Showing papers on "Insulin resistance published in 1974"

Effects of Weight Reduction on Obesity STUDIES OF LIPID AND CARBOHYDRATE METABOLISM IN NORMAL AND HYPERLIPOPROTEINEMIC SUBJECTS

Abstract: Considerable controversy exists over the purported role of obesity in causing hyperglycemia, hyperlipemia, hyperinsulinemia, and insulin resistance; and the potential beneficial effects of weight reduction remain incompletely defined. Hypertriglyceridemia is one of the metabolic abnormalities proposed to accompany obesity, and in order to help explain the mechanisms leading to this abnormality we have proposed the following sequential hypothesis: insulin resistance --> hyperinsulinemia --> accelerated hepatic triglyceride(TG) production --> elevated plasma TG concentrations. To test this hypothesis and to gain insight into both the possible role of obesity in causing the above metabolic abnormalities and the potential benefit of weight reduction we studied the effects of weight loss on various aspects of carbohydrate and lipid metabolism in a group of 36 normal and hyperlipoproteinemic subjects. Only weak to absent correlations (r = 0.03 - 0.46) were noted between obesity and the metabolic variables measured. This points out that in our study group obesity cannot be the sole, or even the major, cause of these abnormalities in the first place. Further, we have observed marked decreases after weight reduction in fasting plasma TG (mean value: pre-weight reduction, 319 mg/100 ml; post-weight reduction, 180 mg/100 ml) and cholesterol (mean values: pre-weight reduction, 282 mg/100 ml; post-weight reduction, 223 mg/100 ml) levels, with a direct relationship between the magnitude of the fall in plasma lipid values and the height of the initial plasma TG level. We have also noted significant decreases after weight reduction in the insulin and glucose responses during the oral glucose tolerance test (37% decrease and 12% decrease, respectively). Insulin and glucose responses to liquid food before and after weight reduction were also measured and the overall post-weight reduction decrease in insulin response was 48% while the glucose response was relatively unchanged. In a subgroup of patients we studied both the degree of cellular insulin resistance and the rate of hepatic very low density (VLDL) TG production before and after weight reduction. These subjects demonstrated significant decreases after weight reduction in both degree of insulin resistance (33% decrease) and VLDL-TG production rates (40% decrease). Thus, weight reduction has lowered each of the antecedent variables (insulin resistance, hyperinsulinemia, and VLDL-TG production) that according to the above hypothesis lead to hypertriglyceridemia, and we believe the overall scheme is greatly strengthened. Furthermore, the consistent decreases in plasma TG and cholesterol levels seen in all subjects lead us to conclude that weight reduction is an important therapeutic modality for patients with endogenous hypertriglyceridemia.

Hyperinsulinemia in pre-weaning diabetes (db) mice

Abstract: Two new strains of diabetes mice (C57BL/ KsJ-m db and C57BL/6J-m db) have been developed with diabetes (db) and the closely linked misty (m) gene coupled on the same chromosome. This permits identification of diabetes mice (m db/m db) by their gray coat color and white feet as early as age 4 days, well before obesity or signs of diabetes are visible. Hyperinsulinemia was evident in diabetes mice of both strains at 10 days of age and the severity increased progressively with age. These elevated concentrations of plasma insulin were associated with mild hypoglycemia. No significant differences were observed with respect to the degrees of hyperinsulinemia or hypoglycemia between diabetes mice of the two strains. The mild hypoglycemia observed in diabetes mice in the presence of a pronounced hyperinsulinemia suggests that insulin resistance occurs as early as age 10 days and may itself be a factor in causing hyperinsulinemia. The sequence of early events occurring in diabetes mice appears to be hyperinsulinemia leading to mild hypoglycemia, followed by compensatory hyperphagia which in turn results in enhanced insulin secretion and obesity.

