Measures Of Beta-cell Function Research Articles

Beta cell glucose sensitivity is decreased by 39% in non-diabetic individuals carrying multiple diabetes-risk alleles compared with those with no risk alleles

Novel type 2 diabetes-susceptibility loci have been identified with evidence that individually they mediate the increased diabetes risk through altered pancreatic beta cell function. The aim of this study was to test the cumulative effects of diabetes-risk alleles on measures of beta cell function in non-diabetic individuals. A total of 1,211 non-diabetic individuals underwent metabolic assessment including an OGTT, from which measures of beta cell function were derived. Individuals were genotyped at each of the risk loci and then classified according to the total number of risk alleles that they carried. Initial analysis focused on CDKAL1, HHEX/IDE and TCF7L2 loci, which were individually associated with a decrease in beta cell function in our cohort. Risk alleles for CDKN2A/B, SLC30A8, IGF2BP2 and KCNJ11 loci were subsequently included into the analysis. The diabetes-risk alleles for CDKAL1, HHEX/IDE and TCF7L2 showed an additive model of association with measures of beta cell function. Beta cell glucose sensitivity was decreased by 39% in those individuals with five or more risk alleles compared with those individuals with no risk alleles (geometric mean [SEM]: 84 [1.07] vs 137 [1.11] pmol min(-1) m(-2) (mmol/l)(-1), p = 1.51 x 10(-6)). The same was seen for the 30 min insulin response (p = 4.17 x 10(-7)). The relationship remained after adding in the other four susceptibility loci (30 min insulin response and beta cell glucose sensitivity, p < 0.001 and p = 0.003, respectively). This study shows how individual type 2 diabetes-risk alleles combine in an additive manner to impact upon pancreatic beta cell function in non-diabetic individuals.

Dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes mellitus.

In type 2 diabetes mellitus there is a progressive loss of beta-cell function. One new approach yielding promising results is the use of the orally active dipeptidyl peptidase-4 (DPP-4) inhibitors like sitagliptin and vildagliptin. To assess the effects of dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes mellitus. Studies were obtained from computerised searches of MEDLINE, EMBASE and The Cochrane Library. Studies were included if they were randomised controlled trials in adult people with type 2 diabetes mellitus and had a trial duration of at least 12 weeks. Two authors independently assessed risk of bias and extracted data. Pooling of studies was performed by means of fixed-effect meta-analysis. Twenty-five studies of good quality were identified, 11 trials evaluated sitagliptin and 14 trials vildagliptin treatment. Altogether, 6743 patients were randomised in sitagliptin and 6121 patients in vildagliptin studies, respectively. Sitagliptin and vildagliptin studies ranged from 12 to 52 weeks duration. No data were published on mortality, diabetic complications, costs of treatment and health-related quality of life. Sitagliptin and vildagliptin therapy in comparison with placebo resulted in an HbA1c reduction of approximately 0.7% and 0.6%, respectively. Data on comparisons with active comparators were limited but indicated no improved metabolic control following DPP-4 intervention in contrast to other hypoglycaemic agents. Sitagliptin and vildagliptin therapy did not result in weight gain but weight loss was more pronounced following placebo interventions. No definite conclusions could be drawn from published data on sitagliptin and vildagliptin effects on measurements of beta-cell function. Overall, sitagliptin and vildagliptin were well tolerated, no severe hypoglycaemia was reported in patients taking sitagliptin or vildagliptin. All-cause infections increased significantly after sitagliptin treatment but did not reach statistical significance following vildagliptin therapy. All published randomised controlled trials of at least 12 weeks treatment with sitagliptin and vildagliptin only reported routine laboratory safety measurements DPP-4 inhibitors have some theoretical advantages over existing therapies with oral antidiabetic compounds but should currently be restricted to individual patients. Long-term data especially on cardiovascular outcomes and safety are urgently needed before widespread use of these new agents. More information on the benefit-risk ratio of DPP-4 inhibitor treatment is necessary especially analysing adverse effects on parameters of immune function. Also, long-term data are needed investigating patient-oriented parameters like health-related quality of life, diabetic complications and all-cause mortality.

