Type 2 diabetes is a common, debilitating disease affecting approximately 7% of the US population. A progressive decline in pancreatic islet 2-cell function, manifest as decreased insulin release, is a fundamental cause of type 2 diabetes, but the reasons for this decrease are not well understood. In addition to insulin secreting 2-cells, pancreatic islets contain an extensive capillary network to facilitate the release of insulin and other islet hormones into the blood. In diabetes, endothelial dysfunction affects several tissues and underlies the development of microvascular complications in organs such as the kidney and eye. In this proposal we will test the hypothesis that diabetic hyperglycemia-induced endothelial dysfunction in the islet contributes to impaired insulin release. We have demonstrated in our preliminary data that endothelial dysfunction, in the absence of hyperglycemia, is sufficient to cause impaired insulin release in transgenic mice that lack endothelial nitric oxide synthase (eNOS) and develop endothelial dysfunction. Additionally, we have shown that markers of endothelial dysfunction (decreased eNOS levels and increased oxidative/nitrative stress in endothelial cells) is present in islets of diabetic db/db mice as early as around one week after the onset of hyperglycemia. These data support our hypothesis and led us to proposed the following specific aims:
Specific Aim 1. To determine whether endothelial dysfunction is sufficient to impair insulin release. eNOS-/- mice that develop endothelial dysfunction and C57BL/6J control mice that do not will be studied for up to 12 weeks. We will determine insulin secretion in vivo and in vitro and will determine the time course of the development of impaired insulin release.
Specific Aim 2. To determine the time course of diabetes-induced endothelial dysfunction in the islet and the role of hyperglycemia in its development. We will first determine the time course of development of islet endothelial dysfunction by studying db/db mice prior to the onset of diabetes, after ~1 week of diabetes and after 8 weeks of diabetes. We will then prevent the development of hyperglycemia with phlorizin treatment to determine whether this can prevent islet endothelial dysfunction.
Specific Aim 3. To determine whether preventing endothelial dysfunction can improve insulin release in db/db diabetic mice. We will prevent the development of endothelial dysfunction in db/db mice by breeding db/+ mice with transgenic mice that overexpress eNOS. We will then determine insulin release in vivo.

Public Health Relevance

Type 2 diabetes is a devastating disease that affects 7% of the US population and whose prevalence is rapidly increasing. Decreased release of the hormone insulin from the pancreatic islet is required for the development of type 2 diabetes. The focus of this proposal is the novel hypothesis that endothelial dysfunction occurs in the pancreatic islet in diabetes and contributes to decreased insulin release.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1-EMNR-N (02))
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Appel, Michael C
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Seattle Institute for Biomedical/Clinical Research
United States
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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
Meier, Daniel T; Entrup, Leon; Templin, Andrew T et al. (2016) The S20G substitution in hIAPP is more amyloidogenic and cytotoxic than wild-type hIAPP in mouse islets. Diabetologia 59:2166-71
Mundinger, Thomas O; Mei, Qi; Foulis, Alan K et al. (2016) Human Type 1 Diabetes Is Characterized by an Early, Marked, Sustained, and Islet-Selective Loss of Sympathetic Nerves. Diabetes 65:2322-30
Meier, Daniel T; Tu, Ling-Hsien; Zraika, Sakeneh et al. (2015) Matrix Metalloproteinase-9 Protects Islets from Amyloid-induced Toxicity. J Biol Chem 290:30475-85
Hogan, Meghan F; Ravnskjaer, Kim; Matsumura, Shigenobu et al. (2015) Hepatic Insulin Resistance Following Chronic Activation of the CREB Coactivator CRTC2. J Biol Chem 290:25997-6006
Brissova, Marcela; Shostak, Alena; Fligner, Corinne L et al. (2015) Human Islets Have Fewer Blood Vessels than Mouse Islets and the Density of Islet Vascular Structures Is Increased in Type 2 Diabetes. J Histochem Cytochem 63:637-45
Hull, Rebecca L; Bogdani, Marika; Nagy, Nadine et al. (2015) Hyaluronan: A Mediator of Islet Dysfunction and Destruction in Diabetes? J Histochem Cytochem 63:592-603
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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