In order to evaluate factors influencing the duration of residual B-cell function in maturityonset diabetics we investigated 104 patients (age 60±11 years) with a mean duration of disease of 11.3±8.7 years by measuring fasting C-peptide (FCP) and fasting blood glucose levels (FBG), C-peptide increment after a standardized breakfast and both mean diurnal plasma glucose (MBG) and mean diurnal C-peptide levels (MCP). C-peptide levels were found to be reciprocally dependent on both the age at onset (positively) and, conversely, on the duration of diabetes (y=0.75+0.026x₁−0.049x₂; R=0.52, t₁=2.76, t₂=−4.08). In particular, the present B-cell secretory capacity appears to be lower the younger the patients were at onset, thus suggesting that inherent impairment of B-cell capacity may play a crucial role in determining age at onset of type II diabetes and thus the duration of their residual B-cell function. Moreover, by analyzing separately the data from patients treated with insulin and oral agents respectively, we found that the influence of the duration of the disease on the rate on B-cell exhaustion is unrelated to the mode of treatment even though B-cell capacity at onset appears to be more severely reduced in insulin-treated subjects who, apart from anything else, were younger at onset. In addition, no significant difference was found in FCP levels between patients showing MBG values above or below 160 mg/dl (1.76±0.66vs 1.57±0.68 ng/ml), whereas MCP values were lower in patients with MBG above 160 mg/dl (2.14±0.92vs 2.55±0.88 ng/ml; p<0.05) who, on the other hand, showed significant reduction in the C-peptide response to breakfast. These data suggest that prolonged metabolic derangement may impair the physiological response of B-cells and eventually lead, via B-cell overstimulation, or via a gap between synthesis and release of insulin, or through other as yet poorly understood mechanisms, to earlier insulin dependence in maturity-onset diabetic patients.