Treatment of Severe Diabetes Mellitus by Insulin Infusion

Abstract: A new and simple form of insulin therapy for diabetic hyperglycaemia and ketoacidosis has been developed using a continuous intravenous infusion of insulin at a rate of 2·4 U/hr to maintain serum insulin concentration at physiological levels. This rate raises the mean serum insulin to 83 μU/ml and has a therapeutic effect which is not augmented by higher infusion rates. The response to such low doses of insulin indicates a need for a reappraisal of currently held theories about insulin resistance in diabetic ketoacidosis. In 11 diabetic patients with a mean plasma glucose of 514 mg/100 ml this therapy produced continuous falls in plasma glucose at a mean rate of 75 mg/100 ml/hr, and 10 out of 11 patients recovered within eight hours. This form of therapy is simple to institute, not complicated by hypoglycaemia, and avoids the confusion and empiricism of previously described forms of therapy.

Further Evidence that Insulin Resistance Exists in Patients with Chemical Diabetes

Abstract: Insulin resistance was estimated in fifty nonobese subjects who were classified as normal (thirty subjects) or as having chemical diabetes (twenty subjects) on the basis of a standard oral glucose tolerance test. Insulin resistance was determined by administering a constant intravenous infusion of epinephrine, propranolol, glucose and exogenous insulin to each subject for 150 minutes and by measuring the resultant steady state plasma glucose levels attained during the last sixty minutes. Under these conditions, endogenous insulin secretion and hepatic glucose output are suppressed, and similar steady state plasma levels of the exogenously infused insulin are achieved in all subjects. Since all patients are challenged with comparable glucose loads, the height of the steady state plasma glucose response becomes a direct measure of an individual9s resistance to insulin-mediated glucose uptake. With this approach we found that the mean (± S.E.) steady state plasma glucose level in patients with chemical diabetes was 224 ± 15 mg. per 100 ml. as compared to 126 ± 12 mg. per 100 ml. in control subjects. This difference was statistically significant ( p

Diurnal variation in response to intravenous glucose.

Abstract: Intravenous glucose tolerance tests (25 g) were performed in the morning and afternoon on 13 apparently normal persons. The individual K values (rate of decline of blood sugar) were all higher in the morning tests, and the mean values were significantly higher in the morning. Fasting blood sugar levels were slightly lower in the afternoon. There was no difference between the fasting morning and afternoon plasma insulin levels, but the levels after glucose were lower in the afternoon. Growth hormone levels were low at all times in non-apprehensive subjects and unaffected by glucose. The results suggest that the impaired afternoon intravenous glucose tolerance, like oral glucose tolerance, is associated with impaired insulin release and insulin resistance.

Insulin resistance, skin changes, and virilization: a recessively inherited syndrome possibly due to pineal gland dysfunction.

Abstract: A syndrome of glucose intolerance associated with hyperinsulinaemia and insulin resistance, skin changes, and mild virilization occurred in two daughters of a first-cousin marriage. The condition is probably inherited as an autosomal recessive trait. It is likely to represent a widespread disturbance in neuro-endocrine control; the primary metabolic error may involve pineal, virilization.

Enlargement of epididymal adipocytes in relation to hyperinsulinemia in obese hyperglycemic mice (ob-ob).

Abstract: The diameters of epididymal fat cells of 12–17-day-old obese and normal littermates were compared following operative removal of the epididymal fat body. The animals were kept alive and checked for obesity at an age of 6 wk. Fat cells of the genetically obese mice began their fast growth between day 12 and day 14. At this age, it is possible to identify on the basis of fat-cell diameters three classes, representing +/+, ob/+, and ob ob , respectively, which shows that the ob allel is incompletely dominant. Measurements of the plasma-insulin concentration revealed that hyperinsulinemia, which is characteristic for the obese hyperglycemic syndrome, is not manifested before the beginning of the fourth week. Since hyperinsulinemia becomes evident at a later stage in development than the rapid increase in growth rate of the fat cells, it seems that the insulin resistance and the hyperinsulinemia cannot be the primary cause of the enlargement of the epididymal adipocytes.