Short-Term Exercise Improves β-Cell Function and Insulin Resistance in Older People with Impaired Glucose Tolerance

There is a high prevalence of diabetes and impaired glucose tolerance (IGT) in the older population. Normal aging is associated with insulin resistance and impaired insulin secretion, with greater defects in people with IGT. Short-term exercise has been found to increase insulin sensitivity, but little is known about acute exercise effects on beta-cell function in older people with IGT. We assessed the effects of 7 consecutive days of supervised aerobic exercise (1 h/d at 60-70% heart rate reserve) in 12 sedentary older people with IGT. Screening included oral glucose tolerance test, stress/maximal O(2) uptake test, and dual-energy x-ray absorptiometry scan. Participants had a frequently sampled iv glucose tolerance test at baseline and 15-20 h after the seventh exercise session. Insulin sensitivity (S(I)), glucose disappearance constant (Kg, a measure of iv glucose tolerance), acute insulin response to glucose (AIRg), and disposition index (AIRg x S(I)), a measure of beta-cell function in relation to insulin resistance, were calculated. Exercise was well tolerated. Body weight, fasting glucose, fasting insulin, and iv glucose tolerance were unchanged with exercise. S(I) increased by 59%, AIRg decreased by 12%, and disposition index increased by 31%. There was no significant change in fasting lipid, catecholamine, leptin, or adiponectin levels. Short-term exercise not only improved insulin resistance but also significantly enhanced beta-cell function in older people with IGT. These effects of short-term exercise on beta-cell function cannot be explained by changes in body weight or circulating levels of lipids, leptin, adiponectin, or catecholamines.

Within-subject variability of measures of beta cell function derived from a 2 h OGTT: implications for research studies

Knowledge of the within-subject variability of a parameter is required to properly design and calculate sample sizes for longitudinal studies. We sought to determine the day-to-day variability of measures of beta cell function derived from an OGTT. Thirty-seven adults (13 with normal glucose tolerance, ten with impaired glucose tolerance, 14 with type 2 diabetes) underwent a standard 2 h 75 g OGTT on two separate days (median time between tests, 7 days; range, 5-14). From these data, the reproducibility of several indices of beta cell function were determined: insulinogenic index (DeltaI(0-30)/DeltaG(0-30)), early C-peptide response (DeltaCP(0-30)/DeltaG(0-30)), incremental AUC insulin to glucose response (incAUC(ins)/incAUC(glu)), integrated insulin secretion response from 0 to 120 min (IS/Glu(0-120)) and indices of beta cell function derived from a mathematical model. Within-subject variability for DeltaI(0-30)/DeltaG(0-30) (CV 57.1%) was higher than DeltaCP(0-30)/DeltaG(0-30) (CV 34.7%). Measures integrated over the full 120 min of the OGTT, incAUC(ins)/incAUC(glu) (CV 24.9%) and IS/Glu(0-120) (CV 17.4%), demonstrated less variability. The mathematical model-derived measures of beta cell glucose sensitivity (CV 20.3%) and potentiation (CV 33.0%) showed moderate variability. The impact of the different measures' variability on sample size (30% change from baseline) is demonstrated by calculated sample sizes of 89 for DeltaI(0-30)/DeltaG(0-30), 37 for DeltaCP(0-30)/DeltaG(0-30), 21 for incAUC(ins)/incAUC(glu) and 11 for IS/Glu(0-120). Some OGTT-derived indices of beta cell function, in particular the insulinogenic index, demonstrate high within-subject variability. Integrated measures that utilise multiple time points and measures that use C-peptide show less variability and may lead to a reduced sample size requirement.

Evaluation of β‐cell mass and function in the Göttingen minipig

Increased knowledge about beta-cell mass and function is important for our understanding of the pathophysiology of type 2 diabetes (T2DM). The relationship between the two is difficult to study in humans, whereas animal models allow studies of consequences of, for example, reduction of beta-cell mass and induction of obesity and procurement of the pancreas for histological examination. An overview of results obtained in the Göttingen minipig in relation to beta-cell function, and mass is provided here. Effects of a primary reduction of beta-cell mass have indicated that not all of the defects of pulsatile insulin secretion in human T2DM can be explained by reduced beta-cell mass. Furthermore, induction of obesity has shown deterioration of beta-cell function and morphological changes in the pancreas. As in humans, obesity leads to an increased beta-cell volume in the minipig, and based on the increased number of islets, neogenesis of islets is an important factor in expansion of beta-cell mass in this species. Measurement of beta-cell function as an estimate of beta-cell mass is, at present, the only method possible in humans, and this approach has been validated using lean and obese minipigs with a range of beta-cell mass. The effects on beta-cell function and mass of obesity of longer duration and/or more pronounced hyperglycaemia remains to be determined, but the models developed so far represent a valuable tool for such investigations.

