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Training Grant-
Biology of Aging

Michelle Kimple

Michelle E. Kimple

Ph.D., University of North Carolina
Assistant Professor, Department of Medicine- Endocrinology

Pharmacologically and Nutritionally Targeting the Diabetic Adult Beta-cell to Improve Function and Mass

In my post-doctoral research with Patrick Casey at Duke University, I demonstrated that the heterotrimeric G protein alpha subunit, Gαz, is a tonic inhibitor of adenylyl cyclase in pancreatic beta-cells, negatively regulating cAMP accumulation and blunting glucose-stimulated insulin secretion. Mice deficient in Gαz secrete more insulin in response to glucose and have improved glucose clearance as compared to wild-type mice. Gαz-null mice also exhibit an increased rate of beta-cell replication, whether stimulated by high-fat diet feeding, aging, or the synergy of the two. Thus, the Gαz signaling pathway may be one physiological and/or pharmacological target to augment both of the beta-cell problems in type 2 diabetes: decreased beta-cell function on a cellular basis, and decreased beta-cell mass on a organismal basis.

Pharmaceutically targeting a specific G protein signaling pathway requires knowing which cell-surface G-protein coupled receptor (GPCR) it is coupled to and which molecule is activating this receptor. Interestingly, we have recently characterized an endogenous molecule that is increased in diabetic mice and activates a β-cell receptor that is specifically coupled to Gαz: prostaglandin E2 (PGE2). PGE2 is the primary endogenous ligand of the E prostanoid receptor family, of which only EP3 is signals through inhibitory G proteins such as Gαz. First, we demonstrated that the EP3 receptor in the beta-cell is specifically coupled to Gαz and not other inhibitory G proteins. Next, we showed that both PGE2 production and islet EP3 expression are significantly up-regulated in mouse models of glucose-intolerance and type 2 diabetes, suggesting that this Gαz-coupled pathway might be playing a role in the islet pathophysiology of these conditions. We have shown that pharmacologically targeting the EP3 receptor in diabetic mouse islets can significantly improve diabetic beta-cell dysfunction, and have significant preliminary data that this will also hold true in type 2 diabetic human islets as well. The translational aspects to this project are a major aim of our current research program.

The essential ω-3 and ω-6 fatty acids serve as precursors to prostaglandins. PGE2 is derived strictly from dietary ω-6 fatty acids, which have become a significant portion of the world's food supply. This shift in dietary fatty acid composition drastically elevates the ω-6/ω-3 balance and may have profound health implications, as ω-6 fatty acids have been shown to produce more pro-inflammatory markers, whereas ω-3 fatty acids yield more anti-inflammatory markers. Additionally, ω-6 and ω-3 compete for common synthetic enzymes for desaturation and elongation and a higher ω-6/ω-3 ratio will promote the formation of longer chain ω-6 fatty acid derived eicosanoids, including PGE2. Therefore, it can be postulated that an increase in ω-3 fatty acids will shift the ω-6/ω-3 balance, reduce PGE2 formation, and enhance insulin secretion. However, the relationship between ω-3 fatty acid consumption in humans and glucose metabolism, particularly in diabetic populations, is controversial. Moreover, a diet high in ω-3 fatty acids appears to be protective against pancreatic cancer and type 1 and 2 diabetes in vitro and in rodent models, but the mechanism behind this protection is unknown. Therefore, we hypothesize that a diet high in ω-3 fatty acids will enhance insulin secretion and help normalize blood glucose in both control and diabetic mice through a reduction in the PGE2-mediated stimulation of β-cell EP3 receptor. Testing this hypothesis in cell culture, established mouse models, and human non-diabetic and type 2 diabetic patients is another major aim of our current research program.

Representative Publications
Yu, D., Yang, S.E., Miller, B.R., Wisinski, J.A., Sherman, D.S., Brinkman, J.A., Tomasiewicz, J.L., Cummings, N.E., Kimple, M.E., Cryns, V.L., & Lamming, D.W. (2018). Short-term methionine deprivation improves metabolic health via sexually dimorphic, mTORC1-independent mechanisms. FASEB Journal. Advance online publication.
View publication via DOI: DOI:10.1096/fj.201701211R

Fenske, R. J., & Kimple, M. E. (2018). Targeting dysfunctional beta-cell signaling for the potential treatment of type 1 diabetes mellitus. Experimental Biology and Medicine, 243(6), 586-591.
View publication via DOI: DOI:10.1177/1535370218761662

Cummings, N.E., Williams, E.M., Kasza, I., Konon, E.N., Schaid, M.D., Schmidt, B.A., ... Kimple, M.E., Alexander, C.M., Merrins, M.J., & Lamming, D.W. (2017). Restoration of metabolic health by decreased consumption of branched-chain amino acids. Journal of Physiology, 596(4), 623-645.
View publication via DOI: DOI:10.1113/JP275075

