Assessment Of Beta-cell Function Research Articles

Is β-cell failure in type 2 diabetes mellitus reversible?

BACKGROUND:In the UK Prospective Diabetes Study (UKPDS), many subjects maintained glycemic goal (HbA1c < 7.0%) at 9 years, showing that β-cell function was preserved and that the initial decline in β-cell function recovered with sulphonylureas. Moreover, obese subjects using high daily doses of insulin for several years rarely require insulin or oral hypoglycemic agents to maintain their glycemic goal following weight loss achieved by gastric bypass surgery. Thus, declining β-cell function during the course of type 2 diabetes mellitus (T2DM) is neither universal nor permanent.OBJECTIVE:To assess β-cell function in morbidly obese subjects before insulin withdrawal and on attaining the glycemic goal with weight loss and oral agents.MATERIALS AND METHODS:Serum C-peptide (CPEP) and glucose (G) concentrations were determined up to 180 min during an oral glucose tolerance test (OGTT) with 75 glucose in 10 obese men with T2DM, before insulin withdrawal, and on achieving the glycemic goal with metformin, glimepiride, and weight loss. Ten age-matched healthy men participated as controls. Cumulative responses (CR) of CPEP and G were calculated by adding differences between the level at each time-period during OGTT and fasting (F) concentration. β-Cell function was expressed as the FCPEP as well as the insulinogenic index (CRCPEP/CRG). Insulin sensitivity was determined as FCEP × FG.RESULTS:FCPEP was decreased, though still present, prior to insulin withdrawal. Moreover, on attaining the glycemic goal over 6-9 months, FCPEP, CRPEP/CRG, and FCPEP × FG improved markedly (P < 0.001).CONCLUSION:Decline in β-cell function in morbidly obese T2DM may not be progressive and is reversible on improving insulin sensitivity and on eliminating the inhibition by exogenous insulin.

Evaluation of β-cell function in diabetic Taiwanese children using a 6-min glucagon test

This study evaluates the effects of glucagon 30 mug/kg (maximal 1 mg) on beta-cell function in children by C-peptide determined before and 6 min after intravenous administration. From 1990 to 2005, 118 Taiwanese children with newly diagnosed diabetes mellitus (98 children with type 1 and 20 children with type 2) and 29 normal Taiwanese children were enrolled in this study. Fasting and 6-min post-glucagon C-peptide levels were analyzed. In the pre-pubertal group, the median fasting serum C-peptide levels were 0.2 and 0.8 nmol/l in type 1 diabetes and normal children, respectively. These levels rose to 0.3 and 1.9 nmol/l after glucagon stimulation. In the pubertal group, the median fasting serum C-peptide levels were 0.3, 1.0 and 0.9 nmol/l in type 1 diabetes, type 2 diabetes and normal children, respectively. They rose to 0.4, 2.5 and 2.7 nmol/l after glucagon stimulation. Both fasting and post-glucagon C-peptide levels in type 1 diabetes patients were significantly lower than those of normal children and children with type 2 diabetes. The optimal cut-off values to distinguish type 1 diabetes patients from those with type 2 as determined by the receiving operating characteristic curve were 0.7 and 1.1 nmol/l, respectively. The sensitivities of both C-peptide values were 93%. The post-glucagon C-peptide level was more powerful in distinguishing type 1 diabetes from type 2 diabetes with higher specificity (95% vs. 85%). The 6-min glucagon test is valuable in assessing beta-cell function in children and can help pediatricians in the differential diagnoses of diabetes mellitus in children.

