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We established a model of chronic portal vein catheterization in an awake nonhuman primate to provide a comprehensive evaluation of the metabolic response to low-carbohydrate/high-fat (LCHF; 20% carbohydrate and 65% fat) and high-carbohydrate/low-fat (HCLF; 65% carbohydrate and 20% fat) meal ingestion. Each meal was given 1 wk apart to five young adult (7.8 ± 1.3 yr old) male baboons. A [U-13C]glucose tracer was added to the meal, and a [6,6-2H2]glucose tracer was infused systemically to assess glucose kinetics. Plasma areas under the curve (AUCs) of glucose, insulin, and C-peptide in the femoral artery and of glucose and insulin in the portal vein were higher ( P ≤ 0.05) after ingestion of the HCLF compared with the LCHF meal. Compared with the LCHF meal, the rate of appearance of ingested glucose into the portal vein and the systemic circulation was greater after the HCLF meal ( P < 0.05). Endogenous glucose production decreased by ∼40% after ingestion of the HCLF meal but was not affected by the LCHF meal ( P < 0.05). Portal vein blood flow increased ( P < 0.001) to a similar extent after consumption of either meal. In conclusion, a LCHF diet causes minimal changes in the rate of glucose appearance in both portal and systemic circulations, does not affect the rate of endogenous glucose production, and causes minimal stimulation of C-peptide and insulin. These observations demonstrate that LCHF diets cause minimal perturbations in glucose homeostasis and pancreatic β-cell activity.

Type 2 diabetes (T2D) is a major worldwide public health concern. Despite a large armamentarium of T2D medications, a large proportion of patients fail to achieve recommended treatment goals for glycemic control. Weight loss has profound beneficial effects on the metabolic abnormalities involved in the pathogenesis of T2D. Accordingly, bariatric surgery, which is the most effective available weight loss therapy, is also the most effective therapy for treating patients with T2D. Surgical procedures that bypass the upper gastrointestinal (UGI) tract are particularly effective in achieving partial and even complete remission of T2D, suggesting that UGI bypass has weight loss-independent effects on glycemic control. Although a number of hypotheses (e.g. a role for multi-organ insulin sensitivity, β-cell function, incretin response, the gut microbiome, bile acid metabolism, intestinal glucose metabolism, and browning of adipose tissue) have been proposed to explain the potential unique effects of UGI tract bypass surgery, none has yet been adequately evaluated to determine therapeutic importance in patients with T2D. Here, we review the efficacy of UGI bypass surgery in treating T2D and the mechanisms that have been proposed to explain its potential weight loss-independent therapeutic effects.

Objective To test the hypothesis that HIV infection impairs the beneficial effects of weight-loss on insulin-sensitivity and adipose-tissue inflammation and endoplasmic reticulum (ER) stress. Methods A prospective clinical trial to evaluate the effects of moderate diet-induced weight-loss on body-composition, metabolic function and adipose-tissue biology in women with obesity who were HIV-seronegative (HIV−) or HIV-positive (HIV+). Body-composition, multi-organ insulin-sensitivity (assessed by using a 2-stage hyperinsulinemic-euglycemic clamp procedure with stable isotopically-labeled tracer infusions), and adipose-tissue expression of markers of inflammation, autophagy and ER stress were evaluated in 8 HIV− and 20 HIV+ women with obesity before and after 6%–8% diet-induced weight-loss. Results Although weight-loss was not different between groups (~7.5%), the decrease in fat-free-mass was greater in HIV+ than HIV− subjects (−4.4±0.7 % vs −1.7±1.0%, P < 0.05). Weight loss improved insulin-sensitivity in adipose-tissue (suppression of palmitate rate of appearance [Ra]), liver (suppression of glucose Ra) and muscle (glucose disposal) similarly in both groups. Weight-loss did not affect adipose-tissue expression of markers of inflammation or ER stress in either group. Conclusions Moderate diet-induced weight-loss improves multi-organ insulin-sensitivity in HIV+ women to the same extent as women who are HIV−. However, weight loss causes a greater decline in FFM in HIV+ than HIV− women.

SummaryHigh-protein (HP) intake during weight loss (WL) therapy is often recommended because it reduces the loss of lean tissue mass. However, HP intake could have adverse effects on metabolic function, because protein ingestion reduces postprandial insulin sensitivity. In this study, we compared the effects of ∼10% WL with a hypocaloric diet containing 0.8 g protein/kg/day and a hypocaloric diet containing 1.2 g protein/kg/day on muscle insulin action in postmenopausal women with obesity. We found that HP intake reduced the WL-induced decline in lean tissue mass by ∼45%. However, HP intake also prevented the WL-induced improvements in muscle insulin signaling and insulin-stimulated glucose uptake, as well as the WL-induced adaptations in oxidative stress and cell structural biology pathways. Our data demonstrate that the protein content of a WL diet can have profound effects on metabolic function and underscore the importance of considering dietary macronutrient composition during WL therapy for people with obesity.

Weight loss from calorie restriction (CR) and/or endurance exercise training (EX) is cardioprotective. However CR and EX also have weight loss-independent benefits.We tested the hypothesis that weight loss from calorie restriction and exercise combined (CREX) improves cardiovascular disease (CVD) risk factors more so than similar weight loss from CR or EX alone.Overweight, sedentary men and women (n = 52; aged 45-65 y) were randomly assigned to undergo 6-8% weight loss by using CR, EX, or CREX. Outcomes were measured before and after weight loss and included maximal oxygen consumption (VO2max), resting blood pressure, fasting plasma lipids, glucose, C-reactive protein, and arterial stiffness [carotid-femoral pulse wave velocity (PWV) and carotid augmentation index (AI)]. Values are means ± SEs.Reductions in body weight (∼7%) were similar in all groups. VO2max changed in proportion to the amount of exercise performed (CR, -1% ± 3%; EX, +22% ± 3%; and CREX, +11% ± 3%). None of the changes in CVD risk factors differed between groups. For all groups combined, decreases were observed for systolic and diastolic blood pressure (-5 ± 1 and -4 ± 1 mm Hg, respectively; both P0.0008), total cholesterol (-17 ± 4 mg/dL; P0.0001), non-HDL cholesterol (-16 ± 3 mg/dL; P0.0001), triglycerides (-18 ± 8 mg/dL; P = 0.03), and glucose (-3 ± 1 mg/dL; P = 0.0003). No changes were observed for HDL cholesterol (P = 0.30), C-reactive protein (P = 0.10), PWV (P = 0.30), or AI (P = 0.84). These changes would be expected to decrease the lifetime risk of CVD from 46% to 36%.Matched weight losses from CR, EX, and CREX have substantial beneficial effects on CVD risk factors. However, the effects are not additive when weight loss is matched. This trial was registered at clinicaltrials.gov as NCT00777621.

Uridine's rise and fall: Food for thought The nucleoside uridine is well known for its role in critical cellular functions such as nucleic acid synthesis. Its role in whole-animal physiology has received comparatively little attention. In mammals, plasma uridine levels are tightly regulated, but the underlying mechanisms are unclear. Studying mouse models, Deng et al. show that plasma uridine levels are controlled by feeding behavior (see the Perspective by Jastroch and Tschöp). Fasting causes an adipocyte-mediated rise in plasma uridine, which triggers a lowering of body temperature. Feeding causes a bile-mediated drop in plasma uridine, which enhances insulin sensitivity in a leptin-dependent manner. Thus, uridine is part of a complex regulatory loop that affects energy balance and potentially contributes to metabolic disease. Science , this issue p. aaf5375 ; see also p. 1124

Lipin 1 is a coregulator of DNA-bound transcription factors and a phosphatidic acid (PA) phosphatase (PAP) enzyme that catalyzes a critical step in the synthesis of glycerophospholipids. Lipin 1 is highly expressed in adipocytes, and constitutive loss of lipin 1 blocks adipocyte differentiation; however, the effects of Lpin1 deficiency in differentiated adipocytes are unknown. Here we report that adipocyte-specific Lpin1 gene recombination unexpectedly resulted in expression of a truncated lipin 1 protein lacking PAP activity but retaining transcriptional regulatory function. Loss of lipin 1-mediated PAP activity in adipocytes led to reduced glyceride synthesis and increased PA content. Characterization of the deficient mice also revealed that lipin 1 normally modulates cAMP-dependent signaling through protein kinase A to control lipolysis by metabolizing PA, which is an allosteric activator of phosphodiesterase 4 and the molecular target of rapamycin. Consistent with these findings, lipin 1 expression was significantly related to adipose tissue lipolytic rates and protein kinase A signaling in adipose tissue of obese human subjects. Taken together, our findings identify lipin 1 as a reciprocal regulator of triglyceride synthesis and hydrolysis in adipocytes, and suggest that regulation of lipolysis by lipin 1 is mediated by PA-dependent modulation of phosphodiesterase 4.

