Biotrack

Molecular mechanisms of pancreatic islet cell dysfunction and destruction in type 2 diabetes

REF: PD 27
Principle investigator:
Anna Novials
Contact details:

anovials(ELIMINAR)@clinic.ub.es, katte(ELIMINAR)@ciberdem.org

RESEARCH LINE NO LONGER AVAILABLE

Research framework

The purpose of our research is to investigate some of the molecular mechanisms that provoke the dysfunction and destruction of pancreatic islets in type 2 diabetes, in order to obtain a better understanding of the pathogenesis of the disease.

Currently we are focusing our research on the study of RE stress, UPR (unfolding protein response), beta secretase activity (BACE2) and apoptosis, as induced by the process of amiloidogenesis. In addition, the prevention of beta-cell death by the overexpression of antiapoptotic genes using non-viral and viral vectors to transduce the pancreas in vivo and also isolated pancreatic islets, promises to have significant implications for defining new targets for diabetes treatment.

Common techniques to be used include: isolation of human, rat and mouse pancreatic islets; immunohistochemistry and functional and morphometric analyses of islets; cell line culture techniques; adenoviral and lentiviral transfection of pancreatic islets and cell lines; real-time quantitative PCR techniques; siRNA and microrray analyses; genomic and epigenetic analyses; and transgenic mice colony management and phenotyping, including glucose tolerance test and insulin tolerance test.

The most relevant publications by our group that support this research are:

  • Involvement of ATP-sensitive potassium K(ATP)) channels in the loss of beta-cell function induced by human islet amyloid polypeptide. Journal of Biological Chemistry, 286, 40857-40866 (2011).
  • BACE2 plays a role in the insulin receptor trafficking in pancreatic beta-cells. American Journal of Physiology-Endocrinology and Metabolism, 299, E1087-E1095 (2010).
  • Calcium elevation in mouse pancreatic beta cells evoked by extracellular human islet amyloid polypeptide involves activation of the mechanosensitive ion channel TRPV4. Diabetologia, 51, 2252-2262 (2008).
  • Impairment of the ubiquitin-proteasome pathway is a downstream endoplasmic reticulum stress response induced by extracellular human islet amyloid polypeptide and contributes to pancreatic beta-cell apoptosis. Diabetes, 56, 2284-2294 (2007).

The expertise of our group has provided added value to this framework of research by describing certain mechanisms related to β-cell toxicity and apoptosis, in particular, those related to pancreatic amyloidogenesis.

Keywords

Pancreatic islets, islet amyloid polypeptide (IAPP), BACE2, apoptosis, beta-cell toxicity, UPR (unfolding protein response)

Main Challenges

The described research requires a solid scientific methodology and the skills necessary to perform sound experiments, as well as the ability to work independently, communicate effectively, and analyze/think critically. It allows the opportunity to fully participate in related projects under the supervision of the PI and to acquire leadership skills within the group, as well as the chance to receive training and gain expertise in the field. Desirable achievements and outcomes include publications in high-impact scientific journals and presentation of results at national and international conferences and meetings.

Team strategic objective in IDIBAPS

The team, “Molecular and Metabolic Alterations in Diabetes”, seeks to generate new knowledge, both basic and clinical, about the molecular, genetic and environmental factors critical to pancreatic beta-cell dysfunction and destruction in type 2 diabetes, with the end goal of identifying potential targets for the prevention and treatment of the disease.

(Read eligibility criteria)