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Showing papers on "Insulin published in 1971"


Journal ArticleDOI
TL;DR: The mean chemotactic index in 31 patients with diabetes mellitus was significantly less than that in 31 matched controls, and it is suggested that this defect in the chemotaxis of diabetic leukocytes could contribute to increased infections in these patients.
Abstract: With a new in vitro method of measuring the chemotaxis of polymorphonuclear leukocytes from peripheral blood, a chemotactic index was calculated. The mean chemotactic index in 31 patients with diabetes mellitus was significantly less (p less than 0.0005) than that in 31 matched controls. The defect in chemotaxis could not be correlated with plasma insulin, plasma glucose, serum carbon dioxide and blood urea nitrogen values, or with any therapeutic agents. Incubation of the leukocytes from 11 normals with glucose in concentrations of 300 to 900 mg per 100 ml did not alter indexes. The defect in chemotaxis of the diabetic leukocyte was corrected by incubation of the cells with insulin in concentrations of 100 μU to 10 mU per milliliter. Insulin with phenol was less effective than insulin without preservative. Insulin was ineffective in the absence of glucose. It is suggested that this defect in the chemotaxis of diabetic leukocytes could contribute to increased infections in these patients.

694 citations


Journal ArticleDOI
TL;DR: Eight insulins and derivatives with biological potencies that differed over a 100-fold range inhibited the binding of insulin to liver membranes in direct proportion to their ability to stimulate glucose oxidation in isolated fat cells.
Abstract: With [125I]insulin at 7 × 10-10 M, 25% of the radioactivity was bound to plasma membranes purified from rat liver. 20% of the [125I]insulin binding was inhibited by unlabeled insulin at 10-9 M (6 ng/ml), equivalent to insulin concentrations in hepatic portal blood; inhibition of [125I]insulin binding was 80% at 10-7 M and 90% at 10-5 M. Eight insulins and derivatives with biological potencies that differed over a 100-fold range inhibited the binding of [125I]insulin to liver membranes in direct proportion to their ability to stimulate glucose oxidation in isolated fat cells. Inactive insulin chains, as well as glucagon, ACTH, and human growth harmone were without effect. The binding of [125I]insulin increased 55-fold as plasma membrane was purified from crude homogenate. Binding was time- and temperature-dependent, and addition of excess insulin produced rapid dissociation of [125I]insulin. This study demonstrates directly the binding of insulin to its biologically important receptors.

497 citations


Journal ArticleDOI
TL;DR: It appears that the presence of "excess" receptors on fat cells renders the cells highly sensitive to insulin.

445 citations


Journal ArticleDOI
TL;DR: The total binding capacity of fat cells is quantitatively recovered in the particulate fraction after homogenization, and the insulin-cell receptor interaction is a simple dissociable process involving a homogeneous species probably present exclusively in the cell membrane.
Abstract: An assay system is described for measurement of specific binding of [125I]insulin to intact fat cells and membrane fractions from such cells. The binding is time- and temperature-dependent and saturable with respect to insulin; the bound insulin is displaced by native insulin but not by oxidized or reduced insulin or by a number of other peptide hormones. A maximum of about 11,000 molecules of insulin can bind per cell. The insulin-receptor association is a bimolecular reaction with a rate constant of 1.5 × 107 M-1 sec-1, while the dissociation is a strictly first-order process with a rate constant of 7.4 × 10-4 sec-1. A dissociation constant of 5.0 × 10-11 M can be calculated from these rate constants, whereas a value of 6.1 × 10-11 M is obtained on the basis of enhancement of glucose oxidation. Complex formation does not result in chemical change or inactivation of insulin or receptor. The total binding capacity of fat cells is quantitatively recovered in the particulate fraction after homogenization. The insulin-cell receptor interaction is a simple dissociable process involving a homogeneous species probably present exclusively in the cell membrane.

405 citations


Journal ArticleDOI
01 Dec 1971-Diabetes
TL;DR: Insulin serves as the body's signal for the fed or fasted state, and certain metabolic states such as obesity or trauma alter the concentration of insulin at which no net transfer of fuel occurs, resulting in insulin resistance or hyper-sensitivity.
Abstract: Insulin serves as the body9s signal for the fed or fasted state. High insulin levels, the “fed” signal, initiate tissue uptake and storage of fuels. Low insulin levels, the “fasted” signal, initiate mobilization of stored fuels from tissue stores, the rate being proportional to the lowness of the insulin. Certain metabolic states such as obesity or trauma alter the concentration of insulin at which no net transfer of fuel occurs, resulting in insulin resistance or hyper-sensitivity.

