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In this study involving severely obese patients with type 2 diabetes, Roux-en-Y gastric bypass and biliopancreatic diversion achieved better glucose control than conventional medical therapy as assessed at 2 years. The prevalence of type 2 diabetes mellitus is rapidly increasing worldwide, in parallel with the current obesity epidemic. In 2010, the global prevalence of type 2 diabetes was estimated at 8.3% of the adult population, a proportion that is projected to increase to 9.9% by 2030. 1 As many as 23% of patients with morbid obesity have type 2 diabetes, 2 and the prevalence of screening-detected diabetes is 8%. 2 Global spending on diabetes was estimated to be at least $376 billion in 2010 and projected to be $490 billion in 2030. 3 Conventional medical treatment of type 2 diabetes only partially achieves adequate . . .

Randomised controlled trials have shown that bariatric surgery is more effective than conventional treatment for the short-term control of type-2 diabetes. However, published studies are characterised by a relatively short follow-up. We aimed to assess 5 year outcomes from our randomised trial designed to compare surgery with conventional medical treatment for the treatment of type 2 diabetes in obese patients. We did our open-label, randomised controlled trial at one diabetes centre in Italy. Patients aged 30–60 years with a body-mass index of 35 kg/m2 or more and a history of type 2 diabetes lasting at least 5 years were randomly assigned (1:1:1), via a computer-generated randomisation procedure, to receive either medical treatment or surgery by Roux-en-Y gastric bypass or biliopancreatic diversion. Participants were aware of treatment allocation before the operation and study investigators were aware from the point of randomisation. The primary endpoint was the rate of diabetes remission at 2 years, defined as a glycated haemaglobin A1c (HbA1c) concentration of 6·5% or less (≤47·5 mmol/mol) and a fasting glucose concentration of 5·6 mmol/L or less without active pharmacological treatment for 1 year. Here we analyse glycaemic and metabolic control, cardiovascular risk, medication use, quality of life, and long-term complications 5 years after randomisation. Analysis was by intention to treat for the primary endpoint and by per protocol for the 5 year follow-up. This study is registered with ClinicalTrials.gov, number NCT00888836. Between April 27, 2009, and Oct 31, 2009, we randomly assigned 60 patients to receive either medical treatment (n=20) or surgery by gastric bypass (n=20) or biliopancreatic diversion (n=20); 53 (88%) patients completed 5 years' follow-up. Overall, 19 (50%) of the 38 surgical patients (seven [37%] of 19 in the gastric bypass group and 12 [63%] of 19 in the bilipancreatic diversion group) maintained diabetes remission at 5 years, compared with none of the 15 medically treated patients (p=0·0007). We recorded relapse of hyperglycaemia in eight (53%) of the 15 patients who achieved 2 year remission in the gastric bypass group and seven (37%) of the 19 patients who achieved 2 year remission in the biliopancreatic diversion group. Eight (42%) patients who underwent gastric bypass and 13 (68%) patients who underwent biliopancreatic diversion had an HbA1c concentration of 6·5% or less (≤47·5 mmol/mol) with or without medication, compared with four (27%) medically treated patients (p=0·0457). Surgical patients lost more weight than medically treated patients, but weight changes did not predict diabetes remission or relapse after surgery. Both surgical procedures were associated with significantly lower plasma lipids, cardiovascular risk, and medication use. Five major complications of diabetes (including one fatal myocardial infarction) arose in four (27%) patients in the medical group compared with only one complication in the gastric bypass group and no complications in the biliopancreatic diversion group. No late complications or deaths occurred in the surgery groups. Nutritional side-effects were noted mainly after biliopancreatic diversion. Surgery is more effective than medical treatment for the long-term control of obese patients with type 2 diabetes and should be considered in the treatment algorithm of this disease. However, continued monitoring of glycaemic control is warranted because of potential relapse of hyperglycaemia. Catholic University of Rome.

