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Lise Højbjerre, Mary Rosenzweig, Flemming Dela, Jens M Bruun, and Bente Stallknecht

Abstract

Objective

We studied how an acute bout of exercise influences expression and concentration of adiponectin and regulators of adiponectin in adipose tissue and plasma.

Design and methods

Eight overweight and eight lean males were examined by large-pore microdialysis in s.c. abdominal adipose tissue (SCAAT) and had arterialized blood sampled. On one day subjects rested for 3 h, exercised for 1 h at 55% of maximal oxygen uptake and rested again for 2.5 h, and on another day subjects rested for 6.5 h. On the day including exercise SCAAT was biopsied before and after exercise.

Results

Exercise increased the SCAAT interstitial adiponectin concentration in both overweight and lean subjects and concentrations did not differ between groups. Plasma adiponectin did not increase during exercise and was similar in overweight and lean subjects. Adiponectin mRNA in SCAAT decreased during exercise and was similar in overweight and lean subjects. Surprisingly, the interstitial adiponectin concentration in SCAAT was only 20% of the plasma concentration. SCAAT interleukin-6 (IL-6) microdialyzate and plasma concentrations and SCAAT IL-6 mRNA increased during exercise in both groups. Tumor necrosis factor-α (TNF-α) plasma concentration did not change during exercise in any of the groups, but SCAAT TNF-α mRNA increased after exercise in both groups. Furthermore, exercise decreased SCAAT leptin mRNA with no change in resistin mRNA.

Conclusions

Acute exercise increases adipose tissue interstitial adiponectin concentration in both overweight and lean subjects with no major changes in plasma adiponectin concentration. The interstitial concentration of adiponectin in SCAAT is only 20% of that in plasma.

Free access

Steen B Haugaard, Ove Andersen, Flemming Dela, Jens Juul Holst, Heidi Storgaard, Mogens Fenger, Johan Iversen, and Sten Madsbad

Objectives: Lipodystrophy and insulin resistance are prevalent among human immunodeficiency virus (HIV)-infected patients on combined antiretroviral therapy (HAART). Aiming to provide a detailed description of the metabolic adverse effects of HIV-lipodystrophy, we investigated several aspects of glucose metabolism, lipid metabolism and β-cell function in lipodystrophic HIV-infected patients.

Methods: [3-3H]glucose was applied during euglycaemic hyperinsulinaemic clamps in association with indirect calorimetry in 43 normoglycaemic HIV-infected patients (18 lipodystrophic patients on HAART (LIPO), 18 patients without lipodystrophy on HAART (NONLIPO) and seven patients who were naïve to antiretroviral therapy (NAÏVE) respectively). β-cell function was evaluated by an intravenous glucose tolerance test.

Results: Compared with NONLIPO and NAÏVE separately, LIPO displayed markedly reduced ratio of limb to trunk fat (RLF; >34%, P < 0.001), hepatic insulin sensitivity (>40%, P < 0.03), incremental glucose disposal (>50%, P < 0.001) and incremental exogenous glucose storage (>50%, P < 0.05). Furthermore, LIPO displayed reduced incremental glucose oxidation (P < 0.01), increased clamp free fatty acids (P < 0.05) and attenuated insulin-mediated suppression of lipid oxidation (P < 0.05) compared with NONLIPO. In combined study groups, RLF correlated with hepatic insulin sensitivity (r = 0.69), incremental glucose disposal (r = 0.71) and incremental exogenous glucose storage (r = 0.40), all P < 0.01. Disposition index (i.e. first-phase insulin response to intravenous glucose multiplied by incremental glucose disposal) was reduced by 46% (P = 0.05) in LIPO compared with the combined groups of NONLIPO and NAÏVE, indicating an impaired adaptation of β-cell function to insulin resistance in LIPO.

Conclusion: Our data suggest that normoglycaemic lipodystrophic HIV-infected patients display impaired glucose and lipid metabolism in multiple pathways involving liver, muscle tissue and β-cell function.

Free access

Rasmus Rabøl, Pernille F Svendsen, Mette Skovbro, Robert Boushel, Peter Schjerling, Lisbeth Nilas, Sten Madsbad, and Flemming Dela

Objective

Polycystic ovarian syndrome (PCOS) is associated with skeletal muscle insulin resistance (IR), which has been linked to decreased mitochondrial function. We measured mitochondrial respiration in lean and obese women with and without PCOS using high-resolution respirometry.

Methods

Hyperinsulinemic–euglycemic clamps (40 mU/min per m2) and muscle biopsies were performed on 23 women with PCOS (nine lean (body mass index (BMI) <25 kg/m2) and 14 obese (BMI >25 kg/m2)) and 17 age- and weight-matched controls (six lean and 11 obese). Western blotting and high-resolution respirometry was used to determine mitochondrial function.

Results

Insulin sensitivity decreased with PCOS and increasing body weight. Mitochondrial respiration with substrates for complex I and complex I+II were similar in all groups, and PCOS was not associated with a decrease in mitochondrial content as measured by mitochondrial DNA/genomic DNA. We found no correlation between mitochondrial function and indices of insulin sensitivity.