Randomized controlled trials (RCTs) are considered the gold standard used to assess the efficacy of treatment. While a well implemented RCT can produce an unbiased estimate of the relative difference between treatment groups, the generalizability of these findings may be limited. Specific threats to the external validity include treatment preference. The purposes of this study were to: (i) assess whether receiving one's treatment preference was associated with weight loss and retention and (ii) whether receiving one's treatment preference modified the relationship between the treatments and weight loss. Treatment preference was assessed in 250 subjects prior to but independent of randomization into either low-carbohydrate or low-fat diets. Treatment preference was a predictor of weight loss (P = 0.002) but not retention (P = 0.90). Participants who received their preference lost less weight (–7.7 kg, 95% confidence interval (CI): –9.3 to –6.1) than participants who did not receive their preference (–9.7 kg, 95% CI: –11.4 to –8.1) and participants who did not report a strong preference at baseline (–11.2 kg, 95% CI: –12.6 to –9.7) (P = 0.04 and P = 0.0004, respectively). Treatment preference did not modify the effect of the treatment on weight loss. Contrary to conceptual predictions, this study failed to identify an interaction between treatment preference and weight loss in the setting of a randomized trial. Until treatment preference effects are definitively ruled out in this domain, future studies might consider stratifying their randomization procedure by treatment preference rather than excluding participants with strong treatment preferences.

OBJECTIVE To provide a comprehensive assessment of multiorgan insulin sensitivity in lean and obese subjects with normal glucose tolerance. RESEARCH DESIGN AND METHODS The hyperinsulinemic-euglycemic clamp procedure with stable isotopically labeled tracer infusions was performed in 40 obese (BMI 36.2 ± 0.6 kg/m2, mean ± SEM) and 26 lean (22.5 ± 0.3 kg/m2) subjects with normal glucose tolerance. Insulin was infused at different rates to achieve low, medium, and high physiological plasma concentrations. RESULTS In obese subjects, palmitate and glucose Ra in plasma decreased with increasing plasma insulin concentrations. The decrease in endogenous glucose Ra was greater during low-, medium-, and high-dose insulin infusions (69 ± 2, 74 ± 2, and 90 ± 2%) than the suppression of palmitate Ra (52 ± 4, 68 ± 1, and 79 ± 1%). Insulin-mediated increase in glucose disposal ranged from 24 ± 5% at low to 253 ± 19% at high physiological insulin concentrations. The suppression of palmitate Ra and glucose Ra were greater in lean than obese subjects during low-dose insulin infusion but were the same in both groups during high-dose insulin infusion, whereas stimulation of glucose Rd was greater in lean than obese subjects across the entire physiological range of plasma insulin. CONCLUSIONS Endogenous glucose production and adipose tissue lipolytic rate are both very sensitive to small increases in circulating insulin, whereas stimulation of muscle glucose uptake is minimal until high physiological plasma insulin concentrations are reached. Hyperinsulinemia within the normal physiological range can compensate for both liver and adipose tissue insulin resistance, but not skeletal muscle insulin resistance, in obese people who have normal glucose tolerance.

Intrahepatic lipid accumulation is extremely common in obese subjects and is associated with the development of insulin resistance and diabetes. Hepatic diacylglycerol and triacylglycerol synthesis predominantly occurs through acylation of glycerol-3-phosphate. However, an alternative pathway for synthesizing diacylglycerol from monoacylglycerol acyltransferases (MGAT) could also contribute to hepatic glyceride pools. MGAT activity and the expression of the three genes encoding MGAT enzymes (MOGAT1, MOGAT2, and MOGAT3) were determined in liver biopsies from obese human subjects before and after gastric bypass surgery. MOGAT expression was also assessed in liver of subjects with nonalcoholic fatty liver disease (NAFLD) or control livers. All MOGAT genes were expressed in liver, and hepatic MGAT activity was readily detectable in liver lysates. The hepatic expression of MOGAT3 was highly correlated with MGAT activity, whereas MOGAT1 and MOGAT2 expression was not, and knockdown of MOGAT3 expression attenuated MGAT activity in a liver-derived cell line. Marked weight loss following gastric bypass surgery was associated with a significant reduction in MOGAT2 and MOGAT3 expression, which were also overexpressed in NAFLD subjects. These data suggest that the MGAT pathway is active and dynamically regulated in human liver and could be an important target for pharmacologic intervention for the treatment of obesity-related insulin resistance and NAFLD.

Nonalcoholic fatty liver disease (NAFLD) is a common complication of obesity, and is associated with abnormalities in hepatic very-low-density lipoprotein (VLDL) metabolism and increased serum triglyceride (TG) concentration (1, 2). Lifestyle modification involving diet-induced weight loss and regular physical activity reduces intrahepatic triglyceride (IHTG) content and improves the metabolic derangements associated with NAFLD (3-17). Very small amounts of weight loss can cause marked decreases (20%-60%) in IHTG content (18-20). In fact, we have found that even 48 h of calorie restriction caused a 20% decrease in IHTG content in obese subjects (21). However, few studies have evaluated the effect of regular physical activity, independent of weight loss, on NAFLD. Current guidelines from the Department of Health and Human Services, the American College of Sports Medicine, and the American Heart Association, recommend that adults perform at least 150 min, but preferably 300 min of moderate-intensity physical activity per week; or at least 75 minutes, but preferably 150 minutes, of vigorous physical activity per week to achieve health benefits (22, 23). Data from two studies have recently shown that 4-12 weeks of vigorous intensity exercise training caused a small decrease in IHTG content (24, 25). However, obese people are more likely to adhere to a moderate intensity than a vigorous intensity exercise program (26), in part, because obese persons have lower levels of pleasure after high intensity exercise (27), and exercise intensity is perceived to be higher in obese than lean subjects (28). The potential benefits of regular moderate intensity exercise on IHTG content and hepatic metabolic function in obese people with NAFLD has not been carefully studied. The purpose of this study was to investigate the effect of the recommended exercise guidelines for moderate intensity endurance exercise training (150-300 min per week) on IHTG content and VLDL kinetics in obese subjects with NAFLD. We hypothesized that exercise training would result in decreased IHTG content and hepatic VLDL-TG and VLDL-apolipoprotein B-100 (apoB-100) secretion rates. Magnetic resonance spectroscopy (MRS) was used to assess IHTG content and stable isotopically labeled tracer techniques were used to assess VLDL-TG and VLDL-apoB-100 kinetics in our study subjects before and after 16 weeks of supervised exercise training.

The prevalence of obesity and type 2 diabetes is increasing worldwide and threatens to shorten lifespan. Impaired insulin action in peripheral tissues is a major pathogenic factor. Insulin stimulates glucose uptake in adipose tissue through the GLUT4 (also known as SLC2A4) glucose transporter, and alterations in adipose tissue GLUT4 expression or function regulate systemic insulin sensitivity. Downregulation of human and mouse adipose tissue GLUT4 occurs early in diabetes development. Here we report that adipose tissue GLUT4 regulates the expression of carbohydrate-responsive-element-binding protein (ChREBP; also known as MLXIPL), a transcriptional regulator of lipogenic and glycolytic genes. Furthermore, adipose ChREBP is a major determinant of adipose tissue fatty acid synthesis and systemic insulin sensitivity. We find a new mechanism for glucose regulation of ChREBP: glucose-mediated activation of the canonical ChREBP isoform (ChREBP-α) induces expression of a novel, potent isoform (ChREBP-β) that is transcribed from an alternative promoter. ChREBP-β expression in human adipose tissue predicts insulin sensitivity, indicating that it may be an effective target for treating diabetes.