Mechanisms of Recovery From Type 2 Diabetes After Malabsorptive Bariatric Surgery Caterina Guidone 1 , Melania Manco 1 , Elena Valera-Mora 1 , Amerigo Iaconelli 1 , Donatella Gniuli 1 , Andrea Mari 2 , Giuseppe Nanni 3 , Marco Castagneto 3 , Menotti Calvani 1 and Geltrude Mingrone 1 Department of Internal Medicine, Catholic University, School of Medicine, Rome, Italy 2 Metabolic Modeling Unit, Institute of Biomedical Engineering, National Research Council, Padova, Italy 3 Department of Surgery, CNR Centro di Fisiopatologia dello Shock, Catholic University, School of Medicine, Rome, Italy Address correspondence and reprint requests to Prof. Geltrude Mingrone, Dipartimento di Medicina Interna, Catholic University, Largo A. Gemelli, 8, 00168 Rome, Italy. E-mail: gmingrone{at}rm.unicatt.it Abstract Currently, there are no data in the literature regarding the pathophysiological mechanisms involved in the rapid resolution of type 2 diabetes after bariatric surgery, which was reported as an additional benefit of the surgical treatment for morbid obesity. With this question in mind, insulin sensitivity, using euglycemic-hyperinsulinemic clamp, and insulin secretion, by the C-peptide deconvolution method after an oral glucose load, together with the circulating levels of intestinal incretins and adipocytokines, have been studied in 10 diabetic morbidly obese subjects before and shortly after biliopancreatic diversion (BPD) to avoid the weight loss interference. Diabetes disappeared 1 week after BPD, while insulin sensitivity (32.96 ± 4.3 to 65.73 ± 3.22 μmol · kg fat-free mass −1 · min −1 at 1 week and to 64.73 ± 3.42 μmol · kg fat-free mass −1 · min −1 at 4 weeks; P < 0.0001) was fully normalized. Fasting insulin secretion rate (148.16 ± 20.07 to 70.0.2 ± 8.14 and 83.24 ± 8.28 pmol/min per m 2 ; P < 0.01) and total insulin output (43.76 ± 4.07 to 25.48 ± 1.69 and 30.50 ± 4.71 nmol/m 2 ; P < 0.05) dramatically decreased, while a significant improvement in β-cell glucose sensitivity was observed. Both fasting and glucose-stimulated gastrointestinal polypeptide (13.40 ± 1.99 to 6.58 ± 1.72 pmol/l at 1 week and 5.83 ± 0.80 pmol/l at 4 weeks) significantly ( P < 0.001) decreased, while glucagon-like peptide 1 significantly increased (1.75 ± 0.16 to 3.42 ± 0.41 pmol/l at 1 week and 3.62 ± 0.21 pmol/l at 4 weeks; P < 0.001). BPD determines a prompt reversibility of type 2 diabetes by normalizing peripheral insulin sensitivity and enhancing β-cell sensitivity to glucose, these changes occurring very early after the operation. This operation may affect the enteroinsular axis function by diverting nutrients away from the proximal gastrointestinal tract and by delivering incompletely digested nutrients to the ileum. AUC, area under the curve BPD, biliopancreatic diversion FFM, fat-free mass GIP, gastrointestinal polypeptide GLP-1, glucagon-like peptide 1 OGTT, oral glucose tolerance test Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “ advertisement ” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted April 17, 2006. Received January 14, 2006. DIABETES

Restoration of Adiponectin Pulsatility in Severely Obese Subjects After Weight Loss Menotti Calvani 1 , Antonio Scarfone 1 , Luigi Granato 1 2 , Elena Valera Mora 1 , Giuseppe Nanni 3 , Marco Castagneto 3 , Aldo V. Greco 1 , Melania Manco 1 and Geltrude Mingrone 1 1 Department of Internal Medicine, Consiglio Nazionale delle Ricerche Centro di Fisiopatologia dello Shock, Catholic University, School of Medicine, Rome, Italy 2 Department of Informatica and Sistemistica, Facoltà di Ingegneria, Università di Roma La Sapienza, Rome, Italy 3 Department of Surgery, Consiglio Nazionale delle Ricerche Centro di Fisiopatologia dello Shock, Catholic University, School of Medicine, Rome, Italy Address correspondence and reprint requests to Prof. Geltrude Mingrone, Dipartimento di Medicina Interna Catholic University, Largo A. Gemelli, 8 00168 Rome, Italy. E-mail: gmingrone{at}rm.unicatt.it Abstract Diurnal variations of adiponectin levels have been studied in normal-weight