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Training Grant-
Biology of Aging

Dawn Belt Davis

Dawn Belt Davis

PhD, MD; University of Chicago
Associate Professor, Department of Medicine- Endocrinology

Pancreatic Beta Cell Mass Regulation and Diabetes Risk in Aging

The Davis Lab is interested in pancreatic beta cell biology. One area of focus is on understanding the mechanisms underlying the proliferative response in the beta cell. Beta cells are normally in a quiescent state, but can be stimulated to divide and expand in response to certain stimuli. When faced with insulin resistance and increased demand for insulin during pregnancy or in the setting of obesity, the beta cell will divide and overall beta cell mass is increased. Conversely, one of the defects in type 2 diabetes is a loss of overall beta cell mass leading to insufficient insulin production. In addition, type 1 diabetes is caused by autoimmune destruction of the beta cell, although there is evidence that a small population of beta cells may continue to attempt to replicate and expand in the setting of ongoing autoimmune attack. Understanding the mechanisms of beta cell proliferation that occur naturally in these adaptive settings may help us identify new therapeutic targets that can help drive beta cell proliferation in the patient with prediabetes, type 2 diabetes, a recent islet transplant, or potentially even type 1 diabetes in combination with immune therapies. Please see our recent review article on beta cell proliferation for more information.

A second area of interest is in beta cell apoptosis. Numerous stressors (including cytokines and endoplasmic reticulum stress) lead to increased beta cell apoptosis in early type 1 diabetes and in type 2 diabetes. We are also studying the ways that the pancreatic islet adapts to stressors and promotes beta cell survival.

Understanding the mechanisms of beta cell proliferation and survival that occur naturally in these adaptive settings may help us identify new therapeutic targets that can help drive beta cell proliferation in the patient with prediabetes, type 2 diabetes, a recent islet transplant, or potentially even type 1 diabetes in combination with immune therapies.

We currently have 2 main lines of investigation in the Davis Laboratory:

1) Tcf19: Tcf19 is a novel protein, known as Transcription Factor 19. We initially identified Tcf19 as a gene that was upregulated in response to obesity in mouse islet with expression that correlated with that of many known cell cycle genes. We have gone on to demonstrate that Tcf19 is necessary for beta cell proliferation and to protect from beta cell apoptosis. This work is highlighted in our 2013 AJP:Endocrinology & Metabolism paper. TCF19 has recently been associated with both type 1 and type 2 diabetes in genome wide association studies, suggesting it is a critically important gene in diabetes pathogenesis via a shared mechanism relevant to both type 1 and type 2 diabetes. Ongoing work on Tcf19 involves molecular and cellular studies to identify the role of this protein in gene transcription, cell cycle regulation, and pro-survival pathways. We have also generated both beta-cell specific and whole body Tcf19 knockout mice, to further understand the importance of this gene in beta cell growth, adaptive proliferation, and survival in various models of insulin resistance and diabetes.

2) Cholecystokinin: The hormone cholecystokinin (CCK) is classically known for its production in the intestine and its role in digestive function. However, CCK is also produced in the pancreatic islet. We have shown that islet-derived CCK is important in protecting beta-cells from apoptosis, as highlighted in our recent publication on transgenic mice that overexpress CCK in the beta cell. We recently found that the expression of CCK in the islet is regulated by another key hormone, glucagon-like peptide-1 (GLP-1) in a novel intra-islet incretin network that provides protection to the beta cell from apoptotic stressors. These findings are described in our recent article (Linneman et al., 2015) and mini-review Linnemann & Davis, 2016). Ongoing work in this area aims to understand the regulation of GLP-1 and CCK within the pancreatic islet and their role in protection from beta cell apoptosis.

Representative Publications
Davis, D.B., Khoraki, J., Ziemelis, M., Sirinvaravong, S., Han, J.Y., & Campos, G.M. (2018). Roux en Y gastric bypass hypoglycemia resolves with gastric feeding or reversal: Confirming a non-pancreatic etiology. Molecular Metabolism. Advance online publication.
View publication via DOI: DOI:10.1016/j.molmet.2017.12.011

Linnemann, A.K., Blumer, J., Marasco, M.R., Battiola, T.J., Umhoefer, H.M., Han, J.Y., Lamming, D.W., & Davis, D.B. (2017). Interleukin 6 protects pancreatic beta-cells from apoptosis by stimulation of autophagy. FASEB Journal, 31(9), 4140-4152.
View publication via DOI: DOI:10.1096/fj.201700061RR

Fontaine, D. A., & Davis, D. B. (2016). Attention to background strain is essential for metabolic research: C57bl/6 and the international knockout mouse consortium. Diabetes, 65(1), 25-33.
View publication via DOI: DOI:10.2337/db15-0982

Linnemann, A.K., & Davis, D.B. (2016). GLP-1 and CCK production and signaling in the pancreatic islet as an adaptive response to obesity. Journal of Diabetes Investigation, 7, 44-49.
View publication via DOI: DOI:10.1111/jdi.12465