Insulin resistance in adipose tissue increases the release of free fatty acids into the circulation, which likely contributes to impaired insulin action in liver and skeletal muscle associated with obesity. However, reliable assessment of adipose tissue insulin resistance requires performing a hyperinsulinemic-euglycemic clamp procedure in conjunction with a fatty acid tracer infusion to determine insulin-mediated suppression of lipolytic rate. We developed a simpler method for evaluating adipose tissue insulin resistance in vivo, determined as the product of palmitate rate of appearance into the bloodstream and plasma insulin concentration during basal conditions. We validated our Adipose Tissue Insulin Resistance Index (ATIRI) by comparison with an assessment of adipose tissue insulin resistance determined by using the hyperinsulinemic-euglycemic clamp procedure in conjunction with a palmitate tracer infusion in 47 obese nondiabetic subjects (body mass index: 40.1 ± 9.3 kg/m(2)). We found the ATIRI correlated closely with adipose tissue insulin resistance assessed during the clamp procedure (r =-0.854, P < 0.001). These results demonstrate that the ATIRI provides a reliable index of adipose tissue insulin resistance in obese subjects.

Background: Hypertriglyceridemia is a common metabolic complication of chronic kidney disease (CKD) and an important risk factor for coronary heart disease in this patient population. The mechanisms responsible for the development of hypertriglyceridemia in subjects with CKD are not clear. Methods: We studied very low density lipoprotein triglyceride (VLDL-TG) and VLDL-apolipoprotein B-100 (VLDL-apoB-100) kinetics in vivo in 6 subjects with non-dialysis-dependent CKD (CKD-ND), 6 subjects with CKD treated with peritoneal dialysis (CKD-PD) and 24 sex-, age- and body mass index-matched control subjects with normal renal function (12 control subjects each matched with the CKD-ND and CKD-PD group, respectively). Results: The secretion rates of VLDL-TG and VLDL-apoB-100 into plasma were not different between CKD-ND or CKD-PD and their respective control groups. The mean residence times of VLDL-TG and VLDL-apoB-100 in plasma, which represents the time VLDL-TG and VLDL-apoB-100 spend in the circulation after secretion by the liver, tended to be greater in subjects with CKD-ND than in control subjects (222 ± 38 vs. 143 ± 21 min, p = 0.07, and 352 ± 102 vs. 200 ± 20 min, p = 0.06, respectively) and were about two-fold greater in subjects with CKD-PD compared with their control group (248 ± 51 vs. 143 ± 21 min and 526 ± 116 vs. 182 ± 16 min, respectively; both p ≤ 0.01). Conclusion: Impaired plasma clearance of VLDL-TG and VLDL-apoB-100 is the major abnormality associated with hypertriglyceridemia in patients with either CKD-ND or CKD-PD.

Obesity is associated with unfavorable alterations in plasma lipid concentrations. Data obtained from studies in cultured cells and rodent models show that Protein Convertase Subtilisn/Kexin 9 (PCSK9), a secreted protein that leads to degradation of LDL receptors in the liver, is an important regulator of plasma LDL cholesterol concentrations. Recent evidence suggests that PCSK9 may also regulate the very low density lipoprotein (VLDL) receptor expression and VLDL-triglyceride (TG) metabolism. The purpose of this study was to determine whether circulating PCSK9 concentrations are correlated with VLDL-triglyceride kinetics in obese people. Plasma PCSK9 concentration and VLDL-TG kinetics were evaluated in 39 nondiabetic, obese subjects (body mass index 36.9 ± 4.3 kg/m 2 ). Body composition was assessed by using dual-energy x-ray absorptiometry, and VLDL-TG kinetics were assessed by using stable isotopically labeled tracer infusion. We found that plasma PCSK9 concentrations correlated significantly with percent body fat ( r = 0.322, P = 0.046) and serum LDL-cholesterol concentrations ( r = 0.333, P = 0.036), but not with VLDL-TG secretion rate ( r = 0.083, P = 0.614) or clearance rate ( r = 0.032, P = 0.845). These data suggest that PCSK9 is likely involved in LDL-cholesterol metabolism, but it is not a clinically important regulator of VLDL kinetics in obese individuals.

Obesity adversely affects myocardial metabolism, efficiency, and diastolic function. Our objective was to determine whether weight loss can ameliorate obesity-related myocardial metabolism and efficiency derangements and that these improvements directly relate to improved diastolic function in humans. We studied 30 obese (BMI30 kg/m2) subjects with positron emission tomography (PET) (myocardial metabolism, blood flow) and echocardiography (structure, function) before and after marked weight loss from gastric bypass surgery (N = 10) or moderate weight loss from diet (N = 20). Baseline BMI, insulin resistance, hemodynamics, left ventricular (LV) mass, systolic function, myocardial oxygen consumption (MVO2), and fatty acid (FA) metabolism were similar between the groups. MVO2/g decreased after diet-induced weight loss (P = 0.009). Total MVO2 decreased after dietary (P = 0.02) and surgical weight loss (P = 0.0006) and was related to decreased BMI (P = 0.006). Total myocardial FA utilization decreased (P = 0.03), and FA oxidation trended lower (P = 0.06) only after surgery. FA esterification and LV efficiency were unchanged. After surgical weight loss, LV mass decreased by 23% (Doppler-derived) E/E' by 33%, and relaxation increased (improved) by 28%. Improved LV relaxation related significantly to decreased BMI, insulin resistance, total MVO2, and LV mass but not FA utilization. Decreased total MVO(2) predicted LV relaxation improvement independent of BMI change (P = 0.02). Weight loss can ameliorate the obesity-related derangements in myocardial metabolism and LV structure and diastolic function. Decreased total MVO2 independently predicted improved LV relaxation, suggesting that myocardial oxygen metabolism may be mechanistically important in determining cardiac relaxation.

OBJECTIVE Leptin therapy improves insulin sensitivity in people with leptin deficiency, but it is not known whether it improves insulin action in people who are not leptin deficient. The purpose of the current study was to determine whether leptin treatment has weight loss–independent effects on insulin action in obese subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS We conducted a randomized, placebo-controlled trial in obese subjects (BMI: 35.4 ± 0.6 kg/m2; mean ± SE) with newly diagnosed type 2 diabetes. Subjects were randomized to treatment with placebo (saline), low-dose (30 mg/day), or high-dose (80 mg/day) recombinant methionyl human (r-Met hu) leptin for 14 days. Multiorgan insulin sensitivity before and after treatment was evaluated by using the hyperinsulinemic-euglycemic clamp procedure in conjunction with stable isotopically labeled tracer infusions to measure glucose, glycerol, and fatty acid kinetics. RESULTS Low-dose and high-dose leptin treatment resulted in a threefold (P < 0.01) and 150-fold (P < 0.001) increase in basal plasma leptin concentrations, respectively. However, neither low-dose nor high-dose therapy had an effect on insulin-mediated suppression of glucose, glycerol, or palmitate rates of appearance into plasma compared with placebo. In addition, leptin treatment did not increase insulin-mediated stimulation of glucose disposal compared with placebo (14.3 ± 3.1, 18.4 ± 3.6, 16.7 ± 2.4 vs. 17.5 ± 2.5, 20.7 ± 3.0, 19.1 ± 3.3 μmol/kg body wt/min before vs. after treatment in the placebo, low-dose, and high-dose leptin groups, respectively). CONCLUSIONS r-Met hu leptin does not have weight loss–independent, clinically important effects on insulin sensitivity in obese people with type 2 diabetes.

OBJECTIVE Ginseng and its active component, ginsenoside Re, are popular herbal products that are advocated for treatment of diabetes. The purpose of this study was to determine whether ginseng or ginsenoside Re improves β-cell function and insulin sensitivity (IS) in insulin-resistant subjects. RESEARCH DESIGN AND METHODS Overweight or obese subjects (BMI = 34 ± 1 kg/m2) with impaired glucose tolerance or newly diagnosed type 2 diabetes were randomized to 30 days of treatment with ginseng root extract (8 g/day), ginsenoside Re (250–500 mg/day), or placebo. β-Cell function was assessed as the disposition index (DI) and measured by a frequently sampled oral glucose tolerance test, and IS was assessed as the relative increase in glucose disposal during a hyperinsulinemic-euglycemic clamp procedure plus stable isotope tracer infusion. RESULTS Values for DI and IS after therapy (Post) were not different from values before therapy (Pre) in the placebo (DI: Pre, 5.8 ± 0.9 × 10−3 and Post, 5.8 ± 0.8 × 10−3, P = 0.99; IS: Pre,165 ± 29% and Post, 185 ± 24%, P = 0.34), ginseng (DI: Pre, 7.7 ± 2.0 × 10−3 and Post, 6.0 ± 0.8 × 10−3, P = 0.29; IS: Pre, 171 ± 72% and Post,137 ± 59%, P = 0.88), and ginsenoside Re (DI: Pre, 7.4 ± 3.0 × 10−3 and Post, 5.9 ± 1.1 × 10−3, P = 0.50; IS: Pre, 117 ± 31% and Post, 134 ± 34%, P = 0.44) groups. Ginsenosides Re, Rb1, and Rb2 were not detectable in plasma after treatment with ginseng root extract or ginsenoside Re. CONCLUSIONS Oral ginseng or ginsenoside Re therapy does not improve β-cell function or IS in overweight/obese subjects with impaired glucose tolerance or newly diagnosed diabetes. Poor systemic bioavailability might be responsible for the absence of a therapeutic effect.

