Weight Gain In Subjects Research Articles

1522. Predictors of Weight Gain in People Living with HIV

Abstract Background Highly effective antiretroviral therapy (ART) and longer life expectancy in people living with HIV (PLWH) has led to increased incidence of lifestyle associated risk factors including overweight and obesity. ART is considered to play an important role in this tendency. Excess weight gain has been reported in PLWH treated with and integrase strand transfer inhibitors (INSTI). For nucleoside/nucleotid reverse transcriptase inhibitor (NRTI) backbone components tenofoviralafenamid (TAF) is associated with higher weight gain compared to tenofovir disoproxil (TDF) and abacavir (ABC). This study aims to investigate ART as predictors of weight gain in a prospective cohort using a target trial emulation. Methods The protocol for the target trial was established to evaluate the impact of baseline backbone treatment and various third components on weight gain over a 2-year follow-up period using the Copenhagen Co-Morbidity in HIV Infection Study (COCOMO) cohort. Data was collected from March 2015 to December 2016 in the Capital Region of Denmark. Adult PLWH were included. Subjects were divided into four different treatment groups according to their backbone components: Lamivudine/emtricitabin (XTC)/TDF, XTC/ABC, XTC/TAF or “other”. Regression standardization was applied to the linear regression outcome adjusted for relevant confounders. Results In total 704 subject were included in the analysis. Overall median weight gain in the 2-years follow up period was 0.7 IQR[-22.4, 26.0] with the largest weight gain in subjects with XTC/TDF at baseline (median 1.0 IQR[-12.6, 26.0]). Regression standardization of the adjusted linear regression model showed no significant difference in weight gain between backbone groups. In the third-component analysis including subjects with XTC/TDF or XTC/ABC backbone, subjects receiving an integrase inhibitor based regimen at baseline tended to have a 0.75 kg higher weight gain compared to NNRTI- and PI-based regimens, but this was not significant S.E. 0.474, (0.17;1.67 95%CI). Conclusion The results suggest that while antiretroviral therapy may contribute to weight gain, the choice of backbone components may not be a significant predictor. Further studies are needed to confirm these findings. Disclosures All Authors: No reported disclosures

Multidisciplinary Approach for Hypothalamic Obesity in Children and Adolescents: A Preliminary Study

Hypothalamic obesity (HO) is delineated by an inexorable weight gain in subjects with hypothalamic disorder (congenital or acquired). The aim of the present study was to evaluate the effect of a multidisciplinary approach on weight trend and metabolic outcome in children and adolescents with hypothalamic disease who were overweight or obese. Thirteen patients (aged 8.1–16.1 years) received a personalized diet, accelerometer-based activity monitoring, and psychological assessment. Height, weight, body mass index (BMI), and serum metabolic parameters were assessed at baseline (T0) and after six months (T1). Metformin was introduced at T1 in four subjects who were then re-evaluated after six months (T2). At T1, weight gain was significantly reduced compared with T0 (0.29 ± 0.79 kg/month vs. 0.84 ± 0.55 kg/month, p = 0.03), and weight standard deviation score (SDS) and BMI SDS did not change significantly, as serum metabolic parameters. The four subjects treated with metformin showed a reduction of weight SDS and BMI SDS at T2. In conclusion, patients treated with our multidisciplinary approach showed, after 6 months, favorable results characterized by decreased weight gain and stabilization of weight SDS and BMI SDS in a condition usually characterized by inexorable weight gain. However, further analysis, larger cohorts, and longer follow-up are needed to confirm these preliminary data.

Factors Related to Weight Gain in Subjects with Sleeve Gastrectomy During Lockdown by the COVID-19 Pandemic.

