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 micrograms/kg i.v. GRF 1-40 was administered to nine poorly controlled IDDM subjects (HbA1 greater than 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 (approximately 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 micrograms/L without insulin infusion, P less than 0.001). This enhancement of GRF-stimulated growth hormone release by insulin was strikingly attenuated (22 +/- 7 micrograms/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.

Enhancement of the GH responsiveness to GH releasing stimuli by lysine vasopressin in type 1 diabetic subjects

“…Further experiments showed a higher GH response to the administration of the minimal effective dose of GH‐RH (0.035 μg/kg) in diabetic than in normal subjects. These findings support the hypothesis of other authors ( Press et al ., 1992 ; Giustina & Wehrenberg, 1994) of an increased GH sensitivity to GH‐RH in diabetic patients. Furthermore, the administration of LVP at a dose (15 μg/kg BW) unable to change the basal secretion of GH significantly enhanced the GH response to the minimal effective dose of GH‐RH in the diabetic patients, but not in the normal subjects.…”

Regulation of growth hormone secretion in lactating sheep

“…Hyperglycaemia, which normally inhibits growth hormone secretion, stimulated release of growth hormone and hyperinsulinaemia also stimulated via a mechanism not involving hypoglycaemia [4,5]. It is interesting to speculate that the lactating ruminant exhibits some of the metabolic disorders characteristic of the insulin-dependent diabetic patient but in a physiological rather than pathological situation.…”

“…Part of the problem appears to be an abnormal regulation of growth hormone secretion from the anterior pituitary with the normal inhibitory action of metabolic events such as hyperglycaemia no longer being effective [4,5]. The lactating ruminant also has elevated plasma growth hormone concentrations and exhibits insulin resistance [6 -91.…”

104 Glucose regulation of growth hormone secretion in lactating sheep

“…In the diabetic subject hyperglycaemia and/or hyperinsulinaemia has been shown to stimulate growth hormone secretion by an, as yet, unidentified mechanism [5]. A similar stimulation of growth hormone secretion by glucose and elevated insulin has also been described in the sheep but these were of limited duration [6] Data are reported here which show the effects of longer infusions of glucose on plasma concentrations of insulin and growth hormone in lactating sheep which have been fed normally or undernourished by 24h starvation.…”

“…A similar abnormal regulation of growth hormone secretion is observed in insulin-dependent diabetes [4,5] Here, too, the high circulating concentrations of non-esterifed fatty acids do not inhibit growth hormone secretion and circulating IGF-1 concentrations are low in view of the high growth hormone levels. In the diabetic subject hyperglycaemia and/or hyperinsulinaemia has been shown to stimulate growth hormone secretion by an, as yet, unidentified mechanism [5].…”