Insulin secretion and insulin sensitivity in diabetic subgroups: studies in the prediabetic and diabetic state

Aims/hypothesis. To evaluate insulin sensitivity and insulin secretion in prediabetic and diabetic subjects with mutations in MODY1 (HNF-4α) and MODY3 (HNF-1α) genes, in subjects with GAD antibodies, latent autoimmune diabetes in adults and in subjects with the common form of Type II (non-insulin-dependent) diabetes mellitus. Methods. Insulin secretion was measured as the incremental 30-min insulin (I30) and insulin glucose ratio (I:G30) during OGTT whereas insulin sensitivity was measured as the insulin sensitivity index during OGTT in 131 carriers of MODY mutations [NGT = 38, IFG/IGT = 21, diabetes mellitus (DM) = 72], in 293 subjects with GADA (NGT = 47, IFG/IGT = 29, DM = 217) and in 2961 subjects with a family history of the common form of Type II diabetes but without MODY mutations or GADA (NGT = 1360, IFG/IGT = 857, DM = 744). A subgroup of the subjects underwent a euglycaemic clamp (n = 210) and intravenous glucose tolerance test (n = 337) for the estimation of insulin sensitivity and first-phase insulin secretion. Results. Non-diabetic subjects with MODY mutations had pronounced impaired insulin secretion (I30, I:G30) compared with the two other groups (p = 0.005). Normal or non-diabetic glucose tolerance was maintained by enhanced insulin sensitivity compared with the other two groups (p < 0.05 and p < 0.005). In contrast to patients with Type II diabetes and with adult latent autoimmune diabetes, MODY patients showed only a modest deterioration in insulin sensitivity at onset of diabetes. The 2-h glucose values inversely correlated with insulin sensitivity in subjects with GADA (r = –0.447, p < 0.001) and subjects from Type II diabetic families (r = –0.426, p < 0.001), whereas no such relation was observed in subjects with MODY mutations (r = 0.151, p = NS). There were no statistically significant differences in insulin secretion or insulin sensitivity between subjects with GADA or subjects with a family history of Type II diabetes, either at the NGT or the IFG/IGT stage. Conclusion/interpretation. Glucose-tolerant carriers of MODY mutations are characterised by a severe impairment in insulin secretion. Enhanced insulin sensitivity is the most likely explanation for the normal glucose tolerance. Whereas subjects with positive GADA or Type II diabetes have impaired insulin sensitivity with increasing glucose concentrations, MODY mutation carriers seem to be protected from the effect of glucose toxicity. [Diabetologia (2000) 43: 1476–1483] Received: 23 March 2000 and in revised form: 29 August 2000     

The role of non-esterified fatty acids in the deterioration of glucose tolerance in Caucasian subjects: results of the Paris Prospective Study

Summary Although an increased plasma non-esterified fatty acid (NEFA) concentration has been shown to increase insulin resistance (Randle cycle), decrease insulin secretion and increase hepatic gluconeogenesis, the effect of NEFA on the deterioration of glucose tolerance has not been studied prospectively in Caucasian subjects. Therefore, we investigated whether plasma NEFA may be regarded as predictors of deterioration of glucose tolerance in subjects with normal (NGT, n = 3671) or impaired (IGT, n = 418) glucose tolerance who were participants in the Paris Prospective study. The subjects were first examined between 1967 and 1972 and underwent two 75-g oral glucose tolerance tests 2 years apart with measurements of plasma glucose, insulin and NEFA concentrations. Glucose tolerance deteriorated from NGT to IGT or non-insulin-dependent diabetes (NIDDM) in 177 subjects and from IGT to NIDDM in 32 subjects. In multivariate analysis, high fasting plasma NEFA in NGT subjects and high 2-h plasma NEFA and low 2-h plasma insulin concentrations in IGT subjects were significant independent predictors of deterioration along with older age, high fasting and 2-h plasma glucose concentrations and high iliac to thigh ratio. When subjects were divided by tertiles of plasma NEFA concentration at baseline, there was an increase in 2-h glucose concentration with increasing NEFA in the subjects who did not deteriorate, but no effect of plasma NEFA in those who deteriorated. In subjects with IGT who deteriorated compared with those who did not 2-h plasma insulin concentration was lower but there was no evidence that this resulted from an effect of plasma NEFA. Our data suggest that a high plasma NEFA concentration is a risk marker for deterioration of glucose tolerance independent of the insulin resistance or the insulin secretion defect that characterize subjects at risk for NIDDM. [Diabetologia (1997) 40: 1101–1106] Received: 11 March 1997 and in revised form: 20 May 1997     