312 citations


Journal ArticleDOI
TL;DR: Inhibition of hepatic glucose production associated with glucose infusion and large increments in insulin levels occurs in the absence of a decrease in the concentration of circulating gluconeogenic substrate, suggesting an hepatic rather than peripheral effect.
Abstract: Splanchnic exchange of glucose, 20 individual amino acids, lactate, and pyruvate was studied in normal subjects in the postabsorptive state and after stimulation of endogenous insulin secretion by infusion of glucose at two dose levels. In the basal state, mean splanchnic glucose production was 3.4 mg/kg per min. A net uptake of lactate, pyruvate, and nine amino acids was observed, with alanine accounting for half of the total splanchnic-amino acid extraction. Infusion of glucose at 25 mg/kg per min for 20 min resulted in a fivefold increase in arterial insulin levels and in reversal of splanchnic glucose balance to a net uptake. Splanchnic uptake of alanine, glycine, phenylalanine, lactate, and pyruvate fell by 30-60% due to a reduction in fractional extraction of these substrates, inasmuch as their arterial concentrations did not decline. Administration of glucose at 2 mg/kg per min for 45 min resulted in a 19 mg/100 ml increase in arterial glucose concentration and a doubling of arterial insulin levels. Despite the small increment in insulin, hepatic glucose production fell by 85%. Splanchnic exchange of amino acids, lactate, and pyruvate was unaltered. Estimated total glucose utilization during the infusion was no greater than in the basal state, indicating lack of stimulation of peripheral glucose uptake. It is concluded that: (a) inhibition of hepatic glucose production associated with glucose infusion and large increments in insulin levels occurs in the absence of a decrease in the concentration of circulating gluconeogenic substrate, suggesting an hepatic rather than peripheral effect; (b) the liver is the primary target organ whereby glucose homeostasis is achieved with small increments in insulin; (c) the relatively greater sensitivity of the liver's response to insulin as compared with an effect of insulin on the peripheral tissues, may be a consequence of the higher levels of endogenous insulin in portal as compared with peripheral blood.

309 citations


Journal ArticleDOI
TL;DR: In this article, the role of calcium in glucose-induced insulin secretion was examined by measuring 45Ca uptake by isolated islets of Langerhans, which were incubated for 90 min in the presence of 45Ca, submitted to successive washings, and finally examined for their radioactive content.
Abstract: The role of calcium in glucoseinduced insulin secretion was examined by measuring 45Ca uptake by isolated islets of Langerhans. The islets were incubated for 90 min in the presence of 45Ca, submitted to successive washings, and finally examined for their radioactive content. Glucose, but not galactose, stimulated 45Ca uptake by the islets. A sigmoidal curve characterized the relationship between 45Ca uptake and the glucose concentration of the incubation medium. Glucose-induced calcium uptake was increased in media in which Na+ had been partially replaced by K+, and inhibited by mannoheptulose, 2-deoxyglucose, epinephrine, diazoxide, low temperature, low pH, high Mg++ concentration, low Ca++ concentration, and in media in which Na+ had been partially replaced by Li+. Under these experimental conditions, the, changes in 45Ca uptake paralleled those in insulin secretion by the islets. However, although glucose failed to induce insulin release at low Ca++ concentration, the reduced uptake of calcium found un...

