Type 2 diabetes affects 9% of the United States population. Impairments in ?-cell secretory function and survival are critical for the development of hyperglycemia. The mechanisms underlying ?-cell dysfunction and death remain incompletely understood. Improving our knowledge of these is critical for the development of better therapies for this debilitating disease. The islet extracellular matrix (ECM), synthesized predominantly by islet endothelial cells, is a critical source of signals that impinge on the ?-cell; ECM components laminin and hyaluronan normally enhance insulin release and/or ?-cell survival. Our preliminary data in islets from human type 2 diabetes and animal models show for the first time that laminin production is decreased, hyaluronan is disrupted/fragmented, and expression of enzymes that can degrade or destabilize laminin and hyaluronan is increased. Our preliminary data also show these findings can be reproduced by culturing primary islet endothelial cells in high glucose. Further, we can reproduce ?-cell dysfunction by culturing ?-cells on this ?diabetic? ECM or culturing them under conditions of laminin ?4-deficiency or hyaluronan fragmentation. Thus, we hypothesize that in type 2 diabetes, reduced laminin production and/or signaling and increased hyaluronan fragmentation in islet endothelial-derived ECM impairs islet ?-cell secretory function and survival. Our studies will encompass the following three specific aims:
Specific Aim 1 : To determine whether overexpression/inhibition of laminin ?4 signaling improves/impairs insulin release. We will use viral overexpression to determine if restoration of normal laminin ?4 levels in ECM from ?diabetic? islet endothelial cells improves insulin release and/or ?-cell survival in vitro. We will also knock out the laminin receptor subunit integrin ?6 in ? cells of adult, non-diabetic mice and assess insulin release in vivo.
Specific Aim 2 : To determine the mechanism(s) by which hyaluronan fragmentation in the islet ECM contributes to impaired insulin release and ?-cell survival. Fragmented hyaluronan has been shown, in non- islet cells, to be proinflammatory, activating toll-like receptors (TLR) and NF?B. Here, we will determine if fragmented hyaluronan in islet ECM impairs ?-cell function and survival via TLR2/4 and NF?B activation.
Specific Aim 3. To determine whether upregulation of enzymes that destabilize hyaluronan (ADAMTSs) and degrade laminin (MMPs) precedes the onset of diabetes. Using RNA-Seq, we will determine if increases in islet endothelial expression of ADAMTS and MMP family members precede diabetes and/or increase with diabetes duration in UCD-T2DM rats and are increased in T2D human islets. We will validate observed changes at the protein and activity levels, and modulate expression of these enzymes in islet endothelial-derived ECM to evaluate their effects on insulin release and ?-cell survival.

Public Health Relevance

Type 2 diabetes is increasingly common in the United States, affecting 9% of the population. Pancreatic islet ?-cell dysfunction and death are critical elements of the pathogenesis of type 2 diabetes, but the mechanism(s) underlying these changes remain unclear. Islet ?-cells exist in close proximity to an extracellular matrix (ECM), which provides critical signals for secretory function and survival. Our preliminary data show that the ECM components laminin and hyaluronan are decreased or disrupted/fragmented, respectively, in type 2 diabetes and/or animal models thereof. We will use human islets and animal models to determine whether the disruption of these two ECM molecules contribute to impaired ?-cell function and survival. These studies will provide novel targets for interventions aimed at preventing ?-cell dysfunction and death, which can ultimately be applied to treat patients with type 2 diabetes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Cellular Aspects of Diabetes and Obesity Study Section (CADO)
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Sato, Sheryl M
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Seattle Institute for Biomedical/Clinical Research
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Hogan, Meghan F; Hull, Rebecca L (2017) The islet endothelial cell: a novel contributor to beta cell secretory dysfunction in diabetes. Diabetologia 60:952-959
Hogan, Meghan F; Liu, Amy W; Peters, Michael J et al. (2017) Markers of Islet Endothelial Dysfunction Occur in Male B6.BKS(D)-Leprdb/J Mice and May Contribute to Reduced Insulin Release. Endocrinology 158:293-303
Hull, Rebecca L; Willard, Joshua R; Struck, Matthias D et al. (2017) High fat feeding unmasks variable insulin responses in male C57BL/6 mouse substrains. J Endocrinol 233:53-64
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Meier, Daniel T; Morcos, Mary; Samarasekera, Thanya et al. (2014) Islet amyloid formation is an important determinant for inducing islet inflammation in high-fat-fed human IAPP transgenic mice. Diabetologia 57:1884-8

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