Insulin Resistance In Man Research Articles

A Possible Relationship Between Testosterone and Lower Urinary Tract Symptoms in Men

In this study we searched for possible associations between serum testosterone levels and the severity of lower urinary tract symptoms in men. In 278 patients with a mean age of 62 years blood levels of total testosterone, albumin, sex hormone-binding globulin, fasting glucose, fasting insulin and high sensitivity C-reactive protein were measured. Free testosterone, bioavailable testosterone and homeostasis model assessment of insulin resistance were calculated. Prostate volume was measured by transrectal ultrasonography and the severity of lower urinary tract symptoms was assessed using the International Prostate Symptom Score. Calculated free testosterone and bioavailable testosterone were negatively related to International Prostate Symptom Score total scores and subscores (voiding symptoms) after adjusting for age, prostate volume, high sensitivity C-reactive protein and homeostasis model assessment of insulin resistance (p <0.05). In addition, calculated free testosterone and bioavailable testosterone were significantly related to the presence of severe lower urinary tract symptoms (International Prostate Symptom Score 20 or greater) using unadjusted and adjusted models (p <0.05), although the odds ratio of bioavailable testosterone was lower than that of calculated free testosterone on multivariate analysis. High sensitivity C-reactive protein was negatively correlated with serum total testosterone (r = -0.128, p = 0.038) and bioavailable testosterone (r = -0.126, p = 0.041), and homeostasis model assessment of insulin resistance was negatively correlated with serum total testosterone (r = -0.236, p <0.001), calculated free testosterone (r = -0.179, p = 0.003) and bioavailable testosterone (r = -0.162, r = 0.007). However, no significant correlation was found between high sensitivity C-reactive protein or homeostasis model assessment of insulin resistance, and International Prostate Symptom Score total scores, voiding symptoms scores and storage symptoms scores. Our findings support the favorable role of endogenous testosterone in lower urinary tract function and suggest that testosterone deficiency may be a pathophysiological mechanism connecting lower urinary tract symptoms and the metabolic syndrome in men.

Mammalian hibernation: a naturally reversible model for insulin resistance in man?

Mammalian hibernators such as ground squirrels store massive amounts of fat each autumn. These fat depots serve as the main source of metabolic fuel throughout the winter, gradually decreasing over a period of months until the animals emerge from hibernation each spring. Fat deposition occurs on an approximately annual, i.e. on a circannual, basis. Although this rhythm occurs in the absence of environmental temperature and light cues, it is entrained by the length of daylight, with peak fat deposition occurring as days shorten in the autumn. Here we examine the circ-annual cycle of hibernation, and then explore the similarities and differences between the obligatory, yet reversible, natural obesity and accompanying insulin resistance of natural hibernation, and the pandemic of human obesity and metabolic syndrome.

Function determines structure in the vasculature: lessons from insulin resistance

vascular dysfunction has been well characterized in both human and experimental insulin resistance. Alterations in a range of features of vascular function have been described with insulin resistance ([15][1], [18][2]), including thickened resistance vessel walls with increased structural stiffness

Interleukin-6 (IL-6) Induces Insulin Resistance in 3T3-L1 Adipocytes and Is, Like IL-8 and Tumor Necrosis Factor-α, Overexpressed in Human Fat Cells from Insulin-resistant Subjects

