The Role of Hepatocyte-Nuclear-Factor-1-A (HNF1A) in the Regulation of Glucose Homeostasis and Pancreatic Hormone Secretion

Maturity-onset-diabetes-of-the-young (MODY) accounts for approximately 2% of all diagnosed diabetes cases worldwide. In the general population, the most common form is the hepatocyte-nuclear-factor- MODY, due to mutations in transcription factor HNF1A. HNF1A gene targets include transporters involved with glucose, cholesterol, bile acid synthesis and fatty acid metabolism. In humans, HNF1A allows insulin to be produced normally in childhood, but the amount of insulin secreted reduces with age, by still unexplained mechanisms. Findings in rodents, suggest that mutations in HNF1A may disrupt the development of beta cells in the embryo, which become dysfunctional in the adult. Others suggest defects in glucose sensing and transport to be the cause. Notably, renal proximal tubular reabsorption of glucose by sodium-glucose-transporter-2 (SGLT2) is reduced in mice carrying homozygous mutations for HNF1A (HNF1A-/-). As a consequence, these animals do not have a severe hyperglycemia, most likely because of renal urinary glucose wasting. However, they do present with endogenous glucose production and fasting glycemia, thus paralleling that of HNF1A-MODY patients. However, whether these subjects have hyperglucagonemia is unknown. The aim of this study is to unveil new hypothesizes for the specific function of HNF1A in islet cell subtypes. To address this, we will perform 3 specific aims: 1. Map HNF1A protein expression in islets across all ages (childhood to old age). 2. Determine the effect of HNF1A deficiency on pancreatic hormone secretion and the islet transcriptome before and after drug therapy (by low-dose sulphonylureas (SU) or GLP1RA therapy). 3. Demonstrate the physiological and pathophysiological relevance of our findings in-vivo using HNF1A-/-mic vs. littermate control mice and floxed allele to different Cre mice to knockout HNF1A gene in alpha cells, beta cells and delta cells during embryogenesis and postnatally.