Insulin resistance in Cushing's disease. Evaluation by studies of insulin binding to erythrocytes.

Studies of 125I -insulin binding to erythrocytes (RBC) from 5 patients with Cushing's disease were performed in an attempt to evaluate the insulin resistance in this disease. Five obese, nondiabetic patients and six normal subjects served as controls. Insulin resistance was present in both the obese, nondiabetic subjects and in the patients with Cushing's disease. Patients with Cushing's disease showed insulin resistance out of proportion to obesity, and of greater severity than in the obese subjects. As in previous studies, the insulin resistance of the obese subjects could be at least partially ascribed to a reduced number of receptors. In contrast, in our patients with Cushing's disease, no physiologically significant changes in the parameters of insulin-receptor interaction could be demonstrated. This suggests that the RBC insulin receptor is not involved in this type of insulin resistance.

Dissociated effects of somatostatin analogs on arginine-induced insulin, glucagon and growth hormone release in acromegalic patients.

Two analogs of somatostatin (Ala2,D-Trp8,D-Cys14-Somatostatin and L-5F-Trp8-Somatostatin) infused into acromegalics at the rate of 4.5 micrograms/min suppressed arginine-stimulated growth hormone release more strongly than 6 micrograms/min somatostatin (110 +/- 11% and 129 +/- 14%, respectively). Under the same conditions the two somatostatin analogs induced a much smaller inhibition of insulin (33 +/- 13% and 44 +/- 18%) and glucagon (28 +/- 10% and 45 +/- 17%, respectively) release than somatostatin did. Somatostatin analogs with dissociated actions could be promising for the treatment of diseases such as acromegaly, diabetes mellitus and some ectopic hormone syndromes.

Acanthosis nigricans, hirsutism, insulin resistance and insulin receptor defect.

A 24-year-old negress with the triad of acanthosis nigricans, hirsutism associated with polycystic ovaries and insulin resistance is reported. Metabolic studies were done 3 years after a bilateral ovarian wedge resection. Partial remission of the hirsutism and return of menstrual cycles occurred after surgery. Extreme resistance to endogenous and exogenous insulin was observed. Three studies of insulin receptors on circulating red blood cells (RBC) showed abnormal inhibition-competition curves, characterized by increased percentage insulin binding at higher unlabelled insulin levels. Scatchard plots suggested an apparent increase in the number of low affinity receptors. Despite the changes in receptor-insulin interaction, the defect does not seem to explain the insulin resistance since binding of insulin to a target tissue (RBC) appeared to be quantitatively normal at physiological insulin levels, suggesting a simultaneous post receptor defect.

The zonal origins of the mineralocorticoid hormones in the 21-hydroxylation deficiency of congenital adrenal hyperplasia.

The 0800 h plasma concentrations of the mineralocorticoid hormones, 18-hydroxydeoxycorticosterone (18-OHDOC), deoxycorticosterone (DOC), corticosterone, 18-hydroxycorticosterone (18-OHB), and aldosterone, in six patients with nonsalt-losing congenital adrenal hyperplasia revealed two groupings of these steroids: in one group, DOC, 18-OHB, and aldosterone were significantly elevated (P less than 0.001) at 51.7 +/- 18.0, 70.8 +/- 14.2, and 22.7 +/- 3.0 ng/dl, respectively; in the other group, corticosterone and 18-OHDOC were normal at 363.6 +/- 76.0 and 7.8 +/- 1.1 ng/dl, respectively. No significant increases in response to upright posture were observed in DOC, 18-OHB, or aldosterone. After a 1-h Cortrosyn stimulation test, the already elevated levels of DOC, 18-OHB, and aldosterone showed slight additional increases, but the normal levels of corticosterone and 18-OHDOC changed little within the normal unstimulated range. In these patients certain mineralocorticoid hormone patterns permit the identification of the zonal origins of steroids. The normal and fixed levels of 18-OHDOC and corticosterone, zona fasciculata steroids, are similar to those of cortisol and imply deficiency of formation and of their precursor, zona fasciculata DOC, a 21-hydroxylated steroid. Both the mineralocorticoid and glucocorticoid pathways distal to 21-hydroxylation are impaired in the zona fasciculata. However, the elevated and partially responsive levels of DOC, 18-OHB, and aldosterone imply that there is greater activation of 21-hydroxylation in the zona glomerulosa than in the zona fasciculata, with its normal fixed steroid levels, and that the elevated level of DOC is primarily from this zone.

Effect of prolonged glyclazide treatment on blood glucose and plasma insulin responses in obese patients with maturity-onset diabetes.

The effects of prolonged treatment with glyclazide [methyl-4-fenyl sulfonyl-1(perhydrocyclopenta(c) pyrrolyl-2)-3 urea] on blood glucose and plasma insulin responses to meals was studied in 8 obese patients with maturity-onset diabetes. Blood sampling was done 1 hr after meals for 2 consecutive days, on days 10 and 90 of therapy. Lower blood glucose curves were achieved on both days 10 and 90 in all patients. Plasma insulin curves in response to meals were higher than control on both days 10 and 90. The results may suggest that the long-term effect of glyclazide on blood glucose is related to a persistent stimulation of insulin secretion rather than to a predominant extrapancreatic action.

The effect of serum ionized calcium elevation on somatostatin inhibition of glucose-induced insulin release in humans.