The Kinetics of Plasma Free Fatty Acid and Triglyceride Transport in Patients with Idiopathic Hypertriglyceridaemia and Their Relation to Carbohydrate Metabolism

Abstract: . Plasma free fatty acid and triglyceride transport kinetics were assessed in 20 patients with idiopathic hypertriglyceridaemia. None of these patients had abnormal glucose tolerance. They included 10 patients in whom the serum triglyceride elevation was due to an increase in the circulating VLDL (Fredrickson Type IV) and 10 in whom the increase in plasma VLDL was associated with hyperchylomicronaemia (Fredrickson Type V). These were compared with a control group of 27 normal subjects.–Increased plasma triglyceride turnover with normal clearance was observed in the Type IV patients suggesting that the hypertriglyceridaemia in these patients was predominantly due to enhancement of plasma triglyceride production. The plasma triglyceride concentration correlated closely with the changes in triglyceride turnover rate.–Studies performed in the Type V patients showed an increase in the plasma triglyceride turnover rate in only 3 subjects, while in the remaining patients the turnover values were similar to those of the control subjects. The increase in serum triglyceride concentration found in some of the patients was due to an increase in plasma triglyceride production. However, in the majority of patients in this group impairment of plasma triglyceride clearance was the predominant abnormality.–In both hypertriglyceridaemic groups the plasma FFA flux was markedly increased and correlated significantly with the degree of hypertriglyceridaemia. The increase in triglyceride turnover observed in Type IV patients and some of the Type V patients correlated closely with the enhancement of plasma FFA flux suggesting that the increase in triglyceride production in these patients was secondary to enhanced lipolysis.–The plasma insulin response to an oral glucose load was markedly increased in both groups of hypertriglyceridaemic patients and correlated significantly with the elevation in serum triglyceride concentration. The plasma insulin response also correlated with the plasma free fatty acid turnover.–The results suggest that the initial lesion in these patients was related to insulin unresponsiveness in adipose tissue resulting in enhanced lipolysis with secondary changes in insulin secretion and plasma triglyceride transport kinetics.

Metabolism of genetically obese rats on normal or high-fat diet

Abstract: Adult genetically obesefafa rats showed a high level of lipogenesis from glucose in liver but not in adipose tissue; pancreatic content and serum levels of insulin were elevated. Glucose uptake and insulin sensitivity were decreased in muscle,fafa rats and their lean littermates fed a high-fat diet showed increased fat deposits. Serum insulin levels were not significantly affected by diet in either group. The larger the fat cells were, the more actively they utilised glucose; insulin sensitivity was influenced both by diet and cell size. Control rats made obese by a high caloric diet did not show insulin resistance in muscle. — The data indicate that in adult obesity in these rats, even in the presence of marked hyperinsulinism, increased lipogenesis in adipose tissue is not a prerequisite. Rather, fat storage is a consequence of increased uptake of circulating triglycerides. On a diet rich in carbohydrate, adipose tissue fatty acids were mainly of hepatic origin; on a high-fat diet they were of dietary origin.

The autoregulation of insulin secretion in the isolated pancreatic islets of lean (obOb) and obese-hyperglycemic (obob) mice.

Abstract: The autoregulation of insulin secretion was studied using perifused and incubated pancreatic islets of normal (obOb) mice and of their obese-hyperglycemic (obob) littermates. Islets secreted more insulin when they were perifused than when they were incubated and insulin was allowed to accumulate in the medium. When rat insulin was added to the incubation medium in the concentration of 250 μU/ml, the secretory activity of the normal islets was suppressed almost completely. The concentration of exogenous insulin required to inhibit the islets of obese mice was higher and increased with the age of the animals, until it reached a value that was 20 to 30 times greater than that found in the circulating blood. Similar concentrations may well exist in the extracellular fluid of the pancreatic islets. It is possible that while insulin resistance of the peripheral tissues may be responsible for the hyperglycemia of the obob mice, the progressive loss of insulin sensitivity of their pancreatic islets and, consequently, of the normal autoregulation of insulin secretion, may play a role in the progressive hyperinsulinism and, hence, of the obesity characteristic of these animals.

Chronic tissue insulin resistance following hemorrhagic shock.

Abstract: Metabolism of fat and muscle tissue was measured for 30 days following shock and reinfusion in rabbits. Tissue insulin resistance in the post-shock period was demonstrated by decreased oxidation of glucose and decreased incorporation of glucose into neutral lipid or glycogen during incubation with insulin. In addition, the insulin stimulated incorporation of amino acids into muscle protein was markedly reduced after shock. Conversely, the capacity of muscle to oxidize leucine was enhanced by shock, even in the presence of insulin. Tissue insulin resistance and increased leucine catabolism are likely to contribute to the general metabolic response to shock and trauma.

