Hyaluronan as a Mediator of Intrauterine Growth Restriction-Induced Islet Dysfunction in Type 2 Diabetes

Grants and Contracts Details


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, in a variety of cell types, HA modulates actin cytoskeleton dynamics via regulation of monomeric G-proteins, which if occurring in β-cells, can have profound effects on GSIS. Taken together, I hypothesize that HA abundance and size distribution 1) is altered in IUGR islets and 2) size- dependently modulates GSIS in vitro. Specific Aim 1: To test the hypothesis that IUGR alters the abundance and size distribution of HA in islets and determine cell-specific binding. At 2 days, 2 weeks and 6 months of age, islets will be isolated and total HA quantified via ELISA and size distribution determined by gel electrophoresis. Using flow-cytometry and immunohistochemistry, we will determine leukocyte, endothelial, and β-cell specific HA binding and expression of the primary HA receptors CD44 and Receptor for Hyaluronan Mediated Motility (RHAMM). Specific Aim 2: To test the hypothesis that HA size-dependently disrupts GSIS in vitro via regulation of Rho family monomeric G-proteins and F-actin dynamics. Primary rat islet cells depleted of leukocytes will be cultured in the presence of exogenous HA of various relevant sizes and concentrations. Insulin secretion in response to glucose will be determined. Furthermore, we will determine whether HA- induced effects on GSIS are dependent upon Rho family GTPase activation and accompanied plasma membrane F-actin dynamics. Finally, we will determine whether exogenous modulation of HA content ex vivo normalizes GSIS in IUGR islets
Effective start/end date6/23/215/31/25


  • National Institute Diabetes & Digestive & Kidney: $573,750.00


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