Showing papers on "Insulin resistance published in 1986"
TL;DR: The results of euglycemic insulin-clamp studies in adults and prepubertal and pubertal children with and without insulin-dependent diabetes suggest that insulin resistance occurs during puberty in both normal children and children with diabetes.
Abstract: Patients with insulin-dependent diabetes mellitus often have poor metabolic control during puberty. To determine whether puberty is associated with decreased insulin-stimulated glucose metabolism, we compared the results of euglycemic insulin-clamp studies in adults and prepubertal and pubertal children with and without insulin-dependent diabetes. In nondiabetic pubertal children, insulin-stimulated glucose metabolism (201 +/- 12 mg per square meter of body surface area per minute) was sharply reduced, as compared with that of prepubertal children and adults (316 +/- 34 and 290 +/- 21 mg per square meter, respectively; P less than 0.01), despite comparable hyperinsulinemia (insulin levels of 80 to 90 microU per milliliter). Similarly, the response to insulin was 25 to 30 percent lower in the diabetic pubertal children than in the diabetic prepubertal children (P less than 0.05) and adults (P = 0.07). At each stage of development, the stimulating effect of insulin on glucose metabolism was decreased by 33 to 42 percent in the children with diabetes (P less than 0.01). In all the groups of children studied, the response to insulin was inversely correlated with mean 24-hour levels of growth hormone (r = -0.52, P = 0.01). Among the diabetic children, the glycosylated hemoglobin levels were substantially higher in the pubertal children than in the prepubertal children (P less than 0.02), although the daily insulin doses tended to be higher. These data suggest that insulin resistance occurs during puberty in both normal children and children with diabetes. The combined adverse effects of puberty and diabetes on insulin action may help explain why control of glycemia is so difficult to achieve in adolescent patients.
975 citations
TL;DR: This 'minimal modelling approach' fits two mathematical models with FSIGT glucose and insulin data: one of glucose disappearance and one of insulin kinetics, and MINMOD is the computer program which identifies the model parameters for each individual.
725 citations
TL;DR: High-fat feeding results in insulin resistance due mainly to effects in oxidative skeletal muscle and BAT, which is concluded to be associated with reduced energy expenditure.
Abstract: High levels of dietary fat may contribute to both insulin resistance and obesity in humans but evidence is limited. The euglycemic clamp technique combined with tracer administration was used to study insulin action in vivo in liver and individual peripheral tissues after fat feeding. Basal and nutrient-stimulated metabolic rate was assessed by open-circuit respirometry. Adult male rats were pair-fed isocaloric diets high in either carbohydrate (69% of calories; HiCHO) or fat (59% of calories; HiFAT) for 24 +/- 1 days. Feeding of the HiFAT diet resulted in a greater than 50% reduction in net whole-body glucose utilization at midphysiological insulin levels (90-100 mU/l) due to both reduced glucose disposal and, to a lesser extent, failure to suppress liver glucose output. Major suppressive effects of the HiFAT diet on glucose uptake were found in oxidative skeletal muscles (29-61%) and in brown adipose tissue (BAT; 78-90%), the latter accounting for over 20% of the whole-body effect. There was no difference in basal metabolic rate but thermogenesis in response to glucose ingestion was higher in the HiCHO group. In contrast to their reduced BAT weight, the HiFAT group accumulated more white adipose tissue, consistent with reduced energy expenditure. HiFAT feeding also resulted in major decreases in basal and insulin-stimulated conversion of glucose to lipid in liver (26-60%) and brown adipose tissue (88-90%) with relatively less effect in white adipose (0-43%). We conclude that high-fat feeding results in insulin resistance due mainly to effects in oxidative skeletal muscle and BAT.(ABSTRACT TRUNCATED AT 250 WORDS)
495 citations
TL;DR: In patients with newly diagnosed Type I diabetes, a transient normalization of insulin action may occur after an initial reduction, along with a partial recovery of endogenous insulin secretion, and these events may contribute to the development of a clinical remission ("honeymoon" period").
Abstract: To examine the natural course of insulin action in Type I diabetes, we followed 15 patients prospectively for one year after the diagnosis of diabetes and also performed a cross-sectional study of 53 additional patients who had had diabetes for 2 to 32 years. Two weeks after diagnosis, the rate of glucose uptake during hyperinsulinemia, a measure of insulin action, was 32 percent lower in the patients with diabetes than in 30 matched normal subjects (P less than 0.01), but it rose to normal during the subsequent three months. At three months after diagnosis, 9 of 21 patients (43 percent) were in clinical remission and did not require insulin therapy. In these patients, insulin action was 40 percent greater (P less than 0.002) than in the patients who continued to need insulin treatment. Fasting plasma C-peptide levels were slightly but not significantly higher in the patients who had a remission than in the other patients. In patients who had had diabetes for one year or more, insulin action was also reduced by an average of 40 percent (although there was considerable variation between patients), and it was inversely related to glycemic control and relative body weight. Thus, in patients with newly diagnosed Type I diabetes, a transient normalization of insulin action may occur after an initial reduction, along with a partial recovery of endogenous insulin secretion, and these events may contribute to the development of a clinical remission ("honeymoon" period). A majority of patients with diabetes of long duration are characterized by varying degrees of insulin resistance.
