David Aaron Jacobson, Ph.D.

Assistant Professor

david.a.jacobson@vanderbilt.edu

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Faculty Appointments
Assistant Professor of Molecular Physiology and Biophysics
Education
Ph.D., Molecular and Medical Genetics, Oregon Health & Science University, Portland, OregonB.S., Washington State University, Pullman, Washington
Office Address
2213 Garland Avenue
Nashville, TN 37232-0615
Research Description
Maintaining physiological blood glucose levels is a complex process critically dependent on insulin secretion. Glucose stimulation of pancreatic beta-cells results in orchestrated electrical signaling that triggers insulin secretion. Our interest is in understanding how beta-cell ion channels are regulated during glucose stimulation and how these mechanisms become perturbed in diabetes.

Research on secretagogue modulation of beta-cell ion channels has primarily focused on the ATP sensitive potassium channel, KATP, which is an essential ion channel for normal glucose stimulated insulin secretion (GSIS). However, rodents with nonfunctional KATP channels and diabetic patients treated with blockers to KATP still exhibit glucose regulated insulin secretion. Thus KATP independent glucose responsive mechanisms play an important role during GSIS in humans. The mechanism(s) for this is unknown; however, as calcium is required for insulin secretion the mechanism must in part be coupled to calcium influx. Therefore, we are investigating the ion channels and their molecular mechanisms of regulation, independent of KATP, that help modulate secretagogue induced calcium influx and insulin secretion. The focus of this research is primarily on voltage-dependent calcium channels (CaV) and leak potassium channels. This research will test hypotheses concerning glucose and G-protein dependent regulation of islet electrical activity by CaV channel phosphorylation and modulation of islet membrane potential by leak potassium channels. These studies utilize molecular biology, genetics, fluorescent microscopy, and electrophysiology techniques on pancreatic islet-cells. Understanding how secretagogues regulate islet electrical activity distinctly from KATP may help to develop new therapies for diabetic patients that target specific elements of the beta-cell excitation-secretion pathway.


Research Keywords
Secretagogue induced mechanisms regulating pancreatic islet electrical activity and hormone secretion
Publications
Golson ML, Dunn JC, Maulis MF, Dadi PK, Osipovich AB, Magnuson MA, Jacobson DA, Gannon M. Activation of FoxM1 Revitalizes the Replicative Potential of Aged ß-Cells in Male Mice and Enhances Insulin Secretion. Diabetes [print-electronic]. 2015 Nov; 64(11): 3829-38. PMID: 26251404, PMCID: PMC4613976, PII: db15-0465, DOI: 10.2337/db15-0465, ISSN: 1939-327X.

Vierra NC, Dadi PK, Jeong I, Dickerson M, Powell DR, Jacobson DA. Type 2 Diabetes-Associated K+ Channel TALK-1 Modulates ß-Cell Electrical Excitability, Second-Phase Insulin Secretion, and Glucose Homeostasis. Diabetes [print-electronic]. 2015 Nov; 64(11): 3818-28. PMID: 26239056, PMCID: PMC4613978, PII: db15-0280, DOI: 10.2337/db15-0280, ISSN: 1939-327X.

Dadi PK, Luo B, Vierra NC, Jacobson DA. TASK-1 Potassium Channels Limit Pancreatic a-Cell Calcium Influx and Glucagon Secretion. Mol. Endocrinol [print-electronic]. 2015 May; 29(5): 777-87. PMID: 25849724, PMCID: PMC4415209, DOI: 10.1210/me.2014-1321, ISSN: 1944-9917.

Dadi PK, Vierra NC, Jacobson DA. Pancreatic ß-cell-specific ablation of TASK-1 channels augments glucose-stimulated calcium entry and insulin secretion, improving glucose tolerance. Endocrinology [print-electronic]. 2014 Oct; 155(10): 3757-68. PMID: 24932805, PMCID: PMC4164933, DOI: 10.1210/en.2013-2051, ISSN: 1945-7170.

Egnatchik RA, Leamy AK, Jacobson DA, Shiota M, Young JD. ER calcium release promotes mitochondrial dysfunction and hepatic cell lipotoxicity in response to palmitate overload. Mol Metab. 2014 Aug; 3(5): 544-53. PMID: 25061559, PMCID: PMC4099508, PII: S2212-8778(14)00092-1, DOI: 10.1016/j.molmet.2014.05.004, ISSN: 2212-8778.

