Profile

Maintaining physiological blood glucose levels is a complex process critically dependent on insulin secretion. Glucose stimulation of pancreatic I?-cells results in orchestrated electrical signaling that triggers insulin secretion. Our interest is in understanding how I?-cell ion channels are regulated during glucose stimulation and how these mechanisms become perturbed in diabetes.

Research on secretagogue modulation of I?-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 primary islet cells from animal models and humans. 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 I?-cell excitation-secretion pathway.

Publications

The following timeline graph is generated from all co-authored publications.

Featured publications are shown below:

  1. Simultaneous Real-Time Measurement of the β-Cell Membrane Potential and Ca(2+) Influx to Assess the Role of Potassium Channels on β-Cell Function. Vierra NC, Dickerson MT, Philipson LH, Jacobson DA (2018) Methods Mol Biol : 73-84
    › Primary publication · 29058185 (PubMed)
  2. TALK-1 channels control β cell endoplasmic reticulum Ca(2+) homeostasis. Vierra NC, Dadi PK, Milian SC, Dickerson MT, Jordan KL, Gilon P, Jacobson DA (2017) Sci Signal 10(497)
    › Primary publication · 28928238 (PubMed) · PMC5672804 (PubMed Central)
  3. A novel mechanism for Ca(2+)/calmodulin-dependent protein kinase II targeting to L-type Ca(2+) channels that initiates long-range signaling to the nucleus. Wang X, Marks CR, Perfitt TL, Nakagawa T, Lee A, Jacobson DA, Colbran RJ (2017) J Biol Chem 292(42): 17324-17336
    › Primary publication · 28916724 (PubMed) · PMC5655510 (PubMed Central)
  4. Chronic β-Cell Depolarization Impairs β-Cell Identity by Disrupting a Network of Ca(2+)-Regulated Genes. Stancill JS, Cartailler JP, Clayton HW, O'Connor JT, Dickerson MT, Dadi PK, Osipovich AB, Jacobson DA, Magnuson MA (2017) Diabetes
    › Primary publication · 28550109 (PubMed)
  5. Osteopontin activates the diabetes-associated potassium channel TALK-1 in pancreatic β-cells. Dickerson MT, Vierra NC, Milian SC, Dadi PK, Jacobson DA (2017) PLoS One 12(4): e0175069
    › Primary publication · 28403169 (PubMed) · PMC5389796 (PubMed Central)
  6. β-arrestin-2 is an essential regulator of pancreatic β-cell function under physiological and pathophysiological conditions. Zhu L, Almaça J, Dadi PK, Hong H, Sakamoto W, Rossi M, Lee RJ, Vierra NC, Lu H, Cui Y, McMillin SM, Perry NA, Gurevich VV, Lee A, Kuo B, Leapman RD, Matschinsky FM, Doliba NM, Urs NM, Caron MG, Jacobson DA, Caicedo A, Wess J (2017) Nat Commun : 14295
    › Primary publication · 28145434 (PubMed) · PMC5296650 (PubMed Central)
  7. Selective Small Molecule Activators of TREK-2 Channels Stimulate Dorsal Root Ganglion c-Fiber Nociceptor Two-Pore-Domain Potassium Channel Currents and Limit Calcium Influx. Dadi PK, Vierra NC, Days E, Dickerson MT, Vinson PN, Weaver CD, Jacobson DA (2017) ACS Chem Neurosci 8(3): 558-568
    › Primary publication · 27805811 (PubMed)
  8. G6PC2 Modulates Fasting Blood Glucose In Male Mice in Response to Stress. Boortz KA, Syring KE, Dai C, Pound LD, Oeser JK, Jacobson DA, Wang JC, McGuinness OP, Powers AC, O'Brien RM (2016) Endocrinology 157(8): 3002-8
    › Primary publication · 27300767 (PubMed) · PMC4967123 (PubMed Central)
