Endocrine Abstracts

Pancreatic beta-cells maintain the body’s glucose levels within a very narrow range. In the face of insulin resistance and obesity, most people do not become diabetic due to the ability of the endocrine pancreas to have compensatory growth. Any limitation on replacement or shortening of lifespan could have dire consequences for glucose homeostasis. Type 2 diabetes develops only when b-cells fail to compensate for increased demand from insulin resistance. While Type 2 diabetes (T2D) increases with age with the majority of patients being above the fifth decade of life, the specific contribution of beta cell aging and senescence to diabetes has had limited study. Yet the deficiency in proliferative response to increased demand may arise partly from the accumulation of senescent beta-cells. Cellular senescence is a state in which cells cease to divide but remain metabolically active with an altered phenotype. Cells in general, and presumably beta cells, senesce in response to stressors and aging, resulting in changes in structure and function that may include irreversible growth arrest and alterations in gene expression. With age, an accumulation of dysfunctional senescent beta-cells likely contributes to impaired glucose tolerance and diabetes.From our studies we have shown that there are differently aged beta cells in the adult pancreas. Even in young (3-4 month old) mice, a population of beta-cells express known aging markers (senescence-associated acidic beta-galactosidase activity (b-Gal),p16Ink4aand p53BP1) and that this population increased with age. Aged beta-cells had impaired function, characterized by higher basal insulin secretion and a lower recruitment to glucose challenges; senescent beta cell secrete a number of cytokines and chemokines, known as senescence-associated secretory profile (SASP) that have detrimental effects on neighboring cells. Importantly acute insulin resistance, induced by the insulin receptor antagonist S961 or high fat diet, resulted in expression of aging markers suggesting that insulin resistance as a driver of accelerated beta-cell aging. Additionally even mild hyperglycemia induces a markedly changed beta cell phenotype and dysfunction. We will address the relationship between beta-cell aging, the development of diabetes and if there are strategies to decrease the load of aged beta-cells in order to improve cellular identity, function and overall metabolic parameters.