Faculty Opinions recommendation of Macrophage PPAR gamma is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones.

Context: African-American women (AAW) have an increased risk of developing type 2 diabetes compared with Caucasian women (CW). Lower insulin sensitivity has been reported in AAW, but the reasons for this racial difference and the contributions of liver versus skeletal muscle are incompletely understood. Objective: We tested the hypothesis that young, nonobese AAW manifest lower insulin sensitivity specific to skeletal muscle, not liver, and is accompanied by lower skeletal muscle mitochondrial oxidative capacity. Participants and Main Outcome Measures: Twenty-two nonobese (body mass index 22.7 ± 3.1 kg/m2) AAW and 22 matched CW (body mass index 22.7 ± 3.1 kg/m2) underwent characterization of body composition, objectively assessed habitual physical activity, and insulin sensitivity with euglycemic clamps and stable-isotope tracers. Skeletal muscle biopsies were performed for lipid content, fiber typing, and mitochondrial measurements. Results: Peripheral insulin sensitivity was 26% lower in AAW (P < .01), but hepatic insulin sensitivity was similar between groups. Physical activity levels were similar between groups. Lower insulin sensitivity in AAW was not explained by total or central adiposity. Skeletal muscle triglyceride content was similar, but mitochondrial content was lower in AAW. Mitochondrial respiration was 24% lower in AAW and correlated with skeletal muscle insulin sensitivity (r = 0.33, P < .05). Conclusion: When compared with CW, AAW have similar hepatic insulin sensitivity but a muscle phenotype characterized by both lower insulin sensitivity and lower mitochondrial oxidative capacity. These observations occur in the absence of obesity and are not explained by physical activity. The only factor associated with lower insulin sensitivity in AAW was mitochondrial oxidative capacity. Because exercise training improves both mitochondrial capacity and insulin sensitivity, we suggest that it may be of particular benefit as a strategy for diabetes prevention in AAW.

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Thyroid hormone receptor-β agonists prevent hepatic steatosis in fat-fed rats but impair insulin sensitivity via discrete pathways

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00573.2012 ◽

2013 ◽

Vol 305 (1) ◽

pp. E89-E100 ◽

Cited By ~ 48

Author(s):

Daniel F. Vatner ◽

Dirk Weismann ◽

Sara A. Beddow ◽

Naoki Kumashiro ◽

Derek M. Erion ◽

...

Keyword(s):

Skeletal Muscle ◽

Insulin Sensitivity ◽

Thyroid Hormone ◽

Hepatic Steatosis ◽

Hormone Receptor ◽

Thyroid Hormone Receptor ◽

Hepatic Insulin Resistance ◽

Lipid Lowering ◽

Hepatic Insulin Sensitivity ◽

Thyroid Hormone Receptor Β

Liver-specific thyroid hormone receptor-β (TRβ)-specific agonists are potent lipid-lowering drugs that also hold promise for treating nonalcoholic fatty liver disease and hepatic insulin resistance. We investigated the effect of two TRβ agonists (GC-1 and KB-2115) in high-fat-fed male Sprague-Dawley rats treated for 10 days. GC-1 treatment reduced hepatic triglyceride content by 75%, but the rats developed fasting hyperglycemia and hyperinsulinemia, attributable to increased endogenous glucose production (EGP) and diminished hepatic insulin sensitivity. GC-1 also increased white adipose tissue lipolysis; the resulting increase in glycerol flux may have contributed to the increase in EGP. KB-2115, a more TRβ- and liver-specific thyromimetic, also prevented hepatic steatosis but did not induce fasting hyperglycemia, increase basal EGP rate, or diminish hepatic insulin sensitivity. Surprisingly, insulin-stimulated peripheral glucose disposal was diminished because of a decrease in insulin-stimulated skeletal muscle glucose uptake. Skeletal muscle insulin signaling was unaffected. Instead, KB-2115 treatment was associated with a decrease in GLUT4 protein content. Thus, although both GC-1 and KB-2115 potently treat hepatic steatosis in fat-fed rats, they each worsen insulin action via specific and discrete mechanisms. The development of future TRβ agonists must consider the potential adverse effects on insulin sensitivity.

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Gender Dimorphic Relationships of Adiposity, Fitness, and Physical Activity with Indices of Skeletal Muscle and Hepatic Insulin Sensitivity in Healthy Older Subjects.

10.1210/endo-meetings.2010.part3.or2.or42-3 ◽

2010 ◽

pp. OR42-3-OR42-3

Author(s):

Ho Won Lee ◽

Ranganath Muniyappa ◽

Karthya Potti ◽

S. Mitchell Harman ◽

John D. Sorkin ◽

...

