Normal insulin sensitivity and IMCL content in overweight humans are associated with higher fasting lipid oxidation

2002 ◽  
Vol 283 (3) ◽  
pp. E556-E564 ◽  
Author(s):  
Gianluca Perseghin ◽  
Paola Scifo ◽  
Massimo Danna ◽  
Alberto Battezzati ◽  
Stefano Benedini ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Lipid Oxidation ◽  
Body Fat ◽  
Resting Energy Expenditure ◽  
Plasma Free Fatty Acid ◽  
Whole Body ◽  
Glucose Disposal ◽  
Family History Of Diabetes ◽  
History Of

Intramyocellular lipid (IMCL) storage is considered a local marker of whole body insulin resistance; because increments of body weight are supposed to impair insulin sensitivity, this study was designed to assess IMCL content, lipid oxidation, and insulin action in individuals with a moderate increment of body fat mass and no family history of diabetes. We studied 14 young, nonobese women with body fat <30% ( n = 7) or >30% ( n = 7) and 14 young, nonobese men with body fat <25% ( n = 7) or >25% ( n = 7) by means of the euglycemic-insulin clamp to assess whole body glucose metabolism, with indirect calorimetry to assess lipid oxidation, by localized1H NMR spectroscopy of the calf muscles to assess IMCL content, and with dual-energy X-ray absorptiometry to assess body composition. Subjects with higher body fat had normal insulin-stimulated glucose disposal ( P = 0.80), IMCL content in both soleus ( P = 0.22) and tibialis anterior ( P = 0.75) muscles, and plasma free fatty acid levels ( P = 0.075) compared with leaner subjects in association with increased lipid oxidation ( P < 0.05), resting energy expenditure ( P = 0.046), resting oxygen consumption ( P = 0.049), and plasma leptin levels ( P < 0.01) in the postabsorptive condition. In conclusion, in overweight subjects, preservation of insulin sensitivity was combined with increased lipid oxidation and maintenance of normal IMCL content, suggesting that abnormalities of these factors may mutually determine the development of insulin resistance associated with weight gain.

Dose-dependent effect of insulin on plasma free fatty acid turnover and oxidation in humans

1990 ◽  
Vol 259 (5) ◽  
pp. E736-E750 ◽  
Author(s):  
R. C. Bonadonna ◽  
L. C. Groop ◽  
K. Zych ◽  
M. Shank ◽  
R. A. DeFronzo
Keyword(s):  
Fatty Acid ◽  
Free Fatty Acid ◽  
Lipid Oxidation ◽  
Plasma Insulin ◽  
Plasma Free Fatty Acid ◽  
Whole Body ◽  
Glucose Disposal ◽  
Body Lipid ◽  
Plasma Ffa ◽  
Dose Dependent

Methodology for measuring plasma free fatty acid (FFA) turnover/oxidation with [1–14C]palmitate was tested in normal subjects. In study 1, two different approaches (720-min tracer infusion without prime vs. 150-min infusion with NaH14CO3 prime) to achieve steady-state conditions of 14CO2 yielded equivalent rates of plasma FFA turnover/oxidation. In study 2, during staircase NaH14CO3 infusion, calculated rates of 14CO2 appearance agreed closely with NaH14CO3 infusion rates. In study 3, 300-min euglycemic insulin clamp documented that full biological effect of insulin on plasma FFA turnover/oxidation was established within 60–120 min. In study 4, plasma insulin concentration was raised to 14 +/- 2, 23 +/- 2, 38 +/- 2, 72 +/- 5, and 215 +/- 10 microU/ml. A dose-dependent insulin suppression of plasma FFA turnover/oxidation was observed. Plasma FFA concentration correlated positively with plasma FFA turnover/oxidation in basal and insulinized states. Total lipid oxidation (indirect calorimetry) was significantly higher than plasma FFA oxidation in the basal state, suggesting that intracellular lipid stores contributed to whole body lipid oxidation. Hepatic glucose production and total glucose disposal showed the expected dose-dependent suppression and stimulation, respectively, by insulin. In conclusion, insulin regulation of plasma FFA turnover/oxidation is maximally manifest at low physiological plasma insulin concentrations, and in the basal state a significant contribution to whole body lipid oxidation originates from lipid pool(s) that are different from plasma FFA.

