Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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

Catabolism of alpha-ketoisocaproate in liver is mediated by cytosolic alpha-ketoisocaproate dioxygenase (KICD) and mitochondrial branched-chain alpha-keto acid dehydrogenase complex (BCKDC). The latter is believed to be involved in the main pathway of the KIC catabolism. In the present study, we measured the activities of KICD and BCKDC in human and rat livers. The KICD activity in human liver was 0.9 mU/g tissue, which was 14.2% of the total activity of BCKDC, and that in rat liver was 4.2 mU/g tissue, which was only 1.0% of the total activity, suggesting that KICD in human liver plays a relatively important role in the alpha-ketoisocaproate catabolism. The KICD activity in human liver was significantly increased by cirrhosis. In rat liver, the enzyme activity was markedly increased by physical training and streptozotocin-induced diabetes, but not by feeding of a diet rich in branched-chain amino acids, although BCKDC activity was increased by feeding of the diet.
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PMID:The alpha-ketoisocaproate catabolism in human and rat livers. 1102 93

Psammomys obesus is a model of type 2 diabetes that displays resistance to insulin and deranged beta-cell response to glucose. We examined the major signaling pathways for insulin release in P. obesus islets. Islets from hyperglycemic animals utilized twice as much glucose as islets from normoglycemic diabetes-prone or diabetes-resistant controls but exhibited similar rates of glucose oxidation. Fractional oxidation of glucose was constant in control islets over a range of concentrations, whereas islets from hyperglycemic P. obesus showed a decline at high glucose. The mitochondrial substrates alpha-ketoisocaproate and monomethyl succinate had no effect on insulin secretion in P. obesus islets. Basal insulin release in islets from diabetes-resistant P. obesus was unaffected by glucagon-like peptide 1 (GLP-1) or forskolin, whereas that of islets of the diabetic line was augmented by the drugs. GLP-1 and forskolin potentiated the insulin response to maximal (11.1 mmol/l) glucose in islets from all groups. The phorbol ester phorbol myristic acid (PMA) potentiated basal insulin release in islets from prediabetic animals, but not those from hyperglycemic or diabetes-resistant P. obesus. At the maximal stimulatory glucose concentration, PMA potentiated insulin response in islets from normoglycemic prediabetic and diabetes-resistant P. obesus but had no effect on islets from hyperglycemic P. obesus. Maintenance of islets from hyperglycemic P. obesus for 18 h in low (3.3 mmol/l) glucose in the presence of diazoxide (375 pmol/l) dramatically improved the insulin response to glucose and restored the responsiveness to PMA. Immunohistochemical analysis indicated that hyperglycemia was associated with reduced expression of alpha-protein kinase C (PKC) and diminished translocation of lambda-PKC. In summary, we found that 1) P. obesus islets have low oxidative capacity, probably resulting in limited ability to generate ATP to initiate and drive the insulin secretion; 2) insulin response potentiated by cyclic AMP-dependent protein kinase is intact in P. obesus islets, and increased sensitivity to GLP-1 or forskolin in the diabetic line may be secondary to increased sensitivity to glucose; and 3) islets of hyperglycemic P. obesus display reduced expression of alpha-PKC and diminished translocation of lambda-PKC associated with impaired response to PMA. We conclude that low beta-cell oxidative capacity coupled with impaired PKC-dependent signaling may contribute to the animals' poor adaptation to a high-energy diet.
Diabetes 2001 Feb
PMID:Defective stimulus-secretion coupling in islets of Psammomys obesus, an animal model for type 2 diabetes. 1127 41

