Over 7% (21M) of the U.S. population has diabetes (over 90% of which is type 2 = T2D). Another 54M have """"""""prediabetes"""""""" (all T2D). The human tragedy aside, direct medical costs associated with diabetes in the United States currently exceed $132 billion a year and consume ~10% of health care costs in industrialized nations. Diabetes is the leading cause of both end stage renal disease and blindness (in people aged 20-74 years), and its association with cardiovascular disease increases mortality rates two-fold. The worldwide prevalence of T2D is projected to more than double over the next 20 years. Although intensive genetic analyses of human populations have confirmed contributory roles for some specific genes, these cannot account - even in the aggregate - for powerful genetic predisposition T2D. Obesity is clearly related to the occurrence of diabetes. Physiologically, this is apparently due to the stress that obesity-related insulin resistance places on the insulin- producing cells of the pancreas. But the molecular basis for this striking association is not known. It is possible that part of this differential susceptibility derives from genetically mediated differences in the starting numbers of insulin producing beta cells among individuals. If so, it is very important to identify the relevant genes. Mouse strains differ widely in susceptibility to diabetes when made obese. We exploited this characteristic to map diabetes-susceptibility regions of the mouse genome in genetics crosses between a diabetes-susceptible and a resistant strain. We used molecular genetic methods to find a novel gene, lisch-like (Ll) that appears to account for some aspects of this strain-related difference in mice. The gene affects the early development and replication of beta cells, leaving animals with the susceptible version of the gene with a reduced beta cell mass that then predisposes them to diabetes. The proposed studies are intended to confirm the role of this gene in the etiology of T2D and to reveal how this novel molecule produces these effects. The Hypothesis underlying the proposed studies is that LL regulates generation and survival of islet beta cells.
In Aim 1 we will examine the systemic and cellular physiology of mice with induced mutations causing under or over-activity of the Ll gene. These studies are designed to confirm the gene's role in diabetes and to understand the molecular physiology of its activity.
In Aim 2 Assays of protein biosynthesis, processing, and sub-cellular localization, signaling properties and structure/function relationships will be employed in gain- and loss-of-function experiments of LL. The human version of the Ll gene is 90% identical to that in the mouse, and is located in a region of the human genome that has been repeatedly linked to T2D in genetic studies. Ll could play a role in that linkage. Elucidation of the mechanisms by which LL loss-of-function produces diabetes-susceptibility may reveal novel pathways critical to cell development and survival in the context of insulin resistance and gluco-/lipotoxicity imposed by obesity.
Nearly twenty one million people in the United States (over 7% of the population), and over 246 million people worldwide are afflicted with type 2 diabetes (T2D);about 54 million Americans have pre-diabetes. If the incidence of T2D continues to increase at the present rate, one in three Americans, and 1 in 2 minorities, born in 2000 will develop diabetes in their lifetime. This project will analyze the molecular function of a newly discovered gene that may account for some aspects of diabetes susceptibility in humans.