Conclusions

In contrast to previous reports, we found no evidence that skeletal muscle mitochondrial respiration is reduced in skeletal muscle of women with PCOS compared with control subjects. Furthermore, mitochondrial content did not differ between our control and PCOS groups. These results question the causal relationship between reduced mitochondrial function and skeletal muscle IR in PCOS.

Free access

Bodil Vistisen, Lars I Hellgren, Torill Vadset, Celena Scheede-Bergdahl, Jørn Wulff Helge, Flemming Dela, and Bente Stallknecht

Objective

In 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.

Design

We 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).

Methods

Each 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.

Results

The 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 and P=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.

Conclusions

The 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.

Free access

Martin Friedrichsen, Rasmus Ribel-Madsen, Brynjulf Mortensen, Christina N Hansen, Amra C Alibegovic, Lise Højbjerre, Mette P Sonne, Jørgen F P Wojtaszewski, Bente Stallknecht, Flemming Dela, and Allan Vaag

Objective

The molecular mechanisms linking physical inactivity and muscle insulin resistance in humans have been suggested to include increased muscle inflammation, possibly associated with impaired oxidative metabolism. We employed a human bed rest study including 20 young males with normal birth weight (NBW) and 20 with low birth weight (LBW) and increased risk of diabetes.

Methodology

The subjects were studied before and after 9 days of bed rest using the euglycemic–hyperinsulinemic clamp and muscle biopsy excision. Muscle inflammatory status was assessed as nuclear factor-κB (NF-κB) activity and mRNA expression of the pro-inflammatory MCP1 (CCL2) and IL6 and the macrophage marker CD68. Furthermore, mRNA expression of genes central to oxidative phosphorylation (OXPHOS) was measured including ATP5O, COX7A1, NDUFB6, and UQCRB.

Results

At baseline, muscle inflammatory status was similar in NBW and LBW individuals. After bed rest, CD68 expression was increased in LBW (P=0.03) but not in NBW individuals. Furthermore, expression levels of all OXPHOS genes were reduced after bed rest in LBW (P≤0.05) but not in NBW subjects and were negatively correlated with CD68 expression in LBW subjects (P≤0.03 for all correlations). MCP1 expression and NF-κB activity were unaffected by bed rest, and IL6 expression was too low for accurate measurements. None of the inflammatory markers correlated with insulin sensitivity.

Conclusions

Although LBW subjects exhibit disproportionately elevated CD68 mRNA expression suggesting macrophage infiltration and reduced OXPHOS gene expression when exposed to bed rest, our data altogether do not support the notion that bed rest-induced (9 days) insulin resistance is caused by increased muscle inflammation.

Restricted access

Signe Stensen, Lærke S Gasbjerg, Liva L. Krogh, Kirsa Skov-Jeppesen, Alexander H. Sparre-Ulrich, Mette H. Jensen, Flemming Dela, Bolette Hartmann, Tina Vilsbøll, Jens J Holst, Mette M. Rosenkilde, Mikkel B. Christensen, and Filip K Knop

Objective: The insulinotropic effect of exogenous, intravenously infused glucose-dependent insulinotropic polypeptide (GIP) is impaired in patients with type 2 diabetes. We evaluated the effects of endogenous GIP in relation to glucose and bone metabolism in patients with type 2 diabetes using a selective GIP receptor antagonist and hypothesized that the effects of endogenous GIP were preserved.

Design: A randomized, double-blinded, placebo-controlled, crossover study.

Methods: Ten patients with overweight/obesity and type 2 diabetes (mean±SD; HbA1c 52±11 mmol/mol; BMI 32.5±4.8 kg/m2) were included. We infused a selective GIP receptor antagonist, GIP(3-30)NH2 (1,200 pmol × kg-1 × min-1), or placebo (saline) during two separate, 230-minute, standardized, liquid mixed meal tests followed by an ad libitum meal. Subcutaneous adipose tissue biopsies were analyzed.

Results: Compared with placebo, GIP(3-30)NH2 reduced postprandial insulin secretion (Δbaseline-subtracted area under the curve (bsAUC)C-peptide%±SEM; -14±6%, p=0.021) and peak glucagon (Δ%±SEM; -11±6%, p=0.046), but had no effect on plasma glucose (p=0.692). Suppression of bone resorption (assessed by circulating carboxy-terminal collagen crosslinks (CTX)) was impaired during GIP(3-30)NH2 infusion compared with placebo (ΔbsAUCCTX;±SEM; -4.9±2 ng/ml × min, p=0.005) corresponding to a ~50% reduction. Compared with placebo, GIP(3-30)NH2 did not affect plasma lipids, ad libitum meal consumption or adipose tissue triglyceride content.

Conclusions: Using a selective GIP receptor antagonist during a meal, we show that endogenous GIP increases postprandial insulin secretion with little effect on postprandial glycemia but is important for postprandial bone homeostasis in patients with type 2 diabetes.