrial fatty acid oxidation. We have studied a consanguineous family with severe neonatal hypoglycemia due to increased insulin levels and where well-established genetic causes of hyperinsulinism had been eliminated. A genome-wide, microsatellite-based screen for homozygous chromosomal segments was performed. Those regions that were inherited in accordance with the presupposed model were searched for mutations in genes encoding metabolic enzymes. A novel, homozygous deletion mutation was found in the gene coding for the SCHAD enzyme. The mutation affected RNA splicing and was predicted to lead to a protein lacking 30 amino acids. The observations at the molecular level were confirmed by demonstrating greatly reduced SCHAD activity in the patients' fibroblasts and enhanced levels of 3-hydroxybutyryl-carnitine in their blood plasma. Urine metabolite analysis showed that SCHAD deficiency resulted in specific excretion of 3-hydroxyglutaric acid. By the genetic explanation of our family's cases of severe hypoglycemia, it is now clear that recessively inherited SCHAD deficiency can result in PHHI. This finding suggests that mitochondrial fatty acid oxidation influences insulin secretion by a hitherto unknown mechanism.
Diabetes 2004 Jan
PMID:Familial hyperinsulinemic hypoglycemia caused by a defect in the SCHAD enzyme of mitochondrial fatty acid oxidation. 1469 19

Hypoglycemia due to hyperinsulinemia is the most common cause of persistent hypoglycemia in infants and children. Recent discoveries in the molecular and biochemical regulation of insulin secretion have dramatically increased our understanding of the disorders responsible for syndromes of hyperinsulinemic hypoglycemia. Here, we briefly review the current knowledge of disorders of the K(ATP) channel, activating mutations of glucokinase and glutamate dehydrogenase (GDH) and other disorders that may be associated with specific phenotypes and permit appropriate targeted therapies. Despite these advances, much remains to be learned. We do not understand the mechanisms or defects in many instances, including defective carbohydrate glycosylation syndromes and perinatal hypoxia, both of which may be associated with hyperinsulinemia. Most importantly, preoperative distinction between diffuse and focal lesions cannot be always reliably made even after selective arterial infusion with calcium, glucose or a sulfonylurea with concurrent hepatic venous sampling for insulin. The ability to distinguish diffuse from localized lesions has profound implications for therapeutic approaches, prognosis and genetic counseling. To date, about 50% of individuals with hyperinsulinemic hypoglycemia of infancy can be correctly categorized. Thus, the challenge continues.
Diabetes Metab Res Rev
PMID:Hyperinsulinemic hypoglycemia of infancy: the challenge continues. 1513 49

Persistent hypoglycemia in the neonate is most often caused by hyperinsulinemia. Recent discoveries in the molecular and biochemical regulation of insulin secretion have increased dramatically our understanding of disorders responsible for syndromes of hyperinsulinemic hypoglycemia. This article focuses on defects and disorders of the KATP channel, activating mutation of glucokinase and glutamate dehydrogenase, and other disorders that may be associated with specific phenotypes to permit appropriate targeted therapies. It is essential to evaluate these entities carefully because of the emerging evidence that at least half, if not more, have focal disease, which can be cured by local excision rather than diffuse disease, which may not be cured even after near total pancreatectomy with risk for future diabetes. Delay in diagnosis may be associated with developmental delay. The mechanisms of hypoglycemia remain incompletely understood.
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PMID:Differential diagnosis and management of neonatal hypoglycemia. 1515 93

Specific amino acids are now known to acutely and chronically regulate insulin secretion from pancreatic beta-cells in vivo and in vitro. Understanding the molecular mechanisms by which amino acids regulate insulin secretion may identify novel targets for future diabetes therapies. Mitochondrial metabolism is crucial for the coupling of amino acid and glucose recognition to the exocytosis of the insulin granules. This is illustrated by in vitro and in vivo observations discussed in the present review. Mitochondria generate ATP, which is the main coupling factor in insulin secretion; however, the subsequent Ca2+ signal in the cytosol is necessary, but not sufficient, for full development of sustained insulin secretion. Hence mitochondria generate ATP and other coupling factors serving as fuel sensors for the control of the exocytotic process. Numerous studies have sought to identify the factors that mediate the amplifying pathway over the Ca2+ signal in nutrient-stimulated insulin secretion. Predominantly, these factors are nucleotides (GTP, ATP, cAMP and NADPH), although metabolites have also been proposed, such as long-chain acyl-CoA derivatives and the key amino acid glutamate. This scenario highlights further the importance of the key enzymes or transporters, glutamate dehydrogenase, the aspartate and alanine aminotransferases and the malate/aspartate shuttle, in the control of insulin secretion. Therefore amino acids may play a direct or indirect (via generation of putative messengers of mitochondrial origin) role in insulin secretion.
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PMID:New insights into amino acid metabolism, beta-cell function and diabetes. 1554 73

