Beta-cell dysfunction in first-degree relatives of patients with non-insulin-dependent diabetes mellitus

To analyse the relationship between age, glucose tolerance, beta-cell function, and insulin sensitivity in preclinical states of non-insulin-dependent (Type 2) diabetes mellitus (NIDDM), we have done a cross-sectional, age-stratified analysis of 86 non-diabetic first-degree relatives of NIDDM patients and 49 controls with similar age, sex, and BMI. A 5 mg kg ideal body weight-1 min-1 for 60 min of continuous infusion of glucose with model assessment (CIGMA) of serum glucose and C-peptide values at the end of the infusion was used to determine glucose tolerance and beta-cell function. Insulin sensitivity was estimated by modelling basal serum glucose and insulin values. Relatives and controls were divided into tertiles on the basis of age. Relatives had higher basal (5.3 vs 5 mmol l-1, p = 0.02) and achieved serum glucose (9.1 vs 8.4 mmol l-1, p = 0.01), lower beta-cell function (128 vs 145%, p = 0.007), and lower insulin sensitivity (37 vs 43%, p = 0.002). Beta-cell function declined with age in relatives (from 139% in young subjects to 134% in intermediate subjects and to 111% in older subjects, p = 0.002) and this decline was associated with an increase in basal serum glucose (from 5.1 to 5.3 and to 5.7 mmol l-1, p = 0.000) and achieved glucose (from 8.3 to 9.1 and to 9.3 mmol l-1, p = 0.038), without significant changes in insulin sensitivity. These trends were observed even after the exclusion of subjects with mild glucose intolerance. We conclude that both beta-cell dysfunction and insulin resistance are present in first-degree relatives of NIDDM. The progression of beta-cell dysfunction and glucose intolerance with age suggests that beta-cell dysfunction is the key factor in the apparition and progression of the disease.