Effects of coronary artery disease and percutaneous intervention on the cardiac metabolism of nonesterified fatty acids and insulin: Implications of diabetes mellitus

Background. Nonesterified fatty acids (NEFA) and insulin have been implicated in the pathogenesis of diabetes mellitus (Type 2 diabetes) and coronary artery disease (CAD). We hypothesized that intracardiac levels of insulin and NEFA within the aortic root, coronary sinus and systemic venous levels would be different in patients with coronary atherosclerosis and/or diabetes. We also studied the metabolic cardiac response following percutaneous coronary intervention (PCI). Methods. A total of 67 subjects (42 males; mean age 60 ± 11 years) were recruited, of which three groups were identified: Group I – those with no CAD or Type 2 diabetes (n = 17); Group II – those with CAD but no Type 2 diabetes (n = 40); and Group III – patients with Type 2 diabetes and CAD (n = 10). Of the whole cohort, 34 patients (51%) proceeded to PCI. NEFA and insulin levels were analysed using enzymatic colorimetric and a monoclonal immuno‐autoanalyser techniques, respectively. Subsequently, fractional extraction (FFE) of both variables was calculated. Results. Nonesterified fatty acids and insulin concentrations were lower in the aortic root versus coronary sinus (both P < 0.05). FFE of NEFA was 2× higher in Group I (P < 0.01) with a sevenfold reduction in insulin FFE in Group III. Following PCI, systemic NEFA levels increased significantly (P < 0.05) with no significant change seen within the coronary sinus (P = NS), whilst a reduction in insulin concentrations at all three sites was observed (all P < 0.01). No significant difference in FFE of NEFA was seen after PCI when comparing Groups II and III. There was a drop in insulin extraction in Group II (nondiabetic subjects, from 12% to ?4%, P = 0.04), compared with an increase seen in Group III (Type 2 diabetes patients, from ?4% to 3%, P = 0.03). Conclusion. There is an intracardiac gradient of NEFA and insulin in Groups I–III. Cardiac NEFA metabolism was higher in those with mild CAD compared with those with obstructive CAD whereas intracardiac insulin extraction was lower in Group III (diabetic) patients. PCI was associated with a systemic rise in NEFA, with a reduction in insulin levels and cardiac utilization, but these effects were blunted in diabetic patients.     

Assessment of insulin sensitivity from plasma insulin and glucose in the fasting or post oral glucose-load state.

OBJECTIVE: To compare insulin sensitivity indexes derived from plasma insulin (I) and glucose (G) in the basal state (Sib) and at the second hour (I2h and G2h) of an oral glucose tolerance test (OGTT, Si2h) (i) with measurements of insulin sensitivity using the insulin modified frequently sampled intravenous glucose tolerance test (FSIVGTT) [Si(IVGTT)] and (ii) with modelling of fasting glucose and insulin by the homeostasis model assessment (HOMA). SUBJECTS: 47 subjects entered the study. 31 subjects were classified as having normal glucose tolerance (NGT), 10 as having impaired tolerance to glucose (IGT) and six as type 2 diabetes mellitus according to the World Health Organisation (WHO) criteria. MEASUREMENTS: Sib and Si2h were calculated as follows. Sib = 10(8)/(I x G x VD), Si2h = 10(8)/(I2hr x G2hr x VD) where VD is an estimate of the apparent glucose distribution volume. A third insulin sensitivity index (SiM) was calculated by averaging Sib and Si2h. HOMA was calculated as follows: I/(22.5 x e(-lnG)) RESULTS: Si(IVGTT), Sib, SI2h and SiM were all significantly higher in subjects with NGT than in those with IGT or type 2 diabetes. Si(IVGTT) was highly correlated (P < or = 0.0001) with the three insulin sensitivity indexes found in the total population, in subjects with NGT and in those with IGT. In type 2 diabetic patients, a significant correlation was only noted when SiM was tested against Si(IVGTT) (P < or = 0.05). In most circumstances, the associations of Si(IVGTT) with Sib, SI2h and SiM were stronger than the corresponding associations with Ib, I2h or HOMA. SiM was the index that correlated best with Si(IVGTT) in the whole group (r = 0.92, P < 0.0001) as well as in NGT (r = 0.86, P < 0.0001), IGT (r = 0.96; P < 0.0001) and type 2 diabetes (r = 0.83, P < or = 0.05) subgroups. CONCLUSIONS: Calculations of sensitivity indexes from G and I concentrations in the basal state and during a conventional 2 h OGTT appear to be useful for coupling in the same simple and single test both a determination of glucose tolerance and an estimate of insulin sensitivity.     

