MECHANISMS OF GROWTH HORMONE HYPERSECRETION IN DIABETES

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My goal is to investigate areas related to diabetes mellitus and hormonal mechanisms in the pathogenesis of complications of diabetes. Experiments designed to elucidate mechanisms underlying the hypersecretion of growth hormone (GH) in diabetes will be performed under the sponsorship of Dr. L. Frohman. The questions to be addressed are: (a) The role of pituitary resistance to somatostatin (SRIH) in hypersecretion of GH in diabetes. Dose-response relationships for growth hormone releasing hormone(GRH)-induced GH secretion during each of a series of graded SRIH infusions will be compared between normal subjects and type I diabetics before and after instituting tight glycemic control. (b) The effect of diabetes on specific features of the diurnal rhythm of GH secretion (baseline concentration vs peak amplitude and frequency) will be assessed to determine whether they implicate specific alterations in control mechanisms. (c) Intracellular glucopenia is thought to mediate the GH response to plasma glucose. The relationship of GH secretion to glucose in normal and diabetic rats will be determined after induction of lesions in the hypothalamic suprachiasmatic nuclei which are known to mediate responses to intracellular glucopenia induced by 2-deoxyglucose. This will establish whether a single mechanism can explain both the acute GS response to glucose and the seemingly opposite chronic adaptation of GH to diabetes or whether multiple mechanisms are required. (d) To address the role of altered secretion of GRH in GH abnormalities in diabetes, an ultra-sensitive GRH immunoassay will be developed. This technique will use a physical marker, the bacterial enzyme luciferase, that should markedly improve sensitivity over that achieved with RIA. Abnormalities in GH secretion in diabetes have long been recognized but the mechanisms involved are not understood. While tight glycemic control normalizes the plasma GH concentration, such control is presently not maintained for long periods in most people with type I diabetes. Information gained from the present investigation should prove useful in determining whether GH suppression will aid in improving glycemic control and in evaluating GH's role in the development of diabetic retinopathy and growth disorders associated with diabetes in childhood. It may also prove useful in planning and evaluating the safety of treatment regimens for biosynthetic GH in growth disorders in non-diabetic children.