Several studies have shown a relationship between interleukin (IL) 6 levels and insulin resistance. We here show that human subcutaneous adipose cells, like 3T3-L1 cells, are target cells for IL-6. To examine putative mechanisms and cross-talk with insulin, 3T3-L1 adipocytes were cultured for different times with IL-6 and tumor necrosis factor alpha (TNF-alpha). IL-6, in contrast to TNF-alpha, did not increase pS-307 of insulin-receptor substrate (IRS)-1 or JNK activation. However, IL-6, like TNF-alpha exerted long term inhibitory effects on the gene transcription of IRS-1, GLUT-4, and peroxisome proliferator-activated receptor gamma. This effect of IL-6 was accompanied by a marked reduction in IRS-1, but not IRS-2, protein expression, and insulin-stimulated tyrosine phosphorylation, whereas no inhibitory effect was seen on the insulin receptor tyrosine phosphorylation. Consistent with the reduced GLUT-4 mRNA, insulin-stimulated glucose transport was also significantly reduced by IL-6. An important interaction with TNF-alpha was found because TNF-alpha markedly increased IL-6 mRNA and protein secretion. These results show that IL-6, through effects on gene transcription, is capable of impairing insulin signaling and action but, in contrast to TNF-alpha, IL-6 does not increase pS-307 (or pS-612) of IRS-1. The link between IL-6 and insulin resistance in man was further corroborated by the finding that the expression of IL-6, like that of TNF-alpha and IL-8, was markedly increased ( approximately 15-fold) in human fat cells from insulin-resistant individuals. We conclude that IL-6 can play an important role in insulin resistance in man and, furthermore, that it may act in concert with other cytokines that also are up-regulated in adipose cells in insulin resistance.

Prolonged adaptation to fat-rich diet and training; effects on body fat stores and insulin resistance in man.

To investigate the effect of prolonged adaptation to training and fat- or carbohydrate-rich diet on body composition and insulin resistance. Longitudinal study. Of three groups two consumed a fat-rich diet, of which one performed regular training (FAT-Train, n=17) and the other maintained normal habitual activity (Fat-Control, n=8). The third group trained and consumed a carbohydrate-rich diet (CHO-Train, n=16). Forty-one untrained, healthy male subjects. Before and after 7 weeks body composition was estimated from skinfold measurements. At rest the respiratory exchange ratio (RER) was determined by the Douglas bag technique. Glycogen was determined in m vastus lateralis and concentrations of insulin and triacylglycerol in serum and glucose, fatty acid and beta-hydroxy-butyrate in plasma was measured. The insulin resistance index was calculated from fasting plasma insulin and glucose values. Across the 7 weeks body weight was reduced (1.3+/-0.3%) in all three groups, however body fat mass was decreased only in the CHO-Train (13%) and maintained in the two FAT-groups. RER at rest was similarly decreased (5%) in the three groups. Plasma insulin tended to decrease (16%) in CHO-Train (P=0.065) and remained unchanged in the two FAT-groups. In contrast plasma glucose (4.6+/-0.1 mmol/l) and plasma FA (453+/-27 micromol/l) remained unchanged across the 7 weeks. The calculated insulin resistance index HOMA-R(mod) was significantly decreased by 19% in CHO-train but remained unchanged in both of the FAT-groups, whereas the calculated insulin secretion index HOMA-beta(mod) was unchanged in all three groups. In the present study we demonstrate that despite of a mild energy deficit body fat mass was maintained after prolonged adaptation to fat-rich diet both when normal physical activity was maintained and when training was performed. In contrast a significant decrease in fat mass was observed when carbohydrate-rich diet and training was combined. Furthermore we observed that the insulin resistance index was significantly decreased only when training was combined with a carbohydrate-rich diet.

Changes in phsophatidylcholine fatty acid composition are associated with altered skeletal muscle insulin responsiveness in normal man

