Showing papers on "Insulin resistance published in 1981"
TL;DR: The feasibility of the minimal model technique to determine the etiology of impaired glucose tolerance is demonstrated and it is demonstrated that subjects (regardless of weight) could be segregated into good and lower tolerance by the product of second-phase beta-cell responsivity and insulin sensitivity.
Abstract: The quantitative contributions of pancreatic responsiveness and insulin sensitivity to glucose tolerance were measured using the "minimal modeling technique" in 18 lean and obese subjects (88-206% ideal body wt). The individual contributions of insulin secretion and action were measured by interpreting the dynamics of plasma glucose and insulin during the intravenous glucose tolerance test in terms of two mathematical models. One, the insulin kinetics model, yields parameters of first-phase (phi 1) and second-phase (phi 2) responsivity of the beta-cells to glucose. The other glucose kinetics model yields the insulin sensitivity parameters, SI. Lean and obese subjects were subdivided into good (KG greater than 1.5) and lower (KG less than 1.5) glucose tolerance groups. The etiology of lower glucose tolerance was entirely different in lean and obese subjects. Lean, lower tolerance was related to pancreatic insufficiency (phi 2 77% lower than in good tolerance controls [P less than 0.03]), but insulin sensitivity was normal (P greater than 0.5). In contrast, obese lower tolerance was entirely due to insulin resistance (SI diminished 60% [P less than 0.01]); pancreatic responsiveness was not different from lean, good tolerance controls (phi 1: P greater than 0.06; phi 2: P greater than 0.40). Subjects (regardless of weight) could be segregated into good and lower tolerance by the product of second-phase beta-cell responsivity and insulin sensitivity (phi 2 . SI). Thus, these two factors were primarily responsible for overall determination of glucose tolerance. The effect of phi 1 was to modulate the KG value within those groups whose overall tolerance was determined by phi 2 . SI. This phi 1 modulating influence was more pronounced among insulin sensitive (phi 1 vs. KG, r = 0.79) than insulin resistant (obese, low tolerance; phi 1 vs. KG, r = 0.91) subjects. This study demonstrates the feasibility of the minimal model technique to determine the etiology of impaired glucose tolerance.
1,625 citations
TL;DR: The mechanisms of insulin resistance in Patients with impaired glucose tolerance and in patients with Type II noninsulin-dependent diabetes are complex, and result from heterogeneous causes.
Abstract: We have assessed the mechanisms involved in the pathogenesis of the insulin resistance associated with impaired glucose tolerance and Type II diabetes mellitus by exploring, by means of the euglycemic glucose-clamp technique, the in vivo dose-response relationship between serum insulin and the overall rate of glucose disposal in 14 control subjects; 8 subjects with impaired glucose tolerance, and 23 subjects with Type II diabetes. Each subject had at least three studies performed on separate days at insulin infusion rates of 40, 120, 240, 1,200, or 1,800 mU/M2 per min. In the subjects with impaired glucose tolerance, the dose-response curve was shifted to the right (half-maximally effective insulin level 240 vs. 135 microunits/ml for controls), but the maximal rate of glucose disposal remained normal. In patients with Type II diabetes mellitus, the dose-response curve was also shifted to the right, but in addition, there was a posal. This pattern was seen both in the 13 nonobese and the 10 obese diabetic subjects. Among these patients, an inverse linear relationship exists (r = -0.72) so that the higher the fasting glucose level, the lower the maximal glucose disposal rate. Basal rates of hepatic glucose output were 74 +/- 4, 82 +/- 7, 139 +/- 24, and 125 +/- 16 mg/M2 per min for the control subjects, subjects with impaired glucose tolerance, nonobese Type II diabetic subjects, and obese Type II diabetic subjects, respectively. Higher serum insulin levels were required to suppress hepatic glucose output in the subjects with impaired glucose tolerance and Type II diabetics, compared with controls, but hepatic glucose output could be totally suppressed in each study group. We conclude that the mechanisms of insulin resistance in patients with impaired glucose tolerance and in patients with Type II noninsulin-dependent diabetes are complex, and result from heterogeneous causes. (a) In the patients with the mildest disorders of carbohydrate homeostasis (patients with impaired glucose tolerance) the insulin resistance can be accounted for solely on the basis of decreased insulin receptors. (b) In patients with fasting hyperglycemia, insulin resistance is due to both decreased insulin receptors and postreceptor defect in the glucose mechanisms. (c) As the hyperglycemia worsens, the postreceptor defect in peripheral glucose disposal emerges and progressively increases. And (d) no postreceptor defect was detected in any of the patient groups when insulin's ability to suppress hepatic glucose output was measured.
