Abstract The metabolic disorders of obesity and type 2 diabetes mellitus (T2DM) impact one in three adults. The inability of insulin to suppress hepatic glucose production and promote glucose uptake into peripheral tissues is a hallmark of T2DM. However, the underlying mechanism of liver insulin resistance remains incompletely understood. This gap in knowledge is an important problem because it hinders the development of targeted metabolic therapies to manage the growing clinical burden of T2DM. The vascular endothelium coordinates the delivery of endocrine hormones and small molecules to target tissues. Yet, how specific endothelial factors exert impacts in metabolic tissues remains undefined. Bone morphogenetic protein (BMP)-binding endothelial regulator (BMPER), highly secreted from vascular endothelium, adapts endothelial cells (ECs) to inflammatory and nutrient stress in diverse organ microenvironments. In new studies, we observed inducible knockout of BMPER (iKO) globally or specifically in endothelium caused hyperinsulinemia, glucose intolerance and insulin resistance independently from obesity and inflammation. These results suggest the vascular endothelium secretes BMPER to maintain glucose homeostasis. Subsequent experiments demonstrated adeno-associated viral BMPER delivery dramatically alleviated diabetes in mice. In humans, BMPER plasma levels are reduced in insulin resistant subjects compared to normoglycemic subjects, supporting an important role for BMPER in defending insulin sensitivity. Mechanistically, we observed BMPER transactivated the insulin signaling pathway in metabolic tissues. Therefore, we hypothesize that BMPER endocytosis promotes insulin sensitivity. To test this hypothesis, we propose the following aims: 1) determine the metabolic consequences of BMPER depletion; 2) establish the anti-diabetic potential of recombinant BMPER; and 3) define the mechanisms that govern BMPER regulation of insulin action. Collectively, these studies suggest an uncharacterized pathway that may define new therapies to minimize the long-term clinical burden of T2DM.

The prevalence of type 2 diabetes mellitus and insulin resistance has rapidly increased over the last several decades. Individuals with type 2 diabetes mellitus, constituting about 90% of all cases of diabetes, are unable to properly use their insulin supply due to insulin resistance. We will elucidate regulatory mechanisms and suggest new and unexpected therapeutic targets and strategies against metabolic syndromes, type 2 diabetes mellitus, dyslipidemia, insulin resistance, NPC disease, nonalcoholic fatty liver disease and other metabolic disorders.