Insulin sensitivity, insulin release and glucagon-like peptide-1 levels in persons with impaired fasting glucose and/or impaired glucose tolerance in the EUGENE2 study

Aims/hypothesis We examined the phenotype of individuals with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) with regard to insulin release and insulin resistance. Methods Non-diabetic offspring (n = 874; mean age 40 ± 10.4 years; BMI 26.6 ± 4.9 kg/m²) of type 2 diabetic patients from five different European Centres (Denmark, Finland, Germany, Italy and Sweden) were examined with regard to insulin sensitivity (euglycaemic clamps), insulin release (IVGTT) and glucose tolerance (OGTT). The levels of glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) were measured during the OGTT in 278 individuals. Results Normal glucose tolerance was found in 634 participants, while 110 had isolated IFG, 86 had isolated IGT and 44 had both IFG and IGT, i.e. about 28% had a form of reduced glucose tolerance. Participants with isolated IFG had lower glucose-corrected first-phase (0–10 min) and higher second-phase insulin release (10–60 min) during the IVGTT, while insulin sensitivity was reduced in all groups with abnormal glucose tolerance. Similarly, GLP-1 but not GIP levels were reduced in individuals with abnormal glucose tolerance. Conclusions/interpretation The primary mechanism leading to hyperglycaemia in participants with isolated IFG is likely to be impaired basal and first-phase insulin secretion, whereas in isolated IGT the primary mechanism leading to postglucose load hyperglycaemia is insulin resistance. Reduced GLP-1 levels were seen in all groups with abnormal glucose tolerance and were unrelated to the insulin release pattern during an IVGTT.     

Loss of the First Phase Insulin Response to Intravenous Glucose in Subjects with Persistent Impaired Glucose Tolerance

Loss of the first phase insulin response to intravenous glucose is one of the earliest detectable defects of beta cell dysfunction in Type 2 diabetes mellitus. Impaired glucose tolerance (IGT) is considered a prediabetic condition, therefore loss of first phase insulin secretion in subjects with IGT would suggest beta cell dysfunction as an early lesion in the development of Type 2 diabetes. Three groups of subjects were studied, 7 subjects with persistent IGT (classified as having IGT at two 75 g oral glucose tolerance tests (OGTT) done 6 months apart), 6 subjects with transient IGT (IGT at the first OGTT, but normal glucose tolerance at a repeat OGTT 6 months later), and 7 normal controls. First phase insulin secretion was studied using an intravenous glucose tolerance test with arterialized blood sampling. Fasting, 3, 4 and 5 min samples were assayed for glucose and insulin (specific two-site immunoradiometric assay). The fasting insulin was similar in all three groups, however the 3 min insulin response was significantly lower in those with persistent impaired glucose tolerance (p < 0.02). Thus subjects with persistent impaired glucose tolerance demonstrated loss of the first phase insulin response as an early indicator of beta cell dysfunction while subjects with transient IGT had a normal insulin response to intravenous glucose. During the OGTT, the 30 min glucose was not significantly different (p = 0.1) but the 30 min insulin to glucose ratio was significantly lower in subjects with persistent IGT (p < 0.03). In the whole group the 30 min insulin to glucose ratio during the OGTT showed a significant correlation with the peak insulin response during the IVGTT (r = 0.76, p < 0.001). This study suggests that beta cell dysfunction with impaired early insulin release is present before the development of Type 2 diabetes.     

NEFA elevation during a hyperglycaemic clamp enhances insulin secretion

Elevated non-esterified fatty acid (NEFA) levels may influence insulin secretion and contribute to the development of Type 2 DM. We investigated the effects of acute NEFA elevation in controls (n = 6) and subjects predisposed to Type 2 DM (n = 6) on basal insulin levels, and following glucose and arginine stimulation. Each subject had one study with a triglyceride (TG) plus heparin infusion (elevated NEFA levels) and another with normal saline. Twenty minutes after the TG or saline infusion began a glucose bolus was given and 10 min later a 90-min hyperglycaemic clamp (∼ 9 mmol l⁻¹) was started. Intravenous arginine was given at 110 min. Elevated NEFA levels (∼ 4000 μmol l⁻¹) did not enhance basal or first phase glucose stimulated insulin levels. During hyperglycaemia, NEFA elevation further increased insulin levels in both groups by 20–44 % (p < 0.05) and C-peptide levels by 17–25 % (p < 0.05). The post-arginine insulin levels during hyperglycaemia were increased by 45 % in the Type 2 DM-risk group (p < 0.02). The glucose infusion rate maintaining matched hyperglycaemia was similar during NEFA elevation and for saline control for both groups. We conclude that acute elevation of NEFA levels enhances glucose and non-glucose-induced insulin secretion. © 1998 John Wiley & Sons, Ltd.     