663 citations
TL;DR: In this paper, the euglycemic insulin clamp technique was used to examine the tissue sensitivity to insulin in 17 chronically uremic and 36 control subjects, and the results indicated that hepatic glucose production was not impaired by uremia.
Abstract: Tissue sensitivity to insulin was examined with the euglycemic insulin clamp technique in 17 chronically uremic and 36 control subjects. The plasma insulin concentration was raised by approximately 100 microU/ml and the plasma glucose concentration was maintained at the basal level with a variable glucose infusion. Under these steady-state conditions of euglycemia, the glucose infusion rate is a measure of the amount of glucose taken up by the entire body. In uremic subjects insulin-mediated glucose metabolism was reduced by 47% compared with controls (3.71 +/- 0.20 vs. 7.38 +/- 0.26 mg/kg . min; P less than 0.001). Basal hepatic glucose production (measured with [3H]-3-glucose) was normal in uremic subjects (2.17 +/- 0.04 mg/kg . min) and suppressed normally by 94 +/- 2% following insulin administration. In six uremic and six control subjects, net splanchnic glucose balance was also measured directly by the hepatic venous catheterization technique. In the postabsorptive state splanchnic glucose production was similar in uremics (1.57 +/- 0.03 mg/kg . min) and controls (1.79 +/- 0.20 mg/kg . min). After 90 min of sustained hyperinsulinemia, splanchnic glucose balance reverted to a net uptake which was similar in uremics (0.42 +/- 0.11 mg/kg . min) and controls (0.53 +/- 0.12 mg/kg . min). In contrast, glucose uptake by the leg was reduced by 60% in the uremic group (21 +/- 1 vs. 52 +/- 8 mumol/min . kg of leg wt; P less than 0.005) and this decrease closely paralleled the decrease in total glucose metabolism by the entire body. These results indicate that: (a) suppression of hepatic glucose production by physiologic hyperinsulinemia is not impaired by uremia, (b) insulin-mediated glucose uptake by the liver is normal in uremic subjects, and (c) tissue insensitivity to insulin is the primary cause of insulin resistance in uremia.
578 citations
TL;DR: The aging process per se appears to have its own deleterious effect on tissue sensitivity to insulin, which probably contributes to the insulin resistance.
Abstract: Glucose tolerance is known to decrease with advancing age. This decline begins in the third or fourth decade of life and is progressive throughout the entire adult life span. The primary cause of this age-related impairment in glucose metabolism results from tissue unresponsiveness to insulin. The plasma insulin response to glucose shows little change with age. Several factors, including decreased physical activity and decreased lean body mass, probably contribute to the insulin resistance. The aging process per se, however, appears to have its own deleterious effect on tissue sensitivity to insulin.
380 citations
TL;DR: The results indicated that estimates of insulin resistance generated by the two methods were highly correlated and indicated that the greater the degree of glucose intolerance, the more severe the insulin resistance.
Abstract: Insulin resistance was quantified with two different methods in 30 subjects with varying degrees of glucose tolerance. One method, the insulin suppression test, is performed by continuously infusing epinephrine, propranolol, insulin, and glucose. Epinephrine and propranolol suppress endogenous insulin release, and steady-state plasma levels of exogenous insulin and glucose are reached in all individuals. Because the steady-state insulin level is the same in all subjects, the height of the steady-state plasma glucose level provides a direct estimate of insulin resistance. The other method, the euglycemic clamp technique, produces a steady-state level of exogenous hyperinsulinemia by means of a primed and continuous insulin infusion. Glucose is also infused at a rate sufficient to prevent an insulin-induced fall in glucose concentration, and the amount of glucose required to maintain the basal plasma glucose level provides the estimate of insulin resistance. The results indicated that estimates of insulin resistance generated by the two methods were highly correlated (r = 0.93). Furthermore, both methods of assessing insulin resistance indicated that the greater the degree of glucose intolerance, the more severe the insulin resistance. These results serve to further emphasize the importance of insulin resistance in the pathogenesis of hyperglycemia in type II diabetes.
377 citations
TL;DR: It is useful to categorize insulin resistance according to known etiologic mechanisms, and such a classification is presented in Table 1.
Abstract: Insulin is produced in the pancreatic B-cell as the primary biosynthetic product pre-proinsulin. This peptide is rapidly converted to proinsulin (MW ~ 9000) which is, in turn, converted to insulin (MW ~ 6000) plus C-peptide (MW ~ 3000) by specific proteolytic steps within the B-cell secretory granule. The normal secretory products are, therefore, insulin, an equimolar amount of C-peptide, and a small amount (~5%) of unconverted proinsulin. After a brief circulation time (t1/2 6-10 min) the hormone interacts with target tissues to exert its biologic effects. One of insulin's major biologic effects is to promote overall glucose metabolism, and abnormalities of this aspect of insulin action can lead to a number of important clinical and pathophysiologic states. Insulin resistance exists when a given, known quantity of insulin produces less than the normal expected biologic effect. Since insulin travels from the B-cell, through the circulation, to the target tissue, events at any one of these loci can influence the ultimate action of the hormone. Therefore, it is useful to categorize insulin resistance according to known etiologic mechanisms, and such a classification is presented in Table 1. Insulin resistance can be due to three general categories of causes: (1) an abnormal B-cell secretory product, (2) circulating insulin antagonists, or (3) a target tissue defect in insulin action. Within each of these categories, subclassifications exist.
