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. KCNK3 Mutation Causes Altered Immune Function in Pulmonary Arterial Hypertension Patients and Mouse Models. West JD, Austin ED, Rizzi EM, Yan L, Tanjore H, Crabtree AL, Moore CS, Muthian G, Carrier EJ, Jacobson DA, Hamid R, Kendall PL, Majka S, Rathinasabapathy A (2021) Int J Mol Sci 22(9)
    › Primary publication · 34065088 (PubMed) · PMC8126011 (PubMed Central)
  2. Antagonistic epistasis of Hnf4α and FoxO1 metabolic networks through enhancer interactions in β-cell function. Kuo T, Du W, Miyachi Y, Dadi PK, Jacobson DA, Segrè D, Accili D (2021) Mol Metab : 101256
    › Primary publication · 34048961 (PubMed) · PMC8225970 (PubMed Central)
  3. A KCNK16 mutation causing TALK-1 gain of function is associated with maturity-onset diabetes of the young. Graff SM, Johnson SR, Leo PJ, Dadi PK, Dickerson MT, Nakhe AY, McInerney-Leo AM, Marshall M, Zaborska KE, Schaub CM, Brown MA, Jacobson DA, Duncan EL (2021) JCI Insight 6(13)
    › Primary publication · 34032641 (PubMed)
  4. Temporal Transcriptome Analysis Reveals Dynamic Gene Expression Patterns Driving β-Cell Maturation. Sanavia T, Huang C, Manduchi E, Xu Y, Dadi PK, Potter LA, Jacobson DA, Di Camillo B, Magnuson MA, Stoeckert CJ, Gu G (2021) Front Cell Dev Biol : 648791
    › Primary publication · 34017831 (PubMed) · PMC8129579 (PubMed Central)
  5. Sexually dimorphic roles for the type 2 diabetes-associated C2cd4b gene in murine glucose homeostasis. Mousavy Gharavy SN, Owen BM, Millership SJ, Chabosseau P, Pizza G, Martinez-Sanchez A, Tasoez E, Georgiadou E, Hu M, Fine NHF, Jacobson DA, Dickerson MT, Idevall-Hagren O, Montoya A, Kramer H, Mehta Z, Withers DJ, Ninov N, Gadue PJ, Cardenas-Diaz FL, Cruciani-Guglielmacci C, Magnan C, Ibberson M, Leclerc I, Voz M, Rutter GA (2021) Diabetologia 64(4): 850-864
    › Primary publication · 33492421 (PubMed) · PMC7829492 (PubMed Central)
  6. RIPK3-mediated inflammation is a conserved β cell response to ER stress. Yang B, Maddison LA, Zaborska KE, Dai C, Yin L, Tang Z, Zang L, Jacobson DA, Powers AC, Chen W (2020) Sci Adv 6(51)
    › Primary publication · 33355143 (PubMed)
  7. Tetraspanin-7 regulation of L-type voltage-dependent calcium channels controls pancreatic β-cell insulin secretion. Dickerson MT, Dadi PK, Butterworth RB, Nakhe AY, Graff SM, Zaborska KE, Schaub CM, Jacobson DA (2020) J Physiol 598(21): 4887-4905
    › Primary publication · 32790176 (PubMed) · PMC8095317 (PubMed Central)
  8. Lactate activation of α-cell K channels inhibits glucagon secretion by hyperpolarizing the membrane potential and reducing Ca entry. Zaborska KE, Dadi PK, Dickerson MT, Nakhe AY, Thorson AS, Schaub CM, Graff SM, Stanley JE, Kondapavuluru RS, Denton JS, Jacobson DA (2020) Mol Metab : 101056
    › Primary publication · 32736089 (PubMed) · PMC7479281 (PubMed Central)
  9. TRESK and TREK-2 two-pore-domain potassium channel subunits form functional heterodimers in primary somatosensory neurons. Lengyel M, Czirják G, Jacobson DA, Enyedi P (2020) J Biol Chem 295(35): 12408-12425