men and in diabetic and nondiabetic obese subjects, but no data have been reported in obese subjects after weight loss. We collected blood samples at 1-h intervals over 24 h from seven severely obese subjects before and after massive weight loss consequent to surgical operation (bilio-pancreatic diversion [BPD]) to measure adiponectin, insulin, glucose, and cortisol levels. Insulin sensitivity was assessed by euglycemic-hyperinsulinemic clamp ( M value). Studies of diurnal variations and pulsatility of adiponectin, insulin, and cortisol were performed. The pulsatility index (PI) of adiponectin increased after BPD from 0.04 to 0.11 μg/min ( P = 0.01). Insulin PI significantly increased after the operation (1.50 vs. 1.08 pmol · l –1 · min –1 , P = 0.01), while cortisol PI did not significantly change. The adiponectin clearance rate changed from 0.001 ± 10 −4 · min −1 before BPD to 0.004 ± 8 · 10 −4 · min −1 after BPD ( P = 0.03). Insulin clearance increased from 0.006 ± 6 · 10 −4 · min −1 before BPD to 0.009 ± 4 · 10 −4 · min −1 after BPD ( P = 0.02). The M value doubled after surgery (27.08 ± 8.5 vs. 53.34 ± 9.3 μmol · kg FFM −1 · min −1 ; P < 0.001) becoming similar to the values currently reported for normal-weight subjects. In conclusion, in formerly severely obese subjects, weight loss paired with the reversibility of insulin resistance restores homeostatic control of the adiponectin secretion, contributing to the reduction of cardiovascular risk already described in these patients. AUC, area under the curve BPD, bilio-pancreatic diversion EHC, euglycemic-hyperinsulinemic clamp FFM, fat-free mass HPA, hypothalamus-pituitary-adrenal NEFA, nonesterified fatty acid PI, pulsatility index TBW, total body water TNF, tumor necrosis factor Footnotes Accepted January 20, 2004. Received November 4, 2003. DIABETES

OBJECTIVE: The surgical option could represent a valid alternative to medical therapy in some diabetic patients. However, no data are available on long-term effects of metabolic surgery on diabetic complications. We aimed to determine whether patients with newly diagnosed type 2 diabetes who underwent bilio-pancreatic diversion (BPD) had less micro- and macrovascular complications than those who received conventional therapy. RESEARCH DESIGN AND METHODS: This was an unblinded, case-controlled trial with 10-years' follow-up, conducted from July 1998 through October 2009 at the Day Hospital of Metabolic Diseases, Catholic University, Rome, Italy. A consecutive sample of 110 obese patients (BMI >35 kg/m²) with newly diagnosed type 2 diabetes was enrolled. The study was completed by 50 subjects. The main outcome measure was long-term effects (10 years) of BPD versus those associated with conventional therapy on microvascular outcome, micro- and macroalbuminuria, and glomerular filtration rate (GFR). Secondary measures included macrovascular outcomes, type 2 diabetes remission, glycated hemoglobin, and hyperlipidemia. RESULTS: Ten-year GFR variation was -45.7 ± 18.8% in the medical arm and 13.6 ± 24.5% in the surgical arm (P < 0.001). Ten-year hypercreatininemia prevalence was 39.3% in control subjects and 9% in BPD subjects (P = 0.001). After 10 years, all BPD subjects recovered from microalbuminuria, whereas microalbuminuria appeared or progressed to macroalbuminuria in control subjects. Three myocardial infarctions, determined by electrocardiogram, and one stroke occurred in control subjects. After the 10-year follow-up, coronary heart disease (CHD) probability was 0.22 ± 0.10 and 0.05 ± 0.04 in the medical and surgical groups, respectively (P < 0.001). Remission from type 2 diabetes was observed in all patients within 1 year of surgery. Surgical and medical subjects had lost 34.60 ± 10.25 and 0.38 ± 6.10% of initial weight at the 10-year follow-up (P < 0.001). CONCLUSIONS: Renal and cardiovascular complications were dramatically reduced in the surgical arm, indicating long-term benefits of BPD on diabetic complications, at least in the case of morbid obesity with decompensated type 2 diabetes.