Bivariate genome-wide scan for metabolic phenotypes in non-diabetic Chinese individuals from the Stanford, Asia and Pacific Program of Hypertension and Insulin Resistance Family Study

Hypertension, obesity, impaired glucose tolerance and dyslipidaemia are metabolic abnormalities that often cluster together more often than expected by chance alone. Since these metabolic variables are highly heritable and are at least partially genetically determined, the clustering of defects in these traits implies that pleiotropic effects, where a common set of genes influences more than one trait simultaneously, are likely. We conducted bivariate linkage analyses for highly correlated traits, aiming to dissect the genetic architecture affecting these traits, in 411 Chinese families participating in the Stanford Asia-Pacific Program of Hypertension and Insulin Resistance Study. We confirmed the pleiotropic effects of the locus at 37 cM on chromosome 20 on the following pairs: (1) fasting insulin and insulin AUC (empirical p = 0.0006); (2) fasting insulin and homeostasis model assessment of beta cell function (HOMA-beta) (empirical p = 0.0051); and (3) HOMA of insulin resistance (IR) and HOMA-beta (empirical p = 0.0044). In addition, the peak logarithm of the odds (LOD) scores of linkage between a chromosomal locus and a trait for the pair fasting insulin and HOMA-IR rose to 5.10 (equivalent LOD score in univariate analysis, LOD([1]) = 4.01, empirical p = 8.0 x 10(-5)) from 3.67 and 3.42 respectively for these two traits in univariate analysis. Additional significant linkage evidence, not shown in single-trait analysis, was identified at 45 cM on chromosome 16 for the pair 1 h insulin and the AUC for insulin, with a LOD score of 4.29 (or LOD([1]) = 3.27, empirical p = 2.0 x 10(-4)). This new locus is also likely to harbour the common genes regulating these two traits (p = 1.73 x 10(-6)). These data help provide a better understanding of the genomic structure underlying the metabolic syndrome.

Homocysteine-Induced Impairment of Insulin Secretion From Clonal Pancreatic BRIN-BD11 β-Cells Is Not Prevented by Catalase

Although detrimental effects of homocysteine attributed to homocysteine auto-oxidation and generation of hydrogen peroxide (H2O2) have been reported in various cell types, such actions have not been considered in pancreatic beta-cells. This study investigates the acute effects of homocysteine on beta-cell integrity and regulation, in particular, the role of H2O2 generated by auto-oxidation. Assessment of beta-cell function was examined during acute 20- or 40-minute incubations with homocysteine using clonal BRIN-BD11 beta-cells. Homocysteine (50-1000 micromol/L) inhibited basal and glucose-induced insulin secretion in a concentration-dependent manner. Insulinotropic responses to alanine, arginine, 2-ketoisocaproate, elevated Ca, tolbutamide, potassium chloride (KCl), forskolin, and phorbol 12-myristate 13-acetate were also significantly reduced by homocysteine. Likewise, preincubation with homocysteine caused a reduction in the insulinotropic responses to glucose and each of the secretagogues tested. Notably, excess catalase (100 microg/mL) in the buffer, although sufficient to remove homocysteine-derived H2O2, did not alleviate the detrimental effects of homocysteine. Collectively, these data suggest that homocysteine impairs insulin secretory function by mechanisms independent of H2O2 generation. Although homocysteine may give rise to reactive oxygen species, these observations indicate detrimental non-oxidative pancreatic beta-cell actions of homocysteine.

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus

The aim of this study was to assess the efficacy and safety of sitagliptin (MK-0431) as monotherapy in patients with type 2 diabetes mellitus and inadequate glycaemic control (HbA(1c) > or =7% and < or =10%) on exercise and diet. A total of 521 patients aged 27-76 years with a mean baseline HbA(1c) of 8.1% were randomised in a 1:2:2 ratio to treatment with placebo, sitagliptin 100 mg once daily, or sitagliptin 200 mg once daily, for 18 weeks. The efficacy analysis was based on an all-patients-treated population using an analysis of covariance, excluding data obtained after glycaemic rescue. After 18 weeks, HbA(1c) was significantly reduced with sitagliptin 100 mg and 200 mg compared with placebo (placebo-subtracted HbA(1c) reduction: -0.60% and -0.48%, respectively). Sitagliptin also significantly decreased fasting plasma glucose relative to placebo. Patients with higher baseline HbA(1c) (> or =9%) experienced greater placebo-subtracted HbA(1c) reductions with sitagliptin (-1.20% for 100 mg and -1.04% for 200 mg) than those with HbA(1c) <8% (-0.44% and -0.33%, respectively) or > or =8% to 8.9% (-0.61% and -0.39%, respectively). Homeostasis model assessment beta cell function index and fasting proinsulin:insulin ratio, markers of insulin secretion and beta cell function, were significantly improved with sitagliptin. The incidence of hypoglycaemia and gastrointestinal adverse experiences was not significantly different between sitagliptin and placebo. Sitagliptin had a neutral effect on body weight. Sitagliptin significantly improved glycaemic control and was well tolerated in patients with type 2 diabetes mellitus who had inadequate glycaemic control on exercise and diet.

