Wednesday, February 5, 2025
2/5/2025
Modified Project Summary/Abstract Section Type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD) are emerging as two of the most critical global health challenges of the 21st century. NAFLD is estimated to affect up to one third of the general population, and NAFLD is nearly universally present in patients with T2D, with 75-100% of participants demonstrating hepatic steatosis, and with 50% and 19% demonstrating nonalcoholic steatohepatitis (NASH) and cirrhosis, respectively. Furthermore, NAFLD represents the most common cause of liver disease in children and adolescents. Studies by our group and others have shown a strong relationship between NAFLD, hepatic insulin resistance and T2D, however the cellular mechanisms that lead to hepatic insulin resistance and increased gluconeogenesis remain to be established. The studies proposed in this grant build on our previous studies that have shown that reduction of hepatic fat content through enhancement of hepatic mitochondrial lipid oxidation can reverse hepatic insulin resistance and diabetes in rodent and nonhuman primate models of NAFLD, NASH and T2D. The Overarching Aims that will be addressed in this grant will be to determine if rates of hepatic mitochondrial oxidation are altered in NAFLD, NASH and T2D and whether promoting chronic increases in rates of hepatic mitochondrial fat oxidation by means of a chronic glucagon infusion will reduce hepatic steatosis and hepatic insulin resistance in individuals with NAFLD. To address these questions we will apply a novel Positional Isotopomer NMR Tracer Analysis (PINTA) method that we have recently developed to: i) Assess rates of hepatic mitochondrial oxidation, pyruvate carboxylase flux and hepatic ketogenesis in participants with NAFLD, NASH and type 2 diabetes, ii) Assess the acute effects of a physiological increase in plasma glucagon concentrations on rates of hepatic mitochondrial oxidation, hepatic pyruvate carboxylase flux and hepatic ketogenesis in control and NAFLD participants and iii) Assess the effects of chronic glucagon treatment on rates of hepatic mitochondrial oxidation, pyruvate carboxylase flux, hepatic ketogenesis, hepatic fat content and hepatic insulin sensitivity in individuals with NAFLD. The results of these studies will provide important new insights regarding the role of altered hepatic mitochondrial function in the pathogenesis of NAFLD, NASH and T2D, which in turn will have important implications for the development of novel liver-targeted mitochondrial uncoupling therapies aimed at increasing hepatic mitochondrial fat oxidation to treat NAFLD, NASH and T2D, which are currently being evaluated in Phase 2b trials. The present study will also provide critical information regarding the acute and chronic effects of glucagon on hepatic mitochondrial oxidation, hepatic gluconeogenesis, hepatic insulin sensitivity and hepatic fat metabolism which has important implications for dual GLP-1/glucagon agonists and triple GLP-1/GIP/glucagon agonists which are now being evaluated in clinical trials for treatment of obesity, NAFLD, NASH and T2D.
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