Medium-chain dicarboxylic acids are produced by higher plants and animals via fatty acid omega-oxidation or by beta-oxidation of longer-chain dicarboxylic acids. In plants, dicarboxylic acids are components of the natural protective polymers cutin and suberin; in animals, dicarboxylic acids are mainly oxidized in mitochondria, where they are transported through four different pathways. Their energy density is intermediate between glucose and fatty acids. Dicarboxylic acid administration does not require insulin or stimulate insulin secretion, and the beta-oxidation of dicarboxylic acids produces succinic acid, a gluconeogenic substrate. Therefore, dicarboxylic acids might be a suitable fuel substrate, particularly in clinical conditions in which marked insulin resistance and/or impairment of aerobic glycolysis occur.Medium-chain dicarboxylic acids are produced by higher plants and animals via fatty acid omega-oxidation or by beta-oxidation of longer-chain dicarboxylic acids. In plants, dicarboxylic acids are components of the natural protective polymers cutin and suberin; in animals, dicarboxylic acids are mainly oxidized in mitochondria, where they are transported through four different pathways. Their energy density is intermediate between glucose and fatty acids. Dicarboxylic acid administration does not require insulin or stimulate insulin secretion, and the beta-oxidation of dicarboxylic acids produces succinic acid, a gluconeogenic substrate. Therefore, dicarboxylic acids might be a suitable fuel substrate, particularly in clinical conditions in which marked insulin resistance and/or impairment of aerobic glycolysis occur.

The primary gene mutated in Charcot-Marie-Tooth type 2A is mitofusin-2 (Mfn2). Mfn2 encodes a mitochondrial protein that participates in the maintenance of the mitochondrial network and that regulates mitochondrial metabolism and intracellular signaling. The potential for regulation of human Mfn2 gene expression in vivo is largely unknown. Based on the presence of mitochondrial dysfunction in insulin-resistant conditions, we have examined whether Mfn2 expression is dysregulated in skeletal muscle from obese or nonobese type 2 diabetic subjects, whether muscle Mfn2 expression is regulated by body weight loss, and the potential regulatory role of tumor necrosis factor (TNF)alpha or interleukin-6. We show that mRNA concentration of Mfn2 is decreased in skeletal muscle from both male and female obese subjects. Muscle Mfn2 expression was also reduced in lean or in obese type 2 diabetic patients. There was a strong negative correlation between the Mfn2 expression and the BMI in nondiabetic and type 2 diabetic subjects. A positive correlation between the Mfn2 expression and the insulin sensitivity was also detected in nondiabetic and type 2 diabetic subjects. To determine the effect of weight loss on Mfn2 mRNA expression, six morbidly obese subjects were subjected to weight loss by bilio-pancreatic diversion. Mean expression of muscle Mfn2 mRNA increased threefold after reduction in body weight, and a positive correlation between muscle Mfn2 expression and insulin sensitivity was again detected. In vitro experiments revealed an inhibitory effect of TNFalpha or interleukin-6 on Mfn2 expression in cultured cells. We conclude that body weight loss upregulates the expression of Mfn2 mRNA in skeletal muscle of obese humans, type 2 diabetes downregulates the expression of Mfn2 mRNA in skeletal muscle, Mfn2 expression in skeletal muscle is directly proportional to insulin sensitivity and is inversely proportional to the BMI, TNFalpha and interleukin-6 downregulate Mfn2 expression and may participate in the dysregulation of Mfn2 expression in obesity or type 2 diabetes, and the in vivo modulation of Mfn2 mRNA levels is an additional level of regulation for the control of muscle metabolism and could provide a molecular mechanism for alterations in mitochondrial function in obesity or type 2 diabetes.

