Showing papers on "Insulin resistance published in 1993"
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TL;DR: A role for TNF-alpha in obesity and particularly in the insulin resistance and diabetes that often accompany obesity is indicated.
Abstract: Tumor necrosis factor-alpha (TNF-alpha) has been shown to have certain catabolic effects on fat cells and whole animals. An induction of TNF-alpha messenger RNA expression was observed in adipose tissue from four different rodent models of obesity and diabetes. TNF-alpha protein was also elevated locally and systemically. Neutralization of TNF-alpha in obese fa/fa rats caused a significant increase in the peripheral uptake of glucose in response to insulin. These results indicate a role for TNF-alpha in obesity and particularly in the insulin resistance and diabetes that often accompany obesity.
7,347 citations
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TL;DR: Obesity, insulin resistance, and low acute plasma insulin response to intravenous glucose (with the degree of obesity and insulin resistance taken into account) were predictors of NIDDM.
Abstract: Background The relative roles of obesity, insulin resistance, insulin secretory dysfunction, and excess hepatic glucose production in the development of non-insulin-dependent diabetes mellitus (NIDDM) are controversial. We conducted a prospective study to determine which of these factors predicted the development of the disease in a group of Pima Indians. Methods A body-composition assessment, oral and intravenous glucose-tolerance tests, and a hyperinsulinemic-euglycemic clamp study were performed in 200 nondiabetic Pima Indians (87 women and 113 men; mean [±SD] age, 26 ±6 years). The subjects were followed yearly thereafter for an average of 5.3 years. Results Diabetes developed in 38 subjects during follow-up. Obesity, insulin resistance (independent of obesity), and low acute plasma insulin response to intravenous glucose (with the degree of obesity and insulin resistance taken into account) were predictors of NIDDM. The six-year cumulative incidence of NIDDM was 39 percent in persons with values belo...
1,524 citations
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TL;DR: Obesity is an independent risk factor for death from coronary heart disease and some forms of cancer as well as sleep apnea, chronic hypoxia and hypercapnia, and degenerative joint disease.
Abstract: The medical hazards of obesity are discussed. Risks include insulin resistance, diabetes mellitus, hypertriglyceridemia, decreased levels of high-density lipoprotein cholesterol, and increased levels of low-density lipoprotein cholesterol. Obesity is also associated with gallbladder disease and some forms of cancer as well as sleep apnea, chronic hypoxia and hypercapnia, and degenerative joint disease. Obesity is an independent risk factor for death from coronary heart disease. A central distribution of body fat enhances the risk for most of these conditions.
1,262 citations
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TL;DR: It seems likely that the cluster of changes associated with resistance to insulin-mediated glucose uptake comprise a syndrome, which plays an important role in the etiology and clinical course of patients with non-insulin-dependent diabetes, high blood pressure, and coronary heart disease.
Abstract: Resistance to insulin-mediated glucose uptake is characteristic of individuals with impaired glucose intolerance or non-insulin-dependent diabetes, and it also occurs commonly in patients with high blood pressure. The physiological response to a decrease in insulin-mediated glucose uptake is an increase in insulin secretion, and as long as a state of compensatory hyperinsulinemia can be maintained, frank decompensation of glucose tolerance can be prevented. However, it is likely that the defect in insulin action and/or the associated hyperinsulinemia will lead to an increase in plasma triglyceride and a decrease in high density lipoprotein-cholesterol concentration, and high blood pressure. It seems likely that the cluster of changes associated with resistance to insulin-mediated glucose uptake comprise a syndrome, which plays an important role in the etiology and clinical course of patients with non-insulin-dependent diabetes, high blood pressure, and coronary heart disease.
925 citations
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TL;DR: In this article, the relation between the fatty acid composition of skeletal-muscle phospholipids and insulin sensitivity was determined in two groups of subjects, including 27 patients undergoing coronary artery surgery and 13 normal men.
Abstract: Background Insulin resistance and hyperinsulinemia are features of obesity, non-insulin-dependent diabetes mellitus, and other disorders. Skeletal muscle is a major site of insulin action, and insulin sensitivity may be related to the fatty-acid composition of the phospholipids within the muscle membranes involved in the action of insulin. Methods We determined the relation between the fatty-acid composition of skeletal-muscle phospholipids and insulin sensitivity in two groups of subjects. In one study, we obtained samples of the rectus abdominis muscle from 27 patients undergoing coronary artery surgery; fasting serum insulin levels provided an index of insulin sensitivity. In the second study, a biopsy of the vastus lateralis muscle was performed in 13 normal men, and insulin sensitivity was assessed by euglycemic-clamp studies. Results In the patients undergoing surgery, the fasting serum insulin concentration (a measure of insulin resistance) was negatively correlated with the percentage of individua...
