Impaired Glucose Tolerance Subjects Research Articles

Markers of endothelial dysfunction in hyperglycaemic Asian Indian subjects

Objective: The aims of this study were the following: (1) to determine the levels of endothelin-1(ET1), soluble adhesion molecules like intracellular adhesion molecule-1 (sICAM-1), and vascular cell adhesion molecule-1 (sVCAM-1) in different stages of glucose intolerance and to identify a suitable marker of endothelial dysfunction and (2) to determine the possible association of these biochemical parameters with diabetic complications and with impaired glucose tolerance (IGT). Research Design and Methods: In this cross-sectional study, plasma ET1, sICAM-1, and sVCAM-1 were measured by enzyme-linked immunosorbent assay (ELISA) in 20 nondiabetic subjects, in 15 subjects with IGT, in 21 Type 2 diabetic subjects without any complication, and in 21 Type 2 diabetic patients with nephropathy and retinopathy. Results: Median ET1 levels were significantly elevated ( P=.004) in IGT subjects (0.31 fmol/ml) when compared with the nondiabetic subjects (0.11 fmol/ml). Subjects with nephropathy (0.50 fmol/ml) had significantly higher ( P=.002) ET1 values when compared with those without complications (0.40 fmol/ml). The levels of sICAM-1 and sVCAM-1 did not show any significant difference among the groups. ET1 showed correlation with age, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting plasma glucose (FPG), 2 h post glucose (2hPG), waist-to-hip ratio (WHR), total white blood corpuscles count, glycosylated haemoglobin (HbA1c), triglycerides (TG), very-low-density lipoprotein cholesterol (VLDLc), and hypertension (HTN). In the multiple linear regression analysis, plasma ET1 was significantly associated with the presence of Type 2 diabetes either with or without complications ( P<.0001 and P=.0098, respectively), WHR ( P=.0063), and sVCAM-1 ( P=.0051). The total variance explained by the above-mentioned parameters was 55%. Conclusion: Elevated levels of ET1 were present in subjects with IGT and in Type 2 diabetic subjects. Such associations with sICAM-1 or sVCAM-1 in these subjects were not seen. ET1 could be an early marker of endothelial dysfunction, which appeared to occur even in the subclinical stages of hyperglycaemia.

The Singapore impaired glucose tolerance follow-up study: does the ticking clock go backward as well as forward?

To 1). document the change in glucose tolerance for subjects with normal glucose tolerance (NGT) and impaired glucose tolerance (IGT) over time, 2). identify baseline factors associated with worsening of glucose tolerance, and 3). determine whether cardiovascular disease (CVD) risk factors associated with IGT improved in tandem with glucose tolerance. Subjects with IGT and NGT (matched for age, sex, and ethnic group) were identified from a cross-sectional survey conducted in 1992. Subjects with IGT (297) and NGT (298) (65.0%) were reexamined in 2000. Glucose tolerance (assessed by 75-g oral glucose tolerance test), anthropometric data, serum lipids, blood pressure, and insulin resistance were determined at baseline and at the follow-up examination. For NGT subjects, 14.0% progressed to IGT and 4.3% to diabetes over 8 years. For IGT subjects, 41.4% reverted to NGT, 23.0% remained impaired glucose tolerant, and 35.1% developed diabetes. Obesity, hypertriglyceridemia, higher blood pressure, increased insulin resistance, and lower HDL cholesterol at baseline were associated with worsening of glucose tolerance in both IGT and NGT subjects. Those with IGT who reverted to NGT remained more obese and had higher blood pressure than those with NGT in both 1992 and 2000. However, serum triglyceride, HDL cholesterol, and insulin resistance values in 2000 became indistinguishable from those of subjects who maintained NGT throughout the study period. Some, but not all, CVD risk factors associated with IGT and with the risk of future diabetes normalize when glucose tolerance normalizes. Continued surveillance and treatment in subjects with IGT, even after they revert to NGT, may be important in the prevention of CVD.

Basal and dynamic proinsulin-insulin relationship to assess beta-cell function during OGTT in metabolic disorders.

