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Serum growth hormone, glucose, and insulin were studied every half hour during a twenty-four-hour period of "daily life" in four groups of subjects: nonobese normal subjects, obese normal subjects, nonobese maturity-onset diabetics, and obese maturity-onset diabetics. It was found that (1) serum growth horomone was uniformly low without meal- and sleep-related peaks in obese normals and diabetics. The twenty-four-hour serum growth hormone level was significantly higher in nonobese subjects than in obese subjects, in both diabetics and normals; (2) the twenty-four-hour serum growth hormone level was more fluctuating and significantly higher in nonobese diabetics than in nonobese normals; (3) there was no difference in the twenty-four-hour serum growth hormone level between obese diabetics and obese normals.

Five diabetic and 14 non-diabetic uraemic patients on long-term haemodialysis were studied during twenty-one 24 h periods including 5 to 7 h of haemodialysis against glucose-free acetate buffered dialysis fluid. Half-hourly blood samples were collected for hormonal and metabolite analysis. In addition, blood samples were analyzed in 40 experiments covering the haemodialysis and a pre-dialysis period. Before dialysis, plasma growth hormone levels were high and fluctuating, but almost always fell to low normal values within the first 2 h of haemodialysis. In the diabetic uraemic patients, the occasional severe hypoglycaemic episodes occurring during haemodialysis did not provoke growth hormone release, and hypoglycaemic reactions were not encountered. Intravenous acetate infusion studies resulted in plasma concentrations ranging from 1.3. to 2.7 mmol, ie. about 60 per cent of the levels reached during haemodialysis and in suppression of growth hormone secretion. It is suggested that the fall in growth hormone levels and the lack of hypoglycaemic symptoms during haemodialysis is due to the use of acetate as a fuel in brain.

We have previously demonstrated that acetate suppresses the basal hypersecretion of growth hormone in diabetic and non-diabetic uremic patients. The present study was designed to clarify the potency and characteristics of the growth hormone suppressive effect of acetate by applying two powerful growth hormone stimuli: arginine infusion and insulin hypoglycemia. In four non-diabetic uremic and three diabetic uremic subjects, arginine infusion caused a rise in plasma growth hormone to 22.8 +/- 3.3 ng/ml and 22.0 +/- 5.6 ng/ml (mean +/- SEM, P less than 0.05). During hemodialysis against acetate buffered dialysis fluid and during a simultaneous acetate infusion, the response to arginine infusion was almost completely inhibited in both groups. In four uremic subjects insulin hypoglycemia elicited an increase in plasma growth hormone to 30.0 +/- 7.0 ng/ml (mean +/- SEM, P less than 0.05). During hemodialysis and acetate infusion the response to insulin hypoglycemia was again almost abolished. The glucagon and insulin responses were unaffected by hemodialysis as well as by acetate infusion. The results demonstrate the high degree of efficiency of the acetate induced growth hormone suppression comparable to that of glucose.

Growth hormone secretion in uremic patients is completely suppressed immediately after initiation of and during hemodialysis using acetate dialysate. The present study demonstrates that growth hormone secretion stimulated by arginine is also inhibited by hemodialysis. Acetate infusion experiments proved that the high blood acetate level obtained during dialysis is at least partly responsible for this growth hormone suppression by unknown mechanisms.

The growth-hormone-release-inhibiting hormone somatostatin was infused in seven juvenile diabetic subjects during an arginine infusion test and in six juvenile diabetic subjects during an L-dopa stimulation test. The plasma growth hormone response to arginine and L-dopa was completely inhibited by somatostatin. The plasma pancreatic glucagon response to arginine was also inhibited by somatostatin. The plasma pancreatic glucagon level was not changed by L-dopa, but somatostatin induced a significant fall in this level. The plasma glucose increase after arginine and L-dopa administration was slightly inhibited by somatostatin. The arginine-induced fall in free fatty acids was prevented by somatostatin, and the L-dopa-induced rise in free fatty acids was enhanced by somatostatin. The growth hormone- and glucagon-surppressive effect of somatostatin may prove useful in controlling the metabolic state and in preventing the development of angiopathy in diabetic patients. A somatostatin preparation with prolonged activity is needed for lifelong administration, but the presently available compound may be of value as an adjunct in the standard treatment of diabetic ketoacidosis and coma.