The fatty acid composition of skeletal muscle cell membrane phospholipids (PLs) is known to influence insulin responsiveness in man. We have recently shown that the fatty acid composition of phosphatidylcholine (PC), and not phosphatidylethanolamine (PE), from skeletal muscle membranes is of particular importance in this relationship. Efforts to alter the PL fatty acid composition in animal models have demonstrated induction of insulin resistance. However, it has been more difficult to determine if changes in insulin sensitivity are associated with changes in the skeletal muscle membrane fatty acid composition of PL in man. Using nicotinic acid (NA), an agent known to induce insulin resistance in man, 9 normal subjects were studied before and after treatment for 1 month. Skeletal muscle membrane fatty acid composition of PC and PE from biopsies of vastus lateralis was correlated with insulin responsiveness using a 3-step hyperinsulinemic-euglycemic clamp. Treatment with NA was associated with a 25% increase in the half-maximal insulin concentration ([ED50] 52.0 +/- 7.5 to 64.6 +/- 9.0 microU/mL, P < .05), consistent with decreased peripheral insulin sensitivity. Significant changes in the fatty acid composition of PC, but not PE, were also observed after NA administration. An increase in the percentage of 16:0 (21% +/- 0.3% to 21.7% +/- 0.4%, P < .05) and decreases in 18:0 (6.2% +/- 0.5% to 5.1% +/- 0.4%, P = .01), long-chain n-3 fatty acids (1.7% +/- 0.2% to 1.4% +/- 0.1%, P < .01), and total polyunsaturated fatty acids ([PUFAs] 8.7% +/- 0.8% to 8.0% +/- 0.8%, P < .05) are consistent with a decrease in fatty acid length and unsaturation in PC following NA administration. The change in ED50 was significantly correlated with the change in PUFAs (r = -.65, P < .05). These studies suggest that the induction of insulin resistance with NA is associated with changes in the fatty acid composition of PC in man.

Insulin signaling and action in fat cells: associations with insulin resistance and type 2 diabetes.

Adipose tissue only accounts for a relatively small proportion (< 10%) of the peripheral glucose utilization in response to insulin. However, the fat cells may still play an important role in insulin resistance and Syndrome X through, for instance, its endocrine functions (production of leptin, TNF alpha, PAI-1, etc.) and involvement in lipid metabolism (FFA release and hydrolysis of triglycerides). The fat cells are also highly sensitive to insulin and may thus be used to elucidate molecular mechanisms for insulin resistance in man. Examinations of the intracellular signaling mechanisms for insulin in fat cells from individuals with Type 2 diabetes revealed markedly lower insulin-stimulated PI3-kinase activity. This was due to a pronounced reduction in the cellular expression of the docking protein, IRS 1, whereas expression of IRS 2 was normal. However, IRS 2-associated PI3-kinase activity was only approximately one-third of that found to be associated with IRS 1 in normal cells. Downstream activation and serine phosphorylation of PKB/Akt by insulin were also markedly reduced in Type 2 diabetes. Furthermore, the dose-response curve for this effect of insulin was similar to that for glucose transport in both normal and Type 2 diabetic cells. Thus, these data show that both PI3-kinase and PKB activation by insulin are markedly reduced in Type 2 diabetes. We also examined whether an attenuated activation of PI3-kinase by insulin can be seen in non-diabetic insulin-resistant states. Approximately 30% of healthy subjects with at least two first-degree relatives with Type 2 diabetes exhibited perturbations in IRS-1 expression and signaling. These individuals were characterized by insulin resistance as well as other markers of Syndrome X. Thus, impaired IRS-1 expression and downstream signaling events in fat cells in response to insulin are associated with insulin resistance and Syndrome X.

Role of substrate competition in the pathogenesis of insulin resistance in man.