834 citations
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TL;DR: It is concluded that in population studies, only the fasting insulin level should be used as a marker of insulin resistance, particularly in subjects with abnormal glucose tolerance, as well as in individuals with varying degrees of glucose tolerance.
Abstract: Epidemiologic studies have correlated fasting and postload insulin levels with the risk of coronary heart disease, assuming that insulin levels are reliable markers of insulin resistance. However, this assumption has not been systematically studied. The author measured insulin response to an oral glucose load and quantitated insulin resistance using the euglycemic hyperinsulinemic clamp technique to evaluate the correlation between insulin level and the degree of insulin resistance in individuals with varying degrees of glucose tolerance. Subjects were randomly selected from previous population studies done in 1987-1989 at the Department of Medicine of the University of Kuopio in east Finland. Altogether, 50 subjects with normal glucose tolerance, 28 with impaired glucose tolerance, and 54 with non-insulin-dependent diabetes mellitus were studied. Correlations of insulin resistance (whole-body glucose uptake in clamp studies) with fasting or postload insulin levels were remarkably consistent, ranging from -0.58 to -0.74 (p < 0.01) in subjects with normoglycemia. In contrast, corresponding correlations were substantially weaker in subjects with impaired glucose tolerance and non-insulin-dependent diabetes. Among these subjects, only the fasting insulin level correlated significantly with insulin resistance (-0.47, p < 0.05 and -0.48, p < 0.01, respectively). The authors conclude that in population studies, only the fasting insulin level should be used as a marker of insulin resistance, particularly in subjects with abnormal glucose tolerance.
775 citations
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TL;DR: This review summarizes the results of 15 controlled studies supplementing defined Cr(III) compounds to subjects with impaired glucose tolerance with the conclusion that chromium deficiency is a factor in the much discussed "Syndrome X" of insulin resistance.
Abstract: This review summarizes the results of 15 controlled studies supplementing defined Cr(III) compounds to subjects with impaired glucose tolerance. Three of these (3-4 mumol Cr/d for > 2 mo) produced no beneficial effects: serum glucose, insulin and lipid concentrations remained unchanged. The remaining 12 interventions improved the efficiency of insulin or the blood lipid profile of subjects (ranging from malnourished children and healthy middle-aged individuals to insulin-requiring diabetics). In addition, three cases of impaired glucose tolerance after long-term total parenteral alimentation responding to Cr supplementation have been reported. Chromium potentiates the action of insulin in vitro and in vivo; maximal in vitro activity requires a special chemical form, termed Glucose Tolerance Factor and tentatively identified as a Cr-nicotinic acid complex. Its complete structural identification is a major challenge to chromium research. The development and validation of a procedure to diagnose chromium status is the second challenge. Such a test would allow the assessment of incidence and severity of deficiency in the population and the selection of deficiency in the population and the selection of chromium-responsive individuals. The third challenge is the definition of chromium's mode of action on parameters of lipid metabolism that have been reported from some studies but not others. Future research along these lines might establish whether chromium deficiency is a factor in the much discussed "Syndrome X" of insulin resistance.
715 citations
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TL;DR: Insulin resistant pattern B subjects are insulin resistant, have higher glucose, insulin, and TG, lower HDL-cholesterol levels, and higher blood pressure than those with pattern A or intermediate.
Abstract: Subjects characterized by a predominance of small LDL particles (pattern B) have changes in plasma triglyceride (TG) and HDL-cholesterol concentrations consistent with the presence of resistance to insulin-mediated glucose uptake. To pursue this issue, plasma glucose and insulin responses to oral glucose, insulin-mediated glucose disposal, and lipoprotein concentrations were measured in subjects categorized on the basis of LDL peak diameter measured by gradient gel electrophoresis. Subjects with pattern B had higher (P < 0.05-0.001) total integrated plasma glucose (20.7 +/- 1.0 mmol/liter.h) and insulin (1,743 +/- 293 pmol/liter.h) responses to oral glucose compared with glucose (16.3 +/- 0.4 and 19.2 +/- 0.8 mmol/liter.h) and insulin (856 +/- 60 and 1,222 +/- 168 pmol/liter.h) responses in those with either pattern A or an intermediate pattern. Pattern B individuals were shown to be more insulin resistant on the basis of higher steady state plasma glucose concentrations (SSPG, 10.4 +/- 1.0, P < 0.002, vs. 7.5 +/- 0.7 and 6.0 +/- 0.4 mmol/liter) after a constant infusion of somatostatin, glucose, and insulin than those with either the intermediate or pattern A subclass. Pattern B subjects also had higher concentrations of (P < 0.001) TG (1.98 +/- 0.15 vs. 1.33 +/- 0.17 and 0.77 +/- 0.05 mmol/liter) and lower (P < 0.01-0.001) HDL cholesterol (1.12 +/- 0.06 vs. 1.34 +/- 0.05 vs. 1.45 +/- 0.05 mmol/liter) than those with either the intermediate or pattern A. Finally, significant (P < 0.001) correlation coefficients existed between LDL diameter and SSPG (r = -0.44); glucose (r = -0.41) and insulin (r = -0.38) responses; TG (r = -0.65) and HDL-cholesterol (r = 0.42) concentrations; and systolic (r = -0.34) and diastolic (r = -0.34) blood pressure. Thus, pattern B subjects are insulin resistant, have higher glucose, insulin, and TG, lower HDL-cholesterol levels, and higher blood pressure than those with pattern A or intermediate.