Somatostatin was infused in various doses into normal subjects and juvenile diabetics for a 24-hour period preceded by a 24-hour control period and followed by another three-hour control period. Saline was infused during the first control period. Meals were served during the two 24-hour periods. Blood samples were taken hourly. Five normal males received a total dose of 4 mg. somatostatin. Four male diabetics received 2 mg., four received 4 mg., and four 6 mg. In the diabetics, somatostatin suppressed plasma growth hormone, glucagon, and glucose throughout the infusion. All parameters rebounded at cessation of infusion. In the normals, somatostatin suppressed plasma growth hormone, glucagon, and insulin but increased plasma glucose. It is concluded that the plasma glucose suppression in the diabetics is mainly due to the suppression of the diabetogenic hormones growth hormone and glucagon. A minor effect of decreased and/or delayed absorption of carbohydrates cannot be excluded in these experiments. The elevated plasma glucose levels in normals must be due to the suppressive effects of somatostatin on insulin secretion.

Somatostatin 5, 10, and 25 mug and saline were given as a 2 min bolus injection to 6 acromegalic patients in basal conditions. A significant dose-response relationship could be demonstrated between somatostatin and the suppressions of plasma growth hormone and insulin. The lowest somatostatin dose tested exerted a significant suppression of both hormones. Insulin suppression after the bolus injection lasted for 15 minutes, while the suppression of growth hormone was maintained for 30-50 minutes. In order to obtain total suppression of the elevated plasma growth hormone levels in acromegalics, 3 patients received 50, 250, and 500 mug of somatostatin as bolus injections at time 0, 90, and 180 minutes, 2 patients received 50 mug of somatostatin as bolus injections 4 times with an interval of 20 minutes between each injection, and finally 3 patients received a large dose of somatostatin, 3000 mug given as an infusion over 2 hours. The single injections of somatostatin were not followed by a satisfactory growth hormone suppression. In the infusion experiments, the average plasma growth hormone level was suppressed only 65%, resulting in individual plasma growth hormone plateaus of 20, 14, and 3.6 ng/ml. Only the lowest of these plateaus would be acceptable from a clinical point of view.

The serum-growth hormone response to exercise is greater and occurs earlier in juvenile diabetics than in nondiabetics. A simple exercise test has been devised which unequivocally reveals the growth hormone hypersecretion of juvenile diabetics. Using this procedure we have shown that after a period of exceedingly strict metabolic control of the diabetes, complete normalization of growth hormone secretion is attained. It is concluded that the abnormalities in serum growth hormone found in juvenile diabetics are of a metabolic origin.

Studies in five male patients with recently diagnosed juvenile diabetes showed a raised mean level of serum growth hormone, which fluctuated considerably over a 24-hour period. It is suggested that the secretion rate of growth hormone is raised in this condition.

Groups of male nonobese juvenile diabetics with recent onset, short term (1-8 yr), and long-term (12-30 yr) diabetes as well as comparable nondiabetic controls were studied during exercise experiments. The chosen exercise load, 450 kg/min for 20 min never induced changes in serum growth hormone in our nondiabetic control subjects. THE PRINCIPAL RESULTS OF THE STUDY WERE AS FOLLOWS: (a) an immediate high rise in serum growth hormone followed the commencement of exercise in all diabetics. The increase and pattern of serum growth hormone was not related to the duration of the diabetes. (b) The abnormal growth hormone response to exercise in diabetics was observed when the patients were in poor control as well as when they were in clinically excellent control (fasting blood glucose level between 100 and 140 mg/100 ml). (c) However, the abnormal serum growth hormone response was significantly diminished when exceedingly strict control was achieved (fasting blood glucose level between 60 and 100 mg/100 ml). In two of these experiments an entirely normal growth hormone pattern was obtained. (d) The change in serum growth hormone pattern during regulation was totally unrelated to the changes in serum free fatty acid patterns. A normal free fatty acid level and exercise pattern was obtained much earlier during the improved control. (e) Fasting serum growth hormone levels were also significantly raised in the juvenile diabetics irrespective of the diabetes duration. (f) Fasting serum growth hormone levels were also significantly decreased during regulation. Furthermore, a significant correlation between blood glucose and fasting serum growth hormone concentration was established. (g) In the juvenile diabetics a significant increase in serum insulin was observed at the point of time when exercise was concluded.

Preliminary studies indicate that somatostatin (SRIF, somatropin release inhibiting factor) can suppress exercise-induced plasma growth hormone rise in normal subjects as well as in diabetics.