The central issue? Visceral fat mass is a good marker of insulin resistance and metabolic disturbance in women with polycystic ovary syndrome

To establish whether visceral fat mass is the most significant variable correlating with insulin resistance and other metabolic parameters in women with polycystic ovary syndrome (PCOS). Prospective cross-sectional trial. Reproductive medicine clinic. Forty women with anovulatory PCOS. Measurements were taken at recruitment, and analysis was performed to define correlations between the outcome measures and the explanatory variables. Visceral and subcutaneous fat by computed tomography scan, insulin resistance, anthropometric measures, markers of the metabolic syndrome and androgens. Strong linear correlation of visceral fat to insulin resistance (r = 0.68, P < 0.001) was observed. There were also statistically significant correlations with fasting insulin (r = 0.73, P < 0.001), homeostasis model assessment beta-cell function (r = 0.50, P = 0.007), triglycerides (r = 0.45, P = 0.003), high-density lipoprotein cholesterol (r = -0.42, P = 0.007), urate (r = 0.47, P = 0.002), Sex hormone binding globulin (r = -0.39, P = 0.01) and luteinising hormone (r = -0.32, P = 0.02). There were no significant correlations of testosterone with fat distribution or metabolic parameters. Insulin resistance showed closest correlation to visceral fat mass (r = 0.68, P < 0.001), then to waist circumference (r = 0.62, P < 0.001), with the weakest correlation being waist:hip ratio (r = 0.36, P = 0.01). The best regression model for predicting insulin resistance is with visceral fat mass and triglycerides as the explanatory variables (r = 0.72, P < 0.001). Visceral fat is the most significant variable correlating with metabolic dysfunction in women with PCOS. Our data support the hypothesis that visceral fat either causes insulin resistance or is a very early effect of it. It also implies that reducing visceral fat should reduce insulin resistance which may account for the observations that exercise and weight loss appear to be more effective interventions than pharmacological treatments. The best anthropometric measure of insulin resistance is waist circumference.

Improved glycaemic control with dipeptidyl peptidase‐4 inhibition in patients with type 2 diabetes: vildagliptin (LAF237) dose response

A novel treatment option for diabetic patients is the enhancement of incretin hormone activity by inhibition of the enzyme dipeptidyl peptidase-4 (DPP-4). This study was designed to establish a dose of the DPP-4-inhibitor vildagliptin (LAF237) that was effective in reducing HbA1c levels and was safe and well tolerated in patients with type 2 diabetes. The study of 279 patients with type 2 diabetes consisted of a 4-week run-in phase where patients received placebo and a 12-week active treatment phase where they received one of the following dosages of vildagliptin: 25 mg twice daily, 25, 50 or 100 mg once daily (qd), or placebo. There was a statistically significant reduction in HbA1c levels in the vildagliptin 50 mg qd (p=0.003) and 100 mg qd groups (p=0.004) compared with the placebo group. The mean 4-h postprandial glucose level was significantly reduced from placebo in the vildagliptin 50 mg qd group (p = 0.012) and mean 4-h postprandial insulin was significantly increased from baseline vs. placebo in the vildagliptin 100 mg qd group (p=0.022). The assessment of beta-cell function (HOMA-B) was significantly increased in the vildagliptin 100 mg qd treatment group (p=0.007). The incidence of adverse events was similar in all treatment groups including placebo. Vildagliptin, at 50 and 100 mg qd, was effective in reducing HbA1c levels compared with placebo in patients with type 2 diabetes. Vildagliptin at dosages up to 100 mg qd appeared safe and well tolerated.