691 citations
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TL;DR: It is suggested that visceral obesity is an important component of the insulin-resistance syndrome (syndrome X) that has been previously described and this cluster of morphological, hormonal, and metabolic alterations observed in abdominal obesity may have substantial implications for the treatment of this condition.
563 citations
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TL;DR: The findings suggest that TNF may exert its anti-insulin effect by interrupting the early insulin-stimulated tyrosine phosphorylation events, which are crucial to insulin transmembrane signaling.
548 citations
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TL;DR: An integrated picture of the multiple symptoms of visceral obesity is based on epidemiological, clinical, experimental, cellular, and molecular evidence.
Abstract: The controversial question of the relationship between obesity and disease has been considerably clearer after the demonstration in several prospective, epidemiological studies that the subgroup of central, visceral obesity is particularly prone to develop cardiovascular disease, stroke, and non-insulin dependent diabetes mellitus. Visceral obesity is associated with multiple central endocrine aberrations. The hypothalamo-adrenal axis is apparently sensitive to stimuli, sex steroid hormone secretion blunted, and hyperandrogenicity is found in women. In addition, there seem to be signs of central dysfunctions in the regulation of hemodynamic factors after stress, and growth hormone secretion appears to be particularly blunted. Several of these endocrine abnormalities are associated with insulin resistance, particularly glycogen synthesis in muscle. Fiber composition with low type I/type II ratio might be secondary to the prevailing hyperinsulinemia, but low capillary density in muscle may well be of importance. In combination with elevated turn-over of free fatty acids (FFA) this will probably provide powerful mechanisms whereby insulin resistance is created. Portal FFA, from the highly lipolytic visceral depots may, in addition, affect hepatic metabolism to induce increased gluconeogenesis, production of very low density lipoproteins as well as to perhaps inhibit clearance of insulin. By these mechanisms a Metabolic Syndrome Visceral adipocytes seem to have a high density of several steroid hormone receptors, directing steroid hormone effects particularly to these depots. The net effect of cortisol is apparently a stimulation of lipid storage, with opposing effects of sex steroid hormones which also facilitate lipid mobilization, regulations most often found at the gene transcription level. Growth hormone inhibits cortisol effects on lipid accumulation, and amplifies the lipid mobilizing effects of steroid hormones. The combined perturbations of hormonal secretions will therefore probably direct triglycerides toward visceral depots. Circulatory and nervous regulatory mechanisms require, however, more attention. The multiple central endocrine and nervous aberrations of visceral obesity suggest neuroendocrine dysregulations, and have features characteristic of the hypothalamic arousal seen after certain types of stress, alcohol intake, and smoking. Such factors can be traced to subjects with visceral fat accumulation. Standardized stress, eliciting a "defeat reaction" in primates is followed by an apparently identical syndrome. This integrated picture of the multiple symptoms of visceral obesity is based on epidemiological, clinical, experimental, cellular, and molecular evidence. The ingredients of positive energy balance, including physical inactivity, stress, smoking, and alcohol consumption are frequent features of modern, urbanized society. Visceral obesity may therefore be an expression of a "Civilization Syndrome."
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TL;DR: Hypertension is common in newly diagnosed type 2 diabetes and is associated with obesity and the association between hypertension and higher triglyceride and insulin levels may be secondary to obesity in this population.
Abstract: Objective: To determine the prevalence of hypertension in newly diagnosed type 2 diabetic patients and its association with risk factors for cardiovascular and diabetic complications.Design: Cross-sectional study.Patients: Newly diagnosed type 2 diabetic patients (n = 3648, mean age 52 years, 59% male) recruited for the UK Prospective Diabetes Study (UKPDS).Measurements: Blood pressure, body mass index, waist:hip ratio, ECG signs of ischaemia and of left ventricular hypertrophy (Minnesota code), fasting plasma glucose, urate, creatinine, insulin, triglycerides, high-density lipoprotein-, low-density lipoprotein- and total cholesterol, urinary albumin: creatinine ratio, retinopathy grading.Results: Thirty-nine per cent of the patients (35% of the males, 46% of the females) were hypertensive (mean blood pressure greater-than-or-equal-to 160 systolic and/or greater-than-or-equal-to 90 mmHg diastolic 2 and 9 months after diagnosis of diabetes, or taking antihypertensive therapy). The hypertensive patients had a greater mean body mass index (30.1 versus 28.0 kg/m2, P 5.0 g/mol; 24 versus 14%, P < 0.0001), of ECG signs of probable and possible ischaemia (24 versus 14%, P < 0.0001) and of left ventricular hypertrophy (8.5 versus 3.8%; P < 0.0001). The prevalence of retinopathy was similar in the two groups.Conclusions: Hypertension is common in newly diagnosed type 2 diabetes and is associated with obesity. The association between hypertension and higher triglyceride and insulin levels may be secondary to obesity in this population. An association between hypertension and cardiovascular complications is already apparent at diagnosis of diabetes.
