J. Rachman et al., RELATIVE HYPERPROINSULINEMIA OF NIDDM PERSISTS DESPITE THE REDUCTION OF HYPERGLYCEMIA WITH INSULIN OR SULFONYLUREA THERAPY, Diabetes, 46(10), 1997, pp. 1557-1562
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.