299 citations



Journal ArticleDOI
01 Dec 1971-Diabetes
TL;DR: The biologic opposition which insulin and glucagon exert upon the liver and adipose tissue suggests that the relative concentrations of these two hormones which perfuse these tissues may determine their net nutrient balance, and these findings are believed to account for certain previously poorly understood clinical observations.
Abstract: The biologic opposition which insulin and glucagon exert upon the liver and adipose tissue suggests that the relative concentrations of these two hormones which perfuse these tissues may determine their net nutrient balance. A review of recent studies of plasma glucagon and insulin levels reveals that the insulin:glucagon ratio (I/G) varies inversely with need for endogenous glucose production, being lowest in total starvation and highest during loading with exogenous carbohydrate. Similarly, the infusion of the glucose precursor, alanine, which in the fasting state causes a fall in I/G, a “catabolic response,” increases I/G during a glucose infusion, an ”anabolic response,/ which must spare alanine from gluconeogenesis. The same bihormonal relationship to need for glucose production has been observed after a protein load; normally after an overnight fast I/G rises in response to a beef meal, an anabolic response, while in the carbohydrate-deprived subject, the I/G does not rise, remaining at a catabolic level; during a glucose infusion the ingestion of a beef meal induces a greatly exaggerated anabolic rise in I/G. These findings are believed to account for certain previously poorly understood clinical observations. They may explain the so-called “protein sparing action” of glucose and the salutory nutritional effect of intravenously administered amino acid preparations when glucose is also provided in large quantities. The inability of diabetics to increase their I/G generally parallels their catabolic state, and, by stimulating glucagon but not insulin, tissue breakdown due to infection or trauma may further reduce the I/G and cause metabolic deterioration. The possible role of the I/G in the response to burns, trauma, infection, and malignancy is considered.

288 citations


Journal ArticleDOI
TL;DR: It now seems probable that glucagon, like insulin, is extremely important in the moment-to-moment control of the homeostasis of glucose, of certain amino acids and perhaps of free fatty acids.
Abstract: THE function of pancreatic glucagon has been questioned for several decades, but it now seems probable that glucagon, like insulin, is extremely important in the moment-to-moment control of the homeostasis of glucose, of certain amino acids and perhaps of free fatty acids. Normal alpha-cell function seems essential to optimal glucoregulation, and abnormal alpha-cell function may cause, contribute to or result from a variety of metabolic disorders, the most common being diabetes mellitus. Biologic Opposition of Glucagon and Insulin Glucagon has been shown to have potent glycogenolytic1 and gluconeogenic2 , 3 activity at concentrations within the physiologic range. In addition, it may have . . .

271 citations


Journal ArticleDOI
09 Aug 1971-JAMA
TL;DR: There was no evidence that phenformin was more effective than any of the other treatments in preventing the occurrence of nonfatal vascular complications associated with diabetes, and the use of Phenformin has been terminated in the UGDP.
Abstract: The University Group Diabetes Program (UGDP), a long-term prospective clinical trial, was designed to evaluate the effects of various hypoglycemic agents on vascular complications in patients with asymptomatic, adult-onset diabetes. This study provided no evidence that phenformin was more efficacious than diet alone or than diet and insulin in prolonging life for the patients studied. In fact, the observed mortality from all causes and from cardiovascular causes for patients in the phenformin treatment group was higher than that observed in any of the other treatment groups. In addition, there was no evidence that phenformin was more effective than any of the other treatments in preventing the occurrence of nonfatal vascular complications associated with diabetes. For these reasons, the use of phenformin has been terminated in the UGDP. Data collection in this study is continuing for all surviving patients. The additional information obtained over a longer period of follow-up on patients in the two insulin groups compared with the patients in the placebo group will provide a more adequate basis for the assessment of the long-term effects of insulin.

Journal ArticleDOI
TL;DR: It is concluded that normal suppression of glucagon secretion by hyperglycemia does not occur when glucose metabolism is blocked or when severe insulin deficiency is produced, and it is suggested that normal glucose metabolism within the alpha cell may be an insulin-requiring process without which hyperglycemic suppressed glucagon release cannot occur.
Abstract: Suppression of pancreatic glucagon secretion by hyperglycemia is a characteristic of normal alpha cell function. However, in diabetic subjects, plasma glucagon is normal or high despite hyperglycemia. It seemed possible that the presence of glucose or its metabolites within the alpha cell might be essential for suppression of glucagon secretion, and that in diabetes an intracellular deficiency of glucose secondary to insulin lack might be responsible for the nonsuppressibility. The present study was designed to determine the effect upon glucagon secretion of blockade of glucose metabolism and of experimental insulin deficiency. Blockade of glucose metabolism was induced in dogs by administration of 2-deoxyglucose or mannoheptulose. A striking rise in glucagon was observed despite accompanying hyperglycemia and hyperinsulinemia, which, in the case of mannoheptulose, was induced by infusing crystalline insulin. To determine if insulin lack also causes paradoxical hyperglucagonemia, dogs were made severely diabetic by alloxan. Fasting glucagon levels ranged from 3 to 22 times normal despite severe hyperglycemia, and were quickly restored to normal by infusing insulin. Diabetes induced in rats by anti-insulin serum was also associated with significant elevation in plasma glucagon. However, diazoxide-induced insulin lack did not increase glucagon in dogs. It is concluded that normal suppression of glucagon secretion by hyperglycemia does not occur when glucose metabolism is blocked or when severe insulin deficiency is produced. It is suggested that normal glucose metabolism within the alpha cell may be an insulin-requiring process without which hyperglycemic suppression of glucagon release cannot occur.