We evaluated whether insulin resistance in obese people is associated with decreased plasma palmitoleate availability. Palmitoleate content (percentage and absolute concentrations) in FFA and VLDL was measured in obese subjects who were either insulin resistant (IR) or insulin sensitive (IS), based on assessment of multiorgan (skeletal muscle, liver, and adipose tissue) insulin sensitivity by using the hyperinsulinemic-euglycemic clamp procedure in conjunction with infusion of stable isotopically labeled tracers. Plasma palmitoleate concentration and the relative contribution of palmitoleate to total plasma FFA concentration in the IS group (0.018 ± 0.002 mmol/l and 4.4% ± 0.2%, respectively) were not significantly different than values in the IR group (0.023 ± 0.003 mmol/l and 4.4% ± 0.4%, respectively). Plasma VLDL-triglyceride palmitoleate concentration and the proportion of VLDL fatty acids as palmitoleate in the IS group (0.09 ± 0.02 mmol/l and 5.7 ± 0.3%, respectively) were also not significantly different than those in the IR group (0.16 ± 0.04 mmol/l and 5.0% ± 0.4%, respectively). These data demonstrate that decreased palmitoleate in plasma and in VLDL is not associated with insulin resistance in skeletal muscle, liver, or adipose tissue in obese people.

The medical costs for a type 2 diabetes patient are two to four times greater than the costs for a patient without diabetes. Bariatric surgery is the most effective weight-loss therapy and has marked therapeutic effects on diabetes. We estimate the economic effect of the clinical benefits of bariatric surgery for diabetes patients with BMI ≥ 35 kg/m². Using an administrative claims database of privately insured patients covering 8.5 million lives 1999-2007, we identify obese patients with diabetes, aged 18-65 years, who were treated with bariatric surgery identified using Healthcare Common Procedure Coding System codes. These patients were matched with nonsurgery control patients on demographic factors, comorbidities, and health-care costs. The overall return on investment (RoI) associated with bariatric surgery was calculated using multivariate analysis. Surgery and control patients were compared postindex with respect to diagnostic claims for diabetes, diabetes medication claims, and adjusted diabetes medication and supply costs. Surgery costs were fully recovered after 26 months for laparoscopic surgery. At month 6, 28% of surgery patients had a diabetes diagnosis, compared to 74% of control patients (P < 0.001). Among preindex insulin users, insulin use dropped to 43% by month 3 for surgery patients, vs. 84% for controls (P < 0.001). By month 1, medication and supply costs were significantly lower for surgery patients (P < 0.001). The therapeutic benefits of bariatric surgery on diabetes translate into considerable economic benefits. These data suggest that surgical therapy is clinically more effective and ultimately less expensive than standard therapy for diabetes patients with BMI ≥ 35 kg/m².

This 56-week, randomized, placebo-controlled trial examined the efficacy and safety of naltrexone plus bupropion as an adjunct to intensive behavior modification (BMOD). A total of 793 participants (BMI = 36.5 ± 4.2 kg/m2) was randomly assigned in a 1:3 ratio to: (i) placebo + BMOD (N = 202); or (ii) naltrexone sustained-release (SR, 32 mg/day), combined with bupropion SR (360 mg/day) plus BMOD (i.e., NB32 + BMOD; N = 591). Both groups were prescribed an energy-reduced diet and 28 group BMOD sessions. Co-primary end points were percentage change in weight and the proportion of participants who lost ≥5% weight at week 56. Efficacy analyses were performed on a modified intent-to-treat population (ITT; i.e., participants with ≥1 postbaseline weight while taking study drug (placebo + BMOD, N = 193; NB32 + BMOD, N = 482)). Missing data were replaced with the last observation obtained on study drug. At week 56, weight loss was 5.1 ± 0.6% with placebo + BMOD vs. 9.3 ± 0.4% with NB32 + BMOD (P < 0.001). A completers analysis revealed weight losses of 7.3 ± 0.9% (N = 106) vs. 11.5 ± 0.6% (N = 301), respectively (P < 0.001). A third analysis, which included all randomized participants, yielded losses of 4.9 ± 0.6 vs. 7.8 ± 0.4%, respectively (P < 0.001). Significantly more NB32 + BMOD- vs. placebo + BMOD-treated participants lost ≥5 and ≥10% of initial weight, and the former had significantly greater improvements in markers of cardiometabolic disease risk. NB32 + BMOD was generally well tolerated, although associated with more reports of nausea than placebo + BMOD. The present findings support the efficacy of combined naltrexone/bupropion therapy as an adjunct to intensive BMOD for obesity.

Aim of this study was to determine whether an increase in adiposity, without a concomitant increase in intrahepatic triglyceride (IHTG) content, is associated with a deterioration in metabolic function. To this end, multiorgan insulin sensitivity, assessed by using a two-stage hyperinsulinemic-euglycemic clamp procedure in conjunction with stable isotopically labeled tracer infusion, and very low-density lipoprotein (VLDL) kinetics, assessed by using stable isotopically labeled tracer infusion and mathematical modeling, were determined in 10 subjects with class I obesity (BMI: 31.6 +/- 0.3 kg/m(2); 37 +/- 2% body fat; visceral adipose tissue (VAT): 1,225 +/- 144 cm(3)) and 10 subjects with class III obesity (BMI: 41.5 +/- 0.5 kg/m(2); 43 +/- 2% body fat; VAT: 2,121 +/- 378 cm(3)), matched on age, sex, and IHTG content (14 +/- 4 and 14 +/- 3%, respectively). No differences between class I and class III obese groups were detected in insulin-mediated suppression of palmitate (67 +/- 3 and 65 +/- 3%, respectively; P = 0.635) and glucose (67 +/- 3 and 73 +/- 5%, respectively; P = 0.348) rates of appearance in plasma, and the insulin-mediated increase in glucose disposal (218 +/- 18 and 193 +/- 30%, respectively; P = 0.489). In addition, no differences between class I and class III obese groups were detected in secretion rates of VLDL-triglyceride (6.5 +/- 1.0 and 6.0 +/- 1.4 micromol/l x min, respectively; P = 0.787) and VLDL-apolipoprotein B-100 (0.40 +/- 0.05 and 0.41 +/- 0.04 nmol/l x min, respectively; P = 0.866), and plasma clearance rates of VLDL-triglyceride (31 (16-59) and 29 (18-46) ml/min, respectively; P = 0.888) and VLDL-apolipoprotein B-100 (15 (11-19) and 17 (11-25) ml/min, respectively; P = 0.608). We conclude that increased adiposity without a concomitant increase in IHTG content does not cause additional abnormalities in adipose tissue, skeletal muscle, and hepatic insulin sensitivity, or VLDL metabolism.