scholarly journals Small intestinal metabolism is central to whole-body insulin resistance

Gut ◽  
2020 ◽  
pp. gutjnl-2020-322073
Author(s):  
Giulia Angelini ◽  
Serenella Salinari ◽  
Lidia Castagneto-Gissey ◽  
Alessandro Bertuzzi ◽  
James Casella-Mariolo ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Insulin Signalling ◽  
Whole Body ◽  
Glucose Disposal ◽  
Jejunal Loop ◽  
Oral Glucose ◽  
Metabolic Signature ◽  
Jejunal Bypass

ObjectiveTo assess the role of jejunum in insulin resistance in humans and in experimental animals.DesignTwenty-four subjects undergoing biliopancreatic diversion (BPD) or Roux-en-Y gastric bypass (RYGB) were enrolled. Insulin sensitivity was measured at baseline and at 1 week after surgery using oral glucose minimal model.We excluded the jejunum from intestinal continuity in pigs and created a jejunal loop with its vascular and nerve supply intact accessible from two cutaneous stomas, and reconnected the bowel with an end-to-end anastomosis. Glucose stable isotopes were given in the stomach or in the jejunal loop.In vitro studies using primary porcine and human hepatocytes or myoblasts tested the effects of plasma on gluconeogenesis or glucose uptake and insulin signalling.ResultsWhole-body insulin sensitivity (SI∙104: 0.54±0.12 before vs 0.82±0.11 after BPD, p=0.024 and 0.41±0.09 before vs 0.65±0.09/pM/min after RYGB, p=not significant) and Glucose Disposition Index increased only after BPD. In pigs, insulin sensitivity was significantly lower when glucose was administered in the jejunal loop than in the stomach (glucose rate of disappearance (Rd) area under the curve (AUC)/insulin AUC∙10: 1.82±0.31 vs 2.96±0.33 mmol/pM/min, p=0.0017).Metabolomics showed a similar pattern before surgery and during jejunal-loop stimulation, pointing to a higher expression of gluconeogenetic substrates, a metabolic signature of impaired insulin sensitivity.A greater hepatocyte phosphoenolpyruvate-carboxykinase and glucose-6-phosphatase gene expression was elicited with plasma from porcine jejunal loop or before surgery compared with plasma from jejunectomy in pigs or jejunal bypass in humans.Stimulation of myoblasts with plasma from porcine jejunal loop or before surgery reduced glucose uptake, Ser473-Akt phosphorylation and GLUT4 expression compared with plasma obtained during gastric glucose administration after jejunectomy in pigs or after jejunal bypass in humans.ConclusionProximal gut plays a crucial role in controlling insulin sensitivity through a distinctive metabolic signature involving hepatic gluconeogenesis and muscle insulin resistance. Bypassing the jejunum is beneficial in terms of insulin-mediated glucose disposal in obesity.Trial registration numberNCT03111953.

scholarly journals Effects of Short-Term Experimental Insulin Resistance and Family History of Diabetes on Pancreatic β-Cell Function in Nondiabetic Individuals

2005 ◽  
Vol 90 (10) ◽  
pp. 5825-5833 ◽  
Author(s):  
Neda Rasouli ◽  
Terri Hale ◽  
Steven E. Kahn ◽  
Horace J. Spencer ◽  
Steven C. Elbein
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Family History ◽  
Outcome Measure ◽  
Cell Mass ◽  
Insulin Response ◽  
Β Cell ◽  
Short Term ◽  
Family History Of Diabetes ◽  
History Of