01 Jan 1971
TL;DR: Results indicate that estradiol and progesterone contribute to enhanced islet insulin secretion and plasma insulin responses to glucose administration during pregnancy, which can be related to hypertrophy of islets following chronic hormonal administration.
Abstract: A B S T R A C T Influences of estrogen and progesterone on the development of hyperinsulinemia and augmented pancreatic islet insulin secretion during pregnancy were assessed in this study. Groups of female rats were injected subcutaneously for 21 days with varying daily dosages of estradiol benzoate or progesterone in oil. On day 21, pancreatic islets were isolated by a collagenase method. Total insulin secretion was measured after 90min incubations of 10 islets in buffered medium containing glucose. Higher physiologic dosages of estradiol or progesterone, singly or in combination, significantly increased islet secretion above values of untreated control rats and were comparable to augmented islet responses of term, 3-wk pregnant rats. Diameter and protein content of islets obtained from steroid-treated and pregnant rats exceeded control measurements in these instances. However, 2-hr preincubations of control islets with 1 or 10 /g/ml of either steroid did not influence subsequent glucose-stimulated insulin output. In related studies, plasma insulin responses during 30 min intravenous glucose tolerance tests were significantly above control responses in term-pregnant rats and animals receiving comparable dosages of steroids for 3 wk. Unlike pregnancy or progesterone treatment, estradiol administration alone or with progesterone significantly lowered postchallenge plasma glucose concentrations.

Journal ArticleDOI
01 Aug 1971-Diabetes
TL;DR: Insulin, a protein of about 5,700 molecular weight, was delivered by aerosol inhalation to three normal volunteers and to four patients with diabetes mellitus and direct evidence of absorption of insulin across mucosae of the respiratory tract was an increase in plasma IRI.
Abstract: Insulin, a protein of about 5,700 molecular weight, was delivered by aerosol inhalation to three normal volunteers and to four patients with diabetes mellitus. Direct evidence of absorption of insulin across mucosae of the respiratory tract was an increase in plasma IRI. Biologic activity of insulin absorbed by inhalation was shown by hypoglycemia temporally correlated with the increase in plasma IRI. No untoward reactions were observed.

Journal ArticleDOI
TL;DR: In this paper, the effects of estrogen and progesterone on the development of hyperinsulinemia and augmented pancreatic islet insulin secretion during pregnancy were assessed in groups of female rats.
Abstract: Influences of estrogen and progesterone on the development of hyperinsulinemia and augmented pancreatic islet insulin secretion during pregnancy were assessed in this study. Groups of female rats were injected subcutaneously for 21 days with varying daily dosages of estradiol benzoate or progesterone in oil. On day 21, pancreatic islets were isolated by a collagenase method. Total insulin secretion was measured after 90-min incubations of 10 islets in buffered medium containing glucose. Higher physiologic dosages of estradiol or progesterone, singly or in combination, significantly increased islet secretion above values of untreated control rats and were comparable to augmented islet responses of term, 3-wk pregnant rats. Diameter and protein content of islets obtained from steroid-treated and pregnant rats exceeded control measurements in these instances. However, 2-hr preincubations of control islets with 1 or 10 μg/ml of either steroid did not influence subsequent glucose-stimulated insulin output. In related studies, plasma insulin responses during 30 min intravenous glucose tolerance tests were significantly above control responses in term-pregnant rats and animals receiving comparable dosages of steroids for 3 wk. Unlike pregnancy or progesterone treatment, estradiol administration alone or with progesterone significantly lowered postchallenge plasma glucose concentrations. These results indicate that estradiol and progesterone contribute to enhanced islet insulin secretion and plasma insulin responses to glucose administration during pregnancy. This change is not acutely produced but can be related to hypertrophy of islets following chronic hormonal administration. Although the data do not distinguish between direct and indirect beta-cytotrophic effects of these sex steroids, metabolic actions of estradiol and progesterone may differ, since estrogen treatment lowers plasma glucose curves following the induction of hyperinsulinemia.