The fasting proinsulin-to-insulin ratio is a currently used marker of beta-cell dysfunction. This ratio is calculated at the basal condition, but its behavior in dynamic conditions, i.e., during glucose stimulation, could be more informative. Given the different kinetics of the peptides, a mathematical model was necessary to analyze the oral glucose tolerance test (OGTT) data of insulin, C-peptide, and proinsulin in 55 healthy (NGT), 30 impaired glucose-tolerant (IGT), and 31 type 2 diabetic (T2DM) subjects. The model provided for secretion and disappearance of the peptides and an index of beta-cell function under dynamic conditions. Total proinsulin secretion during the OGTT was not different (P > 0.053) among NGT (0.17 +/- 0.01 mmol/l in 3 h), IGT (0.22 +/- 0.02), and T2DM (0.21 +/- 0.02) subjects. The proinsulin-to-insulin molar ratio measured from basal samples was higher (P < 0.0001) in T2DM (0.39 +/- 0.05) than in NGT (0.14 +/- 0.01) and IGT (0.13 +/- 0.02) subjects, and similar results (P < 0.003) were found by the dynamic index (0.27 +/- 0.04, 0.14 +/- 0.01, 0.15 +/- 0.01 in T2DM, NGT, IGT subjects, respectively). The basal ratio significantly correlated with the dynamic index, and the regression line slope was lower than 1 (0.43 +/- 0.08, 0.61 +/- 0.10, and 0.56 +/- 0.03 in NGT, IGT, and T2DM subjects, respectively, P < 0.0001). Impaired beta-cell function in T2DM could then be indicated by proinsulin-to-insulin indexes at both basal and dynamic phases.

Lack of association between serum paraoxonase 1 activities and increased oxidized low-density lipoprotein levels in impaired glucose tolerance and newly diagnosed diabetes mellitus.

Several in vitro investigations showed that serum paraoxonase 1 (PON1) that is located on high-density lipoprotein reduces or prevents low-density lipoprotein (LDL) oxidation and therefore retards atherosclerosis. Accordingly, the well documented loss of PON1 activity in patients with overt diabetes mellitus was causally related to the development of micro- and macroangiopathy in the disease course. Because vascular complications start already in prediabetic states, e.g. impaired glucose tolerance (IGT), we investigated serum PON1 activities and circulating levels of oxidized LDL (oxLDL) in 125 IGT subjects, 75 patients with newly diagnosed diabetes mellitus type 2, and 403 individuals with normal glucose tolerance. Using three different substrates (paraoxon, phenylacetate, p-nitrophenylacetate) we found that PON1 activity is not significantly altered in IGT and diabetes mellitus subjects, respectively, when compared with normoglycemic controls. Both IGT subjects and diabetes mellitus patients had significantly increased levels of oxLDL in the circulation. However, serum PON1 activity variations and glutamine/arginine phenotype were not related to the levels of oxLDL. The data suggest that 1) PON1 activity loss is an event occurring later in the course of diabetes mellitus; and 2) PON1 does not affect oxidation of circulating LDL, at least in early diabetes mellitus.

Relation of C-reactive protein to features of the metabolic syndrome in normal glucose tolerant, impaired glucose tolerant, and newly diagnosed type 2 diabetic subjects

To determine the relationship between CRP levels and the components of MS in normal glucose tolerant (NGT), impaired glucose tolerant (IGT), and Type 2 diabetic subjects. A based cross-sectional population study was performed. Eligible subjects, men and non-pregnant women, 30 to 64 year of age, were randomly recruited. Subjects with acute or chronic diseases were excluded. Only newly diagnosed type 2 diabetic or hypertensive subjects were included. Disorders related to CRP increase, also were exclusion criteria. In accordance to WHO proposal, components of MS were: High Blood Pressure, Dyslipidemia, Obesity, and Microalbuminuria, and MS was defined, for the NGT, if at least two of the criteria were fulfilled and in addition the subject had insulin resistance. The MS in IGT and DM subjects was defined if at least two of the criteria were fulfilled. CRP was significantly associated with MS for the NGT (Odds ratio -OR- 3.8, CI(95%) 1.6-14.8), IGT (OR 4.9, CI(95%) 1.2-15.5), and diabetes (OR 5.6, CI(95%) 1.9-10.2). For NGT, after adjustment for obesity, CRP was not longer associated with MS. After adjust for obesity and fasting glucose (FG), the relationship between CRP and MS for IGT was lost. Finally, after adjustment for obesity, FG, and microalbuminuria, CRP was not longer associated with MS for diabetic subjects. This study show a significant relationship between CRP and MS which is maintained only by obesity in the NGT, by obesity and FG in the IGT, and by obesity, FG, and microalbuminuria in the newly diagnosed diabetic subjects.

