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ObjectiveThis report documents that the gastric bypass operation provides long-term control for obesity and diabetes. Summary Background DataObesity and diabetes, both notoriously resistant to medical therapy, continue to be two of our most common and serious diseases. MethodsOver the last 14 years, 608 morbidly obese patients underwent gastric bypass, an operation that restricts caloric intake by (1) reducing the functional stomach to approximately 30 mL, (2) delaying gastric emptying with a c. 0.8 to 1.0 cm gastric outlet, and (3) excluding foregut with a 40 to 60 cm Roux-en-Y gastrojejunostomy. Even though many of the patients were seriously ill, the operation was performed with a perioperative mortality and complication rate of 1.5% and 8.5%, respectively. Seventeen of the 608 patients (<3%) were lost to follow-up. ResultsGastric bypass provides durable weight control. Weights fell from a preoperative mean of 304.4 lb (range, 198 The operation provides long-term control of non-insulin-dependent diabetes mellitus (NIDDM). In those patients with adequate follow-up, 121 of 146 patients (82.9%) with NIDDM and 150 of 152 patients (98.7%) with glucose impairment maintained normal levels of plasma glucose, glycosylated hemoglobin, and insulin. These antidiabetic effects appear to be due primarily to a reduction in caloric intake, suggesting that insulin resistance is a secondary protective effect rather than the initial lesion. In addition to the control of weight and NIDDM, gastric bypass also corrected or alleviated a number of other comorbidities of obesity, including hypertension, sleep apnea, cardiopulmonary failure, arthritis, and infertility. 339

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BACKGROUNDDespite growing evidence that bariatric/metabolic surgery powerfully improves type 2 diabetes (T2D), existing diabetes treatment algorithms do not include surgical options. AIMThe 2nd Diabetes Surgery Summit (DSS-II), an international consensus conference, was convened in collaboration with leading diabetes organizations to develop global guidelines to inform clinicians and policymakers about benefits and limitations of metabolic surgery for T2D. METHODSA multidisciplinary group of 48 international clinicians/scholars (75% nonsurgeons), including representatives of leading diabetes organizations, participated in DSS-II. After evidence appraisal (MEDLINE [1 January 2005-30 September 2015]), three rounds of Delphi-like questionnaires were used to measure consensus for 32 data-based conclusions. These drafts were presented at the combined DSS-II and 3rd World Congress on Interventional Therapies for Type 2 Diabetes (London, U.K., 28-30 September 2015), where they were open to public comment by other professionals and amended face-to-face by the Expert Committee. RESULTSGiven its role in metabolic regulation, the gastrointestinal tract constitutes a meaningful target to manage T2D. Numerous randomized clinical trials, albeit mostly short/midterm, demonstrate that metabolic surgery achieves excellent glycemic control and reduces cardiovascular risk factors. On the basis of such evidence, metabolic surgery should be recommended to treat T2D in patients with class III obesity (BMI ‡40 kg/m 2 ) and in those with class II obesity (BMI 35.0-39.9 kg/m 2 ) when hyperglycemia is inadequately controlled by lifestyle and optimal medical therapy. Surgery should also be considered for patients with T2D and BMI 30.0-34.9 kg/m 2 if hyperglycemia is inadequately controlled despite optimal treatment with either oral or injectable medications. These BMI thresholds should be reduced by 2.5 kg/m 2 for Asian patients. CONCLUSIONSAlthough additional studies are needed to further demonstrate long-term benefits, there is sufficient clinical and mechanistic evidence to support inclusion of metabolic surgery among antidiabetes interventions for people with T2D and obesity. To date, the DSS-II guidelines have been formally endorsed by 45 worldwide medical and scientific societies. Health care regulators should introduce appropriate reimbursement policies.

