Objective Obesity pharmacotherapies result in an exponential time course for energy intake whereby large early decreases dissipate over time. This pattern of declining drug efficacy to decrease energy intake results in a weight loss plateau within approximately one year. We aimed to elucidate the physiology underlying the exponential decay of drug effects on energy intake. Methods We examined the placebo-subtracted energy intake time courses during long-term obesity pharmacotherapy trials for 14 different drugs or drug combinations within the theoretical framework of a proportional feedback control system regulating human body weight. Results Assuming each obesity drug had a relatively constant effect on average energy intake and did not affect other model parameters, our model correctly predicted that long-term placebo-subtracted energy intake was linearly related to early reductions in energy intake according to a pre-specified equation with no free parameters. The simple model explained about 70% of the variance between drug studies with respect to the long-term effects on energy intake, although a significant proportional bias was evident. Conclusions The exponential decay over time of obesity pharmacotherapies to suppress energy intake can be interpreted as a relatively constant effect of each drug superimposed on a physiological feedback control system regulating body weight.
Aim To evaluate the change in insulin sensitivity, β‐cell function and glucose absorption after 28 days of treatment with high and low doses of SAR425899, a novel dual glucagon‐like peptide‐1 receptor/glucagon receptor agonist, versus placebo. Materials and Methods Thirty‐six overweight to obese subjects with type 2 diabetes were randomized to receive daily subcutaneous administrations of low‐dose SAR425899 (0.03, 0.06 and 0.09 mg) and high‐dose SAR425899 (0.06, 0.12 and 0.18 mg) or placebo for 28 days; dose escalation occurred after days 7 and 14. Mixed meal tolerance tests were conducted before treatment (day −1) and on days 1 and 28. Oral glucose and C‐peptide minimal models were used to quantify metabolic indices of insulin sensitivity, β‐cell responsiveness and glucose absorption. Results With low‐dose SAR425899, high‐dose SAR425899 and placebo, β‐cell function from day −1 to day 28 increased by 163%, 95% and 23%, respectively. The change in area under the curve for the rate of meal glucose appearance between 0 and 120 minutes was −32%, −20% and 8%, respectively. Conclusions After 28 days of treatment, SAR425899 improved postprandial glucose control by significantly enhancing β‐cell function and slowing glucose absorption rate.
ObjectiveDespite the fact that most obesity drugs primarily work by reducing metabolizable energy intake, elucidation of the time course of energy intake changes during long-term obesity pharmacotherapy has been prevented by the limitations of self-report methods of measuring energy intake.MethodsWe used a validated mathematical model of human metabolism to provide the first quantification of metabolizable energy intake changes during long-term obesity pharmacotherapy using body weight data from randomized, placebo-controlled trials that evaluated 14 different drugs or drug combinations.ResultsChanges in metabolizable energy intake during obesity pharmacotherapy were reasonably well-described by an exponential pattern comprising three simple parameters, with early large changes in metabolizable energy intake followed by a slow transition to a smaller persistent drug effect.ConclusionsRepeated body weight measurements along with a mathematical model of human metabolism can be used to quantify changes in metabolizable energy intake during obesity pharmacotherapy. The calculated metabolizable energy intake changes followed an exponential time course, and therefore different drugs can be evaluated and compared using a common mathematical framework.
Aim: To gain further insights into the efficacy of SAR425899, a dual glucagon-like peptide-1/glucagon receptor agonist, by providing direct comparison with the glucagon-like peptide-1 receptor agonist, liraglutide, in terms of key outcomes of glucose metabolism.Research Design and Methods: Seventy overweight to obese subjects with type 2 diabetes (T2D) were randomized to receive once-daily subcutaneous administrations of SAR425899 (0.12, 0.16 or 0.20 mg), liraglutide (1.80 mg) or placebo for 26 weeks. Mixed meal tolerance tests were conducted at baseline (BSL) and at the end of treatment (EOT). Metabolic indices of insulin action and secretion were assessed via Homeostasis Model Assessment (HOMA2) and oral minimal model (OMM) methods. Results: From BSL to EOT (median [25th, 75th] percentile), HOMA2 quantified a significant improvement in basal insulin action in liraglutide (35% [21%, 74%]), while secretion enhanced both in SAR425899 (125% [63%, 228%]) and liraglutide (73% [43%, 147%]). OMM quantified, both in SAR425899 and liraglutide, a significant improvement in insulin sensitivity (203% [58%, 440%] and 36% [21%, 197%]), basal beta-cell responsiveness (67% [34%, 112%] and 40% [16%, 59%]), and above-basal beta-cell responsiveness (139% [64%, 261%] and 69% [−15%, 120%]). A significant delay in glucose absorption was highlighted in SAR425899 (37% [52%,18%]).Conclusions: SAR425899 and liraglutide improved postprandial glucose control in overweight to obese subjects with T2D. A significantly higher enhancement in betacell function was shown by SAR425899 than liraglutide.
BackgroundEnergy homeostasis ensures the functionality of the entire organism. The human brain as a missing link in the global regulation of the complex whole body energy metabolism is subject to recent investigation. The goal of this study is to gain insight into the influence of neuronal brain activity on cerebral and peripheral energy metabolism. In particular, the tight link between brain energy supply and metabolic responses of the organism is of interest. We aim to identifying regulatory elements of the human brain in the whole body energy homeostasis.MethodsFirst, we introduce a general mathematical model describing the human whole body energy metabolism. It takes into account the two central roles of the brain in terms of energy metabolism. The brain is considered as energy consumer as well as regulatory instance. Secondly, we validate our mathematical model by experimental data. Cerebral high-energy phosphate content and peripheral glucose metabolism are measured in healthy men upon neuronal activation induced by transcranial direct current stimulation versus sham stimulation. By parameter estimation we identify model parameters that provide insight into underlying neurophysiological processes. Identified parameters reveal effects of neuronal activity on regulatory mechanisms of systemic glucose metabolism.ResultsOur examinations support the view that the brain increases its glucose supply upon neuronal activation. The results indicate that the brain supplies itself with energy according to its needs, and preeminence of cerebral energy supply is reflected. This mechanism ensures balanced cerebral energy homeostasis.ConclusionsThe hypothesis of the central role of the brain in whole body energy homeostasis as active controller is supported.
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