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TL;DR: Testing the hypothesis that reduced skeletal muscle blood flow in response to insulin may at least partially account for the wide range of insulin sensitivity observed in normotensive subjects found it to be inversely proportional to the height of the baseline mean arterial pressure.
Abstract: Insulin resistance has recently been found to be a common feature of essential hypertension. We have tested the hypothesis that reduced skeletal muscle blood flow in response to insulin may at least partially account for the wide range of insulin sensitivity observed in normotensive subjects. To this end, we studied 19 lean (body mass index < or = 27) subjects exhibiting basal mean arterial pressures ranging from 58 to 110 mm Hg. All subjects were normotensive with the exception of one. Each subject was studied at baseline and during a hyperinsulinemic (600 milliunits/m2 per minute) euglycemic clamp to quantitate insulin sensitivity. Mean arterial pressure was monitored invasively, and both leg (muscle) blood flow and cardiac output were measured by indicator dilution techniques, allowing the determination of both systemic and leg (or muscle) vascular resistance. In response to hyperinsulinemia, both cardiac output and leg blood flow increased approximately 37% and 80% (p < 0.01), respectively. Rates of insulin-mediated glucose uptake were inversely correlated with the baseline mean arterial pressure (r = -0.62, p < 0.01). The individual increment in leg blood flow above baseline in response to insulin was inversely proportional to the height of the baseline mean arterial pressure (r = -0.59, p < 0.01). Mean arterial pressure and insulin-mediated glucose uptake were not correlated with either age or body fat content.(ABSTRACT TRUNCATED AT 250 WORDS)
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TL;DR: The acute effect of smoking and snuffing on insulin sensitivity was studied in a group of healthy habitual smokers and showed no change in insulin sensitivity in either smoker or non-smokers.
Abstract: . Objectives. The acute effect of smoking and snuffing on insulin sensitivity was studied in a group of healthy habitual smokers.
Design The euglycaemic clamp technique was combined with the subcutaneous injection of a bolus (0.1 U kg−1) of fast-acting insulin (Actrapid®). Randomized subjects smoked either one cigarette per hour for 6 h, took one bag-packed snuff per hour for 6 h or refrained from nicotine for 48 h before as well as during the clamp.
Subjects. Seven healthy smokers, four females and three males, of normal weight (BMI, mean ± SKM. 21 ± 0.7 kg m−2 with a range of 18.6–23.9), aged 31 ± 2 years (range 24–35 years), who had consumed at least 20 cigarettes per day for at least 5 years were studied. They were recruited through an advertisement in a newspaper. Results. The steady-state plasma nicotine levels were similar during smoking and snuffing. The insulin and glucose levels were also similar during all three clamps. Smoking, but not snuffing, impaired insulin action (P < 0.05) mainly due to a lower peripheral glucose uptake. The mean growth hormone levels during the 6-h study were more than doubled during smoking (P < 0.01) while no significant differences were seen in the other counter-regulatory hormones.
Conclusion. Smoking (also in habitual smokers) acutely impairs insulin action and leads to insulin resistance. Thus, smoking can be of importance for the development of the insulin resistance syndrome associated with risk for cardiovascular disease.
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TL;DR: Dietary fat decreased de novo fatty acid synthesis and basal glycerol release in adipose tissue and tended to increase simultaneously beta-adrenergic lipolytic responses to increased membrane fluidity and a trend toward insulin resistance, which was more marked with saturated fatty acids, occurred in adipOSE tissue.
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TL;DR: In obese NIDDM subjects, a 7-day period of calorie restriction produces approximately half of the overall improvement in HGP, insulin sensitivity and insulin secretion that is obtained after a substantial loss of weight.