PurposeThe COVID-19 pandemic could exacerbate the risk factors for weight gain in patients with previous bariatric surgery. The aim of this study was to evaluate factors related to weight gain during lockdown in patients with a sleeve gastrectomy.Materials and MethodsA group of 48 obese subjects with previous bariatric surgery was enrolled. After a 7-week confinement, a telephone interview was conducted. In this phone call, self-reported body weight gain and different factors were recorded. In order to obtain the basal and pre-surgical data, biochemical and anthropometric parameters were recorded from electronic medical record.ResultsThe mean age was 45.3±8.0 years (range: 23–61) and the mean body mass index (BMI) was 32.5±7.5 kg/m2 (range: 28.6–34.2). Gender distribution was 38 females (79.2%) and 10 males (20.8%). The increase in self-reported body weight was 3.8±2.1 kg during the 7 weeks of confinement. And the self-reported body weight gain was lower in subjects with regular exercise (4.6±0.9 vs 1.1±0.3 kg; p=0.02). The number of face-to-face visits to the nutrition office that did not attend was 0.61±0.81 (range: 0–4) per patient. In the multiple regression analysis with self-reported body weight gain as a dependent variable, the physical activity (minutes/week) remained as a protective factor with a beta coefficient of −0.09 (95% CI: −0.001 to 0.016; p=0.03) and number of face-to-face appointments in the nutrition consultation missed as a risk factor with a beta coefficient of 9.65 (95% CI: 1.17–18.12; p=0.03).ConclusionsThe increase in self-reported body weight is associated with a decrease in physical activity and the loss of face-to-face visits to the Nutrition Unit.

Subthalamic Nucleus Deep Brain Stimulation in Early Stage Parkinson's Disease Is Not Associated with Increased Body Mass Index.

Previous studies suggest that deep brain stimulation of the subthalamic nucleus (STN-DBS) for Parkinson's disease (PD) leads to weight gain. This study analyzes changes in body mass index (BMI) in 29 subjects from a prospective, single-blind trial of DBS in early stage PD (age 50–75, Hoehn & Yahr stage II off medication, treated with antiparkinsonian medications for ≥6 months but <4 years, and without a history of motor fluctuations, dyskinesias, or dementia). Subjects were randomized to DBS plus optimal drug therapy (DBS+ODT; n = 15) or ODT (n = 14) and followed for 24 months. Weight and height were recorded at baseline and each follow-up visit and used to calculate BMI. BMIs were compared within and between groups using nonparametric t-tests. Mean BMI at baseline was 29.7 in the ODT group and 32.3 in the DBS+ODT group (p > 0.05). BMI change over two years was not different between the groups (p = 0.62, ODT = −0.89; DBS+ODT = −0.17). This study suggests that STN-DBS is not associated with weight gain in subjects with early stage PD. This finding will be tested in an upcoming FDA-approved phase III multicenter, randomized, double-blind, placebo-controlled, pivotal clinical trial evaluating DBS in early stage PD (ClinicalTrials.gov identifier NCT00282152).

The pharmacology of oral antidiabetic agents

The therapy of type 2 diabetes mellitus is symptomatic—the immediate treatment goal remains the day-to-day management of hyperglycaemia and the restoration of glycaemic control. This is preferably achieved with minimal risk of hypoglycaemia and without further weight gain in subjects who are often obese. Principal treatment goals for successful long-term glucose management include reduced comorbidities and mortality (particularly through reduced mirco-, and, to some extent, macrovascular risk) along with an alleviation of any presenting diabetic symptomology, including susceptibility to infection, fatigue, thirst and polyuria. To this end, a chemically diverse range of oral antidiabetic agents can be used, singly or in combination, against a range of molecular targets in an attempt to: limit or delay glucose absorption from the gut (with alpha-glucosidase inhibitors, anti-absorptive ‘starch blockers’); enhance pancreatic insulin release (using sulphonylurea and glinide class insulin secretagogues, as well as the gliptin class incretin enhancers); depress hepatic glucose production (principally with the biguanide class, but also with the use of glitazones and gliptins); enhance peripheral insulin sensitivity/insulin receptor signalling (with the glitazone and biguanide classes); and most recently, prevent glucose reabsorption from the renal filtrate (with the novel gliflozin class of glucose ‘wasters’).

Insulin requirement profiles in Japanese hospitalized subjects with type 2 diabetes treated with basal-bolus insulin therapy.