  9. Extranuclear Actions of the Androgen Receptor Enhance Glucose-Stimulated Insulin Secretion in the Male. Navarro G, Xu W, Jacobson DA, Wicksteed B, Allard C, Zhang G, De Gendt K, Kim SH, Wu H, Zhang H, Verhoeven G, Katzenellenbogen JA, Mauvais-Jarvis F (2016) Cell Metab 23(5): 837-51
    › Primary publication · 27133133 (PubMed) · PMC4864089 (PubMed Central)
  10. Activation of FoxM1 Revitalizes the Replicative Potential of Aged β-Cells in Male Mice and Enhances Insulin Secretion. Golson ML, Dunn JC, Maulis MF, Dadi PK, Osipovich AB, Magnuson MA, Jacobson DA, Gannon M (2015) Diabetes 64(11): 3829-38
    › Primary publication · 26251404 (PubMed) · PMC4613976 (PubMed Central)
  11. Type 2 Diabetes-Associated K+ Channel TALK-1 Modulates β-Cell Electrical Excitability, Second-Phase Insulin Secretion, and Glucose Homeostasis. Vierra NC, Dadi PK, Jeong I, Dickerson M, Powell DR, Jacobson DA (2015) Diabetes 64(11): 3818-28
    › Primary publication · 26239056 (PubMed) · PMC4613978 (PubMed Central)
  12. TASK-1 Potassium Channels Limit Pancreatic α-Cell Calcium Influx and Glucagon Secretion. Dadi PK, Luo B, Vierra NC, Jacobson DA (2015) Mol Endocrinol 29(5): 777-87
    › Primary publication · 25849724 (PubMed) · PMC4415209 (PubMed Central)
  13. ER calcium release promotes mitochondrial dysfunction and hepatic cell lipotoxicity in response to palmitate overload. Egnatchik RA, Leamy AK, Jacobson DA, Shiota M, Young JD (2014) Mol Metab 3(5): 544-53
    › Primary publication · 25061559 (PubMed) · PMC4099508 (PubMed Central)
  14. Pancreatic β-cell-specific ablation of TASK-1 channels augments glucose-stimulated calcium entry and insulin secretion, improving glucose tolerance. Dadi PK, Vierra NC, Jacobson DA (2014) Endocrinology 155(10): 3757-68
    › Primary publication · 24932805 (PubMed) · PMC4164933 (PubMed Central)
  15. Direct activation of β-cell KATP channels with a novel xanthine derivative. Raphemot R, Swale DR, Dadi PK, Jacobson DA, Cooper P, Wojtovich AP, Banerjee S, Nichols CG, Denton JS (2014) Mol Pharmacol 85(6): 858-65
    › Primary publication · 24646456 (PubMed) · PMC4014665 (PubMed Central)
  16. Inhibition of pancreatic β-cell Ca2+/calmodulin-dependent protein kinase II reduces glucose-stimulated calcium influx and insulin secretion, impairing glucose tolerance. Dadi PK, Vierra NC, Ustione A, Piston DW, Colbran RJ, Jacobson DA (2014) J Biol Chem 289(18): 12435-45
    › Primary publication · 24627477 (PubMed) · PMC4007438 (PubMed Central)
  17. Ion channels and regulation of insulin secretion in human β-cells: a computational systems analysis. Fridlyand LE, Jacobson DA, Philipson LH (2013) Islets 5(1): 1-15
    › Primary publication · 23624892 (PubMed) · PMC3662377 (PubMed Central)
  18. Multiple functional polymorphisms in the G6PC2 gene contribute to the association with higher fasting plasma glucose levels. 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, MAGIC Investigators, Dadi PK, Jacobson DA, Froguel P, O'Brien RM (2013) Diabetologia 56(6): 1306-16
    › Primary publication · 23508304 (PubMed) · PMC4106008 (PubMed Central)
  19. β-Cell-specific protein kinase A activation enhances the efficiency of glucose control by increasing acute-phase insulin secretion. Kaihara KA, Dickson LM, Jacobson DA, Tamarina N, Roe MW, Philipson LH, Wicksteed B (2013) Diabetes 62(5): 1527-36
    › Primary publication · 23349500 (PubMed) · PMC3636652 (PubMed Central)