Keyword(s):

Physical Activity ◽

Skeletal Muscle ◽

Insulin Sensitivity ◽

Hepatic Insulin Sensitivity ◽

Older Subjects

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Skeletal muscle mitochondria exhibit decreased pyruvate oxidation capacity and increased ROS emission during surgery-induced acute insulin resistance

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00459.2014 ◽

2015 ◽

Vol 308 (8) ◽

pp. E613-E620 ◽

Cited By ~ 4

Author(s):

Martin Hagve ◽

Petter Fosse Gjessing ◽

Ole Martin Fuskevåg ◽

Terje S. Larsen ◽

Øivind Irtun

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Insulin Sensitivity ◽

Mitochondrial Function ◽

Enzyme Activities ◽

Surgical Trauma ◽

Hepatic Insulin Sensitivity ◽

Oxidation Capacity ◽

Peripheral Insulin Sensitivity ◽

Pyruvate Oxidation

Development of acute insulin resistance represents a negative factor after surgery, but the underlying mechanisms are not fully understood. We investigated the postoperative changes in insulin sensitivity, mitochondrial function, enzyme activities, and release of reactive oxygen species (ROS) in skeletal muscle and liver in pigs on the 2nd postoperative day after major abdominal surgery. Peripheral and hepatic insulin sensitivity were assessed by d-[6,6-2H2]glucose infusion and hyperinsulinemic euglycemic step clamping. Surgical trauma elicited a decline in peripheral insulin sensitivity (∼34%, P < 0.01), whereas hepatic insulin sensitivity remained unchanged. Intramyofibrillar (IFM) and subsarcolemma mitochondria (SSM) isolated from skeletal muscle showed a postoperative decline in ADP-stimulated respiration (VADP) for pyruvate (∼61%, P < 0.05, and ∼40%, P < 0.001, respectively), whereas VADP for glutamate and palmitoyl-l-carnitine (PC) was unchanged. Mitochondrial leak respiration with PC was increased in SSM (1.9-fold, P < 0.05) and IFM (2.5-fold, P < 0.05), indicating FFA-induced uncoupling. The activity of the pyruvate dehydrogenase complex (PDC) was reduced (∼32%, P < 0.01) and positively correlated to the decline in peripheral insulin sensitivity ( r = 0.748, P < 0.05). All other mitochondrial enzyme activities were unchanged. No changes in mitochondrial function in liver were observed. Mitochondrial H2O2 and O2·− emission was measured spectrofluorometrically, and H2O2 was increased in SSM, IFM, and liver mitochondria (∼2.3-, ∼2.5-, and ∼2.3-fold, respectively, all P < 0.05). We conclude that an impairment in skeletal muscle mitochondrial PDC activity and pyruvate oxidation capacity arises in the postoperative phase along with increased ROS emission, suggesting a link between mitochondrial function and development of acute postoperative insulin resistance.

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Improved Peripheral and Hepatic Insulin Sensitivity after Lifestyle Interventions in Type 2 Diabetes Is Associated with Specific Metabolomic and Lipidomic Signatures in Skeletal Muscle and Plasma

Metabolites ◽

10.3390/metabo11120834 ◽

2021 ◽

Vol 11 (12) ◽

pp. 834

Author(s):

Elin Chorell ◽

Julia Otten ◽

Andreas Stomby ◽

Mats Ryberg ◽

Maria Waling ◽

...

Keyword(s):

Type 2 Diabetes ◽

Skeletal Muscle ◽

Insulin Sensitivity ◽

Oxidation Rate ◽

Fat Oxidation ◽

Diet Group ◽

Lifestyle Interventions ◽

Hepatic Insulin Sensitivity ◽

Supervised Exercise

Lifestyle interventions with weight loss can improve insulin sensitivity in type 2 diabetes (T2D), but mechanisms are unclear. We explored circulating and skeletal muscle metabolite signatures of altered peripheral (pIS) and hepatic insulin sensitivity (hIS) in overweight and obese T2D individuals that were randomly assigned a 12-week Paleolithic-type diet with (diet-ex, n = 13) or without (diet, n = 13) supervised exercise. Baseline and post-intervention measures included: mass spectrometry-based metabolomics and lipidomics of skeletal muscle and plasma; pIS and hIS; ectopic lipid deposits in the liver and skeletal muscle; and skeletal muscle fat oxidation rate. Both groups lowered BMI and total % fat mass and increased their pIS. Only the diet-group improved hIS and reduced ectopic lipids in the liver and muscle. The combined improvement in pIS and hIS in the diet-group were associated with decreases in muscle and circulating branched-chain amino acid (BCAA) metabolites, specifically valine. Improved pIS with diet-ex was instead linked to increased diacylglycerol (34:2) and triacylglycerol (56:0) and decreased phosphatidylcholine (34:3) in muscle coupled with improved muscle fat oxidation rate. This suggests a tissue crosstalk involving BCAA-metabolites after diet intervention with improved pIS and hIS, reflecting reduced lipid influx. Increased skeletal muscle lipid utilization with exercise may prevent specific lipid accumulation at sites that perturb insulin signaling.

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