343 citations
TL;DR: Mechanisms of insulin resistance can be evaluated by constructing in vivo dose-response curves using the euglycemic glucose clamp technique and a continuum of defects exists exists; in patients with mild insulin resistance, decreased numbers of insulin receptors and the postreceptor defect in insulin action coexist, but the postReceptor defect is the predominant abnormality.
327 citations
TL;DR: Both the spontaneous and experimental animal models have been used effectively to study the etiologies, complications, treatments and prevention of diabetes.
251 citations
TL;DR: Data indicate that nonobese subjects with normal TG levels have the same relationship between degree of insulin sensitivity, insulin response to food, VLDL-TG secretion, and TG concentration previously described in patients with endogenous hypertriglyceridemia.
Abstract: We have previously postulated that resistance to insulin-mediated glucose uptake was the basic metabolic abnormality in patients with endogenous hypertriglyceridemia. In this situation, glucose tolerance would tend to deteriorate, and could only be maintained by the increased secretion of insulin. Although the ensuing hyperinsulinemia might prevent the development of glucose intolerance, we suggested that it would also lead to increased hepatic very low density (VLDL) triglyceride (TG) synthesis and secretion. In the current study we have quantified these four metabolic variables in 16 nonobese human subjects with plasma TG concentrations insulin response to food VLDL-TG secretion rate plasma TG concentration. These data indicate that nonobese subjects with normal TG levels have the same relationship between degree of insulin sensitivity, insulin response to food, VLDL-TG secretion, and TG concentration previously described in patients with endogenous hypertriglyceridemia.
244 citations
TL;DR: The roles of insulin deficiency, insulin resistance, obesity, and genetic factors are discussed in relation to their effects on lipoprotein production and catabolism and improved glycemic control is effective in reducing triglyceride and cholesterol levels in insulin-deficient subjects.
Abstract: Hyperlipidemia is common in diabetic patients. While our understanding of lipid and lipoprotein metabolism in diabetes is incomplete, a pathophysiologic approach to this problem is presented. It is based on the recognition that diabetes is metabolically heterogeneous. Thus the roles of insulin deficiency, insulin resistance, obesity, and genetic factors are discussed in relation to their effects on lipoprotein production and catabolism. The most important defect in insulin-deficient subjects appears to be a deficiency of lipoprotein lipase, which is responsible for the removal of the triglyceride-rich lipoproteins. In non-insulin-dependent subjects there is evidence for a removal defect as well as, in some patients, for overproduction of VLDL-triglyceride. Cholesterol levels may be elevated and it is important to distinguish between VLDL, LDL, and HDL as the causes for these increases. HDL-cholesterol levels may be increased in insulin-dependent subjects, whereas they may be decreased in obese non-insulin-dependent patients. Mild elevations of LDL-cholesterol may occur in inadequately controlled type I and II diabetic patients, while elevated VLDL may raise the serum cholesterol in addition to the triglyceride levels. The rationale for therapy is based on the complications of severe hypertriglyceridemia and the risk of occlusive atherosclerosis. Management is directed at improving glycemic control, altering dietary composition, and reducing calories in obese patients. Improved glycemic control is effective in reducing triglyceride and cholesterol levels in insulin-deficient subjects. The response of the non-insulin-dependent diabetic patient to improved control may be complicated by associated obesity or familial hyperlipidemia. The advantages and disadvantages of fat versus carbohydrate restriction in the diet are discussed. Finally, resistant hyperlipidemia may require drug therapy. Diabetic hyperlipidemia should be viewed as resulting from an interaction between the diabetic syndrome, the genetic background of the patient, and the environment.
205 citations
TL;DR: The "insulin resistant" glucose transport of the adipose cell in the streptozotocin-induced diabetic rat appears to be the consequence of a depletion of glucose transport systems in the intracellular pool.