Cystic fibrosis (CF) patients are reported to experience chronic protein catabolism. Since diabetes or impaired glucose tolerance (IGT) is common in CF, we hypothesized that their protein catabolic state is related to reduced insulin secretion or reduced insulin action. A total of 12 clinically stable adult CF patients with abnormal glucose tolerance and 12 age-, sex-, and lean body mass-matched healthy control subjects underwent protein turnover studies using L-[1-(13)C]leucine, L-[(15)N]phenylalanine, and L-[(2)H(4)]tyrosine, with and without exogenous insulin infusion. In the baseline fasting state, protein metabolism was entirely normal in CF patients, with no evidence of increased protein catabolism. In contrast, striking abnormalities were seen in CF patients when insulin was infused, since they did not experience normal suppression of the appearance rates of leucine, phenylalanine, or tyrosine (indexes of protein breakdown). At an insulin concentration of 45 +/- 2 microU/ml, normal control subjects suppressed the leucine appearance rate by 19 +/- 5% (P < 0.01), ketoisocaproate appearance rate by 10 +/- 3% (P = 0.03), tyrosine appearance rate by 11 +/- 2% (P = 0.03), and phenylalanine appearance rate by 6 +/- 3% (P = 0.07). Phenylalanine conversion to tyrosine decreased by 22 +/- 7% (P = 0.03). At a similar insulin concentration of 44 +/- 3 microU/ml, normal suppression of amino acid appearance did not occur in CF. The leucine appearance rate decreased by 4 +/- 2% (P = 0.65), ketoisocaproate appearance rate by 1 +/- 2% (P = 0.94), tyrosine appearance rate by 0 +/- 6% (P = 0.56), phenylalanine appearance rate by 5 +/- 6% (P = 0.34), and phenylalanine conversion to tyrosine by 5 +/- 6% (P = 0.95). Poor suppression of the amino acid appearance rate in CF was not related to previously documented glucose tolerance status (IGT or CF-related diabetes without fasting hyperglycemia), fasting insulin levels, the acute insulin response, insulin sensitivity, cytokine or counterregulatory hormone levels, resting energy expenditure, caloric intake, pulmonary function, or clinical status. Protein synthesis was not significantly affected by insulin infusion in either normal control subjects or CF patients. In conclusion, clinically stable adult CF patients have normal indexes of protein breakdown and synthesis in the fasting state. In contrast, elevation of plasma insulin to physiological postprandial levels fails to normally suppress indexes of protein breakdown. It is therefore likely that inability to spare protein during the postprandial state is the cause of protein catabolism in these patients.
Diabetes 2001 Jun
PMID:Protein metabolism in clinically stable adult cystic fibrosis patients with abnormal glucose tolerance. 1137 34

The major diabetes quantitative trait locus (Niddm1), which segregates in crosses between GK rats affected with spontaneous type 2-like diabetes and normoglycemic F344 rats, encodes at least two different diabetes susceptibility genes. Congenic strains for the two subloci (Niddm1f and Niddm1i) have been generated by transfer of GK alleles onto the genome of F344 rats. Whereas the Niddm1f phenotype implicated insulin resistance, the Niddm1i phenotype displayed diabetes related to insulin deficiency. Individual islets from 16-week-old congenic rats were characterized for insulin release and oxygen tension (pO(2)). In the presence of 3 mmol/l glucose, insulin release from Niddm1f and Niddm1i islets was approximately 5 pmol. g(-1). s(-1) and pO(2) was 120 mmHg. Similar recordings were obtained from GK and F344 islets. When glucose was raised to 11 mmol/l, insulin release increased significantly in Niddm1f and F344 islets but was essentially unchanged in islets from GK and Niddm1i. The high glucose concentration lowered pO(2) to the same extent in islets from all strains. Addition of 1 mmol/l tolbutamide to the perifusion medium further increased pulsatile insulin release threefold in all islets. The pulse frequency was approximately 0.4 min(-1). alpha-Ketoisocaproate (11 mmol/l) alone increased pulsatile insulin release eightfold in islets from Niddm1f, Niddm1i, and control F344 rats but had no effect on insulin release from GK islets. These secretory patterns in response to alpha-ketoisocaproate were paralleled by reduction of pO(2) in Niddm1f, Niddm1i, and control F344 islets and no change of pO(2) in GK islets. The results demonstrate that Niddm1i carries alleles of gene(s) that reduce glucose-induced insulin release and that are amenable to molecular identification by genetic fine mapping.
Diabetes 2001 Dec
PMID:Phenotyping of individual pancreatic islets locates genetic defects in stimulus secretion coupling to Niddm1i within the major diabetes locus in GK rats. 1172 56

Complete lack of transcription factor PDX-1 leads to pancreatic agenesis, whereas heterozygosity for PDX-1 mutations has been recently noted in some individuals with maturity-onset diabetes of the young (MODY) and in some individuals with type 2 diabetes. To determine how alterations in PDX-1 affect islet function, we examined insulin secretion and islet physiology in mice with one PDX-1 allele inactivated. PDX-1(+/-) mice had a normal fasting blood glucose and pancreatic insulin content but had impaired glucose tolerance and secreted less insulin during glucose tolerance testing. The expression of PDX-1 and glucose transporter 2 in islets from PDX-1(+/-) mice was reduced to 68 and 55%, respectively, whereas glucokinase expression was not significantly altered. NAD(P)H generation in response to glucose was reduced by 30% in PDX-1(+/-) mice. The in situ perfused pancreas of PDX-1(+/-) mice secreted about 45% less insulin when stimulated with 16.7 mm glucose. The K(m) for insulin release was similar in wild type and PDX-1(+/-) mice. Insulin secretion in response to 20 mm arginine was unchanged; the response to 10 nm glucagon-like peptide-1 was slightly increased. However, insulin secretory responses to 10 mm 2-ketoisocaproate and 20 mm KCl were significantly reduced (by 61 and 66%, respectively). These results indicate that a modest reduction in PDX-1 impairs several events in glucose-stimulated insulin secretion (such as NAD(P)H generation, mitochondrial function, and/or mobilization of intracellular Ca(2+)) and that PDX-1 is important for normal function of adult pancreatic islets.
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PMID:Reduction in pancreatic transcription factor PDX-1 impairs glucose-stimulated insulin secretion. 1178 23

