Reduced plasma adiponectin concentrations may contribute to impaired insulin activation of glycogen synthase in skeletal muscle of patients with type 2 diabetes

Højlund, Kurt; Frystyk, Jan; Levin, Klaus; Flyvbjerg, Allan; Wojtaszewski, Jørgen F. P.; Beck‐Nielsen, Henning

doi:10.1007/s00125-006-0240-5

Cited by 61 publications

(69 citation statements)

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“…Metabolic studies and muscle biopsies The euglycaemichyperinsulinaemic clamp studies were performed after an overnight fast as described in detail previously [5,6]. In brief, a 2 h basal tracer equilibration period was followed by infusion of insulin at a rate of 40 mU m −2 min −1 for 4 h. Using this protocol, euglycaemia at a plasma glucose concentration of 5.0-5.5 mmol/l and physiological hyperinsulinaemia at a serum insulin concentration of ∼400 pmol/l were obtained in all groups during the insulinstimulated steady-state period.…”

Section: Methodsmentioning

confidence: 99%

“…In brief, a 2 h basal tracer equilibration period was followed by infusion of insulin at a rate of 40 mU m −2 min −1 for 4 h. Using this protocol, euglycaemia at a plasma glucose concentration of 5.0-5.5 mmol/l and physiological hyperinsulinaemia at a serum insulin concentration of ∼400 pmol/l were obtained in all groups during the insulinstimulated steady-state period. The studies were combined with indirect calorimetry, and rates of total glucose disposal, glucose and lipid oxidation, and non-oxidative glucose metabolism were calculated as described [5,6]. Serum insulin and plasma glucose, triacylglycerol, NEFA and adiponectin were assayed as described [5,6].…”

Section: Methodsmentioning

confidence: 99%

“…The studies were combined with indirect calorimetry, and rates of total glucose disposal, glucose and lipid oxidation, and non-oxidative glucose metabolism were calculated as described [5,6]. Serum insulin and plasma glucose, triacylglycerol, NEFA and adiponectin were assayed as described [5,6]. A muscle biopsy from each individual was obtained from the vastus lateralis muscle in the basal state after the 2 h basal tracer equilibration period using a modified Bergström needle with suction under local anaesthesia.…”

Section: Methodsmentioning

confidence: 99%

“…Skeletal muscle, which is rich in mitochondria, accounts for ∼25% of whole body oxygen consumption in humans in the resting state [2]. Moreover, skeletal muscle is the major site of glucose uptake (∼80%) in response to insulin [3], and correspondingly is an important site of insulin resistance in obesity and type 2 diabetes [4][5][6]. Insulin resistance in skeletal muscle is characterised by impaired insulin stimulation of glucose transport and glycogen synthesis, and shows a strong correlation with intramyocellular lipid content [7,8].…”

Section: Introductionmentioning

confidence: 99%

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Human ATP synthase beta is phosphorylated at multiple sites and shows abnormal phosphorylation at specific sites in insulin-resistant muscle

Højlund

Lefort

et al. 2009

Diabetologia

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Aims/hypothesis Insulin resistance in skeletal muscle is linked to mitochondrial dysfunction in obesity and type 2 diabetes. Emerging evidence indicates that reversible phosphorylation regulates oxidative phosphorylation (OxPhos) proteins. The aim of this study was to identify and quantify site-specific phosphorylation of the catalytic beta subunit of ATP synthase (ATPsyn-β) and determine protein abundance of ATPsyn-β and other OxPhos components in skeletal muscle from healthy and insulin-resistant individuals. Methods Skeletal muscle biopsies were obtained from lean, healthy, obese, non-diabetic and type 2 diabetic volunteers (each group n=10) for immunoblotting of proteins, and hypothesis-driven identification and quantification of phosphorylation sites on ATPsyn-β using targeted nanospray tandem mass spectrometry. Volunteers were metabolically characterised by euglycaemic-hyperinsulinaemic clamps. Results Seven phosphorylation sites were identified on ATPsyn-β purified from human skeletal muscle. Obese individuals with and without type 2 diabetes were characterised by impaired insulin-stimulated glucose disposal rates, and showed a ∼30% higher phosphorylation of ATPsyn-β at Tyr361 and Thr213 (within the nucleotidebinding region of ATP synthase) as well as a coordinated downregulation of ATPsyn-β protein and other OxPhos components. Insulin increased Tyr361 phosphorylation of ATPsyn-β by ∼50% in lean and healthy, but not insulinresistant, individuals. Conclusions/interpretation These data demonstrate that ATPsyn-β is phosphorylated at multiple sites in human skeletal muscle, and suggest that abnormal site-specific phosphorylation of ATPsyn-β together with reduced content of OxPhos proteins contributes to mitochondrial dysfunction in insulin resistance. Further characterisation of phosphorylation of ATPsyn-β may offer novel targets of treatment in human diseases with mitochondrial dysfunction, such as diabetes.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Human ATP synthase beta is phosphorylated at multiple sites and shows abnormal phosphorylation at specific sites in insulin-resistant muscle

