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Insulin-like and anti-insulin effects of human growth hormone (hGH) were examined by determining the effects of two peptides representing portions of the hGH molecule in lean agouti Ala and obese yellow Avy/A and oblob mice. The peptides were the amino terminal segment, residue 1-43 (hGHi-43), which has been shown to potentiate the response to insulin and another peptide, hyperglycemic peptide (HP), with unknown structure, which has anti-insulin activity. The anti-insulin component is an acidic low molecular weight peptide which co-purifies with hGH but was not recognized by antibodies to intact hGH and did not cross-react with anti-hGH,_,, antiserum. The purpose of these studies was to further understand the multiple actions of hGH and its acute and chronic effects on response to insulin. Injections of hGH,-43 dramatically enhanced the effect of insulin on glucose clearance of obese yellow Avy/A and oblob mice and increased the insulin-stimulated glucose oxidation in adipose tissue of yellow mice, but had no direct effect on blood glucose or insulin levels of either genotype. Administration of HP to obese yellow mice produced hyperglycemia and suppressed serum insulin concentrations. Tissues from lean agouti and obese yellow mice treated with HP in vitro showed decreased basal and insulin-stimulated glucose oxidation as well as decreased ' ' C incorporation into lipids. Chronic treatment of obese yellow and oblob mice with HP increased fasting blood glucose and impaired glucose tolerance. The effect of HP was more pronounced in obese yellow mice and the oblob mice were more sensitive to the diabetogenic actions of intact hGH. These data provide further evidence for the existence of two opposing biologic activities derived from disparate amino acid sequences in hGH.Additionally, the data indicate that assays using obese yellow AvY/A mice can distinguish the effects of hGH from those of the individual peptides to a greater degree than assays using obese oblob mice. [P.S.E.B.M. 1989, VOl 1911 uman growth hormone (hGH) produces contradictory actions (insulin-like and anti-insulin) H on carbohydrate metabolism both in vivo and in vitro (1). These multiple and complex actions of I Part of these studies was presented at

A naturally occurring pituitary peptide, human (h) GH-(1-43) potentiates insulin action. The present study has compared the effects of acute (30-60 min) and chronic (3-6 days) injections of synthetic hGH-(1-43), hGH, and insulin in normal, diabetic, hypophysectomized, and diabetic-hypophysectomized rats. Male rats (150-250 g) received injections of saline, insulin (50-200 mU), hGH (200 micrograms), or hGH-(1-43) (200-400 micrograms) with or without insulin. Hormone and glucose were injected simultaneously for glucose tolerance tests. Basal and insulin-stimulated [U-14C]glucose oxidation to 14CO2 in adipose tissue were measured in vitro after in vivo treatments; insulin release by isolated pancreatic islets was determined in vitro. Acute injections of hGH-(1-43) with insulin dramatically increased glucose clearance in diabetic (P less than 0.05) and hypophysectomized (P less than 0.01) rats. In diabetic-hypophysectomized rats acute injections of hGH-(1-43) significantly lowered the elevated basal blood glucose level (P less than 0.025) and stimulated [U-14C]glucose oxidation to 14CO2 in adipose tissue (P less than 0.05); it did not increase the glucose clearance rate during glucose administration. Chronic treatment of diabetic rats with hGH-(1-43) did not lower the elevated blood glucose level significantly, but it stimulated [U-14C]glucose oxidation to 14CO2 in adipose tissue; the oxidation was further stimulated by treatment with insulin. Chronic injections of hGH-(1-43) slightly lowered blood glucose levels in hypophysectomized rats (P less than 0.025) despite a diminished release in vitro of insulin from pancreatic islets (P less than 0.05). Therefore, these experiments show hGH-(1-43) to be an insulin potentiator that increases insulin-stimulated glucose clearance and glucose oxidation without an increase in insulin secretion, and they suggest that the peptide may have a physiological role in regulating carbohydrate metabolism.

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The amino-terminal portion of human growth hormone, residues 1-43 (hGHi-43), has insulin-potentiating action, while a hyperglycemic pituitary peptide (HP), which co-purifies with human growth hormone (hGH), is antagonistic to the action Of insulin. The effects of hGH, hGHi-43, and HP on glucose metabolism were assessed in young (4-5 weeks) and adult (6-8 months) hypophysectomized yellow AvY/A mice which lacked any interfering endogenous pituitary hormones, and compared with age-matched intact obese yellow AYY/A and lean agouti A/a mice. Treatment with hGH1-43 or HP did not promote body growth in hypophysectomized yellow mice; but after 2 weeks of treatment with hGH, there was a significant increase in body weight (P e 0.05). Treatment with HP raised blood glucose and lowered insulin concentrations in obese yellow mice, but not in agouti or hypophysectomized yellow mice. The severely impaired glucose tolerance of the hypophysectomized yellow mice was improved by acute (60 min) and chronic (3 days) treatment with hGH, -, , as well as by 2 weeks of treatment with hGH; in contrast, HP had no effect. Glucose oxidation in adipose tissue from obese yellow mice was low and showed essentially no response to stimulation by insulin at doses lower than 1000 microunits/ml. Basal glucose oxidation rates in adipose tissue taken from agouti and hypophysectomized yellow mice were significantly higher (P < 0.001) than those in tissue from obese yellow mice, and the rates responded significantly (P < 0.05) to 100 microunits/ml insulin. The insulin binding affinities in liver membranes from agouti mice were higher than those from either obese or hypophysectomized yellow mice. The insulin receptor densities were similar in both agouti and obese yellow mice, but higher in hypophysectomized yellow mice (P e 0.05). Treatment with hGHi-43 slightly increased, although not significantly, the insulin receptor density in yellow obese mice while hGH showed essentially no change. Therefore, hypophysectomy appeared to increase tissue response and decrease insulin resistance by increasing receptor numbers and lowering the circulating insulin levels. Furthermore, the insulin-like action of hGH was elicited directly in vivo by hGHi-43 in hypophysectomized yellow mice. [P.S.E.B.M. 1989[P.S.E.B.M. , Vol 1911 T T u m a n growth hormone (hGH or hGH22k) is known to promote body growth and to show H insulin-like and anti-insulin actions in rodents.