Carbohydrates, proteins and lipids share common metabolic pathways which may play important roles in the regulation of glucose metabolism. For the purpose of synthesis of energy-rich equivalents, catabolism of carbohydrates, lipids and several amino acids converge to yield acetyl coenzyme A (CoA) which will subsequently be oxidized in the tricarboxylic acid cycle. Other amino acids are converted to intermediate substrates of the same cycle. Oxidation of acetyl CoA is coupled to the synthesis of ATP and is therefore determined essentially by the rate of ADP formation from ATP or, in other words, by energy expenditure. Since acetyl CoA oxidation is pulled by the rate of ATP hydrolysis and cannot be pushed by substrate provision, excessive synthesis of acetyl CoA from one of the macro nutrients may subsequently interfere with the catabolism of other nutrients. Thus, from a theoretical point of view, an excess supply of lipids or amino acids may possibly interfere with glucose utilisation (Fig. 1). Most amino acids, the glycerol molecules released during hydrolysis of triglycerides and the lactate/pyruvate produced by non-oxidative glycolysis may also be reconverted to glucose in the gluconeogenic pathway. This is known to occur essentially in liver and kidney cells and it is currently estimated that it contributes to 30–60% of overall fasting glucose production (1–3). Obesity is characterized by various degrees of whole body insulin resistance and hyperinsulinemia. Noninsulin dependent diabetes mellitus (NIDDM) is encountered with increased frequency in obese patients, indicating that this condition confers an increased risk for this disease (4). Alterations in the metabolism of lipids and proteins are also encountered in obese patients, due to changes in substrate intake and body composition. In particular, obese patients display increased rates of lipid oxidation and enhanced concentrations of free fatty acids in their blood. Tracer studies demonstrate that they have increased rates of glycerol and free fatty acid turnover, indicating increased lipolysis (5–7). Obese patients also have elevated protein turnover rates (8). This increased availability of lipid and amino acid substrates may possibly exert important effects on glucose metabolism which could contribute to insulin resistance. At the skeletal muscle and adipose cell level where insulin stimulates glucose oxidation, increased oxidation rates of other macro nutrients, driven by their increased blood concentrations, may interfere with glucose oxidation and hence its utilisation. At the level of the liver and kidneys, enhanced provision of glucose precursors may stimulate glucose synthesis and increase hepatic glucose production. The blood glucose concentration is controlled by the balance between the systemic delivery of glucose on the one hand, and glucose utilisation on the other. The former results from glycogenolysis and gluconeogenesis in liver and kidney cells, while the latter corresponds to glucose oxidation, which occurs at a constant rate in insulin-insensitive tissues (e.g. brain, kidney, medullae, etc.) and at variable rates according to insulin concentrations in insulinsensitive tissues (e.g. skeletal muscle, adipose cells, etc.), and glucose storage as glycogen. Insulin regulates blood glucose concentrations by modulating both glucose production and glucose utilisation.

Expression of the putative inhibitor of the insulin receptor tyrosine kinase PC-1 in dermal fibroblasts from patients with syndromes of severe insulin resistance.

To date, mutations in the insulin receptor gene are the only clearly defined cause of extreme insulin resistance in man. Recently, however, some patients with severe insulin resistance have been reported to have marked over-expression of the transmembrane glycoprotein PC-1 in their cultured fibroblasts. This protein appears to act as an endogenous inhibitor of the insulin receptor tyrosine kinase which suggests that primary over-expression of PC-1 may play an aetiological role in some forms of insulin resistance. One sub-type of extreme insulin resistance in which the insulin receptor gene has been reported to be normal is pseudo-acromegalic insulin resistance. The main aim of this study was to determine whether overexpression of PC-1 might contribute to the severe insulin resistance exhibited by some patients with pseudo-acromegaly. DESIGN AND PATIENTS PC-1 phosphodiesterase activity and PC-1 protein and mRNA content were measured in cultured dermal fibroblast from three severely insulin resistant pseudo-acromegalic patients. These were compared with fibroblasts from normoinsulinaemic normoglycaemic controls and from subjects with known genetic defects in the insulin receptor or IRS-1. In the fibroblasts from pseudo-acromegalic insulin resistant subjects PC-1 activity and PC-1 protein and mRNA levels were indistinguishable from the normoinsulinaemic controls. Consistent with this observation, insulin receptor tyrosine kinase activity was similar in extracts from fibroblasts of pseudo-acromegalic subjects and normal controls. Surprisingly, subjects with insulin receptor or IRS-1 mutations had a profound reduction in PC-1 activity (p < or = 0.005), protein (p < or = 0.05) and mRNA levels (P < or = 0.005). The results indicate that PC-1 over-expression does not appear to contribute to the insulin resistant state of pseudo-acromegalic patients. The finding of normal insulin receptor tyrosine kinase activity in these subjects suggests that the site of defective insulin signalling is likely to be distal to the receptor. The unexpected finding that PC-1 activity, protein and mRNA were all dramatically reduced in patients with lesions early in the insulin signalling cascade provides further evidence for a link, albeit as yet poorly understood, between cellular insulin action and the expression of PC-1.

