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Short-Term Exercise Training Does Not Stimulate Skeletal Muscle ATP Synthesis in Relatives of Humans with Type 2 Diabetes

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Short-Term Exercise Training Does Not Stimulate Skeletal Muscle ATP Synthesis in Relatives of Humans with Type 2 Diabetes Diabetes Publish Ahead of Print, published online March 5, 2009 Short-term exercise training does not stimulate skeletal muscle ATP synthesis in relatives of humans with type 2 diabetes Gertrud Kacerovsky-Bielesz1,2, Marek Chmelik2,3, Charlotte Ling4, Rochus Pokan5, Julia Szendroedi1,2, Michaela Farukuoye2, Michaela Kacerovsky2, Albrecht I. Schmid2,3, Stephan Gruber3, Michael Wolzt6, Ewald Moser3, Giovanni Pacini7, Gerhard Smekal5, Leif Groop4, Michael Roden1,2,8 1 1. Medical Department, Hanusch Hospital, Vienna, Austria, 2 Karl-Landsteiner Institute for Endocrinology and Metabolism, Vienna, Austria, 3 MR Center of Excellence, Medical University of Vienna, Austria, 4 Department of Clinical Sciences, Lund University, Malmö, Sweden, 5 Department of Sports and Exercise Physiology, University of Vienna, Austria, 6 Department of Clinical Pharmacology, Medical University of Vienna, Austria, 7 Metabolic Unit, Institute of Biomedical Engineering, CNR, Padova, Italy 8 Institute for Clinical Diabetology, German Diabetes Center - Leibniz Center for Diabetes Research, Department of Medicine/Metabolic Diseases, Heinrich Heine University Düsseldorf, Düsseldorf, Germany Corresponding Author: Michael Roden, MD Email: [email protected] Clinical trial reg. No. NCT00710008, clinicaltrials.gov. Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org Submitted 6 September 2008 and accepted 27 February 2009. This is an uncopyedited electronic version of an article accepted for publication in Diabetes. The American Diabetes Association, publisher of Diabetes, is not responsible for any errors or omissions in this version of the manuscript or any version derived from it by third parties. The definitive publisher-authenticated version will be available in a future issue of Diabetes in print and online at http://diabetes.diabetesjournals.org. Copyright American Diabetes Association, Inc., 2009 Background. We tested the hypothesis that short-term exercise training improves hereditary insulin resistance by stimulating ATP synthesis and investigated associations with gene polymorphisms. Methods. 24 nonobese first-degree relatives of type-2 diabetic patients and 12 controls were studied at rest and 48 hours after three bouts of exercise. In addition to measurements of oxygen uptake and insulin sensitivity (OGTT), ectopic lipids and mitochondrial ATP synthesis were assessed using 1H and 31P magnetic resonance spectroscopy (MRS), respectively. They were genotyped for polymorphisms in genes regulating mitochondrial function, PPARGC1A (rs8192678) and NDUFB6 (rs540467). Results. Relatives had slightly lower (p=0.012) insulin sensitivity than controls. In controls, ATP synthase flux rose by 18% (p=0.0001) being 23% higher (p=0.002) than in relatives after exercise training. Relatives responding to exercise training with increased ATP synthesis (+19%, p=0.009) showed improved insulin sensitivity (p=0.009), whereas “non-responders” failed to increase their insulin sensitivity. A polymorphism in the NDUFB6 gene from respiratory-chain complex I related to ATP synthesis (p=0.02) and insulin sensitivity response to exercise training (p=0.05) ATP synthase flux correlated with O2 uptake and insulin sensitivity. Conclusions. The ability of short-term exercise to stimulate ATP production distinguished individuals with improved insulin sensitivity from those who did not improve their insulin sensitivity. In addition, the NDUFB6 gene polymorphism appeared to modulate this adaptation. This suggests that genes involved in mitochondrial function contribute to the response of ATP synthesis to exercise training. This trial has been registered at ClinicalTrials.gov (NCT 00710008). Exercise training and ATP production ife style intervention is the (18, 19). However, little is known on time recommended strategy for prevention course and onset of changes in glucose and L of type 2 diabetes mellitus (T2DM). energy metabolism independently of acute First-degree relatives of patients with T2DM exercise effects. (REL) have an increased risk of insulin We employed magnetic resonance resistance and T2DM (1, 2). Inherited and spectroscopy (MRS) to measure in vivo flux environmental factors cause insulin resistance of inorganic phosphate (Pi) to ATP through via intracellular lipid and inflammatory ATP synthase (fATPase) as well as IMCL, mediators which interfere with insulin HCL before and after three bouts of cycling signaling leading to an impaired rise of training to test the following hypotheses: (i) glucose-6-phosphate (G6P) due to reduced increased fATPase is an early event in the glucose