Abstract: In obese patients with noninsulin-dependent diabetes mellitus (NIDDM), reducing calorie intake improves glycemic control, often more rapidly than weight loss. Conversely, after weight loss has been achieved, metabolic control can deteriorate once calorie intake is increased, even if there is no regaining of weight. The current study, therefore, tested the hypothesis that restricting calorie consumption has an important role, independent of weight loss, in metabolic regulation of NIDDM patients. Isotopic determinations of hepatic glucose production (HGP), post-absorptively and after ingestion of 75 g glucose (dual glucose isotope method), were made in conjunction with measurement of insulin secretion and insulin sensitivity in seven obese NIDDM volunteers after four periods of controlled calorie intake: 1) 7 days of a baseline weight maintenance diet, 2) followed immediately by 7 days of calorie restriction (800 Cal/day); 3) followed by a weight loss program that consisted of 2 months of a very low calorie...
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TL;DR: It is indicated that metformin treatment improves glycemic control, and lowers insulin resistance and risk factors for cardiovascular disease, including PAI-1, and may therefore be useful in the long-term management of NIDDM subjects who have a high risk of cardiovascular disease.
Abstract: OBJECTIVE To investigate the effects of metformin on glycemic control, insulin resistance, and risk factors for cardiovascular disease in NIDDM subjects from two ethnic groups (Caucasian and Asian) with different risks of cardiovascular disease. RESEARCH DESIGN AND METHODS A total of 27 subjects with NIDDM (17 Caucasian, 10 Asian) were given metformin and placebo each for a 12-wk period in a randomized, double-blind, placebo-controlled crossover study, and the dose was increased after 1 and 6 wk, up to a maximum of 850 mg three times a day. Insulin resistance, glycemic control, and cardiovascular risk factors were assessed before and after each treatment phase. The end of 12 wk of metformin treatment was compared with the end of 12 wk of placebo treatment. RESULTS Metformin treatment was associated with significant improvement in FPG at 6 and 12 wk (mean difference at 12 wk, −3.08 mM, 95% CI −4.12 to −2.04 mM, P −1 · min −1 , interquartile range −0.10 to 1.30 ml · kg −1 · min −1 , P = 0.036). β-cell function calculated by HOMA also improved significantly (median difference 14%, interquartile range 7 to 23%, P P = 0.034), total cholesterol (mean difference −0.52 mM, 95% CI −0.83 to −0.22 mM, P = 0.002), and LDL cholesterol (mean difference −0.40 mM, 95% CI −0.64 to −0.16 mM, P = 0.002) fell significantly on metformin treatment, whereas no significant changes were observed in HDL cholesterol. PAI-1 activity fell significantly (mean difference −5.3 AU/ml, 95% CI −8.2 to −2.4 AU/ml, P = 0.001), but plasma fibrinogen concentrations and platelet function, spontaneous or agonist induced, were unaffected. UAE was lower on metformin treatment (median difference −2.4 μg/min, interquartile range −4.4 to −0.2 μg/min, P = 0.004), but metformin had no significant effect on BP. The effects of metformin on glycemic control and cardiovascular risk factors were generally similar in the two ethnic groups. CONCLUSIONS These findings indicate that metformin treatment improves glycemic control, and lowers insulin resistance and risk factors for cardiovascular disease, including PAI-1, and may therefore be useful in the long-term management of NIDDM subjects who have a high risk of cardiovascular disease.
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TL;DR: It is proposed that increased PAI-1 levels, which are essentially related to the classic metabolic aspect of the insulin resistance syndrome, have to be included in this syndrome.
Abstract: Hyperinsulinemia, a major indicator of insulin resistance, may exert its influence on the risk of coronary artery disease partially through disturbances of the hemostatic system. The relations of fasting insulin concentrations with the degree of coronary atherosclerosis, other coronary risk factors (including some markers of the insulin resistance syndrome such as body mass index and triglyceride), markers of inflammation, and hemostatic factors were investigated in 1484 patients with angina pectoris. Mean insulin levels were higher in patients with one or more coronary vessel stenoses than in those without (9.9 microU/mL compared with 9.0 microU/mL, P < .0001). However, the association the presence of vessel stenoses was stronger in patients with a previous myocardial infarction than in those without. Insulin increased markedly (P < .0001) and independently of other risk factors with age body mass index, triglyceride concentration, and markers of inflammation, such as white blood cell count and C-reactive protein. The strongest relations between insulin and hemostatic factors were observed with fibrinolytic variables, particularly plasminogen activator inhibitor-1 (PAI-1) levels (r = .44, P < .0001). This relation decreased somewhat (r = .29) after simultaneous adjustment for markers of the insulin resistance syndrome, mainly body mass index and triglycerides, but not after adjustment for markers of inflammation. Therefore, we propose that increased PAI-1 levels, which are essentially related to the classic metabolic aspect of the insulin resistance syndrome, have to be included in this syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)
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TL;DR: In both tissues, dexamethasone treatment results in a reduction in insulin-stimulated IRS-1-associated P I3-kinase, which may play a role in the pathogenesis of insulin resistance at the cellular level in these animals.
