Modeling Monogenic Diabetes using Human ESCs Reveals Developmental and Metabolic Deficiencies Caused by Mutations in HNF1A

Cell Stem Cell. 2019 Aug 1;25(2):273-289.e5. doi: 10.1016/j.stem.2019.07.007.


Human monogenic diabetes, caused by mutations in genes involved in beta cell development and function, has been a challenge to study because multiple mouse models have not fully recapitulated the human disease. Here, we use genome edited human embryonic stem cells to understand the most common form of monogenic diabetes, MODY3, caused by mutations in the transcription factor HNF1A. We found that HNF1A is necessary to repress an alpha cell gene expression signature, maintain endocrine cell function, and regulate cellular metabolism. In addition, we identified the human-specific long non-coding RNA, LINKA, as an HNF1A target necessary for normal mitochondrial respiration. These findings provide a possible explanation for the species difference in disease phenotypes observed with HNF1A mutations and offer mechanistic insights into how the HNF1A gene may also influence type 2 diabetes.

Keywords: HNF1A; MODY3; beta cells; cell respiration; diabetes; embryonic stem cells; glycolysis; long non-coding RNA; pancreas.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cell Respiration
  • Cells, Cultured
  • Diabetes Mellitus, Type 2 / metabolism*
  • Diabetes Mellitus, Type 2 / pathology
  • Gene Expression Regulation
  • Hepatocyte Nuclear Factor 1-alpha / genetics
  • Hepatocyte Nuclear Factor 1-alpha / metabolism*
  • Human Embryonic Stem Cells / physiology*
  • Humans
  • Milk Proteins
  • Mutation / genetics
  • Pancreas / pathology*
  • Pancreas / physiology
  • Phenotype
  • RNA, Long Noncoding / genetics


  • HNF1A protein, human
  • Hepatocyte Nuclear Factor 1-alpha
  • Milk Proteins
  • Monogen
  • RNA, Long Noncoding

Supplementary concepts

  • Maturity-Onset Diabetes of the Young, Type 3