  20. G6PC2: a negative regulator of basal glucose-stimulated insulin secretion. Pound LD, Oeser JK, O'Brien TP, Wang Y, Faulman CJ, Dadi PK, Jacobson DA, Hutton JC, McGuinness OP, Shiota M, O'Brien RM (2013) Diabetes 62(5): 1547-56
    › Primary publication · 23274894 (PubMed) · PMC3636628 (PubMed Central)
  21. The physiological effects of deleting the mouse SLC30A8 gene encoding zinc transporter-8 are influenced by gender and genetic background. 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 (2012) PLoS One 7(7): e40972
    › Primary publication · 22829903 (PubMed) · PMC3400647 (PubMed Central)
  22. Channeling dysglycemia: ion-channel variations perturbing glucose homeostasis. Denton JS, Jacobson DA (2012) Trends Endocrinol Metab 23(1): 41-8
    › Primary publication · 22134088 (PubMed) · PMC3733341 (PubMed Central)
  23. Calcium-activated and voltage-gated potassium channels of the pancreatic islet impart distinct and complementary roles during secretagogue induced electrical responses. Jacobson DA, Mendez F, Thompson M, Torres J, Cochet O, Philipson LH (2010) J Physiol 588(Pt 18): 3525-37
    › Primary publication · 20643768 (PubMed) · PMC2988516 (PubMed Central)
  24. The granular chloride channel ClC-3 is permissive for insulin secretion. Deriy LV, Gomez EA, Jacobson DA, Wang X, Hopson JA, Liu XY, Zhang G, Bindokas VP, Philipson LH, Nelson DJ (2009) Cell Metab 10(4): 316-23
    › Primary publication · 19808024 (PubMed) · PMC2778193 (PubMed Central)
  25. A model of action potentials and fast Ca2+ dynamics in pancreatic beta-cells. Fridlyand LE, Jacobson DA, Kuznetsov A, Philipson LH (2009) Biophys J 96(8): 3126-39
    › Primary publication · 19383458 (PubMed) · PMC2718303 (PubMed Central)
  26. The alpha-cell conundrum: ATP-sensitive K+ channels and glucose sensing. Jacobson DA, Wicksteed BL, Philipson LH (2009) Diabetes 58(2): 304-6
    › Primary publication · 19171747 (PubMed) · PMC2628601 (PubMed Central)
  27. Action potentials and insulin secretion: new insights into the role of Kv channels. Jacobson DA, Philipson LH (2007) Diabetes Obes Metab : 89-98
    › Primary publication · 17919183 (PubMed)
  28. Glucose homeostasis, insulin secretion, and islet phospholipids in mice that overexpress iPLA2beta in pancreatic beta-cells and in iPLA2beta-null mice. Bao S, Jacobson DA, Wohltmann M, Bohrer A, Jin W, Philipson LH, Turk J (2008) Am J Physiol Endocrinol Metab 294(2): E217-29
    › Primary publication · 17895289 (PubMed) · PMC2268609 (PubMed Central)
  29. Kv2.1 ablation alters glucose-induced islet electrical activity, enhancing insulin secretion. Jacobson DA, Kuznetsov A, Lopez JP, Kash S, Ammälä CE, Philipson LH (2007) Cell Metab 6(3): 229-35
    › Primary publication · 17767909 (PubMed) · PMC2699758 (PubMed Central)
  30. TRP channels of the pancreatic beta cell. Jacobson DA, Philipson LH (2007) Handb Exp Pharmacol (179): 409-24
    › Primary publication · 17217070 (PubMed)
  31. Modulation of the pancreatic islet beta-cell-delayed rectifier potassium channel Kv2.1 by the polyunsaturated fatty acid arachidonate. Jacobson DA, Weber CR, Bao S, Turk J, Philipson LH (2007) J Biol Chem 282(10): 7442-9
    › Primary publication · 17197450 (PubMed) · PMC2044499 (PubMed Central)
  32. Downstream regulatory element antagonistic modulator regulates islet prodynorphin expression. Jacobson DA, Cho J, Landa LR, Tamarina NA, Roe MW, Buxbaum JD, Philipson LH (2006) Am J Physiol Endocrinol Metab 291(3): E587-95
    › Primary publication · 16621893 (PubMed)