337 citations
TL;DR: The case for insulin as a cardiovascular risk factor is bolstered by theoretical considerations related to its possibly atherogenic effects on serum and arterial wall lipids and the extent to which fat patterning and hyperinsulinemia are genetic or acquired has received relatively little attention.
Abstract: Differences in body fat distribution between diabetics and nondiabetics have been recognized for several decades; diabetics have a more centralized or upper body fat pattern than nondiabetics. Recently, attention has focused on fat patterning and also on hyperinsulinemia as possible risk factors for cardiovascular disease, as well. The case for insulin as a cardiovascular risk factor is bolstered by theoretical considerations related to its possibly atherogenic effects on serum and arterial wall lipids. Empirical evidence for fat patterning and hyperinsulinemia as cardiovascular risk factors rests on six prospective epidemiologic studies, three on fat patterning and three on insulin. Although provocative, none of these studies can be regarded as definitive. In none was a dose-response effect demonstrated, and there are various inconsistencies within and across the studies. Moreover, in none of the studies were hyperinsulinemia and fat patterning evaluated simultaneously. This is of particular importance in view of the well-documented interrelationships between these two variables. For example, insulin resistance and hyperinsulinemia have been found to be greater in women with upper body obesity compared to women with lower body obesity of equivalent degree. Considerable progress has been made recently in understanding the mechanisms of the differential metabolic effects of these two types of obesity. The extent to which fat patterning and hyperinsulinemia are genetic or acquired has received relatively little attention. Further research on this question is warranted since elucidation of any environmental influences on these variables might suggest new clinical and public health control measures.
330 citations
TL;DR: A large body of available evidence indicates that the degree of physical conditioning is an important determinant of insulin sensitivity and overall glucose tolerance and the role of exercise in the treatment of diabetic patients remains to be established.
Abstract: In conclusion, a large body of available evidence indicates that the degree of physical conditioning is an important determinant of insulin sensitivity and overall glucose tolerance. Both acute exercise and chronic physical training are associated with enhanced disposal of a glucose load. Conversely, physical inactivity leads to a deterioration in glucose tolerance. The primary tissue responsible for accelerated glucose disposal following exercise is muscle. After an acute bout of exercise, enhanced glucose transport and augmented glycogen synthesis are largely responsible for the improvement in glucose tolerance. The beneficial effects of chronic physical training on glucose metabolism appear to be explained by multiple factors, including increased muscle mass, augmented muscle blood flow and capillary area, enhanced mitochondrial oxidative enzyme capacity, and activation of the glucose transport system. Despite these well-documented effects of training on glucose metabolism, the precise role of exercise in the treatment of diabetic patients remains to be established. In insulin-dependent (type I) diabetic individuals, acute exercise has been shown to be a helpful adjunct in establishing good glycemic control. However, the role of acute exercise in helping to smooth out glycemic control in non-insulin-dependent (type II) diabetic patients has received little attention. The role of chronic physical training in the treatment of both insulin-dependent (type I) and non-insulin-dependent (type II) diabetic individuals remains to be established.
269 citations
TL;DR: It is concluded that in obesity, the occurrence of hypertension marks the presence of additional hyperinsulinemia and insulin resistance, independent of any impairment of glucose tolerance.
Abstract: An association between hyperinsulinemia and hypertension has been suggested by epidemiological surveys. To assess whether this association is independent of the presence of other hyperinsulinemic states, such as obesity and glucose intolerance, we measured the insulin response to oral glucose in a group of middle-aged moderately obese [144 +/- 4% overweight (mean +/- SEM)] patients (n = 18) with essential hypertension (174 +/- 5/104 +/- 2 mm Hg) and normal glucose tolerance. Normotensive subjects (n = 17) with normal glucose tolerance, matched for age and degree of overweight, served as the control group. The mean insulin response to glucose was twice as high in the hypertensive patients (25.8 +/- 0.2 mU/ml X 2 h) as in the normotensive subjects (11.3 +/- 0.2; P less than 0.001), yet the glucose incremental area was 3-fold higher in the former (10.9 +/- 1.0 g/dl X 2 h) than in the latter (3.5 +/- 0.7; P less than 0.001), thus indicating more severe insulin resistance. In the hypertensive group, systolic blood pressure levels were directly correlated with the 2-h plasma insulin values (r = 0.75; P less than 0.001). Furthermore, the 2-h plasma insulin value and the degree of overweight accounted for 65% of the variation in the systolic blood pressure in a multiple regression model (r = 0.81; P less than 0.001). We conclude that in obesity, the occurrence of hypertension marks the presence of additional hyperinsulinemia and insulin resistance, independent of any impairment of glucose tolerance.
259 citations
TL;DR: Insulin dose-response curves indicate that chronic growth hormone excess is associated with a defect in both hepatic and extrahepatic insulin action and the decrease in glucose utilization at supraphysiological insulin concentrations in the acromegalic subjects and the normal monocyte and erythrocyte insulin binding suggest a postbinding alteration in insulin action.