To assess the total daily inulin dose (TDD) and contribution of basal insulin to TDD and to identify the predictive factors for insulin requirement profiles in subjects with type 2 diabetes, we retrospectively examined insulin requirement profiles of 275 hospitalized subjects treated with basal-bolus insulin therapy (BBT) (mean age, 60.1 ± 12.9 years; HbA1c, 10.2 ± 4.5%). Target plasma glucose level was set between 80 and 129 mg/dL before breakfast and between 80 and 179 mg/dL at 2-hour after each meal without causing hypoglycemia. We also analyzed the relationship between the insulin requirement profiles (TDD and basal/total daily insulin ratio [B/TD ratio]) and insulin-associated clinical parameters. The mean TDD was 0.463 ± 0.190 unit/kg/day (range, 0.16-1.13 unit/kg/day). The mean B/TD ratio was 0.300 ± 0.099 (range, 0.091-0.667). A positive correlation of TDD with B/TD ratio was revealed by linear regression analysis (r=0.129, p=0.03). Stepwise multiple regression analysis identified post-breakfast glucose levels before titrating insulin as an independent determinant of the insulin requirement profile [Std β (standard regression coefficient) = 0.228, p<0.01 for TDD, Std β = -0.189, p<0.01 for B/TD ratio]. The TDD was <0.6 unit/kg/day and the B/TD ratio was <0.4 in the majority (70.2%) of subjects in the present study. These findings may have relevance in improving glycemic control and decreasing the risk of hypoglycemia and weight gain in subjects with type 2 diabetes treated with BBT.

Lower “Awake and Fed Thermogenesis” Predicts Future Weight Gain in Subjects With Abdominal Adiposity

Awake and fed thermogenesis (AFT) is the energy expenditure (EE) of the nonactive fed condition above the minimum metabolic requirement during sleep and is composed of the thermic effect of food and the cost of being awake. AFT was estimated from whole-room 24-h EE measures in 509 healthy subjects (368 Native Americans and 141 whites) while subjects consumed a eucaloric diet. Follow-up data were available for 290 Native Americans (median follow-up time: 6.6 years). AFT accounted for ∼10% of 24-h EE and explained a significant portion of deviations from expected energy requirements. Energy intake was the major determinant of AFT. AFT, normalized as a percentage of intake, was inversely related to age and fasting glucose concentration and showed a nonlinear relationship with waist circumference and BMI. Spline analysis demonstrated that AFT becomes inversely related to BMI at an inflection point of 29 kg/m2. The residual variance of AFT, after accounting for covariates, predicted future weight change only in subjects with a BMI >29 kg/m2. AFT may influence daily energy balance, is reduced in obese individuals, and predicts future weight gain in these subjects. Once central adiposity develops, a blunting of AFT may occur that then contributes to further weight gain.

Pharmacogenetic Aspects of Antipsychotic Drug-induced Weight Gain - A Critical Review

Treatment with several antipsychotic drugs can result in weight gain, which may lead to further morbidity such as type 2 diabetes and cardiovascular disease via the development of metabolic syndrome. These important and problematic metabolic consequences of antipsychotic drug treatment probably reflect a pharmacological disruption of the mechanisms involved in control of food intake and body weight. The extent of weight gain following antipsychotic drug treatment shows substantial variability between individuals, due in part to genetic factors. Common functional polymorphisms in many candidate genes implicated in the control of body weight and various aspects of energy and lipid metabolism have been investigated for association with weight gain in subjects receiving antipsychotic drug treatment, and with metabolic pathology in chronic schizophrenia. Perhaps the strongest and most replicated findings are the associations with promoter polymorphisms in the 5-HT2C receptor and leptin genes, although many other possible genetic risk factors, including polymorphisms in the fat mass and obesity associated (FTO) gene and genes for the alpha2A adrenoceptor and melanocortin4 receptor, have been reported. Genome-wide association studies (GWAS) have also addressed antipsychotic-induced weight gain and other indicators of metabolic disturbances. However there is as yet little consistency between these studies or between GWAS and classical candidate gene approaches. Identifying common genetic factors associated with drug-induced weight gain and its metabolic consequences may provide opportunities for personalized medicine in the predictive assessment of metabolic risk as well as indicating underlying physiological mechanisms.