1P-0302 Importance of the serum levels of lipoprotein (a) in determining the risk of ischemic heart disease in longtime vegetarians

The Trp64Arg variant of the β3-adrenergic receptor (β3-AR) gene is relatively common in Japanese people. We hypothesized that this variant may be associated with obesity and insulin resistance when combined with a westernized lifestyle. To test this hypothesis, we investigated the relationships between the β3-AR gene variant and obesity and insulin resistance in Japanese-American men, who are known to have a higher prevalence of type 2 diabetes mellitus (DM). The subjects were 152 Japanese-American men living in Hawaii, 83 with normal glucose tolerance (NGT), 40 with impaired glucose tolerance (IGT). and 29 with DM. The frequency of the Trp64Arg allele of the β3-AR gene was 0.18, almost identical to that of the mainland Japanese. The prevalence of the Trp64Arg allele was 30.1% in NGT, 35.0% in IGT, and 41.4% in DM subjects (nonsignificant). The Trp64Arg variant of the β3-AR gene showed no significant relationship with obesity or insulin resistance in NGT subjects. However, fasting and 2-hour insulin levels and insulin resistance as determined by homeostasis model assessment (HOMA) were significantly higher in IGT subjects with the Trp64Arg variant. Although indices of obesity were the same in IGT subjects with and without the Trp64Arg variant, differences in the body mass index (BMI) and percent body fat between NGT and IGT subjects were greater for individuals with the Trp64Arg variant. Thus, there is an association between the Trp64Arg variant of the β3-AR gene and insulin resistance in Japanese-Americans with IGT.

Plasma interleukin 8 concentrations in obese subjects with impaired glucose tolerance.

BackgroundInterleukin 8 (IL-8) is a cytokine with atherogenic properties. In vitro studies revealed that it is produced and secreted by human adipocytes. We recently reported that plasma IL-8 is increased in obese subjects with normal glucose tolerance (NGT). The aim of the present study was to measure plasma IL-8 concentrations in subjects with impaired glucose tolerance (IGT).MethodsA total of 44 subjects with marked overweight or obesity (BMI > 27.8 kg/m2), 27 with NGT and 17 with IGT, were recruited for the present study. Plasma IL-8 levels were measured in fasting state, after an oral glucose tolerance test (OGTT) and after euglycemic hyperinsulinemic clamp.ResultsThe studied groups did not differ in fasting IL-8 concentrations. Both OGTT and clamp resulted in a significant increase in plasma IL-8. The change in IL-8 after clamp was similar in both groups. In contrast, after OGTT plasma IL-8 levels (IL-8OGTT) were markedly higher in IGT individuals. In IGT, but not NGT group, IL-8OGTT was positively related to postload glucose and negatively to insulin sensitivity.ConclusionPlasma IL-8 concentrations after glucose load are increased in obese IGT subjects in comparison to normoglycemic weight-matched individuals. Increase in plasma IL-8 might be both insulin-mediated (during clamp) and glucose-mediated (during OGTT).

In vivo evidence for increased oxidation of circulating LDL in impaired glucose tolerance.

Oxidized LDL (oxLDL) is a key mediator in atherogenesis and a marker of coronary artery disease (CAD). Type 2 diabetes is associated with excessive cardiovascular morbidity and mortality. Because atherogenesis starts before diabetes is diagnosed, we investigated whether circulating oxLDL levels are increased in impaired glucose tolerance (IGT). OxLDL levels were measured in 376 subjects with normal glucose tolerance (NGT), 113 patients with IGT, and 54 patients with newly diagnosed type 2 diabetes. After correction for age and BMI, serum levels of oxLDL were significantly increased in IGT versus NGT subjects (P = 0.002). OxLDL levels were not associated with the following parameters of the oxidative/antioxidative balance in the blood: total antioxidant capacity, urate-to-allantoin ratio, and circulating phagocyte oxygenation activity. In stepwise multivariate analysis, LDL cholesterol (P < 0.0005) and triglycerides (P < 0.0005) were the strongest predictors of circulating oxLDL levels, followed by HDL cholesterol (P = 0.003), 2-h postchallenge C-peptide (P = 0.011), fasting free fatty acids (P = 0.013), and serum paraoxonase activity (P = 0.035). The strong correlation of oxLDL with LDL cholesterol and triglycerides indicates that LDL oxidation in IGT is preferentially associated with dyslipidemia. OxLDL increase may explain the high atherogenic potency of dyslipidemia in the prediabetic state.

Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: role of oxidative stress.

Circulating levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) are elevated in diabetic patients. We assessed the role of glucose in the regulation of circulating levels of IL-6, TNF-alpha, and interleukin-18 (IL-18) in subjects with normal or impaired glucose tolerance (IGT), as well as the effect of the antioxidant glutathione. Plasma glucose levels were acutely raised in 20 control and 15 IGT subjects and maintained at 15 mmol/L for 5 hours while endogenous insulin secretion was blocked with octreotide. In control subjects, plasma IL-6, TNF-alpha, and IL-18 levels rose (P<0.01) within 2 hours of the clamp and returned to basal values at 3 hours. In another study, the same subjects received 3 consecutive pulses of intravenous glucose (0.33 g/kg) separated by a 2-hour interval. Plasma cytokine levels obtained at 3, 4, and 5 hours were higher (P<0.05) than the corresponding values obtained during the clamp. The IGT subjects had fasting plasma IL-6 and TNF-alpha levels higher (P<0.05) than those of control subjects. The increase in plasma cytokine levels during the clamping lasted longer (4 hours versus 2 hours, P<0.01) in the IGT subjects than in the control subjects, and the cytokine peaks of IGT subjects after the first glucose pulse were higher (P<0.05) than those of control subjects. On another occasion, 10 control and 8 IGT subjects received the same glucose pulses as above during an infusion of glutathione; plasma cytokine levels did not show any significant change from baseline after the 3 glucose pulses. Hyperglycemia acutely increases circulating cytokine concentrations by an oxidative mechanism, and this effect is more pronounced in subjects with IGT. This suggests a causal role for hyperglycemia in the immune activation of diabetes.

Insulin: in search of a syndrome.

The insulin resistance syndrome has been defined as the clustering of hypertension, dyslipidaemia and impaired glucose tolerance in subjects with high fasting plasma insulin concentrations. The latter are usually taken as a surrogate measure of insulin resistance of whole-body glucose disposal. Although hyperinsulinaemia and insulin resistance are reciprocally related to one another, the association is not very strong. In the data-pooling project of the European Group for the study of Insulin Resistance (EGIR), clamp-derived insulin sensitivity (as the M value) and fasting plasma insulin concentrations were available in 1308 non-diabetic subjects with a wide range of age and body mass index. In this cohort, hyperinsulinaemia (as the upper quartile of fasting plasma insulin distribution in the non-obese segment of the population) and insulin resistance (as the bottom quartile of M value in the same subgroup) were each present in approximately 40% of the whole population, but identified only partially overlapping (60%) subsets of individuals. When the subjects with insulin resistance but without hyperinsulinaemia (n = 198) were compared with the subjects with hyperinsulinaemia but without insulin resistance (n = 267), significant differences emerged in the respective clinical phenotypes. Thus, subjects with 'pure' insulin resistance had a more central fat distribution and presented evidence of excessive lipolysis and endogenous glucose production. In contrast, subjects with 'pure' hyperinsulinaemia had suppressed lipolysis, endogenous glucose production and insulin clearance, higher values of systolic blood pressure and lower values of serum HDL-cholesterol concentrations. The only abnormality common to both phenotypes was the presence of raised serum triglycerides concentrations. This analysis indicates that hyperinsulinaemia and insulin resistance identify partially different subgroups of individuals in a non-diabetic population, and suggests that hyperinsulinaemia and insulin resistance carry distinct pathogenic potential in terms of the components of the insulin resistance syndrome.

Insulin resistance, defective insulin receptor substrate 2-associated phosphatidylinositol-3' kinase activation, and impaired atypical protein kinase C (zeta/lambda) activation in myotubes from obese patients with impaired glucose tolerance.