Abstract: Insulin rapidly stimulates tyrosine kinase activity of its receptor resulting in phosphorylation of its cytosolic substrate, insulin receptor substrate-1 (IRS-1), which in turn associates with phosphatidylinositol 3-kinase (PI 3-kinase), thus activating the enzyme. Glucocorticoid treatment is known to produce insulin resistance, but the exact molecular mechanism is unknown. In the present study we have examined the levels and phosphorylation state of the insulin receptor and IRS-1, as well as the association/activation between IRS-1 and PI 3-kinase in the liver and muscle of rats treated with dexamethasone. After dexamethasone treatment (1 mg/kg per d for 5 d), there was no change in insulin receptor concentration in liver of rats as determined by immunoblotting with antibody to the COOH-terminus of the receptor. However, insulin stimulation of receptor autophosphorylation determined by immunoblotting with antiphosphotyrosine antibody was reduced by 46.7 +/- 9.1%. IRS-1 and PI 3-kinase protein levels increased in liver of dexamethasone-treated animals by 73 and 25%, respectively (P < 0.05). By contrast, IRS-1 phosphorylation was decreased by 31.3 +/- 10.9% (P < 0.05), and insulin stimulated PI 3-kinase activity in anti-IRS-1 immunoprecipitates was decreased by 79.5 +/- 11.2% (P < 0.02). In muscle, the changes were less dramatic, and often in opposite direction of those observed in liver. Thus, there was no significant change in insulin receptor level or phosphorylation after dexamethasone treatment. IRS-1 and PI 3-kinase levels were decreased to 38.6 and 65.6%, respectively (P < 0.01 and P < 0.05). IRS-1 phosphorylation showed no significant change in muscle, but insulin-stimulated IRS-1 associated PI 3-kinase was decreased by 41%. Thus, dexamethasone has differential effects on the proteins involved in the early steps in insulin action in liver and muscle. In both tissues, dexamethasone treatment results in a reduction in insulin-stimulated IRS-1-associated P I3-kinase, which may play a role in the pathogenesis of insulin resistance at the cellular level in these animals.
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TL;DR: Acute hyperinsulinemia in humans suppresses plasma FFA equally in control and obese subjects at this high dose of insulin and decreases plasma triglyceride and VLDL particle size in control subjects, reflecting either stimulation of LPL activity or a greater relative decrease in triglyceride to apoB production.
Abstract: The effects of short-term hyperinsulinemia on the production of both VLDL triglyceride and VLDL apoB were determined semiquantitatively before and during a 6-h euglycemic hyperinsulinemic clamp (40 mU · m −2 · min −1 ) in 17 women (8 chronically hyperinsulinemic obese, BMI = 357 kg/m2; 9 normal weight, BMI = 225 kg/m 2 ) During acute hyperinsulinemia, plasma FFA decreased by ∼ 95% within 1 h in both groups VLDL triglyceride production decreased 66% in the control subjects ( P = 00003) and 67% in obese subjects ( P = 00003) ApoB production decreased 53% in control subjects ( P = 003) but only 8% in obese (NS) Plasma triglycerides decreased by 40% from baseline in control subjects ( P P = NS) Despite the similar decrease in triglyceride and apoB production in control subjects, VLDL particle size (triglyceride-to-apoB ratio) decreased with hyperinsulinemia ( P = 0003) In obese subjects, despite a decrease in triglyceride production similar to that in control subjects but no change in apoB production, VLDL size did not change appreciably Acute hyperinsulinemia in humans: 1 ) suppresses plasma FFA equally in control and obese subjects at this high dose of insulin; 2 ) inhibits VLDL triglyceride production equally in control and obese subjects, perhaps secondary to the decrease in FFA; 3 ) inhibits VLDL apoB production in control but less so in obese subjects, suggesting that obese subjects may be resistant to this effect of insulin; 4 ) decreases plasma triglyceride and VLDL particle size in control subjects, reflecting either stimulation of LPL activity or a greater relative decrease in triglyceride to apoB production; and 5 ) does not decrease plasma triglyceride or VLDL size in obese subjects to the same extent as it does in control subjects Thus, the insulin resistance of obesity affects some but not all aspects of VLDL metabolism
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TL;DR: The results suggest that aminoacid polymorphisms in IRS-1 may be involved in the aetiology of a subset of late-onset NIDDM, and carriers of the codon 972 variant had significantly lower plasma levels of fasting insulin and C-peptide.
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TL;DR: To identify the gene or genes associated with insulin resistance in Type II (non-insulin-dependent) diabetes mellitus, subtraction libraries were prepared from skeletal muscle of normal and diabetic humans and screened with subtracted probes.
