Showing papers on "Insulin resistance published in 1977"
TL;DR: The data suggest that the antibodies present in these three sera bind to different determinants on the insulin receptor, and these antibodies may be useful probes of receptor structure and function.
Abstract: Autoantibodies to the insulin receptor have been detected in the sera of several patients with the Type B syndrome of insulin resistance and acanthosis nigricans. In this study we have used three of these sera (B-1, B-2, and B-3) as probes of the insulin receptor in isolated rat adipocytes. Preincubation of adipocytes with each of the three sera resulted in an inhibition of subsequent [125I]insulin binding. 50% inhibition of binding occurred with serum dilutions of 1:5 to 1:7,500. As in our previous studies with other tissues, Scatchard analysis of the insulin-binding data was curvilinear consistent with negative cooperativity. Computer analysis suggested that in each case the inhibition of binding was due to a decrease in receptor affinity rather than a change in available receptor number.
In addition to the effects on insulin binding, adipocytes pretreated with antireceptor sera also showed alterations in biological responses. All three sera produced some stimulation of basal glucose oxidation. With serum B-3, maximal stimulation of glucose oxidation occurred at a serum concentration that inhibited binding by only 10-15%, whereas with serum B-2 the dilution curves for inhibition of binding and stimulation of glucose oxidation were superimposable. Serum B-1 behaved as a partial agonist; that is, it inhibited binding more effectively than it stimulated glucose oxidation. Cells pretreated with this serum in a concentration which inhibited binding by 80% also showed a five-fold shift to the right in the dose response of insulin-stimulated glucose oxidation, whereas spermine-stimulated glucose oxidation was unaffected. Serum B-2, which contained the highest titer of antireceptor antibodies, also stimulated 2-deoxy-glucose transport, as well as glucose incorporation into lipid and glycogen.
Both the ability of the serum to inhibit binding and stimulate glucose utilization were enriched in purified immunoglobulin fractions and retained in the F(ab′)2 fragment of the IgG. In addition, the bioactivity was blocked by antihuman IgG but not by anti-insulin antibodies. Enzymatic digestion of adipocytes with trypsin resulted in a complete loss of insulin-stimulated bioactivity of serum B-3, but had only minor effects on the glucose oxidation produced by serum B-1 or B-2.
These data suggest that the antibodies present in these three sera bind to different determinants on the insulin receptor. Thus, these antibodies may be useful probes of receptor structure and function.
237 citations
TL;DR: If the subjects are taken as a group, in patients with chemical diabetes and in diabetic patients with fasting hyperglycemia, insulin binding to monocytes is decreased, and plasma insulin levels are inversely related to insulin binding, but it is the basal, not the stimulated levels that are associated with changes in insulin receptors.
Abstract: Insulin binding to isolated circulating monocytes from normal subjects and adult patients with diabetes was studied. The diabetic subjects were nonketotic, and their degree of glucose intolerance varied from an abnormal oral glucose tolerance test (chemical diabetes) to significant fasting hyperglycemia. The results indicated that patients with chemical diabetes had a 45 per cent decrease in insulin binding to monocytes, and this decrease was secondary to a reduction in the number of receptor sites per cell (normals, 15,000 sites per monocyte versus 8,500 sites per mono-cyte for chemical diabetics). When the individual data from the normal and chemical diabetic subjects were examined, a highly significant inverse correlation was found between the amount of insulin bound and both the fasting plasma insulin level (r = 0.61, P > 0.001) and the incremental insulin area during an oral glucose tolerance test (r = 0.49, P > 0.001). Furthermore, insulin binding was closely and inversely correlated to the degree of insulin resistance (r = 0.65, P > 0.001) among these subjects. Thus, the ability to bind insulin is inversely related to both the plasma insulin level and insulin sensitivity, and chemical diabetics who are insulin-resistant and hyperinsulinemic have a decreased ability to bind insulin. Many patients with fasting hyperglycemia also have decreased insulin binding. However, although as a group these pa tients have fasting hyperinsulinemia, they are hypoinsulinemic in response to a glucose challenge. Thus, inclusion of their data with that of the normal and chemical-diabetic patients enhances the relationship between insulin binding and fasting insulin level (r = 0.68, P > 0.001) but obliterates the relationship between insulin binding and incremental insulin area. Furthermore, in these subjects no significant correlation was found between insulin binding and the degree of insulin resistance (r = 0.19, N.S.), suggesting that all or most of the insulin resistance in these subjects was independent of changes in insulin receptors. In conclusion, (1) if the subjects are taken as a group, in patients with chemical diabetes and in diabetic patients with fasting hyperglycemia, insulin binding to monocytes is decreased; (2) over the entire spectrum of adult, nonketotic diabetes, insulin binding is decreased to monocytes from patients with fasting hyperinsulinemia, while subjects with normal insulin levels have normal insulin binding; (3) the insulin resistance of patients with chemical diabetes may be related to a decrease in insulin receptors, but this does not appear to be the case for patients with fasting hyperglycemia; and (4) plasma insulin levels are inversely related to insulin binding, but it is the basal, not the stimulated levels that are associated with changes in insulin receptors.