Abstract: Short-term growth hormone excess is associated with impaired hepatic and extrahepatic responses to insulin in the absence of a change in insulin binding. To determine whether similar defects occur after chronic growth hormone excess, insulin dose-response curves for stimulation of glucose utilization and suppression of glucose production and monocyte and erythrocyte insulin binding were determined in five acromegalic patients and six healthy volunteers of comparable age, sex, and obesity. During infusion of insulin, glucose infusion rates required to maintain euglycemia were significantly lower (P less than 0.02 all) in the acromegalic patients than in the control subjects. Suppression of glucose production was impaired in the acromegalic subjects at insulin concentrations in the physiological range but not at insulin concentrations in the supraphysiological range. In contrast stimulation of glucose utilization was decreased in the acromegalic subjects at both physiological and supraphysiological insulin concentrations. Neither monocyte nor erythrocyte insulin binding differed significantly in the acromegalic and control subjects. These data indicate that chronic growth hormone excess is associated with a defect in both hepatic and extrahepatic insulin action. The decrease in glucose utilization at supraphysiological insulin concentrations in the acromegalic subjects and the normal monocyte and erythrocyte insulin binding suggest a postbinding alteration in insulin action.
232 citations
TL;DR: In obesity, decreased surface binding could explain resistance to submaximal insulin concentrations and diminished insulin-stimulated protein kinase activity and decreased intracellular pool of receptors could provide an explanation for postinsulin-binding defect(s) of insulin action in human liver.
Abstract: We have developed a method to isolate insulin-responsive human hepatocytes from an intraoperative liver biopsy to study insulin action and resistance in man. Hepatocytes from obese patients with noninsulin-dependent diabetes were resistant to maximal insulin concentration, and those from obese controls to submaximal insulin concentration in comparison to nonobese controls. Insulin binding per cell number was similar in all groups. However, insulin binding per surface area was decreased in the two obese groups because their hepatocytes were larger. In addition, the pool of detergent-extractable receptor was further decreased in diabetics. Insulin receptors in all groups were unaltered as determined by affinity-labeling methods. However, insulin-stimulated insulin receptor kinase activity was decreased in diabetics. Thus, in obesity, decreased surface binding could explain resistance to submaximal insulin concentrations. In diabetes, diminished insulin-stimulated protein kinase activity and decreased intracellular pool of receptors could provide an explanation for postinsulin-binding defect(s) of insulin action in human liver.
216 citations
TL;DR: The abnormal kinetics of insulin action in insulin-resistant obese individuals may represent functionally important manifestations of the insulin resistance in this condition.
Abstract: To determine whether abnormal kinetics of insulin's biologic actions contribute to the overall insulin resistance in obesity, we compared the rate of activation and deactivation of insulin's effects to stimulate glucose disposal rate (Rd) and inhibit hepatic glucose output (HGO) in 12 nonobese and 10 obese subjects using the euglycemic clamp technique at insulin infusion rates of 15, 40, 120, and 1,200 mU/M2 per min. In both groups, stimulation of Rd was faster the higher the insulin infusion rate and the time to reach half maximal stimulation (A50 value) in normals was 52 +/- 4, 44 +/- 2, 29 +/- 3, and 21 +/- 2 min at infusion rates of 15, 40, 120, and 1,200 mU/M2 per min, respectively. In the obese subjects, the rate of activation was slower (higher A50 values) with A50 values of 74 +/- 6, P less than 0.001 (compared to normal), 64 +/- 8 min, P less than 0.001, and 28 +/- 3 min, P less than 0.01, at the 40, 120, and 1,200 mU/M2 per min insulin infusions. Deactivation of the insulin effect to stimulate glucose disposal rate (Rd) was faster in the obese group compared with normal individuals after all comparable insulin infusions. In summary: for both groups, the higher the insulin infusion rate, the higher the steady state Rd value, the faster the rate of activation and the slower the subsequent rate of deactivation. In insulin-resistant obese subjects, the rate of activation of insulin action was slower and the rate of deactivation faster at comparable insulin infusion rates. The rate of suppression of HGO was comparable in normal and obese subjects, but the rate of recovery of HGO back to basal values was faster in the obese group. And in view of the phasic manner in which insulin is normally secreted following meals, steady state insulin action is not normally achieved. Therefore, the abnormal kinetics of insulin action in insulin-resistant obese individuals may represent functionally important manifestations of the insulin resistance in this condition.
215 citations
TL;DR: It is concluded that high fat feeding, without a major increase in body weight or basal hyperinsulinaemia, causes widespread but varying degrees of in vivo insulin resistance in peripheral tissues, with major effects in principally oxidative skeletal muscle.
Abstract: We have examined peripheral insulin action in conscious rats chronically fed high fat (60% calories as fat) or high carbohydrate (lab chow) diets using the euglycaemic clamp plus 3 H-2-deoxyglucose technique. A response parameter of individual tissue glucose metabolic rate (the glucose metabolic index, based on tissue deoxyglucose phosphorylation) was used to assess diet effects in eight skeletal muscle types, heart, lung and white and brown adipose tissue. Comparing high fat with high carbohydrate fed rats, basal glucose metabolism was only mildly reduced in skeletal muscle (only diaphragm was significant,p<0.05), but was more substantially reduced in other tissues (e.g. white adipose tissue 61% and heart 33%). No evidence of basal hyperinsulinaemia was found. In contrast, widespread insulin resistance was found during the hyperinsulinaemic clamp (150 mU/l) in high fat fed animals; mean whole body net glucose utilization was 34% lower (p<0.01), and the glucose metabolic index was lower in skeletal muscle (14 to 56%,p< 0.05 in 6 out of 8 muscles), white adipose (27%,p<0.05) and brown adipose tissue (76%,p<0.01). The glucose metabolic index was also lower at maximal insulin levels in muscle and fat, suggesting the major effect of a high fat diet was a loss of insulin responsiveness. White adipose tissue differed from muscle in that incremental responses (maximal insulin minus basal) were not reduced by high fat feeding. The heart showed an effect opposite to other tissues, with an increase in insulin-stimulated glucose metabolism in high fat versus chow fed rats. We conclude that high fat feeding, without a major increase in body weight or basal hyperinsulinaemia, causes widespread but varying degrees of in vivo insulin resistance in peripheral tissues, with major effects in principally oxidative skeletal muscle.