Celiac Disease: The Endocrine Connection

CD is an immune-mediated enteropathy caused by genetically predisposed individuals eating gluten-containing foods (Catassi et al., 2007; Celiac Working Group et al., 2008; Green & Cellier, 2007; Hill et al., 2005). There are several endocrine disorders that are associated with CD. In many of these cases, CD does not present with the typical gastrointestinal symptoms. Nurses working with children who have endocrine conditions need to consider CD as part of the differential and follow-up care plan. This awareness will facilitate more efficient diagnosis and minimize the risk of conditions associated with untreated CD.

S28-01 - Pharmacogenetics of the metabolic consequences of antipsychotic drug treatment

IntroductionSeveral antipsychotic drugs cause profound weight gain which can lead to further morbidity as indicated by the development of metabolic syndrome. These metabolic consequences of antipsychotic drug treatment show substantial variability between individuals, due in part to genetic factors.ObjectivesTo identify genetic polymorphisms contributing to individual variability in the metabolic consequences of antipsychotic drug treatment.MethodsCommon functional polymorphisms in several candidate genes implicated in the control of body weight have been investigated for association with weight gain in subjects initiating antipsychotic drug treatment, and with metabolic pathology in chronic schizophrenia.ResultsIn two studies of initially drug-free patients, we reported a strong association with antipsychotic-induced weight gain of a promoter region polymorphism of the 5-HT2C receptor, which is known to influence gene expression. The gene for leptin, a hormone controlling food intake, also has a functional promoter polymorphism which is associated with antipsychotic-induced weight gain, particularly in the longer term. Both polymorphisms are associated with circulating concentrations of leptin. Findings in chronically-treated patients have revealed association of the leptin gene polymorphism with the incidence of metabolic syndrome, while we find the obesity-related FTO gene is associated with measures of obesity in these subjects, and also interacts with the 5-HT2C gene in influencing weight gain in drug-naive subjects.ConclusionsIdentifying common genetic factors associated drug-induced weight gain and its metabolic consequences may provide clues as to the underlying mechanisms as well as providing opportunities for personalized medicine in the predictive assessment of metabolic risk.

No causal link between obesity and probiotics

1that probiotics increase the risk of obesity. The impact of probiotics in farm animals has been shown to include: an increase in size and weight but not in fat mass 2,3 ; a reduction in fat mass in farm animals that are gaining weight 4,5 ; or no impact on growth 6 . In the livestock industry, probiotics are used to promote growth and lean mass, not adiposity. These observations are consistent with weight gain resulting from improved gut function and resistance to infection rather than from a metabolic imbalance that causes obesity. No human study cited by Raoult showed a statistically significant increase in weight gain for subjects who were given probiot ics compared to those who were given a placebo 7,8 . In spite of the widespread use of probiotics in modern and traditional diets, there is no evidence that the consumption of probiotics leads to weight gain in healthy people. Most probiotics are delivered as dairy products, and in the USA, where levels of obesity are high, consumption of probiotic yogurt (4 kg per person per year) is substantially lower than that in countries such as France, Finland and Japan, where obesity rates are low. The data showing an association between obesity and both a reduction in the levels of Gram-negative bacteria and an increase in the levels of Firmicutes in the gut are mainly based on statistical correlations that cannot distinguish between cause and consequence. Furthemore, these data have been partly con tradicted by numerous other studies, includ ing that of Turnbaugh et al. 9 , which revealed a higher proportion of Actinobacteria and a lower proportion of Bacteroidetes among obese subjects but no significant difference in Firmicute levels. In other studies, comparisons of microbiota using real-time PCR revealed a higher Bacteroidetes/Firmicutes ratio among overweight and obese subjects than among lean ones 10 . At least one study has shown a resultant decrease in body weight and fat mass in obese individuals taking prebiotics 11 . The consumption of probiotics does not lead to any sustained compositional change in the gut microbiota, and there is no suggestion from a multitude of human studies that weight gain is a side effect of probiotic consumption. Probiotic-induced weight gain in ill or undernourished sub jects, which might result from improved gut function, is not an adverse outcome. Unfortunately, Raoult confuses probiotics (live microbes) and prebiotics (selectively fermented substrates for beneficial colonizing microbes) and is inaccurate with regard to the microbio logical identity of different probiotics. Strains of the Bifidobacterium genus, commonly used as probiotics and indicted by Raoult as contributors to increased levels of Firmicutes, are in fact members of the phylum Actinobacteria. Furthermore, there are important strain-to-strain