227 citations
TL;DR: The results indicate that insulin resistance can occur as a secondary manifestation of insulin deficiency, and the higher the steady state plasma glucose level, the more the insulin resistance.
Abstract: Insulin resistance was measured in 16 normal dogs by a method involving the continuous intravenous infusion of epinephrine, propranolol, glucose and insulin. With this approach, endogenous insulin secretion is inhibited, similar steady state levels of exogenous insulin are achieved in all dogs, and the resultant steady state plasma glucose level provides a direct estimate of the ability of insulin to dispose of the infused glucose load. Thus, the higher the steady state plasma glucose level, the more the insulin resistance. Different amounts of alloxan were then administered to these dogs in order to produce insulin deficiency of varying degrees. Insulin resistance was then measured again in each dog. The results indicated that insulin resistance did not develop in dogs with only a moderate degree of insulin deficiency (fasting plasma glucose levels 150 mg/100 ml). Furthermore, the insulin resistance that developed in dogs with severe insulin deficiency could be returned to normal with insulin replacement for one week. These results indicate that insulin resistance can occur as a secondary manifestation of insulin deficiency.
85 citations
TL;DR: Using excess hepatic iron as a marker for inheritance of hemochromatosis, results of liver biopsies on 31 family members suggest an auto-somal dominant mode of inheritance with incomplete expressivity and a relationship between alcohol intake and excess liver iron.
85 citations
TL;DR: The results suggest that true heterogeneity exists in patients with abnormal OGTT's, and that the entire population could be divided into two groups characterized by both normal insulin responsiveness and sensitivity, the other by increased insulin response, associated with greater insulin resistance.
Abstract: Plasma insulin responses and insulin resistance were determined in 75 subjects, defined as having a normal, borderline abnormal, or abnormal oral glucose tolerance test (OGTT). Although considerable heterogeneity of insulin response existed, most patients with abnormal OGTT's had insulin responses greater than normal; none had insulin responses less than normal. The degree of insulin resistance also varied, but most patients with abnormal OGTT's were also abnormally insulin resistant. A significant correlation (r=0.64, p ±0.001) existed between insulin response and the degree of insulin resistance. However, when both variables were taken into consideration, the entire population could be divided into two groups. One group was characterized by both normal insulin responsiveness and sensitivity, the other by increased insulin response, associated with greater insulin resistance. Most patients with abnormal OGTT's fell into the latter group, but some had glucose intolerance without either an exaggerated insulin response or insulin resistance. These results suggest that true heterogeneity exists in patients with abnormal OGTT's.
80 citations
TL;DR: It is striking that fat cells from young, 4–7-wk-old obob mice actually exhibit increased responsiveness to the action of insulin on glucose transport and metabolism when their capacity for fatty acid synthesis is exceedingly high, and it seems possible that this amplified responsiveness to insulin in these very young Obob mice may be intimately involved in the etiology of this obese syndrome.