TL;DR: By reducing total hormone delivery by up to 40%, but given in a pulsatile fashion, insulin is equally potent in controlling HGP as continuous insulin administration, accompanied by an equipotent effect on glucose utilization.
Abstract: To evaluate the role of pulsatile insulin administration, hepatic glucose production (HGP) and utilization were studied in type I diabetic patients in the fasting state and during a euglycemic insulin (1 mU · kg −1 · min −1 i.v.) clamp with continuous and pulsatile insulin administration. In the latter study, insulin was infused at twice the continuous rate with 3-min-on/7-min-off intervals, thereby reducing total insulin delivery by 40%. The restraining effect of pulsatile insulin on basal HGP (1.91 ± 0.35 mg · kg −1 · min −1 ) was equipotent to continuous insulin exposure (1.80 ± 0.17 mg · kg −1 min −1 ). During the insulin-clamp studies, HGP was equally suppressed by pulsed (0.62 ± 0.12 mg · kg −1 min −1 ) as by continuous insulin infusion (0.63 ± 0.12 mg · kg −1 · min −1 ). Insulin-stimulated glucose utilization was not significantly altered in either study (2.55 ± 0.27 vs. 2.92 ± 0.23 mg · kg −1 min −1 ). When in further studies the total insulin dose given during the pulsatile study was infused continuously (0.6 mU · kg −1 · min −1 ), HGP in the basal state and residual HGP during the insulin-clamp study were 25–30% higher than in the pulsatile experiments, whereas glucose utilization was not significantly different. In conclusion, by reducing total hormone delivery by up to 40%, but given in a pulsatile fashion, insulin is equally potent in controlling HGP as continuous insulin administration. This greater efficacy of pulsatile exposure in suppressing HGP is accompanied by an equipotent effect on glucose utilization. Application of pulsatile insulin substitution in intravenous-pump users may reduce systemic hyperinsulinemia and, in the long run, insulin resistance by reversing downregulation of insulin receptors.
TL;DR: In this paper, six nonobese women with polycystic ovarian disease (PCOD) showed significant hyperinsulinemia, compared with controls after oral glucose (P less than 0.05).
TL;DR: It is concluded that epinephrine may override many of the actions of insulin in vivo, and most of these effects are mediated via the beta-adrenergic receptor.
TL;DR: It is concluded that treatment with sulfonylureas or exogenous insulin results in equivalent improvement in insulin action in patients with non-insulin-dependent diabetes mellitus, and the choice between these agents should be based on considerations other than their ability to ameliorate insulin resistance.
Abstract: To determine whether sulfonylureas and exogenous insulin have different effects on insulin action, we studied eight patients with non-insulin-dependent diabetes mellitus before and after three months of treatment with tolazamide and exogenous semisynthetic human insulin, using a randomized crossover design. Therapy with tolazamide and therapy with insulin resulted in similar improvement of glycemic control, as measured by a decrease in mean glycosylated hemoglobin (+/- SEM) from 9.4 +/- 0.7 percent to 7.7 +/- 0.5 percent with tolazamide and to 7.1 +/- 0.2 percent with exogenous insulin (P less than 0.01 for both comparisons). Therapy with either tolazamide or exogenous insulin resulted in a similar lowering (P less than 0.05) of postabsorptive glucose-production rates (from 2.3 +/- 0.1 to 2.0 +/- 0.2 and 1.8 +/- 0.1 mg per kilogram of body weight per minute, respectively) but not to normal (1.5 +/- 0.1 mg per kilogram per minute). Both tolazamide and exogenous insulin increased (P less than 0.05) glucose utilization at supraphysiologic insulin concentrations (from 6.2 +/- 0.7 to 7.7 +/- 0.6 mg per kilogram per minute with tolazamide and to 7.8 +/- 0.6 mg per kilogram per minute with exogenous insulin) to nondiabetic rates (7.9 +/- 0.5 mg per kilogram per minute). Neither agent altered erythrocyte insulin binding at physiologic insulin concentrations. We conclude that treatment with sulfonylureas or exogenous insulin results in equivalent improvement in insulin action in patients with non-insulin-dependent diabetes mellitus. Therefore, the choice between these agents should be based on considerations other than their ability to ameliorate insulin resistance.
TL;DR: It is concluded that skeletal muscles and, to a smaller extent, adipose tissue are involved in the insulin resistance of late pregnancy.