Context: Normal glucose homeostasis is maintained despite reductions in insulin sensitivity by increasing insulin secretion. This ability to compensate for reduced insulin sensitivity is highly heritable, but the mechanisms for this compensation or its failure in type 2 diabetes (T2DM) are unknown. Objective: The objective of this study was to test whether individuals with a family history of T2DM have a fixed decrease in β-cell mass or function that would be revealed as an impaired insulin secretory response to short-term insulin resistance. Design: Glucose tolerance, insulin sensitivity (SI), and insulin response to iv glucose (AIRG) were compared in nondiabetic individuals with and without a family history of diabetes before and after nicotinic acid (NA) treatment. Setting: This study was performed at the Ambulatory General Clinical Research Center. Subjects: Healthy, nonobese, nondiabetic individuals with or without a family history of T2DM were studied. Interventions: Oral NA was given, with a final dose of 2 g/d, for at least 7 d. Main Outcome Measure: The main outcome measure was the disposition index (insulin sensitivity × insulin response) in response to NA. Results: Postchallenge plasma glucose levels rose during NA therapy regardless of family history. Neither group adequately increased their AIRG to maintain the disposition index. Family members did not differ from controls at baseline or after NA treatment for any outcome measure, but only 28 of 52 subjects experienced a 25% or greater fall in SI with NA treatment. Conclusions: Short-term β-cell compensation to NA-induced insulin resistance was incomplete and did not differ by genetic predisposition. A genetic defect controlling β-cell growth in response to chronic insulin resistance better explains differences in the ability to compensate for insulin resistance than an inherited, fixed defect in β-cell mass.

Role of nuclear receptors in the modulation of insulin secretion in lipid-induced insulin resistance

2008 ◽  
Vol 36 (5) ◽  
pp. 891-900 ◽  
Author(s):  
Mary C. Sugden ◽  
Mark J. Holness
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Nuclear Receptors ◽  
Feedback Loop ◽  
Farnesoid X Receptor ◽  
Lipid Lowering ◽  
Whole Body ◽  
Glucose Disposal ◽  
Healthy Individuals

In healthy individuals, a hyperbolic relationship exists between whole-body insulin-sensitivity and insulin secretion. Thus, for any difference in insulin-sensitivity, a reciprocal proportionate change occurs in insulin secretion. Such a feedback loop is evident in healthy individuals ingesting diets high in saturated fat and in late pregnancy where, despite lipid-induced insulin resistance, glucose tolerance is maintained through augmented GSIS (glucose-stimulated insulin secretion). NRs (nuclear receptors) are members of a superfamily of ligand-regulated and orphan transcription factors. On activation by a cognate ligand, many ligand-activated NRs recruit the RXR (retinoid X receptor) for heterodimer formation. Such NRs include the PPARs (peroxisome-proliferator-activated receptors), which are involved in lipid sensing and liporegulation. PPARs exert important lipid-lowering effects in vivo, thereby opposing the development of lipid-induced insulin resistance by relieving the inhibition of insulin-stimulated glucose disposal by muscle and lowering the necessity for augmented GSIS to counter lipid-induced insulin resistance. Long-chain fatty acids are proposed as natural PPAR ligands and some specific endogenous pathways of lipid metabolism are believed to generate PPAR agonists. Other NRs, e.g. the LXR (liver X receptor), which senses expansion of the metabolically active pool of cholesterol, and the FXR (farnesoid X receptor; NR1H4), which, like the LXR, is involved in sterol metabolism, also modulate systemic lipid levels and insulin-sensitivity. In this review, we discuss how these NRs impact insulin secretion via effects on the insulin-sensitivity–insulin secretion feedback loop and, in some cases, via direct effects on the islet itself. In addition, we discuss interactions between these nutrient/metabolite-responsive NRs and NRs that are central to the action of metabolically important hormones, including (i) the glucocorticoid receptor, critical for maintaining glucose homoeostasis in stress, inflammation and during fasting, and (ii) the thyroid hormone receptors, vital for maintenance of oxidative functions. We present data indicating that the RXR occupies a key role in directly modulating islet function and that its heterodimerization with at least two of its partners modulates GSIS.

Insulin Resistance of Stress: Sites and Mechanisms

1993 ◽  
Vol 85 (5) ◽  
pp. 525-535 ◽  
Author(s):  
Luigi S. Brandi ◽  
Donatella Santoro ◽  
Andrea Natali ◽  
Fiorella Altomonte ◽  
Simona Baldi ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Acid ◽  
Free Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Glucose Oxidation ◽  
Plasma Free Fatty Acid ◽  
Whole Body ◽  
Glucose Disposal ◽  
Acid Oxidation ◽  
Free Fatty Acid Oxidation

