Knud Lundbæk

INHIBITION OF INSULIN SECRETION BY SOMATOSTATIN

Abstract Injection of somatostatin, the hypothalamic growth-hormone-inhibiting factor, lowered basal plasma-insulin levels. In intravenous glucose-tolerance tests in five normal subjects, glucose-induced insulin release was markedly suppressed and the glucose-disappearance rate was lowered after somatostatin. Perfusion experiments on the isolated canine pancreas showed that somatostatin acts directly on the beta cells, causing suppression of the initial and the late sustained insulin release phase.

DIABETES, DIABETIC ANGIOPATHY, AND GROWTH HORMONE

Abstract Raised plasma-growth-hormone (G.H.) levels in juvenile diabetes, the persistence of abnormal G.H. response to exercise even in well-controlled diabetics, the inhibitory effect of hypophysectomy on the progression of diabetic retinopathy and the normalisation of skin capillary fragility after this operation all point to a role for G.H. hypersecretion in the development of diabetic angiopathy.

Some Actions of Growth Hormone Release Inhibiting Factor

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.

The Inhibition by Somatostatin of the Thyrotropin Response to Thyrotropin-Releasing Hormone in Normal Subjects

The influence of somatostatin on the TRH-induced TSH secretion was studied in 6 normal subjects. A consistent inhibitory effect of somatostatin was observed. The inhibitory effect occurred with a time lag of more than 5 minutes. In 4 of the subjects a secondary rise in serum TSH was observed after the cessation of somatostatin infusion, suggesting mechanisms other than simple competition at receptor sites.

24-Hour Studies of the Effects of Somatostatin on the Levels of Plasma Growth Hormone, Glucagon, and Glucose in Normal Subjects and Juvenile Diabetics

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 diabetogenk 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.

FAILURE OF SOMATOSTATIN TO CORRECT MANIFEST DIABETIC KETOACIDOSIS

Juvenile diabetic patients were studied 60-72 hours after insulin withdrawal when moderate ketoacidosis had developed. Somatostatin infusion for 4 hours in five patients resulted in almost complete suppression of plasma pancreatic glucagon and growth hormone, a fall in plasma-cyclic-adenosine-monophosphate (A.M.P.) concentrations, and a large fall in plasma-glucose concentration. After infusion plasma concentrations of these substances rose again. Blood-ketone-bodies, plasma-free-fatty-acids (F.F.A.), and plasma glycerol concentrations, however, did not decrease appreciably with somatostatin administration. In three patients 2 to 3 h somatostatin infusions were twice superimposed upon a continuous 9-5 h insulin infusion (1 unit/h). An insulin effect was noticeable within 30 minutes, with pronounced falls in the concentrations of plasma glucose, pancreatic glucagon, F.F.A., and blood-ketone-bodies. There was no significant change in these patterns when somatostatin was administered or withdrawn. These results do not indicate that somatostatin infusion would be useful in the treatment of manifest diabetic ketoacidosis.

Growth hormone enhances basement membrane thickening in experimental diabetes. A preliminary report.

SummaryInjection of porcine growth hormone (200 μg) or saline 5 days a week for 16 to 20 weeks in streptozotocin-diabetic rats showed that compared to saline growth hormone produced a 2 1/2-fold larger increase in glomerular capillary basement membrane thickness (2p=0.027). The possible significance of this effect of an elevated level of growth hormone for diabetic microangiopathy is discussed.

Somatostatin as a Tool in Studies of Basal Carbohydrate and Lipid Metabolism in Man: Modifications of Glucagon and Insulin Release

Somatostatin (SRIF) was given to normal subjects in the fasting state as well as during glucose infusions. During basal conditions a decrease was observed in blood glucose, plasma insulin, and plasma pancreatic glucagon. Plasma free fatty acids (FFA) showed a late 50 per cent increase, beginning approximately 15 min after start of the infusion, whereas basal plasma growth hormone was unchanged. When glucose was infused in other experiments, to suppress plasma pancreatic glucagon before somatostatin administration, no fall in blood glucose was seen in five out of six experiments, and plasma FFA showed no variations. The results suggest that plasma pancreatic glucagon is of major importance for the maintenance of basal blood glucose.

Twenty-Four-Hour Serum Growth Hormone Levels in Maturity-Onset Diabetics

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.

PLASMA-INSULIN IN MILD JUVENILE DIABETES

Abstract The fasting plasma-insulin levels and the response to various stimuli in three patients with mild juvenile diabetes suggested an abnormal regulation of insulin secretion as well as peripheral insulin resistance resembling that found in older patients.