Abstract: In vivo studies have shown that insulin resistance in late pregnancy results from a decreased sensitivity of liver and peripheral tissues. In the present study, measurements of the rates of glucose utilization by skeletal muscles (soleus, extensor digitorum longus, epitrochlearis, and diaphragm), white adipose tissue, and brain of virgin and 19-day pregnant rats were performed in the basal condition and during a euglycemic, hyperinsulinemic (400 microU/ml) clamp to quantify the partition of glucose utilization and to identify the tissues other than liver responsible for insulin resistance. Fetal and placental glucose utilization rates were also measured in pregnant rats. The fetal glucose utilization rate (22 mg/min/kg) was very high and was not stimulated by physiologic maternal hyperinsulinemia. By contrast, the placental glucose utilization rate (29 mg/min/kg) was increased by 30% during hyperinsulinemia. The glucose utilization rate of the conceptus represented 23% of the maternal glucose utilization rate in the basal state. Glucose utilization rates in the basal condition were not statistically altered by pregnancy in brain, skeletal muscles, and white adipose tissue. During hyperinsulinemia (400 microU/ml), glucose utilization rates in extensor digitorum longus, epitrochlearis, and white adipose tissue were 30-70% lower in pregnant than in virgin rats. Insulin sensitivity of glucose metabolism in all the tissues tested other than brain was 50% lower in pregnant than in virgin rats. We conclude that skeletal muscles and, to a smaller extent, adipose tissue are involved in the insulin resistance of late pregnancy.
TL;DR: It is found that insulin induces progressive insulin resistance with sequential effects at multiple sites in the insulin action pathway, including decreased coupling efficiency between occupied receptors and stimulated glucose transport, a postreceptor defect in insulin responsiveness of the glucose transport system, and receptor downregulation.
Abstract: We have examined the ability of insulin to regulate insulin action in primary cultured adipocytes, and found that insulin induces progressive insulin resistance in this target tissue. To assess effects at both receptor and postreceptor sites, we cultured cells in the absence (control) and presence of 100 ng/ml insulin, and, after various times, measured the dose response of insulin's ability to bind cell-surface receptors and stimulate 2-deoxyglucose transport. In control cells, insulin binding (0.2 ng/ml) was increased 10-13% due to an apparent increase in receptor affinity (6-24 h). A comparable increase in affinity was also observed in treated cells; however, concomitantly, insulin decreased the number of cell-surface receptors causing a slowly progressive net decrease in binding after a 6-10-h lag (maximal 30% at 24 h). When insulin action was assessed in control cells, the functional consequence of increased receptor binding was hypersensitization (i.e., increased insulin sensitivity) manifested by a leftward shift in the 2-deoxyglucose dose-response curve. On the other hand, in the treated cells, insulin produced insulin resistance initially by decreasing insulin sensitivity. The ED50 for insulin stimulation of glucose transport increased 84% from 0.31 to 0.57 ng/ml at 6 h without a net change in insulin binding; this was the result of a decrease in coupling efficiency between occupied receptors and the insulin effect. Receptor uncoupling progressively increased in severity, but before the full effect was reached insulin also caused a rapid decline in maximally stimulated glucose transport rates (between 6 and 10 h). This decrease in insulin responsiveness (maximal 52%) exacerbated overall insulin resistance, and was indicative of a postreceptor defect in the glucose transport system. Finally, insulin-induced receptor downregulation contributed, along with uncoupling, to a further decrease in insulin sensitivity, and constituted a more long-term regulatory mechanism. We also observed that insulin could regulate the basal glucose transport system by preventing a progressive rise in basal transport observed in control cells. In conclusion, primary cultured adipocytes can be used to study long-term regulation of insulin action. We found that insulin induces progressive insulin resistance with sequential effects at multiple sites in the insulin action pathway, including decreased coupling efficiency between occupied receptors and stimulated glucose transport, a postreceptor defect in insulin responsiveness of the glucose transport system, and receptor downregulation. These mechanisms may be relevant to the cellular defects in insulin action present i
TL;DR: It is hypothesized that failure to activate glucose storage is a major defect causing in vivo insulin resistance in subjects with normal glucose tolerance, and demonstrated that in normal subjects at both physiological and maximally stimulating plasma insulin concentrations, glucose storage was a major factor in distinguishing between those with low or high rates of insulin-mediated glucose disposal.
Abstract: In vivo “resistance” to the action of insulin on glucose uptake is commonly found in obesity and is characteristic of noninsulin-dependent diabetes mellitus in obese subjects. To investigate the relationship among glucose uptake, glucose oxidation, and nonoxidative glucose disposal (storage) in subjects with normal glucose tolerance, we studied 25 Caucasians and 79 southwestern American Indians, including lean and obese subjects in both groups. The euglycemic clamp technique with simultaneous indirect calorimetry was used to determine rates of glucose uptake and glucose oxidation. These studies were performed at two rates of insulin infusion (40 and 400 mU/m2- min), with resulting mean plasma insulin concentrations of 113 and 1839 μU/ml, respectively. At the lower insulin infusion rate, there was no glucose storage in subjects with a glucose uptake rate of about 2.2 mg/kg fat free mass min. In contrast, glucose storage accounted for over 45% of the glucose disposal in subjects with glucose uptake rates ov...
TL;DR: It is indicated that modest sustained hyperin- sulinemia may lead to decreased insulin action in the presence of normal monocyte insulin-receptor binding and normal pancreatic insulin secretion.