Studies of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2) gene in relation to insulin sensitivity among glucose tolerant caucasians

Aims/hypothesis: We examined whether the Pro12-Ala polymorphism of the human peroxisome proliferator-activated receptor-γ2 (PPAR- γ 2) gene was related to altered insulin sensitivity among glucose-tolerant subjects or a lower accumulated incidence or prevalence of IGT and Type II (non-insulin-dependent) diabetes mellitus among Scandinavian Caucasians. Methods: The Pro12Ala polymorphism was examined using PCR-RFLP. Whole-body insulin sensitivity measured under hyperinsulinaemic-euglycaemic conditions was estimated in a population-based sample of 616 glucose tolerant Swedish Caucasian men at age 70. In addition, insulin sensitivity index was measured using IVGTT and Bergman minimal modelling in a population-based sample of 364 young healthy Danish Caucasians. Finally, we evaluated whether the polymorphism predicted Type II diabetes and IGT in 841 seventy-year-old Swedish men. A case-control study was carried out in 654 unrelated Danish Type II diabetic patients and 742 Danish glucose tolerant subjects matched for age and sex. Results: Whole-body insulin sensitivity was significantly improved in carriers compared with non-carriers of the Ala-allele of the codon 12 polymorphism in Swedish Caucasian men (6.0 ± 2.5 vs 5.6 ± 2.5 mg · kg^–1· min^–1· [mU/l]^–1· 100, p = 0.044). The same tendency, but not significant, was observed in the insulin sensitivity index among the group of young healthy Danish Caucasians. The incidence of Type II diabetes and IGT among the Swedish subjects at the age of 70 was similar in the three genotype-groups of the Pro12Ala variant and the Ala-allele was not related to a lower prevalence of Type II diabetes in Danish Caucasians. Conclusion/interpretation: The Ala-allele of the PPAR-γ2 polymorphism is associated with improved whole body insulin sensitivity among Swedish Caucasians. [Diabetologia (2001) 44: 1170–1176] Received: 27 March 2001 and in revised form: 5 June 2001     

Relationships between insulin secretion after intravenous and oral glucose administration in subjects with glucose tolerance ranging from normal to overt diabetes

Aims Acute insulin release (AIR) in response to intravenous glucose injection (IVGTT) can be abolished in diabetic subjects when their response to oral glucose is maintained. To elucidate this phenomenon, we examined the relationships between fasting plasma glucose (FPG) and the secretory responses to an IVGTT and an oral glucose test (OGTT). Methods We measured AIR and secretion after a 75‐g OGTT in 221 subjects [age 37 ± 11 years, body mass index (BMI) 28 ± 5 kg/m²; mean ± sd ] with normal glucose tolerance (NGT, n = 147), impaired FPG/impaired glucose tolerance (IFG/IGT, n = 28) and Type 2 diabetes (n = 46). Insulin secretion was calculated by C‐peptide deconvolution; pancreatic B‐cell glucose sensitivity was obtained by OGTT modelling. Results Both AIR [186 (185), 142 (164) and 10 (16) pmol/l, median (interquartile range)] and B‐cell glucose sensitivity [98 (64), 66 (53) and 16 (20) pmol min^?1 m^?2 l mmol^?1] decreased across glucose tolerance category (P < 0.0001). However, AIR became ~0 at ~7 mmol/l FPG, whereas B‐cell glucose sensitivity declined gradually throughout the FPG range. In addition, for FPG > 7 mmol/l, AIR was no longer related to FPG, whereas a strong relationship between FPG and B‐cell glucose sensitivity was preserved (ρ = ?0.71, P < 0.0001). In a multivariate regression model, adjusting for sex, age and BMI, glucose sensitivity [standardized regression coefficient (std.r.) = ?0.67, P < 0.0001], but not AIR (std.r. = 0.03, P = 0.55), was an independent predictor of FPG. Conclusions AIR vanishes at fasting or 2‐h glucose levels, at which levels some B‐cell glucose sensitivity is retained; therefore, AIR has a limited ability to quantify B‐cell function in hyperglycaemic states.     

