UMLS:C0011860 - FACTA Search

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Query: UMLS:C0011860 (type 2 diabetes)
57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of the present study was to assess the beta cell response to glimepiride, administered orally, during and following a hyperglycaemic clamp in 14 NIDDM patients (7 males), aged 62.5 (St. Dev. 7.7) years with a body mass index of 27.3 (2.8) kg m(-2) and HbA(Ic) of 7.0 (0.7)% at baseline, in a placebo controlled study. All patients were on stable treatment with a second generation sulphonylurea for at least 8 weeks prior to randomization and received placebo (P) or 5 mg glimepiride (G) daily for 7 days and 10 mg prior to a hyperglycaemic clamp (10.9 mmol l(-1) for 60 min, preceded by i.v. insulin infusion to stabilize fasting blood glucose levels at 4.0 mmol l(-1)). The clamp was followed by an observation period of 2 h in 5 subjects and 3.5 h in the next 9 subjects, during which blood glucose and plasma insulin, C-peptide and proinsulin levels were measured at regular intervals to determine the effect of glimepiride on the interaction between changes in glycaemia and plasma levels of beta cell products. Neither G nor P elicited a first phase insulin response. Areas under plasma insulin curve during the 1 h hyperglycaemic clamp were 94.2 (39.5) vs 69.1 (26.5) pmol.h l(-1) in G and P clamps, respectively (p = 0.002). Total areas (AUC) under the plasma insulin curve were 377 (145) vs 271 (113) pmol.h l(-1) in G and P clamps (< 0.05). Total AUCs of C-peptide were 309 (96) and 259 (102 pmol.h.(-1), in G and P clamps, respectively, p = 0.01. Total AUCs of proinsulin were 176 (77) versus 119 (56) pmol.h l(-1) in G and P clamps, respectively, p = 0.004. Five hours after G and P administration blood glucose levels were 4.7) 92.1) mmol(-1) in the G clamp vs 6.2 (1.9) mmol l(-1) in the P clamp (p = 0.001). The number of hypoglycaemic events (blood glucose < 3.0 mmol l(-1)) in the 3.5 h observation period was 3 in G clamps vs 0 in P clamps (p = ns). In conclusion, glimepiride stimulates the second phase insulin and proinsulin secretion. The lowering of blood glucose levels is not accompanied by a commensurate inhibition of the insulin secretion. Further studies are required to compare this new drug with currently available oral hypoglycaemic agents, with respect to glycaemic control and the risk of hypoglycaemia.
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PMID:Beta cell response to oral glimepiride administration during and following a hyperglycaemic clamp in NIDDM patients. 922 93

Women with gestational diabetes tend to progress to noninsulin-dependent diabetes (NIDDM) with a high cumulative incidence relative to the general population. These women have also been shown to be insulin resistant and may represent a variant of the insulin resistance syndrome or Syndrome X. Our previous studies indicated that administered insulin was associated with an increase in blood pressure in women with gestational diabetes, raising the question that insulin levels per se contribute to blood pressure in these women. We developed a means by which the insulin levels of a given pregnant individual might be estimated called the Fraction of Circulating Insulin Level Relative to Normal (FOCILRN = C-PEPTIDE/2.0 + TOTAL DAILY INSULIN DOSE/CALCULATED DAILY INSULIN REQUIREMENT BASED ON WEIGHT AND GESTATIONAL WEEK). The formula was applied to 15 nonhypertensive pregnant women of comparable obese phenotype (Rubenesque) with varying degrees of glucose tolerance (4 normal, 5 gestational diabetes treated with diet alone, 4 gestational diabetes treated with insulin, and 2 noninsulin-dependent diabetes). Blood pressure was quantified at the beginning of the study (gestational weeks 24-34) and again 4-8 weeks later using a 24-hr monitor. Correlation analysis was used to test for a relationship between the FOCILRN and blood pressure. The increase in mean arterial pressure was found to be continuous and linear with increasing insulin exposure as quantified by FOCILRN. The correlation was significant for all subjects (r = 0.961, p < 0.001) and remained significant even with removal of patients with NIDDM (r = 0.857, p < 0.001). The nighttime heart rate, systolic and diastolic blood pressures were found to be significantly correlated with FOCILRN (r = 0.651, p < 0.01, r = 0.724, p < 0.001, and r = 0.831, p < 0.001, respectively). The difference between the maximum and minimum diastolic blood pressure values between 12:00 AM and 6:00 AM between sessions 1 and 2 significantly differed among the groups with women on insulin having the highest FOCILRN having the least variation in blood pressure. In nonhypertensive women of obese phenotype (Rubenesque), increasing insulin exposure is associated with increasing mean arterial blood pressure and less variability of nocturnal blood pressure. These data provide support for the hypothesis that insulin may mediate blood pressure response in genetically vulnerable individuals. The identification of the Rubenesque phenotype during gestation may be a clinically useful marker for individuals at risk for Syndrome X.
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PMID:The Rubenesque pregnancy: a progression towards higher blood pressure correlates with a measure of endogenous and exogenous insulin levels. 925 24