Abstract: Hyperinsulinemia is frequently associated with a variety of insulin-resistant states and has been implicated causally in the development of insulin resistance. This study examines the metabolic consequences of prolonged hyperinsulinemia in humans. Basally and 1 h after cessation of a 20-h infusion of insulin (0.5 mU · kg−1 · min−1, aimed at elevating plasma insulin levels to ∼30 mU/L) or normal saline, subjects were assessed for 1 ) glucose turnover with 3-[3H]glucose; 2 ) insulin sensitivity, as measured by either the euglycemic glucose-clamp technique or the intravenous glucose tolerance test (IVGTT) minimal model method of Bergman; and 3 ) monocyte insulin-receptor binding. Hepatic glucose production (Ra) was suppressed by >95% during each euglycemic clamp and during the 20-h insulin infusion. After the insulin infusion, Ra and glucose utilization rate returned to the initial basal level within 1 h, as did insulin levels. At that time, insulin sensitivity was significantly decreased, as measured by the “insulin action” parameter during the 40- to 80-min phase of the clamp (0.049 ± 0.003 vs. 0.035 ± 0.007 min−1 P < .05) and during the 80- to 120-min phase (0.047 ± 0.005 vs. 0.039 ± 0.007 min−1, .05 < P < .1). The IVGTT minimal model analysis revealed a fall in the rate of glucose disposal (KGTT) (2.8 ± 0.6 vs. 1.9 ± 0.2 min−1 P < .05), which was entirely explained by a decrease in insulin sensitivity (SI, 9.4 ± 0.3 vs. 3.8 ± 0.2 min−1 · μU−1 · ml−1, P < .02); there was no change in glucose-mediated glucose disposal (SG, 0.029 ± 0.004 vs. 0.029 ± 0.004 min−1) or pancreatic Ybgr;-cell responsiveness (o1, 2.7 ± 0.4 vs. 2.6 ± 0.5 μU · ml−1 · min mg−1 · dl−1; o2, 7.8 ± 2.4 vs. 7.8 ± 2.4 μU · ml−1 · min−2 – mg−1 · dl−1). Monocyte insulin-receptor binding was unaffected by the prolonged hyperinsulinemia.
Our studies indicate that modest sustained hyperin- sulinemia may lead to decreased insulin action in the presence of normal monocyte insulin-receptor binding and normal pancreatic insulin secretion. If the monocyte reflects insulin binding in the key insulin-sensitive tissues, this defect in insulin action probably lies at a postreceptor level.
TL;DR: The results indicate that tritiated isotopes do not necessarily equally reflect the pattern of glucose metabolism in diabetic and nondiabetic man.
Abstract: To determine whether [2(3)H], [3(3)H], and [6(14)C]glucose provide an equivalent assessment of glucose turnover in insulin-dependent diabetes mellitus (IDDM) and nondiabetic man, glucose utilization rates were measured using a simultaneous infusion of these isotopes before and during hyperinsulinemic euglycemic clamps. In the nondiabetic subjects, glucose turnover rates determined with [6(14)C]glucose during insulin infusion were lower (P less than 0.02) than those determined with [2(3)H]glucose and higher (P less than 0.01) than those determined with [3(3)H]glucose. In IDDM, glucose turnover rates measured with [6(14)C]glucose during insulin infusion were lower (P less than 0.05) than those determined with [2(3)H]glucose, but were not different from those determined with [3(3)H]glucose. All three isotopes indicated the presence of insulin resistance. However, using [3(3)H]glucose led to the erroneous conclusion that glucose utilization was not significantly decreased at high insulin concentrations in the diabetic patients. [6(14)C] and [3(3)H]glucose but not [2(3)H]glucose indicated impairment in insulin-induced suppression of glucose production. These results indicate that tritiated isotopes do not necessarily equally reflect the pattern of glucose metabolism in diabetic and nondiabetic man.
TL;DR: Significant correlations among basal levels of plasma insulin, and both testosterone and androstenedione were demonstrated in evaluating the relationship between hyperandrogenemia, insulin resistance, and acanthosis nigricans.
Abstract: The roles of hyperandrogenemia and obesity in the syndrome of severe insulin resistance with acanthosis nigricans were evaluated in studies of 11 females with this condition. Our results in these subjects were compared to evaluations of control subjects matched for degree of androgen excess or obesity. Fasting insulin levels were 3-, 5-, and 15-fold higher in the obese (OB), hyperandrogenemic (HO), and acanthosis nigricans (AN) groups, respectively, when compared to normal females. Responsiveness to a standard bolus of exogenous insulin was 78% of normal in the OB group, 40% of normal in the HO group, and 30% of normal in the AN group. Insulin binding to monocytes from both the OB group, and the HO group was modestly diminished primarily due to decreased receptor number. As a group, AN subjects when compared to either normal or weight-matched controls, demonstrated a significant decease in monocyte insulin binding predominantly due to a decrease in receptor number. However, two patients in the AN group had normal insulin binding suggesting a postreceptor mechanism for the insulin resistance in at least some of these subjects. In vivo glucose utilization insulin dose response curves were determined in 3 acanthotic subjects using the euglycemic clamp technique. All 3 of these subjects had a right shift of the curve and diminished maximal utilization, consistent with combined receptor and postreceptor defects in insulin action. In evaluating the relationship between hypeandrogenemia, insulin resistance, and acanthosis nigricans, significant correlations among basal levels of plasma insulin, and both testosterone and androstenedione were demonstrated. Further, the severity of the acanthosis nigricans was directly related to the degree of hyperinsulinemia and was not correlated to the level of androgens. Our data suggest that the insulin resistance seen in obese acanthotic subjects cannot be attributed to hyperandrogenemia or obesity, since control subjects matched for severity of androgen excess or degree of obesity had much less insulin resistance.