OBJECTIVE Insulin resistance is commonly associated with obesity. Studies conducted in obese mouse models found that endoplasmic reticulum (ER) stress contributes to insulin resistance, and treatment with tauroursodeoxycholic acid (TUDCA), a bile acid derivative that acts as a chemical chaperone to enhance protein folding and ameliorate ER stress, increases insulin sensitivity. The purpose of this study was to determine the effect of TUDCA therapy on multiorgan insulin action and metabolic factors associated with insulin resistance in obese men and women. RESEARCH DESIGN AND METHODS Twenty obese subjects ([means ± SD] aged 48 ± 11 years, BMI 37 ± 4 kg/m2) were randomized to 4 weeks of treatment with TUDCA (1,750 mg/day) or placebo. A two-stage hyperinsulinemic-euglycemic clamp procedure in conjunction with stable isotopically labeled tracer infusions and muscle and adipose tissue biopsies were used to evaluate in vivo insulin sensitivity, cellular factors involved in insulin signaling, and cellular markers of ER stress. RESULTS Hepatic and muscle insulin sensitivity increased by ∼30% (P < 0.05) after treatment with TUDCA but did not change after placebo therapy. In addition, therapy with TUDCA, but not placebo, increased muscle insulin signaling (phosphorylated insulin receptor substrateTyr and AktSer473 levels) (P < 0.05). Markers of ER stress in muscle or adipose tissue did not change after treatment with either TUDCA or placebo. CONCLUSIONS These data demonstrate that TUDCA might be an effective pharmacological approach for treating insulin resistance. Additional studies are needed to evaluate the target cells and mechanisms responsible for this effect.

Background & Aims Visceral adipose tissue (VAT) is an important risk factor for the metabolic complications associated with obesity. Therefore, a reduction in VAT is considered an important target of obesity therapy. We evaluated whether reducing VAT mass by surgical removal of the omentum improves insulin sensitivity and metabolic function in obese patients. Methods We conducted a 12-month randomized controlled trial to determine whether reducing VAT by omentectomy in 22 obese subjects increased their improvement following Roux-en-Y gastric bypass (RYGB) surgery in hepatic and skeletal muscle sensitivity to insulin study 1. Improvement was assessed by using the hyperinsulinemic-euglycemic clamp technique. We also performed a 3-month, longitudinal, single-arm study to determine whether laparoscopic omentectomy alone, in 7 obese subjects with type 2 diabetes mellitus (T2DM), improved insulin sensitivity study 2. Improvement was assessed by using the Frequently Sampled Intravenous Glucose Tolerance Test. Results The greater omentum, which weighed 0.82 kg (95% confidence interval: 0.67–0.97), was removed from subjects who had omentectomy in both studies. In study 1, there was an approximate 2-fold increase in muscle insulin sensitivity (relative increase in glucose disposal during insulin infusion) and a 4-fold increase in hepatic insulin sensitivity 12 months after RYGB alone and RYGB plus omentectomy, compared with baseline values ( P P > .87) or group × time interactions ( P > .36). In study 2, surgery had no effect on insulin sensitivity ( P = .844) or use of diabetes medications. Conclusions These results demonstrate that decreasing VAT through omentectomy, alone or in combination with RYGB surgery, does not improve metabolic function in obese patients.

Hepatic steatosis is associated with insulin resistance, but it is not clear whether increased intrahepatic triglyceride (IHTG) content causes the resistance or is a marker. Subjects with familial hypobetalipoproteinemia (FHBL) have high levels of IHTG because of a genetic defect in hepatic export of triglycerides, and provide a unique cohort to study the relationship between steatosis and insulin sensitivity.One group of lean subjects with normal IHTG content (2.2% +/- 0.6% of liver volume) (n = 6), and 3 groups of overweight and obese subjects matched for body mass index, were studied: (1) normal IHTG content (3.3% +/- 0.5%; n = 6), (2) high IHTG content (21.4% +/- 2.6%) due to nonalcoholic fatty liver disease (NAFLD; n = 6), and (3) high IHTG content (18.1% +/- 2.2%) due to FHBL (n = 3). A hyperinsulinemic-euglycemic clamp procedure, in conjunction with glucose tracer infusion, was used to determine multiorgan insulin sensitivity.Hepatic insulin sensitivity (reciprocal of glucose rate of appearance [micromol x kg fat-free mass(-1) x min(-1)] x insulin [mU/L]) was greatest in the Lean group (2.0 +/- 0.4); it was the same among subjects with FHBL (0.8 +/- 0.1) and the group with normal IHTG content, matched for body mass index (0.7 +/- 0.1), but greater than the NAFLD group (0.3 +/- 0.1) (P

UCP2 -866GA (rs659366) has been implicated in cardiometabolic disease and represents a novel candidate gene for beta-blocker response, particularly among patients with diabetes. We assessed the function of -866GA and its role as a modifier of beta-blocker treatment outcomes by diabetes status in an acute coronary syndrome (ACS) cohort.ACS patients with genetic samples and 12 months of follow-up for cardiac rehospitalizations or death (n=468) were assessed. The influence of -866GA on beta-blocker treatment outcomes was evaluated in those with diabetes and without. To assess functional correlates of -866GA, we compared uncoupling protein 2 (UCP2) expression in the skeletal muscle of obese participants by genotype and compared the activity of UCP2 luciferase promoters with -866G and -866A alleles.An interaction between -866GA and beta-blocker treatment was found in individuals with diabetes (P=0.002) but not those without (P=0.79). Among G/G individuals with diabetes, discharge beta-blocker use was associated with an 80% reduction in cardiac rehospitalization (adjusted hazard ratio: 0.20; 95% confidence interval: 0.04-1.02). In contrast, among A-carrier patients with diabetes, there was an 11-fold increase in cardiac rehospitalizations with discharge beta-blocker therapy (adjusted hazard ratio: 11.75; 95% confidence interval: 1.28-108.2). Promoter activity assays showed that -866G had greater cyclic AMP response element binding protein-responsiveness compared with -866A, and compared with -866A carriers G/G individuals exhibited increased UCP2 expression in the skeletal muscle.We identified a significant interaction between -866GA and beta-blocker response among ACS patients with diabetes. Furthermore, -866G conferred greater gene transcriptional activity than -866A in cell lines and in obese patients. These findings may help us gain insight into the mechanisms underlying the beneficial and detrimental effects of beta-blockers in those with diabetes.

Aim: Although weight loss usually decreases very-low-density lipoprotein–triglyceride (VLDL-TG) secretion rate, the change in VLDL-TG kinetics is not directly related to the change in body weight. Circulating leptin also declines with weight loss and can affect hepatic lipid metabolism. The aim of this study was to determine whether circulating leptin is associated with weight loss-induced changes in VLDL-TG secretion. Methods: Ten extremely obese subjects were studied. VLDL-TG secretion rate and the contribution of systemic (derived from lipolysis of subcutaneous adipose tissue TG) and non-systemic fatty acids (derived primarily from lipolysis of intrahepatic and intraperitoneal TG, and de novo lipogenesis) to VLDL-TG production were determined by using stable isotopically labelled tracer methods before and 1 year after gastric bypass surgery. Results: Subjects lost 33 ± 12% of body weight, and VLDL-TG secretion rate decreased by 46 ± 23% (p = 0.001), primarily because of a decrease in the secretion of VLDL-TG from non-systemic fatty acids (p = 0.002). Changes in VLDL-TG secretion rates were not significantly related to reductions in body weight, body mass index, plasma palmitate flux, free fatty acid or insulin concentrations. The change in VLDL-TG secretion was inversely correlated with the change in plasma leptin concentration (r = −0.72, p = 0.013), because of a negative association between changes in leptin and VLDL-TG secretion from non-systemic fatty acids (r = −0.95, p < 0.001). Conclusions: Weight loss-induced changes in plasma leptin concentration are inversely associated with changes in VLDL-TG secretion rate. Additional studies are needed to determine whether the correlation between circulating leptin and VLDL-TG secretion represents a cause-and-effect relationship.