Neuman, J. C., Schaid, M. D., Brill, A. L., Fenske, R. J., Kibbe, C. R., Fontaine, D. A., ... Kimple, M. E. (2017). Enriching islet phospholipids with eicosapentaenoic acid reduces prostaglandin E2 signaling and enhances diabetic beta-cell function. Diabetes, 66(6), 1572-1585.
View publication via DOI: DOI:10.2337/db16-1362

Carboneau, B. A., Allan, J. A., Townsend, S. E., Kimple, M. E., Breyer, R. M., & Gannon, M. (2017). Opposing effects of prostaglandin E2 receptors EP3 and EP4 on mouse and human beta-cell survival and proliferation. Molecular Metabolism, 6(6), 548-559.
View publication via DOI: DOI:10.1016/j.molmet.2017.04.002

Fenske, R. J., Cadena, M. T., Harenda, Q. E., Wienkes, H. N., Carbajal, K., Schaid, M. D., ... & Kimple, M. E (2017). The inhibitory G protein alpha-subunit, Galphaz, promotes type 1 diabetes-like pathophysiology in NOD mice. Endocrinology, 158(6), 1645-1658.
View publication via DOI: DOI:10.1210/en.2016-1700

Hernandez, R., Graves, S. A., Gregg, T., VanDeusen, H. R., Fenske, R. J., Wienkes, H. N., ... Kimple, M. E., Merrins, M. J., & Cai, W. (2017). Radiomanganese pet detects changes in functional beta-cell mass in mouse models of diabetes. Diabetes, 66(8), 2163-2174.
View publication via DOI: DOI:10.2337/db16-1285

Neuman, J. C., Fenske, R. J., & Kimple, M. E. (2017). Dietary polyunsaturated fatty acids and their metabolites: Implications for diabetes pathophysiology, prevention, and treatment. Nutrition and Healthy Aging, 4(2), 127-140.
View publication via DOI: DOI:10.3233/nha-160004

Rodriguez, C. I., Castro-Perez, E., Prabhakar, K., Block, L., Longley, B. J., Wisinski, J. A., Kimple, M. E., & Setaluri, V. (2017). EPAC-RAP1 axis-mediated switch in the response of primary and metastatic melanoma to cyclic AMP. Molecular Cancer Research, 15(12), 1792-1802.
View publication via DOI: DOI:10.1158/1541-7786.mcr-17-0067

Schaid, M. D., Wisinski, J. A., & Kimple, M. E. (2017). The EP3 receptor/gz signaling axis as a therapeutic target for diabetes and cardiovascular disease. AAPS Journal, 19(5), 1276-1283.
View publication via DOI: DOI:10.1208/s12248-017-0097-1

Arriola Apelo, S. I., Neuman, J. C., Baar, E. L., Syed, F. A., Cummings, N. E., Brar, H. K., Pumper, C. P., Kimple, M. E., & Lamming, D. W. (2016). Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system. Aging Cell, 15(1), 28-38.
View publication via DOI: DOI:10.1111/acel.12405

Wisinski, J. A., & Kimple, M. E. (2016). Platelet dysfunction in type 1 diabetes: Stressing the thromboxanes. Diabetes, 65(2), 349-351.
View publication via DOI: DOI:10.2337/dbi15-0032

Gregg, T., Poudel, C., Schmidt, B. A., Dhillon, R. S., Sdao, S. M., Truchan, N. A., Baar, E. L., Fernandez, L. A., Denu, J. M., Eliceiri, K. W., Rogers, J. D., Kimple, M. E., Lamming, D. W., & Merrins, M. J. (2016). Pancreatic beta-cells from mice offset age-associated mitochondrial deficiency with reduced KATP channel activity. Diabetes, 65(9), 2700-10.
View publication via DOI: DOI:10.2337/db16-0432

Fontana, L., Cummings, N. E., Arriola Apelo, S. I., Neuman, J. C., Kasza, I., Schmidt, B. A., ... Merrins, M. J., Alexander, C. M., Kimple, M. E., & Lamming, D. W. (2016). Decreased consumption of branched chain amino acids improves metabolic health. Cell Reports, 16(2), 520-30.
View publication via DOI: DOI:10.1016/j.celrep.2016.05.092

Brill, A. L., Wisinski, J. A., Cadena, M. T., Thompson, M. F., Fenske, R. J., Brar, H. K., ... Kimple, M. E. (2016). (2016). Synergy between galphaz deficiency and glp-1 analog treatment in preserving functional beta-cell mass in experimental diabetes. Molecular Endocrinology, 30(5), 543-556.
View publication via DOI: DOI:10.1210/me.2015-1164

Busch, R. A., Heneghan, A. F., Pierre, J. F., Neuman, J. C., Reimer, C. A., Wang, X., ... Kimple, M. E. ... Kudsk, K. A. (2016). Bombesin preserves goblet cell resistin-like molecule beta during parenteral nutrition but not other goblet cell products. JPEN, 40(7), 1042-1049.
View publication via DOI: DOI:10.1177/0148607115585353

