Sunday, December 22, 2024
12/22/2024
Project Summary / Abstract Nonalcoholic fatty liver disease (NAFLD), characterized by excessive deposition of fat in the liver, is the most common pediatric liver disease (~13% prevalence among 2-19 years old) and is exacerbated by obesity and insulin resistance. Presently, there are no treatment options for pediatric NAFLD that produce meaningful and durable hepatic fat reductions. Pharmacotherapy may be able to close the tremendous gap in clinical care. Sodium glucose co-transporter-2 inhibitors (SGLT2i) represent an attractive and potentially effective treatment option for NAFLD with supportive data in adults and animal models but has yet to be examined in pediatrics. In adults with type 2 diabetes and obesity, SGLT2i medications reduce body weight, improve insulin sensitivity, and decrease hepatic fat. Unlike adults, the vast majority of adolescents with obesity and NAFLD are insulin resistant but have yet to develop type 2 diabetes. Thus, the pediatric population is ideal to test the first central hypothesis that SGLT2i therapy drives reductions of hepatic fat in the absence of diabetes. SGLT2i paradoxically increases fasting endogenous glucose production (EGP), which is not commonly encountered with other insulin sensitization medications. Therefore, the second central hypothesis is that SGLT2i augments hepatic mitochondrial fatty acid beta-oxidation, producing the acetyl-CoA that stimulates gluconeogenesis-derived EGP in a pediatric, non- diabetic population. The collaborative transdisciplinary team is uniquely positioned to leverage a randomized, controlled trial to test whether the SGLT2i empagliflozin may be a successful treatment for pediatric NAFLD. A focused, mechanistic clinical trial will be performed studying older adolescents (ages 16-≤20 years; n=40) with MRI-determined NAFLD (hepatic fat ≥5.5%) and obesity (BMI ≥30kg/m2) without T2D, to examine the response to 10mg, once-daily oral dose of empagliflozin for 26-weeks to identify mechanisms of action and initial efficacy of the SGLT2i agent empagliflozin as a treatment for pediatric NAFLD, through the following Specific Aims: (1) Use SGLT2i treatment to quantify the dynamic relationship between hepatic fat content and insulin sensitivity in an adolescent population. Gold-standard 2-stage hyperinsulinemic-euglycemic clamps and MRI-determined NAFLD will be used to determine whether SGLT2i driven reductions in hepatic fat are associated with the degree of improvement in both hepatic and peripheral insulin sensitivity. (2) To determine the mechanisms through which SGLT2 inhibition decreases hepatic fat content. Non-invasively delivered dual stable isotope tracers and magnetic resonance spectroscopy-based methods will be used to quantify adipose tissue lipolysis, hepatic fat oxidation (both terminal oxidation and ketogenesis), and the gluconeogenic and glycogenolytic components of EGP, to determine whether the degree of hepatic fat reduction correlates with the degree to which SGLT2i drives hepatic fat oxidation. This study represents a novel and innovative investigation into a promising medical therapy for a highly prevalent disease in the pediatric population, which currently has limited treatment options.
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