Glucose Tolerance, Insulin Secretion, and Insulin Sensitivity in Children and Adolescents with Cystic Fibrosis and No Prior History of Diabetes

To determine the prevalence of abnormalities of glucose metabolism in pediatric outpatients with cystic fibrosis (CF). Children and adolescents (n = 73, mean age 15.0 +/- 3.7 years) with CF not previously diagnosed with diabetes underwent 3-hour oral glucose tolerance testing. All subjects with CF were clinically stable and were not being treated for active infection. A reference group of young lean adults was used for comparison. Subjects were classified as having normal glucose tolerance (NGT) or abnormal glucose metabolism (AGM), including impaired glucose tolerance (IGT), impaired fasting glucose (IFG), or diabetes, by standard criteria. The insulinogenic index was calculated as a measure of beta-cell function, and insulin resistance was estimated with the homeostatic model assessment. The reference group was significantly older than the patients with CF, but in the control subjects, the AGM and NGT were comparable in body mass index z-scores (-0.8 +/- 1.3, -0.6 +/- 1.1, -0.21 +/- 0.9 kg/m2). Thirty-eight percent of subjects with CF had AGM: 43% IGT, 29% IFG, 14% IGT/IFG, and 14% diabetes. In spite of distinct differences in glycemic response, the subjects with NGT and AGM had marked abnormalities of insulin secretion relative to the control subjects (Insulinogenic index 5.8 +/- 1.0, 5.3 +/- 0.8, and 53.5 +/- 10.0 uU/mL/mmol/L, respectively; P < .0001). Insulin sensitivity did not differ among the 3 groups, although there was a trend toward greater insulin resistance in the subjects with AGM (homeostatic model assessment: CF-NGT 1.5 +/- 0.2, CF-AGM 1.9 +/- 0.3, REF 1.3 +/- 0.1, P = NS). Abnormalities in glucose metabolism are frequent in young patients with CF without a prior diagnosis of diabetes and are associated with marked defects in insulin secretion. Given the poor beta-cell function in patients with CF, even small reductions in insulin sensitivity may be an important determinant of AGM.

The importance of β-cell management in type 2 diabetes

Despite intervention with effective oral glucose-lowering agents, most patients with type 2 diabetes will experience a gradual loss of glycaemic control. Irrespective of underlying levels of insulin resistance, the progressive failure and loss of beta-cells are ultimately responsible for the onset of frank type 2 diabetes. The mechanisms responsible for loss of beta-cell function are likely to be multifactorial, but may involve toxicity because of elevated glucose and/or lipid levels, increased secretory demand because of insulin resistance, amyloid deposition and altered levels of cytokines. Preservation of beta-cell function is now gaining recognition as a critical target in the management of type 2 diabetes. For patients with frank type 2 diabetes, preservation of beta-cell function has the potential to reduce or stabilise the progression of type 2 diabetes and to decrease the need for additional oral glucose-lowering agents and/or insulin therapy. There is a growing body of animal/preclinical evidence for improved and preserved beta-cell function with current glucose-lowering agents, such as the thiazolidinediones, metformin and the glucagon-like peptide-1 analogue, exenatide. Clinical studies incorporating indirect measures of beta-cell function also support a protective effect with some agents. A number of novel therapies that are currently under investigation may also offer beta-cell structural and functional protection, including dipeptidyl peptidase IV inhibitors and cannabinoid receptor type 1 blockers. Emerging evidence from interventional trials suggests that both intensive lifestyle changes and pharmacotherapy can delay or possibly prevent the onset of type 2 diabetes in high-risk individuals. For patients newly diagnosed with type 2 diabetes, early and aggressive intervention strategies that combine maximal glucose-lowering efficacy alongside potential beta-cell preserving properties may provide an opportunity to delay or prevent progression of the disease.