Journal ArticleDOI
TL;DR: The objective was to evaluate the effect of increased dietary carbohydrate in diabetes mellitus, glucose and immunoreactive insulin levels, which were measured in normal persons and subjects with mild diabetes.
Abstract: To evaluate the effect of increased dietary carbohydrate in diabetes mellitus, glucose and immunoreactive insulin levels were measured in normal persons and subjects with mild diabetes maintained on basal (45 per cent carbohydrate) and high carbohydrate (85 per cent carbohydrate) diets. Fasting plasma glucose levels fell in all subjects and oral glucose tolerance (0 to 120-minute area) significantly improved after 10 days of high carbohydrate feeding. Fasting insulin levels also were lower on the high carbohydrate diet; however, insulin responses to oral glucose did not significantly change. These data suggest that the high carbohydrate diet increased the sensitivity of peripheral tissues to insulin.

Journal ArticleDOI
TL;DR: In vitro proinsulin can be rapidly and quantitatively cleaved by a combination of pancreatic trypsin and carboxypeptidase B in vitro to yield intact insulin, the C-peptide, and free arginine and lysine.

Journal ArticleDOI
TL;DR: Modification of the membranes with several protein reagents suggests that tyrosyl and possibly histidyl residues may be important in the binding interaction, and no evidence is present for the involvement of sulfhydryl, tryptophanyl, or carboxyl groups of the membrane.

Journal ArticleDOI
01 Apr 1971-Diabetes
TL;DR: It is suggested that dehydration and hyperosmolarity may play significant roles in the etiology of HNC, and that therapy should, therefore, be directed at restoration of normal osmolarity and correction of water deficits with 0.45 per cent saline and moderate amounts of insulin.
Abstract: Clinical and metabolic data of twenty patients with hyperosmolar nonketotic coma (HNC) and ten patients in keto-acidosis (DA) are compared HNC patients were older; fewer were previously known diabetics; more had multiple chronic diseases Common precipitating factors in HNC included infection, dehydration and administration of diabeto-genic drugs Blood glucose and urea nitrogen, plasma sodium, bicarbonate and osmolarity were significantly higher in HNC Plasma potassium and chloride levels were similar in both groups Patients with HNC had significantly lower plasma levels of free fatty acids, cortisol and growth hormone Plasma insulin levels in HNC were low and not significantly different from those observed in KA Patients with HNC required more fluids and less insulin therapy Mortality was 20 per cent in HNC, lower than that generally observed in this condition, but higher than that of KA, 0 per cent On the basis of the above findings, it is suggested that dehydration and hyperosmolarity may play significant roles in the etiology of HNC, and that therapy should, therefore, be directed at restoration of normal osmolarity and correction of water deficits with 045 per cent saline and moderate amounts of insulin

Journal ArticleDOI
John H. Exton1, S. B. Lewis1, R. J. Ho1, G. A. Robison1, Charles R. Park1 
TL;DR: More recent observations on the interaction of glucagon, epinephrine, and insulin in the control of hepatic metabolism are presented.
Abstract: It is now well established that insulin exerts direct effects on mammalian liver to inhibit the production of glucose and urea and to promote the uptake of potassium ions. It has been proposed that these effects of insulin may be partly due to a decrease in liver cyclic AMP.l The proposal is based on the following observations: ( 1) insulin produces a small but significant decrease in the level of cyclic AMP in the perfused rat liver; (2) depletion of insulin in vivo by treatment with insulin antiserum or alloxan results in a twofold increase in liver cyclic AMP; (3) exogenous cyclic AMP and hormones such as glucagon and epinephrine which raise the level of cyclic AMP produce effects on the liver which are opposite to those caused by insulin; (4) insulin antagonizes the actions of epinephrine, glucagon, or cyclic AMP in the perfused liver; and ( 5 ) insulin reduces the accumulation of liver cyclic AMP in the presence of glucagon. In this article we will present more recent observations on the interaction of glucagon, epinephrine, and insulin in the control of hepatic metabolism. The investigations have employed the isolated rat liver perfused by a modification of the technique of Mortimore.* The perfusion medium consisted of Krebs-Henseleit bicarbonate buffer containing 3 % bovine albumin and 20% bovine erythrocytes. Livers were from fed rats weighing 100-150 g and the perfusion flow rate was about 7 ml per minute. The perfusions were carried out in two ways. In most cases, livers were perfused for one hour with recirculating medium and hormones were infused into the portal vein at a constant rate. In these experiments, the hormone concentrations were calculated by dividing the quantity of hormone infused during the hour by the final volume of perfusate. Since this does not allow for degradation of hormone, the values are doubtlessly overestimated. In the second type of experiment livers were perfused initially for 20 minutes with recirculating media containing no additions in order to establish steady metabolic rates and levels of cyclic AMP. The perfusion system was then changed to one with nonrecirculating medium by diverting the perfusate leaving the liver into a beaker. After a six-minute control period, infusions of hormone were commenced and livers and effluent media were sampled at designated intervals. In these experi-

