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)

Proinsulin is converted to insulin by the concerted action of two sequence-specific subtilisin-like proteases termed prohormone convertase 2 (PC2) and prohormone convertase 3 (PC3). PC3 is a type I proinsulin-processing enzyme that initiates the sequential processing of proinsulin to insulin by cleaving the proinsulin molecule on the COOH-terminal side of the dibasic peptide, Arg31-Arg32, joining the B-chain and C-peptide. Thus, PC3 plays a key role in regulating insulin biosynthesis. Expressions of insulin and PC3, but not PC2, are coordinately regulated by glucose, consistent with the important role of PC3 in regulating proinsulin processing. NIDDM is associated with increased secretion of proinsulin and proinsulin-like molecules, suggesting that mutations in the PC3 gene may be involved in the development of this disorder. To examine this hypothesis, we have isolated and characterized the human PC3 gene and screened it for mutations in a group of Japanese subjects with NIDDM. The PC3 gene consists of 14 exons spanning more than 35 kb. The exon-intron organization of PC2 and PC3 genes are conserved, consistent with a common evolutionary origin for the prohormone convertase gene family. Single-strand conformational analysis and nucleotide sequencing of the entire coding region of the PC3 gene in 102 Japanese subjects with NIDDM revealed missense mutations in exons 2 (Arg/Gln53) and 14 (Gln/Glu638), neither of which was associated with NIDDM in this population. These data suggest that genetic variation in the PC3 gene is unlikely to be a major contributor to NIDDM susceptibility in Japanese.
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PMID:Human prohormone convertase 3 gene: exon-intron organization and molecular scanning for mutations in Japanese subjects with NIDDM. 866 40

The GK rat is a spontaneous model of NIDDM. The insulin response to 16.7 mmol/l glucose was markedly impaired in both isolated perfused pancreas and isolated islets from GK rats compared with control Wistar rats. Depolarization with 30 mmol/l KCl in the presence of 3.3 mmol/l glucose and 250 micromol/l diazoxide induced similar insulin responses in perfused pancreases of GK and control rats. In contrast, the glucose-stimulated insulin release was also severely impaired in GK pancreases in the depolarized state. Forskolin (1 micromol/l) markedly enhanced insulin release at 3.3 mmol/l glucose in GK but not control pancreases (54 +/- 15 vs. 3 +/- 1 pmol/10 min, P < 0.001). Dibutyryl cAMP (1 mmol/l) exerted effects similar to forskolin on insulin release in the perfused pancreas. In depolarized pancreases of GK but not control rats, forskolin also induced a marked insulin response at 3.3 mmol/l glucose (163 +/- 48 vs. 16 +/- 1 pmol/20 min, P < 0.03). Similarly, in studies on isolated islets from GK rats cultured in 5.5 or 16.7 mmol/l glucose for 48 h, forskolin (5 pmol/l) restored insulin release in response to 16.7 mmol/l glucose but had no effect on islet glucose utilization at 3.3 or 16.7 mmol/l glucose. Forskolin markedly stimulated insulin release at 3.3 mmol/l glucose in GK but not control rat islets cultured for 48 h in 5.5 mmol/l glucose, whereas 20 mmol/l arginine had an almost identical effect in both islet varieties. However, in islets cultured in 16.7 mmol/l glucose, forskolin stimulated insulin release similarly both in control and GK islets at 3.3 mmol/l glucose. In conclusion, this study suggests that the insulinotropic effects of glucose are coupled to a direct regulation of the exocytotic machinery in the pancreatic beta-cell. This pathway is markedly impaired in GK rats, contributing to defective insulin response to glucose. In this model, cAMP generation restores the insulin response to 16.7 mmol/l glucose and exerts a marked insulin release even at 3.3 mmol/l glucose.
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PMID:Impaired coupling of glucose signal to the exocytotic machinery in diabetic GK rats: a defect ameliorated by cAMP. 866 45