Impaired glucose tolerance (IGT) is characterized by insulin resistance. Recently, defects in the insulin-signaling cascade have been implicated in the pathogenesis of insulin resistance. To study insulin signaling in IGT, we used human skeletal muscle cells in primary culture from patients with IGT and control subjects. In these cultured myotubes, we assessed insulin-induced 2-deoxyglucose uptake and early steps of the metabolic insulin-signaling cascade. Myotubes in culture from patients with IGT had insulin-induced glucose uptake that was roughly 30-50% less than that from control subjects. This insulin resistance was associated with impaired insulin receptor substrate (IRS)-2-associated phosphatidylinositol 3' (PI3) kinase activation and IRS-2 tyrosine phosphorylation as well as significantly decreased protein kinase C (PKC)-zeta/lambda activation in response to insulin. IRS-1- associated PI3 kinase activation and insulin receptor autophosphorylation were comparable in the two groups. Protein expression levels for the insulin receptor, IRS-1, IRS-2, the p85 regulatory subunit of PI3 kinase, Akt, PKC-zeta/lambda, GLUT1, and GLUT4 were also similar in the two groups. In conclusion, myotubes from patients with IGT have impaired insulin-induced glucose uptake. This is associated with impaired IRS-2-associated PI3 kinase activation and PKC-zeta/lambda activation. Our results suggest that these defects may contribute to insulin resistance in IGT patients.

Type 1 diabetes-related autoantibodies are rare in Alaska native populations

Objectives. When clinical data were initially gathered from the Alaskan Eskimos in the 1950’s, diabetes mellitus was noted to be quite rare. The prevalence of diabetes has increased significantly since that time, with rates of 10% reported recently in some Alaska native populations. Our goal was to understand the pathogenesis of diabetes among these groups, with the hypothesis that Alaskan Eskimos were predominantly affected by type 2 diabetes, not by latent autoimmune diabetes in adults (LADA).Study design. Population based case control studyMethods. We tested sera from subjects in two Eskimo villages for the presence of type 1 diabetes-related autoantibodies against glutamic acid decarboxylase (GAD65Ab) and tyrosine phosphatase-like islet antigen-2 (IA-2Ab). Results. Among subjects from one Inupiat village (#1) and one SiberianYup’ik village (#2), there were 21 subjects with diabetes mellitus (DM), 17 with impaired glucose tolerance (IGT), and 226 healthy controls with normal glucose tolerance (NGT). In village 1, GAD65 antibodies were not present in either diabetic subjects or those with IGT. One of the healthy controls (1%;1/97) was positive for GAD65Ab. Similarly, no subjects from this village with DM or IGT had positive IA-2Ab titers, and one healthy control (1%;1/97) was positive for IA-2Ab. In village 2, no DM subject was GAD65Ab positive. One (10%;1/10) of the IGT subjects and two (1.6%;2/129) of the healthy controls were positive for GAD65Ab. In this village, two of the DM subjects (12%;2/17), one of the IGT subjects (10%;1/10), and one of the healthy controls (0.8%;1/129) were IA-2Ab positive. No individual was positive for both GAD65Ab and IA-2Ab. Conclusion. Alaskan Inupiat and Siberian Yup’ik Eskimos appear to be predominantly affected by type 2 diabetes, not LADA.

Type 1 diabetes-related autoantibodies are rare in Alaska native populations

When clinical data were initially gathered from the Alaskan Eskimos in the 1950's, diabetes mellitus was noted to be quite rare. The prevalence of diabetes has increased significantly since that time, with rates of 10% reported recently in some Alaska native populations. Our goal was to understand the pathogenesis of diabetes among these groups, with the hypothesis that Alaskan Eskimos were predominantly affected by type 2 diabetes, not by latent autoimmune diabetes in adults (LADA). Population based case control study We tested sera from subjects in two Eskimo villages for the presence of type 1 diabetes-related autoantibodies against glutamic acid decarboxylase (GAD65Ab) and tyrosine phosphatase-like islet antigen-2 (IA-2Ab). Among subjects from one Inupiat village (#1) and one SiberianYup'ik village (#2), there were 21 subjects with diabetes mellitus (DM), 17 with impaired glucose tolerance (IGT), and 226 healthy controls with normal glucose tolerance (NGT). In village 1, GAD65 antibodies were not present in either diabetic subjects or those with IGT. One of the healthy controls (1%; 1/97) was positive for GAD65Ab. Similarly, no subjects from this village with DM or IGT had positive IA-2Ab titers, and one healthy control (1%; 1/97) was positive for IA-2Ab. In village 2, no DM subject was GAD65Ab positive. One (10%; 1/10) of the IGT subjects and two (1.6%;2/129) of the healthy controls were positive for GAD65Ab. In this village, two of the DM subjects (12%;2/17), one of the IGT subjects (10%; 1/10), and one of the healthy controls (0.8%;1/129) were IA-2Ab positive. No individual was positive for both GAD65Ab and IA-2Ab. Alaskan Inupiat and Siberian Yup'ik Eskimos appear to be predominantly affected by type 2 diabetes, not LADA.