1. Stress is associated with a severe, yet reversible, form of insulin resistance. The aim of this study was to quantify the kinetics of insulin action (sensitivity and responsiveness) on intermediary metabolism during post-surgical stress. 2. We studied nine patients 6–8 h after major uncomplicated surgery, and eight healthy subjects matched for age, weight, glucose tolerance and duration of fast. A three-step isoglycaemic insulin clamp was combined with indirect calorimetry, [6-3H]glucose infusion and the forearm technique. 3. The following significant (P <0.05 or less) abnormalities were found in the patients. Hepatic glucose production was higher at baseline, and less suppressed by insulin. Whole-body glucose disposal was impaired at all insulin doses (by 33–60%). Glucose oxidation was depressed throughout the dose range but its increments in response to insulin were normal. In contrast, non-oxidative glucose disposal was essentially unresponsive. At all insulin levels, forearm glucose extraction was markedly depressed and forearm lactate release was in excess of concurrent glucose uptake, suggesting ongoing glycogenolysis despite insulin. Total lipolysis (plasma free fatty acid and glycerol levels) promptly responded to insulin but remained higher than in the control subjects throughout. In the forearm, even the highest insulin dose could not suppress net free fatty acid and glycerol release. Total lipid oxidation was increased throughout the insulin range, and calculated direct free fatty acid (as opposed to plasma free fatty acid) oxidation was virtually unaffected by insulin. Protein oxidation was slightly (35%) increased, but was suppressed normally in response to insulin. Energy expenditure was 20% higher at baseline, and tailed to rise with insulin. Arterial blood pH values were consistently (if slightly) lower, and net forearm proton release was higher, both at baseline and daring insulin infusion. 4. Post-surgical unsulin resistance is characterized by normal sensitivity but decreased responsiveness of glucose oxidation, lipolysis and plasma free fatty acid oxidation, whereas glycogen synthesis and direct free fatty acid oxidation are virtually unresponsive. For both glucose and lipid metabolism, the insulin resistance is particularly severe in forearm tissues, in which mild metabolic acidosis may play an additional role.

Increased intrahepatic triglyceride is associated with peripheral insulin resistance: in vivo MR imaging and spectroscopy studies

2007 ◽  
Vol 293 (6) ◽  
pp. E1663-E1669 ◽  
Author(s):  
Jong-Hee Hwang ◽  
Daniel T. Stein ◽  
Nir Barzilai ◽  
Min-Hui Cui ◽  
Julia Tonelli ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Magnetic Resonance ◽  
Subcutaneous Fat ◽  
Liver Fat ◽  
Whole Body ◽  
Glucose Disposal ◽  
Resonance Spectroscopy ◽  
Euglycemic Hyperinsulinemic Clamp ◽  
Triglyceride Accumulation

Recent studies have indicated that the mass/content of intramyocellular lipid (IMCL), intrahepatic triglyceride (IHTG), visceral fat (VF), and even deep abdominal subcutaneous fat (SF) may all be correlated with insulin resistance. Since simultaneous measurements of these parameters have not been reported, the relative strength of their associations with insulin action is not known. Therefore, the goals of this study were 1) to simultaneously measure IMCL, IHTG, VF, and abdominal SF in the same nondiabetic individuals using noninvasive 1H-magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) and 2) to examine how these fat stores are correlated with systemic insulin sensitivity as measured by whole body glucose disposal (Rd) during euglycemic-hyperinsulinemic clamp studies. Positive correlations were observed among IMCL, IHTG, and VF. There were significant inverse correlations between whole body Rd and both IMCL and VF. Notably, there was a particularly tight inverse correlation between IHTG and whole body Rd ( r = −0.86, P < 0.001), consistent with an association between liver fat and peripheral insulin sensitivity. This novel finding suggests that hepatic triglyceride accumulation has important systemic consequences that may adversely affect insulin sensitivity in other tissues.

