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. glucose tolerance testing (IVGTT) between the years 1964–82. During 25 ± 6 years follow-up, comprising 2,758 person years, the FH− cohort (54 ± 9 years) had an age-adjusted incidence rate of type 2 diabetes of 1.8 per 1,000 person years, similar to that in other population-based studies, but significantly lower than 16.7 for the FH+ cohort. Even when the two study populations were subdivided by initial values of S I and S G derived from IVGTT's performed at study entry, there was a 10- to 20-fold difference in age-adjusted incidence rates for diabetes in the FH− vs. FH+ individuals with low S I and low S G . The acute insulin response to glucose was not predictive of the development of diabetes when considered independently or when assessed as a function of S I , i.e., the glucose disposition index. These data demonstrate that low glucose disposal rates are robustly associated with the development of diabetes in the FH+ individuals, but insulin resistance per se is not sufficient for the development of diabetes in individuals without family history of disease and strongly suggest a familial factor, not detectable in our current measures of the dynamic responses of glucose or insulin to an IVGTT is an important risk factor for type 2 diabetes. Low S I and low S G , both measures of glucose disposal, interact with this putative familial factor to result in a high risk of type 2 diabetes in the FH+ individuals, but not in the FH− individuals.

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. More than 10 years before the development of diabetes, subjects who developed the disease had lower values of both SI (mean 3·2 [SD 2·4] vs 8·1 [6·7] 10-3 I min-1 pmol-1 insulin; p<0·0001) and SG (1·6 [0·9] vs 2·3 [1·2] 10-2 min-1, p<0·0001) than did those who remained normoglycaemic). For the subjects with both SI and SG below the group median, the cumulative incidence of type 2 diabetes during the 25 years was 76% (95% confidence interval 54-99). By contrast, no subject with both SI and SG above the median developed the disease. Subjects with low SI/high SG or high SI/low SG had intermediate risks. Insulin secretion, especially first phase, tended to be increased rather than decreased in this prediabetic phase and was appropriate for the level of insulin resistance. The development of type 2 diabetes is preceded by and predicted by defects in both insulin-dependent and insulin-independent glucose uptake; the defects are detectable when the patients are normoglycaemic and in most cases more than a decade before diagnosis of disease.

We have followed-up 35 islet cell antibody-positive first degree relatives of patients with Type 1 (insulin-dependent) diabetes mellitus for an average of 1,300 days with sequential intravenous glucose tolerance tests. At the time of analysis and manuscript submission approximately half (18 of 35) had developed diabetes during follow-up. At initial intravenous glucose tolerance test, 11 had a 1+3 min insulin secretion below the first percentile of insulin secretion compared to 225 similarly studied normal control subjects. Six islet cell antibody positive relatives on follow-up developed an intravenous glucose tolerance test less than the first percentile. Fifteen out of 17 (88%) of these islet cell antibody positive relatives with secretion ever found to be below the first percentile are now overtly diabetic (positive predictive value=88%) and insulin-treated, while only 3 of 18 (17%) without an intravenous glucose tolerance test demonstrating loss of first phase insulin secretion have progressed to diabetes (with approximately 1,300 days of follow-up for both groups relative risk or odds ratio with intravenous glucose p<0.001). tolerance test ever below vs never below the first percentile=38, Intravenous glucose tolerance test response below the first percentile preceded diabetes by an average of 656 days. Even when first phase insulin secretion is below the first percentile, the absolute value of 1+3 min insulin above basal insulin correlates with the time to development of diabetes (r=0.586, p<0.001). With our current duration of follow-up, the negative predictive value (intravenous glucose tolerance test never below the first percentile) is 83%, and overall accuracy 86%. Incidence rates of diabetes development amongst our islet cell antibody positive relatives with follow-up while intravenous glucose tolerance test is below the first percentile is 0.48 per year (15 conversions to diabetes amongst 17 relatives in 30.8 patient years of follow-up) vs 0.05 per year (three diabetic patients in 55.5 patient years) with intravenous glucose tolerance test greater than the first percentile.

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., less than 10 yr). The ability to predict type I diabetes with selected assays will allow trials for prevention of diabetes and trials to assess whether prediction will decrease morbidity and mortality at onset of diabetes.