The effects of physical training on insulin secretion and effectiveness and on glucose metabolism in obesity and Type 2 (non-insulin-dependent) diabetes mellitus

Summary Obese subjects with normal glucose tolerance (n=55), and, in another study, a group of patients with Type 2 (non-insulin-dependent) diabetes (n=33), and controls (n=13) matched for body weight and age but with normal glucose tolerance, participated in an individualized physical training program for 3 months. Under controlled dietary conditions, metabolic studies were performed before and in steady state after the last exercise session after training in the subjects showing signs of physical training in VO₂ max and heart rate measurements. No changes occurred in body weight, body cell mass, body fat or adipose tissue cellularity. Oral glucose tolerance was improved in the patients with diabetes mellitus only. In both diabetic and control subjects initially elevated C-peptide concentrations decreased, while low C-peptide values increased and which was particularly pronounced in diabetic subjects with subnormal values. Peripheral insulin values did not change. Glucose disposal rate measured with the glucose clamp technique was similar in diabetic patients and control subjects. An improvement was seen at both submaximal and maximal insulin levels in both groups, correlating with improvement in glucose tolerance in the diabetic subjects.No changes were found in adipocytes in insulin binding or the antilipolytic effect of insulin at submaximal insulin levels, but there was a normalization of a decreased glucose incorporation into triglycerides.These results indicate that both insulin secretion and effectiveness are altered by physical training in different ways in different clinical entities. They suggest that in insulin resistant conditions with high insulin secretion (as indicated by high C-peptide concentrations) the increased peripheral insulin sensitivity is followed by a decreased insulin secretion. This is not associated with an improvement of glucose tolerance. In Type 2 diabetes with low insulin secretion, an increased insulin secretion results from physical training, perhaps due to accompanying sensitization of the autonomic nervous system. Peripheral insulin concentrations are not altered, suggesting that the extra insulin produced is captured by the liver. This mechanism, as well as the improved peripheral insulin responsiveness seen in the whole body and also seen at the cellular level, probably both contribute to an improvement in glucose tolerance.     

A Higher Proinsulin Response to Glucose Loading Predicts Deteriorating Fasting Plasma Glucose and Worsening to Diabetes in Subjects with Impaired Glucose Tolerance

To evaluate the clinical significance of proinsulin determination, we measured glucose, insulin, C-peptide and proinsulin during 75-g oral glucose loading in 59 patients. In a 2.5-year follow-up study of 37 subjects with impaired glucose tolerance (IGT) at the initial test, 11 patients changed from IGT to a normal state and 5 patients showed worsening to overt Type 2 diabetes with elevation of fasting plasma glucose; 21 patients remained unchanged. Although our data showed that both fasting (IGT: p = 0.4523) and 120-min plasma glucose (IGT: p = 0.8168) values at the initial test were not significantly correlated with increased fasting plasma glucose levels in a 2.5-year follow-up study, subjects with a higher 120-min proinsulin response to glucose during the initial OGTT showed a significant correlation (IGT: p <0.0001) with increased fasting plasma glucose levels after follow-up period and developed Type 2 diabetes. The present findings suggest that the proinsulin response to glucose loading might be a useful indicator for predicting worsening to diabetes in subjects with impaired glucose tolerance.     

The interplay of insulin resistance and beta-cell dysfunction involves the development of type 2 diabetes in Chinese obeses

Type 2 diabetes mellitus (T2DM) is a heterogeneous disorder characterized by defects in insulin secretion and action and obesity plays an important role in the deterioration of glucose metabolism. In the present study we evaluated the degree of insulin resistance and first-phase insulin secretion of β-cell in obese subjects with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and T2DM in Chinese. A total of 220 subjects underwent standard 75 g oral glucose tolerance test (OGTT) and insulin-modified frequently sampled intravenous glucose tolerance test (FSIGT). Insulin sensitivity index (S _I) was assessed by the reduced sample number (n = 12) of Bergman’s minimal model method with FSIGT. Insulin secretion capacities were determined by the insulinogenic index (I _{30 min} − I _{0 min})/(G _{30 min} − G _{0 min}) in OGTT and the acute insulin response to glucose (AIR) in FSIGT. The disposition index (DI), the product of AIR and S _I was used to determine whether AIR was adequate to compensate for insulin resistance. The S _I in healthy lean control group was significantly higher than that in NGT, IGT, and T2DM group, but there was no significant difference among NGT, IGT, and T2DM group. The AIR in NGT group was significantly greater than that in control group, but then it was progressively decreased in IGT and T2DM group. The value of DI in control group was significantly higher than that in those three abnormal groups, and was decreased from NGT to IGT and T2DM group with significant difference. It indicates that obese subjects with different glucose tolerances have a similar degree of insulin resistance but differ in insulin secretion in Chinese Han population.     

