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Rebecca L. Hull, Ph.D.

Metabolism, Endocrinology and Nutrition

Research Associate Professor of Medicine


Focus

My research focuses on cellular mechanisms underlying islet secretory dysfunction and loss of beta-cell mass in diabetes. Our interest lies not only in beta-cell intrinsic mechanisms of failure, but also how other cell types in the islet modulate beta cell function and dysfunction. We are currently investigating the role of the islet endothelial cell in determining islet function, and studying the composition of the islet extracellular matrix under conditions of health and disease. Our studies utilize a variety of physiology, cell biology and histochemical approaches.


Research Interest

My laboratory studies mechanisms underlying islet dysfunction in models of type 2 diabetes. This research falls into three main areas:

Islet endothelial dysfunction. The islet has an extensive capillary network, comprising endothelial cells and other supporting cell types. We hypothesize that endothelial dysfunction affects the islet, as occurs in other vascular beds in diabetes, and that this may contribute to islet secretory dysfunction in diabetes. We use several animal and cell-based models to investigate this question.

Extracellular matrix in the islet. Normal islet function, and thus glucose homeostasis, requires communication among the many cell types that comprise the islet. The extracellular matrix is a key regulator of cell-cell signaling. Ongoing projects in this area include identification of novel islet extracellular matrix components and how these are dysregulated in models of diabetes.

Islet amyloid deposition. Islet amyloid deposits occur in the vast majority of individuals with type 2 diabetes and the extent of amyloid deposition is associated with decreased beta cell mass in humans and animal models. This has been a focus of my research for many years. Ongoing studies include understanding the role of heparan sulfate proteoglycans in islet amyloid formation.



Publications

Hull RL, Andrikopoulos S, Verchere CB, Vidal J, Wang F, Cnop M, Prigeon RL, Kahn SE, Increased dietary fat promotes islet amyloid formation and ß-cell secretory dysfunction in a transgenic mouse model of islet amyloid. Diabetes 52:372-9, 2003.

Potter-Perigo S, Hull RL, Tsoi C, Braun KR, Andrikopoulos S, Teague J, Verchere CB, Kahn SE, Wight TN. Proteoglycans synthesized and secreted by pancreatic islet ß-cells bind amylin. Arch Biochem Biophys, 413:182-190, 2003.

Hull RL, Kodama K, Utzschneider KM, Carr DB, Prigeon RL, Kahn SE: Dietary fat induced obesity results in ß-cell hyperplasia but not increased insulin release: evidence for specificity of impaired ß-cell adaptation. Diabetologia 48:1350-1358, 2005.

Hull RL, Shen Z, Watts MR, Kodama K, Carr DB, Utzschneider KM, Zraika S, Wang F, Kahn SE: Long term treatment with rosiglitazone and metformin reduce the extent of, but do not prevent, islet amyloid deposition in mice expressing the gene for human islet amyloid polypeptide. Diabetes 54:2235-2244, 2005.

Hull RL, Kodama K, Watts M, Shen Z, Utzschneider KM, Carr DB, Vidal J, Kahn SE: Genetic background determines the extent of islet amyloid formation in human islet amyloid polypeptide transgenic mice. Am J Physiol: Endo Metab, 289: E703-E709, 2005.

Zraika S, Hull RL, Udayasankar J, Utzschneider KM, Tong J, Gerchman F, Kahn SE: Glucose- and time-dependence of islet amyloid formation in vitro. Biochem Biophys Res Commun, 354:234-239, 2007. PMC1831460

Hull RL, Zraika S, Udayasankar J, Kisilevsky R, Szarek WA, Wight TN, Kahn SE: Inhibition of glycosaminoglycan synthesis and protein glycosylation with WAS-406 and azaserine result in reduced islet amyloid formation in vitro. Am J Physiol Cell Physiol, 293:C1586-C1593, 2007. PMC2365901.

Udayasankar J, Kodama K, Hull RL, Zraika S, Aston-Mourney K, Subramanian SL, Tong J, Faulenbach MV, Vidal J, Kahn SE: Amyloid formation results in recurrence of hyperglycemia following islet transplantation of human islet amyloid polypeptide transgenic mouse islets. Diabetologia, 52:145-153, 2009. PMC2734275.

Zraika S, Hull RL, Udayasankar J, Aston-Mourney K, Subramanian SL, Kisilevsky R, Szarek WA, Kahn SE: Oxidative stress is induced by islet amyloid formation and time-dependently mediates amyloid-induced beta cell apoptosis. Diabetologia, 52: 626-635, 2009. PMC2719780.

Hull RL, Zraika S, Udayasankar J, Aston-Mourney K, Subramanian SL, Kahn SE: Amyloid formation in hIAPP transgenic mouse islets and pancreas and human pancreas is not associated with endoplasmic reticulum stress. Diabetologia, 52:1102–1111, 2009. PMC2734275.

Masters SL, Dunne A, Subramanian SL, Hull RL, Tannahill GM, Sharp FA, Becker C, Franchi L, Yoshihara E, Chen Z, Mullooly N, Mielke LA, Harris J, Coll RC, Mills KH, Mok KH, Newsholme P, Nuñez G, Yodoi J, Kahn SE, Lavelle EC, O’Neill LA. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes. Nat Immunol, 11:897-904, 2010. PMC3103663

Jurgens CA, Toukatly MN, Fligner CL, Udayasankar J, Subramanian SL, Zraika S, Aston-Mourney K, Carr DB, Westermark P, Westermark GT, Kahn SE, Hull RL: Beta-cell loss in human type 2 diabetes is related to islet amyloid deposition. American Journal of Pathology, 178:2632-2640, 2011. PMC3123989.

Aston-Mourney K, Hull RL, Zraika S, Udayasankar J, Subramanian SL, Kahn SE: Exendin-4 increases islet amyloid deposition but offsets the resultant beta-cell toxicity in human islet amyloid polypeptide transgenic mouse islets. Diabetologia, 54:1756-1765, 2011. PMC3220951

Subramanian SL, Hull RL, Zraika S, Aston-Mourney K, Udayasankar J, Kahn SE: cJUN N-terminal kinase (JNK) activation mediates islet amyloid-induced beta cell apoptosis in cultured human islet amyloid polypeptide transgenic mouse islets. Diabetologia, 55:166-174, 2011. PMC3249975