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

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

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

Truchan, N. A., Brar, H. K., Gallagher, S. J., Neuman, J. C., & Kimple, M. E. (2015). A single-islet microplate assay to measure mouse and human islet insulin secretion. Islets, 7(3), e1076607.
View publication via DOI: DOI:10.1080/19382014.2015.1076607

Oropeza, D., Jouvet, N., Budry, L., Campbell, J. E., Bouyakdan, K., Lacombe, J., Perron, G., Bergeron, V., Neuman, J. C., Brar, H. K., Fenske, R. J., Meunier, C., Sczelecki, S., Kimple, M. E., Drucker, D. J., Screaton, R. A., Poitout, V., Ferron, M., Alqu (2015). Phenotypic characterization of MIMIP-CreERT1Lphi mice with transgene-driven islet expression of human growth hormone. Diabetes, 64(11), 3798-3807.
View publication via DOI: DOI:10.2337/db15-0272

Neuman, J. C., Truchan, N. A., Joseph, J. W., & Kimple, M. E. (2014). A method for mouse pancreatic islet isolation and intracellular cAMP accumulation. Journal of Visualized Experiments, 88, e50374.
View publication via DOI: DOI:10.3791/50374

Kimple, M.E., Neuman, J.C., Linnemann, A.K., & Casey, P.J. (2014). Inhibitory G proteins and their receptors: Emerging therapeutic targets for obesity and diabetes. Experimental & Molecular Medicine, 46.
View publication via DOI: DOI:10.1038/emm.2014.40

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

Kimple, M.E., Brill, A.L., & Pasker, R.L. (2013). Overview of affinity tags for protein purification. Current Protocols in Protein Science, 73.
View publication via DOI: DOI:10.1002/0471140864.ps0909s73

Kimple, M. E., Moss, J. L., Brar, H. K., Rosa, T., Pasker, R. L., Truchan, N. A., Newgard, C. B., & Casey, P.J. (2012). Deletion of Gαz protects against diet-induced glucose intolerance via expansion of β-cell mass. Journal of Biological Chemistry, 287(24), 20344-55.
View publication via DOI: DOI:10.1074/jbc.M112.359745

Kelly, P., Bailey, C. L., Fueger, P. T., Newgard, C. B., Casey, P. J., & Kimple, M. E. (2010). Rap1 promotes multiple pancreatic islet cell functions and signals through mTOR complex 1 to enhance proliferation. Journal of Biological Chemistry, 285(21), 15777-85.
View publication via DOI: DOI:10.1074/jbc.M109.069112

Kimple, M. E., Hultman, R. C., & Casey, P. J. (2009). Signaling through Gz. In R. A. Bradshaw & E. Dennis (Eds.), Handbook of Cell Signaling (2nd Ed.) (pp. 1649-1653). Burlington, Massachusetts: Academic Press.

Kimple, M. E., Joseph, J. W., Bailey, C. L., Fueger, P. T., Hendry, I. A., Newgard, C. B., & Casey, P.J. (2008). Gαz negatively regulates insulin secretion and glucose clearance. Journal of Biological Chemistry, 283(8), 4560-7.
View publication via DOI: DOI:10.1074/jbc.M706481200

Pagliarini, D.J., Wiley, S.E., Kimple, M.E., Dixon, J.R., Kelly, P., Casey, P.J., ...Dixon, J.E. (2005). Involvement of a mitochondrial phosphatase in the regulation of ATP production and insulin secretion in pancreatic β cells. Molecular Cell, 19(2), 197-207.
View publication via DOI: DOI:10.1016/j.molcel.2005.06.008

Kimple, M. E., Nixon, A. B., Kelly, P., Bailey, C. L, Young, K. H., Fields, T.A., & Casey, P. J. (2005). A role for Gz in pancreatic islet beta-cell biology. Journal of Biological Chemistry, 280(36), 31708-31713.
View publication via DOI: DOI:10.1074/jbc.M506700200

Kimple, R. J., Kimple, M. E., Betts, L., Sondek, J., & Siderovski, D. P. (2002). Structural determinants for GoLoco-induced inhibition of nucleotide release by Gα subunits. Nature, 416, 878-881.
View publication via DOI: DOI:10.1038/416878a

Kimple, M.E., & Sondek, J. (2002). An affinity tag for protein purification and detection based on the disulfide-linked complex of InaD and NorpA. BioTechniques, 33(3), 578-590.

Kimple, M. E., Siderovski, D. P., & Sondek, J. (2001). Functional relevance of the disulfide-linked complex of the N-terminal PDZ domain of InaD with NorpA. EMBO Journal, 20(16), 4414-4422.
View publication via DOI: DOI:10.1093/emboj/20.16.4414

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