The chronic administration of pituitary growth hormone (GH) to man and certain animals, such as the dog, can produce hyperinsulinemia, hyperglycemia and insulin resistance, particularly when doses of the hormone greater than that required to promote growth are employed. At present, little is known about the molecular events that precipitate the diabetogenic response to GH. Therefore, the specific aim of the work in this proposal is to initiate an investigation of the molecular mechanism(s) of the diabetogenic action of GH. S-carboxymethylated human GH will be used rather than native GH in the studies to be conducted, since its ratio of diabetogenic activity to insulin-like and anabolic activities is quite high, and hence metabolic effects produced by this substance should relate to the diabetogenic action of GH and should not be obscured by the hormone's intrinsic insulin-like or anabolic effects. Further, the obese (ob/ob) mouse will be utilized for the proposed studies, since it responds in a predictable fashion to chronic GH treatment with marked hyperinsulinemia, hyperglycemia and glucose intolerance. Using this model system, experiments will be carried out to test the following hypotheses: a) That the hyperglycemia and glucose intolerance produced by GH in the ob/ob mouse result from enhanced glucose production and reduced sensitivity of peripheral tissues to insulin, b) That GH acts directly on hepatocytes to influence glucose production by altering glycogenolysis and/or gluconeogenesis, c) That GH exerts its action on hepatic glucose production by influencing the release from plasma membranes of intracellular mediators that alter the activity of enzymes involved in glucose metabolism, d) That a distinct class of receptors exist on hepatocyte membranes that mediate the diabetogenic effect of GH on the liver, e) That GH acts directly on adipocytes to reduce their ability to respond to insulin with enhanced glucose transport and/or glucose utilization, f) That GH exerts its action on adipocyte glucose transport by limiting the ability of insulin to mobilize glucose transporters to the plasma membrane, g) That GH exerts its action on adipocyte glucose utilization by influencing the release from plasma membranes of intracellular mediators that alter the activity of enzymes involved in carbohydrate and lipid metabolism, and h) That the diabetogenic effects of GH on liver and adipose tissue are not direct, but are mediated either by a proteolytically-processed form of the hormone or by a humoral factor produced in response to the hormone.