Mutant insulin receptors in syndromes of insulin resistance

To date, mutations of the insulin receptor remain the only well-established causes of severe insulin resistance. There is a broad correlation between the extent of impairment of signal transduction seen when the mutant receptors are expressed in vitro with the severity of the clinical phenotype. Thus leprechaunism, Rabson-Mendenhall syndrome and Type A insulin resistance appear to represent points on a continuum of severity of receptor dysfunction, rather than completely distinct syndromes. In other syndromes of insulin resistance, insulin receptor abnormalities remain the exception. However, functional studies of expressed naturally occurring insulin receptor mutations have acted as experiments of nature and greatly aided attempts to dissect the structure-function relationships of the receptor. The next few years will no doubt begin to reveal the contributions made by defects in the post-receptor signalling cascade to the syndromes of insulin resistance in man.

Alcohol and glucose metabolism in skeletal muscles in the rat.

Ethanol is known to cause an acute and profound insulin resistance in man and the rat primarily via effects on glucose utilization. This paper examines the nature of these inhibitory effects on whole-body glucose utilization using the euglycaemic hyperinsulinaemic clamp in the conscious unrestrained rat. We confirm that ethanol infusion causes an acute insulin resistance, the rate of glucose infusion required to maintain euglycaemia (GIR) being decreased markedly by ethanol. To ensure that the GIR is a measure of whole-body glucose disposal, glucose turnover and hepatic glycogen levels were measured. These studies showed that ethanol totally suppressed hepatic glucose production. The reduction in GIR is associated with marked decreases in glucose uptake and glycogen synthesis in most skeletal muscles. In oxidative but not in non-oxidative muscles, the activation of glycogen synthase in response to insulin was decreased by ethanol, suggesting that a defect in glycogen synthase activation may be responsible for the decrease in glycogen synthesis. The basis of the inhibitory effects of ethanol on insulin-stimulated glucose metabolism in muscle is unknown, but may involve membrane-associated impairments in insulin signalling and/or the glucose transport system.

High-fat feeding induces tissue-specific alteration in proportion of activated insulin receptors in rats

High dietary fat intake causes glucose intolerance and insulin resistance in man and in laboratory rats. We studied possible mechanisms of this insulin resistance in rat kidney, muscle and liver. In high-fat fed rats the body weight, plasma insulin concentration, plasma glucose levels, and serum triglyceride concentration were significantly higher than in the control rats. 125I-insulin binding to kidney basolateral membrane insulin receptors from high-fat fed rats was lower than in control rats. Basal as well as insulin-stimulated tyrosine kinase activity per insulin receptor was higher in the high-fat fed group, accompanied by increased autophosphorylation of the beta-subunit of the receptor and higher proportion of tyrosine-phosphorylated insulin receptors. In contrast, both in the skeletal muscle and the liver the insulin-stimulated tyrosine kinase activity per insulin receptor was significantly lower in high-fat fed animals, accompanied by diminished autophosphorylation of the beta-subunit of the receptor and lower proportion of tyrosine-phosphorylated receptors. Our results indicate tissue-specific alterations in transmembrane signaling induced by high-fat feeding in target tissues for insulin which in turn might contribute to the observed insulin resistance.

Artificial induction of intravascular lipolysis by lipid-heparin infusion leads to insulin resistance in man.