Presymptomatic autoantibody markers of insulin-dependent (Type 1) diabetes mellitus (IDDM) are less well characterized in adults than in children. We quantitated anti-GAD, anti-ICA512 and ICA by titration to endpoint and compared frequencies and levels in 139 Finnish women from whom 390 serum samples had been archived during antecedent pregnancies for 10 years before and up to 1 year after diagnosis of diabetes. Also, we compared the autoantibody status in adults with IDDM with that of children with newly diagnosed IDDM. Of the 35 women seropositive for 1 or more autoantibodies, 77% developed IDDM, 11% non-insulin-dependent (Type 2) diabetes mellitus (NIDDM), 9% gestational diabetes mellitus requiring insulin (GDM-ins) and 3% GDM controlled by diet. The frequency of antibodies during the 10-year presymptomatic period was 83% for anti-glutamic acid decarboxylase (GAD), 52% for anti-ICA512 and 41% for islet cell antibodies (ICA) for those who developed IDDM, 25%, 17%, and 0% for NIDDM, 12%, 4%, and 8% for GDM-ins and 1%, 0%, and 1% for GDM-diet. Anti-GAD was found most consistently in early samples; 13 of 15 with a single autoantibody at their first test had anti-GAD. Among those who developed IDDM, the frequency of anti-GAD was constant, anti-ICA512 increased threefold, and ICA increased slightly before diagnosis. Levels of the autoantibodies varied between subjects, but were relatively stable in individual subjects. Comparison of tests on the women, and children after diagnosis of IDDM, showed the frequencies and levels to be the same for anti-GAD but lower for anti-ICA512 and ICA in adults. Our observations show in women the long latency of seropositivity before overt IDDM, the predominance of anti-GAD among these three serological markers, and the presence of these markers in NIDDM presumably representing a NIDDM phase of autoimmune insulitis.
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PMID:Autoantibodies associated with presymptomatic insulin-dependent diabetes mellitus in women. 927 95

Non-insulin-dependent diabetes mellitus (NIDDM) is associated histopathologically with islet amyloid deposits of which a major component is islet amyloid polypeptide (IAPP)/amylin. We examined whether endogenous IAPP controls insulin secretion via a local effect within pancreatic islets and whether overexpression of this peptide contributes to pancreatic beta-cell dysfunction in this disease. Transgenic mice expressing human IAPP in pancreatic beta cell were used in this study. Human IAPP expression did not influence the mouse proinsulin mRNA level and insulin content. Glucose-induced insulin secretion was decreased in the isolated pancreatic islets of transgenic mice. MIN6, a glucose-responsive pancreatic beta-cell line, was transfected with human IAPP cDNA by a lipofectin method. Human IAPP expression was confirmed by RNA blot and immunohistochemical analysis. In two transfectants expressing the largest amount of human IAPP, insulin secretion was increased in response to glucose stimulation; however, the magnitude of the insulin response in cells transfected with human IAPP was smaller than in control clones. Insulin content was not influenced by the expression. We conclude that endogenous IAPP inhibits insulin secretion via an autocrine effect within pancreatic islets, and that the impaired insulin secretion in this disease may be partly caused by overexpression of IAPP.
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PMID:Expression of human islet amyloid polypeptide/amylin impairs insulin secretion in mouse pancreatic beta cells. 928 94

The structure of IGF-I is similar to that of insulin, having 43% sequence homology with human proinsulin. Both peptides can induce metabolic and mitogenic effects through their own specific receptors, which also share many structural and functional similarities. Primarily involved in the regulation of growth, IGF-I may have a role in the control of glucose homeostasis, facilitated by changes in its binding proteins. RhIGF-I can reduce hyperglycaemia in patients with severe insulin resistance by direct effects mediated via the IGF-I receptor. Improvements in insulin sensitivity, and reductions in blood glucose levels and HbA1c values have also been seen in subjects with NIDDM. Enhanced insulin sensitivity with low dose rhIGF-I has been observed in adolescents and young adults with IDDM. These effects are closely related to reductions in growth hormone levels, but there is also evidence of complex interactions with insulin at the post receptor level and with IGFBP-1. In recent randomised, double-blind, placebo controlled trials, rhIGF-I given as an adjunct to insulin therapy reduced to HbA1c values. Although the ideal dosage to obtain therapeutic efficacy without complications has yet to be determined, rhIGF-I may have an important role in the treatment of hyperglycaemia and insulin resistance in diabetes.
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PMID:Does recombinant human insulin-like growth factor-1 have a role in the treatment of diabetes? 930 Feb 21

