Mechanisms of insulin resistance in human obesity: evidence for receptor and postreceptor defects.

Kolterman, Orville G.; Insel, J; Saekow, Mark; Olefsky, Jerrold M.

doi:10.1172/jci109790

Cited by 622 publications

(297 citation statements)

References 40 publications

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“…The greater hyperinsulinemia in the absence of hyperaminoacidemia would have been expected to further increase glucose uptake, whose dose response has been shown to be half-maximal at 800 and maximal above 6,000 pmol/l (25,26). Nevertheless, despite 77% higher insulin in Hyper-3 glucose R d was not significantly different.…”

Section: Discussionmentioning

confidence: 95%

Fed-state clamp stimulates cellular mechanisms of muscle protein anabolism and modulates glucose disposal in normal men

Adegoke

Chevalier

Morais

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

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H]glucose kinetics in healthy men were compared between hyperinsulinemic, euglycemic, isoaminoacidemic (Hyper-1, n ϭ 10) and Hyper-3 (n ϭ 9) clamps. In Hyper-3 vs. Hyper-1, nonoxidative leucine R d [rate of disappearance (synthesis)] was stimulated more (45 Ϯ 4 vs. 24 Ϯ 4 mol/min, P Ͻ 0.01) and endogenous R a [rate of appearance (breakdown)] was inhibited similarly; hence net balance increased more (86 Ϯ 6 vs. 49 Ϯ 2 mol/min, P Ͻ 0.001). Glucose R d was similar; thus Hyper-3 metabolic clearance rate (331 Ϯ 23 vs. 557 Ϯ 41 ml/min, P Ͻ 0.0005) and R d/insulin (M, 0.65 Ϯ 0.10 vs. 1.25 Ϯ 0.10 mg ⅐ min Ϫ1 ⅐ pmol Ϫ1 ⅐ l, P Ͻ 0.001) were less, despite higher insulin (798 Ϯ 74 vs. 450 Ϯ 24 pmol/l, P Ͻ 0.005). In vastus lateralis muscle biopsies, phosphorylation of Akt (P ϭ 0.025), mammalian target of rapamycin (mTOR), ribosomal protein S6 kinase (p70 S6K1 ; P ϭ 0.008), S6 (P ϭ 0.049), and 4E-binding protein 1 (4E-BP1; P ϭ 0.001) increased. With decreased eukaryotic initiation factor-4E (eIF4E) ⅐ 4E-BP1 complex (P ϭ 0.01), these are consistent with increased mTOR complex 1 (mTORC1) signaling and translation initiation of protein synthesis. Although mRNA expression of ubiquitin, MAFbx 1, and MuRF-1 was unchanged, total ubiquitinated proteins decreased 20% (P Ͻ 0.01), consistent with proteolysis suppression. The Hyper-3 clamp increases whole body protein synthesis, net anabolism, and muscle protein translation initiation pathways and decreases protein ubiquitination. The main contribution of hyperaminoacidemia is stimulation of synthesis rather than inhibition of proteolysis, and it attenuates the expected increment of glucose disposal. translation initiation; ubiquitin pathway; leucine kinetics; glucose turnover; insulin resistance THE HYPERINSULINEMIC EUGLYCEMIC CLAMP is the "gold standard" for determining in vivo insulin sensitivity of glucose metabolism. Although the conventional clamp achieves hyperinsulinemia within the postprandial range, it does not replicate postmeal circulating metabolite concentrations. Indeed, it generates hypoaminoacidemia by insulin inhibition of protein catabolism, thereby preventing the testing of insulin sensitivity of protein anabolism by decreasing amino acid (AA) availability (6,38,46). Since insulin stimulation of protein synthesis and inhibition of proteolysis are unambiguously established in vitro, and abnormal protein metabolism occurs in both type 1 (45) and type 2 diabetes (17, 19) we have previously used an hyperinsulinemic, euglycemic, isoaminoacidemic clamp (8) to explore whole body protein turnover. This has established the presence of postabsorptive and clamp insulin resistance of protein metabolism in obesity (10), type 2 diabetes (37), and aging (7) and, additionally, sex differences in clamp responses (9). However, this "Hyper-1" clamp does not replicate postprandial physiology, in which plasma insulin, glucose, and AA concentrations increase and free fatty acids (FFA) decrease. Daily repletion of overnight protein depletion must take place at high rates postprandially. We...