Although extensive evidence indicates that free fatty acids can decrease glucose utilization in vitro, it is still controversial how an increase in lipolysis affects glucose metabolism in man. To test the hypothesis that an increase in lipolysis is related to insulin resistance, we examined the effect of lipid-heparin infusion on glucose metabolism in ten normal subjects by the euglycaemic glucose clamp technique and isotopic determination of glucose turnover. In the control euglycaemic clamp studies with insulin infusion at 0.2 and 1.0 mU.kg-1.min-1, endogenous glucose production was suppressed from the basal rate of 2.0 +/- 0.3 mg.kg-1min-1 to 1.1 +/- 0.7 mg.kg-1.min-1 and -0.4 +/- 0.7 mg.kg-1min-1 respectively. Glucose utilization increased from the basal rate of 2.0 +/- 0.3 mg.kg-1min-1 to 2.3 +/- 0.5 mg.kg-1min-1 and 5.9 +/- 1.8 mg.kg-1min-1 respectively. When the euglycaemic clamp studies were coupled with lipid-heparin infusion at comparable low and high rates of insulin infusion, endogenous glucose production increased (1.8 +/- 0.7 mg.kg-1.min-1, p less than 0.001, and 0.3 +/- 0.6 mg.kg-1.min-1, p less than 0.05, respectively), and glucose utilization decreased (2.1 +/- 0.3 mg.kg-1.min-1, not significant, and 3.2 +/- 0.7 mg.kg-1.min-1, p less than 0.001 respectively). These data suggest that the artificial induction of intravascular lipolysis by lipid-heparin infusion leads to a state of insulin resistance in man.

Importance of substrate competition in the mechanism of insulin resistance in man

Carbohydrate (CHO) oxidation induced by a glucose or fructose (0.5 g/kg × h) infusion over two hours was compared for 160 minutes by means of continuous indirect calorimetry in seven normal subjects without or with a concomitant infusion of Intralipid, a neutral fat emulsion. The glucose infusion was accompanied by a rise over basal values in both glucose (99 ± 10 mg/dL) and insulin (36 ± 7 μU/mL) plasma levels, with a further rise of both curves during the Intralipid infusion (140 ± 7 mg/dL and 53 ± 12 μU/mL). By contrast, plasma glucose and insulin rose only minimally during the fructose infusion (3.5 ± 2.9 mg/dL and 5.3 ± 1.4 μU/mL, respectively, without Intralipid, and 10.6 ± 2.1 mg/dL and 9.6 ± 2.0 μU/mL with Intralipid). During the two-hour sugar infusion, a mean quantity of 68.7 g glucose or fructose was infused. The total CHO oxidation was 15.6 ± 1.2 g for glucose and 21.6 ± 2.6 for fructose infusion for the 160 minutes of the test. During the Intralipid infusion, CHO oxidation was inhibited with values of 5.9 ± 1.3 g for glucose ( P < .005) and 13.8 ± 1.8 g ( P < .05) for fructose infusion. Lipid oxidation was increased in both cases during the Intralipid infusion. These results show that the lipid-induced inhibition of CHO oxidation observed with glucose infusion also occurs to some extent with fructose, suggesting that insulin might not be primarily involved. They suggest a metabolic origin for insulin resistance during elevated fat metabolism.

Production of insulin resistance by hyperinsulinaemia in man.

It has been proposed that hyperinsulinaemia may cause or exacerbate insulin resistance. The present studies were undertaken to test this hypothesis in man. Glucose utilization, glucose production, and overall glucose metabolism at submaximally and maximally effective plasma insulin concentrations (approximately 80 and approximately 1700 mU/l), and monocyte and adipocyte insulin binding were measured in normal volunteers on two occasions: once after 40 h of hyperinsulinaemia (25-35 mU/l) produced by infusion of insulin and once after infusion of saline (75 mmol/l; plasma insulin approximately 10 mU/l). After 40 h of hyperinsulinaemia, glucose utilization and overall glucose metabolism at submaximally and maximally effective plasma insulin concentrations were both slightly, but significantly, reduced compared with values observed after the infusion of saline (p less than 0.05), whereas glucose production rates were unaffected. Monocyte and adipocyte binding were also unaffected. These results indicate that hyperinsulinaemia of the magnitude observed in insulin resistant states, such as obesity, can produce insulin resistance in man. Assuming that human insulin sensitive tissues possess spare insulin receptors and that monocyte and adipocyte insulin binding accurately reflect insulin binding in insulin-sensitive tissues, the decreased maximal responses to insulin and the lack of change in insulin binding suggest that this insulin resistance occurred at a post-binding site.