ObjectivesThe objective of this prospective, single-site, 2-year dietary intervention study was to evaluate the effects of moderate weight reduction and subsequent partial weight regain on cardiovascular structure and function.BackgroundObesity is associated with adverse cardiac and vascular structural and functional alterations.MethodsSixty obese subjects (age 46 ± 10 years, body mass index 37 ± 3 kg/m2) were evaluated during their participation in a weight loss study. Cardiac and vascular ultrasound studies were performed at baseline and at 3, 6, 12, and 24 months after start of intervention.ResultsForty-seven subjects (78%) completed the entire 2-year follow-up. Average weight loss was 7.3 ± 4.0%, 9.2 ± 5.6%, 7.8 ± 6.6%, and 3.8 ± 7.9% at 3, 6, 12, and 24 months, respectively. Age- and sex-adjusted mixed linear models revealed that the follow-up time was significantly associated with decreases in weight (p < 0.0001), left ventricular (LV) mass (p = 0.001), and carotid intima-media thickness (p < 0.0001); there was also significant improvement in LV diastolic (p ≤ 0.0001) and systolic (p = 0.001) function. Partial weight regain diminished the maximal observed beneficial effects of weight loss, however cardiovascular parameters measured at 2 years still showed a net benefit compared with baseline.ConclusionsDiet-induced moderate weight loss in obese subjects is associated with beneficial changes in cardiovascular structure and function. Subsequent weight regain is associated with partial loss of these beneficial effects. (The Safety and Effectiveness of Low and High Carbohydrate Diets; NCT00079547)

The cardiometabolic syndrome represents a cluster of metabolic abnormalities that are risk factors for cardiovascular disease. The mechanism(s) responsible for developing the cardiometabolic syndrome is not known, but it is likely that multi-organ insulin resistance, which is a common feature of the cardiometabolic syndrome, is involved. Insulin resistance is an important risk factor for type 2 diabetes and can cause vasoconstriction and renal sodium reabsorption leading to increased blood pressure. Alterations in adipose tissue fatty acid and adipokine metabolism are involved in the pathogenesis of insulin resistance. Excessive rates of fatty acid release into the bloodstream can impair the ability of insulin to stimulate muscle glucose uptake and suppress hepatic glucose production. Non-infectious systemic inflammation, associated with adipocyte and adipose tissue macrophage cytokine production, can also cause insulin resistance. In addition, increased free fatty acid delivery to the liver can stimulate hepatic very-low-density lipoprotein triglyceride production leading to dyslipidemia.

Obesity in adolescents is associated with metabolic risk factors for type 2 diabetes, particularly insulin resistance and excessive accumulation of intrahepatic triglyceride (IHTG). The purpose of this study was to evaluate the effect of moderate weight loss on IHTG content and insulin sensitivity in obese adolescents who had normal oral glucose tolerance. Insulin sensitivity, assessed by using the hyperinsulinemic-euglycemic clamp technique in conjunction with stable isotopically labeled tracer infusion, and IHTG content, assessed by using magnetic resonance spectroscopy, were evaluated in eight obese adolescents (BMI >or=95th percentile for age and sex; age 15.3 +/- 0.6 years) before and after moderate diet-induced weight loss (8.2 +/- 2.0% of initial body weight). Weight loss caused a 61.6 +/- 8.5% decrease in IHTG content (P = 0.01), and improved both hepatic (56 +/- 18% increase in hepatic insulin sensitivity index, P = 0.01) and skeletal muscle (97 +/- 45% increase in insulin-mediated glucose disposal, P = 0.01) insulin sensitivity. Moderate diet-induced weight loss decreases IHTG content and improves insulin sensitivity in the liver and skeletal muscle in obese adolescents who have normal glucose tolerance. These results support the benefits of weight loss therapy in obese adolescents who do not have evidence of obesity-related metabolic complications during a standard medical evaluation.

OBJECTIVE—Obesity is associated with insulin resistance and type 2 diabetes, although the mechanisms linking these pathologies remain undetermined. Recent studies in rodent models revealed endoplasmic reticulum (ER) stress in adipose and liver tissues and demonstrated that ER stress could cause insulin resistance. Therefore, we tested whether these stress pathways were also present in obese human subjects and/or regulated by weight loss. RESEARCH DESIGN AND METHODS—Eleven obese men and women (BMI 51.3 ± 3.0 kg/m2) were studied before and 1 year after gastric bypass (GBP) surgery. We examined systemic insulin sensitivity using hyperinsulinemic-euglycemic clamp studies before and after surgery and collected subcutaneous adipose and liver tissues to examine ER stress markers. RESULTS—Subjects lost 39 ± 9% body wt at 1 year after GBP surgery (P < 0.001), which was associated with a marked improvement in hepatic, skeletal muscle, and adipose tissue insulin sensitivity. Markers of ER stress in adipose tissue significantly decreased with weight loss. Specifically, glucose-regulated protein 78 (Grp78) and spliced X-box binding protein-1 (sXBP-1) mRNA levels were reduced, as were phosphorylated elongation initiation factor 2α (eIF2α) and stress kinase c-Jun NH2-terminal kinase 1 (JNK1) (all P values CONCLUSIONS—This study presents important evidence that ER stress pathways are present in selected tissues of obese humans and that these signals are regulated by marked weight loss and metabolic improvement. Hence, this suggests the possibility of a relationship between obesity-related ER stress and metabolic dysfunction in obese humans.

Abdominal obesity is associated with metabolic risk factors for coronary heart disease (CHD). Although we previously found that using liposuction surgery to remove abdominal subcutaneous adipose tissue (SAT) did not result in metabolic benefits, it is possible that postoperative inflammation masked the beneficial effects. Therefore, this study provides a long-term evaluation of a cohort of subjects from our original study. Body composition and metabolic risk factors for CHD, including oral glucose tolerance, insulin resistance, plasma lipid profile, and blood pressure were evaluated in seven obese (39 +/- 2 kg/m(2)) women before and at 10, 27, and 84-208 weeks after large-volume liposuction. Liposuction surgery removed 9.4 +/- 1.8 kg of body fat (16 +/- 2% of total fat mass; 6.1 +/- 1.4 kg decrease in body weight), primarily from abdominal SAT; body composition and weight remained the same from 10 through 84-208 weeks. Metabolic endpoints (oral glucose tolerance, homeostasis model assessment of insulin resistance, blood pressure and plasma triglyceride (TG), high-density lipoprotein (HDL)-cholesterol, and low-density lipoprotein (LDL)-cholesterol concentrations) obtained at 10 through 208 weeks were not different from baseline and did not change over time. These data demonstrate that removal of a large amount of abdominal SAT by using liposuction does not improve CHD metabolic risk factors associated with abdominal obesity, despite a long-term reduction in body fat.

Nonalcoholic fatty liver disease (NAFLD) and insulin resistance are common in overweight adolescents.The purpose of this study was to determine the relation between NAFLD and insulin sensitivity in liver and skeletal muscle by studying overweight adolescents with a normal or high intrahepatic triglyceride (IHTG) content, who were matched for age, sex, body mass index (BMI; in kg/m(2)), and Tanner stage.Stable-isotope-labeled tracer infusion and the hyperinsulinemic-euglycemic clamp procedure were used to assess skeletal muscle and hepatic insulin sensitivity, and magnetic resonance spectroscopy was used to assess the IHTG content in 10 overweight (BMI = 35.9 +/- 1.3) adolescents with NAFLD (IHTG = 28.4 +/- 3.4%) and 10 overweight (BMI = 36.6 +/- 1.5) adolescents with a normal IHTG content (3.3 +/- 0.5%).The baseline plasma glucose concentration and the rate of appearance of glucose in plasma were the same in subjects with a normal (87.1 +/- 1.2 mg/dL, 16.2 +/- 1.1 micromol . kg fat-free mass(-1) . min(-1)) or high (89.2 +/- 2.5 mg/dL, 16.3 +/- 1.2 micromol . kg fat-free mass(-1) . min(-1)) IHTG content. However, compared with subjects who had a normal IHTG content, subjects with NAFLD had a lower hepatic insulin sensitivity index, based on baseline glucose kinetics and insulin concentrations (4.0 +/- 0.5 compared with 2.4 +/- 0.4; P0.05) and an impaired increase in glucose uptake during insulin infusion (169 +/- 28.1% compared with 67 +/- 9.6% above baseline; P0.01). In addition, the plasma triglyceride concentration was greater and the plasma HDL-cholesterol concentration was lower in subjects with NAFLD than in those with a normal IHTG content.An elevated IHTG content in overweight adolescents is associated with dyslipidemia and with insulin-resistant glucose metabolism in both liver and skeletal muscle.