Journal ArticleDOI
01 Jan 1971-Diabetes
TL;DR: An isolated in vitro canine pancreas per fusion preparation is described which is suitable for prolonged study of insulin secretion and a feedback mechanism of insulin on insulin secretion from the beta cell has been demonstrated at levels of perfusate insulin which occur in vivo.
Abstract: An isolated in vitro canine pancreas per fusion preparation is described which is suitable for prolonged (five hours) study of insulin secretion. The preparation remains in good condition throughout the experimental period judged by various parameters. Feedback inhibition of insulin on insulin secretion was studied in the preparation. Experiments were performed at different concentrations of glucose in the influx medium. At 150 mg. per cent of glucose a considerable reduction of the insulin secretion was obtained when exogenous porcine insulin was added to the influx medium in concentrations from 180 μU./ml. to 420 μU./ml. In eight experiments where the exogenous insulin concentration in the influx medium was equal to or exceeded pre-inhibition efflux values the obtained insulin inhibition amounted to 25-78 per cent of the pre-inhibition values. In one of the eight experiments the exogenous insulin concentration was less than the pre-inhibition value; however, the same effect was obtained. A feedback mechanism of insulin on insulin secretion from the beta cell has thus been demonstrated at levels of perfusate insulin which occur in vivo.

Journal ArticleDOI
TL;DR: Although the insulin "resistance" of adipose tissue was reversed by weight loss and reduction of fat cell size, these studies also demonstrate that the insulin sensitivity of adiposes cells of similar sizes can vary widely depending upon the state of nutrition and growth of the animal.
Abstract: Glucose metabolism and insulin sensitivity of isolated rat epididymal fat cells and of their delipidated derivatives ("ghosts") was studied as a function of cellular lipid content (fat cell size), cellular protein content, animal age, and state of nutrition in an effort to examine the relationship of adipose cell size to adipose tissue insulin sensitivity.In ad libitum-fed rats, basal rates of glucose-1-(14)C incorporation into CO(2) and triglyceride are similar over a wide range of adipose cell size. In contrast, the insulin sensitivity of intact fat cells from rats fed ad libitum is inversely related to their lipid content: the larger the cell, the less the response to insulin. This "resistance" of the enlarged adipose cell to the action of insulin was demonstrated by a reduction in the per cent rise above the basal rate as well as in the absolute rate of glucose oxidation and lipogenesis caused by insulin. The protein content of fat cells was found to be relatively constant over a wide range of fat cell size. Thus, enlarged insulin "resistant" fat cells contained the same amount of protein as smaller insulin "sensitive" cells. These relationships between insulin sensitivity and cellular lipid or protein content were true regardless of whether cells of different sizes were obtained from animals of different body weights and ages, or from different portions of the epididymal fat pads of animals of the same weight and age.Acute delipidation of intact fat cells did not appear to alter these relationships between basal glucose metabolism, insulin sensitivity, and cell size. "Ghosts" prepared from fat cells of widely different sizes metabolized glucose to CO(2) and triglyceride at similar rates. The insulin sensitivity of the fat cell "ghost" appeared to be inversely related to the size of the intact cell from which it was derived: the larger the intact cell the less insulin sensitive its "ghost."Although the insulin "resistance" of adipose tissue was reversed by weight loss and reduction of fat cell size, these studies also demonstrate that the insulin sensitivity of adipose cells of similar sizes can vary widely depending upon the state of nutrition and growth of the animal. Thus, factors other than cell size can also influence the insulin sensitivity of the adipose tissue.