Insulin resistance in experimental shock.

Abstract: Previously adrenalectomized (ADX) rats were bled to a mean arterial pressure of 40 mm Hg and maintained for 1½ hours. Basal glucose uptake by isolated soleus muscle from ADX normal rats and ADX rats subjected to shock ("shock" muscles) increased with the increase in medium glucose concentration and uptake was similar in both groups of muscles. This indicates that shock per se did not produce any alterations in the basal glucose carrier mechanism. Insulin (0.1 unit/ml) increased uptake in ADX control but not in ADX shock muscles. Maximal stimulation of glucose uptake in shock muscles was observed at an insulin concentration of 0.2 unit/ml insulin. These experiments provide the first direct evidence that the responsiveness of tissues to insulin is altered during shock. This alteration could not be due to increased steroid or epinephrine output during shock.

A study of carbohydrate metabolism in postnecrotic cirrhosis of liver

Abstract: Intravenous glucose tolerance, insulin tolerance, tolbutamide, and glucagon tests were carried out in 21 patients with postnecrotic cirrhosis. Based arbitrarily on the bromsulphthalein retention they were divided into group A, nine patients with less impaired liver function, and group B, 12 patients with greater impairment of liver function. Intravenous glucose and insulin tolerances were reduced in both groups. The hypoglycaemic effect of tolbutamide was similar in the controls and in both groups of cirrhotic patients but this was achieved at higher plasma insulin levels in group B indicating resistance of the liver to the effect of endogenous insulin. The blood glucose response to glucagon was markedly impaired in group B patients which is consistent with this hypothesis. In contrast to the insulin response to glucose and tolbutamide, the insulin response to glucagon was reduced in the cirrhotic patients. Fasting human growth hormone and free fatty acid levels were elevated in both groups but they were not considered to be important factors in the production of insulin resistance.

Diabetes in Remission: Insulin Secretory Dynamics

Abstract: Insulin secretory capacity and sensitivity to exogenous insulin were examined in eight nonobese, ketosis-prone young diabetics at the time of a clinical remission during which they could be managed without any insulin therapy. The insulin secretory capacity of these patients was assessed with oral glucose, intravenous glucose and an oral mixed meal test. The insulin responses were variable and relatively subnormal compared to those in normal controls, but definite and substantial responses were found in the majority of the patients to all the stimuli. When small amounts of crystalline insulin were administered intravenously to produce peripheral venous insulin levels in the physiologic range, these patients responded with a normal decrease in blood glucose and plasma free fatty acid levels suggesting maintenance of in vivo insulin sensitivity. Since ketosis-prone, insulin-dependent diabetics are generally characterized by nearly complete failure of beta-cell function, the present finding supports the concept that clinical remission of diabetes is dependent on a functional recovery of the beta cell. Furthermore, it seems likely that no significant “insulin resistance” that often accompanies severe diabetes is present in this remission state.

Relationship Between Insulin Response During the Intravenous Glucose Tolerance Test, Rate of Fractional Glucose Removal and the Degree of Insulin Resistance in Normal Adults

Abstract: We studied the relationship between the absolute insulin response during the intravenous glucose tolerance test (IVGTT) and both the fractional glucose disposal rate (KG) during the IVGTT and the degree of insulin resistance as measured by a separate infusion study, the pancreatic suppression test (PST), in normal adults. Insulin response during the IVGTT was analyzed in four ways: (1) early (area under the one, three and five minute response curve); (2) middle (ten minute insulin value); (3) late (area under the twenty to sixty minute response curve); and (4) total (area under the entire response curve). Only weak to modest correlations existed between the four measures of insulin response and KG, and the only statistically significant correlation (r = .39, p < .05) existed between the middle insulin response and KG. However, significant correlations were found between the degree of insulin resistance measured during the PST and the early (r = .40, p < .05), middle (r = .59, p < .005), late (r = .71, p < .001) and total (r = .66, p < .001) insulin responses. Whereas the height of the insulin response during an IVGTT has only a modest correlation with the KG, it correlates quite well with the degree of insulin resistance.

Insulin secretion in malignant hyperpyrexia.

