ESPE Abstracts (2015) 84 P-1-102

ESPE2015 Poster Presentations Poster Category 1 Perinatal (11 abstracts)

The Role of HNF1B in Human Pancreas Development and Diabetes

Ranna El Khairi a , Andrew Hattersley c & Ludovic Vallier a,


aWellcome Trust Sanger Institute, Cambridge, UK; bDepartment of Surgery, Wellcome Trust-MRC Stem Cell Institute Anne McLaren Laboratory, University of Cambridge, Cambridge, UK; cInstitute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK

Background: Diabetes mellitus is a heterogeneous disorder with multiple aetiologies. Monogenic diabetes accounts for an estimated 2–5% of cases and is often associated with impaired pancreas development and β-cell dysfunction. Heterozygous mutations in the transcription factor, HNF1B, result in multi-system disease including diabetes due to β-cell dysfunction, hepatic insulin resistance and pancreatic hypoplasia. However, the mechanisms that underlie development of diabetes in HNF1B mutation carriers are still not fully understood due to lack of an appropriate model system. Human pluripotent stem cells (PSCs) are capable of self-renewal and have the potential to differentiate into any cell type in the body. They are therefore ideally suited to model human developmental diseases.

Objective and hypotheses: We propose to use a human pluripotent stem cell-based model system to determine the molecular mechanisms by which HNF1B mutations cause pancreatic hypoplasia and diabetes.

Method: Human PSC models of HNF1B-associated diabetes will be created through knockout of HNF1B in human embryonic stem cells (ESCs) and generation of induced pluripotent stem cells (iPSC) from patients. HNF1B deficient PSCs will be differentiated along pancreatic and hepatic lineages to investigate the effect of HNF1B mutations on human pancreas and liver development and function.

Results: Initial experiments analysed the normal expression pattern of HNF1B and showed upregulation of HNF1B at the foregut stage, and during pancreatic and liver specification. Preliminary experiments also showed that hPSCs-derived hepatocyte-like cells can potentially be used to study insulin-mediated regulation of metabolism in hepatocytes.

Conclusion: Human cellular models can be used to study the molecular mechanisms by which specific genotypes and epigenetic factors cause diabetes. The differentiation of PSCs along the pancreatic and hepatic lineages presents a unique tool to identify new genes that contribute to diabetes pathogenesis and novel therapeutic targets.

Funding: This work was supported by funding from the Wellcome Trust.

Article tools

My recent searches

No recent searches.

My recently viewed abstracts