Abstract: To identify the gene or genes associated with insulin resistance in Type II (non-insulin-dependent) diabetes mellitus, subtraction libraries were prepared from skeletal muscle of normal and diabetic humans and screened with subtracted probes. Only one clone out of 4000 was selectively overexpressed in Type II diabetic muscle as compared to muscle of non-diabetic or Type I diabetic individuals. This clone encoded a new 29-kilodalton member of the Ras-guanosine triphosphatase superfamily and was termed Rad (Ras associated with diabetes). Messenger ribonucleic acid of Rad was expressed primarily in skeletal and cardiac muscle and was increased an average of 8.6-fold in the muscle of Type II diabetics as compared to normal individuals.
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TL;DR: Insulin resistance is more closely associated with abdominal adiposity than with age, and measurements at most central body sites were significantly larger in the insulin-resistant older subjects.
Abstract: Studies have shown that insulin resistance increases with age, independent of changes in total adiposity. However, there is growing evidence that the development of insulin resistance may be more closely related to abdominal adiposity. To evaluate the independent effects of aging and regional and total adiposity on insulin resistance, we performed hyperinsulinemic euglycemic clamps on 17 young (21-33 yr) and 67 older (60-72 yr) men and women. We assessed FFM and total and regional adiposity by hydrodensitometry and anthropometry. Insulin-stimulated GDRs at a plasma insulin concentration of approximately 450 pM averaged 45.6 +/- 3.3 mumol.kg FFM-1 x min-1 (mean +/- SE) in the young subjects, 45.6 +/- 10.0 mumol.kg FFM-1 x min-1 in 24 older subjects who were insulin sensitive, and 23.9 +/- 11.7 mumol.kg FFM-1 x min-1 in 43 older subjects who were insulin resistant. Few significant differences were apparent in skin-fold and circumference measurements between young and insulin-sensitive older subjects, but measurements at most central body sites were significantly larger in the insulin-resistant older subjects. Waist girth accounted for > 40% of the variance in insulin action, whereas age explained only 10-20% of the total variance and < 2% of the variance when the effects of waist circumference were statistically controlled. These results suggest that insulin resistance is more closely associated with abdominal adiposity than with age.
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TL;DR: It is found that an increase in sympathetic nervous system activation (within the normal range of physiological responses) can cause acute insulin resistance in the forearm of healthy volunteers.
Abstract: Inferences about the association between sympathetic overactivity and insulin resistance have been drawn from the infusion of sympathomimetic amines in supraphysiological doses. We used the isolated perfused human forearm to investigate the effect of reflex-induced sympathetic nervous system activation on the peripheral utilization of glucose in the skeletal muscles of 14 healthy men. Local hyperinsulinemia in the forearm (132 +/- 25 microunits/mL for 90 minutes) induced a significant increase in the utilization of glucose from baseline (16.4 +/- 3.1 mg.dL-1.min-1 per 100 mL forearm volume) to a plateau (85.7 +/- 15.1 mg.dL-1.min-1 per 100 mL forearm volume) between 40 and 60 minutes of insulin infusion but did not alter the utilization of oxygen. Reflex sympathetic nervous system activation was elicited by unloading of cardiopulmonary receptors with bilateral thigh cuff inflation to 40 mm Hg between 60 and 90 minutes of insulin infusion. Blood flow in the forearm was significantly decreased with inflation of thigh cuffs (average decrease of 19%, p < 0.0001). As a result of thigh cuff inflation, there was a reduction in the utilization of glucose (a decrease of 23%, p < 0.02), whereas oxygen utilization was unchanged. We find that an increase in sympathetic nervous system activation (within the normal range of physiological responses) can cause acute insulin resistance in the forearm of healthy volunteers. The reflex caused no change in oxygen utilization, but the same stimulus elicited a decrease in the utilization of glucose.(ABSTRACT TRUNCATED AT 250 WORDS)
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TL;DR: Clinical trials have demonstrated that acarbose generally improves glycaemic control in patients with non-insulin-dependent diabetes mellitus (NIDDM) managed with diet alone, or with other antidiabetic therapy, as evidenced by decreased postprandial plasma glucose and glycosylated haemoglobin levels.
Abstract: Acarbose delays digestion of complex carbohydrates and disaccharides to absorbable monosaccharides, by reversibly inhibiting alpha-glucosidases within the intestinal brush border, thereby attenuating postprandial blood glucose peaks. Clinical trials have demonstrated that acarbose generally improves glycaemic control in patients with non-insulin-dependent diabetes mellitus (NIDDM) managed with diet alone, or with other antidiabetic therapy, as evidenced by decreased postprandial plasma glucose and glycosylated haemoglobin levels. It does not appear to directly alter insulin resistance, but may lower postprandial plasma insulin levels. Fasting plasma glucose, triglyceride and/or cholesterol levels may also be decreased. Acarbose also improved metabolic control in patients with insulin-dependent diabetes mellitus (IDDM), frequently decreasing insulin requirements, although further studies are required in this indication. Improved metabolic control appears to delay or prevent long term vascular complications of diabetes, and indeed, acarbose appeared to inhibit development of such complications in preliminary animal studies, but this finding requires confirmation in clinical studies. While acarbose seldom causes systemic adverse effects, it is associated with a high incidence of gastrointestinal disturbances such as flatulence, abdominal distension, borborygmus and diarrhoea, caused by fermentation of unabsorbed carbohydrates. However, these symptoms tend to subside with continued treatment and adherence to an appropriate diet. Thus, acarbose appears to be a worthwhile adjunctive therapeutic option for patients with NIDDM inadequately managed by diet alone, or with pharmacological therapy, and possibly also for patients with IDDM. However, further long term efficacy and tolerability data are required, particularly in the latter indication.