Abstract: It now appears established that glucose utilization in isolated fat cells prepared from adult obob mice, as well as spontaneosly obese rats, exhibits a markedly impaired responsiveness to insulin compared to controls. In neither case do decreased insulin receptors or a defective insulin effector system contribute significantly to this impaired response. The principal findings that support this conclusion are that (1) the impaired responsiveness of glucose metabolism in these cells is not overcome by addition of supermaximal concentrations of the hormone and (2) the hexose transport activity in these same fat cells is fully sensitive to activation by insulin under conditions where glucose utilization is not. Thus in both model systems the activity of one or more intracellular enzymes involved in glucose metabolism must be decreased and accounts for the defective response. Recent studies on fat cells from the spontaneously obese rat have identified the pentose shunt and fatty acid synthesis as the key inhibited pathways that lead to their inability to utilize glucose at rates comparable to the activity of insulin-stimulated hexose transport. Further studies will be required to identify the altered metabolic parameters that account for the impaired insulin responsiveness in fat cells from the adult obob mouse. In addition, it is striking that fat cells from young, 4–7-wk-old obob mice actually exhibit increased responsiveness to the action of insulin on glucose transport and metabolism when their capacity for fatty acid synthesis is exceedingly high. It seems possible that this amplified responsiveness to insulin in these very young obob mice may be intimately involved in the etiology of this obese syndrome. Experiments on human fat cells in obesity have been contradictory and indicate that dietary intake and age play major roles in determining the responsiveness of glucose metabolism in these cells to insulin. Too little biochemical information is available on these cells to allow definite conclusions with regard to the cellular locus which contributes most to altered insulin responsiveness. However, the few key studies available suggest that, when observed, impaired insulin responsiveness of fat cells from obese humans also reflects altered metabolic activities rather than insulin receptors or the hormone effector system. That these latter cellular components play a major role in the insulin resistance of muscle or liver remains a possibility that future studies must clarify.
76 citations
TL;DR: Low doses of insulin given as continuous intravenous infusions or as hourly intramuscular injections are as effective as large doses in treating severe ketoacidosis and are particularly suitable for use in nonspecialist centers.
Abstract: Severe diabetic ketoacidosis remains a lethal condition. Many deaths occur during therapy and are avoidable. Treatment includes rehydration, administration of insulin and potassium, and clinical care. For many years very large doses of insulin were used. Recently, it has been suggested that such large doses are unnecessary and lead to undue hypokalemia, hypoglycemia, and osmotic disequilibria. Many studies are now available that show that low doses of insulin given as continuous intravenous infusions (4 to 10 units/hr) or as hourly intramuscular injections (20 units initially, then 5 units/ hr) are as effective as large doses in treating severe ketoacidosis. The new regimens are simple to use, predictable, and safe. Potassium shifts are less than with large insulin doses and insulin resistance has been shown to be a relatively minor problem. The new regimens are particularly suitable for use in nonspecialist centers. ( Arch Intern Med 137:1367-1376, 1977)
60 citations
TL;DR: In this article, the ability of insulin to inhibit epinephrine-stimulated lipolysis was compared in large and small rat adipocytes, obtained from older, obese animals.
58 citations
TL;DR: After immunosuppressive therapy for eight months, the diabetic syndrome disappeared completely and anti-receptor antibodies in the serum were no longer detectable and insulin sensitivity returned to normal, however, the patient's glucose tolerance deteriorated after the temporary termination of cyclophosphamide treatment and the lowering of prednisolone dosage.
Abstract: A 45-year-old, non-obese female patient with no previous history of insulin administration was found to have extreme insulin resistance and abnormally high plasma immunoreactive insulin in the absence of anti-insulin antibodies in the serum. Clinically, there was no ketonuria. The patient also had evidence of Sjogren's syndrome with several immunologic features including hypergammaglobulinemia, positive antinuclear antibodies, accelerated erythrocyte sedimentation rate and leukopenia. Plasma pancreatic glucagon and C-peptide were elevated, but other endocrinologic abnormalties were not present. In this patient the insulin resistance appeared to be due to anti-insulin receptor antibodies which could be detected even in 1:500 dilution of serum. Immunosuppressive therapy with prednisolone and cyclophosphamide resulted in a decreased level of serum gamma globulin and a concomitant decrease of blood glucose level. After immunosuppressive therapy for eight months, the diabetic syndrome disappeared completely and anti-receptor antibodies in the serum were no longer detectable. Furthermore, insulin sensitivity returned to normal. However, the patient's glucose tolerance deteriorated after the temporary termination of cyclophosphamide treatment and the lowering of prednisolone dosage.
56 citations
TL;DR: Evidence of oppositely directed, simultaneous changes in glucagon and insulin receptor binding in partially nephrectomized rats is provided, which may account for the hypersensitivity to glucose and contribute to resistance to insulin observed in the glucose intolerance of uremia.