Abstract: An increased glucose-induced insulin response has been observed in patients susceptible to malignant hyperpyrexia. This raises the possibility that the membrane abnormality present in the calcium-storing membranes in the muscle cell in malignant hyperpyrexia may be present also in the beta cell of the pancreas.

The effect of oxytetracycline on insulin resistance in obese mice.

Abstract: 1. Chronic oxytetracycline treatment was found to improve the insulin resistance of the obese-hyperglycaemic mouse. 2. The improved response to insulin was accompanied by decreased concentrations of circulating insulin and glucose, by a decrease in the lipid content of the liver and by an increase in the insulin-receptor sites of the liver and adipose tissue. 3. The increase in insulin-receptor sites preceded the fall in blood glucose. 4. Comparable studies done on food-restricted animals indicated that although chronic food restriction corrected the hyperinsulinaemia it did not restore the insulin-receptor sites or the hyperglycaemia.

Immunogenicity of "single peak" beef-pork insulin in diabetic subjects.

Abstract: Highly purified insulins of the “single-component” or “monocomponent” varieties have been previously reported to be nonimmunogenic Since mass production of insulins with a high degree of purity is not convenient, a “single-peak” insulin with large molecular weight substances removed, has been developed in U-100 concentration To evaluate its immunogenicity, three groups of diabetic subjects were studied Seven patients previously untreated with insulin were given single-peak beef-pork insulin for forty-five to 435 days; in undiluted sera, insulin-I131 binding reached a mean of 18 per cent (range, 2 to 46 per cent) In comparison, fifteen diabetics treated with standard USP beefpork insulin for ninety days or more showed a mean insulin-I131 binding of 15 per cent (range, 35 to 38 per cent) Six patients who had received USP insulin were treated with the single-peak preparation Five of these had a mean insulin-I131 binding of 16 per cent (range, 2 to 38 per cent) before single-peak therapy and a mean binding of 27 per cent (range, 6 to 44 per cent) after treatment with single-peak insulin for 105 to 230 days The sixth patient had severe chronic insulin resistance and required up to 400 U per day of USP insulin; treatment with single-peak insulin for five weeks produced no fall in antibody titer, and insulin requirements remained high: an initial response to only 50 U per day of fish (bonito) insulin demonstrated that resistance was due to immunogenicity U-100 single-peak beef-pork insulin reduces lipoatrophy but does not appear to offer obvious immunologic advantages over standard USP insulin

Insulin, glucagon and growth hormone in primary adult myxoedema.

Abstract: Previous studies have shown that in patients with primary adult myxoedema (PAM) the rise in blood glucose (BG) and plasma insulin (IRI) after various stimuli is higher and more sustained than in normals, so that in this condition insulin resistance may be hypothesized. In the search for factors involved glucose (BG), insulin (IRI), glucagon (IRG), (assayed with an antiserum which is not specific for pancreatic glucagon) and growth hormone (GH), have been determined in blood during the oral glucose tolerance test, OGTT, (100 g), arginine intravenous infusion, ATT (30 g/30 min), and insulin-induced hypoglycemia, ITT (0.1 kg), in patients with PAM, without clinical diabetes, and in normal control subjects. During OGTT, glucose and IRI levels were higher than normal; on the other hand, IRG (probably gut glucagon, or enteroglucagon) levels were lower than in normals. During ATT blood glucose in PAM was slightly higher than normal at 30′ and lower at 90′ and 120′; insulin levels were higher than normal at any time; GH and IRG (very likely pancreatic glucagon, or nesidioglucagon) responses were lower than normal. During ITT, blood glucose levels dropped slowly but progressively and GH levels were lower than normal. It is concluded that in primary adult myxoedema glucagon, both enteric and pancreatic, and growth hormone secretions are impaired. The resistance to insulin action observed in PAM does not seem to be due to an excess of growth hormone or (nesidioglucagon).