Abstract: The effects of insulin-dependent diabetes mellitus on glucose transport activity and on the concentrations of glucose transport systems in the plasma and low density microsomal membranes in adipose cells isolated from streptozotocin-induced diabetic rats have been examined. Glucose transport activity was assessed by measuring 3-O-methylglucose transport and the concentration of glucose transport systems estimated by measuring specific D-glucose-inhibitable cytochalasin B-binding. Basal glucose transport activity decreases from 0.19 to 0.12 fmol/cell per min with the induction of diabetes, but remains constant per unit cellular surface area and is accompanied by a constant 6 pmol of glucose transport systems/mg of membrane protein in the plasma membrane fraction. Maximally insulin-stimulated glucose transport activity decreases from 3.16 to 1.05 fmol/cell per min and from 0.26 to 0.12 amol/micrometers 2 per min, and is accompanied by a decrease from 25 to 15 pmol of glucose transport systems/mg of plasma membrane protein. These diminished effects of insulin on glucose transport activity and the concentration of glucose transport systems in the plasma membrane fraction are paralleled by a 45% decrease in the basal number of glucose transport systems per milligram of membrane protein in the low density microsomal membrane fraction, the source of those glucose transport systems appearing in the plasma membrane in response to insulin. Thus, the "insulin resistant" glucose transport of the adipose cell in the streptozotocin-induced diabetic rat appears to be the consequence of a depletion of glucose transport systems in the intracellular pool.
TL;DR: The data are consistent with the hypothesis that Cr supplementation raises high-density lipoprotein cholesterol and improves insulin sensitivity in those with evidence of insulin resistance but normal glucose tolerance, and in those having normal glucose levels together with elevated insulin levels at base-line.
TL;DR: In nonobese patients with NIDDM, insulin resistance is characterized by a shift to the right of the insulin dose-response curve, which can be accounted for solely by an insulin receptor defect, but in these patients, impaired insulin secretion rather than insulin resistance appears to be the predominant metabolic abnormality.
Abstract: To determine whether receptor and/or postreceptor abnormalities of insulin action were responsible for insulin resistance in nonobese patients with non-insulin-dependent diabetes mellitus (NIDDM) and to assess the role of insulin resistance in their impaired glucose tolerance, insulin dose-response characteristics, insulin binding to monocytes, and insulin secretion were compared in 10 nonobese patients with NIDDM and six age-weight-matched nondiabetic volunteers. The insulin resistance of the diabetics was characterized by a shift to the right of their insulin dose-response curve (Km 81 +/- 4 microunits/ml vs. 58 +/- 2 microunits/ml in the nondiabetics P less than 0.001) but a normal maximal response to insulin. Although monocyte insulin binding was decreased in the diabetics (P less than 0.01), their response to insulin was appropriate for the number of insulin receptors occupied indicating normal postreceptor function. Insulin secretion was markedly reduced in diabetic subjects (52 +/- 22 vs. 471 +/- 90 microunits . ml-1 . 10 min-1 in the nondiabetic subjects, P less than 0.001) and was more strongly correlated with fasting plasma glucose (r = 0.92, P less than 0.001) and intravenous glucose tolerance (Kivgtt) (r = 0.98, P less than 0.001) than was insulin sensitivity (Km) (r = 0.23, NS, and r = 0.57, P less than 0.05, respectively). We conclude that in nonobese patients with NIDDM, insulin resistance is characterized by a shift to the right of the insulin dose-response curve, which can be accounted for solely by an insulin receptor defect. However, in these patients, impaired insulin secretion rather than insulin resistance appears to be the predominant metabolic abnormality.
TL;DR: It is not known whether the alterations of HDL play any role in the increased atherosclerosis of diabetic patients, but when diabetic and nondiabetic subjects are compared at similar relative body weight and serum triglyceride levels, there seems to be no difference in the mean HDL cholesterol values.
Abstract: The concentration of high density lipoproteins (HDL) in patients with diabetes mellitus is highly variable. Subnormal HDL cholesterol levels are present in untreated patients with insulin-deficient juvenile diabetes, but the values return to the normal range after beginning insulin therapy. During conventional subcutaneous insulin treatment the diabetic patients often exhibit increased mean HDL cholesterol concentrations, even in the presence of poor diabetic control. HDL concentration is not related to blood glucose or fast hemoglobin levels. However, in the presence of overt ketoacidosis and upon development of advanced diabetic nephropathy, HDL levels fall. In noninsulin-dependent diabetes low HDL cholesterol values are common, but they are associated more with obesity and hypertriglyceridemia than with the diabetic state itself. Thus, when diabetic and nondiabetic subjects are compared at similar relative body weight and serum triglyceride levels, there seems to be no difference in the mean HDL cholesterol values. The possible effects on HDL of treatment by diet and particularly by oral antidiabetic agents are not yet clear; published results are controversial in this respect. Alterations of HDL in diabetes are probably based on the presence of insulin deficiency or, more commonly, on hyperinsulinemia and insulin resistance. HDL (particularly the subfraction HDL 2 ) concentration is regulated by two endothelial lipolytic enzymes, lipoprotein lipase and hepatic lipase, both of which are insulin sensitive. Peripheral hyperinsulinemia is produced in insulin-dependent diabetics by insulin treatment. This results in an increase of tissue lipoprotein lipase activity, which in turn augments HDL levels. In obese diabetic patients the peripheral tissues are resistant to insulin and, accordingly, the lipoprotein lipase activity is subnormal. Furthermore, the hepatic lipase activity is often increased and may contribute to the lowering of HDL by increased removal of HDL cholesterol. It is not known whether the alterations of HDL play any role in the increased atherosclerosis of diabetic patients.