Abstract: To investigate the role of glucagon and insulin receptor binding in the glucagon hypersensitivity and insulin resistance which characterize the glucose intolerance of uremia, liver plasma membranes were prepared from control rats (blood urea nitrogen [BUN] 15+/-1 mg/100 ml, creatinine 0.7+/-0.2 mg/100 ml), and from 70% nephrectomized rats (BUN 30+/-2 mg/100 ml, creatinine 2.2+/-0.2 mg/100 ml), and from 90% nephrectomized rats (BUN 46+/-3 mg/100 ml, creatinine 4.20+/-0.7 mg/100 ml), 4 wk after surgery. As compared to controls, the 90% nephrectomized rats had significantly higher levels of plasma glucose (95+/-4 vs. 125+/-11 mg/100 ml), plasma insulin (28+/-9 vs. 52+/-11 muU/ml), and plasma glucagon (28+/-5 vs. 215+/-18 pg/ml). Similar, but less marked, elevations were observed in the 70% nephrectomized animals. In liver plasma membranes from nephrectomized rats, specific binding of (125)I-glucagon was increased by 80-120%. Furthermore, glucagon (2 muM)-stimulated adenylate cyclase activity in nephrectomized rats was twofold higher than in controls. In contrast, fluoridestimulated adenylate cyclase activity was similar in both groups of rats. In marked contrast to glucagon binding, specific binding of (125)I-insulin to liver membranes from nephrectomized rats was reduced by 40-50% as compared to controls. Data analysis suggested that the changes in both glucagon and insulin binding are a consequence of alterations in binding capacity rather than changes in affinity. Liver plasma membranes from nephrectomized rats degraded (125)I-glucagon and (125)I-insulin to the same extent as control rats. THESE RESULTS DEMONSTRATE THAT: (a) the 70 and 90% nephrectomized rats simulate the hyperglycemia, hyperinsulinemia, and hyperglucagonemia observed in clinical uremia; (b) in these animals specific binding of glucagon to liver membranes is increased and is accompanied by higher glucagon-stimulated adenylate cyclase activity; and (c) specific binding of insulin is markedly decreased. These findings thus provide evidence of oppositely directed, simultaneous changes in glucagon and insulin receptor binding in partially nephrectomized rats. Such changes may account for the hypersensitivity to glucagon and may contribute to resistance to insulin observed in the glucose intolerance of uremia.
53 citations
TL;DR: It is suggested that chicken cells are equipped with insulin receptors which are less numerous than in mammalian cells, which may explain, partly at least, the physiological state of insulin resistance observed in the chicken.
Abstract: Specific binding of chicken and porcine insulin was demonstrated in isolated chicken hepatocytes, chicken liver plasma membranes and chicken erythrocytes. In the liver, the binding reaction was characterized by a sensitivity and an apparent affinity which were similar to those observed in rat liver and, in contrast, by a decreased number of binding sites. In chicken liver, there were about 5 times fewer binding sites per mg of membrane protein or per unit of cell surface area than in rat liver. In chicken erythrocytes, the number of insulin binding sites per cell was even lower than in chicken hepatocytes. This decreased insulin binding was not accounted for by a faster insulin degradation in chicken tissues. Glucagon binding sites also appeared to be less numerous in chicken than in rat liver, at least at low glucagon concentration; however, the decrease in maximal binding capacity in chicken liver involved insulin and not glucagon binding. That chicken cells are equipped with insulin receptors which are less numerous than in mammalian cells may explain, partly at least, the physiological state of insulin resistance observed in the chicken.
TL;DR: D-fructose exerts beneficial effects as a component of diets for mild and well-balanced diabetes, but should be taken within caloric restriction, as obesity impairs D-glucose tolerance and increases the insulin resistance of peripheral tissue.
