Abstract
BackgroundAccumulating evidence suggests that the metabolic effects of metformin and fermentable fibers are mediated, in part, through diverging or overlapping effects on the composition and metabolic functions of the gut microbiome. Pre-clinical animal models have established that the addition of fiber to metformin monotherapy improves glucose tolerance. However, possible synergistic effects of combination therapy (metformin plus fiber) have not been investigated in humans. Moreover, the underlying mechanisms of synergy have yet to be elucidated. The aim of this study is to compare in adolescents with obesity the metabolic effects of metformin and fermentable fibers in combination with those of metformin or fiber alone. We will also determine if therapeutic responses correlate with compositional and functional features of the gut microbiome.MethodsThis is a parallel three-armed, double-blinded, randomized controlled trial. Adolescents (aged 12–18 years) with obesity, insulin resistance (IR), and a family history of type 2 diabetes mellitus (T2DM) will receive either metformin (850 mg p.o. twice/day), fermentable fibers (35 g/day), or a combination of metformin plus fiber for 12 months. Participants will be seen at baseline, 3, 6, and 12 months, with a phone follow-up at 1 and 9 months. Primary and secondary outcomes will be assessed at baseline, 6, and 12 months. The primary outcome is change in IR estimated by homeostatic model assessment of IR; key secondary outcomes include changes in the Matsuda index, oral disposition index, body mass index z-score, and fat mass to fat-free mass ratio. To gain mechanistic insight, endpoints that reflect host-microbiota interactions will also be assessed: obesity-related immune, metabolic, and satiety markers; humoral metabolites; and fecal microbiota composition, short-chain fatty acids, and bile acids.DiscussionThis study will compare the potential metabolic benefits of fiber with those of metformin in adolescents with obesity, determine if metformin and fiber act synergistically to improve IR, and elucidate whether the metabolic benefits of metformin and fiber associate with changes in fecal microbiota composition and the output of health-related metabolites. This study will provide insight into the potential role of the gut microbiome as a target for enhancing the therapeutic efficacy of emerging treatments for T2DM prevention.Trial registrationClinicalTrials.gov NCT04578652. Registered on 8 October 2020.
Highlights
Background and rationale {6a} Childhood obesity is a major risk factor for the development of insulin resistance (IR) and type 2 diabetes mellitus (T2DM) in youth
Consumption of either supplemental fiber or a high-fiber diet promoted weight loss and improved hemoglobin A1c (HbA1c) in adults with T2DM on MET monotherapy [39]. These findings suggest that separate pathways underlie the effects of MET and fermentable fibers, as fermentable fibers enhanced responses to MET
We predict that the combination of MET and fiber will have a synergistic effect, being more effective than MET or fiber alone at 12 months in improving IR and body mass index (BMI) in the adolescents with obesity
Summary
Background and rationale {6a} Childhood obesity is a major risk factor for the development of insulin resistance (IR) and type 2 diabetes mellitus (T2DM) in youth. Limited or modest success has been reported for lifestyle interventions with behavioral modifications, such as diet and physical activity, they remain the most commonly applied therapies for IR and the underlying obesity in both adults and adolescents [1]. For youth-onset T2DM, MET monotherapy has shown a 52% failure rate, while MET plus intensive lifestyle therapy has shown a failure rate of 47%, as estimated by an uncontrolled intervention trial [1, 4]. Accumulating evidence suggests that the metabolic effects of metformin and fermentable fibers are mediated, in part, through diverging or overlapping effects on the composition and metabolic functions of the gut microbiome. Possible synergistic effects of combination therapy (metformin plus fiber) have not been investigated in humans. We will determine if therapeutic responses correlate with compositional and functional features of the gut microbiome
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