Recently, a missense mutation replacing tryptophan with arginine at codon 64 of the beta 3-adrenergic receptor gene was shown to be associated with insulin resistance in nondiabetic subjects and to an earlier onset of NIDDM in Pima Indians. We studied whether the codon 64 amino acid polymorphism of the beta 3-adrenergic receptor gene in a cohort of young healthy Danes was associated with high birth weight, accelerated weight gain during childhood and adolescence, present obesity, or impaired insulin sensitivity. The protocol included 380 unrelated white subjects in whom insulin sensitivity and secretion were measured during a combined intravenous glucose and tolbutamide tolerance test. A number of biochemical and anthropometric characteristics were determined for each subject. The subjects were genotyped for the codon 64 polymorphism by applying polymerase chain reaction restriction fragment-length polymorphism screening with the use of endonuclease BstN1. The allelic frequency of the mutated allele was 7% (95% CI: 5-10%), and it was similar in obese and nonobese subjects. The beta 3-adrenergic receptor gene variant was not related to birth weight or weight gain during childhood or adolescence. In its heterozygous form, the gene variant was not associated with an altered insulin sensitivity index (SI) or other features of the insulin resistance syndrome (BMI, blood pressure, fasting serum lipid levels, or fasting serum fibrinolytic variables). Three homozygous carriers of the polymorphism were identified, and each had a significantly higher BMI (27.4 +/- 1.3 vs. 23.5 +/- 3.7 kg/m2 [mean +/- SD]; P = 0.032), lower SI [4.9 +/- 2.9 vs. 15.4 +/- 9.0 10(-5) x (min x pmol/l)-1; P = 0.013], and higher fasting serum C-peptide (730 +/- 155 vs. 471 +/- 158 pmol/l; P = 0.016) than the wild-type carriers. The homozygous carriers also had significantly higher levels of fasting serum triglyceride (P = 0.042) and serum LDL cholesterol (P = 0.013). When adjustments were made for age, sex, BMI, and VO2max in a multiple regression analysis, a significantly negative association was found between homozygosity for the codon 64 variant and the SI (P = 0.009). We conclude that in young healthy Danes, the homozygous form but not the heterozygous form of the codon 64 amino acid polymorphism of the beta 3-adrenergic receptor may be associated with obesity and, independent of BMI, with a low SI. Since only three homozygous carriers were identified among 380 subjects, the results must be interpreted with caution, and studies of larger population samples are needed.
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PMID:Insulin sensitivity and body weight changes in young white carriers of the codon 64 amino acid polymorphism of the beta 3-adrenergic receptor gene. 869 Jan 60

To examine the effect of sulfonylurea withdrawal on the proinsulin (PI) to immunoreactive insulin (IRI) ratio in subjects with noninsulin dependent diabetes mellitus (NIDDM), we measured fasting and arginine-stimulated PI and IRI levels in 15 subjects with NIDDM (mean age, 64.4 yr; body mass index, 27.3 kg/m2) during chronic treatment with glyburide (n = 12) or other sulfonylureas (n = 3) and after withdrawal from the medication for 2-4 weeks. Additionally, we performed iv glucose tolerance tests to measure the insulin sensitivity index, glucose effectiveness at zero insulin, iv glucose tolerance, and the acute insulin response to glucose. Discontinuation of sulfonylurea therapy resulted in an increase in fasting plasma glucose from 10.5 +/- 0.8 to 13.1 +/- 0.9 mmol/L (P < 0.001). This was associated with a decrease in the fasting IRI concentration (120 +/- 21 to 92 +/- 21 pmol/L; P < 0.005) and the fasting PI concentration (58 +/- 10 to 41 +/- 7 pmol/L; P < 0.01); however, the PI/IRI ratio did not differ (50 +/- 6% during medication and 48 +/- 5% after withdrawal; P = 0.43). Similarly, the acute PI/IRI ratio did not change (8.6 +/- 2.4% on therapy; 8.4 +/- 1.2% off therapy; P = 0.91). No change was observed in other metabolic parameters, including insulin sensitivity index (0.76 +/- 0.21 x 10(-5) min-1/pM on therapy; 0.76 +/- 0.19 x 10(-5) min-1/pM off therapy), acute insulin response to arginine (225 +/- 37 pmol/L on therapy; 225 +/- 40 pmol/L off therapy), acute insulin response to glucose (10 +/- 6 pmol/L on therapy; 5 +/- 4 pmol/L off therapy), glucose effectiveness at zero insulin (0.0127 +/- 0.0007 min-1 on therapy; 0.0119 +/- 0.0009 min-1 off therapy), and iv glucose tolerance (0.85 +/- 0.05%/min on therapy; 0.71 +/- 0.07%/min off therapy). We conclude that sulfonylurea therapy does not correct the elevated PI/IRI ratio or absent first phase insulin response of NIDDM and does not have an effect on parameters of peripheral tissue glucose uptake.
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PMID:Effect of sulfonylurea withdrawal on proinsulin levels, B cell function, and glucose disposal in subjects with noninsulin-dependent diabetes mellitus. 878 86

