Search

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.

Diabetic small vessel disease, or diabetic microangiopathy, is known to be a specific vascular abnormality, caused in some way by the metabolic and endocrine aberrations characterizing diabetes mellitus. It is not present at the acute onset of classical juvenile diabetes, but develops slowly in the course of many years.

Symptomatic diabetic neuropathy is present only in a few percent of the total diabetic population. In contrast abnormalities of the various parts of the nervous system can be demonstrated very early using neurophysiological techniques. These abnormalities are reversible at first, but progressive with duration of diabetes. Similar nervous abnormalities are present in experimental diabetes in the rat. The earliest structural changes have been demonstrated to be a decreased calibre of the myelinated axons. An abnormality in the axonal transport of proteins is possibly the very first change to appear. These recent results have enabled us to propose a hypothesis concerning the sequence of events in the development of the peripheral nerve abnormalities.

A morphometric study of the common peroneal nerve in early experimental diabetes in rats showed that fibre size was diminished. The reduction in the size of the axon was twice that of the myelin sheath. This may contribute to the understanding of the impaired motor conduction velocity found in diabetics shortly after the onset of their disease.

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.

In juvenile diabetes there is a renal hypertrophy: glomerular volume and capillary lumen of the individual glomeruli are about twice the size of healthy ones. The hypertrophy is associated with a hyperfunction (increased glomerular filtration and tubular reabsorption). If the diabetes is strictly controlled these changes may regress, which suggests a metabolically induced hypertrophy. Long-standing diabetes is characterized by a phase of intermittent proteinuria which gradually becomes permanent. Diabetic angiopathy is the result of many years of abnormal metabolism, presumably with involvement of the growth hormone and glucose. Whereas microangiopathy is considered specific for diabetes, it is still a matter for discussion whether a diabetic macroangiopathy exists. The results of numerous investigations suggest that it does.

Based on the literature and on experience and on experience with 23 cases the clinical diagnosis of insulinomas is reviewed. In clinical praxis the diagnostic steps can usually be simplified to a demonstration of fasting, symptomatic hypoglycaemia. Hence, we have used the 72-hour fast as the single diagnostic test for insulinomas during the last 5 years. Pro-insulin measurements may be a valuable supplementary tool. Other diagnostic tests are probably of little importance.

The state of the blood vessels is normal at the clinical onset of juvenile diabetes. Vascular changes develop slowly and progressively. According to the growth hormone hypothesis, elevated serum growth hormone is one casual factor in the development of diabetic angiopathy. The hypothesis proposes an effect of growth hormone not on blood glucose but directly on blood vessels. This hypothesis is based on serum growth hormone studies and on a controlled clinical trial of the effect of hypophysectomy on small blood vessels. An animal model of large-vessel disease in diabetes is briefly described. There is a large molecule in diabetic serum causing proliferation of aortic myomedial cells in culture. Growth hormone causes a similar proliferation. A short summary is given of the present situation in somatostatin research relating to diabetes mellitus.

A review is given of the early 1976 situation in somatostatin research: the effects on pituitary hormones and the effects outside the pituitary gland, the production of somatostatin outside the hypothalamus, the artificial analogues, the problem of "side effects", and the mode of action. The possible clinical applications of somatostatin and somatostatin analogues are discussed.

Als Ende der vierziger Jahre das Konzept der diabetischen Angiopathie entwickelt wurde, tauchten zwei schwierige Fragen auf — die Einbeziehung des Befalls der grosen Gefase und das Problem der Neuropathie. Damals herrschte die Vorstellung, das Retinopathie, Nierenerkrankungen, etc. „arteriosklerotische Komplikationen“ seien; diese Anschauung wurde gewohnlich in dem Satz formuliert: „Diabetes begunstigt die Entwicklung der Arteriosklerose“. Vor dem Hintergrund dieser Lehrmeinung entstand das neue Konzept aus der Erkenntnis, das einige der auffalligsten Gefasveranderungen bei Diabetikern keinerlei Ahnlichkeit mit denjenigen aufwiesen, die bei Nichtdiabetikern mit „Arteriosklerose“ oder „Atherosklerose“ beobachtet wurden. Man erkannte auch, das bestimmte Gefasanomalien, die bis dahin gewohnlich getrennt beschrieben worden waren, haufig bei ein und demselben Patienten nachgewiesen werden konnten. Aufgrund statistischer Auswertung von Befunden unausgewahlter Patienten mit einer Diabetesdauer von 15–25 Jahren wurde der Schlus gezogen, das die verschiedenen Gefasanomalien alle „der Ausdruck einer generalisierten, spezifisch spatdiabetischen Gefaserkrankung“ seien, namlich der diabetischen Angiopathie (Lundbaek, 1953, 1954).