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Subjects with Early-Onset Type 2 Diabetes Show Defective Activation of the Skeletal Muscle PGC-1␣/Mitofusin-2 Regulatory Pathway in Response to Physical Activity

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Subjects with Early-Onset Type 2 Diabetes Show Defective Activation of the Skeletal Muscle PGC-1␣/Mitofusin-2 Regulatory Pathway in Response to Physical Activity Pathophysiology/Complications ORIGINAL ARTICLE Subjects With Early-Onset Type 2 Diabetes Show Defective Activation of the Skeletal Muscle PGC-1␣/Mitofusin-2 Regulatory Pathway in Response to Physical Activity 4 MARÍA ISABEL HERNANDEZ´ -ALVAREZ, FRANCIS FINUCANE, MD tive treatments to improve insulin sensi- 1,2,3 1,2,3 MSC MARC LIESA, PHD tivity. We have been studying the effects 4 5 HOOD THABIT, MD CHIARA CHIELLINI, PHD of a variety of exercise and dietary regi- 4 1,2,3 NICOLE BURNS, MSC DEBORAH NAON, MSC mens in these very insulin-resistant pa- 4 1,2,3 SYED SHAH, MD ANTONIO ZORZANO, PHD 4 4 tients. We recently demonstrated that a IMAD BREMA, MD OHN OLAN MD 4 J J. N , 3-month, four times weekly, aerobic ex- MENSUD HATUNIC, MD ercise intervention in subjects with early- onset type 2 diabetes failed to improve OBJECTIVE — Type 2 diabetes is associated with insulin resistance and skeletal muscle VO2max and had no significant effect on mitochondrial dysfunction. We have found that subjects with early-onset type 2 diabetes show whole-body or hepatic insulin sensitivity incapacity to increase VO2max in response to chronic exercise. This suggests a defect in muscle (3). Equally obese nondiabetic control mitochondrial response to exercise. Here, we have explored the nature of the mechanisms subjects had a 20% increase in VO2max involved. following the same regime. This sug- gested the possibility that, in these dia- RESEARCH DESIGN AND METHODS — Muscle biopsies were collected from young betic patients, chronic exercise training type 2 diabetic subjects and obese control subjects before and after acute or chronic exercise protocols, and the expression of genes and/or proteins relevant to mitochondrial function was failed to activate a mitochondrial oxida- measured. In particular, the regulatory pathway peroxisome proliferator–activated receptor ␥ tive response. coactivator (PGC)-1␣/mitofusin-2 (Mfn2) was analyzed. Defective mitochondrial function in skeletal muscle has been reported in a va- RESULTS — At baseline, subjects with diabetes showed reduced expression (by 26%) of the ␣ riety of insulin-resistant states, including mitochondrial fusion protein Mfn2 and a 39% reduction of the -subunit of ATP synthase. Porin type 2 diabetes (4,5). Muscle mitochon- expression was unchanged, consistent with normal mitochondrial mass. Chronic exercise led to a 2.8-fold increase in Mfn2, as well as increases in porin, and the ␣-subunit of ATP synthase in dria from type 2 diabetic subjects show muscle from control subjects. However, Mfn2 was unchanged after chronic exercise in individ- reduced size and reduced activity of the uals with diabetes, whereas porin and ␣-subunit of ATP synthase were increased. Acute exercise electron transport chain (4,6). In parallel, caused a fourfold increase in PGC-1␣ expression in muscle from control subjects but not in type 2 diabetes is associated with reduced subjects with diabetes. expression of genes of oxidative metabo- lism as well as repression of the mito- CONCLUSIONS — Our results demonstrate alterations in the regulatory pathway that con- fusin-2 (Mfn2) gene, which encodes the trols PGC-1␣ expression and induction of Mfn2 in muscle from patients with early-onset type 2 diabetes. Patients with early-onset type 2 diabetes display abnormalities in the exercise- mitochondrial fusion protein mitofusin-2 dependent pathway that regulates the expression of PGC-1␣ and Mfn2. (7–9). Decreased expression of nuclear genes encoding proteins of oxidative Diabetes Care 33:645–651, 2010 phosphorylation has been reported in skeletal muscle of nondiabetic individuals arly-onset type 2 diabetes is increas- obesity and severe insulin resistance in with a family history of type 2 diabetes ing in prevalence, in parallel with the young people with a strong family history (8,9), along with reduced in vivo oxida- E worldwide obesity epidemic (1), and of type 2 diabetes (1,2). Weight reduction tive phosphorylation (5). These findings is typically characterized by early-onset and increased physical exercise are effec- suggest that mitochondrial abnormalities in type 2 diabetes may have a heritable ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● component. From the 1Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain; the 2Departament de Chronic exercise induces mitochon- Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain; the drial biogenesis in skeletal muscle and en- 3CIBER de Diabetes y de Enfermedades Metabo´licas Asociadas (CIBERDEM), Barcelona, Spain; the 4Met- abolic Research Unit, Department of Endocrinology, Hospital 5, St. James’ Hospital, Trinity College hances mitochondrial function (10). Dublin, Dublin, Ireland; and the 5Institute of Internal Medicine, Catholic University School of Medicine, Exercise is known to induce PGC-1␣ Rome, Italy. (11), which in turn induces the transcrip- Corresponding author: John J. Nolan, [email protected]. tion of different nuclear genes encoding Received 22 July 2009 and accepted 14 December 2009. Published ahead of print at http://care. diabetesjournals.org on 23 December 2009. DOI: 10.2337/dc09-1305. mitochondrial proteins (12,13). One ex- M.I.H.