PROJECT SUMMARY Type 2 diabetes (T2D) burden rests disproportionately on ethnic minorities and economically distressed Appalachian communities. These populations also have high rates of low birth weight (LBW), which itself is an independent risk factor for T2D. One major cause of LBW is uteroplacental insufficiency and subsequent intrauterine growth restriction (IUGR). We model uteroplacental insufficiency in late gestation pregnant rats by ligating the uterine arteries. The growth-restricted offspring display diminished glucose-stimulated insulin secretion (GSIS), reduced islet capillary density, and decreased β-cell proliferation. We recently sequenced the IUGR islet transcriptome at 2 weeks of age, revealing increased expression of Hyaluronan Synthase 2 (Has2), which makes the extracellular matrix glycosaminoglycan hyaluronan (HA), and Cd44, the principal HA receptor. HA has size-dependent opposing effects on angiogenesis and inflammation, with native high molecular weight (HMW) HA being inhibitory and its enzymatic or oxidative fragmentation to LMW-HA being activating. Previous studies show increased HA in serum and adipose tissue of humans with T2D, and attenuating HA levels or CD44 activity improves insulin sensitivity. Studies have yet to quantify islet HA in T2D despite evidence that HA and HA-binding proteins are normal islet components and HA levels are altered in T2D. To determine whether HA contributes to IUGR-mediated islet dysfunction, we will determine HA abundance, size, and cell type-specific interactions. There is a paucity of research regarding effects of HA on β-cell function. However, HA modulates actin cytoskeleton dynamics via regulation of monomeric G-proteins in a variety of cell types, which if occurring in β-cells, can have profound effects on GSIS. Taken together, I hypothesize that HA abundance and size distribution are altered in IUGR islets, and HA size-specifically modulates GSIS in vitro. The goal of Specific Aim 1 is to determine whether IUGR alters abundance, size distribution and cell type-specific binding of HA in islets. The goal of Specific Aim 2 is to determine whether HA size-specifically alters GSIS in vitro via modulation of monomeric G-proteins and associated actin dynamics. In a move toward an interventional approach, we will examine whether pharmacological modulation of HA content normalizes GSIS in IUGR islets ex vivo. Successful completion of the proposed studies will fill a key knowledge gap regarding changes in islet- associated HA in T2D and provide strong evidence that HA negatively impacts β-cell function. These data will provide rationale and demonstrate feasibility for my future R01 grant application investigating an etiological role for HA in IUGR-mediated T2D.

PROJECT NARRATIVE Low birth weight is an independent risk factor for type 2 diabetes in adulthood. Populations that have high rates of low birth weight are the same populations with disproportionate incidence of type 2 diabetes. Using a well- characterized animal model and cell cultures studies, the proposed research shows that fetal growth restriction dysregulates an extracellular matrix molecular, hyaluronan, in islets which disrupts insulin secretion.