Molecular genetics and phenotypic characteristics of MODY caused by hepatocyte nuclear factor 4α mutations in a large European collection

Heterozygous mutations in the gene of the transcription factor hepatocyte nuclear factor 4alpha (HNF-4alpha) are considered a rare cause of MODY with only 14 mutations reported to date. The description of the phenotype is limited to single families. We investigated the genetics and phenotype of HNF-4alpha mutations in a large European Caucasian collection. HNF-4alpha was sequenced in 48 MODY probands, selected for a phenotype of HNF-1alpha MODY but negative for HNF-1alpha mutations. Clinical characteristics and biochemistry were compared between 54 HNF-4alpha mutation carriers and 32 familial controls from ten newly detected or previously described families. Mutations in HNF-4alpha were found in 14/48 (29%) probands negative for HNF-1alpha mutations. The mutations found included seven novel mutations: S34X, D206Y, E276D, L332P, I314F, L332insCTG and IVS5nt+1G>A. I314F is the first reported de novo HNF-4alpha mutation. The average age of diagnosis was 22.9 years with frequent clinical evidence of sensitivity to sulphonylureas. Beta cell function, but not insulin sensitivity, was reduced in diabetic mutation carriers compared to control subjects (homeostasis model assessment of beta cell function 29% p<0.001 vs controls). HNF-4alpha mutations were associated with lower apolipoprotein A2 (p=0.001), A1 (p=0.04) and total HDL-cholesterol (p=0.02) than in control subjects. However, in contrast to some previous reports, levels of triglycerides and apolipoprotein C3 were normal. HNF-4alpha mutations are common when no HNF-1alpha mutation is found in strictly defined MODY families. The HNF-4alpha clinical phenotype and beta cell dysfunction are similar to HNF-1alpha MODY and are associated with reduced apolipoprotein A2 levels. We suggest that sequencing of HNF-4alpha should be performed in patients with clinical characteristics of HNF-1alpha MODY in whom mutations in HNF-1alpha are not found.

Application of hyperglycemic clamp technique in the assessment of beta-cell function in obese individuals with glucose intolerance