Relative conributions of beta-cell function and tissue insulin sensitivity to fasting and postglucose-load glycemia

We performed hyperglycemic clamps in 283 nondiabetic Caucasians and, with multiple linear regression, determined the contribution of beta-cell function and tissue insulin sensitivity to variations in glycemia and insulinemia during oral glucose tolerance tests (OGTTs). Impaired glucose tolerance (IGT) subjects had reduced insulin sensitivity (P < .02) and beta-cell function (P < .0001). Normal glucose tolerance (NGT) subjects with first-degree type 2 diabetic relatives had reduced first and second phase insulin secretion (both, P < .05), but normal insulin sensitivity (P = .37). Beta-Cell function and insulin sensitivity accounted for one fourth of the variability in glucose tolerance. Fasting plasma glucose in subjects with NGT (n = 185) was a function of both phases of insulin secretion and of insulin sensitivity (all, P < .05), whereas, in IGT subjects (n = 98), it was a function of first phase insulin secretion and insulin sensitivity (P < .01). Two-hour glycemia was a function of second phase secretion and insulin sensitivity (P < .01). Fasting and 2-hour plasma insulin levels were determined by insulin sensitivity (and glycemia) in NGT subjects (P < .001), but by second phase secretion in IGT (P < .001). We conclude that beta-cell function is reduced in subjects with IGT; glycemia and insulinemia are not regulated by the same mechanisms in IGT and NGT; insulin sensitivity does not contribute to insulinemia in IGT; family history of diabetes influences beta-cell function, but not insulin sensitivity in Caucasians.     

Evidence for Impaired Pancreatic Beta Cell Function in South African Indians with Impaired Glucose Tolerance

In a prospective study of South African Indians with impaired glucose tolerance (IGT), the serum insulin response during a 75 g oral glucose tolerance test (OGTT) was examined in 128 subjects who were classified as IGT 1 year previously (year 0) and in 60 matched control subjects. Based on the results at year 1, study subjects were divided into three groups, using World Health Organization criteria for glucose tolerance: IGT (n = 47), diabetes (n = 41), and transient IGT (normal glucose tolerance) (n = 40). When compared with the control group, despite higher plasma glucose concentrations, the IGT group showed similar fasting insulin, but lower 30-min insulin response (57.4 ± 1.9 mUI^?1 vs 86.5 ± 1.8, p<0.001) and lower 30-min insulin/glucose ratio (7.4 ± 5.2 vs 13.3 ± 8.7, p < 0.001). The insulinogenic index was lower in the IGT group than in the control group at 30, 60, 90, and 120 min (p < 0.01, p < 0.001, p < 0.001, p < 0.001, respectively). The 2-h insulin response was higher in the IGT group (106.7 ± 1.9 mUI^?1 vs 59.2 ± 1.9, p < 0.01). The IGT group displayed a delayed pattern of insulin response with maximum levels only at 2-h. Insulin area was similar in the two groups. In the transient IGT group, despite similar plasma glucose levels, the insulin responses at 0, 15, 30, and 60 min (p < 0.01, p < 0.001, p < 0.001, p < 0.001, respectively) were lower than in the control group; the 30-min insulin/glucose ratio (7.1 ± 5.1 vs 13.3 ± 8.7, p < 0.001) and 60-min insulinogenic index (46.9 ± 86.3 vs 123.4 ± 206.3, p < 0.001) were also lower in the transient IGT group. This study has shown that IGT in South African Indians is characterized by a diminished early phase insulin response and delayed (2-h) hyperinsulinaemia during OGTT. Such findings would suggest that in this population group impaired early beta cell function is an important pathophysiological abnormality underlying IGT.     

Rosiglitazone improves insulin sensitivity, glucose tolerance and ambulatory blood pressure in subjects with impaired glucose tolerance.

