Pathogenesis of youth onset pre-diabetes and Type 2 diabetes

PROJECT SUMMARY
The TODAY and RISE studies revealed a rapid decline in β-cell function and its unresponsiveness to two of the
most commonly used treatments for T2D in pediatrics. This dire scenario is further aggravated by the rising
prevalence of Non-Alcoholic Fatty Liver Disease (NAFLD) affecting ~40% of obese youth in the US. Hence, there
is a pressing need for effective approaches to preserve β-cell function and reduce NAFLD in obese youth, in
order to prevent disease progression. To investigate the roles of insulin resistance, beta-cell dysfunction, and
NAFLD in the earliest stage of T2D: Impaired Glucose Tolerance (IGT), we formed 2 large multiethnic cohorts:
The Pathogenesis of Youth Onset Diabetes (PYOD) study (NCT01967849), and The Yale Pediatric
NAFLD/NASH Cohort (NCT01966627). In a series of studies using these cohorts, we found that beta-cell
function relative to insulin sensitivity gradually decreases in obese youth across rising 2-hr glucose levels and
degrees of Hepatic Steatosis. Importantly, in the current grant cycle, we identified in obese youth the key role
of a reduced incretin effect early in the pathophysiology of glucose dysregulation and NAFLD. Taken together,
these studies provide a strong scientific premise for using novel approaches to understand the
interconnectedness among beta-cell dysfunction, impaired incretin system, and NAFLD in the onset of
prediabetes. Our Primary Objective is: To determine the mechanisms by which Liraglutide, the first GLP-1
analogue, might restore glucose homeostasis by examining its effects on ß-cell and alfa cell function and hepatic
fat content in obese youth with IGT and NAFLD/NASH. The Specific Aims and Hypotheses (H) are Aim
1&H1: A: Using a randomized, double-blind, placebo-controlled, parallel-group, clinical trial design (RCT), we
will test whether a 6-month (6-M) treatment with Liraglutide, (Victoza 1.8 mg) improves ß-cell function and
decreases glucagon levels, compared to placebo, and B: whether the functional improvements in ß-cell function
following 6-M of active treatment can be sustained 3-M after the withdrawal of therapy in obese youth with IGT
and NAFLD/NASH. Aim 2&H2: A: To test whether a 6-M treatment with Liraglutide decreases MRI-PDFF
measured hepatic steatosis compared to placebo, via changes in de Novo Lipogenesis (DNL), and B: whether
the effects persist after a 3-M washout period. C: To explore the efficacy of Liraglutide in reducing hepatic fibrosis
measured by Magnetic Resonance Elastography (MRE) after 6-M of treatment. Overall Approach: Our team
will use an innovative study design that incorporates rigorous and detailed MRI imaging of the liver, coupled with
clamp-techniques and the use of stable isotopes to gain insights into the mechanisms by which Liraglutide might
affect beta-cell function relative to insulin sensitivity and reduce intrahepatic fat accumulation in youth with IGT
and NAFLD. Collectively, the proposed mechanistic RCT study, will provide important proof-of-concept, safety
data and advance our understanding of the pathogenesis and treatment of two highly prevalent endo-hepatic
metabolic disorders in pediatrics: Impaired glucose tolerance and NAFLD/NASH.

Grant Number: 5R01DK111038-10
NIH Institute/Center: NIH
Principal Investigator: SONIA CAPRIO