Glucagon-like peptide 1 (GLP-1) is a natural enteric incretin hormone, which is a potent insulin secretogogue in vitro and in vivo in humans. Its effects on overnight glucose concentrations and the specific phases of insulin response to glucose and nonglucose secretogogues in subjects with NIDDM are not known. We compared the effects of overnight intravenous infusion of GLP-1 (7-36) amide with saline infusion, on overnight plasma concentrations of glucose, insulin, and glucagon in eight subjects with NIDDM. The effects on basal (fasting) beta-cell function and insulin sensitivity were assessed using homeostasis model assessment (HOMA) and compared with seven age- and weight-matched nondiabetic control subjects. The GLP-1 infusion was continued, and the first- and second-phase insulin responses to a 2-h 13 mmol/l hyperglycemic clamp and the insulin response to a subsequent bolus of the nonglucose secretogogue, arginine, were measured. These were compared with similar measurements recorded after the overnight saline infusion and in the control subjects who were not receiving GLP-1. The effects on stimulated beta-cell function of lowering plasma glucose per se were assessed by a separate overnight infusion of soluble insulin, the rate of which was adjusted to mimic the blood glucose profile achieved with GLP-1. Infusion of GLP-1 resulted in significant lowering of overnight plasma glucose concentrations compared with saline, with mean postabsorptive glucose concentrations (2400-0800) of 5.6 +/- 0.8 and 7.8 +/- 1.4 mmol/l, respectively (P < 0.0002). Basal beta-cell function assessed by HOMA was improved from geometric mean (1 SD range), 45% beta (24-85) to 91% beta (55-151) by GLP-1 (P < 0.0004). First-phase incremental insulin response to glucose was improved by GLP-1 from 8 pmol/l (-8-33) to 116 pmol/l (12-438) (P < 0.005), second-phase insulin response to glucose from 136 pmol/l (53-352) to 1,156 pmol/l (357-3,748) (P < 0.0002), and incremental insulin response to arginine from 443 pmol/l (172-1,144) to 811 pmol/l (272-2,417) (P < 0.002). All responses on GLP-1 were not significantly different from nondiabetic control subjects. Reduction of overnight glucose by exogenous insulin did not improve any of the phases of stimulated beta-cell function. Prolonged intravenous infusion of GLP-1 thus significantly lowered overnight glucose concentrations in subjects with NIDDM and improved both basal and stimulated beta-cell function to nondiabetic levels. It may prove to be a useful agent in the reduction of hyperglycemia in NIDDM.
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PMID:Normalization of insulin responses to glucose by overnight infusion of glucagon-like peptide 1 (7-36) amide in patients with NIDDM. 886 56

