Acute insulin secretion as a predictor of weight gain in healthy humans.

Objective: We sought to determine the role of the acute insulin secretory response to glucose (AIRg) in predicting weight gain in normoglycemic persons with no family history of diabetes, who are at low risk for development of disease.

Research Methods And Procedures: One hundred five individuals (64 men and 41 women) who underwent measures of weight and AIRg and insulin sensitivity index (S(I)) by intravenous glucose tolerance test between 1963 and 1983 were surveyed again for weight between 1994 and 1999, with a mean follow-up of 26 +/- 4 years.

Results: Mean change in weight was 8 +/- 10 kg.

Insulin resistance is a poor predictor of type 2 diabetes in individuals with no family history of disease.

In normoglycemic offspring of two type 2 diabetic parents, low insulin sensitivity (S(I)) and low insulin-independent glucose effectiveness (S(G)) predict the development of diabetes one to two decades later. To determine whether low S(I), low S(G,) or low acute insulin response to glucose are predictive of diabetes in a population at low genetic risk for disease, 181 normoglycemic individuals with no family history of diabetes (FH-) and 150 normoglycemic offspring of two type 2 diabetic parents (FH+) underwent i.v.

Acute postchallenge hyperinsulinemia predicts weight gain: a prospective study.

The relationships of insulin secretion and insulin action to body weight are incompletely understood. Obesity is associated with reduced sensitivity to insulin and high fasting and postprandial serum insulin levels. However, it is unknown whether insulin secretion rises to compensate for insulin resistance or high insulin secretion promotes body weight gain and the development of insulin resistance.

Natural history of impaired glucose tolerance: follow-up at Joslin Clinic.

The goal of this study was to examine follow-up data on the offspring of two parents with NIDDM who have IGT to identify predictors of progression to NIDDM. The study group consisted of 80 individuals with IGT (WHO criteria), 28 of whom had IGT at baseline, and 52 who developed it during follow-up. Both an oral glucose tolerance test (OGTT) and an intravenous glucose tolerance test (IVGTT) were performed at baseline.

Late progression to diabetes and evidence for chronic beta-cell autoimmunity in identical twins of patients with type I diabetes.

Previous studies suggest that after 6 years of discordance, identical twin pairs rarely become concordant for type I diabetes. With up to 39 years of follow-up from the onset of diabetes in the index twin, we determined how many discordant twins have evidence of beta-cell autoimmunity and how many develop overt diabetes. We longitudinally followed 23 pairs of identical twins (or triplets) that were selected from a total group of 30 pairs because they were discordant for type I diabetes when first ascertained.

Role of glucose and insulin resistance in development of type 2 diabetes mellitus: results of a 25-year follow-up study.

Type 2 diabetes mellitus is characterised by resistance of peripheral tissues to insulin and a relative deficiency of insulin secretion. To find out which is the earliest or primary determinant of disease, we used a minimum model of glucose disposal and insulin secretion based on intravenous glucose tolerance tests to estimate insulin sensitivity (SI), glucose effectiveness (ie, insulin-independent glucose removal rate, SG), and first-phase and second-phase beta-cell responsiveness in normoglycaemic offspring of couples who both had type 2 diabetes. 155 subjects from 86 families were followed-up for 6-25 years.

Familial clustering of insulin sensitivity.

This study's objective was to determine whether there is familial clustering of insulin sensitivity (SI) or insulin-independent glucose uptake (SG), which would be evidence that they are genetically determined traits. Outpatients had a 3-h intravenous glucose tolerance test. Nondiabetic individuals (n = 183), ranging in age from 16 to 60 yr, were from 105 families that had 2 parents with non-insulin-dependent diabetes mellitus.

Prognostically significant heterogeneity of cytoplasmic islet cell antibodies in relatives of patients with type I diabetes.

A significant proportion of relatives of patients with insulin-dependent (type I) diabetes with high titers of cytoplasmic islet cell autoantibodies (ICAs) do not progress to overt diabetes with up to 8 yr of follow-up. This may reflect that follow-up of such relatives has not been long enough to observe diabetes, that despite expression of identical ICAs, some relatives will not progress to diabetes; or that there is heterogeneity in what is identified as ICA. We identified a subset of ICA that was restricted in its species (not reacting with mouse islets) and cell-type reactivity within islets (beta-cell specific).

Specific association of HLA-DR4 with increased prevalence and level of insulin autoantibodies in first-degree relatives of patients with type I diabetes.

First-degree relatives of patients with insulin-dependent (type I) diabetes (n = 264 from 106 families) were evaluated with HLA typing and determination of competitive insulin autoantibodies (CIAAs) and islet cell autoantibodies (ICAs). The levels of CIAAs in 30 relatives exceeded our upper limit of normal (greater than or equal to 39 nU/ml), and 30 had high-titer ICAs (greater than or equal to 40 Juvenile Diabetes Foundation units [JDF U]). Eleven of the HLA-typed relatives developed diabetes during follow-up.

Slow glucose removal rate and hyperinsulinemia precede the development of type II diabetes in the offspring of diabetic parents.

Objective: To determine whether insulin resistance or insulin deficiency is primary in the pathogenesis of type II diabetes.

Design: Cohort analytic study of persons with normal glucose tolerance but with a high risk for developing type II diabetes (average follow-up time, 13 years).

Setting: Outpatients had an intravenous glucose tolerance test and were contacted periodically to ascertain diagnoses of diabetes.

Predicting type I diabetes.