Infusion of insulin impairs human adipocyte glucose metabolism in vitro without decreasing adipocyte insulin receptor binding.

To determine whether hyperinsulinaemia can cause insulin resistance in man and, if so, whether this occurs at a receptor or post-receptor site, nine normal volunteers were infused with insulin for 6 h at a rate (2 mU X kg-1 X min-1) which resulted in steady-state plasma insulin concentrations of 140 +/- 13 mU/l and four subjects were infused with saline (0.45%). Isolated adipocytes and monocytes were used as models for studying insulin binding, while adipocytes were also used to study insulin action in vitro. Adipocyte insulin binding did not decrease following infusion of insulin (4.6 +/- 0.5 versus 4.4 +/- 0.4% per 2 X 10(5) cells, before and after, respectively), whereas monocyte insulin binding did (7.2 +/- 0.6 versus 6.2 +/- 0.6% per 10(7) cells, p less than 0.05). Initial rates of adipocyte 3-0-methyl glucose transport were decreased in the absence of insulin (basal) and at submaximally effective (33.3 pmol/l) but not at maximally effective insulin concentrations. At all insulin concentrations and in the absence of insulin, rates of glucose conversion to lipids were decreased more than 50% (p less than 0.05), whereas rates of glucose oxidation were unaffected. This decrease in the rates of conversion of glucose to lipids could not be accounted for by the decrease in rates of glucose transport. These results suggest that hyperinsulinaemia can cause insulin resistance in man and that, at least initially, this occurs at a post-receptor site. Furthermore, the discordant effect of hyperinsulinaemia on monocyte and adipocyte insulin binding indicates that monocyte insulin binding may not always reflect insulin binding in insulin-sensitive tissues.

Insulin resistance in Cushing's syndrome.

It is well established that cortisol excess causes insulin resistance in man, but the mechanisms responsible for this insulin resistance are poorly understood. We studied five women with Cushing's syndrome with impaired oral glucose tolerance tests and seven normal subjects, plotting the shape of the insulin-induced disposal dose-response curve obtained by means of the euglycemic clamp procedure during four different plasma insulin plateaus at four infusion rates of 21, 73, 760, and 1200 mU/M2 . min. Glucose disposal (M = mg/M2 . min) was calculated as glucose amount infused to maintain euglycemia. In Cushing's syndrome the dose-response curve was shifted to the right in comparison with normal subjects, with a significantly lower M (337 +/- 35 vs. 657 +/- 76 P less than 0.01) during the highest insulin infusion rate [maximal glucose disposal (MGD)] without any significant difference in the levels of insulin half-maximally effective in the stimulation of glucose utilization. Neither erythrocyte nor monocyte maximum insulin receptor binding were different between the two populations. Four Cushing's syndrome patients were studied again after surgical treatment. A marked improvement of MGD was observed without any significant change in insulin-binding capacity. These results, particularly the marked decrease in MGD, a typical feature of postreceptor defects, indicate that cortisol-induced insulin resistance in man is due to an impairment of peripheral insulin action located beyond the hormone-receptor binding step.

Effects of growth hormone on insulin action in man. Mechanisms of insulin resistance, impaired suppression of glucose production, and impaired stimulation of glucose utilization.