TL;DR: Dietary fat may impair amino acid transport into the mammary gland and milk protein synthesis by inducing insulin resistance in cows fed high fat diets.
TL;DR: The present data supports the view that antilipolysis in human fat cells is not involved in the insulin resistance seen in obesity, starvation, diabetes and hyperinsulinemia.
Abstract: The antilipolytic effect of insulin in vitro was investigated in conditions known to be associated with resistance to the effect of insulin on glucose metabolism. Human subcutaneous adipose tissue was obtained from 14 obese subjects before and during starvation for 7 days, 12 untreated non-insulin dependent diabetics (NIDDM), 6 untreated insulin dependent diabetics (IDDM), and 10 nonobese control subjects. The tissue was incubated with and without insulin in concentration ranging from 1-10,000 microunits/ml. Responsiveness (maximum effect) and sensitivity to insulin were determined under basal induction conditions, since insulin had a bimodal effect on noradrenaline stimulated lipolysis. Under normal conditions both insulin sensitivity and insulin responsiveness were positively correlated with the basal rate of lipolysis. In obesity, IDDM and NIDDM there were no change in insulin sensitivity or in insulin responsiveness. When the obese subjects were divided into one hyperinsulinemic group (6 individuals) and one group with normal fasting serum insulin levels (7 individuals) a similar antilipolytic effect of insulin was observed in the two groups. During starvation there was a 20-fold increase in insulin sensitivity (p less than 0.01) but no change in insulin responsiveness in femoral fat and only a decrease in responsiveness (p less than 0.01) in abdominal fat. The present data supports the view that antilipolysis in human fat cells is not involved in the insulin resistance seen in obesity, starvation, diabetes and hyperinsulinemia.
TL;DR: Exposure of 3T3-L1 cells to dexamethasone, a synthetic glucocorticoid, resulted in decreased binding of insulin to its receptor and decreased insulin stimulation of 2-deoxyglucose uptake, and the magnitude of these changes was concentration dependent over a range of 0.1 –100 nM dexamETHasone.
Abstract: Glucocorticoid excess in vivo has been shown to cause decreases in insulin sensitivity and insulin receptor binding in target tissues. It has not been previously possible to produce all of these changes in vitro because of limitations of the isolated rat adipocyte as an experimental model. We have studied the effects of glucocorticoid hormones on insulin binding and insulin action in differentiated mouse 3T3-L1 fatty fibroblasts, in an attempt to develop a complete in vitro model of the insulin resistance associated with glucocorticoid excess. Exposure of 3T3-L1 cells to dexamethasone, a synthetic glucocorticoid, resulted in decreased binding of insulin to its receptor and decreased insulin stimulation of 2-deoxyglucose uptake. Although some effect of dexamethasone on these parameters was observed after 24 h, more than 3 days were required for maximal inhibition of both binding and biological response. The magnitude of these changes was concentration dependent over a range of 0.1 –100 nM dexamethasone. Ex...
TL;DR: The results indicate that the mechanism of the postreceptor defect in insulin action, which exists in many obese patients, is related to a decrease in the activity of the glucose transport effector system.
Abstract: We have studied insulin-stimulated 3-O-methyl glucose transport by isolated adipocytes prepared from 10 normal and 11 obese individuals. The results demonstrated that the insulin-glucose transport dose-response curves were shifted to the right in cells from the obese patients, and that the magnitude of this rightward shift was significantly correlated to the reduction in adipocyte insulin receptors in individual subjects (r = 0.48, P less than 0.01). In three obese patients a rightward shift in the dose-response curve could be demonstrated and there was no decrease in maximal insulin effect. This corresponded to in vivo glucose clamp results showing only a rightward shift in the insulin dose-response curve for overall glucose disposal in these three subjects (1980. J. Clin. Invest. 65: 1272-1284). In the remaining eight obese patients, the in vitro glucose transport studies showed not only a rightward shift in the dose-response curves but also a marked decrease in basal and maximally insulin-stimulated rates of transport, indicating a postreceptor defect in insulin action. Again, this was consistent with the in vivo glucose clamp studies demonstrating a marked postreceptor defect in these individuals. In conclusion, these results indicate that the mechanism of the postreceptor defect in insulin action, which exists in many obese patients, is related to a decrease in the activity of the glucose transport effector system.