Serum insulin concentrations have been used as markers of insulin resistance in population studies examining the relationship between insulin resistance and blood pressure, but the relationship is variable among studies. We hypothesized that differences in cross-reactivity of insulin assays with proinsulin and its split/des-amino products might account for the variation. We therefore examined fasting and post-glucose load serum insulin concentrations (determined by both specific and conventional assays), insulin sensitivity (measured by the euglycaemic clamp technique), and blood pressure, in a group of 56 diabetic (NIDDM) and non-diabetic subjects. Insulin concentrations as measured by the two methods were highly correlated (r = 0.97, p < 0.0001), and the relationships among serum insulin concentrations, insulin sensitivity and blood pressure were independent of assay method; for example, in non-diabetic subjects the univariate correlation between log10AUC insulin and insulin sensitivity index was similar with both methods [r = -0.81 vs. r = -0.82, p < 0.0001 (specific vs. conventional assay)]. Discrepancies between studies in the relationship between serum insulin concentrations and blood pressure are unlikely to be due to cross-reactivity of conventional insulin assays with proinsulin-like molecules.
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PMID:Specific insulin assays, insulin sensitivity and blood pressure. 930 31

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

Non-diabetic first degree relatives of non-insulin-dependent diabetic (NIDDM) families are at increased risk of developing diabetes mellitus, and have been studied to identify early metabolic abnormalities. Hormone concentrations measured by specific enzyme immunoassays were assessed in non-diabetic relatives of North European extraction, and control subjects with no family history of diabetes were matched for age, sex and ethnicity. A 75-g oral glucose tolerance test was conducted and those with newly diagnosed NIDDM were excluded. Basal insulin resistance was determined by homeostasis model assessment (HOMA), and hepatic insulin clearance by C-peptide:insulin molar ratio. Relatives (n = 150) were heavier (BMI: p < 0.0001) than the control subjects (n = 152), and had an increased prevalence of impaired glucose tolerance (15 vs 3%, p < 0.01). The relatives had increased fasting proinsulin levels and decreased C-peptide levels following the glucose load, while insulin levels were increased at all time points. To examine whether the differences in hormone levels were secondary to the differences in glucose tolerance and adiposity, we studied 100 normal glucose tolerant relatives and control subjects pair-matched for age, sex, waist-hip ratio and BMI. The differences in proinsulin levels were no longer apparent. However, the relatives remained more insulin resistant, and had decreased C-peptide levels and C-peptide:insulin ratios at all time points. In conclusion, we have identified several metabolic abnormalities in the normal glucose tolerant relatives, and propose that the decreased hepatic insulin clearance helps to maintain normoglycaemia in the face of combined insulin resistance and decreased insulin secretion.
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PMID:Multiple metabolic abnormalities in normal glucose tolerant relatives of NIDDM families. 934

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

Plasma levels of proinsulin and its conversion intermediates are elevated in NIDDM patients. Recent studies have suggested that proinsulin levels are also increased relative to insulin levels in subjects who subsequently develop NIDDM. This may be due to insulin resistance or a defect in proinsulin processing or insulin secretion. If insulin resistance is the trigger, the proinsulin-to-insulin ratio would be higher in insulin-resistant subjects than in insulin-sensitive subjects. We examined the association of fasting proinsulin, 32,33 split proinsulin, and the proinsulin-to-insulin ratio with insulin sensitivity (SI), estimated by a frequently sampled intravenous glucose tolerance test and the minimal model in 138 normoglycemic subjects ages 53-61 years. We also investigated the relation of proinsulins and the proinsulin-to-insulin ratio to acute insulin response (AIR). Fasting specific insulin (r = -0.64), intact proinsulin (r = -0.43), and 32,33 split proinsulin (r = -0.54) concentrations were inversely correlated and the proinsulin-to-insulin ratio positively (r = 0.31) correlated with SI (P < 0.001). Fasting specific insulin (r = 0.64), intact proinsulin (r = 0.35), and 32,33 split proinsulin (r = 0.45) concentrations were positively correlated and proinsulin-to-insulin ratio (r = -0.40) inversely correlated with AIR (P < 0.001). The proinsulin-to-insulin ratio increased by increasing levels of SI (quartiles of SI from low to high: 0.048, 0.078, 0.078, 0.068; P = 0.012) and decreased by increasing AIR (quartiles of AIR from low to high: 0.088, 0.068, 0.058, 0.058; P = 0.005). These associations were independent of age, sex, BMI, and waist-to-hip ratio. Furthermore, the relation between the proinsulin-to-insulin ratio and AIR was independent of SI. In conclusion, in normoglycemic subjects, insulin resistance (low SI) was associated with a low rather than a high proinsulin-to-insulin ratio. Subjects who maintained normoglycemia with a low AIR had an increased proinsulin-to-insulin ratio compared with those who needed high AIR to maintain normoglycemia. These results suggest that, in subjects with normal glucose tolerance, insulin resistance does not induce increased proinsulin relative to insulin secretion, but rather is associated with enhanced processing of proinsulin.
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PMID:The relation of proinsulin, insulin, and proinsulin-to-insulin ratio to insulin sensitivity and acute insulin response in normoglycemic subjects. 939 85

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