Journal ArticleDOI
TL;DR: This treatment reduced the nitrogen and potassium losses of severely burned patients to low values which could easily be replaced by a normal diet.

Journal ArticleDOI
TL;DR: There is strong evidence that the effects of tryptic digestion result exclusively from perturbations of superficial structures of the cell membrane, and there is no evidence that this specific and well characterized effect oftryptic digestion is subject to facile and spontaneous repair.

Journal ArticleDOI
01 Oct 1971-Diabetes
TL;DR: The insulin-reversible glucosyltransferase elevation of the diabetic renal cortex reflects the increased basement membrane synthesis occurring in this tissue and indicates that this process is directly or indirectly under the control of this hormone.
Abstract: Kidney glucosyltransferase (UDP-glucose: galactosylhydroxylysine-basement membrane glucosyltransferase), which is involved in the synthesis of the hydroxylsine-linked disaccharide units of glomerular basement membrane, has been measured in the renal cortices of normal and alloxan diabetic rats. The level of this enzyme in diabetic kidneys was found to be significantly elevated over that of age-matched controls, expressed either as specific or total activity, at all times studied (one to five months). However the difference between the normal and diabetic animalsincreased with the duration of the disease. When short-term diabetics were treated with insulin, the level of the glucosyltransferase could be restored to normal. Insulin treatment of long-term diabetic animals, which were more difficult to control, brought the enzyme level close to normal but did not completely restore it. The glucosyltransferase activity in several other tissues of the alloxan diabetic rat, including lung, liver, testes, spleen, and uterus, did not show any significant elevation over that of the normal. Measurement in kidney of a glycosyltransferase (UDP-galactose :N-acetylglucosamine-glycoprotein galactosyltransferase) involved in the synthesis of a different type of carbohydrate unit did not show the marked elevation noted for the glucosyltransferase. It is believed that the insulin-reversible glucosyltransferase elevation of the diabetic renal cortex reflects the increased basement membrane synthesis occurring in this tissue and indicates that this process is directly or indirectly under the control of this hormone.

Journal ArticleDOI
01 May 1971-Diabetes
TL;DR: The results suggest that the integrity of the microtubular-microfilamentous system is required for glucose to exert its normal stimulant action upon insulin secretion.
Abstract: The beta cell of the islets of Langerhans has been shown to contain a microtubular-microfilamentous system. The possible role of this system in the insulin secretory process was investigated by examining the effect upon glucoseinduced insulin secretion of mitotic spindle-inhibitors and microtubules-stabilizers. Inhibition of secretion was observed when the pieces of pancreas were pre-incubated for ninety minutes with either colchicine (0.01 to 1.0 mM) or vincristine (0.01 mM) prior to measurement of their secretory response to a high glucose concentration. Significant reduction of glucose-induced secretion was also noticed in thepresence of D 2 O (25 per cent or more, v/v), 2-methyl-2,4-pentanediol (0.5 to 1.0 per cent, v/v) and ethanol (1.0 per cent, v/v). The inhibitory effect of D 2 O was reversible. The stimulant action of glucose upon both calcium uptake and insulin biosynthesis by isolated islets was inhibited by mannoheptulose, but unaffected by either vincristine or D 2 O, suggesting that the latter agents did not interfere with glucose metabolism in the beta cell. These results suggest that the integrity of the microtubular-microfilamentous system is required for glucose to exert its normal stimulant action upon insulin secretion. It is hypothesized that glucose-induced calcium uptake by the beta cell could trigger the release of insulin by causing the contraction of such system, favoring the migration of the secretory granules and their extrusion in the process of emiocytosis.

Journal ArticleDOI
TL;DR: During two successive three-week periods, seven obese subjects were fed isocaloric diets, the first low, the second high in carbohydrate, and in all, basal plasma insulin levels decreased 50 p...
Abstract: During two successive three-week periods, seven obese subjects were fed isocaloric diets, the first low, the second high in carbohydrate. In all, basal plasma insulin levels decreased 50 per cent on the low-carbohydrate diet and increased on the high-carbohydrate diet. Three obese subjects were fed, during three successive four-week periods, 1500-calorie diets with high, then low, and then high-carbohydrate content. Basal plasma insulin levels were significantly reduced on the low-carbohydrate diet. Refeeding of the high-carbohydrate diet, despite continued weight loss, resulted in markedly increased basal plasma insulin. In both protocols, most patients also exhibited a decreased insulin secretory response to oral glucose when on a low intake of carbohydrate and an increased response on a high intake. Thus the hyperinsulinemia characteristic of obesity may be a result, in part, of dietary factors rather than exclusively a consequence of the insulin antagonism associated with obesity.