Abstract: Publisher Summary Crystalline D-fructose is produced and offered as an unusually sweet sugar and also a beneficial sweetening agent for people with certain ailments or for athletes in whom it is said to provide quick energy. This chapter provides an overview of the literature on the metabolism of D-fructose. D-fructose in the human diet is derived mainly from sucrose, fruits, and honey. Liver is the principal site of D-fructose metabolism. D-fructose is transported to the liver from the small intestine by way of the portal blood-vessel. D-fructose transport values suggest that, at physiological D-fructose concentrations, membrane transport limits the rate of uptake, thereby protecting the liver from severe depletion of adenine nucleotide. It is noted that same pathway is followed for D-fructose metabolism in liver, intestine, and kidney. D-fructose exerts beneficial effects as a component of diets for mild and well-balanced diabetes, but should be taken within caloric restriction, as obesity impairs D-glucose tolerance and increases the insulin resistance of peripheral tissue. D-fructose lessens dental plaque and results in fewer caries than sucrose.
TL;DR: While increased plasma concentrations of cortisol and free fatty acids may be involved in the maintenance of IR during DKA, elevated levels of plasma growth hormone and glucagon are not necessary for this phenomenon.
Abstract: It has been generally accepted that insulin resistance (IR) exists in diabetic subjects during episodes of ketoacidosis (DKA). However, little experimental data exist regarding this question. We have studied IR in nine untreated diabetic subjects (mean age 20 yr) both during their initial episode of DKA and after 2–7 wk of insulin therapy. The experimental protocol consisted of a 150-min intravenous infusion of glucose (6 mg/kg/min) and insulin (80 mU/min). Under these conditions steady-state plasma glucose (SSPG) and insulin (SSPI) levels were reached by 90 min and maintained for the duration of the study. Since all subjects achieved similar SSPI and all received the same glucose load, the SSPG could be used as a measure of an individual's IR. In addition, steady-state plasma levels of glucagon, cortisol, growth hormone, and free fatty acids were measured in an attempt to gain insight into their roles in the maintenance of IR during DKA. Although mean (± SE) SSPI levels were the same during both study periods (93 ± 4 versus 92 ± 4 μU/ml), there was a marked difference between the initial and posttherapy SSPG levels for the nine subjects 342 ± 32 versus 104 ± 16 mg/100 ml,p < .001). Mean steady-state plasma levels of growth hormone, corticol, and free fatty acids were significantly higher during the initial studies, but only cortisol and free fatty acid levels correlated significantly with their corresponding SSPG levels. Steady-state plasma glucagon levels were the same during both study periods, and individual levels did not correlate with associated SSPG levels. These studies demonstrate that significant IR was present in these subjects during DKA as compared to the posttherapy period. Furthermore, the results suggest that while increased plasma concentrations of cortisol and free fatty acids may be involved in the maintenance of IR during DKA, elevated levels of plasma growth hormone and glucagon are not necessary for this phenomenon.
TL;DR: It is suggested that diabetes mellitus occurs frequently in patients with thalassemia on HTP and that insulin resistance and hyperglucagonemia, possibly due to cirrhosis, are important etiologic factors.
Abstract: To investigate the development of diabetes mellitus in patients with thalassemia major, plasma glucose and immunoreactive insulin (IRI) levels following oral glucose and intravenous tolbutamide and glucose disappearance rates following intravenous insulin were measured in 10 patients before and during five years on a high transfusion program (HTP). Plasma immunoreactive glucagon (IRG) levels following oral glucose, intravenous insulin, and arginine were measured during the sixth year. Serial percutaneous liver biopsies were performed on seven patients. The oral glucose tolerance tests (OGTT) and mean peak IRI levels were normal in nine of 10 patients before HTP. After HTP was begun a progressive deterioration of OGTT occurred despite normal IRI levels. Following tolbutamide, the mean per cent fall in plasma glucose in the patients before HTP was significantly less than in controls (p Of seven survivors after six years of HTP, three had normal OGTT and four had chemical diabetes; mean peak IRI levels were normal, but fasting IRG levels were significantly higher than in controls (p These data suggest that diabetes mellitus occurs frequently in patients with thalassemia on HTP and that insulin resistance and hyperglucagonemia, possibly due to cirrhosis, are important etiologic factors.
TL;DR: It is suggested that no abnormality exists in the insulin receptor in myotonic dystrophy, and insulin resistance is not suspected.
Abstract: Insulin binding was studied using circulating monocytes obtained from seven patients with myotonic dystrophy and seven control subjects. During an oral glucose tolerance test the 2 h plasma glucose value was significantly higher in patients with myotonic dystrophy compared to controls, and 5 out of the 7 patients demonstrated hyperinsulinemia. This combination of abnormal glucose tolerance and hyperinsulinemia suggests insulin resistance. There was no difference in insulin binding to monocyte receptors between the two groups. These results suggest that no abnormality exists in the insulin receptor in myotonic dystrophy.