To study the changes of insulin secretion in Chinese individuals with impaired glucose tolerance and diabetes and the relationship between insulin release and overweight/obesity. Sixty-four individuals were divided into 6 groups according to glucose tolerance (GT) and body weight: normal weight with normal glucose tolerance (NW-NGT) group, NW with impaired glucose tolerance (NW-IGT) group, NW with diabetes (NW-DM) group, overweight or obese (OW/OB) with NGT (OW/OB-NGT) group, OW/OB with IGT (OW/OB-IGT) group, OW/OB with DM (OW/OB-DM) group. The subjects were required to fast for 12 hours and then underwent oral glucose tolerance test (OGTT) and hyperglycemic clamp. 1. The first-phase insulin release, the sum of insulin concentrations during the first 10 minutes (at the 2(nd), 4(th), 6(th), 8(th), and 10(th) minutes) were 186 mU/L +/- 38 mU/L in the IGT groups, significantly lower than that of the NGT groups (P = 0.001). The first-phase insulin release of the DM groups was 71 mU/L +/- 10 mU/L, significantly lower than those of the NW-NGT group and IGT group (257 mU/L +/- 22 mU/L and 164 mU/L +/- 47 mU/L respectively, both P < 0.01). The second-phase insulin release, the average insulin concentration during the 20th to 150th minutes of the DM groups was 31 mU/L +/- 4 mU/L, significantly lower than those of the NGT and IGT groups (74 mU/L +/- 5 mU/L and 45 mU/L +/- 19 mU/L, P < 0.01 and P < 0.04). The 2nd-phase insulin release was not significantly different between the NGT and IGT groups (P = 0.13). The maximum insulin release (INS-Max), the average insulin concentration during the last 30 minutes (120th to 150th minutes), of the DM groups was 40 mU/L +/- 6 mU/L, significantly lower than those of the NGT and IGT groups (P < 0.05). The INS-MAX was not significantly different between the NGT and IGT groups (P = 0.12). The first-phase insulin release, second-phase insulin release, and INS-MAX of the NW-IGT group were 164 mU/L +/- 47 mU/L, 45 mU/L +/- 19 mU/L, and 53 mU/L +/- 22 mU/L respectively, all significantly higher than those of the NW-IGT group (61 mU/L +/- 17 mU/L, 27 mU/L +/- 5 mU/L, and 34 mU/L +/- 6 mU/L respectively, P < 0.05) and those of the DM groups (61 mU/L +/- 17 mU/L, 27 mU/L +/- 5 mU/L, and 34 mU/L +/- 6 mU/L respectively, P < 0.05). 3. The first-phase insulin release, second-phase insulin release, and INS-MAX of the OW/OB-NGT group were 546 mU/L +/- 62 mU/L, 138 mU/L +/- 18 mU/L, and 163 mU/L +/- 24 mU/L respectively, all significantly higher than those of the NW-NGT group (257 mU/L +/- 22 mU/L, 74 mU/L +/- 6 mU/L, and 97 mU/L +/- 8 mU/L, respectively, P < 0.05). The first- phase insulin secretion in the OW/OB-IGT group and OW/OB-DM group were 201 mU/L +/- 47 mU/L and 82 mU/L +/- 9 mU/L respectively, both significantly lower than that of the OW/OB- NGT group (P < 0.05). 1. The insulin release is progressively decreased in Chinese individuals with IGT and DM. The individuals with IGT have lower first phase insulin release. In addition to decreased first phase insulin release, subjects with DM have reduced second-phase and maximum insulin release. 2. Simply overweight/obese individuals have higher insulin secretion, while overweight or obese individuals with IGT and DM have reduced first phase insulin release.

Use and abuse of HOMA modeling.

Homeostatic model assessment (HOMA) is a method for assessing beta-cell function and insulin resistance (IR) from basal (fasting) glucose and insulin or C-peptide concentrations. It has been reported in >500 publications, 20 times more frequently for the estimation of IR than beta-cell function. This article summarizes the physiological basis of HOMA, a structural model of steady-state insulin and glucose domains, constructed from physiological dose responses of glucose uptake and insulin production. Hepatic and peripheral glucose efflux and uptake were modeled to be dependent on plasma glucose and insulin concentrations. Decreases in beta-cell function were modeled by changing the beta-cell response to plasma glucose concentrations. The original HOMA model was described in 1985 with a formula for approximate estimation. The computer model is available but has not been as widely used as the approximation formulae. HOMA has been validated against a variety of physiological methods. We review the use and reporting of HOMA in the literature and give guidance on its appropriate use (e.g., cohort and epidemiological studies) and inappropriate use (e.g., measuring beta-cell function in isolation). The HOMA model compares favorably with other models and has the advantage of requiring only a single plasma sample assayed for insulin and glucose. In conclusion, the HOMA model has become a widely used clinical and epidemiological tool and, when used appropriately, it can yield valuable data. However, as with all models, the primary input data need to be robust, and the data need to be interpreted carefully.

Importance of quantifying insulin secretion in relation to insulin sensitivity to accurately assess beta cell function in clinical studies.

Insulin sensitivity and insulin secretion are mutually related such that insulin resistance is compensated by increased insulin secretion. A correct judgement of insulin secretion therefore requires validation in relation to the insulin sensitivity in the same subject. Mathematical analyses of the relationship between insulin sensitivity and insulin secretion has revealed a hyperbolic function, such that the product of the two variables is constant. This product is usually called the disposition index. Several techniques may be used for its estimation such as data derived from the frequently sampled i.v. glucose tolerance test, the oral glucose tolerance test or the glucose-dependent arginine stimulation test or the euglycemic hyperinsulinemic clamp technique in combination with a test on insulin secretion. Using these techniques the compensatory increase in beta cell function in insulin resistance has been verified in obesity, in pregnancy and after glucocorticoid administration as has the defective beta cell function as the underlying cause of impaired glucose tolerance and type 2 diabetes. Similarly, combined analysis of insulin sensitivity and insulin secretion has shown a down-regulation of beta cell function in increased insulin sensitivity accompanying weight reduction in obesity and following exercise. Acknowledging this inverse relationship between insulin secretion and insulin sensitivity therefore requires estimation of both variables for correct assessment in any individual.