TL;DR: Findings suggest excessive degradation or sequestration of insulin at the site of injection in patients with diabetes that is insensitive to subcutaneous insulin but sensitive to intravenous insulin.
Abstract: Patients with diabetes that is insensitive to subcutaneous insulin but sensitive to intravenous insulin have recently been described. We have studied this phenomenon is five female diabetics (14 to 31 years of age) who required excessive amounts of insulin (2.5 to 30.0 units per kilogram of body weight per day) to avoid recurrent ketoacidosis. Known causes of insulin resistance were excluded. All patients had normal responses to conventional doses of intravenous insulin (0.35 to 0.9 unit per kilogram per day). Four patients required continuous intravenous infusion of insulin for one to six months. When a mixture of aprotinin (a protease inhibitor) and regular porcine insulin was given subcutaneously, conventional doses (0.7 to 1.4 units per kilogram per day) produced euglycemia; plasma levels of free insulin rose, and ketonuria disappeared. Four patients had episodes of spontaneous, severe hypoglycemia before and during aprotinin therapy, necessitating continuous infusion of glucose for two to 14 days. Although no insulin was administered, hyperinsulinemia (50 to 2000 muU of free insulin per milliliter [359 to 14,350 pmol per liter]) was present. These findings suggest excessive degradation or sequestration of insulin at the site of injection.
TL;DR: One-third of the subjects studied appear to have only insulin deficiency as the basis of their diabetes, while two-thirds seem to have an underlying resistance to insulin that is not corrected by insulin therapy, indicating that heterogeneity exists among subjects with type II diabetes mellitus.
Abstract: Insulin resistance has been demonstrated previously in both glucose-intolerant and untreated type II diabetics. Although the former group had hyperinsulinemia in the fasting state and after an oral glucose load, the hyperglycemic type II subjects were relatively insulin deficient after carbohydrate ingestion. In an attempt to define the role that insulin deficiency might have played in the pathophysiology of insulin resistance in this latter group, we measured the steadystate plasma glucose level (SSPG) during a constant infusion of glucose (6 mg/kg/min) and insulin (80 mU/min) in 15 nonobese insulin-deficient type II diabetics before and after insulin replacement therapy. Hepatic glucose output (HGO) and plasma clearance of glucose (PCG) during these studies were also determined using an infusion of 3-3H-glucose.
Before insulin treatment, 13 of 15 subjects had SSPG levels above the range reported in normal subjects. Two type II patients appeared to be normally sensitive to insulin. Although all subjects were more sensitive to insulin after 1–8 wk of insulin therapy, they could be clearly divided into two groups. Thus, five patients were now normally sensitive to insulin (SSPG:75 ± 5.3 mg/dl) while 10 patients were still significantly resistant (SSPG: 227±11.3 mg/dl). HGO during the infusion studies was high in the resistant group pretreatment and did not change posttreatment (3.54 ± 0.32 vs. 3.14 ± 0.78 mg/kg/min). HGO was lower before insulin therapy and decreased by > 50% after therapy in the sensitive group (1.93 ± 0.07 vs. 0.71 ± 0.32 mg/kg/min). PCG determinations revealed a similar pattern of response. Retrospective analysis of the two groups revealed no significant differences in their baseline characteristics. Fasting plasma glucose and hemoglobin A1c levels also did not differ between the two groups before or after insulin therapy.
These results indicate that heterogeneity exists among subjects with type II diabetes mellitus. One-third of the subjects studied appear to have only insulin deficiency as the basis of their diabetes, while two-thirds seem to have an underlying resistance to insulin that is not corrected by insulin therapy.
TL;DR: The primary mechanism responsible for the fattening of FL birds appears to be greater insulin release from the pancreas of the FL birds soon after hatching, indicating a normal sensitivity to insulin at a young age.
Abstract: Effects of dietary protein or energy level on growth and physiological parameters were investigated in growing chickens selected for high (fat line, FL) or low (lean line, LL) abdominal fat but similar body weight. The FL birds deposited consistently more abdominal fat (about two-fold) and had poorer feed conversion, irrespective of diet. Increasing the ratio of energy to protein increased fat deposition similarly but at different levels. Body weight and feed consumption showed only minor and inconsistent differences and feed consumption following a fast and body temperature in the fed or the fasted-state showed no differences between lines. Fasting plasma glucose levels were similar for both lines at hatching but consistently lower in FL birds thereafter. This was matched by higher fasting plasma insulin levels. A similar relationship was also observed in fed FL birds at 2 weeks of age. Glucose disposal rate was faster in FL birds at 4 and 6 weeks but normal by 8 weeks. The glucose-induced insulin release was higher in FL birds at 6 and 8 weeks, indicating a normal sensitivity to insulin at a young age, with the development of a tissue insulin resistance by 8 weeks of age. The primary mechanism responsible for the fattening of FL birds appears therefore to be greater insulin release from the pancreas of the FL birds soon after hatching.