TL;DR: It is suggested that desensitization therapy for insulin allergy can lead to insulin resistance of the immune type.
TL;DR: Diaphragms from burned rats showed the same increase in glucose uptake in response to 0.1 U insulin/ml in vitro as those of controls, suggesting that the insulin resistance in vivo is not due to a decrease in the capacity of muscle to bind and respond to insulin.
Abstract: Alteration in the insulin regulation of carbohydrate metabolism following 20% surface burn injury in the rat was biphasic. At 4 hr after burn there was fasting hyperglycemia (92 +/- 6 (SE) mg/100 ml above controls) and a pronounced intolerance to 1 gm glucose/kg IV. Fasting serum insulin did not differ from controls and failed to rise appreciably following glucose administration. Two to four days after burn, the ability to cope with exogenous glucose was near normal or normal and the insulin response to standard glucose load was 41-69% higher than in the controls, indicating the presence of insulin resistance. This pattern was not altered by feeding the burned and control rats with glucose intragastrically, thus eliminating lower postburn food intake as the causal factor of exaggerated insulin response to IV glucose. Diaphragms from burned rats showed the same increase in glucose uptake in response to 0.1 U insulin/ml in vitro as those of controls, suggesting that the insulin resistance in vivo is not due to a decrease in the capacity of muscle to bind and respond to insulin.
TL;DR: A constant and important hyperinsulinism, fasting and postabsorptive, is demonstrated in obese children of all ages, even before five years and at the beginning of obesity, suggesting that hyperinsulinemia is associated with obesity from its onset rather than being a long-term consequence of overweight.
Abstract: In 158 obese children, aged from three months to 15 years, blood glucose, immunoreactive insulin, and free fatty acid levels were measured during a standard oral glucose tolerance test carried out prior to treatment. The results were analyzed for the total sample as well as for three age groups: 0–5 years, 6–10 years, and 11–15 years and compared with those of 70 normal-weight children matched for age and sex. Glucose tolerance is normal in the obese children. It is different from the controls only two hours after glucose loading, when a slight but significant elevation is found. The glucose levels at one and two hours are significantly higher in the obese children of group III than in the younger ones. Fasting F.F.A. levels are similar in normal and obese children, but the F.F.A. decrease following glucose absorption is significantly diminished in the obese. The F.F.A. levels of the youngest obese are significantly higher than those of the older ones. A constant and important hyperinsulinism, fasting and postabsorptive, is demonstrated in obese children of all ages, even before five years and at the beginning of obesity. Age- and sex-related differences in insulin secretion are much more marked in the obese than in normal children. The degree of hyperinsulinemia is related to the degree of obesity, but not to its duration. The results suggest that hyperinsulinism is associated with obesity from its onset rather than being a long-term consequence of overweight. However, the origin of hyperinsulinism in obesity and the mechanism of insulin resistance still remain obscure.
TL;DR: It is suggested that a relative excess of anti-insulin IgE may be associated with the insulin allergic state.
Abstract: Anti-insulin IgE and IgG were estimated in sera of diabetic patients. Using a paper radioimmunosorbent technique, detectable titers of anti-insulin IgE were found in all insulin-treated diabetics who were non-allergic to insulin. Patients with generalized insulin allergy, and immune-type insulin-resistance had higher titers of anti-insulin IgE. Anti-insulin IgG was present in all insulin-treated patients. The titers were significantly higher in insulin-resistant diabetics. Four of the 12 cases with insulin allergy had undetectable anti-insulin IgG titers. The ratios of 125I-insulin bound by IgE and IgG were significantly higher in 11 (91%) patients with systemic insulin-allergy. It is suggested that a relative excess of anti-insulin IgE may be associated with the insulin allergic state.
TL;DR: It is concluded that the impaired carbohydrate metabolism seen in MD is due to peripheral insulin resistance affecting various organs including the liver and it is suggested that the excessive beta-cell response is secondayr to the peripheral resistance.