Improvement of glycemic status by insulin is associated with profound changes in amino acid metabolism in type 1 diabetes. In contrast, a dissociation of insulin effect on glucose and amino acid metabolism has been reported in type 2 diabetes. Type 2 diabetic patients are reported to have reduced muscle oxidative enzymes and VO(2max). We investigated the effect of 11 days of intensive insulin treatment (T(2)D+) on whole-body amino acid kinetics, muscle protein synthesis rates, and muscle functions in eight type 2 diabetic subjects after withdrawing all treatments for 2 weeks (T(2)D-) and compared the results with those of weight-matched lean control subjects using stable isotopes of the amino acids. Whole-body leucine, phenylalanine and tyrosine fluxes, leucine oxidation, and plasma amino acid levels were similar in all groups, although plasma glucose levels were significantly higher in T(2)D-. Insulin treatment reduced leucine nitrogen flux and transamination rates in subjects with type 2 diabetes. Synthesis rates of muscle mitochondrial, sarcoplasmic, and mixed muscle proteins were not affected by glycemic status or insulin treatment in subjects with type 2 diabetes. Muscle strength was also unaffected by diabetes or glycemic status. In contrast, the diabetic patients showed increased tendency for muscle fatigability. Insulin treatment also failed to stimulate muscle cytochrome C oxidase activity in the diabetic patients, although it modestly elevated citrate synthase. In conclusion, improvement of glycemic status by insulin treatment did not alter whole-body amino acid turnover in type 2 diabetic subjects, but leucine nitrogen flux, transamination rates, and plasma ketoisocaproate level were decreased. Insulin treatments in subjects with type 2 diabetes had no effect on muscle mitochondrial protein synthesis and cytochrome C oxidase, a key enzyme for ATP production.
Diabetes 2002 Aug
PMID:Synthesis rate of muscle proteins, muscle functions, and amino acid kinetics in type 2 diabetes. 1214 50

Genetic variation in the gene for a cytosolic cysteine protease, calpain-10, increases the susceptibility to type 2 diabetes apparently by altering levels of gene expression. In view of the importance of altered beta-cell function in the pathophysiology of type 2 diabetes, the present study was undertaken to define the effects on insulin secretion of exposing pancreatic islets to calpain inhibitors for 48 hours. Exposure of mouse islets to calpain inhibitors (ALLN, ALLM, E-64-d, MDL 18270, and PD147631) of different structure and mechanism of action for 48 hours reversibly suppresses glucose-induced insulin secretion by 40% to 80%. Exposure of islets to inhibitors of other proteases, ie, cathepsin B and proteasome, did not affect insulin secretion. The 48-hour incubation with calpain inhibitors also attenuates insulin secretory responses to the mitochondrial fuel alpha-ketoisocaproate (KIC). The same incubation also suppresses glucose metabolism and intracellular calcium ([Ca(2+)](i)) responses to glucose or KIC in islets. In summary, long-term inhibition of islet calpain activity attenuates insulin secretion possibly by limiting the rate of glucose metabolism. A reduction of calpain activity in islet could contribute to the development of beta-cell failure in type 2 diabetes thereby providing a link between genetic susceptibility to diabetes and the pathophysiologic manifestations of the disease.
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PMID:A 48-hour exposure of pancreatic islets to calpain inhibitors impairs mitochondrial fuel metabolism and the exocytosis of insulin. 1275 79

