Pituitary Response to Growth Hormone–Releasing Hormone in IDDM: Abnormal Responses to Insulin and Hyperglycemia

Abstract

In poorly controlled insulin-dependent diabetes mellitus (IDDM), hyperglycemia fails to inhibit the pituitary response to growth hormone–releasing factor (GRF). To evaluate whether this derangement is reversed by a simultaneous elevation of circulating insulin, 0.3 μg/kg i.v. GRF 1–40 was administered to nine poorly controlled IDDM subjects (HbA1 > 11.1%) with and without concomitant infusion of insulin. In the absence of insulin, the poorly controlled IDDM subjects demonstrated a growth hormone response to GRF similar to that of nondiabetic subjects, despite marked hyperglycemia (∼ 16.8 mM). When insulin was infused into these same patients (insulin clamp) to produce combined hyperinsulinemia (528 ± 90 pM) and hyperglycemia (16.5 ± 1.98 mM), the GRF-induced growth hormone rise was markedly exaggerated (65 ± 11 vs. 20 ± 4 μg/L without insulin infusion, P < 0.001). This enhancement of GRF-stimulated growth hormone release by insulin was strikingly attenuated (22 ± 7 μg/L) in five well-controlled diabetic subjects studied under conditions of similar hyperinsulinemia (486 ± 84 pM) and hyperglycemia (16.41 ± 0.95 mM). In contrast, in nondiabetic subjects, acute hyperinsulinemia reduced the growth hormone response to GRF. We conclude that the failure of hyperglycemia to block the pituitary response to GRF in poorly controlled diabetes is not attributable to the lack of a coincident increase in circulating insulin. The paradoxical stimulatory effect of insulin on GRF-induced growth hormone release may contribute to the high spontaneous growth hormone levels characteristically seen in poorly controlled insulin-treated patients, and its attenuation after intensive insulin therapy may contribute to the reversal of growth hormone hypersecretion in well-controlled diabetic patients.