Abstract: Carbohydrate metabolism was studied in fourteen patients with myotonia dystrophica (MD) using oral glucose, fructose and galactose tolerance tests. Insulin responses to tolbutamide, glucagon, arginine and leucine were determined and insulin resistance was measured with exogenous iv insulin. Glucose tolerance was impaired in twelve of the fourteen subjects while hyperinsulinism was found in all patients studied. Insulin response to the various substances was excessive. The insulin tolerance test revealed insulin resistance in all patients and this generally correlated well with the degree of hyperinsulinism to provocative tests. Serum galactose levels after an oral load were much lower in MD compared to normal subjects and were associated with a correspondingly greater rise in glucose, indicating an increased conversion of galactose to glucose. A similar response to oral galactose was found in diabetics. The hyperinsulinism seen with the fructose and galactose tests corresponded well to the rise in glucose...
TL;DR: Response to the endotoxin, Pseudomonas polysaccharide, (Piromen®) was used as a model for infection induced insulin resistance in seven control subjects and seven juvenile diabetics.
Abstract: Response to the endotoxin, Pseudomonas polysaccharide, (Piromen®) was used as a model for infection induced insulin resistance in seven control subjects and seven juvenile diabetics. All subjects had iv GTTs with measurement of several glucoregulatory hormones on 3 successive days: GTT–1; GTT–2, 3 h after Piromen (0.6 µg/kg), and GTT–3. A continuing iv infusion delivering 0.5 to 4.0 units of regular insulin/h was given to the diabetic subjects throughout the entire study period. Doses were adjusted so as to maintain mean plasma glucose concentrations between 120 and 220 mg/dl. However, the insulin infusion dose during each iv GTT was kept constant at 0.5 units/h. Following endotoxin the control subjects developed fasting hyperglycemia, mild glucose intolerance, basal and glucose stimulated hyperinsulinemia, hyperglucagonemia, and elevated plasma levels of growth hormone, ACTH, and cortisol. In the diabetic subjects given endotoxin, basal glucose values and those following iv GTT–2 were unchanged from comp...
TL;DR: The results suggest that therapeutic weight reduction not only reverses insulin resistance but also restores beta cell sensitivity and enhances beta cell capacity.
Abstract: A patient with obesity and diabetes mellitus had insulin secretion studies done during a 3-year cycle of weight loss and regain in the course of which she progressed from frank diabetes to a normal state of carbohydrate tolerance and then back to her original diabetic state. The results suggest that therapeutic weight reduction not only reverses insulin resistance but also restores beta cell sensitivity and enhances beta cell capacity. The eventual re-establishment of a degree of obesity, hyperinsulinemia, and carbohydrate intolerance virtually identical to that originally seen is compatible with a primary disorder involving hypothalamic control of adipose stores and insulin secretion.
TL;DR: Findings indicate that there is not a basic defect in insulin receptors of LD patients, and a secondary disruption of binding, e.g. by a circulating factor, remains possible.
Abstract: Confluent fibroblasts were assayed for insulin binding to determine whether there was an inherent abnormality in receptor function to explain the insulin resistance of lipoatrophic diabetes (LD). Cells from three patients and four controls were compared for confluent density, receptor saturation, specific and non-specific binding and the concentration of unlabelled hormone producing 50% competition for binding with labelled ligand. Cells from patients with LD did not differ significantly in any of these characteristics from the controls. These findings indicate that there is not a basic defect in insulin receptors of LD patients. A secondary disruption of binding, e.g. by a circulating factor, remains possible.
TL;DR: There was no correlation between age and the height of the plasma glucose response to an oral glucose challenge in this population of nonobese, healthy ambulatory men.
Abstract: The relationship of age to insulin resistance was determined in 100 nonobese men whose ages ranged from 22 to 69 years. Seventy of the 100 subjects had normal glucose tolerance, and 30 had chemical diabetes. Insulin resistance was estimated by measuring the steady-state plasma glucose response to a continuous infusion of insulin, glucose, epinephrine, and propranolol. This approach permitted inhibition of endogenous insulin release, achievement of a comparable steady-state plasma level of exogenous insulin, and use of the height of the steady-state plasma glucose response as a direct estimate of insulin resistance. With this experimental method, no correlation was found between age and insulin resistance over the age span of the experimental population. Furthermore, there was no correlation between age and the height of the plasma glucose response to an oral glucose challenge in this population of nonobese, healthy ambulatory men.