The effect of somatostatin on the insulin response to an acute intravenous glucose load was studied in five normal subjects before and after induction hypercalcaemia. In the normocalcaemic state, the insulin response to glucose was depressed by somatostatin. In the hypercalcaemic state, insulin responses to glucose in the presence of somatostatin, were partially restored and appeared to be related to the level of increment of serum ionized calcium. It is concluded that, in the human being, hypercalcaemia and somatostatin have opposite actions on glucose-stimulated insulin secretion.

The adrenal response to exogenous adrenocorticotrophin in patients with infections due to Neisseria meningitidis.

The adrenal response to a soluble form of beta1-24-corticotropin (tetracosactrin [ACTH]: 250 microgram administered intramuscularly) was studied in 28 patients with meningitis due to Neisseria meningitidis (21 with petechiae and seven without) and in six patients with Salmonella typhi bacteremia. Six normal subjects also were tested for adrenal responsiveness at four different times of the day (8 A.M., 12 noon, 4 P.M., and 10 P.M.) and served as controls. The results showed that, whatever the time of testing, patients with meningococcal infections and typhoid fever had unstimulated (basal) levels of plasma cortisol above the 99% confidence limits for the mean unstimulated cortisol levels for the normal subjects. Furthermore, although patients with meningitis without petechiae and subjects with S. typhi bacteremia responded to ACTH stimulation in a manner similar to that of the normal subjects, most subjects with meningitis with petechiae did not have increased levels of plasma cortisol after treatment with ACTH. This lack of response could not be ascribed entirely to the higher basal levels of plasma cortisol in these patients. Patients with meningitis associated with petechiae may have a relatively decreased adrenal response to stimulation with exogenous ACTH.

Carbohydrate metabolism in thyrotoxicosis: studies on insulin secretion before and after remission from the hyperthyroid state.

The effects of thyrotoxicosis on insulin secretion were studied in 11 patients with Graves' disease and compared with the results obtained in 6 of the patients after they had attained clinical remission. Constant glucose infusion (CGI) and acute tolbutamide infusion (AIT) tests were chosen to investigate beta-cell function. For similar means of fasting plasma glucose, basal plasma insulin mean was significantly higher during thyrotoxicosis. During AIT, mean peak insulin was obtained earlier in the hyperthyroid state (2 min) than after remission (4 min), being its level higher in the hyperthyroid state. During CGI, early insulin responses to similar plasma glucose increments, were comparable for both hyper and euthyroid subjects. After 10 minutes of CGI, insulin concentrations in the hyperthyroid state did not increase as in the euthyroid state in spite of comparable increments of plasma glucose, being similar plateau insulin levels attained thereafter. These results suggest the presence of an insulin-resistant state in hyperthyroidism which may either disappear during a chronic glucose infusion and/or be accompanied by a deficient late glucose-induced insulin release.

Plasma insulin disappearance curve after intravenous insulin injection in human hyperthyroidism.

The disappearance curves of plasma insulin after intravenous injection of unlabelled pork insulin was studied in nine young female hyperthyroid subjects with Graves' disease and eleven young female normal subjects, who served as controls. Comparison of the curves by analysis of variance did not reveal statistical differences between them (F obtained = 2.8, F F 0.05 = 4.41), implying that there was no significant differences in the transference of injected insulin from plasma to the extra-vascular space between hyper- and euthyroid subjects. The results may suggest that the metabolism of insulin is not appreciably affected in hyperthyroidism.

Interaction of calcium ions with serum albumin in chronic renal failure.

In order to study the effect of the uremic environment on serum calcium-albumin interaction, ten adult subjects with chronic renal failure (creatinine clearances below 20 ml/min) and five adult normal subjects, had their serum ionic calcium (Orion SS-20) determined at three different serum pH values. At similar serum protein levels, the correlations between serum ionic calcium pH were: (a) normals: number of pairs = 15, r = -0.90, p less than 0.01, Ca2+ = 4.54-0.484 pH. (b) uremics: number of pairs=15, r=-0.97, p less than 0.01, Ca2+=4.02-0.429 pH. These regressions were similar as far as the slopes (Fslope=0.62, p greater than 0.05) but had different intercepts (Fintercepts=64.34, p less than 0.01). These results confirm that uremics, when compared to normal subjects, present an ionic hypocalcemia at any level of serum pH. They also show that serum calcium-albumin interaction is normal in uremia. In view of the above results, it can be suggested that, among several possible causes, alterations in the binding-affinity of calcium ions to serum albumin can be excluded as an additional factor of secondary hyperparathyroidism in uremia.

Mechanism of action of phenethylbiguanide (phenformin) in man. III. interrelationship between ethanol and phenethylibiguanide (PBG) in normal and diabetic subjects.

A standard 4-hr ethanol infusion (236 mg/min) after a 3-day fast with and without phenformin (25 mg q.i.d.), with blood drawn every hour for 8 hr, was performed on five normal subjects, eight obese nondiabetics, seven obese chemical diabetics, and four nonobese diabetics. Control infusion induced in all subjects a decline in blood sugar levels during and/or after the alcohol challenge, with a parallel decrease in basal plasma insulin. Hypoglycemia and the decrease in insulin secretion were associated with increased plasma free fatty acid concentration. Addition of phenethylbiguanide (PBG) to the preparatory 3-day fast resulted in a greater drop in the blood glucose levels of the normal control subjects, obese and nonobese diabetics; in the obese nondiabetics, however, significantly lower degree of blood glucose decrease than control was elicited. Furthermore, obese nondiabetics altered their blood glucose-insulin interaction with apparent increased responsivess of the B cells of PBG. The results suggest that effects of phenformin on blood glucose levels are more dependent on the metabolic state of the patient than on a property of the drug itself.