Persistence of impaired pancreatic β-cell function in children treated for acute lymphoblastic leukaemia

Treatment for acute lymphoblastic leukaemia can induce alterations of glucose metabolism, but long-term follow-up data on this topic are still absent. We aimed to study glucose metabolism by intravenous and oral glucose tolerance testing in 32 children affected by acute lymphoblastic leukaemia and who were off-therapy for at least 1 year. 22 (69%) children presented with impaired first-phase insulin response, which in nine children was associated with impaired glucose tolerance and in one child with overt diabetes. Fasting insulin (4.65 mU/L, 95% CI 1.1-8.1; p=0.008), insulinogenic index (0.46; 0.02-0.98; p=0.03), and homoeostatic model assessment beta-cell function (80.1, 7.2-153; p=0.02) were reduced in the children with impaired insulin response. Chemotherapy for acute lymphoblastic leukaemia is associated with beta-cell function damage, which persists even after therapy has been stopped.

Methods for clinical assessment of insulin sensitivity and beta-cell function.

The quantitative assessment of insulin sensitivity (IS) and beta-cell function (BCF) is fundamental in the study of metabolic disorders. The most relevant experimental tests and data analysis methods for assessing both IS and BCF are described and their characteristic features discussed. Advantages and limitations of each method are comparatively reviewed to help investigators choose the most suitable test for their needs. The problem of properly relating BCF to IS is also addressed. Particular attention is paid to the oral glucose tolerance test, which has recently received considerable interest. The role of mathematical models in IS and BCF assessment is also emphasized.

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.

Altered homeostatic adaptation of first- and second-phase beta-cell secretion in the offspring of patients with type 2 diabetes: studies with a minimal model to assess beta-cell function.

We adapted a minimal model to assess beta-cell function during a hyperglycemic glucose clamp and to uncover peculiar aspects of the relationship among beta-cell function, plasma glucose, and insulin sensitivity (IS) in offspring of Caucasian patients with type 2 diabetes (OfT2D). We pooled two data sets of OfT2D (n = 69) and control subjects (n = 45) with normal glucose regulation. Plasma C-peptide was measured during a hyperglycemic clamp ( approximately 10 mmol/l) to quantify model-based first-phase secretion and glucose sensitivity of second-phase secretion (beta). IS was quantified during the hyperglycemic clamp. In the pooled data, first-phase secretion was linearly and negatively related to fasting plasma glucose, but not IS; OfT2D lay on a distinct line shifted to the left of the control subjects. In contrast, beta was negatively related to IS, and OfT2D lay on a distinct line shifted more and more to the left of the control subjects, as IS was worse. Thus, in OfT2D lower beta-cell adaptive responses exist between ambient glycemia and first-phase insulin secretion and between IS and second-phase secretion. Under conditions leading to decreased insulin sensitivity, these disturbed relationships may lead to progression to diabetes in OfT2D.

The prevalent Gly1057Asp polymorphism in the insulin receptor substrate-2 gene is not associated with impaired insulin secretion.

