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Smith S.R.,Translational Research Institute for Metabolism and Diabetes | Smith S.R.,Pennington Biomedical Research Center | Fujioka K.,Scripps Research Institute | Gupta A.K.,Louisiana State University | And 5 more authors.
Diabetes, Obesity and Metabolism | Year: 2013

The effects of combination naltrexone/bupropion therapy on body composition and visceral adipose tissue (VAT) mass were examined in a subset (n=107) of obese subjects from a Phase 2 trial that compared the efficacy and safety of placebo, naltrexone monotherapy, bupropion monotherapy or one of three naltrexone/bupropion dose combinations for 24weeks. Body composition data were obtained using dual-energy X-ray absorptiometry and computed tomography. Eighty subjects completed the substudy. Naltrexone/bupropion resulted in weight loss and a greater reduction in body fat (-14.0±1.3%) than placebo (-4.0±2.0%), naltrexone monotherapy (-3.2±2.5%) and bupropion monotherapy (-4.1±2.9%; all p<0.01). Reduction in VAT mass was also greater with naltrexone/bupropion (-15.0±1.8%) than placebo (-4.6±2.7%), naltrexone monotherapy (-0.1±3.5%) and bupropion monotherapy (-2.3±4.2%; all p<0.01). Reductions in body fat and VAT mass with naltrexone/bupropion were proportional with weight loss. Weight loss with naltrexone/bupropion was not associated with a greater relative reduction in lean mass than placebo or the monotherapies. © 2013 Blackwell Publishing Ltd. Source

Vijgen G.H.E.J.,Maastricht University | Sparks L.M.,Maastricht University | Sparks L.M.,Translational Research Institute for Metabolism and Diabetes | Bouvy N.D.,Maastricht University | And 4 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2013

Context: Since the discovery of functional brown adipose tissue (BAT) in adult humans, there has been a renewed interest in the physiology of human BAT. Imaging studies from our laboratory and others have shown increased glucose uptake in adipose tissue regions assumed to be BAT in humans. We have also shown that human BAT from the supraclavicular (SCV) region is positive for uncoupling protein-1. To date, however, the oxidative capacity of this adipose tissue (AT) depot has not been characterized in humans. Objective: We hypothesize that oxidative capacity is increased in the AT of the SCV region known to contain human BAT. Design: This was an observational prospective cohort study. Setting: The study was conducted at a referral center. Patients: Participants were 13 patients for whom thyroid gland surgery was indicated. Main Outcome Measure: Basal cellular oxygen consumption in human AT biopsy samples from the SCV region, known to be [18F]fluorodeoxyglucose positron emission tomography-computed tomography-positive, was compared with the cellular oxygen consumption in subcutaneous white adipose tissue (WAT) from the same region of the same subject. Results: We show for the first time that AT from the human BAT region displays increased oxygen consumption (P < .05), on average 300% higher, than subcutaneous WAT of the same individual. The contribution of the proton leak to maximal respiration increased with age in the WAT but not in the AT from the BAT region. Conclusions: These results suggest that human adipose tissue from the BAT region can be distinguished from subcutaneous WAT by a higher basal oxidative capacity. Additional studies are warranted to further elucidate the metabolic and bioenergetic characteristics of this AT depot in humans. Copyright © 2013 by The Endocrine Society. Source

Cheng S.-L.,Sanford Burnham Institute for Medical Research | Behrmann A.,Sanford Burnham Institute for Medical Research | Shao J.-S.,University of Texas M. D. Anderson Cancer Center | Ramachandran B.,Sanford Burnham Institute for Medical Research | And 7 more authors.
Diabetes | Year: 2014

When fed high-fat diets, male LDLR-/- mice develop obesity, hyperlipidemia, hyperglycemia, and arteriosclerotic calcification. An osteogenic Msx-Wnt regulatory program is concomitantly upregulated in the vasculature. To better understand the mechanisms of diabetic arteriosclerosis, we generated SM22-Cre;Msx1( fl/fl);Msx2(fl/fl);LDLR-/- mice, assessing the impact of Msx1+Msx2 gene deletion in vascular myofibroblast and smooth muscle cells. Aortic Msx2 and Msx1 were decreased by 95% and 34% in SM22-Cre;Msx1(fl/fl);Msx2(fl/fl);LDLR-/- animals versus Msx1(fl/fl);Msx2(fl/fl);LDLR-/- controls, respectively. Aortic calcium was reduced by 31%, and pulse wave velocity, an index of stiffness, was decreased in SM22-Cre;Msx1(fl/fl);Msx2(fl/fl);LDLR-/- mice vs. controls. Fasting blood glucose and lipids did not differ, yet SM22-Cre;Msx1(fl/fl);Msx2(fl/fl);LDLR-/- siblings became more obese. Aortic adventitial myofibroblasts from SM22-Cre;Msx1(fl/fl);Msx2(fl/fl);LDLR-/- mice exhibited reduced osteogenic gene expression and mineralizing potential with concomitant reduction in multiple Wnt genes. Sonic hedgehog (Shh) and Sca1, markers of aortic osteogenic progenitors, were also reduced, paralleling a 78% reduction in alkaline phosphatase (TNAP)- positive adventitial myofibroblasts. RNA interference revealed that although Msx1+Msx2 supports TNAP and Wnt7b expression, Msx1 selectively maintains Shh and Msx2 sustains Wnt2, Wnt5a, and Sca1 expression in aortic adventitial myofibroblast cultures. Thus, Msx1 and Msx2 support vascular mineralization by directing the osteogenic programming of aortic progenitors in diabetic arteriosclerosis. © 2014 by the American Diabetes Association. Source

