Biomedical subjects
Publications and source records attributed to R I Misbin.
A defect in the binding of insulin to circulating monocytes occurs when obese patients are hospitalized and fed a liberal carbohydrate diet. Under ordinary circumstances, most obese patients have normal insulin binding despite very high concentrations of serum insulin. These results show that insulin does not necessarily regulate its own receptor in vivo--as it does in vitro.
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Administration of dichloroacetate (DCA) to normal rats resulted in a fall in serum glucose and triglycerides and a rise in ketone bodies. Insulin and cholesterol levels were unchanged. The effects of DCA on lipid metabolism were examined in isolated rat hepatocytes. At 10 mM DCA, the incorporation of tritiated water into fatty acids (saponifiable lipids) was inhibited by 33 +/- 4% (mean +/- SEM, N = 5). No effect on incorporation into cholesterol (measured as nonsaponifiable lipids) was observed. DCA inhibited the incorporation of 14C-glucose into lipid but had no effect on glucose oxidation. Fatty acid oxidation was increased by 76 +/- 7% (mean +/- SEM, N = 6). However, DCA had no effect on the recovery of newly synthesized lipid. Thus, inhibition of tritiated water incorporation into fatty acids represents decreased synthesis rather than increased turnover. DCA did not affect the incorporation of 14C-palmitate into triglycerides or phospholipids. Cell viability, as assessed by incorporation of 3H-isoleucine into protein and trypan blue exclusion, was not affected by DCA. These results suggest that DCA lowers serum triglycerides through inhibition of fatty acid synthesis and stimulation of fatty acid oxidation by liver.
Women differ markedly from men in their metabolic response to caloric deprivation. To determine if these differences could be attributed solely to changes in insulin concentration, a group of 8 women was matched with a group of 7 men so that the mean fall in serum insulin during a 72-h fast did not differ between the groups. Glucose levels fell to a greater degree in the women than in the men. The serum concentrations of free fatty acids and ketone bodies rose more rapidly in the women and closely paralleled the earlier rise in glucagon concentrations. Over the first 36 h of fasting the change in free fatty acids was positively correlated to the change in glucagon and negatively correlated to the change in insulin. For the second 36 h of fasting, only changes in glucagon correlated with changes in free fatty acids. These correlations were true for both sexes and support the hypothesis that glucagon plays a physiologically significant role the regulation of lipolysis during starvation.
The binding of insulin to a specific receptor on IM-9-cultured human lymphocytes was studied in vitro under conditions simulating diabetic ketoacidosis. Compared with control incubations at pH 7.4, binding was reduced by 19 per cent at pH 7.1 and by 48 per cent at pH 6.8. Addition of beta-hydroxybutyrate, at concentrations similar to those seen clinically, "restored" insulin binding toward normal. We suggest that, by counteracting the effects of acidosis, ketoacids themselves maintain normal insulin-receptor binding in diabetic ketoacidosis. These data also illustrate that small molecules, present in vivo, can significantly alter the interactions between a hormone and its receptor in vitro.
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Since phenformin's introduction into clinical medicine, a total of 552 cases of lactic acidosis have been reported in patients taking this hypoglycemic agent. In 306 cases, sufficient documentation was available to establish the diagnosis with reasonable certainty (blood lactate, 6 meq/litre or greater, and blood pH, 7.33 or less). The mortality rate among insulin-treated patients (15%) was considerably less than the mortality rate in the group as a whole (42%). Taken together with results from animal studies, these data suggest that insulin is the treatment of choice for phenformin-associated lactic acidosis. Sodium bicarbonate should be administered to patients with severe acidosis, but should be withheld from patients with mild acidosis. Overly aggressive administration of sodium bicarbonate can be deleterious and should be avoided. Although dialysis has been suggested by some authors for the treatment of phenformin-associated lactic acidosis, the mortality rate among dialyzed patients (48%) was roughly the same as for the group as a whole (42%).
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Removal of unlabeled insulin was studied in the perfused rat liver. Insulin removal followed first-order kinetics over the range of concentrations found in the portal vein of postabsorptive rats, but deviated from first-order kinetics in experiments with a wider concentration range. Clearance was more than twice as great at concentrations normally found in the portal vein in the postabsorptive state (0.40-1.1nM or about 60-100 muU/ml) than at concentrations expected after pancreatic stimulation (4.5-7.0 nM). Saturation of the liver's capacity to remove insulin, however, was not observed even at higher levels. Insulin clearance diminished when the flow rate was reduced. It was not significantly altered by prolonged starvation. Our results suggest that when the insulin concentration is high a greater percentage escapes hepatic degradation then when it is low. Hepatic insulin clearance is in part dependent on the portal flow rate. The kinetics of insulin removal by the perfused liver cannot be accounted for by the properties of insulin-degrading enzymes described by others.
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The efficacy and tolerability of aminoglutethimide for the treatment of Cushing's syndrome was assessed in 66 cases three of which are described in the present paper. Aminoglutethimide provided palliation from the signs and symptoms of hypercorticism in 13 of 21 patients with metastatic adrenocortical carcinoma and four of six patients with ectopic ACTH production due to metastatic carcinomas. All six of the patients with adrenal adenomas showed clinical and biochemical improvement, while 14 of the 33 patients with bilateral adrenal hyperplasia of pituitary origin improved. Adverse reactions attributed to aminoglutethimide such as drowsiness, rash, and nausea occurred in 58 per cent of cases. These data suggest that aminoglutethimide has a place in controlling the signs and symptoms of adrenocorticoid excess in patients with Cushing's syndrome due to malignancy and is effective preoperative therapy for patients with adrenal adenomas and bilateral hyperplasia.
Aminoglutethimide blocks several cytochrome P-450 mediated steroid hydroxylation steps, including those required for conversion of cholesterol to pregnenolone and for the aromatization of androgens to estrogens. Through these actions it blocks adrenal steroidogenesis and the production of estrogens in extraglandular tissues. Aminoglutethimide is indicated for treatment of certain patients with Cushing's syndrome and breast cancer. Other potential uses (prostate carcinoma, low renin hypertension, etc.) remain investigational. For treatment of Cushing's syndrome, aminoglutethimide is usually given alone or in combination with metyrapone. In women with breast carcinoma, replacement hydrocortisone must be administered with aminoglutethimide to prevent reflex ACTH hypersecretion from overcoming adrenal inhibition. Administration of aminoglutethimide to patients with Cushing's syndrome results in improvement in clinical status in 56% of cases. Results are most favorable in patients with adrenal tumors and patients with ectopic ACTH production. Aminoglutethimide and replacement glucocorticoid produce objective disease regression in 32% of unselected postmenopausal patients with metastatic breast carcinoma and in 52% of women whose tumors are estrogen receptor positive. Responses are similar in duration and frequency to those produced by surgical adrenalectomy and hypophysectomy and the antiestrogen, tamoxifen.
Insulin degradation in IM-9 cultured human lymphocytes occurs extracellularly. In the presence of 0.1% bovine serum albumin, insulin degradation products are formed that are soluble in 5% trichloroacetic acid. In the presence of 5% bovine serum albumin, the major products of insulin degradation are insoluble in 5% trichloroacetic acid and have little or no biological activity. Inhibition of binding with Concanavalin A or antireceptor antibody does not affect the rate of insulin degradation.