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New Article: Scientific Reports

Maturity-onset diabetes of the young (MODY) is one of the hereditary forms of diabetes mellitus caused by mutations in an autosomal dominant gene disrupting insulin production. Patients with MODY1 typically develops diabetes (persistent hyperglycemia) before the age of 25 years, but this may not appear until later decades. The degree of insulin deficiency is slowly progressive. Many patients with MODY1 are treated with sulfonylureas for years before insulin is required.

MODY 1 is caused by a loss-of-function mutation in the HNF4α gene. HNF4α is part of a transcription network, including HNF1α (responsible for MODY3) and perhaps HNF1β (MODY5 – see Early Developmental Perturbations in a Human Stem Cell Model of MODY5/HNF1B Pancreatic Hypoplasia), which plays a role in the early development of the pancreas, liver, and intestines. In the pancreas these genes influence the expression of insulin, the principal glucose transporter (GLUT2), and several proteins involved in glucose and mitochondrial metabolism.

We used a combination of global proteomics and cellular biology techniques to investigate the differentiation capacity of insulin-producing cells using a seven-step differentiation protocol (as established by Rezania et al.) of induced pluripotent stem cells, generated from either healthy subjects or MODY1 patients.

Our data show that a human HNF4A mutation is neither blocking the expression of the insulin genes nor the development of insulin-producing cells in vitro. Our analyses also suggest key developmental signalling pathways representing potential targets for improving the efficiency of the current differentiation protocols.

Future studies are required on improving later differentiation stages up to mature insulin-producing β-like cells, which should also reveal the impact of HNF4A-directed transcriptional perturbations on β-cell survival and function.

The paper can be read here.

Probing the missing mature β-cell proteomic landscape in differentiating patient iPSC-derived cells Heidrun Vethe, Yngvild Bjørlykke, Luiza M. Ghila, Joao A. Paulo, Hanne Scholz, Steven P. Gygi, Simona Chera & Helge Ræder
Scientific Reports.2017 Jul 6;7(1):4780. doi: 10.1038/s41598-017-04979-w.

 

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New Article: Stem Cell Reports

Maturity-onset diabetes of the young (MODY) is a type of autosomal dominant monogenic diabetes classically characterized by non-ketotic, non-insulin-dependent diabetes occurring before the age of 25 years. Patients with MODY5 commonly exhibit pancreatic hypoplasia due to an autosomal dominant mutation in the HNF1B gene.

Previously, our collaborators from Joslin Diabetes Center, the research group of Rohit Kulkarni, turned skin cells (fibroblasts), donated by Norwegian patients, into induced pluripotent stem (iPS) cells, which are cells that can be coaxed to develop any tissue in the body. Now, using a customised protocol, they differentiated these iPSC into pancreatic progenitors and compared family controls with 2 mutation carriers (of which one of them has developed diabetes, whereas the other has not). Time-course analyses revealed complex compensatory mechanisms acting at the transcriptional level. These data suggest that, even though the diabetes onset occurs relatively late in life, there are compensated perturbations early during pancreatic development. Future studies are required on later differentiation stages up to mature insulin-producing β-like cells, which should reveal the impact of transcriptional perturbations on β-cell formation and function.

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The paper can be read here.

Early Developmental Perturbations in a Human Stem Cell Model of MODY5/HNF1B Pancreatic Hypoplasia Teo AK, Lau HH, Valdez IA, Dirice E, Tjora E, Raeder H, Kulkarni RN.
Stem Cell Reports. 2016 Feb 8. pii: S2213-6711(16)00024-2.

New article: Journal of Proteome Research (January 2015)

Patients with carboxyl-ester lipase-maturity-onset diabetes of the young (CEL-MODY) display distinct disease stages toward the development of monogenic diabetes and exocrine pancreatic disease. The finding of differentially increased proteins, some related to MAPK signaling, in a discovery proteomics study of secretin-stimulated duodenal juice in three CEL-MODY patients, prompted us to monitor their abundance in an extensive number of CEL-MODY subjects at different disease stages and controls using targeted proteomics.

Patients with carboxyl-ester lipase-maturity-onset diabetes of the young (CEL-MODY) display distinct disease stages toward the development of monogenic diabetes and exocrine pancreatic disease. The finding of differentially increased proteins, some related to MAPK signaling, in a discovery proteomics study of secretin-stimulated duodenal juice in three CEL-MODY patients, prompted us to monitor their abundance in an extensive number of CEL-MODY subjects at different disease stages and controls using targeted proteomics. In the current study, published in Journal of Proteome Research (January 2015), we demonstrated the feasibility of selected reaction monitoring assays to quantify protein levels in secretin-stimulated duodenal juice. Furthermore, we defined a set of five peptides for potential use as diagnostic tests in CEL-MODY patients. And finally, we proposed a further set of seven proteins with a likely pathogenic role in CEL-MODY disease progression.

The paper can be read here.