Insulin Release in Impaired Glucose Tolerance

The availability of quantitative indexes describing beta-cell function in normal life conditions is important for the characterization of impaired mechanisms of insulin secretion in pathophysiological states. Recently, an oral C-peptide minimal model has been proposed and applied to subjects with normal glucose tolerance (NGT) during graded up-and-down glucose infusion protocols (40-min periods at 4, 8, 16, 8, 4, and 0 mg.kg(-1).min(-1)) and oral glucose tolerance tests. These tests are characterized by slow glucose and C-peptide dynamics, which reproduce prandial conditions. In view of the importance of beta-cell dysfunction in the pathogenesis of type 2 diabetes, our aim was to test and use the oral minimal model in subjects with impaired glucose tolerance (IGT) to identify deranged mechanisms of beta-cell function. Plasma C-peptide and glucose data from graded up-and-down glucose infusions were analyzed in nine NGT and four IGT subjects using the classic deconvolution approach and the oral minimal model, and indexes of beta-cell function were derived. An index of insulin sensitivity was also obtained for each subject from minimal model analysis of glucose and insulin levels achieved during the test. Both deconvolution and minimal model analyses revealed that individuals with IGT have a relative defect in the ability to secrete enough insulin to adequately compensate for insulin resistance. Additionally, minimal model analysis suggests that insulin secretory defect in IGT arises from delays in the timing of the beta-cell response to glucose.

Incidencia significativa de la diabetes tipo 2 en la población española de alto riesgo. Resultados del Estudio ITG (2)

Our purpose was to estimate the incidence of type 2 diabetes among a high risk population with or without impaired glucose tolerance (IGT), analysing the progression to diabetes. Multicenter cohort study on high risk individuals without diabetes (WHO-85 criteria) in primary health care. Subjects underwent an oral glucose tolerance test measuring fasting plasma glucose (FPG) and plasma glucose at 2 hours (2hPG). Mean follow-up was 37.2 months (4.3-69.7). Phenotypic features, diagnostic variation, diabetes incidence and predictive factors (multivariate analysis and Cox proportional hazards model) were assessed. We included 243 individuals (148 females), aged 59.7 (10) years, with FPG < 7.8 mM and 2hPG < 11.1 mM. 137 IGT subjects (56.4%) and 106 (43.6%) normal glucose tolerance (NGT) subjects with a similar risk factor impact were evaluated. After the study was closed, 63 (25.9%) subjects developed diabetes: 43 (31.4%) with baseline IGT and 20 (18.9%) with NGT. Overall diabetes incidence increased over time but not proportionally. Mean annual incidence was 9.2% and it dropped to 4.6% when FPG was used as the unique diagnosis criterion (ADA-97). Male under 65 years with both overweight and IGT reported the highest incidence. HbA1c, FPG and 2hPG were independent predictors. Increased HDL cholesterol showed a protective effect on diabetes incidence. The IGT diagnosis interval was a much better predictor [OR = 2.06 (1.56-2.72)] of diabetes development than the impaired FPG diagnosis interval [OR = 1.37 (0.93-2.04)]. FPG predicted but undervalued diabetes incidence in high risk population. The IGT (2hPG) diagnosis interval predicted diabetes development better than the impaired fasting plasma glucose diagnosis interval. Increased diabetes incidence in high risk Spanish population, particularly with regard to IGT, means that primary preventive resources should be increased.

Visceral fat is a major contributor for multiple risk factor clustering in Japanese men with impaired glucose tolerance.

