ABSTRACT
AIMS: Exenatide is a glucagon-like peptide 1 (GLP-1) mimetic which induces weight loss predominantly, it is presumed, via decreased food intake. However, circulating GLP-1 is also a determinant of energy expenditure. We sought to quantify the effect of exenatide on energy expenditure (EE) and energy intake. MATERIALS AND METHODS: In this single-center, randomized double-blind placebo controlled trial, we randomized 80 healthy, non-diabetic volunteers with obesity (46 women, age: 34.4⯱â¯8.7â¯y, body fat by DXA: 44.2⯱â¯7.8%) to subcutaneous exenatide 10⯵g twice daily or placebo. Subjects were admitted to our clinical research unit for measurement of 24â¯h-EE in a whole-room indirect calorimeter and ad libitum food intake using an automated vending machine paradigm before and after randomization. Furthermore, energy expenditure and ad libitum food intake measures were repeated at 24-week after readmission for 7-day inpatient stay. Body weight was obtained weekly for up to 5â¯weeks and was recorded at each monthly follow up visit up to 24â¯weeks. RESULTS: Prior to randomization, participants over ate during the 3-day vending machine period in the whole study group (114.6⯱â¯35.2%), expressed as percentage of weight maintaining energy needs (WMEN) with those who were eventually randomized to exenatide overeating more (121.6⯱â¯37.7%) compared to placebo group (107.6⯱â¯31.5%). In the exenatide group, ad libitum absolute energy intake decreased by 1016.1⯱â¯724.5â¯kcal/day (95% CI: -1250.9 to -781.2) versus a 245.1⯱â¯710.5â¯kcal/day (95% CI: -475.4 to -14.7) decrease in placebo (Δâ¯=â¯-624.8â¯Kcal/day, pâ¯<â¯0.0001) whereas the reduction in ad libitum caloric intake relative to WMEN was a more modest 366.8⯱â¯752.1â¯kcal/day (95% CI: -614.0 to -119.6) decrease compared to 8.0⯱â¯860.1â¯kcal/day (95% CI: -286.8 to 270.8) reduction in placebo (Δâ¯=â¯-382.3â¯Kcal/day, pâ¯=â¯0.03). The decrease was uniform across all macronutrients groups. No differences in 24hEE or substrate oxidation rates were found. In the exenatide group, body weight decreased more over the 5â¯weeks (ßâ¯=â¯-0.039â¯kg/week, pâ¯=â¯0.02) and was lower compared to placebo at the end of fifth week (-1.48⯱â¯0.77â¯kg; 95% CI: -3.02 to 0.05, pâ¯=â¯0.06). At the 24-week follow up, there was no difference in energy intake between exenatide group and placebo group and the treatment group decreased 24-h EE more compared to placebo (ßâ¯=â¯-160.6â¯Kcal/day, 95% CI: -307.6 to 13.6, pâ¯=â¯0.03) compared to their pre-randomization measurement. However, this reduction was not present after adjustment for changes in FM and FFM (ßâ¯=â¯-87â¯kcal/day, pâ¯=â¯0.14). No difference was observed in body weight (Δâ¯=â¯-1.72â¯kg, 95% CI: -5.77 to 2.30, pâ¯=â¯0.39) in exenatide versus placebo over 24â¯weeks. CONCLUSION: Compared with placebo, exenatide decreased early ad libitum energy intake but did not change 24â¯h-EE. However, the reduction was more modest in relative versus absolute terms (i.e. below that needed for WMEN). Thus, although rate of weight change was greater in the exenatide treated subjects at 5â¯weeks, the absolute difference in weight was not significant. These findings indicate that although exenatide reduces food intake, it may be more beneficial in blunting overeating and thus may serve to more prevent weight regain following initial weight loss.
Subject(s)
Anti-Obesity Agents/pharmacology , Energy Intake/drug effects , Energy Metabolism/drug effects , Exenatide/pharmacology , Obesity/drug therapy , Adult , Anti-Obesity Agents/therapeutic use , Body Mass Index , Double-Blind Method , Exenatide/therapeutic use , Female , Humans , Male , Treatment OutcomeABSTRACT
BACKGROUND: Uric acid (UA) is known to be associated with excess adiposity and insulin resistance. Our aim was to investigate the relationship between UA and the factors associated with the metabolic syndrome and type 2 diabetes mellitus (T2DM), both initially and longitudinally. METHODS: Serum UA was assessed as a potential determinant of concurrent blood pressure, serum lipids, glucose regulation measured via an oral glucose tolerance test (OGTT), acute insulin response (AIR), and insulin action (M) measured with hyperinsulinemic-euglycemic clamps in 245 participants (72% Native American, 56% male). UA was also assessed as a predictor of the above variables in 60 participants with follow-up data available (median follow-up time=11.2 years [interquartile range (IQR)=8.1, 13.6 years]. The impact of UA on the risk of T2DM was determined as 36 of the 245 participants developed T2DM after the baseline visit. RESULTS: UA was negatively associated with both concurrent and future M, such that for every 1 mg/dL increase in serum UA, M decreased 7.6% (P<0.001) and future M decreased 6.3% (P=0.02). However, UA was not associated with AIR (P=0.7). UA concentrations were a predictor of T2DM [hazard risk ratio (HRR)=1.5; P=0.02]. UA was positively associated with both concurrent blood pressure and lipids and also predicted future increases in blood pressure and total cholesterol. CONCLUSIONS: Not only did UA associate with concomitant insulin action, blood pressure, and lipids, it also predicted future declines in insulin action and T2DM. UA is a potential target for preventing decreases in insulin sensitivity and rises in blood pressure and cholesterol.