AIMS: To determine the effects of rosiglitazone on insulin sensitivity, glucose tolerance and ambulatory blood pressure when administered to subjects with persistent impaired glucose tolerance (IGT). METHODS: Eighteen subjects with persistent IGT were randomized to receive rosiglitazone 4 mg twice daily or matching placebo for 12 weeks. Evaluation at baseline and at the end of treatment included measurement of whole body insulin sensitivity during a euglycaemic hyperinsulinaemic clamp and deriving an insulin sensitivity index. Changes in glucose and insulin concentration were determined after oral glucose tolerance test (OGTT) and mixed meal tolerance tests, and 24-h ambulatory blood pressure was monitored. RESULTS: Rosiglitazone significantly improved the insulin sensitivity index by 2.26 micro g/kg per min per pmol/l relative to placebo (P = 0.0003). Four of nine subjects receiving rosiglitazone reverted to normal glucose tolerance and 5/9 remained IGT, although four of these had improved 2-h glucose values. In the placebo group, 1/9 subjects progressed to Type 2 diabetes and 8/9 remained IGT. Following OGTT and meal tolerance test, glucose and insulin area under curve were reduced over 3 and 4 h, respectively. Compared with placebo, ambulatory blood pressure decreased significantly in the rosiglitazone group by 10 mmHg systolic (P = 0.0066) and 8 mmHg diastolic (P = 0.0126). CONCLUSIONS: Consistent with its effects in patients with Type 2 diabetes, rosiglitazone substantially improved whole body insulin sensitivity and the glycaemic and insulinaemic responses to an OGTT and meal tolerance test in subjects with persistent IGT. Furthermore, rosiglitazone reduced systolic and diastolic ambulatory blood pressure in these subjects.     

The effect of defective early phase insulin secretion on postload glucose intolerance in impaired fasting glucose

Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are two risk groups for type 2 diabetes. Type 2 diabetes is characterized by both impaired insulin secretion and insulin resistance but their relative contribution to the development of hyperglycemia may differ due to heterogeneity of the disease. Combined glucose intolerance (CGI), on the other hand, seems to represent a more advanced stage of prediabetes that bears a distinctly higher risk of progression to diabetes and its comorbidities. This study has the aim to compare isolated IFG and CGI categories with respect to the degree of early phase insulin secretion abnormalities and insulin resistance. Subjects who had IFG (fasting glucose: 110-126 mg/dl) were included in the study. A 75-g oral glucose tolerance test (OGTT) with insulin response was done and subjects were classified according to the WHO criteria. Six subjects were excluded because they had diabetic glucose tolerance. A total of 66 patients (53.4 +/- 11.1 years, female/male: 48/18) were divided into two groups according to their glucose tolerance in OGGT (Group 1: isolated IFG and group 2: CGI). Early phase insulin secretion was measured by intravenous glucose tolerance test (IVGTT) and OGTT. Insulin resistance was assessed by the R value of the homeostasis model assessment (HOMA). We did not find any statistically significant difference between groups according to age, gender, body mass index (BMI), fasting glucose, fasting insulin, insulin-AUC (0-180 min) and HOMA-R values. In OGGT there was no statistically significant difference between 0', 30', 60' and 90' insulin levels of the groups; only 120' and 180' insulin levels were higher in CGI than in IFG group (p<0.05). In IVGTT, there was no statistically significant difference between glucose levels of the groups. Furthermore, insulin response to intravenous glucose was higher in IFG than in CGI (p<0.05). Our data demonstrate that isolated IFG and CGI are similar with respect to the degree of insulin resistance, and that subjects with CGI had a more prominent deficit in early phases of insulin secretion.     

Circulating lipids and cardiovascular risk in newly diagnosed non-insulin-dependent diabetic subjects in India

Circulating concentrations of total cholesterol, triglycerides, non-esterified fatty acids (NEFA), glycerol, and 3-hydroxybutyrate (3-HB) were measured in 133 subjects with normal glucose tolerance (NGT), 78 with impaired-glucose-tolerance (IGT) and 189 non-insulin dependent (Type 2) diabetic (NIDDM) patients. Plasma cholesterol concentration was similar in the three groups; NGT (4.2 (2.3–7.5) mmol l⁻¹ , median (range)), IGT (4.7 (2.7–6.3)) and NIDDM (4.3 (2.3–6.9)). Plasma triglycerides (NGT 0.88 (0.37–2.80), IGT 1.26 (0.43–3.82) and NIDDM 1.38 (0.62–3.91) mmol l⁻¹ ) and NEFA (NGT 0.81 (0.29–1.58), IGT 1.02 (0.33–1.87) and NIDDM 1.02 (0.48–2.77) mmol l⁻¹ ) were higher in the two hyperglycaemic groups, but blood 3-HB concentration was similar in the three groups. Plasma cholesterol concentration in these subjects is lower than that reported in white Caucasians in the UK and USA and migrant Indian NIDDM patients in the UK. In NIDDM patients plasma cholesterol concentration was related to age, body mass index (BMI), and plasma glucose concentration while plasma triglyceride concentration was related to plasma NEFA and insulin (IRI) concentration. Evidence of ischaemia on electrocardiography in patients with diabetes was associated with higher age, blood pressure, plasma triglyceride, glucose, and IRI concentrations. © 1997 by John Wiley & Sons, Ltd.     

