This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.It is well known that Type 2 diabetes mellitus (T2DM) is a major public health problem that only will become worse in the near future. The pathogenesis of type 2 diabetes (T2DM) is characterized by defects in insulin secretion and insulin action. In recent studies we have shown that hyperinsulinemia and insulin resistance are present long before the development of hyperglycemia in Mexican-American (MxAm) non-diabetic subjects genetically predisposed to T2DM, i.e. individuals with two T2DM parents have one of the highest prevalence rates of T2DM (~50%) among ethnic groups. With support of a Career Development Award, we have recently demonstrated that in MxAmFH+, a 4-day intravenous lipid infusion (Lyposyn III) that causes a physiologic elevation in the plasma FFA concentration (~500-700 mU/ml) significantly impairs insulin secretion. In contrast, the same lipid infusion in matched controls without a family history of T2DM (FH-) enhanced beta-cell function. This is the first clinical study showing that elevated plasma FFA concentration has a 'lipotoxic' effect on insulin secretion in non-diabetic subjects predisposed to develop T2DM. This observation in humans confirmed earlier reports in vitro and in vivo in animals that prolonged FFA exposure could be deleterious to beta-cell function.This novel finding represents a first step toward understanding the potential role of lipotoxicity in the development of pancreatic beta-cell failure in MxAmFH+. However, the precise role of beta cell lipotoxicity in relationship to other factors (i.e., glucose toxicity, insulin resistance, among others) in the pathogenesis of T2DM needs to be more carefully characterized. No studies have focused on the complex interaction between elevated plasma FFA levels, hyperglycemia, and insulin resistance on insulin secretion in MxAm subjects genetically predisposed to T2DM. We plan to expand these findings in the following areas: (1) the mechanisms by which an elevation in plasma FFA impairs beta-cell function in FH+ subjects, in particular how lipotoxicity interacts with other factors, such as glucose toxicity and insulin resistance; (2) to what degree beta-cell lipotoxicity is dependent upon the genetic build of FH+ subjects vs. acquired defects in insulin action (i.e., obesity and/or insulin resistance) that may contribute to exhaust insulin secretory reserve; and (3) whether ameliorating beta-cell lipotoxicity by pharmacologically lowering plasma FFA (i.e., with acipimox, an antilipolytic agent) can improve insulin secretion in subjects prone to beta-cell failure, such as MxAm FH+ subjects.In summary, the magnitude of the epidemic of T2DM requires a better understanding of the mechanisms that lead to beta cell failure and new strategies on how to prevent T2DM. This proposal will fill an important gap in our understanding of the factors that lead to beta-cell failure and T2DM in the MxAm population. The knowledge gained will serve as the backbone for prevention programs in subjects at high risk of developing T2DM.Subjects will receive liver and muscle MRS scans.
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