The significance of abdominal visceral fat accumulation was evaluated in Japanese men with impaired glucose tolerance (IGT). The IGT subjects (n = 123) were aged 55 +/- 9 years with a BMI of 24 +/- 3 kg/m(2). The 148 control subjects with normal glucose tolerance (NGT) were matched for age and BMI. IGT and NGT were classified according to the 1985 World Health Organization criteria. Abdominal fat distribution was analyzed by computed tomography at umbilical level. Plasma lipid, glucose, and insulin concentrations and blood pressure (BP) were measured. In subjects with IGT, the average visceral fat area (VFA) was significantly greater than in subjects with NGT. Fasting insulin, the sum of insulin concentrations during an oral glucose tolerance test, insulin resistance according to a homeostasis model assessment for insulin resistance (HOMA-IR), systolic BP, and serum triglyceride were significantly higher, whereas the DeltaI(30-0)/DeltaG(30-0) was significantly lower, in subjects with IGT. Subjects with IGT and NGT were then divided into three subgroups according to the number of risk factors they possessed (dyslipidemia, hypertension, neither, or both). In both IGT and NGT subjects, BMI, VFA, subcutaneous fat area, fasting insulin, HOMA-IR, and insulin secretion of the homeostasis model assessment were significantly higher in the double-risk factor subgroup than in the no-risk factor subgroup, and VFA was a potent and independent variable in association with the presence of a double risk factor. Visceral fat accumulation is a major contributor for multiple risk factor clustering in Japanese men with IGT and NGT.

Changes in tumor necrosis factor-alpha system and insulin sensitivity during an exercise training program in obese women with normal and impaired glucose tolerance.

Tumor necrosis factor-alpha (TNFalpha) plays an important role in the pathogenesis of insulin resistance and type 2 diabetes. Plasma levels of the soluble (s) fractions of TNFalpha receptors, especially sTNFR2, are good indicators of TNFalpha system activation in obesity. The aim of the present study was to assess the effect of exercise training on the TNFalpha system and to evaluate the relationship with changes in insulin sensitivity. Sixteen obese women (body mass index (BMI)>27.8 kg/m(2)), 8 with normal (NGT) and 8 with impaired glucose tolerance (IGT), participated in an exercise training program which lasted for 12 weeks and included exercise performed on a bicycle ergometer at an individual intensity of 70% maximal heart rate, for 30 min, 5 days a week. Anthropometrical measurements and blood biochemical analyses were performed, and plasma TNFalpha, sTNFR1 and sTNFR2 levels were assessed. Insulin sensitivity was evaluated using the hyperinsulinemic euglycemic clamp technique (insulin infusion: 50 mU x kg(-1)xh(-1)). At baseline, despite similar anthropometrical parameters, IGT subjects were markedly more insulin resistant and had higher TNFalpha and sTNFR2 concentrations. Exercise training increased insulin sensitivity and decreased TNFalpha and sTNFR2 levels, while sTNFR1 remained unchanged. The decrease in sTNFR2 was significantly related to the increase in insulin sensitivity; that relationship remained significant after adjustment for the concurrent changes in BMI, waist circumference, percentage of body fat, plasma glucose, insulin and free fatty acids. Regular physical exercise decreases TNFalpha system activity and that decrease may be responsible for the concurrent increase in insulin sensitivity.

Usefulness of stable HbA 1c for supportive marker to diagnose diabetes mellitus in Japanese subjects

To evaluate the adequacy and usefulness of the stable glycated hemoglobin (HbA 1c) value of 6.5% suggested by the Japan Diabetic Society in 1999 for supportive diagnostic marker of diabetes, we assessed the sensitivity and specificity of an HbA 1c value of 6.5% in patients who were newly diagnosed by the 75 g oral glucose tolerance test (75g-OGTT). A total of 866 Japanese subjects underwent the 75g-OGTT and HbA 1c measurement (normal range: 4.3–5.8%). They were divided into three groups [normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and diabetes mellitus (DM)], using the WHO criteria, since no subject with impaired fasting glycemia (IFG) was observed. The cut-off value of HbA 1c separating DM from NGT or DM from IGT on cumulative distribution curve analysis was 5.9% (sensitivity 0.76 and specificity 0.86) and 5.9% (sensitivity 0.76 and specificity 0.77), respectively. The sensitivity of an HbA 1c of 6.5% for separation of DM from NGT or IGT by the same analysis was 0.49 and 0.49, respectively. Similarly, the specificity for separation of DM from NGT or IGT was 0.98 and 0.98, respectively. These results mean that 49% of diabetic subjects show an HbA 1c≧6.5%, and 51% have an HbA 1c less than 6.5%, while only 2% of NGT and IGT subjects have an HbA 1c≧6.5%, and 98% have a value less than 6.5%. Therefore, the sensitivity of an HbA 1c value of 6.5% in separating DM from NGT or IGT is low, and thus 6.5% is too high value to use when screening for diabetes. However, the specificity is very high, so an HbA 1c of 6.5% is a useful supportive marker to diagnose diabetes.