Preoperative oral carbohydrate treatment attenuates immediate postoperative insulin resistance

2001 ◽  
Vol 280 (4) ◽  
pp. E576-E583 ◽  
Author(s):  
Mattias Soop ◽  
Jonas Nygren ◽  
Peter Myrenfors ◽  
Anders Thorell ◽  
Olle Ljungqvist
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Treatment Group ◽  
Whole Body ◽  
Glucose Disposal ◽  
Peripheral Tissues ◽  
Major Mechanism ◽  
Replacement Surgery ◽  
Oxidation Rates ◽  
Postoperative Changes

Postoperative insulin resistance is a well-characterized metabolic state that has been shown to correlate with the length of postoperative stay in hospital. Preoperative intravenous or oral carbohydrate treatment has been shown to attenuate the development of postoperative insulin resistance measured 1 day after surgery. To study the effects of preoperative oral carbohydrate treatment on postoperative changes in insulin resistance and substrate utilization, in the absence of postoperative confounding factors, 15 patients were double-blindly treated with either a carbohydrate-rich beverage (12.5%) ( n = 8) or placebo ( n = 7) before undergoing total hip replacement surgery. Insulin sensitivity, endogenous glucose release, and substrate oxidation rates were measured before and immediately after surgery. Whole body insulin sensitivity decreased by 18% in the treatment group vs. 43% in the placebo group ( P < 0.05, Student's t-test for unpaired data). In both groups, the major mechanism of insulin resistance was an inhibition of insulin-induced nonoxidative glucose disposal after surgery. The better preservation of insulin sensitivity in the treatment group was attributable to a less reduced glucose disposal in peripheral tissues and increased glucose oxidation rates.

scholarly journals Whole body overexpression of PGC-1α has opposite effects on hepatic and muscle insulin sensitivity

2009 ◽  
Vol 296 (4) ◽  
pp. E945-E954 ◽  
Author(s):  
Huiyun Liang ◽  
Bogdan Balas ◽  
Puntip Tantiwong ◽  
John Dube ◽  
Bret H. Goodpaster ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Troponin I ◽  
Physiological Stress ◽  
Fiber Type ◽  
Glucose Production ◽  
Hepatic Insulin Resistance ◽  
Whole Body ◽  
Glucose Disposal ◽  
Peripheral Tissues

Type 2 diabetes is characterized by fasting hyperglycemia, secondary to hepatic insulin resistance and increased glucose production. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a transcriptional coactivator that is thought to control adaptive responses to physiological stimuli. In liver, PGC-1α expression is induced by fasting, and this effect promotes gluconeogenesis. To examine whether PGC-1α is involved in the pathogenesis of hepatic insulin resistance, we generated transgenic (TG) mice with whole body overexpression of human PGC-1α and evaluated glucose homeostasis with a euglycemic-hyperinsulinemic clamp. PGC-1α was moderately (∼2-fold) overexpressed in liver, skeletal muscle, brain, and heart of TG mice. In liver, PGC-1α overexpression resulted in increased expression of hepatocyte nuclear factor-4α and the gluconeogenic enzymes phospho enolpyruvate carboxykinase and glucose-6-phosphatase. PGC-1α overexpression caused hepatic insulin resistance, manifested by higher glucose production and diminished insulin suppression of gluconeogenesis. Paradoxically, PGC-1α overexpression improved muscle insulin sensitivity, as evidenced by elevated insulin-stimulated Akt phosphorylation and peripheral glucose disposal. Content of myoglobin and troponin I slow protein was increased in muscle of TG mice, indicating fiber-type switching. PGC-1α overexpression also led to lower reactive oxygen species production by mitochondria and reduced IKK/IκB signaling in muscle. Feeding a high-fat diet to TG mice eliminated the increased muscle insulin sensitivity. The dichotomous effect of PGC-1α overexpression in liver and muscle suggests that PGC-1α is a fuel gauge that couples energy demands (muscle) with the corresponding fuel supply (liver). Thus, under conditions of physiological stress (i.e., prolonged fast and exercise training), increased hepatic glucose production may help sustain glucose utilization in peripheral tissues.

scholarly journals Effect of gender on lipid-induced insulin resistance in obese subjects

2008 ◽  
Vol 158 (1) ◽  
pp. 61-68 ◽  
Author(s):  
Bodil Vistisen ◽  
Lars I Hellgren ◽  
Torill Vadset ◽  
Celena Scheede-Bergdahl ◽  
Jørn Wulff Helge ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Body Mass ◽  
Plasma Concentrations ◽  
Whole Body ◽  
Glucose Disposal ◽  
Muscle Lipid ◽  
Obese Subjects ◽  
Skeletal Muscle Insulin Sensitivity