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Section: Discussionmentioning

confidence: 95%

Fed-state clamp stimulates cellular mechanisms of muscle protein anabolism and modulates glucose disposal in normal men

Adegoke

Chevalier

Morais

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

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“…18 On the other hand, at maximally effective insulin concentrations, non-rate-limiting steps of insulin action are overcome, and thus, reductions in IMGU are likely to be the result of a defect in a rate-limiting step for overall IMGU, such as glucose and insulin delivery or glucose transport. 19 In this regard, Natali et al 2 nous glucose differences across the forearm of hypertensive patients in response to physiological insulin concentrations when compared with normotensive subjects. Although we did not study frankly hypertensive subjects, our data do not indicate a relation between MAP and skeletal muscle glucose extraction.…”

Section: Discussionmentioning

confidence: 99%

Skeletal muscle blood flow. A possible link between insulin resistance and blood pressure.

et al. 1993

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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 £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/m 2 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. The femoral arteriovenous glucose difference during hyperinsulinemia was not correlated with either basal mean arterial pressure or the rate of insulin-mediated glucose uptake. In summary, among normotensive subjects, 1) the rate of insulin-mediated glucose uptake is inversely proportional to the basal mean arterial pressure, 2) the increase in insulin-mediated muscle blood flow is inversely related to the basal mean arterial pressure, and 3) muscle glucose extraction is not related to the basal mean arterial pressure or the rate of insulin-mediated glucose uptake. In conclusion, attenuated insulin-mediated skeletal muscle blood flow appears to be a major cause of insulin resistance in subjects with elevated mean arterial pressure. Our data in normotensive subjects do not exclude the coexistence of other defects in glucose uptake and metabolism; nevertheless, they strongly support a hemodynamic basis for the insulin resistance observed in patients with hypertension.

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“…[Diabetologia (2003) 46:459-469] Keywords Adiponectin, Acrp30, adipoQ, central obesity, subcutaneous fat, intra-abdominal fat, insulin sensitivity, lipids, hepatic lipase, cardiovascular disease, leptin. It is well recognized that obesity and insulin resistance are closely related [1,2,3,4]. Android body fat distribution is associated with insulin resistance more than is a gynoid body fat distribution [5], with the site of abdominal fat distribution being an additional determinant of insulin sensitivity [6,7,8,9,10,11].…”

Section: Introductionmentioning

confidence: 99%

Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex

et al. 2003

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Aims/hypothesis. Increased intra-abdominal fat is associated with insulin resistance and an atherogenic lipoprotein profile. Circulating concentrations of adiponectin, an adipocyte-derived protein, are decreased with insulin resistance. We investigated the relationships between adiponectin and leptin, body fat distribution, insulin sensitivity and lipoproteins. Methods. We measured plasma adiponectin, leptin and lipid concentrations, intra-abdominal and subcutaneous fat areas by CT scan, and insulin sensitivity index (S I ) in 182 subjects (76 M/106F). Results. Adiponectin concentrations were higher in women than in men (7.4±2.9 vs 5.4±2.3 µg/ml, p<0.0001) as were leptin concentrations (19.1±13.7 vs 6.9±5.1 ng/ml, p<0.0001). Women were more insulin sensitive (S I : 6.8±3.9 vs 5.9±4.4×10 −5 min −1 /(pmol/l), p<0.01) and had more subcutaneous (240±133 vs 187±90 cm 2 , p<0.01), but less intra-abdominal fat (82±57 vs 124±68 cm 2 , p<0.0001). By simple regression, adiponectin was positively correlated with age (r=0.227, p<0.01) and S I (r=0.375, p<0.0001), and negatively correlated with BMI (r=−0.333, p<0.0001), subcutaneous (r=−0.168, p<0.05) and intra-abdominal fat (r=−0.35, p<0.0001). Adiponectin was negatively correlated with triglycerides (r=−0.281, p<0.001) and positively correlated with HDL cholesterol (r=0.605, p<0.0001) and Rf, a measure of LDL particle buoyancy (r=0.474, p<0.0001). By multiple regression analysis, adiponectin was related to age (p<0.0001), sex (p<0.005) and intra-abdominal fat (p<0.01). S I was related to intraabdominal fat (p<0.0001) and adiponectin (p<0.0005). Both intra-abdominal fat and adiponectin contributed independently to triglycerides, HDL cholesterol and Rf. Conclusion/interpretation. These data suggest that adiponectin concentrations are determined by intra-abdominal fat mass, with additional independent effects of age and sex. Adiponectin could link intra-abdominal fat with insulin resistance and an atherogenic lipoprotein profile. [Diabetologia (2003) 46:459-469] Keywords Adiponectin, Acrp30, adipoQ, central obesity, subcutaneous fat, intra-abdominal fat, insulin sensitivity, lipids, hepatic lipase, cardiovascular disease, leptin. It is well recognized that obesity and insulin resistance are closely related [1,2,3,4]. Android body fat distribution is associated with insulin resistance more than is a gynoid body fat distribution [5], with the site of abdominal fat distribution being an additional determinant of insulin sensitivity [6,7,8,9,10,11]. We found in both lean and obese subjects that the intraabdominal fat (IAF) depot is a stronger determinant of insulin sensitivity than the subcutaneous fat (SCF) depot [11], while SCF is the main determinant of the plasma concentration of leptin [11], an adipocyte-derived hormone regulating energy metabolism [12,13].

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Mechanisms of insulin resistance in human obesity: evidence for receptor and postreceptor defects.

Cited by 622 publications

References 40 publications

Fed-state clamp stimulates cellular mechanisms of muscle protein anabolism and modulates glucose disposal in normal men

Fed-state clamp stimulates cellular mechanisms of muscle protein anabolism and modulates glucose disposal in normal men

Skeletal muscle blood flow. A possible link between insulin resistance and blood pressure.

Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex

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