TL;DR: Physical training improves glucose tolerance in some noninsulin-dependent diabetic subjects and in insulin-dependent patients, it may diminish insulin requirements and it may also have a role in retarding the development of cardiovascular complications.
TL;DR: A positive relationship was demonstrated between oxymetholone administration and the presence of glucose intolerance and insulin resistance in patients with aplastic anemia.
Abstract: Because of a suspected association between the drug oxymetholone and abnormal glucose metabolism, we determined immunoreactive insulin (IRI) and plasma glucose during oral glucose tolerance testing in seven patients with aplastic anemia, six of whom received oxymetholone therapy. All patients receiving oxymetholone therapy had abnormal glucose and/or IRI values. This finding was independent of GH, cortisol, and glucagon. In one patient, glucose and IRI levels were normal before oxymetholone but became abnormally elevated after the use of this drug. Furthermore, normal glucose and IRI values were present in the single patient not receiving oxymetholone. Thus, a positive relationship was demonstrated between oxymetholone administration and the presence of glucose intolerance and insulin resistance.
TL;DR: Cultured lymphocytes transformed by Epstein--Barr virus were employed to study insulin receptors from a patient with extreme insulin resistance associated with the syndrome of leprechaunism, finding the receptor's binding function was abnormal in having decreased sensitivity to alterations in temperature and pH.
Abstract: Cultured lymphocytes transformed by Epstein--Barr virus were employed to study insulin receptors from a patient with extreme insulin resistance associated with the syndrome of leprechaunism. With cultured lymphocytes from normal subjects, insulin binding to its receptor is exquisitely sensitive to changes in temperature and pH. In cells from normal subjects, insulin binding was increased by approximately 250% as the temperature was decreased from 37 degrees C to 12 degrees C. In contrast, with cells from the leprechaun, insulin binding was only approximately 30% higher at 12 degrees C than at 37 degrees C. Similarly, insulin binding to cells from the leprechaun was markedly less sensitive to changes in pH, as compared to cells from normal subjects. Binding studies suggested that the number of insulin receptors per cell was within the normal range in this patient. Despite the unusual characteristics of insulin binding in cells from this insulin-resistant patient, the receptors were typical in at least two respects: (i) binding was inhibited normally by antibodies to the receptor; and (ii) the specificity for insulin analogs was normal (chicken insulin greater than porcine insulin much greater than guinea pig insulin greater than porcine proinsulin). This patient has an inborn error affecting insulin receptor function. The receptor's binding function was abnormal in having decreased sensitivity to alterations in temperature and pH. However, the level of insulin binding to cells from the leprechaun was within normal limits. Consequently, the hormonal resistance probably results from a decreased ability of the receptor to couple insulin binding to insulin action.
TL;DR: In this paper, it has been shown that insulin resistance may be a more frequent cause of carbohydrate intolerance or contributing factor in carbohydrate intolerance than was hitherto appreciated, and that these may be manifested by an increase in the concentration of insulin necessary for a half-maximal effect or a decrease in the maximal response to insulin (decreased responsiveness), or both.
TL;DR: It is demonstrated that erythrocyte insulin receptors are not decreased in normal human pregnancy despite the presence of hyperinsulinemia and insulin resistance, suggesting that some factor exists in pregnancy that modulates insulin receptors in a positive manner and are consistent with the possibility that the insulin resistance in pregnancy is related to a postreceptor abnormality.
Abstract: We have studied insulin binding to isolated erythrocytes from 28 nondiabetic, pregnant women and have compared these results to similar data obtained in nonpregnant, nondiabetic women. In the nonpregnant subjects insulin binding was 35% higher during the follicular stage of the menstrual cycle as compared to the luteal phase. In the pregnant women insulin binding was comparable to that seen in the nonpregnant women during the follicular phase but was higher than that seen during the luteal phase of the menstrual cycle. Insulin binding was measured in 5 pregnant women during the third trimester and in the postpartum period. In these subjects insulin binding to erythrocytes declined by 31% after delivery. These results demonstrate that erythrocyte insulin receptors are not decreased in normal human pregnancy despite the presence of hyperinsulinemia and insulin resistance. Providing erythrocyte insulin receptors are reflective of insulin receptors in other tissues in human pregnancy, these findings suggest t...
