Investigation of the Role of HNF1A in Increasing Susceptibility to Type 1 Diabetes

Contact PI: Karla Leavens, MD, PhD, Children's Hospital of Philadelphia

Start Date: March 2021


Abstract

While broadly caused by both genetic and environmental factors, the underlying pathophysiology of
type 1 diabetes in each individual is likely a unique combination ultimately triggering the autoimmune
destruction of pancreatic b-cells. The transcription factor HNF1a was recently found to be highly associated
with type 1 diabetes in a large population study. HNF1a clearly plays an important role in the b-cell as
heterozygous mutations result in the most common form of monogenic diabetes, MODY3, and numerous
genome-wide association studies have linked it to type 2 diabetes. However, its precise role in the b-cell,
especially in relation to the pathogenesis of type 1 diabetes, remains unknown. To investigate this role, we
recently generated and published on human β-cell models of HNF1A-deficiency, including human stem cellderived
β-cells. One of the most notable defects in HNF1A-deficient cells is a significant decrease in
mitochondrial respiration capacity. In addition, gene expression analysis of these stem cell-derived β-cells, in
tandem with analysis of β-cells from a MODY3 donor patient, revealed broad defects in insulin secretion,
cellular respiration, and cell stress response. Gene set enrichment analysis comparing HNF1A-deficient stem
cell-derived β-cells and pancreatic islets from type 1 donors also show similar profiles in the genes regulating
these processes as well. In addition, HNF1A gene expression itself is significantly downregulated in b-cells
from type 1 diabetes donors compared with controls. Preliminary studies in a human β-cell line suggest that
knockdown of HNF1A results in increased cell death following treatment with inflammatory cytokines.
Together, these data suggest that HNF1a serves to integrate the cellular response to stress and metabolism in
the β-cell, and we propose that this novel pathway contributes to β-cell death in at-risk individuals.
In this project, we aim to characterize the association between type 1 diabetes and HNF1a, as well as
the connections between type 1 diabetes and mitochondrial metabolism and ER stress more broadly. Based
on our preliminary data, we hypothesize that loss or downregulation of HNF1A increases susceptibility of the bcell
to stress, thereby contributing to the development of type 1 diabetes. We are focusing on the role of
HNF1a in cellular energy balance and ER stress response in the β-cell and how these processes influence
cellular response to immune attack and hyperglycemia. To address these questions, we are performing parallel
experiments in HNF1A-deficient stem cell-derived β-cells and in a second human β-cell model system, EndoC-
βH3 cells with acute knockdown of HNF1A by siRNA. We are exposing our HNF1A-deficient human β-cell
models to conditions that mimic the development of type 1 diabetes, including cytokines, hyperglycemia and
ZnT8-responsive CD8+ T cells. Under these conditions, we are analyzing the influence of HNF1A deficiency
on mitochondrial respiration, cellular energy balance, the unfolded protein response, T cell-mediated killing,
apoptosis and cell death. These studies will contribute to our knowledge of the link between β-cell-intrinsic
defects caused by HNF1a deficiency and type 1 diabetes. Understanding the early disease mechanisms which
contribute to the development of type 1 diabetes in at-risk individuals is essential to the development of
therapeutics, especially as these could be targeted to halt or reverse disease progression.

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