Association of the α2A Adrenergic Receptor -1291C/G Polymorphism and Antipsychotic-Induced Weight Gain in European–Americans

To investigate the -1291 C/G promoter polymorphism (rs1800544) of the adrenergic alpha-2A receptor (ADRA2A) with clozapine-/olanzapine-induced weight gain in European-Americans and African-Americans. The alpha-adrenergic receptors inhibit lipolysis in the adipose tissue and are involved in weight gain regulation. Moreover, two previous studies indicated an association with antipsychotic-induced weight gain with the same polymorphism in Asian populations. We analyzed a relatively large (n=129) and well-characterized group of patients and monitored them for a period of 6-14 weeks. Our refined sample consisted of 60 European-Americans and 39 African-Americans on clozapine or olanzapine, prospectively. In European-Americans, we observed a significant difference in weight gain across the genotypic categories (p=0.046). The carriers of the C allele gained more weight compared with the subjects homozygous for the GG allele (CC + CG vs GG; 3.73 +/- 4.13 kg vs 0.23 +/- 2.92 kg; p=0.013). We did not find a significant association in African-Americans, although the sample size was probably too small. Our observations suggest a possible role of ADRA2A polymorphisms in clozapine-/olanzpaine-induced weight gain in subjects of European descent.

Insulin-Stimulated Increase in Serum Leptin Levels Precedes and Correlates with Weight Gain during Insulin Therapy in Type 2 Diabetes

Infusion of insulin acutely stimulates leptin production and chronic insulin treatment is associated with elevated serum leptin levels and body weight in subjects with type 2 diabetes. The objective of the study was to investigate the relationship between insulin administration, leptin levels, and weight gain in subjects with type 2 diabetes. This was a post hoc analysis of two randomized, controlled trials. The study was conducted at an outpatient clinic. Subjects included 35 (study 1) and 32 (study 2) poorly controlled oral hypoglycemic agent (OHA)-treated type 2 diabetic subjects. Study 1: subjects were investigated during a hyperinsulinemic, euglycemic glucose clamp and 12 months after being randomly allocated to start insulin or continue on OHAs. Study 2: 1 yr treatment with either OHAs and lifestyle intervention or insulin with or without concomitant lifestyle intervention. Changes in serum leptin levels during clamp and during 1 yr of treatment in relationship to changes in body weight. Study 1: during acute insulin infusion leptin levels increased by 10% (P < 0.001). During 1 yr of insulin therapy, mean body weight increased by 6%, whereas the fasting leptin levels increased by 108% (both P < 0.001). The weight gain observed at 1 yr correlated with the increase in leptin levels observed during the clamp (r = 0.62, P = 0.003). Study 2: mean body weight increased by 4% (P < 0.01), whereas leptin levels increased by 56% (P < 0.001) during 1 yr of insulin treatment and the increase in leptin preceded the increase in body weight. Significant correlations were observed between insulin's effect on serum leptin levels and the increase in weight that accompanied insulin therapy.

Hypercaloric diets differing in fat composition have similar effects on serum leptin and weight gain in female subjects with anorexia nervosa

Weight regain in subjects with anorexia nervosa is associated with an increase in serum leptin concentrations that is hypothesized to impair full weight restoration. As diets rich in n-3 polyunsaturated fatty acids (PUFA) have been described to lower serum leptin concentrations, we tested the hypothesis that consumption of a hypercaloric diet rich in n-3 PUFA is associated with an attenuated increase in serum leptin and a higher efficiency of body weight gain in subjects with anorexia nervosa. Twenty-five female subjects with anorexia nervosa were enrolled into this controlled dietary intervention study. Four subjects discontinued therapy or participation in the study prematurely, and six were excluded. 15 subjects completed the study. Subjects consumed hypercaloric diets rich in either saturated fatty acids (SFA, n = 8) or n-3 PUFA (n = 7) for 5 weeks. Primary endpoints were the change in serum leptin concentrations and body weight gain relative to energy consumed. Serum leptin concentrations increased distinctly throughout the study (P < .001), and to a similar extend in both groups [+2.9 (SD 2.4) vs. +2.8 (SD 3.4) ng/mL in the SFA- and n-3 PUFA group, respectively; P = .487]. The efficiency of body weight gain also did not differ significantly between groups, with a body weight gain of 63.1 (SD 12.4) vs. 79.2 (SD 26.0) g per 4.2 MJ (1000 kcal) consumed in the SFA- and n-3 PUFA group, respectively (P = .132). Hypercaloric diets rich in either SFA or n-3 PUFA do not differ in their effects on serum leptin concentrations and the efficiency of body weight gain in female subjects with anorexia nervosa.