Raphemot R, Swale DR, Dadi PK, Jacobson DA, Cooper P, Wojtovich AP, Banerjee S, Nichols CG, Denton JS. Direct activation of ß-cell KATP channels with a novel xanthine derivative. Mol. Pharmacol [print-electronic]. 2014 Jun; 85(6): 858-65. PMID: 24646456, PMCID: PMC4014665, PII: mol.114.091884, DOI: 10.1124/mol.114.091884, ISSN: 1521-0111.

Dadi PK, Vierra NC, Ustione A, Piston DW, Colbran RJ, Jacobson DA. Inhibition of pancreatic ß-cell Ca2+/calmodulin-dependent protein kinase II reduces glucose-stimulated calcium influx and insulin secretion, impairing glucose tolerance. J. Biol. Chem [print-electronic]. 2014 May 5/2/2014; 289(18): 12435-45. PMID: 24627477, PMCID: PMC4007438, PII: M114.562587, DOI: 10.1074/jbc.M114.562587, ISSN: 1083-351X.

Baerenwald DA, Bonnefond A, Bouatia-Naji N, Flemming BP, Umunakwe OC, Oeser JK, Pound LD, Conley NL, Cauchi S, Lobbens S, Eury E, Balkau B, Lantieri O, , Dadi PK, Jacobson DA, Froguel P, O'Brien RM. Multiple functional polymorphisms in the G6PC2 gene contribute to the association with higher fasting plasma glucose levels. Diabetologia [print-electronic]. 2013 Jun; 56(6): 1306-16. PMID: 23508304, PMCID: PMC4106008, DOI: 10.1007/s00125-013-2875-3, ISSN: 1432-0428.

Kaihara KA, Dickson LM, Jacobson DA, Tamarina N, Roe MW, Philipson LH, Wicksteed B. ß-Cell-specific protein kinase A activation enhances the efficiency of glucose control by increasing acute-phase insulin secretion. Diabetes [print-electronic]. 2013 May; 62(5): 1527-36. PMID: 23349500, PMCID: PMC3636652, PII: db12-1013, DOI: 10.2337/db12-1013, ISSN: 1939-327X.

Pound LD, Oeser JK, O'Brien TP, Wang Y, Faulman CJ, Dadi PK, Jacobson DA, Hutton JC, McGuinness OP, Shiota M, O'Brien RM. G6PC2: a negative regulator of basal glucose-stimulated insulin secretion. Diabetes [print-electronic]. 2013 May; 62(5): 1547-56. PMID: 23274894, PMCID: PMC3636628, PII: db12-1067, DOI: 10.2337/db12-1067, ISSN: 1939-327X.

Fridlyand LE, Jacobson DA, Philipson LH. Ion channels and regulation of insulin secretion in human ß-cells: a computational systems analysis. Islets. 2013 Jan; 5(1): 1-15. PMID: 23624892, PMCID: PMC3662377, PII: 24166, DOI: 10.4161/isl.24166, ISSN: 1938-2022.

Pound LD, Sarkar SA, Ustione A, Dadi PK, Shadoan MK, Lee CE, Walters JA, Shiota M, McGuinness OP, Jacobson DA, Piston DW, Hutton JC, Powell DR, O'Brien RM. The physiological effects of deleting the mouse SLC30A8 gene encoding zinc transporter-8 are influenced by gender and genetic background. PLoS ONE [print-electronic]. 2012; 7(7): e40972. PMID: 22829903, PMCID: PMC3400647, PII: PONE-D-11-24034, DOI: 10.1371/journal.pone.0040972, ISSN: 1932-6203.

Denton JS, Jacobson DA. Channeling dysglycemia: ion-channel variations perturbing glucose homeostasis. Trends Endocrinol. Metab [print-electronic]. 2012 Jan; 23(1): 41-8. PMID: 22134088, PMCID: PMC3733341, PII: S1043-2760(11)00152-4, DOI: 10.1016/j.tem.2011.09.004, ISSN: 1879-3061.

Jacobson DA, Mendez F, Thompson M, Torres J, Cochet O, Philipson LH. Calcium-activated and voltage-gated potassium channels of the pancreatic islet impart distinct and complementary roles during secretagogue induced electrical responses. J. Physiol. (Lond.) [print-electronic]. 2010 Sep 9/15/2010; 588(Pt 18): 3525-37. PMID: 20643768, PMCID: PMC2988516, PII: jphysiol.2010.190207, DOI: 10.1113/jphysiol.2010.190207, ISSN: 1469-7793.