A genetic and physiological study of impaired glucose homeostasis control in C57BL/6J mice

C57BL/6J mice exhibit impaired glucose tolerance. The aims of this study were to map the genetic loci underlying this phenotype, to further characterise the physiological defects and to identify candidate genes. Glucose tolerance was measured in an intraperitoneal glucose tolerance test and genetic determinants mapped in an F2 intercross. Insulin sensitivity was measured by injecting insulin and following glucose disposal from the plasma. To measure beta cell function, insulin secretion and electrophysiological studies were carried out on isolated islets. Candidate genes were investigated by sequencing and quantitative RNA analysis. C57BL/6J mice showed normal insulin sensitivity and impaired insulin secretion. In beta cells, glucose did not stimulate a rise in intracellular calcium and its ability to close KATP channels was impaired. We identified three genetic loci responsible for the impaired glucose tolerance. Nicotinamide nucleotide transhydrogenase (Nnt) lies within one locus and is a nuclear-encoded mitochondrial proton pump. Expression of Nnt is more than sevenfold and fivefold lower respectively in C57BL/6J liver and islets. There is a missense mutation in exon 1 and a multi-exon deletion in the C57BL/6J gene. Glucokinase lies within the Gluchos2 locus and shows reduced enzyme activity in liver. The C57BL/6J mouse strain exhibits plasma glucose intolerance reminiscent of human type 2 diabetes. Our data suggest a defect in beta cell glucose metabolism that results in reduced electrical activity and insulin secretion. We have identified three loci that are responsible for the inherited impaired plasma glucose tolerance and identified a novel candidate gene for contribution to glucose intolerance through reduced beta cell activity.

The hyperbolic law?a 25-year perspective

In people with normal glucose tolerance, a decrease in insulin action is accompanied by up-regulation of insulin secretion, and vice versa. This is interpreted as a compensatory increase of insulin secretion, which maintains normoglycaemia despite decreased insulin sensitivity. In this issue of Diabetologia [1], Dr Hockaday deplores the fact that a landmark paper by the late Robert Turner and colleagues (himself included), which dates back to 1979, is rarely cited when this quasi-hyperbolic relationship is under discussion [2]. And Dr Hockaday is right, because the “hyperbola” in Fig. 7 of that paper, after two algebraic transformations (the insulin resistance factor being equivalent to 1/[insulin sensitivity] plus switching axes, the fraction of functioning beta cells being equivalent to beta cell function with opposite orientation), becomes the hyperbola now commonly used with acute insulin response (AIR) as a function of insulin sensitivity (Fig. 1a and b). In their abstract the authors already claim that “the height of basal plasma insulin is a function of the degree of insulin resistance.” Hence, Dr Hockaday appropriately claims that the concept was already shaped in their paper, which was published 25 years ago, 2 years before the classical paper of Bergman and co-workers [3]. However, it is not surprising that this paper went somewhat unnoticed by the “hyperbola aficionados,” because its main focus, and that of Fig. 7 in particular, was on factors involved in the pathogenesis of hyperglycaemia. In contrast, the concept of the hyperbola is now used to illustrate the fact that in a healthy individual any decrease in insulin sensitivity is compensated by up-regulation of beta cell function, and vice versa [4, 5]. The concept is self-sufficient at this level, and does not necessarily explain the development of hyperglycaemia. Its fundamental importance remains, however, because measurements of beta cell function can only be interpreted appropriately when a (more or less) simultaneous measure of insulin sensitivity is available [6]. These ideas were not fully developed in the 1979 paper. The beauty of Bergman’s simplification lies in the introduction of the so-called disposition index as the mathematical product of insulin action and beta cell function [7]. The disposition index is a way of measuring the ability of the beta cells to compensate for insulin resistance. This compensation is thought to be perfect when the disposition index remains constant in the face of decreasing insulin action; only when glucose tolerance becomes impaired, does the disposition index actually fall. Turner and co-workers used “HOMA factors” for insulin resistance and per cent beta cell function, which, in essence, are the product and ratio respectively of basal insulin and glucose concentrations. This is to some extent a self-fulfilling construct, because the product and ratio of any set of numbers will inevitably produce a hyperbola. The intrinsic dependence of the two HOMA factors thus limits the validity of any conclusions drawn from the data they provide. The “modern” hyperbola is clearly more informative, because it arose from variables that are not only independent but also employ stimulated measures of insulin secretion (or beta cell function) and insulin sensitivity such as the IVGTT and the euglycaemic clamp. It leads to the remarkable conclusion that the stimulated beta cell somehow knows whether the organism it belongs to can dispose of more or less glucose during the hyperinsulinaemic–euglycaemic clamp, i.e. whether it is in an insulin-sensitive or in an insulin-resistant person. The burning question relates to the nature of the signal that alerts the beta cell to the presence of insulin resistance. This latter point is addressed with acuity by Dr Hockaday in his next paragraph: “The disturbance brought about, for instance, by a decrease in insulin sensitivity is most unlikely to be completely compensated, for if so, the compensating M. Stumvoll (*) 3rd Medical Department, University of Leipzig, Philipp-Rosenthal-Str. 27, 04301 Leipzig, Germany e-mail: michael.stumvoll@medizin.uni-leipzig.de Tel.: +49-341-9713380 Fax: +49-341-9713389