TL;DR: It is suggested that a significant degree of insulin resistance exists in women with hyper thecosis and that insulin stimulates ovarian stromal androgen synthesis and thus may play a role in the pathogenesis of ovarian hyperthecosis.
TL;DR: A non-insulin-dependent diabetic patient with fasting hyperinsulinemia, an elevated insulin:C-peptide molar ratio, normal insulin counterregulatory hormone levels, and an adequate response to exogenously administered insulin is identified.
Abstract: We have identified a non-insulin-dependent diabetic patient with fasting hyperinsulinemia (90 microU/ml), an elevated insulin:C-peptide molar ratio (1.68; normal, 0.05-0.20), normal insulin counterregulatory hormone levels, and an adequate response to exogenously administered insulin. Insulin-binding antibodies were absent from serum, erythrocyte insulin receptor binding was normal, and greater than 90% of circulating immunoreactive insulin coeluted with 125I-labeled insulin on gel filtration. The patient's insulin diluted in parallel with a human standard in the insulin radioimmunoassay, confirming close molecular similarity. The patient's insulin was purified from serum and shown to possess both reduced binding and ability to stimulate glucose uptake and oxidation in vitro. Analysis of the patient's insulin by high-performance liquid chromatography (HPLC) revealed two products: 7.3% of insulin immunoreactivity coeluted with the human standard, while the remaining 92.7% eluted as a single peak with increased hydrophobicity. Family studies confirmed the presence of hyperinsulinemia in four of five relatives in three generations, with secretion of an abnormal insulin documented by HPLC in the three tested. Leukocyte DNA was harvested from the propositus and the insulin gene cloned. One allele was normal, but the other displayed a thymine for guanine substitution at nucleotide position 1298 from the putative cap site, resulting in a leucine for valine substitution at position 3 of the insulin A chain. Insulin Wakayama is therefore identified as [LeuA3] insulin.
TL;DR: Peripheral hyperinsulinemia is required to normalize both fasting leucine metabolism and blood glucose concentrations and it is concluded that in type 1 diabetes a resistance to the metabolic effects of insulin on both glucose and amino acid metabolism is present.
Abstract: To determine whether a resistance to insulin in type 1, insulin-dependent diabetes mellitus (IDDM) is extended to both glucose and amino acid metabolism, six normal subjects and five patients with IDDM, maintained in euglycemia with intravenous insulin administration, were infused with L-[4,5-3H]leucine (Leu) and [1-14C]alpha ketoisocaproate (KIC). Steady-state rates of leucine-carbon appearance derived from protein breakdown (Leu + KIC Ra) and KIC (approximately leucine) oxidation were determined at basal and during sequential euglycemic, hyperinsulinemic (approximately 40, approximately 90 and approximately 1,300 microU/ml) clamps. In the euglycemic postabsorptive diabetic patients, despite basal hyperinsulinemia (24 +/- 6 microU/ml vs. 9 +/- 1 microU/ml in normals, P less than 0.05), Leu + KIC Ra (2.90 +/- 0.18 mumol/kg X min), and KIC oxidation (0.22 +/- 0.03 mumol/kg X min) were similar to normal values (Leu + KIC Ra = 2.74 +/- 0.25 mumol/kg X min) (oxidation = 0.20 +/- 0.02 mumol/kg X min). During stepwise hyperinsulinemia, Leu + KIC Ra in normals decreased to 2.08 +/- 0.19, to 2.00 +/- 0.17, and to 1.81 +/- 0.16 mumol/kg X min, but only to 2.77 +/- 0.16, to 2.63 +/- 0.16, and to 2.39 +/- 0.08 mumol/kg X min in the diabetic patients (P less than 0.05 or less vs. normals at each clamp step). KIC oxidation decreased in normal subjects to a larger extent than in the diabetic subjects. Glucose disposal was reduced at all insulin levels in the patients. In summary, in IDDM: (a) Peripheral hyperinsulinemia is required to normalize both fasting leucine metabolism and blood glucose concentrations. (b) At euglycemic hyperinsulinemic clamps, lower glucose disposal rates and a defective suppression of leucine-carbon appearance and oxidation were observed. We conclude that in type 1 diabetes a resistance to the metabolic effects of insulin on both glucose and amino acid metabolism is present.
TL;DR: Sand rats maintained on a diet providing a free choice between laboratory chow and salt bush can be regarded as a model for the development of type II diabetes in humans evoked by nutritional affluence and results suggest that in the hyperinsulinemic stage, uptake of glucose by muscle and adipose tissue is reduced, but insulin suppresses gluconeogenesis and stimulates hepatic synthesis and adipOSE tissue uptake of TG.