Tacrolimus causes posttransplant diabetes mellitus, although the pathogenetic mechanisms remain controversial. We studied the mechanism of tacrolimus-induced impairment of insulin secretion using isolated rat pancreatic islets. Tacrolimus caused reductions in DNA and insulin contents per islet during 7-d culture. Tacrolimus time-dependently suppressed glucose-stimulated insulin secretion, and at a therapeutic concentration of 0.01 micromol/liter, it suppressed glucose-stimulated insulin secretion to 32 +/- 5% of the control value after 7-d incubation. Tacrolimus did not change islet glucose utilization and oxidation, ATP production, insulin mRNA expression, or the capacity for high glucose to increase intracellular Ca(2+), but altered the rapid frequency oscillations of Ca(2+) concentration. Tacrolimus suppressed insulin secretion stimulated by mitochondrial fuel (combination of l-leucine and l-glutamine, and alpha-ketoisocaproate) and glibenclamide, but not by l-arginine. Tacrolimus suppressed insulin secretion induced by carbachol and by a protein kinase C agonist in the presence or absence of extracellular Ca(2+). Under stringent Ca(2+)-free conditions, tacrolimus did not affect mastoparan-induced insulin secretion, but suppressed its glucose augmentation. Our results suggest that tacrolimus impairs glucose-stimulated insulin secretion downstream of the rise in intracellular Ca(2+) at insulin exocytosis, and that protein kinase C-mediated (Ca(2+)-dependent and independent) and Ca(2+)-independent GTP signaling pathways may be involved. However, tacrolimus-induced impaired insulin secretion was reversed 3 d after removal of the drug. Our study demonstrated that tacrolimus impairs insulin secretion at multiple steps in stimulus-secretion coupling.
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PMID:Tacrolimus impairment of insulin secretion in isolated rat islets occurs at multiple distal sites in stimulus-secretion coupling. 1496 91

Most patients at risk for developing type 2 diabetes are hyperinsulinemic. Hyperinsulinemia may be a response to insulin resistance, but another possible abnormality is insulin hypersecretion. BTBR mice are insulin resistant and hyperinsulinemic. When the leptin(ob) mutation is introgressed into BTBR mice, they develop severe diabetes. We compared the responsiveness of lean B6 and BTBR mouse islets to various insulin secretagogues. The transamination product of leucine, alpha-ketoisocaproate (KIC), elicited a dramatic insulin secretory response in BTBR islets. The KIC response was blocked by methyl-leucine or aminooxyacetate, inhibitors of branched-chain amino transferase. When dimethylglutamate was combined with KIC, the fractional insulin secretion was identical in islets from both mouse strains, predicting that the amine donor is rate-limiting for KIC-induced insulin secretion. Consistent with this prediction, glutamate levels were higher in BTBR than in B6 islets. The transamination product of glutamate, alpha-ketoglutarate, elicited insulin secretion equally from B6 and BTBR islets. Thus formation of alpha-ketoglutarate is a requisite step in the response of mouse islets to KIC. alpha-Ketoglutarate can be oxidized to succinate. However, succinate does not stimulate insulin secretion in mouse islets. Our data suggest that alpha-ketoglutarate may directly stimulate insulin secretion and that increased formation of alpha-ketoglutarate leads to hyperinsulinemia.
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PMID:Alpha-Ketoisocaproate-induced hypersecretion of insulin by islets from diabetes-susceptible mice. 1574 Dec 43

Hydrogen sulfide (H(2)S) was historically recognized as a toxic gas generated by natural resources. However, its enzymatic production from L-cysteine has recently been demonstrated in mammals. Cystathionine beta-synthase and cystathionine gamma-lyase, both of which can produce H(2)S, were expressed in mouse pancreatic islet cells and the beta-cell line, MIN6. L-cysteine and the H(2)S donor NaHS inhibited glucose-induced insulin release from islets and MIN6 cells. These inhibitory effects were reproduced when insulin release was stimulated by alpha-ketoisocaproate, tolbutamide, or high K+. L-cysteine and NaHS inhibited glucose-potentiated insulin release in the copresence of diazoxide and high K+. Real-time imaging of intracellular Ca2+ concentration ([Ca2+](i)) demonstrated that both L-cysteine and NaHS reversibly suppressed glucose-induced [Ca2+](i) oscillation in a single beta-cell without obvious changes in the mean value. These substances inhibited Ca2+ - or guanosine 5'-0-3-thiotriphosphate-induced insulin release from islets permeabilized with streptolysin-O. L-cysteine and NaHS reduced ATP production and attenuated glucose-induced hyperpolarization of the mitochondrial membrane potential. Finally, L-cysteine increased H(2)S content in MIN6 cells. We suggest here that L-cysteine inhibits insulin release via multiple actions on the insulin secretory process through H(2)S production. Because the activities of H(2)S-producing enzymes and the tissue H(2)S contents are known to increase under diabetic conditions, the inhibition may participate in the deterioration of insulin release in this disease.
Diabetes 2006 May
PMID:L-cysteine inhibits insulin release from the pancreatic beta-cell: possible involvement of metabolic production of hydrogen sulfide, a novel gasotransmitter. 1664 96


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