Insulinogenic indices among type 2 Diabetic Nigerians

Abnormal pancreatic beta cell function is known to occur in type 2 diabetes mellitus. However, direct measurement ofpancreatic beta cell function is cumbersome and virtually out of reach of most laboratories in developing countries.Fortunately, insulinogenic indices may be used as surrogate measures of beta cell function. To study insulinogenic indicesamong type 2 diabetic Nigerians. A cross sectional study involving 40 type 2 diabetic patients and 36 age- and sex-matchedcontrol subjects was undertaken. Diabetic patients and control subjects underwent standard oral glucose tolerance tests(OGTT). Fasting and post OGTT plasma insulin levels were measured using an ELISA technique, while plasma glucoselevels were determined by a glucose oxidase method. Insulinogenic indices were calculated at time 30, 60, 90 and 120minutes of OGTT. Diabetic subjects and controls were statistically compared. At 30, 60 and 90 minutes of OGTT, type-2diabetic patients had significantly much lower insulinogenic indices compared to control subjects (p < 0.001). At 120 minutesof OGTT, however, the difference between the two groups was not statistically significant. Only BMI showed a positivecorrelation with insulinogenic index at 30 minutes of OGTT (r = +0.607, p < 0.001). There was no significant correlationbetween insulinogenic indices and duration since diagnosis of diabetes mellitus. Type 2 diabetic patients exhibit lowerinsulinogenic indices suggesting poor pancreatic beta cell function. (Int J Diabetes Metab 13: 167-169, 2005)

Beta cell function and its relation to insulin action in humans: a critical appraisal.

The importance of both insulin resistance and beta cell dysfunction in the pathogenesis of glucose intolerance is widely recognised. Also popular is the concept that beta cell secretory function must be viewed in the context of extant insulin resistance. This For Debate moves from the premise that, whilst insulin action in vivo can be measured directly by a variety of essentially coherent techniques, measurement of beta cell function is more problematic. We therefore concisely survey the principal in vivo techniques that explore the diverse aspects of beta cell function and conclude that: (i) inter-correlation of clinical tests is only modest in non-diabetic subjects and poor in diabetic individuals; (ii) no single clinical test allows beta cell function to be assessed with accuracy and specificity comparable to those of insulin sensitivity; and (iii) short of complex experiments, mathematical modelling is necessary to interpret insulin secretory responses. Next we discuss the hyperbola paradigm used to describe the reciprocal relation of beta cell function to insulin sensitivity and suggest that: (i) insulin responses reflecting the basal beta cell tone are indeed inversely related to insulin action across degrees of glucose intolerance; (ii) modes of beta cell function that selectively reflect the dynamic response to acutely changing glucose concentrations are largely independent of insulin action; and (iii) when measured by experiment or resolved by modelling, quantitatively the most important of these dynamic secretion parameters is the glucose dose-response curve (glucose sensitivity). In fact, glucose excursions following glucose ingestion (i.e. glucose tolerance) are best explained by dynamic parameters of beta cell function.