Journal ArticleDOI
TL;DR: It is concluded that either beta adrenergic blockade or alpha stimulation enhances HGH secretion and inhibits insulin secretion and fat mobilization, whereas either alpha blockade or beta stimulation stimulates insulin secretionand fat mobilization and inhibits H GH secretion.
Abstract: In order to determine whether an adrenergic mechanism is involved in the secretion of growth hormone and insulin, the effect of adrenergic-blocking or -stimulating agents on plasma human growth hormone (HGH), immunoreactive insulin, blood free fatty acids (FFA), and glucose levels was studied in normal human subjects. The intravenous infusion of propranolol, a beta adrenergic-blocking agent, caused a rise in plasma HGH, a transient decrease in blood FFA, and no significant change in plasma insulin. This increase in plasma HGH was inhibited either by the combined administration of isoproterenol, a beta adrenergic-stimulating agent, along with propranolol or by oral glucose loading immediately before the start of propranolol infusion. The concomitant administration of epinephrine and propranolol brought about a rise in plasma HGH comparable with that produced by propranolol alone, without any significant change in blood FFA. Alpha adrenergic blockade by the intravenous infusion of phenotolamine significantly suppressed plasma HGH responses to insulin-induced hypoglycemia and to arginine infusion, and enhanced plasma insulin response to arginine infusion. It also stimulated lipid mobilization significantly. The intravenous infusion of alpha adrenergic-stimulating agents, phenylephrine and methoxamine, caused an increase in plasma HGH, a slight decrease in blood FFA, and no significant change in plasma insulin. This increase in plasma HGH was significantly inhibited by the simultaneous administration of phentolamine along with methoxamine. On the contrary, a beta adrenergic stimulant, isoproterenol, raised plasma insulin and blood FFA, and abolished the plasma HGH response to propranolol. Another beta stimulator, isoxsuprine, raised blood FFA but not plasma insulin. It is concluded that either beta adrenergic blockade or alpha stimulation enhances HGH secretion and inhibits insulin secretion and fat mobilization, whereas either alpha blockade or beta stimulation stimulates insulin secretion and fat mobilization and inhibits HGH secretion.

Journal ArticleDOI
TL;DR: It is suggested that glucose does not stimulate insulin release by increasing the concentration of cyclic AMP in islet cells, however, the concentration in islets may modulate the effect of glucose on the release process.
Abstract: 1. Concentrations of cyclic AMP (adenosine 3′:5′-cyclic monophosphate) and rates of insulin release were measured in islets of Langerhans isolated from rat pancreas and incubated for various times in the presence of glucose, 3-isobutyl-1-methylxanthine, caffeine, theophylline, adrenaline and diazoxide. 2. Caffeine and theophylline produced small but significant increases in both cyclic AMP and release of insulin when they were incubated in the presence of 10mm-glucose. 3. 3-Isobutyl-1-methylxanthine produced a marked increase in the intracellular concentration of cyclic AMP in the presence of 5mm- and 10mm-glucose. However, insulin release was stimulated only in the presence of 10mm-glucose. 4. In response to rising concentrations of extracellular glucose (5–20mm) there was no detectable increase in the intracellular concentration of cyclic AMP even though there was a marked increase in the rate of insulin release. 5. In response to 10mm-glucose insulin release occurred in two phases and 3-isobutyl-1-methylxanthine potentiated the effect of glucose on both phases. The intracellular concentration of cyclic AMP remained constant with glucose and rose within 10min to its maximum value with 3-isobutyl-1-methylxanthine. 6. Adrenaline and diazoxide inhibited insulin release and lowered the intracellular concentration of cyclic AMP when islets were incubated with glucose or 3-isobutyl-1-methylxanthine. 7. It is suggested that glucose does not stimulate insulin release by increasing the concentration of cyclic AMP in islet cells. However, the concentration of cyclic AMP in islet cells may modulate the effect of glucose on the release process.

Journal ArticleDOI
TL;DR: It is concluded that insulin has no direct effect on the regulation of glucose-6-P dehydrogenase levels under the authors' experimental conditions.