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Role of pancreatic beta-cell regeneration in the pathofisiology and treatment of insulin resistance and type 2 diabetes

Final Report Summary - BCELL-T2D (Role of pancreatic beta-cell regeneration in the pathofisiology and treatment of insulin resistance and type 2 diabetes)

Diabetes is a devastating illness declared by the World Health Organisation (WHO) as the 21st century epidemic. Type 2 diabetes develops through a multi-stage process. The body becomes unable to use insulin effectively and the pancreatic beta-cells try to compensate producing more insulin, a condition known as insulin resistance. Eventually the beta-cells become exhausted and at this point, this condition frequently progresses to diabetes.

Diabetes develops after a substantial decrease in the number of beta-cells (increase in cell death/decrease in proliferation and neogenesis) and/or the impairment of insulin secretion needed to maintain euglycemia. The molecular mechanisms by which beta-cells fail to compensate for insulin resistance remain elusive.

Through this proposal we have tried to shed light on:

1. the identification of the molecular mechanisms that lead to impaired beta-cell proliferation in the pathophysiology of type 2 diabetes; and
2. the therapeutic role of beta-cell proliferation in the treatment of type 2 diabetes.

In order to answer these two questions we have exhaustively characterised the db/db mouse model of obesity and diabetes, identifying three different stages, first pure insulin resistance (four to nine weeks of age), second, insulin resistance and frank diabetes (10 to 18 weeks of age) and third, advanced diabetes and its complications (after 19 weeks of age). In each stage we have studied beta-cell mass, finding an increased expansion of beta-cell mass in the db/db mice compared to their controls, in the compensatory phase (insulin resistance) that disappears along the evolution of the disease. This beta-cell mass expansion is based on beta-cell proliferation. Interestingly, also the percentage of glucagon positive-cells increases through the time, only in males, after diabetes debut. In other hand we have characterised a subcolony of db/db mice that present compensatory hyperinsulinemia and do not develop diabetes. The mechanisms underlying this compensation are based on beta-cell mass expansion.

To understand if acute interventions inducing beta-cell proliferation are able to maintain beta-cell mass and pancreas compensation, we have studied the role of a new molecule that controls cell cycle entry in other cell types, cyclin C. We have generated an adenovirus containing cyclin C complementary deoxyribonucleic acid (cDNA) and we have delivered it into the primary rat beta-cells. The results obtained through these techniques point to cyclin C as an inductor of cell cycle entrance to S phase, interestingly, we have found cyclin C overexpression is not enough to complete cell cycle progression. We are now interested in studying the role of cyclin C in vivo and second if sustained beta-cell proliferation will be able to prevent diabetes debut.

We have also investigated the effect of small molecules, obtained from our collaboration with chemists from the IPNA-CSIC (Spain), on beta-cell proliferation, beta-cell death and function. We have found a compound, epoxypukalide, which induces beta-cell proliferation meanwhile maintaining beta-cell function; furthermore, this product protects beta-cells from cytokine-induced cell death.

This project has established a detailed characterisation of the db/db mouse model, metabolic and mechanistic. We have detected some potential therapeutic targets to induce beta-cell proliferation. We have studied cyclin C role on beta-cell proliferation and finally, we have found a small molecule, obtained from a gorgonian choral, which induces beta-cell proliferation, meanwhile protecting beta-cell death and function.