ALTERATIONS IN IMMUNOREACTIVE PROINSULIN AND INSULIN-CLEARANCE INDUCED BY WEIGHT-LOSS IN NIDDM

Subjects with overt non-insulin-dependent diabetes mellitus (NIDDM) we re studied in comparison to obese nondiabetic control subjects and pat ients with subclinical diabetes. Pancreatic insulin secretion rates we re measured by deconvolution of peripheral C-peptide over a 24-h perio d while subjects consumed an isocaloric mixed diet. Subjects mere then placed on caloric restriction for at least 6 weeks, during which time body weight fell by at least 10%. Refeeding with solid mixed meals wa s then resumed for at least 2 weeks until isocaloric intake was attain ed, and then the meal profiles were repeated. Before weight loss, insu lin, C-peptide, and insulin secretion rates were significantly higher in subjects with subclinical diabetes than in the other two groups. Pr oinsulin concentrations were significantly greater in the two diabetic groups than in control subjects, but, when expressed as a percentage of the total insulin immunoreactivity, the differences were significan t only in the group with overt diabetes. Weight loss because of hypoca loric feeding resulted in a significant increase in the rate of cleara nce of endogenously secreted insulin but did not affect the clearance of C-peptide. In obese subjects and those with subclinical diabetes, w eight loss was associated with a reduction in insulin secretion rates, presumably as a result of improvements in insulin sensitivity. In pat ients with overt diabetes and hyperglycemia, weight loss improved beta -cell responsiveness to glucose and was associated with an increase in insulin clearance and a reduction in proinsulin immunoreactivity. As a result of changes in insulin clearance and the contribution of proin sulin to total insulin immunoreactivity, measurement of total insulin- like immunoreactivity alone may provide misleading information in comp aring beta-cell function before and after weight loss in patients with insulin resistance, glucose intolerance, and diabetes.