-A. and H.T. contributed equally to this work. A.Z. and J.J.N. share senior authorship. ample is Mfn2, which is induced by © 2010 by the American Diabetes Association. Readers may use this article as long as the work is properly PGC-1␣ through interaction with the cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons. transcription factor ERR␣ (14). This may org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby be particularly relevant, since it has been marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. reported that Mfn2 regulates not just mi- care.diabetesjournals.org DIABETES CARE, VOLUME 33, NUMBER 3, MARCH 2010 645 PGC-1␣/mitofusin-2 pathway in early type 2 diabetes tochondrial fusion but also mitochondrial Table 1—Baseline characteristics of subjects in the chronic exercise study function through changes in mitochon- drial membrane potential and the expres- Youth with type 2 sion of OXPHOS subunits (15). The Control subjects diabetes stimulatory effect of exercise on mitochon- drial biogenesis and function has also been n 67 reported in muscle in insulin-resistant con- Male:female ratio 0:6 5:2 ditions such as obesity (6) and aging (16) Age (years) 22 Ϯ 127Ϯ 1* and in type 2 diabetes (17). Duration of diabetes (years) NA 3.2 Ϯ 1.5 Subjects who took part in the chronic Treatment for diabetes NA Met 7; Met/SU 1 exercise protocol (3) underwent skeletal Weight (kg) 108.7 Ϯ 10.6 108.1 Ϯ 6.7 muscle biopsies at baseline and after 3 BMI (kg/m2) 37.78 Ϯ 3.43 33.23 Ϯ 1.81 months of exercise training. To address Systolic blood pressure (mmHg) 104 Ϯ 3 122 Ϯ 5* mechanistic questions, we measured the Diastolic blood pressure (mmHg) 71 Ϯ 372Ϯ 3 expression of mitochondrial proteins Waist circumference (cm) 113.2 Ϯ 4.6 117.4 Ϯ 3.2 from this initial study. We then con- Waist-to-hip ratio 0.91 Ϯ 0.03 1.00 Ϯ 0.09 ducted an acute (short-term) exercise in- A1C (%) 5.5 Ϯ 0.2 8.2 Ϯ 0.6† tervention protocol in a similar cohort of Fasting glucose (mmol/) 5.2 Ϯ 0.2 9.1 Ϯ 0.8† patients with early-onset type 2 diabetes Fasting insulin (pmol/l) 91.1 Ϯ 9.4 77.1 Ϯ 12.3 and examined the expression in muscle Fasting C-peptide (␮g/l) 3.4 Ϯ 0.3 3.1 Ϯ 0.4 biopsies of a range of specific mitochon- Total cholesterol (mmol/l) 4.33 Ϯ 0.21 4.50 Ϯ 0.42 drial genes and proteins. We hypothe- HDL (mmol/) 1.11 Ϯ 0.08 0.88 Ϯ 0.03* sized that the lack of a whole-body LDL (mmol/l) 2.57 Ϯ 0.23 2.34 Ϯ 0.35 response to exercise training in the early- Triglycerides (mmol/l) 1.41 Ϯ 0.27 3.05 Ϯ 0.64* onset type 2 diabetic subjects may be a Free fatty acids (mmol/l) 0.635 Ϯ 0.053 0.820 Ϯ 0.104 consequence of alterations in the abun- Glucose disposal (␮mol/min/kg/mU/l) 26.25 Ϯ 4.66 16.13 Ϯ 4.16 ⅐ Ϫ1 ⅐ Ϫ1 Ϯ Ϯ dance or activity of relevant mitochon- Vo2max (ml kg min ) 28.61 1.94 22.67 1.57* drial proteins in skeletal muscle. Data are means Ϯ SE, unless specified otherwise. *Significantly different from control group (P Ͻ 0.05). †Significantly different from control group (P Ͻ 0.01). Met, metformin; SU, sulfonylurea. RESEARCH DESIGN AND METHODS — Subjects with early- onset type 2 diabetes (i.e., diagnosed be- fore age 25 years and negative for GAD hypoglycemic agents were on stable Aerobic capacity (VO2peak). Maximal antibodies) were recruited from our doses throughout the duration of the oxygen consumption was measured by clinic, along with obese and otherwise study. Subjects on the combination treadmill, as previously described (3). healthy subjects who were as far as possible therapy had their insulin doses reduced Muscle biopsy. Muscle biopsies were ϳ matched for age and BMI, but with normal by 20% during the course of the taken either after an overnight fast or im- glucose tolerance and without family his- study. mediately after the most recent session of tory of diabetes. All subjects were sedentary. exercise, as described below. All gave written informed consent for the Baseline studies Biopsies were obtained under local study, which had been approved by the lo- Baseline studies were identical for both anesthesia from the vastus lateralis mus- cal research ethics committee.
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