Dietary intakes and plasma concentrations of carotenoids and tocopherols in relation to glucose metabolism in subjects at high risk of type 2 diabetes: the Botnia Dietary Study

The role of antioxidants in the pathogenesis of type 2 diabetes is uncertain. We evaluated cross-sectional relations of dietary intakes and plasma concentrations of antioxidants with glucose metabolism in a high-risk population. The subjects were 81 male and 101 female first- and second-degree, nondiabetic relatives of patients with type 2 diabetes. Antioxidant intake data were based on 3-d food records. Subjects taking supplements containing beta-carotene or alpha-tocopherol were excluded. Plasma antioxidant concentrations were measured by HPLC. By using multiple linear regression analysis and adjusting for demographic, anthropometric, and lifestyle covariates, we studied whether dietary and plasma alpha- and beta-carotene, lycopene, and alpha- and gamma-tocopherol were related to fasting and 2-h concentrations of glucose and nonesterified fatty acids during an oral-glucose-tolerance test, to the homeostasis model assessment index of insulin resistance, and to measures of beta cell function (incremental 30-min serum insulin concentration during an oral-glucose-tolerance test and first-phase insulin secretion during an intravenous-glucose-tolerance test). In men, dietary carotenoids were inversely associated with fasting plasma glucose concentrations (P < 0.05), plasma beta-carotene concentrations were inversely associated with insulin resistance (P = 0.003), and dietary lycopene was directly related to baseline serum concentrations of nonesterified fatty acids (P = 0.034). In women, dietary alpha-tocopherol and plasma beta-carotene concentrations were inversely and directly associated, respectively, with fasting plasma glucose concentrations (P < 0.05). In both sexes, cholesterol-adjusted alpha-tocopherol concentrations were directly associated with 2-h plasma glucose concentrations (P < 0.05). The data suggest an advantageous association of carotenoids, which are markers of fruit and vegetable intake, with glucose metabolism in men at high risk of type 2 diabetes.

Genetic variability of the SUR1 promoter in relation to beta-cell function and Type II diabetes mellitus.

We aimed to examine the promoter of SUR1 for genetic variation and to determine if variants were associated with Type II (non-insulin-dependent) diabetes mellitus or measures of beta-cell function. We examined 465 bp upstream of the ATG site in 46 Type II diabetic patients and 15 glucose tolerant control subjects by SSCP-heteroduplex analysis. We identified an a --> t substitution 437 bp upstream of the ATG site. The allelic frequency was similar in 455 unrelated Type II diabetic patients and in 203 glucose tolerant control subjects matched for age (0.036, [95 % CI 0.019-0.053] vs 0.034 [95 % CI 0.009-0.059]; p = 0.92). Among the glucose tolerant subjects there were no differences between non-carriers (n = 189) and carriers (n = 14) of the variant in fasting values or 30 min values of plasma glucose and serum insulin during an oral glucose tolerance test. In a study of 233 glucose tolerant offspring of and spouses to Danish Caucasian Type II diabetic patients, non-carriers (n = 193) and carriers (n = 37) of the -437 a/t polymorphism did not differ in glucose or tolbutamide stimulated insulin response during an intravenous glucose tolerance test with intravenous tolbutamide injection [AUCs-insulin (0-8) min, 2290 +/- 1660 vs 2308 +/- 1935 pmol/l x min and AUCs-insulin(20-30 min), 3113 +/- 2033 vs. 3393 +/- 2830 pmol/l x min, respectively]. We have identified a novel a/t polymorphism of the SUR1 gene promoter which is not associated with Type II diabetes mellitus or measures of beta-cell function. Previous reported non-functional variants of SUR1 associated with Type II diabetes mellitus still need to be accounted for.

Relationship of beta-cell function and autoantibodies to progression and nonprogression of subclinical type 1 diabetes: follow-up of the Seattle Family Study.

A total of 85 islet cell antibody (ICA)+ or insulin autoantibody (IAA)+ relatives of patients with type 1 diabetes have been followed as part of the Seattle Family Study for a mean of 2.8 years. Of the subjects followed, 10 developed diabetes during this time period. The presence of GAD antibodies was strongly associated with the development of diabetes. In contrast, the presence of IAAs did not influence the risk of diabetes among ICA+ GAD+ subjects. When either the initial absolute acute insulin response to glucose (AIRg) or the AIR percentile, which accounts for the individual's insulin sensitivity, was below the 10th percentile of normal subjects, the risk of diabetes approached 50% at 5 years. However, impaired beta-cell function did not influence the risk of diabetes among those who were GAD+. There were 13 subjects with low AIRg and 13 subjects with two or more antibodies who had not progressed to diabetes during the course of the study. Other measurements of beta-cell function or demographic characteristics were not different in this group of nonprogressors compared with those with low AIRg who did not progress to diabetes. We conclude that ICA+ relatives with GAD antibodies or low AIRg have a high risk for development of diabetes, but among ICA+ GAD+ relatives, the addition of IAA or a single determination of AIRg does not enhance the prediction of diabetes. We suggest that prediction of diabetes risk depends on both the type and the number of antibodies present. In addition, there are a group of ICA+ relatives with low AIRg and/or multiple antibodies who have not progressed to diabetes over the course of the study.