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.PARTICIPANTS:One hundred and fifty-five normal offspring, ranging in age from 16 to 60 years, of two parents with type II diabetes and 186 normal control subjects in the same age range who had no family history of diabetes.MEASUREMENTS AND MAIN RESULTS:Two phenotypic characteristics distinguished the offspring of diabetic parents from control subjects. They had slower glucose removal rates (Kg) (P less than 0.01) and higher insulin levels (fasting and during the second phase of insulin response to intravenous glucose; P less than 0.0001) than did control subjects, even after adjustment for differences in obesity. Sixteen percent of the offspring developed type II diabetes. Mean Kg at baseline was 1.7%/min among offspring who subsequently developed diabetes, 2.2%/min among offspring who remained nondiabetic, and 2.3%/min among control subjects. Corresponding means for first-phase insulin were 498, 354, and 373 pM, respectively, whereas second-phase insulin means were 329, 117, and 87 pM, respectively. In multivariate analysis, low Kg and high serum insulin levels independently increased the risk for developing diabetes among the offspring of diabetic parents.CONCLUSIONS:One to two decades before type II diabetes is diagnosed, reduced glucose clearance is already present. This reduced clearance is accompanied by compensatory hyperinsulinemia, not hypoinsulinemia, suggesting that the primary defect is in peripheral tissue response to insulin and glucose, not in the pancreatic beta cell.

Insulin-producing (5-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 < .001) among siblings for age at onset of diabetes mellitus. Taken together with the lack of markers for an autoimmune process, these findings suggest that diabetes mellitus in this syndrome results from genetically programmed selective p-cell death.

Three new mononuclear complexes of nickel(II) pyridinecarboxamides (picolinamide – pia, nicotinamide – nia, isonicotinamide – isn), [Ni(OCOCH3)(pia)2(H2O)]·(CH3COO)·2H2O (1), [Ni(nia)2(H2O)4](CH3COO)2·2H2O (2) and [Ni(OCOCH3)2(isn)2(H2O)]·C3H7NO (3) have been synthesized. The turquoise (1) and green (2, 3) crystals of the compounds were prepared by the reaction of nickel(II) acetate tetrahydrate and pyridinecarboxamides in different solvents by standard method under reflux (1) and by solvothermal method (2, 3). The compounds were characterized structurally by single-crystal X-ray diffraction analysis, magnetically and spectrally by FT-IR spectroscopy. All complexes consist of six coordinated central Ni2+ ion with pyridinecarboxamides, acetate ligands and/or water molecules. The interactions between building units in the crystal structures include intra- and intermolecular hydrogen bonds in all compounds and π–π interactions in complexes 1 and 2. Magnetic properties of the compounds were measured between 2 K and 300 K giving the results: μeff = 3.0 BM for compound 1, μeff = 2.8 BM for 2 and 2.6 BM for compound 3 in paramagnetic region. Experimental values of the IR spectra are comparable with literature data and are in good agreement with results of the structural analysis.

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. Of those with impaired glucose tolerance, 6/11 (55%) developed IDDM, as did 1/14 with normal OGTT. Of the children with a low "K rate" on IVGTT, 75% developed IDDM, compared to 1/13 with a normal "K rate". All four children (100%) whose first phase (1' + 3') insulin secretion never exceeded the first percentile developed IDDM within nine months, while no child with first phase insulin secretion above the first percentile (0/16) developed IDDM during 19 +/- 9 months (mean +/- SD) of follow-up. Thus, in our experience the oral glucose tolerance test is a less accurate predictor of impending IDDM; immunological abnormalities have the highest positive predictive value, while the first phase insulin secretion during an intravenous glucose tolerance test has the highest negative predictive value and the greatest overall accuracy of prediction.

thin needle is no more difficult or painful than subcutaneous injection. Hence an intramuscular injection can be recommended (as part of an intensive educational program) to be performed when a more rapid insulin action is desired, e.g., before eating quickly absorbed carbohydrates, or in case of ketoacidotic deterioration. Depending on the thickness of the subcutaneous fat tissue layer, length of the needle, and injection technique used, the absorption of insulin in the deltoid area may follow the intramuscular route and its pharmacokinetics and biological action can thus be manipulated.

Antibodies in sera from newly diagnosed insulin-dependent diabetes mellitus (IDDM) patients are directed to a human islet cell protein of relative molecular mass (Mr) 64,000. Since IDDM seems to develop after a prodromal period of beta-cell autoimmunity, this study has examined whether 64,000 Mr antibodies could be detected in 14 individuals who subsequently developed IDDM and five first degree relatives who have indications of altered beta-cell function. Sera were screened by immunoprecipitation on total detergent lysates of human islets and positive sera retested on membrane protein preparations. Antibodies to the 64,000 Mr membrane protein were consistently detected in 11/14 IDDM patients, and in all 5 first degree relatives. 10 IDDM patients were already positive in the first samples, obtained 4-91 mo before the clinical onset of IDDM, whereas 1 patient progressed to a high 64,000 Mr immunoreactivity, at a time where a commencement of a decline in beta-cell function was detected. 64,000 Mr antibodies were detected before islet cell cytoplasmic antibodies (ICCA) in two patients. In the control groups of 21 healthy individuals, 36 patients with diseases of the thyroid and 5 SLE patients, the 64,000 Mr antibodies were detected in only one individual, who was a healthy sibling to an IDDM patient. These results suggest that antibodies against the Mr 64,000 human islet protein are an early marker of beta-cell autoimmunity and may be useful to predict a later development of IDDM.