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TL;DR: Dietary-induced magnesium deficiency increases thromboxane urinary concentration and enhances angiotensin-induced aldosterone synthesis, which are associated with a decrease in insulin action, suggesting that magnesium deficiency may be a common factor associated with insulin resistance and vascular disease.
Abstract: Evidence suggests that magnesium deficiency may play an important role in cardiovascular disease. In this study, we evaluated the effects of a magnesium infusion and dietary-induced isolated magnes...
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TL;DR: Insulin resistance is characterized by alterations of lipid metabolism, particularly elevated plasma triacylglycerol and decreased HDL-cholesterol concentrations and the presence of small, dense LDL particles.
Abstract: Insulin resistance is characterized by alterations of lipid metabolism, particularly elevated plasma triacylglycerol and decreased HDL-cholesterol concentrations and the presence of small, dense LDL particles. These observations are difficult to interpret in terms of cause and effect. In this review
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TL;DR: Small, dense LDL is an integral feature of the insulin resistance syndrome, and nongenetic variation in these risk factors is important in explaining their associations with LDL subclass phenotype.
Abstract: BACKGROUNDLow-density lipoprotein (LDL) subclass phenotype B, characterized by predominance of small, dense LDL particles, is associated with elevated plasma triglycerides and apolipoprotein B and with lower high-density lipoprotein (HDL) cholesterol and apolipoprotein A-I. Because these abnormalities resemble the dyslipidemia of insulin resistance, we examined associations of LDL subclass phenotype with plasma insulin levels and with other aspects of the insulin resistance syndrome.METHODS AND RESULTSLDL subclass phenotypes were determined by gradient gel electrophoresis in 682 female twins aged 30 to 91 years who participated in the second examination of the Kaiser Permanente Women Twins Study. Prevalence of phenotype B and the intermediate phenotype (I) increased strongly with age, obesity, and non-insulin-dependent diabetes. In multivariate analysis of nondiabetic women, phenotype B or I was independently associated with each aspect of the insulin resistance syndrome, including higher plasma triglycer...
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TL;DR: Impaired insulin sensitivity is a feature of insulin-dependent diabetic patients with microalbuminuria, which adds, with other factors, to the increased risks of renal and cardiovascular disease in these patients.
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TL;DR: Insulin resistance in Type 2 diabetes is predominantly associated with either hypertension or microalbuminuria or with both, and the highest triglyceride and lowest HDL cholesterol concentrations were observed in Type 1 diabetic patients with both hypertension and micro Albuminuria.
Abstract: We examined the impact of hypertension and microalbuminuria on insulin sensitivity in patients with Type 2 (non-insulin-dependent) diabetes mellitus using the euglycaemic insulin clamp technique in 52 Type 2 diabetic patients and in 19 healthy control subjects. Twenty-five diabetic patients had hypertension and 19 had microalbuminuria. Hypertension per se was associated with a 27% reduction in the rate of total glucose metabolism and a 40% reduction in the rate of non-oxidative glucose metabolism compared with normotensive Type 2 diabetic patients (both p<0.001). Glucose metabolism was also impaired in normotensive microalbuminuric patients compared with normotensive normoalbuminuric patients (29.4±2.2 vs 40.5±2.8 μmol · kg lean body mass−1 · min−1; p=0.012), primarily due to a reduction in non-oxidative glucose metabolism (12.7±2.9 vs 21.1±2.6 μmol · kg lean body mass−1 ·min−1; p=0.06). In a factorial ANOVA design, however, only hypertension (p=0.008) and the combination of hypertension and microalbuminuria (p=0.030) were significantly associated with the rate of glucose metabolism. The highest triglyceride and lowest HDL cholesterol concentrations were observed in Type 2 diabetic patients with both hypertension and microalbuminuria. Of note, glucose metabolism was indistinguishable from that in control subjects in Type 2 diabetic patients without hypertension and microalbuminuria (40.5±2.8 vs 44.4±2.8 μmol · kg lean body mass−1 · min−1). We conclude that insulin resistance in Type 2 diabetes is predominantly associated with either hypertension or microalbuminuria or with both.