TL;DR: It is concluded that glucocorticoids increase insulin binding in vitro in cultured human lymphocytes but that competing influences in vivo such as increasing circulating insulin concentration, redistribution of cell types in the circulation, and possibly other influences prevent these changes from occurring in circulating monocytes.
Abstract: We have studied the effect of glucocorticoid exposure on the insulin receptor of short term cultures of human lymphocytes (IM-9 cells) and the effect of short term administration of these agents to normal volunteers. When cultured human lymphocytes were exposed to lO-5 M hydrocortisone for 18 h at 37 C, insulin binding increased due to an increase in the number of receptors per cell. The effect had appropriate specificity in terms of concentration and type of steroid used. By contrast, hGH binding to these cells was decreased under similar circumstances of incubation, due to a decrease in the number of hGH receptors per cell. When prednisone (40 mg/day) was given to normal subjects for 3 days, a moderate state of insulin resistance was induced characterized by a modest increase in blood glucose and a more pronounced increase in plasma insulin concentration. Under these circumstances there was no change in tracer insulin binding to peripheral monocytes nor changes in the concentration of insulin necessary ...
TL;DR: Results indicate that decreased sensitivity of insulin for peripheral glucose utilization may play an important role in the pathogenesis of diabetes and an effort to maintain or enhance tissue insulin sensitivity in diabetes mellitus is more important than attempts to stimulate the deteriorating pancreatic beta-cells to secrete more insulin.
Abstract: Insulin sensitivity has been determined in primary nonobese diabetics and subjects with borderline glucose intolerance by a newly devised technique using glucose, insulin, and somatostatin infusion. Insulin sensitivity for glucose utilization was decreased in both adult- and juvenile-onset diabetics. Eight out of 88 diabetics had normal insulin sensitivty and were free from microvascular complications. In lean subjects with borderline glucose intolerance, insulin sensitivity was decreased, although an overlap with normal was noted. All obese subjects with borderline glucose intolerance had reduced insulin sensitivity. An inverse relationship was observed between insulin sensitivity and fasting plasma glucose (FPG), and a significant correlation was observed between FPG and steady state plasma glucose levels (SSPG; r = 0.57; P less than 0.001). Improvement of diabetic control in eight diabetics with sulfonylureas decreased SSPG in all (P less than 0.05), although normalization of SSPG was observed in only one. These results indicate that decreased sensitivity of insulin for peripheral glucose utilization may play an important role in the pathogenesis of diabetes. Elevated FPG levels reflect the presence of decreased insulin sensitivity in diabetes mellitus. Although decreased sensitivity is difficult to normalize, it can be enhanced by improving the diabetic control. An effort to maintain or enhance tissue insulin sensitivity in diabetes mellitus may be more important than attempts to stimulate the deteriorating pancreatic beta-cells to secrete more insulin.
TL;DR: Investigating carbohydrate tolerance in response to a standard oral glucose tolerance test and an iv insulin tolerance test in a group of GH-deficient children before and after short term (acute) and prolonged (chronic) human GH (hGH) administration suggested enhanced insulin sensitivity.
Abstract: We investigated carbohydrate tolerance in response to a standard oral glucose tolerance test (OGTT) and an iv insulin tolerance test (IVITT) in a group of GH-deficient children before and after short term (acute) and prolonged (chronic) human GH (hGH) administration Erythrocyte and monocyte insulin receptor binding were assessed during each treatment phase In the untreated state, OGTT responses demonstrated basal hypoinsulinemia and diminished insulin secretion compared to controls Glucose responses, however, were only slightly greater than the controls IVITT suggested enhanced insulin sensitivity However, we were unable to demonstrate significant differences in either erythrocyte or monocyte insulin receptor binding to account for these findings After chronic hGH administration, insulin secretion increased following oral glucose ingestion, but glucose tolerance was impaired, while the sensitivity to exogenous insulin was unchanged Alterations in insulin binding did not appear to be associated with
TL;DR: It is concluded that there is a general relationship between monocyte and erythrocyte insulin binding, but important differences exist in the way their insulin receptors are regulated.
Abstract: Blood cells have been widely used to evaluate the status of the insulin receptor in man. The insulin receptor of human monocytes has been shown to mirror pathophysiologic states of insulin receptors in target tissues of animal models. Thus, comparison of the properties of the insulin receptor studied simultaneously in erythrocytes and monocytes is appropriate. We studied 19 normal subjects and 32 patients with diverse conditions such as acromegaly, insulinomas, insulin-dependent diabetes mellitus, corticosteroid administration, and the Type A and B forms of insulin resistance. We find that specific insulin binding at tracer concentrations significantly correlate (P o ) and affinity of the receptor at the lowest insulin concentration (Ke) do not significantly correlate (P