Abstract: Sand rats ( Psammomys obesus ) maintained on a diet providing a free choice between laboratory chow and salt bush ( Atriplex halimus ) were classified into four groups differing in extent of the diabetic syndrome: A, normoglycemic-normoinsulinemic; B, normoglycemichyperinsulinemic; C, hyperglycemic-hyperinsulinemic; or D, hyperglycemic with reduced insulin levels. The metabolic pattern of these groups was characterized by measuring 1) the uptake of fatty acid-labeled, very-lowdensity lipoprotein-borne triglycerides (VLDL-TG) and [ 3 H]%-2-deoxyglucose (2-DOG) into muscle and adipose tissues; 2) incorporation of [ 14 C]alanine into glycogen in vivo; 3) gluconeogenesis from lactate, pyruvate, and alanine in hepatocytes; 4) the effect of insulin on glycogen synthesis from glucose; 5) the oxidation of albumin-bound [1- 14 C]palmitate and [ 14 C]glucose in strips of soleus muscle; 6) activities of muscle and adipose tissue lipoprotein lipase; and 7) activities of rate-limiting enzymes of glycolysis, gluconeogenesis, and fatty acid synthesis in liver. In group A, uptake of VLDL-TG and activity of lipoprotein lipase were higher in adipose tissue and lower in muscle than in albino rats. In the liver, gluconeogenesis and the activity of phosphoenolpyruvate carboxykinase, as well as lipid synthesis and the activity of NAOP-malate dehydrogenase,were higher than in albino rats, whereas activity of pyruvate kinase was lower. In group B, uptake of VLDL-TG by adipose tissue and muscle and lipoprotein lipase activity were similar or higher than in group A. Uptake of 2-DOG by muscle and adipose tissue and activity of liver phosphoenolpyruvate carboxykinase were lower than in group A. In groups C and D, uptake of VLDL-TG and lipoprotein lipase activity in muscle were further increased. In adipose tissue a progressive decrease in VLDL-TG uptake and lipoprotein lipase activity was found, and uptake of 2-DOG by muscle and adipose tissue was further reduced. In the liver, gluconeogenesis was increased, and activity of phosphoenolpyruvate carboxykinase reached a maximum in group D. These results suggest that in the hyperinsulinemic stage (group B), uptake of glucose by muscle and adipose tissue is reduced, but insulin suppresses gluconeogenesis and stimulates hepatic synthesis and adipose tissue uptake of TG. Hyperglycemia manifests itself when insulin resistance results in increased gluconeogenesis and a further reduction in peripheral glucose uptake. These characteristics can be regarded as a model for the development of type II diabetes in humans evoked by nutritional affluence.
TL;DR: When compared with lean patients, obese patients with previous gestational diabetes had significantly greater insulin response to the intravenous glucose tolerance test and insulin resistance, consistent with reported findings of an early and progressive development of overt diabetes in patients who had Gestational diabetes.
TL;DR: It is concluded that hyperandrogenism in obese patients with polycystic ovaries does not appear to be a primary factor leading to the insulin-resistant state.
TL;DR: It is concluded that this syndrome is extremely rare and that misdiagnosis is common, and the clinical diagnosis of subcutaneous-insulin resistance is confirmed.
Abstract: In numerous patients with diabetes mellitus, a defect in the absorption of subcutaneously injected insulin has been suspected as an explanation for diabetic instability. The common clinical characteristic of these patients is poor metabolic control when insulin is injected subcutaneously, but good metabolic control when the insulin is infused intravenously. We have used three approaches to attempt to identify patients with "subcutaneous-insulin resistance." First, we performed a series of studies of subcutaneous-insulin absorption in 16 patients referred to us with a presumptive diagnosis of resistance to subcutaneous insulin; in none of these patients did we detect an abnormal response of blood glucose levels to insulin administered subcutaneously. Plasma free-insulin levels rose normally after injection. Second, we assayed insulin-degrading activity in subcutaneous biopsy specimens obtained from 25 patients throughout North America and Europe who had been diagnosed as resistant to subcutaneous insulin. In none of these patients did the insulin-degrading activity of subcutaneous tissue exceed the mean value (+/- 2 SD) of eight subcutaneous biopsy specimens obtained from control patients with diabetes. Third, we performed studies of tritiated-insulin absorption in three additional diabetic patients and three control patients with nonbrittle diabetes. These studies also suggested normal absorption of insulin. In none of the patients we studied were we able to confirm the clinical diagnosis of subcutaneous-insulin resistance. We therefore conclude that this syndrome is extremely rare and that misdiagnosis is common.
TL;DR: Five patients with fatal acute liver failure, given 5 g h‐1 of glucose for the previous 12 h, were investigated by the hyper‐ and euglycaemic glucose ‘clamp’ technique, and the results compared with reported control values exhibited pronounced insulin insensitivity and hyperinsulinaemia.
Abstract: Five patients with fatal acute liver failure, given 5 g h-1 of glucose for the previous 12 h, were investigated by the hyper- and euglycaemic glucose 'clamp' technique, and the results compared with reported control values. Initial average blood glucose concentration was normal (6.0 mmol l-1, range 5.0-8.8). Plasma insulin and C-peptide concentrations were increased about tenfold (1450 pmol l-1, range 330-4021, and 3000 pmol l-1, range 670-7650, respectively). The whole body glucose metabolic rate was decreased to about half control values (21 mumol min-1 kg-1, range 6-28) and the insulin sensitivity of the glucose metabolism was decreased to about 15% (9.4 m3 min-1 kg-1, range 3.6-14.4). The calculated metabolic clearance of insulin was normal (520 ml min-1 (m2)-1, range 305-1027) and the calculated systemic delivery rate of insulin was about sixfold increased (1135 pmol min-1 (m2)-1, range 474-2010). The initial glucagon concentrations were fifty-fold increased (550 pmol 1, range 72-1309) and not suppressible by glucose and insulin. The patients thus exhibited pronounced insulin insensitivity and hyperinsulinaemia, attributable primarily to pancreatic hypersecretion. The reason for the relation between, and the pathogenetic importance of, these findings is not known.