Decreased insulin response to glucose in islet cell antibody-negative siblings of type 1 diabetic children.

Measurement of beta-cell function is an important marker of progression to diabetes in individuals at risk for the disease. Although the peak incidence for the disease occurs before 17 years of age, normal values for insulin secretion were not available in this age group. We performed a simplified intravenous glucose tolerance test in 167 normal children, and in 98 islet cell antibody (ICA)-negative and 12 ICA-positive siblings of diabetic patients. Their age range was 1-16 yr. The first phase of insulin secretion, evaluated as the sum of plasma insulin concentrations at 1 and 3 min, increased with age and was significantly lower in ICA-negative siblings (86 +/- 6 microU/ml, P < 0.002) than in normal controls (115 +/- 6 microU/ml). This difference was not apparent before 8 yr of age. None of the ICA-negative siblings developed diabetes after an average of 4.5 yr. ICA-positive siblings at first study had a first phase insulin response similar to that of ICA negative siblings, but significantly lower than that of the normal controls (74 +/- 13 microU/ml, P < 0.02). The reason for the decreased insulin secretion in ICA-negative siblings is unknown, but could involve a defect in the growth of beta-cell mass or insulin secretion that could be part of the multifactorial pathogenesis of type 1 diabetes.

Defects in beta-cell function and insulin sensitivity in normoglycemic streptozocin-treated baboons: a model of preclinical insulin-dependent diabetes.

During the preclinical period of human insulin-dependent diabetes, both impaired pancreatic beta-cell function and increased insulin resistance are found, although normoglycemia is preserved. To better understand the changes in beta-cell function and insulin sensitivity that occur in preclinical insulin-dependent diabetes, we performed a panel of in vivo beta-cell function tests and measured insulin sensitivity in adolescent male baboons both in normal health and after a small dose of streptozocin which did not induce hyperglycemia. Nine animals were studied before (stage 1) and 1 week after receiving a low dose of streptozocin (stage 2). There was no change in fasting plasma glucose or insulin. The mean glucose disposal rate (Kg) remained within the normal range, but dropped from 2.0 +/- 0.2% +/- SE) to 1.2 +/- 0.1%/min (P less than 0.01), the acute insulin response to arginine (AIR(arg)) fell from 67.7 +/- 19.4 microU/mL (485.8 +/- 139.2 pmol/L) to 32.8 +/- 7.2 microU/mL (235.3 +/- 51.7 pmol/L; P less than 0.05), and the acute insulin response to glucose (AIR(gluc)) fell from 881 +/- 243 microU/mL.10 min (6321 +/- 1744 pmol/L.10 min) to 334 +/- 82 microU/mL.10 min (2396 +/- 588 pmol/L.10 min; P less than 0.01). The most dramatic change, however, was in the ability of hyperglycemia to potentiate AIR(arg) (expressed as the slope of potentiation). This was reduced by 94% from 1.8 +/- 0.5 to 0.1 +/- 0.1 (P less than 0.01), with almost no overlap in values between stages 1 and 2. Insulin sensitivity was also lower 1 week after streptozocin treatment. When the animals were restudied 8 weeks after streptozocin treatment (stage 3) most measures of beta-cell function were not significantly different from those in stage 1. The fasting plasma glucose level was 85.4 +/- 4.3 mg/dL (4.7 +/- 0.2 mmol/L), Kg was 1.8 +/- 0.3%/min, fasting plasma insulin was 35.9 +/- 8.5 microU/mL (257.6 +/- 61.0 pmol/L), AIR(arg) was 67.0 +/- 15.4 microU/mL (480.7 +/- 110.5 pmol/L), and AIR(gluc) was 615.3 +/- 265.3 microU/mL.10 min (4413 +/- 1901 pmol/L.10 min), and tissue insulin sensitivity was 2.7 +/- 0.4 x 10(4) min/microU.mL. These values show extensive overlap with those of stage 1, from which they are not significantly different. The slope of glucose potentiation, however, remained low in all animals at stage 3.(ABSTRACT TRUNCATED AT 400 WORDS)