RELATIVE HYPERPROINSULINEMIA OF NIDDM PERSISTS DESPITE THE REDUCTION OF HYPERGLYCEMIA WITH INSULIN OR SULFONYLUREA THERAPY

Subjects with NIDDM have increased plasma proinsulin concentrations, c ompared with nondiabetic subjects, both in absolute terms and as a pro portion of circulating insulin-like molecules. It remains uncertain wh ether this reflects a primary beta-cell defect in proinsulin processin g or is secondary to hyperglycemia. We addressed this question by asse ssing the effects of reducing hyperglycemia on relative hyperproinsuli nemia in subjects with NIDDM. Eight subjects with NIDDM underwent thre e 8-week periods in a randomized crossover design of therapy with diet alone, sulfonylurea (gliclazide), or insulin (ultralente). The effect s on beta-cell peptide concentrations were assessed 1) fasting, 2) in response to hyperglycemic clamping, and 3) in response to an injection of the nonglucose secretogogue arginine and compared with measurement s in seven nondiabetic control subjects. Both sulfonylurea and insulin therapy substantially reduced fasting plasma glucose and glycosylated hemoglobin (HbA(1c)) concentrations, compared with diet therapy alone . The diabetic subjects on diet therapy had relative hyperproinsulinem ia, assessed relative to C-peptide concentrations, fasting and in resp onse to hyperglycemic clamping and arginine, compared with control sub jects. Neither sulfonylurea nor insulin therapy altered the relative h yperproinsulinemia. Insulin therapy reduced fasting proinsulin concent rations from geometric mean 29.4 (1 SD range, 14.6-59.0) pmol/l on die t therapy to 18.7 (7.3-48.1) pmol/l (P = 0.05). A similar trend was ev ident with fasting C-peptide concentrations with a reduction from 0.9 (0.6-1.4) nmol/l on diet therapy to 0.6 (0.4-0.9) nmol/l (P = 0.06), s o that the relative hyperproinsulinemia, assessed as the ratio of fast ing proinsulin to C-peptide, was unchanged by insulin. Similarly, insu lin therapy failed to reduce the ratio of proinsulin to C-peptide conc entrations in response to a hyperglycemic clamp and in the acute incre mental response to arginine. Failure to improve the relative hyperproi nsulinemia of NIDDM, despite significant reduction of hyperglycemia wi th exogenous insulin therapy, supports the hypothesis that relative hy perproinsulinemia in NIDDM is a reflection of a primary beta-cell defe ct rather than being secondary to hyperglycemia.