TL;DR: The pharmacologic and physiologic basis for different modes of insulin therapy are examined, the results of some recent studies are reviewed, and some general recommendations concerning insulin administration in the uncontrolled diabetic state are made.
Journal Article•
TL;DR: The voracious hunger and profuse perspiration were reduced, the patient's serum lipids became normal, her blood glucose fell, and her sensitivity to exogenous insulin increased.
Abstract: Congenital generalized lipodystrophy is considered to be a diencephalic syndrome with disturbance of hypothalamic transmitters. After puberty and arrest of growth the patients develop a serious untreatable diabetes mellitus. One of our patients, a girl 15 years of age, developed a lipodystrophic diabetes with fasting blood glucose levels above 300 mg/100 ml, increased serum insulin with insulin resistance, and hyperlipidaemia. Daily administration of fenfluramine gave a dramatic improvement. The voracious hunger and profuse perspiration were reduced, the patient's serum lipids became normal, her blood glucose fell, and her sensitivity to exogenous insulin increased. A normalization of the urinary excretion of the serotonin metabolite, 5-OH-indole acetic acid, was observed.
TL;DR: The binding of insulin to human circulating monocytes, although reflective of insulin resistance in diabetes mellitus and obesity, may not be to traditional receptors, and the binding of glucagon to lymphocyte/monocyte mixtures may be to function-linked receptors.
TL;DR: It is concluded that the gestagenic compounds tested decrease insulin receptor concentration, and only drastic reduction of the number of binding sites results in significant perturbations of carbohydrate metabolism.
Abstract: Specific insulin receptors were measured in isolated fat cells of rats after treatment with clomegestone acetate. Under conditions when peripheral insulin insensitivity was observed, the number of insulin receptors was simultaneously reduced. A similar though smaller decrease in insulin receptor concentration was seen in rats after treatment with cyproterone acetate, a compound which did not cause insulin resistance. It is concluded that the gestagenic compounds tested decrease insulin receptor concentration. Only drastic reduction of the number of binding sites results in significant perturbations of carbohydrate metabolism.
TL;DR: It is suggested that the coexistence of fasting and metabolic acidosis led to increased renal gluconeogenesis in rats subjected to bilateral ureterotomy, and the combination of increased renal glucose production and insulin resistance was responsible for the development of fasting hyperglycemia.
Abstract: Rats which had been fasted for the previous 24 hr were subjected to either sham surgery, bilateral nephrectomy, or bilateral ureterotomy. The fast was continued for another 24 hr before the animals were decapitated and blood was obtained for determination of serum glucose, insulin, and urea nitrogen levels. A moderate but statistically significant (p < 0.02) fall in serum glucose levels occurred in rats made uremic by bilateral nephrectomy. In contrast, rats made equally uremic by bilateral ureterotomy developed a significant (p < 0.001) elevation of both serum glucose and insulin levels. The combination of hyperglycemia and hyperinsulinemia suggested that insulin resistance had developed in these rats, and this was confirmed by demonstrating that the hypoglycemic effect of exogenously administered insulin was attenuated in rats following bilateral ureterotomy as compared to sham-operated rats. Unilateral ureterotomy did not lead to the same metabolic response, and the difference in serum glucose levels between sham-operated and bilaterally ureterotomized rats disappeared when a 5% glucose solution was substituted for tap water as the rat's drinking water. It is suggested that the coexistence of fasting and metabolic acidosis led to increased renal gluconeogenesis in rats subjected to bilateral ureterotomy, and the combination of increased renal glucose production and insulin resistance was responsible for the development of fasting hyperglycemia.
TL;DR: After injury the concentration of intracellular glucose was increased, and positively correlated with that in plasma, showing that the loss of sensitivity to insulin after injury is due to impairment of an intrACEllular metabolic step.
Abstract: Intracellular glucose concentrations in skeletal muscle have been measured in normal and injured rats individually infused with 51Cr-EDTA as an extracellular space marker. In normal rats, even when infused with glucose at a high rate, membrane transport appeared to be the rate-limiting step in glucose utilization by muscle. After injury the concentration of intracellular glucose was increased, and positively correlated with that in plasma, showing that the loss of sensitivity to insulin after injury is due to impairment of an intracellular metabolic step-