Højlund

Lefort

et al. 2009

Diabetologia

Self Cite

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show abstract

“…Plasma glucose levels were clamped at approximately 5 mmol/l, using a variable infusion rate of 20% glucose based on bedside plasma glucose measurements (ABL800 Flex, Radiometer, Copenhagen, Denmark) every 10-20 min. Serum insulin, plasma free fatty acids (FFA), and glucose concentrations were measured as described (Hojlund et al 2006). The basal and insulin-stimulated steady-state periods were defined as the last 20 min of the 120-basal and 180-min insulin infusion periods, respectively.…”

Section: Euglycemic Hyperinsulinemic Clampmentioning

confidence: 99%

Testosterone therapy increased muscle mass and lipid oxidation in aging men

Frederiksen

Højlund

Hougaard

et al. 2011

AGE

115

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The indication for testosterone therapy in aging hypogonadal men without hypothalamic, pituitary, or testicular disease remains to be elucidated. The aim of this study was to investigate the effect of testosterone therapy on insulin sensitivity, substrate metabolism, body composition, and lipids in aging men with low normal bioavailable testosterone levels using a predefined cutoff level for bioavailable testosterone. A randomized, double-blinded, placebocontrolled study of testosterone treatment (gel) was done on 38 men, aged 60-78 years, with bioavailable testosterone <7.3 nmol/l and a waist circumference >94 cm. Insulin-stimulated glucose disposal (Rd) and substrate oxidation were assessed by euglycemic hyperinsulinemic clamps combined with indirect calorimetry. Lean body mass (LBM) and total fat mass (TFM) were measured by dual x-ray absorptiometry, and serum total testosterone was measured by tandem mass spectrometry. Bioavailable testosterone was calculated. Coefficients (b) represent the placebo-controlled mean effect of intervention. LBM (b=1.9 kg, p=0.003) increased while HDL-cholesterol (b=−0.12 mmol/l, p=0.043) and TFM decreased (b=−1.2 kg, p=0.038) in the testosterone group compared to placebo. Basal lipid oxidation (b=5.65 mg/min/m 2 , p=0.045) increased and basal glucose oxidation (b=−9.71 mg/min/m 2 , p = 0.046) decreased in response to testosterone therapy even when corrected for changes in LBM. No significant changes in insulin-stimulated Rd was observed (b=−0.01mg/min/m 2 , p=0.92). Testosterone therapy increased muscle mass and lipid oxidation in aging men with low normal bioavailable testosterone levels; however, our data did not support an effect of testosterone on whole-body insulin sensitivity using the euglycemic hyperinsulinemic clamp technique.

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Current literature in diabetes

2006

Diabetes Metabolism Res

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In order to keep subscribers up‐to‐date with the latest developments in their field, John Wiley & Sons are providing a current awareness service in each issue of the journal. The bibliography contains newly published material in the field of diabetes/metabolism. Each bibliography is divided into 26 sections: 1 Reviews & Symposia; 2 General; 3 Genetics; 4 Epidemiology; 5 Immunology; 6 Obesity; 7 Prediction and Prevention; 8 Intervention: a) General; b) Care; c) Drug Therapy; d)Economics; e) Gene therapy; f) Nursing; g) Nutrition; h) Surgery; i) Transplantation; 9 Pathology and Complications: a) General; b) Cardiovascular; c) Eye disease; d) Gestational and fetal; e) Neurological; f) Podiatrical; g) Renal; 10 Endocrinology & Metabolism; 11 Experimental Studies; 12 Diagnosis and Techniques. Within each section, articles are listed in alphabetical order with respect to author

show abstract

Reduced plasma adiponectin concentrations may contribute to impaired insulin activation of glycogen synthase in skeletal muscle of patients with type 2 diabetes

Cited by 61 publications

References 50 publications

Human ATP synthase beta is phosphorylated at multiple sites and shows abnormal phosphorylation at specific sites in insulin-resistant muscle

Human ATP synthase beta is phosphorylated at multiple sites and shows abnormal phosphorylation at specific sites in insulin-resistant muscle

Testosterone therapy increased muscle mass and lipid oxidation in aging men

Current literature in diabetes

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