Disruption of the insulin receptor substrate-2 was shown to cause type 2 diabetes in mice. This could be largely attributed to abnormal beta-cell development. In humans, a prevalent polymorphism in insulin receptor substrate-2 (Gly1057Asp) was not found be associated with type 2 diabetes in linkage and association studies. We tested the hypothesis that an extreme challenge of the beta cell might reveal subtle abnormalities in carriers of this polymorphism undetected by conventional insulin secretion tests. Therefore, in addition to assessing beta-cell function by oral glucose tolerance testing (n = 318, normal glucose tolerance), we measured the secretory response to maximal stimulation by hyperglycemia (10 mM), glucagon-like peptide-1, and arginine administered in an additive fashion (n = 77, nondiabetic). The allelic frequency of the Asp allele was approximately 37%. Neither the beta-cell function indices from the oral glucose tolerance test nor the secretory response during the hyperglycemic clamp differed measurably between carriers and controls. Moreover, maximal plasma C-peptide concentrations in response to the combined glucose, glucagon-like peptide-1, and arginine stimulus was not different between Gly/Gly (10,745 +/- 1,186 pmol/liter) and X/Asp (10,800 +/- 490 pmol/liter, P = 0.99). In conclusion, our findings strongly suggest that the Gly1057Asp polymorphism in insulin receptor substrate-2 is not associated with beta-cell dysfunction. The normal maximal insulin secretory response makes it unlikely that this common polymorphism results in abnormal beta-cell development.

Fate of the pancreas after asynchronous kidney loss in patients undergoing simultaneous kidney/pancreas transplantation

We analyzed the clinical evolution of pancreas allografts in simultaneous pancreas-kidney transplantation (SPKT) cases after asynchronous kidney allograft loss and kidney retransplantation at a single non-United States center.We performed a retrospective analysis of 168 SPKT from December 2000 to June 2007.The 5-year kidney allograft survival rate was 71%. Excluding cases of death with a functioning graft after SPKT (n = 35; 74.4%), 12 kidney allografts were lost due to acute rejection (n = 7; 15%) or chronic allograft nephropathy (n = 5; 10.6%). Delayed graft function contributed to kidney allograft loss. Five of 12 patients underwent kidney retransplantation. Sixty percent of pancreas allografts were lost after this procedure, which was attributed to either the diabetogenic effects of the immunosuppressive regimen or to the perioperative stress. Oral glucose tolerance tests performed before kidney retransplantation identified patients with good pancreas allograft function versus those with intolerance on glucose tests who received reduced glucocorticoid doses.In SPKT, pancreas allograft function was seriously affected by kidney retransplantation. Oral glucose tolerance tests performed before kidney retransplantation were helpful to assess beta-cell function and suggest prescription of lower steroid doses to decrease the pancreas allograft dysfunction.

Hyperhomocysteinemia in type 2 diabetes: relationship to macroangiopathy, nephropathy, and insulin resistance.

The aim of this study was to determine the distribution of plasma total homocysteine (tHcy) concentrations in type 2 diabetic patients and to assess whether high tHcy values were related to chronic complications (particularly macroangiopathy and nephropathy) and/or the degree of insulin resistance. Fasting tHcy levels were measured in 122 type 2 diabetic patients in whom the presence of chronic complications (e.g., macroangiopathy, microalbuminuria, macroproteinuria, decreased creatinine clearance, hypertension, retinopathy, and neuropathy) was recorded alongside an assessment of insulin resistance by the homeostasis model assessment (HOMA). We found that 31% of the cohort (group 1) had raised tHcy (mean +/- 1 SD) values (20.8 +/- 5.1 micromol/l), whereas 69% (group 2) had normal values (10.2 +/- 2.0 micromol/l). The prevalence of macroangiopathy was higher in group 1 than in group 2 subjects (70 vs. 42%, P < 0.01); the prevalence of coronary artery disease was particularly higher in group 1 (46 vs. 21%, P < 0.02). The prevalence of impaired renal function, evidenced by decreased creatinine clearance, was higher in group 1 (32 vs. 10%, P < 0.005). Other clinical and biological characteristics of both groups were comparable, although group 1 had lower levels of folic acid than group 2 (5.2 +/- 2.9 vs. 7.0 +/- 3.4 ng/ml, P < 0.01). No differences were found for microalbuminuria (33 vs. 31%), retinopathy (45 vs. 42%), or neuropathy (70 vs. 59%) between groups 1 and 2, respectively The degree of insulin resistance was similar in groups 1 and 2 (46 +/- 21 and 42 +/- 20% of HOMA-insulin sensitivity) as was the assessment of beta-cell function (63 +/- 28 and 65 +/- 46%, respectively). No differences in tHcy levels were found between subjects receiving metformin and those not receiving metformin. In contrast, the plasma tHcy level was higher in diabetic patients treated with fibrates (P = 0.0016). Elevated plasma tHcy levels in type 2 diabetes is associated with a higher prevalence of macroangiopathy and nephropathy when assessed from creatinine clearance indexes and is not associated with different degrees of insulin resistance.

