MODY3 Diabetes

DefiniGEN provide disease modelled MODY3 diabetes human pancreatic cells which are highly functional CRISPR gene-edited human pancreatic cells. Neonatal diabetes mellitus (NDM) is a rare but potentially devastating metabolic disorder characterized by hyperglycemia combined with low levels of insulin. The neonatal diabetes cell products display the disease phenotype in combination with general function comparable to human primary pancreatic islets. These cell products can offer disease modelling and drug discovery researchers unprecedented tool for elucidating the underlying mechanisms of this key form of monogenic diabetes.

• Highly standardized cell product containing >97% human pancreatic cells with consistent performance and biologically relevant data
• Disease circuit verified confirmed mutation in the HNF1-alpha transcription factor gene – insertion of C at codon 872 producing a frameshift mutation
• Phenotypic analysis of the cells using GSIS assays demonstrates that the insulin response to glucose challenge is dysfunctional in these disease modelled cell products in contrast to DefiniGEN’s isogenic wild-type control pancreatic cell products.

Def-PANC MODY3 Cell Morphology

In contrast to Def-PANC WT cells which display normal tightly packed pancreatic cell morphology. Def-PANC MODY3 cells display aberrant morphology expected from developmental retardation caused by the HNF1a mutation.

Figure 1. Def-PANC MODY3 cell morphology. The homozygous Def-PANC MODY3 disease modelled cells display aberrant morphology in both monolayer and microislet culture.

Disease circuit verification

MODY3 pancreatic disease model with mutation in HNF1-alpha transcription factor gene – insertion of C at codon 872 producing frameshift mutation – isogenic control available.

Figure 2. Sanger sequencing of Def-PANC MODY3 mutation. The sequence analysis shows heterozygous HNF1a with single base insertion of a C in a polyC tract codon 291 for Proline.

GLUT + PKLR Expression Analysis

The expected down regulation of pancreatic cell function gene sets is observed in Def-PANC MODY3 cells in both the disease model variants.

Figure 3. Down regulation of key genes in Def-PANC MODY3 cells. Heterozygous and homozygous Def-PANC MODY3 cells show progressive gene change effects in key HNF1a gene regulated including PKLR and GLUT-2.

Pancreatic Key Marker Analysis

The expression of crucial pancreatic genes in sequentially reduced in dsiease modelled Def-PANC cells.

Figure 4. Def-PANC MODY3 cell marker analysis. QPCR analysis shows the expected reduction in key pancreatic cell markers in the Def-PANC disease models with a gene dosage dependent effect being observed.