Massive Weight Loss Decreases Corticosteroid-Binding Globulin Levels and Increases Free Cortisol in Healthy Obese Patients An adaptive phenomenon? Melania Manco , MD, PHD 1 , José M. Fernández-Real 2 , Maria E. Valera-Mora 3 , Henri Déchaud 4 , Giuseppe Nanni 5 , Vincenzo Tondolo 5 , Menotti Calvani 3 , Marco Castagneto 5 , Michel Pugeat 4 and Geltrude Mingrone 3 1 Liver Unit, “Bambino Gesù” Hospital and Research Institute, Rome, Italy 2 Department of Diabetes, Endocrinology, and Nutrition, University Hospital of Girona, Girona, Spain 3 Department of Internal Medicine, Catholic University, Rome, Italy 4 Fédèration d'Endocrinologie, Hospital Neuro-Cardiologique, Hospices Civils, Lyon, France 5 Department of Surgery, Catholic University; Rome, Italy Address correspondence and reprint requests to Melania Manco, MD, PhD, via Pineta Sacchetti, 484, 00168, Rome, Italy. E-mail: melaniamanco{at}tiscali.it Abstract OBJECTIVE —Obesity, insulin resistance, and weight loss have been associated with changes in hypothalamic-pituitary-adrenal (HPA) axis. So far, no conclusive data relating to this association are available. In this study, we aim to investigate the effects of massive weight loss on cortisol suppressibility, cortisol-binding globulin (CBG), and free cortisol index (FCI) in formerly obese women. RESEARCH DESIGN AND METHODS —Ten glucose-normotolerant, fertile, obese women (BMI >40 kg/m 2 , aged 38.66 ± 13.35 years) were studied before and 2 years after biliopancreatic diversion (BPD) when stable weight was achieved and were compared with age-matched healthy volunteers. Cortisol suppression was evaluated by a 4-mg intravenous dexamethasone suppression test (DEX-ST). FCI was calculated as the cortisol-to-CBG ratio. Insulin sensitivity was measured by an euglycemic-hyperinsulinemic clamp, and insulin secretion was measured by a C-peptide deconvolution method. RESULTS —No difference was found in cortisol suppression after DEX-ST before or after weight loss. A decrease in ACTH was significantly greater in control subjects than in obese ( P = 0.05) and postobese women ( P ≤ 0.01) as was the decrease in dehydroepiandrosterone ( P ≤ 0.05 and P ≤ 0.01, respectively). CBG decreased from 51.50 ± 12.76 to 34.33 ± 7.24 mg/l ( P ≤ 0.01) following BPD. FCI increased from 11.15 ± 2.85 to 18.16 ± 6.82 ( P ≤ 0.05). Insulin secretion decreased (52.04 ± 16.71 vs. 30.62 ± 16.32 nmol/m −2 ; P ≤ 0.05), and insulin sensitivity increased by 163% ( P ≤ 0.0001). Serum CBG was related to BMI ( r 0 = 0.708; P = 0.0001), body weight ( r 0 = 0.643; P = 0.0001), body fat percent ( r 0 = 0.462; P = 0.001), C-reactive protein ( r 0 = 0.619; P = 0.004), and leptin ( r 0 = 0.579; P = 0.007) and negatively to M value ( r 0 = −0.603; P = 0.005). CONCLUSIONS —After massive weight loss in morbidly obese subjects, an increase of free cortisol was associated with a simultaneous decrease in CBG levels, which might be an adaptive phenomenon relating to environmental changes. This topic, not addressed before, adds new insight into the complex mechanisms linking HPA activity to obesity. BPD, biliopancreatic diversion CBG, cortisol-binding globulin CRP, C-reactive protein DEX, dexamethasone DEX-ST, DEX suppression test FCI, free cortisol index FFM, fat-free mass HPA, hypothalamic-pituitary-adrenal OGTT, oral glucose tolerance test RIA, radioimmunoassay Footnotes M.C. is employed by Sigma-Tau (Italy). A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C Section 1734 solely to indicate this fact. Accepted December 21, 2006. Received June 30, 2006. DIABETES CARE

The HAIR-AN syndrome is a rare multisystem disorder in women, that consists of hyperandrogenism (HA), insulin resistance (IR) and acanthosis nigricans (AN). The IR is likely due to a primary defect of the insulin receptor. We report the case of a 42-year-old Caucasian woman with HAIR-AN syndrome, impaired glucose tolerance (IGT), mild hyperlipemia, and hypertension, who underwent biliopancreatic diversion (BPD). Within 24 months follow-up after BPD, impaired glucose tolerance, mild hyperlipemia, and hypertension completely reversed. Although insulin sensitivity, estimated by the euglycemic hyperinsulinemic clamp, did not improve, signs and symptoms of hyperandrogenism and acanthosis nigricans resolved fully. In HAIR-AN syndrome, malabsorptive bariatric surgery is effective in improving hyperandrogenism and acanthosis nigricans, with noteworthy esthetic consequences. BPD was followed by disappearance of co-morbidities of the syndrome, such as IGT, hypertension and hyperlipemia.