Glucagon-Like Peptide 1 Increases Secretory Burst Mass of Pulsatile Insulin Secretion in Patients With Type 2 Diabetes and Impaired Glucose Tolerance

The insulinotropic gut hormone glucagon-like peptide (GLP)-1 increases secretory burst mass and the amplitude of pulsatile insulin secretion in healthy volunteers without affecting burst frequency. Effects of GLP-1 on secretory mechanisms in type 2 diabetic patients and subjects with impaired glucose tolerance (IGT) known to have impaired pulsatile release of insulin have not yet been studied. Eight type 2 diabetic patients (64+/-9 years, BMI 28.9+/-7.2 kg/m2, HbA1c 7.7+/-1.3%) and eight subjects with IGT (63+/-10 years, BMI 31.7+/-6.4 kg/m2, HbA1c 5.7+/-0.4) were studied on separate occasions in the fasting state during the continued administration of exogenous GLP-1 (1.2 pmol x kg(-1) x min(-1), started at 10:00 P.M. the evening before) or placebo. For comparison, eight healthy volunteers (62+/-7 years, BMI 27.7+/-4.8 kg/m2, HbA1c 5.4+/-0.5) were studied only with placebo. Blood was sampled continuously over 60 min (roller-pump) in 1-min fractions for the measurement of plasma glucose and insulin. Pulsatile insulin secretion was characterized by deconvolution, autocorrelation, and spectral analysis and by estimating the degree of randomness (approximate entropy). In type 2 diabetic patients, exogenous GLP-1 at approximately 90 pmol/l improved plasma glucose concentrations (6.4+/-2.1 mmol/l vs. placebo 9.8+/-4.1 mmol/l, P = 0.0005) and significantly increased mean insulin burst mass (by 68%, P = 0.007) and amplitude (by 59%, P = 0.006; deconvolution analysis). In IGT subjects, burst mass was increased by 45% (P = 0.019) and amplitude by 38% (P = 0.02). By deconvolution analysis, insulin secretory burst frequency was not affected by GLP-1 in either type 2 diabetic patients (P = 0.15) or IGT subjects (P = 0.76). However, by both autocorrelation and spectral analysis, GLP-1 prolonged the period (lag time) between subsequent maxima of insulin concentrations significantly from approximately 9 to approximately 13 min in both type 2 diabetic patients and IGT subjects. Under placebo conditions, parameters of pulsatile insulin secretion were similar in normal subjects, type 2 diabetic patients, and IGT subjects based on all methodological approaches (P > 0.05). In conclusion, intravenous GLP-1 reduces plasma glucose in type 2 diabetic patients and improves the oscillatory secretion pattern by amplifying insulin secretory burst mass, whereas the oscillatory period determined by autocorrelation and spectral analysis is significantly prolonged. This was not the case for the interpulse interval determined by deconvolution. Together, these results suggest a normalization of the pulsatile pattern of insulin secretion by GLP-1, which supports the future therapeutic use of GLP-1-derived agents.

Impaired glucose tolerance without hypertriglyceridemia does not enhance postprandial lipemia.

Postprandial lipemia has been thought to be one of risk factors for coronary heart disease, and enhances in potential patients for atherosclerotic disease. Patients with impaired glucose tolerance (IGT) often show hypertriglyceride, which is caused by enhanced portprandial lipemia. Therefore, postprandial lipemia in patients with IGT and without hypertriglyceridemia has not been cleared. We have examined the levels of plasma triglyceride and chylomicron remnants after a high fat meal load (1250 kcal, 40% fat and 420 mg cholesterol) in 13 normotriglyceridemic subjects with IGT and 10 controls with normal glucose tolerance (NGT). Chylomicron remnants were evaluated as remnant-like particles (RLP) that were not bound to an immunoaffinity gel mixture containing apo A-I and apo B-100 monoclonal antibody. RLP cholesterol levels 4 hours after the fat load were significantly lower in IGT subjects than in NGT subjects. Increase of RLP cholesterol after the fat meal load only significantly correlated with increase of insulin during the first 30 min after a 75 g oral glucose tolerance test, but not fasting lipid, insulinogenic index and HOMA-R (homeostasis model) in all subjects. These results suggest that postprandial response does not enhance in IGT subjects, and may associate with early-phase insulin secretion and without insulin resistance in normotriglyceridemic men with IGT or NGT.