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Aims/hypothesis: Insulin resistance and insulin deficiency are proposed as risk factors for IGT and type 2 diabetes. We assessed the predictive value of initial parameters for the outcome of an OGTT performed 24.3+/-2.9 years later in an unselected healthy non-obese population., Methods: The K-value of an IVGTT was determined in 267 healthy subjects (mean+/-SD: age 31.0+/-12.0 years, BMI 21.8+/-2.8 kg/m(2)). First-phase insulin response to a glucose infusion test was estimated as an incremental 5- or 10-min (DeltaI5 or DeltaI10) value, and as insulinogenic indices (DeltaI5/DeltaG5 or DeltaI10/DeltaG10) adjusted for insulin sensitivity determined by homeostasis model assessment for insulin resistance ([DeltaI5/DeltaG5]/HOMA-IR)., Results: At follow-up, six subjects had type 2 diabetes and 47 had IGT; 214 retained normal glucose tolerance. Insulin sensitivity and early (30 min) insulin response decreased with decreasing outcome OGTT. Blood glucose (2 h) at OGTT correlated positively with initial age and BMI, and negatively with DeltaI5/DeltaG5, (DeltaI5/DeltaG5)/HOMA-IR and K-value. In multiple linear regression analysis, (DeltaI5/DeltaG5)/HOMA-IR, DeltaI10, K-value, age, HOMA estimate of insulin secretion, and fasting plasma glucose were significantly associated with 2-h OGTT blood glucose. Similar results were obtained on comparing differences between subjects with normal and decreased (IGT+diabetes) glucose tolerance., Conclusions/interpretation: In 267 non-obese healthy subjects, initial K-value and first-phase insulin response to glucose adjusted for insulin sensitivity, but not insulin sensitivity itself, were strong predictors of the outcome of an OGTT performed 25 years later. Thus, in contrast to obese or other high-risk populations, in lean subjects, decreased beta cell function, but not insulin resistance itself, determines future glucose tolerance.

We have investigated the association of a family history of diabetes with glucose tolerance in a population of Swedish men. All men 35-54 years of age in 1992 and living in four different local municipalities of the outer Stockholm area were screened by questionnaire. From 10236 completed questionnaires 1622 men, selected for presence of such a history but without known diabetes, as well as 1507 men without a family history underwent an oral glucose tolerance test. Diabetes (2 h-plasma glucose levels > 11.0 mmol/l) was detected in 55 and impaired glucose tolerance (plasma glucose levels 7.8-11.0 mmol/l) in 172 subjects. The odds ratio of diabetes, associated with a family history, was 4.1, confidence interval 2.1-8.3 and for impaired glucose tolerance 1.6, confidence interval 1.2-2.3. Influence of a family history was measurable also within the range of normal 2-h glucose concentrations: compared to 2-h glucose levels < 3.8 mmol/l; the odds ratio associated with a family history was 1.4, confidence interval 1.1-1.7 and 1.3, confidence interval 1.1-1.6 for concentrations 4.8-5.7 mmol/l and 5.8-7.7 mmol/l respectively. The odds ratio of diabetes and impaired glucose tolerance among men with a family history increased with number and closeness of relatives with diabetes but was not affected by the gender of the family member. Overweight (BMI > 25.0 kg/m2) increased the odds ratio of diabetes in subjects with a family history, the odds ratio being 24, confidence interval 3-177, when both conditions were present. In subjects with Type II (non-insulin-dependent) diabetes mellitus discovered during the investigation, the presence of a family history of diabetes was associated with decreased insulin secretion rather than insulin resistance as assessed by fasting insulin, homeostasis model assessment, and the 2-h insulin response to the oral glucose tolerance test. We conclude that a family history of diabetes strongly but independently of gender associates with decreased glucose tolerance. Furthermore, the results are compatible with a major role for low insulin secretion in the diabetogenic influence of a family history of diabetes in middle-aged Swedish men. Lastly, the very high risk for diabetes in middle-aged men with both a family history of diabetes and obesity indicates that such people should, for the purpose of therapeutic intervention, be identified in the general population.

We have compared insulin responses to L-arginine before and during dexamethasone treatment in healthy subjects, previously classified as subjects with either high or low insulin response according to a standardized glucose infusion test. Arginine stimulation was administered as a 150 mg/kg bolus followed by 10 mg.kg-1.min-1 to six subjects with high insulin response and to seven subjects with low insulin response. Before dexamethasone treatment the incremental insulin level during 0-10 min of arginine was higher in subjects with high (36.5 +/- 6.8 microU/ml) than in subjects with low response (14.5 +/- 2.3 microU/ml), p less than 0.01 for difference. Dexamethasone treatment (6 mg/day for 60 h) markedly enhanced the insulin response to arginine in subjects with high response (+99% 0-30 min) but failed to affect the subjects with low response (+4% 0-30 min). The C-peptide response to arginine exhibited similar differences between groups. Decreased responsiveness to arginine in subjects with low insulin response, especially during dexamethasone treatment, suggests a Beta-cell capacity defect although a decreased potentiating-sensing effect of glucose cannot be completely ruled out.