Predictors of recovery of ovarian function after weight gain in subjects with amenorrhea related to restrictive eating disorders

Objective. The aim of the present study was to investigate the anthropometric and endocrine characteristics of subjects with amenorrhea related to eating disorders after weight recovery, in order to identify factors connected with the resumption of menses.Methods. Clinical data, body composition parameters and serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), thyroid-stimulating hormone (TSH), free triiodothyronine, free thyroxine, cortisol, leptin and insulin were assessed in two groups of young women classified according to menstrual status after weight rehabilitation: 43 subjects who displayed persistent amenorrhea and 34 who resumed menses. Univariate and multivariate logistic regression analyses were used to examine the relationships between the different parameters and menstrual recovery.Results. The patients who resumed menses had low initial weight and BMI, and a greater difference between current and initial BMI (ΔBMI), than those with amenorrhea. No differences were observed in lean mass, body fat or bone density between the two groups. Moreover, the reduction in FSH and the increase in LH, insulin and leptin emerged as significant predictors of menstrual recovery. Increased ΔBMI and insulin continued to be positive predictors in the multivariate analysis.Conclusion. Following weight rehabilitation, the individual's metabolic set point before weight loss and the current insulin levels appear significant in predicting the reactivation of reproductive function.

Influence of Topiramate on Olanzapine-Related Weight Gain in Women

In a randomized controlled trial, we compared the efficacy of topiramate versus placebo in women undergoing olanzapine therapy and found that topiramate effectively contributed to weight loss in short-term treatment and had a positive effect on health-related quality of life, the patients' actual state of health, and psychological impairments. The aim of this observational study was to assess whether topiramate has a sustained benefit in long-term treatment of olanzapine-associated weight gain in subjects who had participated in the previous randomized controlled trial comparing topiramate with placebo. The subjects (topiramate group, n = 25; former placebo group, n = 18) were observed in an 18-month open-label study. After unblinding, subjects from the former topiramate group continued treatment with topiramate, whereas subjects from the former placebo group received neither placebo nor topiramate. The subjects were seen every 6 months, weighed, and tested with the SF-36 Health Survey, Scale of Well-Being, and the Adjective Checklist. According to the intent-to-treat principle, the repeated-measures analysis showed a significant interaction for the group-by-time effect for change of weight (P < 0.01) on the Scale of Well-Being (P < 0.01), all scales of the Adjective Checkist (all P < 0.01), and 5 scales (physical functioning, role limitations due to physical health, social functioning, mental health, and vitality) of the SF-36 Health Survey (all P < 0.01). Topiramate was well tolerated and seems to be effective and safe in the long-term treatment of olanzapine-related adiposity in women. Furthermore, positive changes in the patients' state of health, psychological impairments, and health-related quality of life could be also observed.

Association study of olanzapine-induced weight gain and therapeutic response with SERT gene polymorphisms in female schizophrenic patients

We investigated the relationships between L/S promoter (SERTPR) and l/s intron2 (SERTin2) genetic variants of serotonin transporter (SERT) polymorphisms with olanzapine-induced weight gain and treatment response in 94 female schizophrenic patients treated with olanzapine for up to 3 months. Body mass index (BMI) was calculated for each patient prior to olanzapine administration and 3 months afterwards. To assess and evaluate improvement of clinical psychotic symptoms and therapeutic response to the antipsychotic, all patients were rated using the Positive and Negative Syndrome ScaLe (PANSS). Overall, the presence of S SERTPR allelic variant and SS genotype was associated with significantly higher weight gain in subjects who were non-obese at the time of admission. The presence of L SERTPR variant was associated with significantly better treatment response measured with total PANSS and general PANSS subscale, while the presence of l SERTin2 variant determined better treatment response only in several items. No evidence of linkage disequilibrium between the two loci was found in the sample. These findings identify genetic factors associated with oLanzapine-induced weight gain and treatment response in femaLe schizophrenic patients.

