AMPK-mediated regulation and roles of miR-125b and miR-184 in pancreatic beta-cell function.

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Diabetes affects 8% of the world population. When poorly treated, blood sugar levels run dangerously high, which can lead to blindness, kidney failure, limb loss and death. In the UK the NHS spends over £10 billion every year on diabetes care, but we are no closer to a cure. In fact, the incidence of type 2 diabetes (which accounts for >90% cases) continues to rise unabated. Central to the development of diabetes is the failure of beta-cells, which are dispersed throughout the pancreas in the islets of Langerhans. The failing beta-cells are unable to secrete enough insulin to lower blood sugar levels. Crucially, a high prevailing blood sugar will itself further accelerate beta-cell failure in a vicious cycle. A deeper understanding of the molecules that control beta-cell function and survival is essential for the development of better targeted drugs that can prevent, slow down or even reverse beta cell demise and hence effectively treat diabetes. I have spent most of my career studying microRNAs (miRNAs), which are tiny molecules inside cells that have recently been discovered to regulate the genes that are required for a cell to function normally. There are more than 2000 different miRNAs in the human body and all cells, including the beta-cells, need miRNAs to work adequately. It has also been demonstrated that alteration of miRNAs can lead to diabetes. Nevertheless, very little is known about which miRNAs are important for beta-cell function, how they exert their influence and how their actions are controlled. I have now demonstrated that two miRNAs, miR-184 and miR-125b, are closely related to the activity of AMPK. AMPK is an enzyme that helps the beta-cell recognize what the prevailing blood sugar level is and it is vital to their survival and normal functioning. Furthermore, I have demonstrated that these miRNAs themselves go up and down in response to changes in the amount of the sugar. All of this points to AMPK and its related miRNAs as being important potential drug targets for diabetes. In fact, existing diabetes medications are already thought to work in part by modulating AMPK, but our understanding of the exact mechanisms and molecular interactions is patchy, which limits the development of even more effective treatments. In this project I will use state-of-the-art techniques to:1. Fully elucidate the contribution of miR-184 and miR-125b (and their interactions with AMPK) towards beta-cell function and survival.2. Show the real-life importance of this in animal models and donated human beta-cells - this is hugely important to ensure that this new knowledge can be potentially translated into highly effective new treatments for diabetes.