Trigonella foenum graecum is a well-known hypoglycemic agent used in traditional Indian medicines. It was previously reported that oral administration of its seed powder for 3 weeks to alloxan diabetic rats stabilized glucose homeostasis and free radical metabolism in liver and kidney. In the present study, we further investigated the effects of 3 weeks alloxan induced diabetes on the histological structure and function of liver and kidney and the protective effect of T. foenum graecum seed powder (TSP) oral administration to the diabetic rats utilizing enzyme analysis and light and transmission electron microscopy. The activity of the enzyme, glutamate dehydrogenase was significantly higher whereas the activity of D-beta-hydroxybutyrate dehydrogenase enzyme was significantly lower in liver and kidney of alloxan-induced diabetic rats. Histopathological studies showed liver degenerative and early nephropathic changes in diabetic rats. Ultrastructure of the diabetic liver revealed a reduction in the rough endoplasmic reticulum and swelling of mitochondria in the hepatocytes. TSP treatment to the diabetic rats effectively prevented the alteration in the activities of the two enzymes and partially prevented the structural abnormalities thus suggesting a protective effect of TSP on the liver and kidney of the diabetic rats. The role of TSP in reversing the diabetic state at the cellular level besides the metabolic normalization further proves its potential as an antidiabetic agent.
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PMID:Trigonella foenum graecum seed powder protects against histopathological abnormalities in tissues of diabetic rats. 1564 37

Effects of STZ diabetes and treatment with insulin on cerebral mitochondrial metabolism in the male and female rats were examined. Diabetic state resulted in generalized decrease in the state 3 respiration rates in the males with practically all the substrates except glutamate where the opposite effect was seen. Diabetic state had no adverse effect on the respiratory activity in the females. Insulin treatment had no restorative effect in the males. By contrast in the females, adverse effects were noted. The cytochromes contents decreased in STZ diabetes with the effect being more pronounced in the males; treatment with 1 unit of insulin restored the cytochromes contents. STZ diabetes also resulted in decreased dehydrogenases activities with the effect being more pronounced in the females: insulin treatment resulted in hyper-stimulation of glutamate dehydrogenase and succinate DCIP reductase activities; restoration of malate dehydrogenase activity was only partial. The results point out that STZ diabetes and insulin treatments differentially affect cerebral mitochondrial energy metabolism in the male and female rats.
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PMID:Insulin status differentially affects energy transduction in cerebral mitochondria from male and female rats. 1662 78

Insulin-induced hypoglycemic coma in animals with alloxan diabetes was observed at a higher basal glucose level in the blood compared to healthy animals. It was associated with inhibition of glycolysis and glycogenolysis and decreased activities of succinate dehydrogenase and glutamate dehydrogenase in the cerebral hemispheres and brainstem.
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PMID:Glycolysis and oxidtion enzyme activity in rat brain during insulin-induced hypoglycemia against the background of alloxan-induced diabetes mellitus. 1684 27

Hypoglycemic coma induced by administration of a large dose of insulin, was accompanied by the increased rates of glycolysis, glycogenolysis, activity of lactate dehydrogenase, succinate dehydrogenase, isocitrate dehydrogenase, and increased concentration of glycogen. Under these conditions triacylglycerol content decreased administration of the large dose of insulin to rats with alloxan diabetes increased not only rates of glycolysis, glycogenolysis and lactate dehydrogenase activity and also activities of aspartate transaminase and glutamate dehydrogenase. Data obtained suggest the increased utilization of amino acids for energy supply of myocardium under conditions of hypoglycemia induced by insulin adminisration to diabetic animals.
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PMID:[Changes of some energy exchange parameters in the rat heart under insulin hypoglycemia]. 1728 54

Hypoglycemic coma caused by insulin injection to rats with alloxan-induced diabetes was accompanied by an increase in the concentrations of urea and uric acid and decrease in the content of free amino acids in blood plasma. Activities of glutamate dehydrogenase, AMP deaminase, glutaminase, ALT, and AST in the liver of experimental animals increased.
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PMID:Parameters of nitrogen metabolism during insulin hypoglycemia in rats with alloxan-induced diabetes. 1914 18

Low-protein diet impairs insulin secretion in response to nutrients and may induce several metabolic disorders including diabetes, obesity, and cardiovascular disease. In the present study, the influence of leucine supplementation on glutamate dehydrogenase (GDH) expression and glucose-induced insulin secretion (GIIS) was investigated in malnourished rats. Four groups were fed with different diets for 12 weeks: a normal-protein diet (17%) without or with leucine supplementation or a low (6%)-protein diet without (LP) or with leucine supplementation (LPL). Leucine (1.5%) was supplied in the drinking water. Western blotting analysis revealed reduced GDH expression in LP, whereas LPL displayed improved GDH expression, similar to control. The GIIS and leucine-induced insulin release were also enhanced in LPL compared with LP and similar to those observed in rats fed a normal-protein diet without leucine supplementation. In addition, GDH allosteric activators produced an increased insulin secretion in LPL. These findings indicate that leucine supplementation was able to increase GDH expression leading to GIIS restoration, probably by improved leucine metabolic pathways.
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PMID:Preliminary report: leucine supplementation enhances glutamate dehydrogenase expression and restores glucose-induced insulin secretion in protein-malnourished rats. 2001 23


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