Studies on the mechanisms of insulin resistance in childhood obesity

Abstract: We have shown that childhood obesity is associated with hyperinsulinemia involving the acute and chronic pools of insulin similarly. To define the mechanism(s) responsible for this, we have measured the response of plasma insulin, glucagon, growth hormone (GH) and free fatty acids (FFA) to various stimuli in 10 obese children and matched lean controls. To allow direct assessment of the uptake of glucose by peripheral tissue (impedance) we have utilized the technique of Shen (continuous infusions of glucose, insulin, epinephrine and propranolol) to suppress endogenous insulin secretion and hepatic glucose output. All patients had normal glucose tolerance. Basal insulin levels (94 vs. 10 μU/ml) and tissue impedance (247 vs. 86) were increased (p < 0.01) in obese patients. Younger obese children (3-6 yr.) had intermediate plasma insulin and tissue impedance values (30 and 168). The plasma glucagon and GH responses to arginine were blunted in obese patients. Fasting FFA and triglyceride (TG) levels and the FFA and TG responses to oral lipomul and heparin were similar in both groups. These studies demonstrate progressive impairment of glucose uptake by peripheral tissues in childhood obesity and suggest a basic tissue defect in carbohydrate metabolism.

Metabolic studies and autonomic function in children with partial lipodystrophy

Abstract: Studies of carbohydrate metabolism in 6 children with partial lipodystrophy (none of whom had evidence of renal disease) showed raised fasting serum insulin concentrations. In 4 of the children hyperinsulinaemia was found after oral glucose. Plasma glucose levels within the normal range in all tests indicated that the hyperinsulinaemia was due to insulin resistance. Plasma growth hormone concentration was normal in all children, and plasma cortisol concentration was normal in 5. Concentrations of plasma nonesterified fatty acid (NEFA), serum triglyceride, and cholesterol in fasting blood were normal. Adipose tissue from nondystrophic areas showed an increased proportion of palmitoleic acid. No abnormality of the autonomic nervous system was found. Treatment of 2 patients with propranolol did not improve their lipodystrophy. The metabolic abnormalities present at an early age of the disease show that partial lipodystrophy should not be regarded only as a cosmetic disorder.

Metabolic abnormalities in BHE rats.

Abstract: At age 50 days the “carbohydrate sensitive” BHE strain of rat showed hyperinsulinemia which gradually subsided toward normalcy at 10 months. Insulin resistance of adipose tissue and depletion of pancreatic insulin content were evident at age 5 months. The BHE rat showed a tendency to hyperlipemia which increased with age. Prior to the appearance of the hyperlipemia, the fasting sera contained pre-Β-lipoproteins. The conversion of glucose into lipidsin vivo was significantly higher in the hyperinsulinemic BHE rat than in the normoinsulinemic Wistar rat.

A Possible Role of Circulating Lipoprotein-Triglycerides in the Increase in Concentration of Free Fatty Acids and in Insulin Resistance in “Total” Lipodystrophy

Abstract: The mechanism responsible for the increase in concentration of free fatty acids in lipodystrophy was investigated in a 20-yr-old woman with a total absence of adipose tissues. The fasting concentration of plasma free fatty acid was not related to either the concentration of plasma glucose, immunoreactive insulin or growth hormone. The concentration of free fatty acid and glycerol did not increase significantly after the administration of norepinephrine. During a period on a high-fat diet the concentration of free fatty acids increased, and this was associated with an increase in the concentration of plasma triglycerides. The composition of free fatty acids in plasma closely resembled that of the plasma triglycerides. Post-heparin lipoprotein lipase activity was normal. It is suggested that circulating lipoprotein triglyceride was hydrolyzed by lipoprotein lipase on capillary surfaces at the peripheral sites and the resultant free fatty acids entered the circulation instead of being taken up by ad...

Effect of a low dose of alloxan on blood glucose, islet beta cell granulation, body weight, and insulin resistance of ob/ob mice

Abstract: The effects of a low dose of alloxan on the blood glucose, islet beta cell granulation, body weight, insulin resistance, glucose tolerance, and responses to fasting and growth hormone were studied inob/ob mice, which respond to a single low dose of alloxan with a rapid (24 h) and long-term (108 day) significant decrease in blood glucose levels, and increase in islet beta cell granulation. Three weeks after alloxan administration, insulin resistance is ameliorated in alloxan-treated obese mice whose body weight is not significantly different from their obese controls. A low dose of alloxan has a therapeutic influence on glucose management inob/ob mice: reduced glycemia, improved glucose tolerance, and increased tolerance to fasting. Growth hormone induces a similar hyperglycemic response in alloxan-treated and control