Obesity and insulin resistance are important risk factors for the development of noninsulin-dependent diabetes (NIDDM) and are prevalent among predisposed first degree relatives of diabetic individuals. Recent molecular screening and analysis of a common missense mutation of the beta 3-adrenergic receptor gene suggested this locus as a strong candidate for increased obesity, earlier age of diabetes onset, and insulin resistance. To test the hypothesis that the beta 3-adrenergic receptor locus affects diabetes susceptibility, obesity as measured by body mass index, and components of the insulin resistance syndrome, we examined the role of this region in families ascertained for two or more NIDDM siblings. Linkage analysis was conducted using both parametric and nonparametric analyses, including multipoint sibling pair analysis. We found no evidence for linkage to NIDDM as a dichotomous trait and no evidence for linkage to body mass index, waist/hip ratio, insulin levels, or glucose levels as quantitative traits or to reported age of onset among NIDDM individuals. The Trp64 Arg missense mutation was present in 11% of the population. The mutation was not associated with NIDDM, and Arg64 carriers did not have earlier NIDDM onset, higher body mass index, or higher waist/hip ratio than Trp64 homozygotes. Among relatives, Arg64 carriers had significantly lower fasting glucose levels and lower waist/hip ratios than Trp64 homozygotes, but no characteristics of the insulin resistance syndrome. We conclude that the beta 3-adrenergic receptor locus does not play an important role in NIDDM susceptibility or in the insulin resistance syndrome among members of families with a strong predisposition to NIDDM.
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PMID:Role of the beta 3-adrenergic receptor locus in obesity and noninsulin-dependent diabetes among members of Caucasian families with a diabetic sibling pair. 895 53

Defective insulin secretion plays a crucial role in insulin-dependent (Type 1) and non-insulin-dependent (Type 2) diabetes mellitus as well as in many secondary forms of the disease. Glucagon is a potent stimulus for the islet beta-cell, and intravenous bolus injection of 1 mg glucagon has been widely used to assess endogenous insulin secretion for clinical or research purposes. Plasma C-peptide levels (less commonly insulin) are usually measured immediately before and 6 min after glucagon injection. The C-peptide response to glucagon is well-correlated with the beta-cell response to mixed meals or other stimuli commonly used to characterize endogenous insulin secretion (oral or intravenous glucose, standard meals, arginine, etc.) and has the advantage of shorter duration and simple standardization. The glucagon test shows good intra-subject reproducibility, although in diabetic patients it may be influenced by variable prevailing blood glucose levels. Several applications of the glucagon test have been developed. In Type 1 diabetes, the glucagon test has been used to discriminate between patients with and without residual insulin secretion. This can be especially important during the first few months, or even years, following initiation of insulin therapy when attempts to stop the immunological destruction of the beta-cell are made. Assessment of endogenous insulin secretion is also important after pancreas or islet transplantation. In patients with Type 2 diabetes mellitus, in which residual endogenous insulin secretion is common, characterization of the disease may help in the choice of therapy for the individual patient (insulin, sulphonylureas or combined therapy). Thus, the glucagon test is a simple, reliable and useful tool for clinical evaluation of diabetes mellitus.
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PMID:Assessment of residual insulin secretion in diabetic patients using the intravenous glucagon stimulatory test: methodological aspects and clinical applications. 898 47