Currently, there are three markers that are being studied with the potential to give a high positive predictive value for the development of type I diabetes (insulin-dependent diabetes caused by autoimmune beta-cell destruction) and that can be utilized to predict the disease in susceptible relatives: 1) high-titer cytoplasmic islet cell antibodies, 2) insulin autoantibodies detected with fluid-phase radiobinding assays, and 3) first-phase insulin release after intravenous glucose less than 1st percentile. With the combination of these assays, it seems to be possible to identify first-degree relatives with a high probability of developing type I diabetes within a limited time span (i.e.

Analysis of metabolic progression to type I diabetes in ICA+ relatives of patients with type I diabetes.

We intensively studied 5 islet cell-antibody-positive (ICA+) first-degree relatives of type I (insulin-dependent) diabetic patients before overt diabetes. In total, 55 intravenous glucose tolerance tests (IVGTTs) and 83 fasting plasma glucose determinations were made over a maximum 4-yr period before diabetes. The 5 prediabetic relatives (not diabetic when initially studied but subsequently progressed to overt diabetes) as a group showed a progressive rise in fasting glucose (r = 0.

Long-term results of pancreatic resection and segmental pancreatic autotransplantation for chronic pancreatitis.

Thirteen patients who underwent extensive pancreatic resection and segmental autotransplantation and who have a median follow-up of 62 months are presented. Eleven patients had technically successful grafts. Three of six patients who underwent total pancreatectomy and three of five patients who underwent near-total resection remain insulin-independent.

Life-table analysis of progression to diabetes of anti-insulin autoantibody-positive relatives of individuals with type I diabetes.

Cytoplasmic islet cell antibody-negative (ICA-; less than 20 Juvenile Diabetes Foundation units, n = 1670) and ICA+ (n = 42) first-degree relatives of type I (insulin-dependent) diabetic individuals were studied for competitive insulin autoantibodies (CIAAs) with a radioassay. Overall, 3.7% of first-degree relatives (64 of 1712) were CIAA+.

Production of insulin antibodies by mice rejecting insulin transfected cells.

Antibodies to insulin appear prior to the development of Type I diabetes and their concentration may correlate with the rate of autoimmune beta cell destruction. In order to study potential mechanisms involved in the production of antibodies to insulin, we transplanted different strains of mice with histoincompatible non-islet cells (AtT20-Ins and NIH-3T3-Ins) synthesizing homologous insulin, in contrast to immunization with non-transfected cells and insulin in Freund's adjuvant. The pituitary cell line (AtT20) and the fibroblast cell line (NIH-3T3) were transfected with the rat insulin-II gene (which encodes an insulin molecule identical to that of mouse insulin-II).

Radioassay determination of insulin autoantibodies in NOD mice. Correlation with increased risk of progression to overt diabetes.

In an initial cross-sectional study, 29 female and 25 male nondiabetic weaned nonobese diabetic (NOD) mice of various ages (age range 30-300 days, mean 108 +/- 10 days) and 11 unweaned NOD pups were evaluated for competitive insulin autoantibodies (CIAAs) with a fluid-phase radioassay. Eleven of 54 (20%) weaned NOD mice had CIAA levels above the range (greater than 39 nU/ml) of 81 control mice. The group of NOD mice that progressed to diabetes had a significantly higher level of CIAAs than NOD mice that did not progress to diabetes (NOD mice progressing to diabetes: CIAA 63 +/- 12 nU/ml; NOD mice not progressing to diabetes: CIAA 8 +/- 4 nU/ml; P less than .

First-trimester hemoglobin A1 and risk for major malformation and spontaneous abortion in diabetic pregnancy.

The relationship between the level of hemoglobin A1 (Hb A1) in the first trimester and major malformations and spontaneous abortions was examined in 303 insulin-requiring diabetic gravidas. During the study period, all patients with insulin-requiring diabetes mellitus antedating pregnancy who registered for prenatal care prior to 12 weeks' gestation and who had a known outcome were included. Thirty-five percent of the patients entered with a first-trimester Hb A1 of greater than 11.

Genetically programmed selective islet beta-cell loss in diabetic subjects with Wolfram's syndrome.

Insulin-producing beta-cells were selectively absent from the islets of Langerhans in postmortem specimens from two patients with Wolfram's syndrome. In families with multiple cases of this syndrome, we found a very high concordance rate (r = .910, P less than .

Transient hyperglycemia in childhood: identification of a subgroup with imminent diabetes mellitus.

Transient hyperglycemia may represent the earliest manifestation of IDDM. In a series of 30 children referred for transient hyperglycemia, 8/30 (27%) developed IDDM within 10 months of their initial evaluation. Three children with detectable cytoplasmic islet cell antibodies (ICA) and/or positive insulin autoantibodies (CIAA) all developed IDDM, compared to 21% of ICA negative children and 13% who were CIAA negative.

Electrocatalytic glucose sensor.

High surface area platinum subjected to the appropriate electrical potential cycling regimes exhibits considerable electrocatalytic activity towards glucose oxidation. We have developed a special data processing method, the compensated net charge (CNC) method, to take advantage of the electrocatalytic activity of platinum. This method involves the determination of the net oxidation charge during one complete cycle of a cyclic voltammogram applied to the platinum electrode in a potentiodynamic mode.

Competitive insulin autoantibody assay. Prospective evaluation of subjects at high risk for development of type I diabetes mellitus.

A quantitative fluid-phase radioassay for autoantibodies reacting with insulin (competitive insulin autoantibody assay, CIAA) was developed. The assay's features include 1) use of a physiologic amount of 125I-labeled insulin, 2) parallel incubations with supraphysiologic cold insulin (competitive), and 3) an incubation time of 7 days and a single-step multiple-wash polyethylene glycol separation. Mean +/- SE CIAA levels in 50 controls were 8 +/- 1.