Therapeutic targets in African-American youth with type 2 diabetes

National Institute Of Diabetes And Digestive And Kidney Diseases

Investigators

Linked publications, trials & patents

Abstract

This is a 3-month randomized trial in youth with type 2 diabetes with 2 intervention arms (metformin alone and metformin and liraglutide). This project successfully screened 39 individuals, enrolled 24 and completed study on 22 participants to meet study primary outcomes. The study was closed to recruitment in Spring 2023 and data analysis completed. Abstracts of primary study findings were presented at national meetings American Diabetes Association Scientific Sessions 2023 and International Society for Pediatric and Adolescent Diabetes 2022. The primary data support improved glycemia and -cell function in youth on short-term combination therapy with metformin and liraglutide independent of changes in new glucose produced by the liver. Metformin was ineffective alone or in combination with liraglutide for lower rates of new glucose produced by the liver and further research is needed to explore therapeutics that will target this early pathological feature. These findings add two important contributions to the field. First, we provide integrative evidence that early combination therapy with metformin and a GLP-1 RA improves glycemia primarily through enhancing beta-cell function, independent of changes in glucose production Y-T2D. Second, the data posits that extra-hepatic mechanisms for metformin are primary drivers for its glucose lowering effects and interventions that target multiple pathways, including high lipolytic rates, are needed to address the persistently high rates of gluconeogenesis in Y-T2D. Metformin pharmacokinetics or medication adherence were not associated with change in HbA1c or gluconeogenesis. Two factors predicted lower rates of gluconeogenesis: (1) increased palmitate fatty acid flux and lipolysis and (2) a single nucleotide polymorphism of metformin transporter (rs622342 A>C, OCT1, SLC22A1), a solute carrier in hepatocytes and intestinal cells (MADORS 2024 abstract, manuscript in preparation). This polymorphism is enriched in African ancestry populations (minor allele frequency ~25%) suggesting that studies, like ours, with a targeted ancestry-directed approach are needed to understand the heritability of metformin intolerance and clearance. In addition, we showed pathways upregulating short-chain fatty acids and bile acid metabolism were associated with metformin and liraglutide treatment and increased gut bacterial abundance. The MIGHTY studies shed renewed light on the complexity of gluconeogenic pathways—which are tightly regulated by neuro-hormonal, substrate, and genetic factors —and spotlight the need for novel interventions to abrogate multiple highly conserved pathways contributing to high rates of gluconeogenesis in Y-T2D. Manuscripts for secondary and exploratory outcomes are being prepared. We published additional research related to this project developing a new model for assessing insulin sensitivity and secretion and the effect of liraglutide on youth with severe obesity.