The peroxisome proliferator activated receptor (PPAR gamma) plays a key role in adipogenesis and adipocyte gene expression and is the receptor for the thiazolidinedione class of insulin-sensitizing drugs. The tissue expression and potential for regulation of human PPAR gamma gene expression in vivo are unknown. We have cloned a partial human PPAR gamma cDNA, and established an RNase protection assay that permits simultaneous measurements of both PPAR gamma1 and PPAR gamma2 splice variants. Both gamma1 and gamma2 mRNAs were abundantly expressed in adipose tissue. PPAR gamma1 was detected at lower levels in liver and heart, whereas both gamma1 and gamma2 mRNAs were expressed at low levels in skeletal muscle. To examine the hypothesis that obesity is associated with abnormal adipose tissue expression of PPAR gamma, we quantitated PPARgamma mRNA splice variants in subcutaneous adipose tissue of 14 lean and 24 obese subjects. Adipose expression of PPARgamma 2 mRNA was increased in human obesity (14.25 attomol PPAR gamma2/18S in obese females vs 9.9 in lean, P = 0.003). This increase was observed in both male and females. In contrast, no differences were observed in PPAR gamma1/18S mRNA expression. There was a strong positive correlation (r = 0.70, P < 0.001) between the ratio of PPAR gamma2/gamma1 and the body mass index of these patients. We also observed sexually dimorphic expression with increased expression of both PPAR gamma1 and PPAR gamma2 mRNAs in the subcutaneous adipose tissue of women compared with men. To determine the effect of weight loss on PPAR gamma mRNA expression, seven additional obese subjects were fed a low calorie diet (800 Kcal) until 10% weight loss was achieved. Mean expression of adipose PPAR gamma2 mRNA fell 25% (P = 0.0250 after a 10% reduction in body weight), but then increased to pretreatment levels after 4 wk of weight maintenance. Nutritional regulation of PPAR gamma1 was not seen. In vitro experiments revealed a synergistic effect of insulin and corticosteroids to induce PPAR gamma expression in isolated human adipocytes in culture. We conclude that: (a) human PPAR gamma mRNA expression is most abundant in adipose tissue, but lower level expression of both splice variants is seen in skeletal muscle; to an extent that is unlikely to be due to adipose contamination. (b) RNA derived from adipose tissue of obese humans has increased expression of PPAR gamma 2 mRNA, as well as an increased ratio of PPAR gamma2/gamma1 splice variants that is proportional to the BMI; (c) a low calorie diet specifically down-regulates the expression of PPAR gamma2 mRNA in adipose tissue of obese humans; (d) insulin and corticosteroids synergistically induce PPAR gamma mRNA after in vitro exposure to isolated human adipocytes; and (e) the in vivo modulation of PPAR gamma2 mRNA levels is an additional level of regulation for the control of adipocyte development and function, and could provide a molecular mechanism for alterations in adipocyte number and function in obesity.

clinicaltrials.gov Identifier: NCT00465829.

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; 10.1152/ajpendo.00416.2001.-The purpose of this study was to test the hypothesis that muscle fiber type is related to obesity. Fiber type was compared 1) in lean and obese women, 2) in Caucasian (C) and African-American (AA) women, and 3) in obese individuals who lost weight after gastric bypass surgery. When lean (body mass index 24.0 Ϯ 0.9 kg/m 2 , n ϭ 28) and obese (34.8 Ϯ 0.9 kg/m 2 , n ϭ 25) women were compared, there were significant (P Ͻ 0.05) differences in muscle fiber type. The obese women possessed fewer type I (41.5 Ϯ 1.8 vs. 54.6 Ϯ 1.8%) and more type IIb (25.1 Ϯ 1.5 vs. 14.4 Ϯ 1.5%) fibers than the lean women. When ethnicity was accounted for, the percentage of type IIb fibers in obese AA was significantly higher than in obese C (31.0 Ϯ 2.4% vs. 19.2 Ϯ 1.9%); fewer type I fibers were also found in obese AA (34.5 Ϯ 2.8% vs. 48.6 Ϯ 2.2%). These data are consistent with the higher incidence of obesity and greater weight gain reported in AA women. With weight loss intervention, there was a positive relationship (r ϭ 0.72, P Ͻ 0.005) between the percentage of excess weight loss and the percentage of type I fibers in morbidly obese patients. These findings indicate that there is a relationship between muscle fiber type and obesity. adiposity; African-American; insulin resistance; morbid obesity; skeletal muscle SKELETAL MUSCLE IS A HETEROGENEOUS organ consisting of different muscle fiber phenotypes. In human skeletal muscle, histochemical staining for pH-sensitive myosin ATPase activity has revealed two major classifications of fiber type, the type I and type II fibers (3,28,31). The fast-twitch, type II fibers can be broadly categorized into type IIa and type IIb fibers, although other subclasses exist (3,29,31). The type I, or slow-twitch, muscle fibers tend to be oxidative and vascularized, whereas the type IIb fibers (fast twitch) are glycolytic in nature (28, 31). The type I fibers are also insulin sensitive compared with type II muscle (8,13,17).In humans, there can be substantial heterogeneity of muscle fiber types within a given mixed muscle group. Simoneau and Bouchard (32) concluded that, in the vastus lateralis, Ն25% of the North American Caucasian population possessed either less than 35% or more than 65% type I fibers; a range of 13-98% type I fibers has been reported (31). Several factors may be linked with such variance. We have observed that obese individuals exhibit fewer type I and more type IIb muscle fibers than lean subjects (9). Other research has reported a negative relationship between adiposity and the relative percentage of type I muscle fibers (9, 21, 36) and an increased percentage of type IIb muscle fibers in patients with type 2 diabetes (9, 23), in their insulin-resistant offspring (27), and in obese subjects (18,19,21,23). Such findings make it tempting to speculate that there is a relationship between muscle fiber composition and obesity.The purpose of the current study was to test the hypothesis that muscle fiber type is related to obesity. We tested this hypothesis in...