Background: Although weight loss and exercise ameliorates frailty and improves cardiac risk factors in obese older adults, the long-term effect of lifestyle intervention on bone metabolism and mass is unknown. Objective: The objective was to evaluate the effects of diet-induced weight loss in conjunction with exercise on bone metabolism and mass in obese older adults. Design and Setting: We conducted a one-year randomized, controlled clinical trial in a university-based research center. Participants: Twenty-seven frail, obese (body mass index = 39 ± 5 kg/m2), older (age 70 ± 5 yr) adults participated in the study. Intervention: Participants were randomly assigned to diet and exercise (treatment group; n = 17) or no therapy (control group; n = 10). Outcome Measures: Body weight decreased in the treatment group but not in the control group (−10 ± 2 vs. +1 ± 1%, P < 0.001). Compared with the control group, the treatment group had greater changes in bone mass, bone markers, and hormones, including 1) bone mineral density (BMD) in total hip (0.1 ± 2.1 vs. −2.4 ± 2.5%), trochanter (0.2 ± 3.3 vs. −3.3 ± 3.1%), and intertrochanter (0.3 ± 2.7 vs. −2.7 ± .3.0%); 2) C-terminal telopeptide (12 ± 35 vs. 101 ± 79%) and osteocalcin (−5 ± 15 vs. 66 ± 61%); and 3) leptin (2 ± 12 vs. −30 ± 25%) and estradiol (0.1 ± 14% vs. −14 ± 21%) (all P < 0.05). Changes in weight (r = 0.55), bone markers (r = −0.54), and leptin (r = 0.61) correlated with changes in hip BMD (all P < 0.05). Conclusion: Weight loss, even when combined with exercise, decreases hip BMD in obese older adults. It is not known whether the beneficial effects of weight loss and exercise on physical function lower the overall risk of falls and fractures, despite the decline in hip BMD.

Obesity and aging increase the risk of type 2 diabetes (T2D). We evaluated whether weight loss therapy improves pancreatic endocrine function and insulin sensitivity in obese older adults.Twenty-four obese (BMI: 38 +/- 2 kg/m(2)) older (age: 70 +/- 2 years) adults completed a 6-month randomized, controlled trial. Participants were randomized to diet and exercise (treatment group) or no therapy (control group). beta-Cell function (assessed using the C-peptide minimal model), alpha-cell function (assessed by the glucagon response to an oral glucose load), insulin sensitivity (assessed using the glucose minimal model), and insulin clearance rate were evaluated using a 5-h modified oral glucose tolerance test.Body weight decreased in the treatment group, but did not change in the control group (-9 +/- 1% vs. 0 +/- 1%; P0.001). Insulin sensitivity doubled in the treatment group and did not change in the control group (116 +/- 49% vs. -11 +/- 13%; P0.05). Even though indices of beta-cell responsivity to glucose did not change (P0.05), the disposition index (DI), which adjusts beta-cell insulin response to changes in insulin sensitivity, improved in the treatment group compared with the control group (100 +/- 47% vs. -22 +/- 9%; P0.05). The glucagon response decreased in the treatment but not in the control group (-5 +/- 2% vs. 4 +/- 4%; P0.05). Insulin secretion rate did not change (P0.05), but insulin clearance rate increased (51 +/- 25%; P0.05), resulting in lower plasma insulin concentrations.Weight loss therapy concomitantly improves beta-cell function, lowers plasma glucagon concentrations, and improves insulin action in obese older adults. These metabolic effects are likely to reduce the risk of developing T2D in this population.

OBJECTIVE— Lipin 1 plays critical roles in controlling energy metabolism. We sought to determine the expression of lipin 1 isoforms (lipin 1α and -β) in liver and adipose tissue of obese subjects and to evaluate cellular mechanisms involved in the regulation of lipin 1 expression by physiologic stimuli. RESEARCH DESIGN AND METHODS— The expression of lipin 1α and -β was quantified in liver and adipose tissue of extremely obese (average BMI 60.8 kg/m2) human subjects undergoing gastric bypass surgery (GBS). Second, the expression of lipin 1 was evaluated in HepG2 cells in response to overexpression of peroxisome proliferator–activated receptor-γ coactivator (PGC)-1α under normal or hyperinsulinemic conditions. RESULTS— The expression of lipin 1β in liver and adipose tissue was inversely related to BMI, fasting plasma insulin concentration, and the homeostasis model assessment of insulin resistance but was significantly increased by marked weight loss and insulin sensitization following GBS. Hepatic lipin 1β mRNA levels were strongly correlated with the expression of PGC-1α, and overexpression of PGC-1α in HepG2 cells increased lipin 1 expression. Conversely, hyperinsulinemic culture conditions downregulated the expression of lipin 1β, PGC-1α, and their known target genes involved in mitochondrial metabolism in HepG2 cells. Finally, overexpression of lipin 1β or PGC-1α reversed the effect of hyperinsulinemia on the expression of their target genes. CONCLUSIONS— These studies suggest that hepatic lipin 1β and PGC-1α expression are downregulated by obesity and obesity-related metabolic perturbations in human subjects, likely due to alterations in insulin concentration or sensitivity.

Malnutrition is associated with an increased incidence of perioperative morbidity and mortality. To evaluate the effect of malnutrition on the metabolic and inflammatory response to surgery in patients with oesophageal cancer, we studied the effects of oesophagectomy in six patients with major (13·9 (se 1·3) %) weight loss and five patients with minor (0·7 (se 0·6) %) weight loss in the 6 months before to surgery. Rates of appearance (Ra) of glucose, glycerol, leucine and urea were determined by stable isotopically labelled tracer infusion before and after surgery. C-reactive protein was measured as an inflammation marker. BMI was lower in the patients with major weight loss than those with minor weight loss (20·3 (se 0·7) and 24·9 (se 1·5) kg/m2, P = 0·02). With the exception of greater glucose Ra in the major weight loss than minor weight loss subjects (11·1 (se 0·3) v. 9·5 (se 0·3) μmol/kg per min, P = 0·01), there were no differences in substrate kinetics before surgery between groups. Surgery increased glucose Ra, leucine Ra and urea Ra by 41, 24 and 58 %, respectively, in the total group. Changes in substrate kinetics in response to surgery were not different between patients with major and minor weight loss. Surgery increased C-reactive protein concentrations to a comparable extent in both groups. In conclusion, major upper gastrointestinal tract surgery in patients with oesophageal cancer elicits a catabolic response, characterized by increased inflammation, glucose production and protein breakdown. However, this catabolic response does not seem to be influenced by pre-operative nutritional status.

Obesity is an important risk factor for cardiometabolic diseases, including diabetes, hypertension, dyslipidemia, and coronary heart disease (CHD). Several leading national and international institutions, including the World Health Organization (WHO) and the National Institutes of Health, have provided guidelines for classifying weight status based on BMI (1,2). Data from epidemiological studies demonstrate a direct correlation between BMI and the risk of medical complications and mortality rate (e.g., 3,4). Men and women who have a BMI ≥30 kg/m2 are considered obese and are generally at higher risk for adverse health events than are those who are considered overweight (BMI between 25.0 and 29.9 kg/m2) or lean (BMI between 18.5 and 24.9 kg/m2). Therefore, BMI has become the “gold standard” for identifying patients at increased risk for adiposity-related adverse health outcomes. Body fat distribution is also an important risk factor for obesity-related diseases. Excess abdominal fat (also known as central or upper-body fat) is associated with an increased risk of cardiometabolic disease. However, precise measurement of abdominal fat content requires the use of expensive radiological imaging techniques. Therefore, waist circumference (WC) is often used as a surrogate marker of abdominal fat mass, because WC correlates with abdominal fat mass (subcutaneous and intra-abdominal) (5) and is associated with cardiometabolic disease risk (6). Men and women who have waist circumferences greater than 40 inches (102 cm) and 35 inches (88 cm), respectively, are considered to be at increased risk for cardiometabolic disease (7). These cut points were derived from a regression curve that identified the waist circumference values associated with a BMI ≥30 kg/m2 in primarily Caucasian men and women living in north Glasgow (8). An expert panel, organized by the National Heart, Lung and Blood Institute, has recommended that WC be measured as part …