ObjectiveIn obese subjects, chronically elevated plasma concentrations of non-esterified fatty acids (NEFAs) exert a marked risk to contract insulin resistance and subsequently type 2 diabetes. When NEFA is acutely increased due to i.v. infusion of lipid, glucose disposal during a hyperinsulinemic–euglycemic clamp is reduced. This effect has been explained by a NEFA-induced decrease in skeletal muscle insulin sensitivity caused by accumulation of the lipid intermediates such as ceramide and diacylglycerol in the myocytes. However, neither the lipid-induced reduction of glucose disposal nor the intramyocellular lipid deposition has been compared directly in obese females and males.DesignWe studied eight obese females and eight obese males (body mass index (BMI): 32.6±1.4 and 32.8±0.8 respectively, non significant (NS)) matched for cardiorespiratory fitness relative to lean body mass (43.7±1.6 and 47.6±1.3 ml/kg min respectively, NS).MethodsEach subject underwent two hyperinsulinemic–euglycemic clamps with infusion of lipid or saline respectively. Furthermore, the subjects exercised during the last half an hour of each clamp.ResultsThe lipid-induced reduction in glucose disposal during the clamp was similar in females and males (46±10 and 60±4% respectively, NS). However, whole-body insulin sensitivity as well as non-oxidative glucose disposal was higher in obese females compared with obese males both during lipid and saline infusion (P<0.001 andP=0.01 respectively). Muscle ceramide, triacylglycerol (TAG), diacylglycerol (DAG), and glycogen content were similar between sexes and remained unchanged during the clamp and when exercise was superimposed.ConclusionsThe lipid-induced inhibition of glucose disposal is similar in obese females and males. However, obese females are more insulin sensitive compared with obese males (both during saline and lipid infusion), which is not due to differences in the concentration of the muscle lipid intermediates such as ceramide and DAG.

scholarly journals Hepatic Insulin Extraction in NAFLD Is Related to Insulin Resistance Rather Than Liver Fat Content

2018 ◽  
Vol 104 (5) ◽  
pp. 1855-1865 ◽  
Author(s):  
Kristina M Utzschneider ◽  
Steven E Kahn ◽  
David C Polidori
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Body Fat ◽  
Subcutaneous Fat ◽  
Insulin Clearance ◽  
Liver Fat ◽  
Glucose Disposal ◽  
Oral Glucose ◽  
Cross Sectional ◽  
Hepatic Insulin Extraction

Abstract Context Total insulin clearance is decreased in nonalcoholic fatty liver disease (NAFLD), but the relationship between liver fat and hepatic insulin extraction (HIE) is unknown. Objective This cross-sectional study addresses the hypothesis that HIE is reduced in NAFLD and investigates metabolic and/or anthropometric characteristics most closely associated with insulin clearance. Participants Nondiabetic subjects with NAFLD (n = 13) and age- and body mass index (BMI)-matched controls with normal liver enzymes (n = 15) underwent abdominal CT, dual-energy X-ray absorptiometry, oral glucose tolerance test (OGTT), and labeled two-step hyperinsulinemic-euglycemic clamps. Outcome Measurements Liver fat was estimated by the CT liver/spleen ratio. Hepatic and extrahepatic insulin clearances were modeled using clamp and OGTT data. Results Extrahepatic insulin clearance and HIE were not different between NAFLD and controls and did not correlate with liver fat. HIE was positively correlated with insulin sensitivity [rate of glucose disposal (Rd; low r = +0.7, P &lt; 0.001; high r = +0.6, P = 0.001), adiponectin (r = +0.55, P = 0.004), and insulin-mediated suppression of clamp nonesterified free fatty acid (NEFA; r = +0.67, P &lt; 0.001)] but was not associated with fasting NEFA, insulin-mediated suppression of glucose production, or measures of adiposity. Extrahepatic insulin clearance was positively associated with percent body fat (r = +0.44, P = 0.02) and subcutaneous fat (r = +0.42, P = 0.03) but not BMI, intra-abdominal fat, liver fat, Rd, adiponectin, or NEFA. Conclusions HIE is not directly associated with hepatic steatosis but is associated with muscle and adipose tissue insulin resistance. The data suggest differential regulation of insulin clearance with extrahepatic insulin clearance being associated with body fat and not insulin sensitivity.

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