Deriy LV, Gomez EA, Jacobson DA, Wang X, Hopson JA, Liu XY, Zhang G, Bindokas VP, Philipson LH, Nelson DJ. The granular chloride channel ClC-3 is permissive for insulin secretion. Cell Metab. 2009 Oct; 10(4): 316-23. PMID: 19808024, PMCID: PMC2778193, PII: S1550-4131(09)00262-9, DOI: 10.1016/j.cmet.2009.08.012, ISSN: 1932-7420.

Fridlyand LE, Jacobson DA, Kuznetsov A, Philipson LH. A model of action potentials and fast Ca2+ dynamics in pancreatic beta-cells. Biophys. J. 2009 Apr 4/22/2009; 96(8): 3126-39. PMID: 19383458, PMCID: PMC2718303, PII: S0006-3495(09)00502-5, DOI: 10.1016/j.bpj.2009.01.029, ISSN: 1542-0086.

Jacobson DA, Wicksteed BL, Philipson LH. The alpha-cell conundrum: ATP-sensitive K+ channels and glucose sensing. Diabetes. 2009 Feb; 58(2): 304-6. PMID: 19171747, PMCID: PMC2628601, PII: 58/2/304, DOI: 10.2337/db08-1618, ISSN: 1939-327X.

Bao S, Jacobson DA, Wohltmann M, Bohrer A, Jin W, Philipson LH, Turk J. Glucose homeostasis, insulin secretion, and islet phospholipids in mice that overexpress iPLA2beta in pancreatic beta-cells and in iPLA2beta-null mice. Am. J. Physiol. Endocrinol. Metab [print-electronic]. 2008 Feb; 294(2): E217-29. PMID: 17895289, PMCID: PMC2268609, PII: 00474.2007, DOI: 10.1152/ajpendo.00474.2007, ISSN: 0193-1849.

David A. Jacobson and Louis H. Philipson. Pancreatic Beta Cells in Health and Disease. [place unknown: publisher unknown]; 2008.

Jacobson DA, Philipson LH. Action potentials and insulin secretion: new insights into the role of Kv channels. Diabetes Obes Metab. 2007 Nov; 9 Suppl 2: 89-98. PMID: 17919183, PII: DOM784, DOI: 10.1111/j.1463-1326.2007.00784.x, ISSN: 1462-8902.

Jacobson DA, Kuznetsov A, Lopez JP, Kash S, Ammälä CE, Philipson LH. Kv2.1 ablation alters glucose-induced islet electrical activity, enhancing insulin secretion. Cell Metab. 2007 Sep; 6(3): 229-35. PMID: 17767909, PMCID: PMC2699758, PII: S1550-4131(07)00222-7, DOI: 10.1016/j.cmet.2007.07.010, ISSN: 1550-4131.

Jacobson DA, Weber CR, Bao S, Turk J, Philipson LH. Modulation of the pancreatic islet beta-cell-delayed rectifier potassium channel Kv2.1 by the polyunsaturated fatty acid arachidonate. J. Biol. Chem [print-electronic]. 2007 Mar 3/9/2007; 282(10): 7442-9. PMID: 17197450, PMCID: PMC2044499, PII: M607858200, DOI: 10.1074/jbc.M607858200, ISSN: 0021-9258.

Jacobson DA, Philipson LH. TRP channels of the pancreatic beta cell. Handb Exp Pharmacol. 2007; (179): 409-24. PMID: 17217070, DOI: 10.1007/978-3-540-34891-7_24, ISSN: 0171-2004.

Jacobson DA, Cho J, Landa LR, Tamarina NA, Roe MW, Buxbaum JD, Philipson LH. Downstream regulatory element antagonistic modulator regulates islet prodynorphin expression. Am. J. Physiol. Endocrinol. Metab [print-electronic]. 2006 Sep; 291(3): E587-95. PMID: 16621893, PII: 00612.2005, DOI: 10.1152/ajpendo.00612.2005, ISSN: 0193-1849.

Available Postdoctoral Position Details
Posted: 8/8/2015
Positions in islet biology and electrophysiology are currently available.