Qi Q.,Harvard University | Bray G.A.,Harvard University | Bray G.A.,Louisiana State University | Smith S.R.,Translational Research Institute for Metabolism and Diabetes | And 3 more authors.
Circulation | Year: 2011

Background Common genetic variants in the insulin receptor substrate 1 (IRS1) gene have been recently associated with insulin resistance and hyperinsulinemia. We examined whether the best-associated variant modifies the long-term changes in insulin resistance and body weight in response to weight-loss diets in Preventing Overweight Using Novel Dietary Strategies (POUNDS LOST) trial. Methods and Results-We genotyped IRS1 rs2943641 in 738 overweight adults (61% were women) who were randomly assigned to 1 of 4 diets varying in macronutrient contents for 2 years. We assessed the progress in fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR) and weight loss by genotypes. At 6 months, participants with the risk-conferring CC genotype had greater decreases in insulin (P=0.009), HOMA-IR (P=0.015), and weight loss (P=0.018) than those without this genotype in the highest-carbohydrate diet group whereas an opposite genotype effect on changes in insulin and HOMA-IR (P≤ 0.05) was observed in participants assigned to the lowest-carbohydrate diet group. No significant differences were observed across genotypes in the other 2 diet groups. The tests for genotype by intervention interactions were all significant (P&l; 0.05). At 2 years, the genotype effect on changes in insulin and HOMA-IR remained significant in the highest-carbohydrate diet group (P< 0.05). The highest carbohydrate diet led to a greater improvement of insulin and HOMA-IR (P for genotype-time interaction ≤ 0.009) in participants with the CC genotype than those without this genotype across 2-year intervention. Conclusions-Individuals with the IRS1 rs2943641 CC genotype might obtain more benefits in weight loss and improvement of insulin resistance than those without this genotype by choosing a high-carbohydrate and low-fat diet. © 2011 American Heart Association, Inc. Source

Pratley R.E.,Florida Hospital Diabetes Institute | Pratley R.E.,Translational Research Institute for Metabolism and Diabetes | Pratley R.E.,Sanford Burnham Institute for Medical Research
Clinical Interventions in Aging | Year: 2014

Older people have the highest prevalence of type 2 diabetes mellitus (T2DM) of any age group and are thus frequent users of glucose-lowering agents. Because individuals 65 years or older are underrepresented in clinical studies, there is a lack of information regarding the efficacy and safety of available treatments in this population. Additionally, a high prevalence of comorbidities, polypharmacy, and frailty can make treatment of T2DM in this population challenging. Safety is an important consideration when choosing a treatment for older individuals. Renal impairment is quite common in older patients with T2DM and can contribute to hypoglycemia. Hypoglycemia can lead to serious consequences, such as falls and fractures, and cognitive changes. As such, hemoglobin A1c treatment targets, typically <7% in the general population, are less stringent in older people, with the goal being an individualized target that balances efficacy and safety. Many glucose-lowering agents can cause adverse events detrimental to older individuals, such as hypoglycemia (insulin, sulfonylureas), weight gain (sulfonylureas, thiazolidinediones), gastrointestinal events (metformin), and fractures (thiazolidinediones), and are contraindicated or require dose adjustments in those with renal impairment (most oral/injectable agents). Orally administered dipeptidyl peptidase (DPP)-4 inhibitors have a low risk of hypoglycemia and are generally well tolerated. Linagliptin is the only DPP-4 inhibitor excreted through nonrenal pathways and therefore does not require any dose adjustment in older patients with kidney disease. This paper reviews the findings of a recent study by Barnett et al assessing the efficacy and safety of the DPP-4 inhibitor linagliptin in patients with T2DM aged 70 years or older, which concluded that linagliptin may be a useful glucose-lowering option for older patients with T2DM. © 2014 Pratley. Source

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