    › Primary publication · 32641496 (PubMed) · PMC7458809 (PubMed Central)
  10. Dapagliflozin Does Not Directly Affect Human α or β Cells. Dai C, Walker JT, Shostak A, Bouchi Y, Poffenberger G, Hart NJ, Jacobson DA, Calcutt MW, Bottino R, Greiner DL, Shultz LD, McGuinness OP, Dean ED, Powers AC (2020) Endocrinology 161(8)
    › Primary publication · 32428240 (PubMed) · PMC7375801 (PubMed Central)
  11. The pore-forming subunit MCU of the mitochondrial Ca uniporter is required for normal glucose-stimulated insulin secretion in vitro and in vivo in mice. Georgiadou E, Haythorne E, Dickerson MT, Lopez-Noriega L, Pullen TJ, da Silva Xavier G, Davis SPX, Martinez-Sanchez A, Semplici F, Rizzuto R, McGinty JA, French PM, Cane MC, Jacobson DA, Leclerc I, Rutter GA (2020) Diabetologia 63(7): 1368-1381
    › Primary publication · 32350566 (PubMed) · PMC7286857 (PubMed Central)
  12. Coregulator Sin3a Promotes Postnatal Murine β-Cell Fitness by Regulating Genes in Ca Homeostasis, Cell Survival, Vesicle Biosynthesis, Glucose Metabolism, and Stress Response. Yang X, Graff SM, Heiser CN, Ho KH, Chen B, Simmons AJ, Southard-Smith AN, David G, Jacobson DA, Kaverina I, Wright CVE, Lau KS, Gu G (2020) Diabetes 69(6): 1219-1231
    › Primary publication · 32245798 (PubMed) · PMC7243292 (PubMed Central)
  13. Neuronal L-Type Calcium Channel Signaling to the Nucleus Requires a Novel CaMKIIα-Shank3 Interaction. Perfitt TL, Wang X, Dickerson MT, Stephenson JR, Nakagawa T, Jacobson DA, Colbran RJ (2020) J Neurosci 40(10): 2000-2014
    › Primary publication · 32019829 (PubMed) · PMC7055140 (PubMed Central)
  14. Ion Channels of the Islets in Type 2 Diabetes. Jacobson DA, Shyng SL (2020) J Mol Biol 432(5): 1326-1346
    › Primary publication · 31473158 (PubMed) · PMC7720859 (PubMed Central)
  15. Structure-Activity Relationships, Pharmacokinetics, and Pharmacodynamics of the Kir6.2/SUR1-Specific Channel Opener VU0071063. Kharade SV, Sanchez-Andres JV, Fulton MG, Shelton EL, Blobaum AL, Engers DW, Hofmann CS, Dadi PK, Lantier L, Jacobson DA, Lindsley CW, Denton JS (2019) J Pharmacol Exp Ther 370(3): 350-359
    › Primary publication · 31201216 (PubMed) · PMC6691189 (PubMed Central)
  16. Glucose-mediated inhibition of calcium-activated potassium channels limits α-cell calcium influx and glucagon secretion. Dickerson MT, Dadi PK, Altman MK, Verlage KR, Thorson AS, Jordan KL, Vierra NC, Amarnath G, Jacobson DA (2019) Am J Physiol Endocrinol Metab 316(4): E646-E659
    › Primary publication · 30694690 (PubMed) · PMC6482666 (PubMed Central)
  17. Neurog3-Independent Methylation Is the Earliest Detectable Mark Distinguishing Pancreatic Progenitor Identity. Liu J, Banerjee A, Herring CA, Attalla J, Hu R, Xu Y, Shao Q, Simmons AJ, Dadi PK, Wang S, Jacobson DA, Liu B, Hodges E, Lau KS, Gu G (2019) Dev Cell 48(1): 49-63.e7
    › Primary publication · 30620902 (PubMed) · PMC6327977 (PubMed Central)
  18. Androgen excess in pancreatic β cells and neurons predisposes female mice to type 2 diabetes. Navarro G, Allard C, Morford JJ, Xu W, Liu S, Molinas AJ, Butcher SM, Fine NH, