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)

We investigated the relationship between the Trp64Arg mutation in the beta 3-adrenergic receptor gene and insulin sensitivity, which was evaluated by the euglycemic-hyperinsulinemic-clamp technique, in 54 patients with impaired glucose tolerance (IGT) or non-insulin dependent diabetes mellitus (NIDDM) who were not receiving insulin therapy. The frequencies of Trp/Trp, Trp/Arg, and Arg/Arg genotypes in the patients were 63.0, 33.3, and 3.7%, respectively, which did not differ significantly from those of the 227 controls (67.0, 33.3, and 3.7%, respectively, which did not differ significantly from those of the 227 controls (67.0, 31.3, and 1.8%, respectively). The mean glucose infusion rate of the 34 patients with Trp/Trp did not differ from that of the 18 patients with Trp/Arg (4.3 +/- 2.2 and 5.3 +/- 2.4 mg/kg/min, respectively); while that of the 2 patients with Arg/Arg was 11.5 mg/kg/min. There were no differences in the BMI or fat distribution in the abdomen between each genotype of patients, although the frequency of the Arg64 allele tended to increase with body mass index (BMI) in the control subjects under 60 years of age, which suggests that the mutation is involved in weight gain.
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PMID:Trp64Arg mutation of beta 3-adrenergic receptor and insulin sensitivity in subjects with glucose intolerance. 961 78

Subjects with NIDDM have increased plasma proinsulin concentrations, compared with nondiabetic subjects, both in absolute terms and as a proportion of circulating insulin-like molecules. It remains uncertain whether this reflects a primary beta-cell defect in proinsulin processing or is secondary to hyperglycemia. We addressed this question by assessing the effects of reducing hyperglycemia on relative hyperproinsulinemia in subjects with NIDDM. Eight subjects with NIDDM underwent three 8-week periods in a randomized crossover design of therapy with diet alone, sulfonylurea (gliclazide), or insulin (ultralente). The effects on beta-cell peptide concentrations were assessed 1) fasting, 2) in response to hyperglycemic clamping, and 3) in response to an injection of the nonglucose secretogogue arginine and compared with measurements in seven nondiabetic control subjects. Both sulfonylurea and insulin therapy substantially reduced fasting plasma glucose and glycosylated hemoglobin (HbA1e) concentrations, compared with diet therapy alone. The diabetic subjects on diet therapy had relative hyperproinsulinemia, assessed relative to C-peptide concentrations, fasting and in response to hyperglycemic clamping and arginine, compared with control subjects. Neither sulfonylurea nor insulin therapy altered the relative hyperproinsulinemia. Insulin therapy reduced fasting proinsulin concentrations from geometric mean 29.4 (1 SD range, 14.6-59.0) pmol/l on diet therapy to 18.7 (7.3-48.1) pmol/l (P < 0.05). A similar trend was evident with fasting C-peptide concentrations with a reduction from 0.9 (0.6-1.4) nmol/l on diet therapy to 0.6 (0.4-0.9) nmol/l (P = 0.06), so that the relative hyperproinsulinemia, assessed as the ratio of fasting proinsulin to C-peptide, was unchanged by insulin. Similarly, insulin therapy failed to reduce the ratio of proinsulin to C-peptide concentrations in response to a hyperglycemic clamp and in the acute incremental response to arginine. Failure to improve the relative hyperproinsulinemia of NIDDM, despite significant reduction of hyperglycemia with exogenous insulin therapy, supports the hypothesis that relative hyperproinsulinemia in NIDDM is a reflection of a primary beta-cell defect rather than being secondary to hyperglycemia.
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PMID:Relative hyperproinsulinemia of NIDDM persists despite the reduction of hyperglycemia with insulin or sulfonylurea therapy. 931 49

Proliferative diabetic retinopathy is an important cause of visual impairment. We investigated whether the polymorphism of the beta 3-adrenoreceptor (beta 3-AR) gene, which is associated with insulin resistance and an earlier onset of NIDDM, was associated with proliferative diabetic retinopathy (PDR) in 215 Japanese NIDDM patients with a duration of diabetes of > or = 10 years. The polymorphism of the beta 3-AR gene was determined by polymerase chain reaction-restriction fragment length polymorphism analysis. The Trp64Arg allele of the beta 3-AR gene was significantly more frequent in the NIDDM patients with PDR (P = 0.002), but not in those with non-PDR (P = 0.151), than in NIDDM patients without diabetic retinopathy. Those with the mutation had an earlier onset of diabetes, a longer duration of diabetes, and higher current and maximal BMI values, compared with those without the mutation. Moreover, this mutation was also associated with higher serum triglyceride and decreased HDL-cholesterol levels. When adjustment was made for age, age at diagnosis, duration of diabetes, current BMI, systolic blood pressure, HbA1e, and serum lipids in a multiple regression analysis, a significant association was found between the Trp64Arg allele and diabetic retinopathy (P = 0.039). The Arg/Arg or Arg/Trp genotype was significantly associated with PDR, compared with the Trp/Trp genotype, with an odds ratio of 2.55 (95% CI 1.25-5.16). We concluded that the beta 3-AR gene polymorphism is a newly identified risk factor for PDR.
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PMID:Beta 3-adrenoreceptor gene polymorphism: a newly identified risk factor for proliferative retinopathy in NIDDM patients. 931 61

One form of maturity-onset diabetes of the young, MODY3, is characterized by a severe insulin secretory defect, compared with MODY2, a glucokinase-deficient diabetes. It has recently been shown that mutations of the gene encoding the transcription factor hepatocyte nuclear factor (HNF)-1 alpha cause MODY3. Because of the rapid progress to overt diabetes and the high prevalence of required insulin treatment in patients with MODY3, we screened the HNF-1 alpha gene for mutations in Japanese subjects with IDDM. Ten exons and flanking introns of the HNF-1 alpha gene in these subjects were amplified by polymerase chain reaction and direct sequencing of the products. Mutations were identified in three (5.5%) of the 55 unrelated subjects with IDDM. A missense mutation of R272H (replacement of Arg by His in codon 272) in the DNA binding domain of HNF-1 alpha was found in a subject who developed IDDM 1 year after diagnosis of NIDDM at 8 years of age. A frameshift mutation of P291 fsinsC (insertion of a C in a polyC tract around codon 291 for Pro), which would generate a mutant truncated protein of 340 amino acids, was found in a subject who started insulin treatment when hyperglycemia and ketonuria were noticed at 13 years of age. A missense mutation of R583G (replacement of Arg by Gly in codon 583) in the transactivation domain of HNF-1 alpha was found in a subject with sudden-onset IDDM at 20 years of age. None of these mutations were present in 100 nondiabetic subjects (200 normal chromosomes). These results indicate that the HNF-1 alpha gene defects could lead to the development of not only early-onset NIDDM but also IDDM, implicating the importance of subclassification of HNF-1 alpha-deficient IDDM from a classical type of autoimmune-based IDDM in Japanese.
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PMID:Identification of mutations in the hepatocyte nuclear factor (HNF)-1 alpha gene in Japanese subjects with IDDM. 931 63

Hepatocyte nuclear factor-4 alpha (HNF-4 alpha) is a member of the nuclear receptor superfamily, a class of ligand-activated transcription factors. A nonsense mutation in the gene encoding this transcription factor was recently found in a white family with one form of maturity-onset diabetes of the young, MODY1. Here, we report the exon-intron organization and partial sequence of the human HNF-4 alpha gene. In addition, we have screened the 12 exons, flanking introns and minimal promoter region for mutations in a group of 57 unrelated Japanese subjects with early-onset NIDDM/MODY of unknown cause. Eight nucleotide substitutions were noted, of which one resulted in the mutation of a conserved arginine residue, Arg127 (CGG)-->Trp (TGG) (designated R127W), located in the T-box, a region of the protein that may play a role in HNF-4 alpha dimerization and DNA binding. This mutation was not found in 214 unrelated nondiabetic subjects (53 Japanese, 53 Chinese, 51 white, and 57 African-American). The R127W mutation was only present in three of five diabetic members in this family, indicating that it is not the only cause of diabetes in this family. The remaining seven nucleotide substitutions were located in the proximal promoter region and introns. They are not predicted to affect the transcription of the gene or mRNA processing and represent polymorphisms and rare variants. The results suggest that mutations in the HNF-4 alpha gene may cause early-onset NIDDM/MODY in Japanese but they are less common than mutations in the HNF-1 alpha/MODY3 gene. The information on the sequence of the HNF-4 alpha gene and its promoter region will facilitate the search for mutations in other populations and studies of the role of this gene in determining normal pancreatic beta-cell function.
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PMID:Organization and partial sequence of the hepatocyte nuclear factor-4 alpha/MODY1 gene and identification of a missense mutation, R127W, in a Japanese family with MODY. 931 65

The spontaneously diabetic non-obese GK (Goto-Kakizaki) rat exhibits high basal plasma glucose and insulin levels and poor glucose-induced insulin secretion, which makes it a suitable model for non-insulin dependent diabetes mellitus, NIDDM. The aim of this study was to investigate the handling of cytosolic free Ca2+ concentration ([Ca2+]i), the key regulator of insulin secretion, in GK rat single pancreatic islets. For this purpose the influence of high glucose (16.7 mM) and arginine (20 mM) on [Ca2+]i was studied in GK and Wistar rat islets, which served as controls. The data obtained suggest that glucose which through its metabolism generates ATP needed for closure of the KATP channels and membrane depolarization, induces a delayed [Ca2+]i response in the GK rat pancreatic islet. This delay in [Ca2+]i response is likely to result from a defective metabolism of glucose in the diabetic islet.
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PMID:Delayed Ca2+ response to glucose in diabetic GK rat. 934 82

The production of insulin from proinsulin involves cleavage of intact proinsulin into proinsulin conversion intermediates by the processing of enzymes PC2 and PC3 before fully processed insulin is produced. Intact proinsulin and these conversion intermediates are measured in many immunoreactive insulin (IRI) assays, and therefore contribute to the absolute IRI measurement. The proportion of basal IRI made up of proinsulin (PI)-like molecules (PI/IRI) is increased in NIDDM. Whether stimulated IRI levels are similarly made up of disproportionately increased PI/IRI or whether the relative proportions of proinsulin and its conversion intermediates are altered has not been evaluated. An index of the efficiency of proinsulin processing within the pancreatic beta-cell can be achieved by measuring PI/IRI immediately following acute stimulation of beta-cell secretion, and then determining the proportion of intact proinsulin and proinsulin conversion intermediates contributing to circulating proinsulin-like molecules. In this study, we determined the PI/IRI levels under basal and arginine-stimulated conditions in 17 healthy and 16 NIDDM subjects; high-performance liquid chromatography (HPLC) was also performed in a subset of these subjects to measure the relative contribution of intact proinsulin and its conversion intermediates to total proinsulin-like molecules. In NIDDM subjects, levels of both basal (44.6 +/- 9.6 vs. 9.3 +/- 1.5 pmol/l; P = 0.0007) and stimulated (64.0 +/- 12.7 vs. 19.8 +/- 2.8 pmol/l; P = 0.001) proinsulin-like molecules were higher than in healthy subjects. Although IRI was higher in NIDDM than in control subjects under basal conditions (106 +/- 19 vs. 65.1 +/- 8.1 pmol/l; P = 0.05), it was lower in NIDDM than in control subjects following stimulation (increment: 257 +/- 46 vs. 416 +/- 51 pmol/l; P = 0.03). PI/IRI ratios were increased in NIDDM subjects under both basal (43.3 +/- 5.0 vs. 14.0 +/- 1.3%; P < 0.0001) and stimulated (increment: 10.1 +/- 2.1 vs. 2.5 +/- 0.2%; P = 0.0006) conditions, compatible with the release of a disproportionately increased amount of proinsulin-like products. HPLC analysis revealed that, in the stimulated state, intact proinsulin made up 40.1 +/- 6.7% of proinsulin-like molecules in NIDDM individuals (n = 9) and 30.1 +/- 5.6% in healthy subjects (n = 7; NS). The remainder of the proinsulin-like molecules comprised the des-31,32-split proinsulin conversion intermediate. The increase in PI/IRI in NIDDM under basal and especially under stimulated conditions suggests that proinsulin conversion is indeed perturbed in this disorder. Because the relative proportions of intact and des-31,32-split proinsulin are similar in both healthy and NIDDM subjects, the orderly cleavage of proinsulin at its two junctions appears preserved. However, at the time of exocytosis, the secretory granule in the islet of NIDDM subjects contains an increased proportion of incompletely processed proinsulin, presumably reflecting a slower rate of conversion or granules' reduced time of residence in beta-cells.
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PMID:Release of incompletely processed proinsulin is the cause of the disproportionate proinsulinemia of NIDDM. 935 18

The periodontal condition of 30 type II non-insulin-dependent diabetic patients (NIDDM) was evaluated and compared to that of 30 non-diabetic patients (age range, 30-77 years). Glycosylated hemoglobin and fasting glucose tests were used to measure the metabolic control of the patients, and the BANA (N-benzoyl-DL-arginine-naphthylamide) test was used to analyze subgingival microbiota. At the end of the study, the diabetic group was subdivided into three groups according to the degree of diabetic control: controlled, moderately controlled and poorly controlled. The non-parametric chi square test was used for statistical analyses: BANA test--no statistically significant differences were found between the two groups when analyzed as a whole. When the diabetic patients were subdivided and compared to the control group, significance was detected (P < 0.01) in the total frequencies of the BANA scores (negative, moderately positive and positive: 1, 2, and 3, respectively) in the 5-, 6-, and 7-mm pockets and also in the 4-mm pockets in the poorly controlled group.
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PMID:Periodontal disease progression in type II non-insulin-dependent diabetes mellitus patients (NIDDM). Part II--Microbiological analysis using the BANA test. 948 34

We studied the effects of troglitazone (200-800 mg daily) or placebo on carbohydrate metabolism in 18 subjects with type 2 diabetes (mean age, 66 yr; body mass index, 27.7 kg/m2) at baseline and after taking medication for 12 weeks. We measured fasting proinsulin (PI) and immunoreactive insulin (IRI) levels in all subjects. Thirteen subjects underwent additional metabolic studies, including injection of arginine to determine the acute insulin response, and an i.v. glucose tolerance test to measure the insulin sensitivity index (SI) and glucose effectiveness at zero insulin using the minimal model, i.v. glucose tolerance, and acute insulin response to glucose. Troglitazone treatment resulted in a decrease in fasting plasma glucose from 11.2 +/- 0.7 to 9.6 +/- 0.9 mmol/L (P = 0.02). This was associated with a decrease in the fasting IRI concentration (111 +/- 20 to 82 +/- 13 pmol/L; P = 0.02) and a trend toward a decrease in the fasting PI concentration (43 +/- 11 to 25 +/- 4 pmol/L; P = 0.06). A significant decrease in PI/IRI was observed (38.3 +/- 3.6% to 32.6 +/- 3.2%; P = 0.04). Troglitazone therapy was also associated with a decrease in the acute insulin response to arginine (226 +/- 34 to 167 +/- 25 pmol/L; P = .01) and a near-significant percent increase in S(I) (75 +/- 35%; P = 0.06). Glucose effectiveness at zero insulin, i.v. glucose tolerance, and acute insulin response to glucose did not change. Thus, we found that the decrease in plasma glucose during troglitazone therapy is associated with a dose-related decrease in PI/IRI and an increase in S(I), suggesting that changes in both B cell function and insulin sensitivity contribute to the improvement in metabolic status.
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PMID:Effect of troglitazone on B cell function, insulin sensitivity, and glycemic control in subjects with type 2 diabetes mellitus. 950 34

We report the characterization of a new insulinotropic compound, 4-hydroxyisoleucine. This amino acid has been extracted and purified from fenugreek seeds, which are known in traditional medicine for their antidiabetic properties. 4-Hydroxyisoleucine increases glucose-induced insulin release, in the concentration range of 100 micromol/l to 1 mmol/l, through a direct effect on isolated islets of Langerhans from both rats and humans. The stimulating effect of 4-hydroxyisoleucine was strictly glucose dependent; indeed, ineffective at low (3 mmol/l) or basal (5 mmol/l) glucose concentrations, the amino acid potentiated the insulin secretion induced by supranormal (6.6-16.7 mmol/l) concentrations of glucose. In addition, in the isolated perfused rat pancreas, we could show 1) that the pattern of insulin secretion induced by 4-hydroxyisoleucine was biphasic, 2) that this effect occurred in the absence of any change in pancreatic alpha- and delta-cell activity, and 3) that the more glucose concentration was increased, the more insulin response was amplified. Moreover, 4-hydroxyisoleucine did not interact with other agonists of insulin secretion (leucine, arginine, tolbutamide, glyceraldehyde). Therefore, we conclude that 4-hydroxyisoleucine insulinotropic activity might, at least in part, account for fenugreek seeds' antidiabetic properties. This secretagogue may be considered as a novel drug with potential interest for the treatment of NIDDM.
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PMID:4-Hydroxyisoleucine: a novel amino acid potentiator of insulin secretion. 951 14


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