In middle-aged siblings of patients with type 2 diabetes mellitus normal glucose tolerance is associated with insulin resistance and with increased insulin secretion. The SPIDER study

OBJECTIVES: To evaluate the frequency of impaired glucose tolerance (IGT) and of Type 2 diabetes mellitus (Type 2 DM) in siblings of patients with Type 2 DM, and to assess insulin release and insulin sensitivity in siblings with normal glucose tolerance (NGT), compared with NGT spouses of probands without family history of Type 2 DM. DESIGN AND METHODS: We evaluated 87 families including 103 Type 2 DM patients (87 probands), and we carried out an oral glucose tolerance test (OGTT) in 130 siblings and in 60 spouses. Among NGT subjects, 12 siblings and 16 spouses underwent a low-dose insulin-glucose infusion test (LDIGIT) to evaluate C-peptide release and insulin sensitivity. RESULTS: After the OGTT, 24 siblings were classified as having Type 2 DM, 31 as IGT, and only 14 spouses as IGT (P=0.0012 vs siblings). NGT siblings (n=75) showed higher insulin levels at 120 min than NGT spouses (n=46) at OGTT, in spite of identical blood glucose levels; at LDIGIT, NGT siblings secreted more C-peptide and showed a lower insulin sensitivity than NGT spouses. CONCLUSIONS: These data indicate that middle-aged siblings of probands with Type 2 DM have a high frequency of IGT and Type 2 DM, and that NGT siblings have increased insulin resistance and increased insulin secretion when compared with adequate controls.     

Elevated plasma non-esterified fatty acid levels and insulin secretion in non-diabetic relatives of type 2 diabetic patients

OBJECTIVE: High non-esterified fatty acid (NEFA) levels impair glucose-stimulated insulin secretion from islets derived from non-diabetic Zucker rats that are genetically predisposed to diabetes. We therefore examined the effect of elevated plasma NEFA levels on insulin secretion in non-diabetic first-degree relatives of type 2 diabetic patients who are at increased risk of developing diabetes. SUBJECTS AND STUDY DESIGN: Normal glucose tolerant relatives (n = 9) and control subjects with no family history of diabetes were pair-matched for age, sex, body mass index (BMI), insulin sensitivity and early insulin response during an oral glucose tolerance test (OGTT). Plasma NEFA levels were raised from 0 to 340 minutes by the infusion of 20% Intralipid and heparin. From 180 minutes, insulin secretion rates (IRSs) were assessed by stepped low-dose glucose infusion. RESULTS: The mean (geometric mean +/- 95% CI) NEFA levels were comparable between relatives and control subjects (2.7 [2.1-3.6] and 2.1 [1.7-2.7] mmol/l, paired analysis, NS). Similarly, plasma glucose levels achieved at each glucose infusion step were comparable between the groups. However, there were no significant differences between the groups for ISR throughout the study. CONCLUSIONS: Sustained elevation of plasma non-esterified fatty acid levels does not decrease insulin secretion in non-diabetic relatives of type 2 diabetic patients, and is therefore unlikely to be important in the development of the impaired pancreatic beta-cell function in type 2 diabetes mellitus.     

On the interplay beween insulin secretion and sensitivity as determinants of glucose tolerance

Both insulin secretion and sensitivity have been claimed to be the main characteristics in the determination of future detoriation in glucose tolerance. In this cross-sectional study insulin secretion and insulin sensiturity were determined in 228 subjects with varying degrees of glucose tolerance. Insulin secretion was measured in an intravenous glucose tolerance test (IVGTT) and insulin sensitivity by the hyperinsulinaemic euglycaemic clamp test. Both the early insulin response in the IVGTT (increment) and the glucose disposal rate in the clamp test (M-value) were found to be related hyperbolically to fasting glucose (r=–0.63 and –0.66, respectively; bothP<0.0001) and in a second-order polynomial manner to the glucose disappearence rate (k-value) in the IVGTT (r=0.53 and 0.48, respectively; bothP<0.0001). Multiple regression analysis showed the insulin increment in the IVGTT and theM-value in the clamp test to be equally important determinants of glucose tolerance, together explaining about 50% of the variation in fasting glucose and thek-value in the IVGTT. In conclusion, in this cross-sectional study insulin secretion and sensitivity studied over a broad range of glucose tolerance were found to be of amost equal importance in the determination of glucose tolerance. However, low levels of insulin increment in the IVGTT were more often associated with glucose intolerance than was a low insulin sensitivity.