Expression of Mfn2 , the Charcot-Marie-Tooth Neuropathy Type 2A Gene, in Human Skeletal Muscle Effects of Type 2 Diabetes, Obesity, Weight Loss, and the Regulatory Role of Tumor Necrosis Factor α and Interleukin-6 Daniel Bach 1 , Deborah Naon 1 , Sara Pich 1 , Francesc X. Soriano 1 , Nathalie Vega 2 , Jennifer Rieusset 2 , Martine Laville 2 , Christelle Guillet 3 , Yves Boirie 3 , Harriet Wallberg-Henriksson 4 , Melania Manco 5 , Menotti Calvani 5 , Marco Castagneto 5 , Manuel Palacín 1 , Geltrude Mingrone 5 , Juleen R. Zierath 4 , Hubert Vidal 2 and Antonio Zorzano 1 1 Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, and IRB-PCB, Parc Científic de Barcelona, Barcelona, Spain 2 Institut National de la Santé et de la Recherche Médicale Unité-449 and Centre de Recherche en Nutrition Humaine de Lyon, Faculté de Médecine R.T.H., Laennec Lyon, France 3 Unite du Metabolisme Proteino-Energetique, UMR Universite d’Auvergne/INRA, CRNH, Centre Hospitalier Universitaire, Clermont-Ferrand, France 4 Department of Surgical Sciences, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden 5 Istituto di Medicina Interna, Facoltà di Medicina e Chirurgia, Università Cattolica, Roma, Italy Address correspondence and reprint requests to Dr. Antonio Zorzano, Universitat de Barcelona, Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Avda. Diagonal 645, Barcelona, Spain, 08071. E-mail: azorzano{at}pcb.ub.es Abstract The primary gene mutated in Charcot-Marie-Tooth type 2A is mitofusin-2 ( Mfn2 ). Mfn2 encodes a mitochondrial protein that participates in the maintenance of the mitochondrial network and that regulates mitochondrial metabolism and intracellular signaling. The potential for regulation of human Mfn2 gene expression in vivo is largely unknown. Based on the presence of mitochondrial dysfunction in insulin-resistant conditions, we have examined whether Mfn2 expression is dysregulated in skeletal muscle from obese or nonobese type 2 diabetic subjects, whether muscle Mfn2 expression is regulated by body weight loss, and the potential regulatory role of tumor necrosis factor (TNF)α or interleukin-6. We show that mRNA concentration of Mfn2 is decreased in skeletal muscle from both male and female obese subjects. Muscle Mfn2 expression was also reduced in lean or in obese type 2 diabetic patients. There was a strong negative correlation between the Mfn2 expression and the BMI in nondiabetic and type 2 diabetic subjects. A positive correlation between the Mfn2 expression and the insulin sensitivity was also detected in nondiabetic and type 2 diabetic subjects. To determine the effect of weight loss on Mfn2 mRNA expression, six morbidly obese subjects were subjected to weight loss by bilio-pancreatic diversion. Mean expression of muscle Mfn2 mRNA increased threefold after reduction in body weight, and a positive correlation between muscle Mfn2 expression and insulin sensitivity was again detected. In vitro experiments revealed an inhibitory effect of TNFα or interleukin-6 on Mfn2 expression in cultured cells. We conclude that body weight loss upregulates the expression of Mfn2 mRNA in skeletal muscle of obese humans, type 2 diabetes downregulates the expression of Mfn2 mRNA in skeletal muscle, Mfn2 expression in skeletal muscle is directly proportional to insulin sensitivity and is inversely proportional to the BMI, TNFα and interleukin-6 downregulate Mfn2 expression and may participate in the dysregulation of Mfn2 expression in obesity or type 2 diabetes, and the in vivo modulation of Mfn2 mRNA levels is an additional level of regulation for the control of muscle metabolism and could provide a molecular mechanism for alterations in mitochondrial function in obesity or type 2 diabetes. BPD, bilio-pancreatic diversion Mfn2, mitofusin-2 TNF, tumor necrosis factor Footnotes Accepted June 1, 2005. Received January 7, 2005. DIABETES