Baan, M., Krentz, K. J., Fontaine, D. A., & Davis, D. B. (2016). Successful in vitro fertilization and generation of transgenics in Black and Tan Brachyury (BTBR) mice. Transgenic Research, 25(6), 847-854.
View publication via DOI: DOI:10.1007/s11248-016-9974-0

Linnemann, A. K., Neuman, J. C., Battiola, T. J., Wisinski, J. A., Kimple, M. E., & Davis, D. B (2015). Glucagon-like peptide-1 regulates cholecystokinin production in beta-cells to protect from apoptosis. Molecular Endocrinology, 29(7), 978-987.
View publication via DOI: DOI:10.1210/me.2015-1030

Oleson, B. J., McGraw, J. A., Broniowska, K. A., Annamalai, M., Chen, J., Bushkofsky, J. R., Davis, D. B., Corbett, J. A., & Mathews, C. E. (2015). Distinct differences in the responses of the human pancreatic ?-cell line EndoC-?H1 and human islets to proinflammatory cytokines. American Journal of Physiology - Regulatory, Integrative and Comparative Physiology, 309(5), R525-R534.
View publication via DOI: DOI:10.1152/ajpregu.00544.2014

Pierre, J. F., Neuman, J. C., Brill, A. L., Brar, H. K., Thompson, M. F., Cadena, M. T., Connors, K. M., Busch, R. A., Heneghan, A. F., Cham, C. M., Jones, E. K., Kibbe, C. R., Davis, D. B., Groblewski, G. E., Kudsk, K. A., & Kimple, M. E. (2015). The gastrin-releasing peptide analog bombesin preserves exocrine and endocrine pancreas morphology and function during parenteral nutrition. American Journal of Physiology - Gastrointestinal and Liver Physiology, 309(6), G431-G442.
View publication via DOI: DOI:10.1152/ajpgi.00072.2015

Baan, M., Kibbe, C. R., Bushkofsky, J. R., Harris, T. W., Sherman, D. S., & Davis, D. B. (2015). Transgenic expression of the human growth hormone minigene promotes pancreatic beta-cell proliferation. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, 309(7), R788-794.
View publication via DOI: DOI:10.1152/ajpregu.00244.2015

Weeks, A. C., Kimple, M. E., & Davis, D. B. (2015). The importance of exclusion of obstructive sleep apnea during screening for adrenal adenoma and diagnosis of pheochromocytoma. Journal of Investigative Medicine High Impact Case Reports, 3(3), 2324709615607062.
View publication via DOI: DOI:10.1177/2324709615607062

Kale, G., Pelley, E. M., & Davis, D. B. (2015). Giant bilateral adrenal myelolipomas in a patient with congenital adrenal hyperplasia. Endocrinology, Diabetes, and Metabolism: Case Reports, 150079.
View publication via DOI: DOI:10.1530/EDM-15-0079

Lavine, J. A., Kibbe, C. R., Baan, M., Sirinvaravong, S., Umhoefer, H. M., Engler, K. A., Meske, L. M., Sacotte, K. A., Erhardt, D. P., & Davis, D. B. (2015). Cholecystokinin expression in the B-cell leads to increased B-cell area in aged mice and protects from streptozotocin-induced diabetes and apoptosis. American Journal of Physiology - Endocrinology and Metabolism, 309(10), E819-E828.
View publication via DOI: DOI:10.1152/ajpendo.00159.2015

Campos, G.M., Ziemelis, M., Paparodis, R., Ahmed, M., Davis, D.B. (2014). Laparoscopic reversal of Roux-en-Y Gastric Bypass: Technique and utility for treatment of endocrine complications. Surgery for Obesity and Related Diseases, 10(1), 36-43.
View publication via DOI: DOI:10.1016/j.soard.2013.05.012

Linnemann, A. K., Baan, M., & Davis, D. B. (2014). Pancreatic beta-cell proliferation in obesity. Advances in Nutrition, 5(3), 278-288.
View publication via DOI: DOI:10.3945/an.113.005488

Krautkramer, K. A., Linnemann, A. K., Fontaine, D. A., Whillock, A. L., Harris, T. W., Schleis, G. J., . . . Kimple, M. E., & Davis, D. B. (2013). Tcf19 is a novel islet factor necessary for proliferation and survival in the ins-1 ?-cell line. American Journal of Physiology - Endocrinology and Metabolism, 305(5), E600-E610.
View publication via DOI: DOI:10.1152/ajpendo.00147.2013

Dhital, S.M., Shenker, Y., Meredith, M., Davis, D.B. (2012). A retrospective study comparing Neutral Protamin Hagedorn insulin with glargine insulin as basal therapy in prednisone-associated diabetes mellitus in hospitalized patients. Endocrine Practice, 18(5), 712-9.
View publication via DOI: DOI:10.4158/EP11371.OR

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