Obesity is an important risk factor for cardiometabolic diseases, including diabetes, hypertension, dyslipidemia, and coronary heart disease (CHD). Several leading national and international institutions, including the World Health Organization and the National Institutes of Health, have provided guidelines for classifying weight status based on body mass index (BMI; in kg/m) (1, 2). Data from epidemiologic studies demonstrate a direct correlation between BMI and the risk of medical complications and mortality rate (eg, 3, 4). Men and women who have a BMI 30 are considered obese and are generally at higher risk for adverse health events than are those who are considered overweight (BMI between 25.0 and 29.9) or lean (BMI between 18.5 and 24.9). Therefore, BMI has become the gold standard for identifying patients at increased risk of adiposity-related adverse health outcomes. Body fat distribution is also an important risk factor for obesity-related diseases. Excess abdominal fat (also known as central or upper-body fat) is associated with an increased risk of cardiometabolic disease. However, precise measurement of abdominal fat content requires the use of expensive radiological imaging techniques. Therefore, waist circumference (WC) is often used as a surrogate marker of abdominal fat mass, because WC correlates with abdominal fat mass (subcutaneous and intraabdominal) (5) and is associated with cardiometabolic disease risk (6). Men and women who have WCs 40 in (102 cm) and 35 in (88 cm), respectively, are considered to be at increased risk for cardiometabolic disease (7). These cutpoints were derived from a regression curve that identified the WC values associated with a BMI 30 in primarily Caucasian men and women living in north Glasgow, Scotland (8). An expert panel, organized by the National Heart, Lung, and Blood Institute (NHLBI), has recommended that WC be measured as part of the initial assessment and be used to monitor the efficacy of weight-loss therapy in overweight and obese patients who have a BMI 35 (7). However, measurement of WC has not been widely adopted in clinical practice, and the anatomical, metabolic, and clinical implications of WC data can be confusing. Therefore, Shaping America’s Health: Association for Weight Management and Obesity Prevention; NAASO, The Obesity Society; and the American Diabetes Association convened a panel, composed of members with expertise in obesity management, obesity-related epidemiology, adipose tissue metabolic pathophysiology, statistics, and nutrition science, to review the published scientific literature and hear presentations from other experts in these fields. The Consensus Panel met

Obesity is associated with an increased prevalence and severity of infections. The mechanism(s) responsible for the increased risk of infections is unclear. We evaluated the effects of excessive adiposity and weight loss on peripheral blood mononuclear cell (PBMC) chemokine (macrophage chemoattractant protein-1 [MCP-1) and cytokine (interferon-gamma [IFNgamma]) production, which is an important component of the immune response to infectious pathogens.Lipopolysaccharide (LPS)and phorbol 12-myristate 13-acetate plus ionomycin (PMA + I)-stimulated PBMC MCP-1 and IFNgamma production were determined in six extremely obese subjects (body mass index [BMI] = 62.4 +/- 8.6 kg/m(2)) before and 1 year after gastric bypass surgery and in six age-matched lean subjects (BMI = 22.7 +/- 1.4 kg/m(2)).At baseline, LPS-stimulated MCP-1 production and PMAI-stimulated IFNgamma production by PBMCs were 93.6% +/- 4.9% and 88.8% +/- 9.6% lower, respectively, in obese than in lean subjects (p0.03). Obese subjects lost 30.3% +/- 10.6% of their body weight at 1 year after gastric bypass surgery (p0.001). Weight loss completely restored LPS-stimulated MCP-1 production and PMA+I-stimulated IFNgamma production in obese subjects to normal.Agonist-stimulated production of IFNgamma and MCP-1 are markedly suppressed in subjects with extreme obesity. Weight loss completely normalizes the ability of stimulated PBMCs to produce MCP-1 and IFNgamma. These findings could have important implications in understanding the increased risk of infections associated with obesity, and demonstrate a unique beneficial effect of weight loss on immune function.

The protease inhibitor (PI) ritonavir (RTV) has been associated with elevated resting lipolytic rate, hyperlipidemia, and insulin resistance/glucose intolerance. The purpose of this study was to examine relationships between lipolysis and fatty acid (FA) oxidation during rest, moderate exercise and recovery, and measures of insulin sensitivity/glucose tolerance and fat redistribution in HIV-positive subjects taking RTV ( n = 12), HAART but no PI ( n = 10), and HIV-seronegative controls ( n = 10). Stable isotope tracers [1-13C]palmitate and [1,1,2,3,3-2H5]glycerol were continuously infused with blood and breath collection during 1-h rest, 70-min submaximal exercise (50% V̇o2 peak), and 1-h recovery. Body composition was evaluated using DEXA, MRI, and MRS, and 2-h oral glucose tolerance tests with insulin monitoring were used to evaluate glucose tolerance and insulin resistance. Lipolytic and FA oxidation rates were similar during rest and recovery in all groups; however, they were lower during moderate exercise in both HIV-infected groups [glycerol Ra: HIV + RTV 5.1 ± 1.2 vs. HIV + no PI 5.9 ± 2.8 vs. Control 7.4 ± 2.2 μmol·kg fat-free mass (FFM)−1·min−1; palmitate oxidation: HIV + RTV 1.6 ± 0.8 vs. HIV + no PI 1.6 ± 0.8 vs. Control 2.5 ± 1.7 μmol·kg FFM·min, P < 0.01]. Fasting and orally-challenged glucose and insulin values were similar among groups. Lipolytic and FA oxidation rates were blunted during moderate exercise in HIV-positive subjects taking HAART. Lower FA oxidation during exercise was primarily due to impaired plasma FA oxidation, with a minor contribution from lower nonplasma FA oxidation. Regional differences in adipose tissue lipolysis during rest and moderate exercise may be important in HIV and warrant further study.

PET studies have provided mixed evidence regarding central D2/D3 dopamine receptor binding and its relationship with obesity as measured by body mass index (BMI). Other aspects of obesity may be more tightly coupled to the dopaminergic system. We characterized obesity-associated behaviors and determined if these related to central D2 receptor (D2R) specific binding independent of BMI. Twenty-two obese and 17 normal-weight participants completed eating- and reward-related questionnaires and underwent PET scans using the D2R-selective and nondisplaceable radioligand (N-[11C]methyl)benperidol. Questionnaires were grouped by domain (eating related to emotion, eating related to reward, non-eating behavior motivated by reward or sensitivity to punishment). Normalized, summed scores for each domain were compared between obese and normal-weight groups and correlated with striatal and midbrain D2R binding. Compared to normal-weight individuals, the obese group self-reported higher rates of eating related to both emotion and reward (p p = 0.06) and lower non-food reward behavior (p p p

The workshop entitled 'Interventions to Slow Aging in Humans: Are We Ready?' was held in Erice, Italy, on October 8-13, 2013, to bring together leading experts in the biology and genetics of aging and obtain a consensus related to the discovery and development of safe interventions to slow aging and increase healthy lifespan in humans. There was consensus that there is sufficient evidence that aging interventions will delay and prevent disease onset for many chronic conditions of adult and old age. Essential pathways have been identified, and behavioral, dietary, and pharmacologic approaches have emerged. Although many gene targets and drugs were discussed and there was not complete consensus about all interventions, the participants selected a subset of the most promising strategies that could be tested in humans for their effects on healthspan. These were: (i) dietary interventions mimicking chronic dietary restriction (periodic fasting mimicking diets, protein restriction, etc.); (ii) drugs that inhibit the growth hormone/IGF-I axis; (iii) drugs that inhibit the mTOR-S6K pathway; or (iv) drugs that activate AMPK or specific sirtuins. These choices were based in part on consistent evidence for the pro-longevity effects and ability of these interventions to prevent or delay multiple age-related diseases and improve healthspan in simple model organisms and rodents and their potential to be safe and effective in extending human healthspan. The authors of this manuscript were speakers and discussants invited to the workshop. The following summary highlights the major points addressed and the conclusions of the meeting.

The majority of the patients with type 2 diabetes (T2DM) show remission after Roux-en-Y gastric bypass (RYGB). This is the result of increased postoperative insulin sensitivity and β-cell secretion. The aim of the present study was to elucidate the importance of the preoperative β-cell function in T2DM for the chance of remission after RYGB. Fifteen patients with and 18 without T2DM had 25 g oral (OGTT) and intravenous (IVGTT) glucose tolerance tests performed at inclusion, after a diet-induced weight loss, and 4 and 18 months after RYGB. Postoperative first phase insulin secretion rate (ISR) during the IVGTT and β-cell glucose sensitivity during the OGTT increased in T2DM. Postoperative insulin sensitivity and the disposition index (DI) markedly increased in both groups. By stratifying the T2DM into two groups according to highest (T2DMhigh) and lowest (T2DMlow) baseline DI, a restoration of first phase ISR and β-cell glucose sensitivity were seen only in T2DMhigh. Remission of type 2 diabetes was 71 and 38% in T2DMhigh and T2DMlow, respectively. Postoperative postprandial GLP-1 concentrations increased markedly, but did not differ between the groups. Our findings emphasize the importance of the preoperative of β-cell function for remission of diabetes after RYGB.