The present studies were undertaken to assess the mechanisms responsible for growth hormone-induced insulin resistance in man. The insulin dose-response characteristics for suppression of glucose production and stimulation of glucose utilization and their relationship to monocyte insulin binding were determined in six normal volunteers after 12-h infusion of growth hormone and 12-h infusion of saline. The infusion of growth hormone (2 micrograms . kg-1 . h-1) increased plasma growth hormone nearly threefold (to congruent to 9 ng/ml) within the range observed during sleep and exercise. This increased plasma insulin (14 +/- 1 versus 8 +/- 1 microunits/ml, P less than 0.005) concentrations without significantly altering plasma glucose concentrations or basal rates of glucose production and utilization. Insulin dose-response curves for both suppression of glucose production (half-maximal response at 37 +/- 3 versus 20 +/- 3 microunits/ml, P less than 0.01) and stimulation of glucose utilization (half-maximal response at 98 +/- 8 versus 52 +/- 8 microunits/ml, P less than 0.01) were shifted to the right with preservation of normal maximal responses to insulin. Monocyte insulin binding was unaffected. Thus, except at near maximal insulin receptor occupancy, the action of insulin on glucose production and utilization per number of monocyte insulin receptors occupied was decreased. These results indicate that increases in plasma growth hormone within the physiologic range can cause insulin resistance in man, which is due to decreases in both hepatic and extrahepatic effects of insulin. Assuming that insulin binding to monocytes reflects insulin binding in insulin sensitive tissues, this decrease in insulin action can be explained on the basis of a postreceptor defect.

Cortisol-induced insulin resistance in man: impaired suppression of glucose production and stimulation of glucose utilization due to a postreceptor detect of insulin action.

The present studies were undertaken to assess the mechanisms responsible for cortisol-induced insulin resistance in man. The insulin dose-response characteristics for suppression of glucose production and stimulation of glucose utilization and their relationship to monocyte and erythrocyte insulin receptor binding were determined in six normal volunteers after 24-h infusion of cortisol and 24-h infusion of saline. The infusion of cortisol (2 microgram kg-1 min-1) increased the plasma cortisol concentration approximately 4-fold (37 +/- 3 vs. 14 +/- 1 microgram/dl; P less than 0.01) to values observed during moderately severe stress in man. This hypercortisolemia increased postabsorptive plasma glucose (126 +/- 2 vs. 97 +/- 2 mg/dl; P less than 0.01) and plasma insulin (16 +/- 2 vs. 10 +/- 2 microU/ml; P less than 0.01) concentrations and rates of glucose production (2.4 +/- 0.1 vs. 2.1 +/- -0.1 mg kg-1 min-1; P less than 0.01) and utilization (2.5 +/- 0.1 vs. 2.1 +/- 0.1 mg kg-1 min -1; P less than 0.01). Insulin dose-response curves for both suppression of glucose production (half-maximal response at 81 +/- 19 vs. 31 +/ 5 microU/ml; P less than 0.05) and stimulation of glucose utilization (half-maximal response at 104 +/- 9 vs. 64 +/- 7 microU/ml; P less than 0.01) were shifted to the right, with preservation of normal maximal responses to insulin. Neither monocyte nor erythrocyte insulin binding was decreased. However, except at near-maximal insulin receptor occupancy, the action of insulin on glucose production and utilization per number of monocyte and erythrocyte insulin receptors occupied was decreased. These results indicate that the cortisol-induced insulin resistance in man is due to the decrease in both hepatic and extrahepatic sensitivity to insulin. Assuming that insulin binding to monocytes and erythrocytes reflects insulin binding in insulin-sensitive tissues, this decrease in insulin action can be explained on the basis of a postreceptor defect.

Mechanisms of insulin resistance in man: Assessment using the insulin dose-response curve in conjunction with insulin-receptor binding

During the past few years it has become increasingly apparent that insulin resistance may be a more frequent cause of carbohydrate intolerance or contributing factor in carbohydrate intolerance than was hitherto appreciated. Abnormal insulin action may result from prereceptor, receptor or postreceptor defects. These may be manifested by an increase in the concentration of insulin necessary for a half-maximal effect (decreased sensitivity) or a decrease in the maximal response to insulin (decreased responsiveness), or both. Alterations in sensitivity and responsiveness to insulin can be distinguished only by evaluating insulin dose-response curves. When used in conjunction with measurements of insulin binding to its receptor, the characteristics of these curves can provide insight into the mechanism or mechanisms responsible for insulin resistance.