Growth hormone's role in diabetic microangiopathy.

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.

Somatostatin in maturity-onset diabetes.

Plasma FFA, glucagon, insulin, glucose, and growth hormone were followed every hour during 24 hours of saline infusion, 24 hours of somatostatin (4mg.) infusion, and three hours without infusion in six nonobese and six obese maturity-onset diabetic men. Somatostatin induced the same changes in the parameters of both groups of diabetic patients: A rise in plasma FFA, which gradually disappeared after some hours of infusion, a suppression of plasma glucagon and insulin, and an augmentation of plasma glucose both postprandially and during the night. Plasma growth hormone was suppressed in the nonobese patients, but somatostatin could not further suppress the low and nonfluctuating plasma growth hormone concentration in the obese maturity-onset diabetics. The results indicate that a preparation with a pattern of hormone suppression like that of somatostatin will not be useful in the control of maturity-onset diabetes, because it suppresses insulin and elevates the blood glucose concentration.

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.

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 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.

Effects of somatostatin on basal levels of plasma growth hormone and insulin in acromegalics: dose-response studies and attempted total growth hormone suppression.

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 clinical diagnosis of insulinoma.

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.

[Diabetic angiopathy. A new concept of pathogenesis (author's transl)]. / Diabetische Angiopathie. Neue Konzepte der Pathogenese.

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.

Neuropathy in experimental diabetes: an animal model.

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.

Nervous system abnormality and nervous disease in diabetes.

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.

Somatostatin: a review of its effects especially in human beings.

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.

Pathological changes in the central and peripheral nervous system of young long-term diabetics : I. Diabetic encephalopathy.

A study of the clinical observations and the neuropathological findings in the brain of 16 juvenile diabetics dying of diabetic angiopathy after many years of diabetes is presented. A characteristic histological pattern was observed in all the cases consisting of diffuse degenerative abnormalities of the brain tissue, often with severe pseudocalcinosis or with atrophy of the dentate nucleus, demyelinisation of the cranial nerves, fibrosis of the leptomeninges and angiopathy. The degenerative changes were so pronounced that a dual pathogenesis seems likely; viz. an ischemia caused by the angiopathy and a primary diabetic abnormality of the brain tissue. The clinical symptoms of cerebral disease varied from insignificant to pronounced. A correlation was found between the symptoms and the number of areas of softening in the brain. The histological pattern differs from that seen in other clinical conditions and justifies the term diabetic encephalopathy.

The effect of somatostatin on the rise of growth hormone and glucagon secretion induced by arginine and L-dopa in diabetic patients.

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.