transport/phosphorylation (2, 3). response to short term exercise training, (ii) These alterations can coexist with excessive responses of fATPase and insulin sensitivity storage of intramyocellular or hepatocellular are different in REL compared with healthy lipids (IMCL, HCL) and impaired controls (CON), and (iii) the responses are mitochondrial function and/or number in modulated by polymorphisms in genes which insulin resistant states such as aging (4), free are mutually linked to exercise capacity, fatty acids (FFA) elevation (5) and in some energy metabolism and insulin sensitivity in (6-8) but not all (9, 10) humans at risk of or epidemiologic studies. with T2DM. Non-diabetic REL suffering from severe insulin resistance present with METHODS elevated FFA, IMCL and HCL along with Volunteers. We recruited healthy REL of one impaired ATP synthesis possibly due to (n=19) or two (n=5) parents with T2DM, reduced mitochondrial contents (11). which was confirmed by hyperglycemia, oral Inherited and acquired factors associate with antidiabetic medication or insulin use. Twelve gene expression of the respiratory chain CON matched for sex, age, body mass index components, NDUFB6 and COX7A1, and (BMI) and physical activity were recruited as their transcriptional co-activators, PGC-1α/β, controls (Table 1). The participants which determine maximum oxygen uptake underwent medical history and physical (VO2max) and insulin action (12, 13). It examination. All participants were weight- remains unclear whether altered ATP stable over the last 6 months prior to the synthesis results from increased availability of study. None of them was smoking or lipid and/or adipokines such as adiponectin, regularly performing intense exercise. the nicotinamide phosphoribosyltransferase. Study protocols. Volunteers gave written visfatin, and retinol binding protein-4 (RBP4) informed consent to the study which was (14). approved by the institutional ethical board It is further uncertain whether such and performed according to the Declaration of abnormalities are reversible by exercising Helsinki. All participants remained on an and/or occur independently of effects on isocaloric diet, refrained from any physical insulin action. Long-term endurance exercise exercise for three days and fasted for 12 h training increases insulin sensitivity in before the start of the studies. On day 1, sedentary young and elderly (15), REL (16), participants underwent a frequent sampling glucose intolerant, obese or T2DM (17). 75-g OGTT and MRS. On day 2, they Exercise training for at least 4 weeks performed exercise testing. On days 3 and 5, enhances fat oxidation along with increased they exercised on a cycling ergometer. On mitochondrial mass and enzyme activities 3 Exercise training and ATP production day 7, measurements of day 1 were repeated collected before and in 30-min intervals for in identical fashion. 150 min for measurements of glucose, insulin Dietary assessment. Throughout the study, all and C-peptide. Dynamic insulin sensitivity volunteers were on a dietary plan reflecting was assessed by OGIS using the 120-min isocaloric diet in line with the American formula, which yields a measure of glucose Diabetes Association recommendations. clearance that has been widely exploited and Dietary intake over the last year and dietary validated against whole body insulin compliance were assessed with a modified sensitivity obtained from the euglycemic- interviewer-administered 107-item food hyperinsulinemic clamp (20). Beta cell frequency questionnaire adjusted for local function was assessed from the insulinogenic dietary habits index (21). (http://www.unihohenheim.de/wwwin140/inf Magnetic resonance spectroscopy (MRS). o/interaktives/foodfreq.htm). During the one- Participants were studied in a 3-T MR week intervention, volunteers counted all spectrometer (Bruker, Germany). A 10-cm food and beverages consumed employing circular double resonant 1H/31P surface coil common household measures to obtain six- was used for quantifying HCL and days dietary records. Nutrient/fluid intake on phosphorus metabolites. A 28-cm birdcage the days before the studies were analyzed coil was positioned over the right lower leg using 24-hour recalls. In the evenings before for measuring IMCL in soleus and tibialis the studies, participants consumed identically anterior (ant.) muscles. For non-localized 31P composed carbohydrate-enriched dinners at MRS, the right calf was positioned on the identical times. On study days, participants surface coil with the medial head of the right did not receive any calories except for the gastrocnemius muscle in the coil center. The OGTT until completion of the MRS integral of the region of phosphomonoesters measurements. (PME) covering G6P (7.1-7.4 ppm), Genotyping. Genomic DNA was extracted phosphodiesters (PDE), Pi and from blood of all participants
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