Metformin is the most prescribed first-line anti-diabetic drug. It has been widely accepted that metformin lowers blood glucose primarily by reducing glucose output in the liver, and to a lesser extent by increasing peripheral glucose uptake. However, exactly how metformin can do so remains controversial and debated. The brain has (re)emerged as an important regulator of whole-body glucose metabolism. The central nervous system (CNS) is known to regulate glucose output and glucose uptake in the peripheral tissues, thereby changing whole-body glucose balance. We previously found that the small GTPase Rap1 in the brain or in the hypothalamus strongly influences glucose balance without affecting energy balance. Remarkably, we have further revealed that forebrain-specific Rap1 deficient mice are selectively resistant to metformin's glucose-lowering action, but retain sensitivity to other classes of anti-diabetic drugs. This preliminary discovery suggests a previously completely unrecognized CNS process potentially accounting for the anti- diabetic mechanism of metformin. To elucidate the neural mechanisms by which metformin lowers blood glucose, we will test the hypothesis that metformin acts centrally to lower hyperglycemia via inhibition of Rap1 in the ventromedial hypothalamic nucleus (VMH), a well-established site for glycemic control. This hypothesis is formulated on the basis of our exciting, solid preliminary data through genetic, anatomical, pharmacological and electrophysiology studies, which are for the first time presented here. The following three Specific Aims will be addressed to test our hypothesis: 1) using state-of-the-art in vivo methodologies such as euglycemic clamp and stable-isotope tracer techniques, we will investigate exactly how metformin in the brain regulates systemic glucose metabolism, 2) using in vivo GCaMP and chemogenetic tools, we will establish the importance of VMH SF1 neurons for the therapeutic action of metformin; and 3) experiments in Aim 3 will use loss-of-function and gain-of-function studies to conclusively determine the role of Rap1 in the VMH for metformin's anti-diabetic action. Together, these Aims will uncover an entirely novel site(s) and molecular mechanism(s) of action of metformin. This proposal will uncover a long-speculated mechanism explaining how metformin exerts its anti-diabetic actions by establishing a previously unknown connection between metformin, the brain (VMH) and the small GTPase Rap1. Lastly, the outcomes are thus likely to open a new area of pathophysiological and therapeutic discovery of type 2 diabetes.
Metformin is the most commonly used for the treatment for patients with type2 diabetes that affects hundreds of millions of people worldwide. Our proposal will reveal a novel neural pathway of antidiabetic actions, which is also targeted by metformin, and will potentially create new therapeutic modalities for type 2 diabetes.