In diabetic nephropathy a major current concept for pathogenesis is increased collagen accumulation in the glomerulus by increased collagen synthesis and decreased degradation. In the present study, we tested the hypothesis whether arginine is able to influence kidney lipid peroxidation, glycoxidation, collagen accumulation, glucose-mediated cross-linking, hydroxy radical attack, protein oxidation, nitric oxide formation and albuminuria in the diabetic kk mouse. Ten diabetic kk mice were given arginine 50 mg/kg body weight, 10 diabetic kk mice were not treated and used as negative controls and 10 kk mice were kept as healthy controls. Our results show that oral administration of low-dose arginine reduces kidney collagen accumulation as reflected by kidney hydroxyproline, cross-linking as reflected by pentosidine, lipid peroxidation, glycoxidation as reflected by carboxymethyl lysine, kidney weight and albuminuria in the diabetic kk mouse. Albuminuria in untreated animals was closely correlated with lipid peroxidation. Our results in the spontaneously diabetic kk mouse representing type 2 diabetes mellitus therefore confirm and extend recent findings of collagen reduction by arginine in a different animal model. The mechanism of reducing proteinuria can be assigned to the blocking of lipid peroxidation products by L-arginine.
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PMID:Arginine reduces kidney collagen accumulation, cross-linking, lipid peroxidation, glycoxidation, kidney weight and albuminuria in the diabetic kk mouse. 904 44

Clustering of risk factors for cardiovascular disease related to insulin resistance may account for the increased incidence of vascular disease in these conditions and in non-diabetic subjects. To investigate the relationship between a coding polymorphism in the insulin receptor substrate-1 gene and the presence of cardiovascular risk factors, 209 patients with NIDDM and 452 subjects investigated for coronary artery disease (CAD) were studied. In the NIDDM subjects 22 (10.5%) were heterozygous at codon 972 for a polymorphism which codes for a glycine to arginine substitution and 187 (89.5%) were homozygous for the wild type. Patients with the mutation had lower levels of cholesterol compared with wild type (mean, 95% confidence intervals), 5.3 (4.9-5.8) vs 6.0 (5.9-6.2) mmol/l, respectively (P = 0.002), triglyceride 1.7 (1.4-2.1) vs 2.2 (2.0-2.4) mmol/l (P = 0.051), factor VII:C activity 109.5 (85.5-133.5) vs 133.5 (127-140)% (P = 0.057) and PAI-1 antigen, 16.0 (10.5-24.3) vs 22.2 (20.0-24.6) ng/ml (P = 0.054). There were no differences in body mass index, indices of glycaemic control, fasting insulin or the prevalence of hypertension. In patients with CAD, 55 (12.7%) were carriers of the mutation (including three homozygotes) (NIDDM vs CAD, NS). Although similar trends in cholesterol, factor VII, PAI-1 antigen and triglyceride existed between carriers of the mutation and the wild type, none reached statistical significance. The results indicate that the IRS-1 gene is not implicated in the pathogenesis of NIDDM or CAD.
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PMID:Insulin receptor substrate-1 gene polymorphism and cardiovascular risk in non-insulin dependent diabetes mellitus and patients undergoing coronary angiography. 921 52

The selective impairment of glucose-induced insulin secretion in NIDDM can be attributed to defects in the glucose-signaling system. An alteration in the activity of phosphofructokinase (PFK), a key enzyme in the glycolytic pathway, may play a role in the abnormal glucose-induced insulin secretion. In this study, we evaluated insulin secretion in transgenic (Tg) mice overexpressing the liver-type subunit of phosphofructokinase (PFKL). Three independently derived Tg-PFKL lines showed random and postprandial hyperglycemia with diminished acute insulin response following intravenous glucose tolerance load. Isolated islets of Tg-PFKL mice exhibited a shift to the right of the glucose insulin dose curve. However, the maximal insulin secretory capacity, as well as the potentiation effect by arginine, were retained. PFK activity in Tg-PFKL islets was increased by 30-70%, because of the overexpression of PFKL. Conceivably, a selective overexpression of the PFKL isoform in Tg-PFKL mice altered the enzymatic properties of the tetrameric PFK and thereby affected glucose metabolism. A similar phenomenon was previously observed in transfected PC12-PFKL cells. The data show that overexpression of PFKL in transgenic mice was associated with diminished glucose-induced insulin response and suggest a mechanism to explain the role of beta-cell PFK activity in glucose-induced insulin secretion.
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PMID:Impaired glucose-induced insulin response in transgenic mice overexpressing the L-phosphofructokinase gene. 928 40


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