Assessment of insulin sensitivity and beta-cell function from measurements in the fasting state and during an oral glucose tolerance test.

We aimed to find if the relation between insulin sensitivity and beta-cell function assessed from fasting and OGTT measurements has a physiological shape (hyperbolic with the reference methods). Healthy women without diabetic first-degree relatives underwent a 75 g OGTT with plasma glucose and insulin (n = 35) concentrations being measured at 0, 30, 60 and 120 min. Beta-cell function and insulin sensitivity were estimated using previously described indices from fasting (1 for beta-cell function, 6 for insulin sensitivity) and OGTT measurements (3 for beta-cell function and 5 for insulin sensitivity). A hyperbolic relation was tested for the 21 beta-cell function-insulin sensitivity pairs using a non-lineal regression method. The assessment of beta-cell function from OGTT was impossible in seven women and one had outlier indices. For the remaining 27 women, only 8 combinations adjusted to a hyperbolic relation. The best adjustment was achieved using the fasting glucose to insulin ratio as the estimation of insulin sensitivity and the homeostasis model assessment (HOMA) index (single fasting sample) as the estimation of beta-cell function (r2 0.802, k 869.71, p < 0.001). In this group of healthy women, the estimation of insulin sensitivity and beta-cell function by most methods using OGTT-derived glucose and insulin measurements did not adjust to a hyperbolic relation but all fasting indices combinations did. Beta-cell function estimated with the HOMA index and insulin sensitivity with fasting glucose to insulin ratio had the best adjustment.

Oral insulin administration and residual (β-cell function in recent-onset type 1 diabetes: a multicentre randomised controlled trial

Oral administration of autoantigens can slow the progression of beta-cell destruction in non-obese diabetic mice. We investigated whether oral administration of recombinant human insulin could protect residual beta-cell function in recent-onset type 1 diabetes. We enrolled 131 autoantibody-positive diabetic patients aged 7-40 years within 2 weeks of diagnosis (no ketoacidosis at diagnosis, weight loss <10%, polyuria for <6 weeks). They were randomly assigned 2.5 mg or 7.5 mg oral insulin daily or placebo for 1 year, in addition to subcutaneous insulin therapy. Serum C-peptide concentrations were measured in the fasting state and after stimulation, to assess beta-cell function. Autoantibodies to beta-cell antigens were assayed. Analyses were by intention to treat. Baseline C-peptide and haemoglobin A1c concentrations were similar in the three groups. During follow-up, there were no differences between the groups assigned 2.5 mg or 7.5 mg oral insulin or placebo in subcutaneous insulin requirements, haemoglobin A1c concentrations, or measurements of fasting (mean at 12 months 0.18 [SD 0.17], 0.17 [0.17], and 0.17 [0.12] nmol/L) or stimulated C-peptide concentrations (glucagon-stimulated 0.39 [0.38], 0.37 [0.39], and 0.33 [0.24] nmol/L; meal-stimulated 0.72 [0.60], 0.49 [0.49], and 0.57 [0.51 nmol/L]. Neither age nor C-peptide concentration at entry influenced treatment effects. No differences were seen in the time-course or titres of antibodies to insulin, glutamic acid decarboxylase, or islet antigen 2. At the doses used in this trial, oral administration of insulin initiated at clinical onset of type 1 diabetes did not prevent the deterioration of beta-cell function.