Biology of Incretins: GLP-1 and GIP

This review focuses on the mechanisms regulating the synthesis, secretion, biological actions, and therapeutic relevance of the incretin peptides glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The published literature was reviewed, with emphasis on recent advances in our understanding of the biology of GIP and GLP-1. GIP and GLP-1 are both secreted within minutes of nutrient ingestion and facilitate the rapid disposal of ingested nutrients. Both peptides share common actions on islet beta-cells acting through structurally distinct yet related receptors. Incretin-receptor activation leads to glucose-dependent insulin secretion, induction of beta-cell proliferation, and enhanced resistance to apoptosis. GIP also promotes energy storage via direct actions on adipose tissue, and enhances bone formation via stimulation of osteoblast proliferation and inhibition of apoptosis. In contrast, GLP-1 exerts glucoregulatory actions via slowing of gastric emptying and glucose-dependent inhibition of glucagon secretion. GLP-1 also promotes satiety and sustained GLP-1-receptor activation is associated with weight loss in both preclinical and clinical studies. The rapid degradation of both GIP and GLP-1 by the enzyme dipeptidyl peptidase-4 has led to the development of degradation-resistant GLP-1-receptor agonists and dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes. These agents decrease hemoglobin A1c (HbA1c) safely without weight gain in subjects with type 2 diabetes. GLP-1 and GIP integrate nutrient-derived signals to control food intake, energy absorption, and assimilation. Recently approved therapeutic agents based on potentiation of incretin action provide new physiologically based approaches for the treatment of type 2 diabetes.

P1185 EFFICACY OF CYPROHEPTADINE IN PROMOTING WEIGHT GAIN: A META-ANALYSIS

Introduction: Cyproheptadine has been used as an appetite stimulant to promote weight gain in both children and adults, but its efficacy remains controversial. Our goal was to systematically examine the existing evidence of the efficacy of cyproheptadine as a weight promoter. Methods: We conducted a computerized literature search and ascertained additional studies from reference lists and trial authors. Our inclusion criteria were: 1) human subjects; 2) randomized allocation of subjects to study arms; 2) placebo-controlled, parallel group or crossover design; 4) primary or secondary outcome of weight gain. Using a data abstraction form, two independent reviewers extracted the data and determined eligibility for analyses. For each study arm, we calculated the change in mean weight as a percentage of the arm’s mean baseline weight. To permit comparisons of weight gain between trials of varying duration, we defined our summary statistic as net percentage change in weight(treatment minus control) divided by the trial duration in months. Results: 37 studies of cyproheptadine with a primary or secondary outcome of weight gain were identified for article retrieval. 9 studies with a total of 336 subjects met inclusion criteria and contained sufficient data to calculate a summary statistic. 2 trials were in children (age 4–13 years), 3 trials were in adults (19–58 years) and 4 trials were mixed. Trial length was 4 to 16 weeks, and percent of follow-up ranged from 56–100%. Using a random effects model, the pooled estimate of net percentage change in mean weight per month was +1.8% (95%CI +1.0%, +2.6%, p<0.001). Subanalysis of the 5 studies in subjects with no organic etiology led to a slightly increased effect estimate of +2.0% (95%CI +1.2%, +2.9%). Conclusion: Cyproheptadine may induce a modest, but clinically meaningful degree of short-term weight gain in subjects with underweight or loss of appetite. Limited existing data suggest that cyproheptadine deserves further study as a weight-promoting agent.

Reduced lipolysis as possible cause for greater weight gain in subjects with the Pro12Ala polymorphism in PPARgamma2

Reduced lipolysis as possible cause for greater weight gain in subjects with the Pro12Ala polymorphism in PPARgamma2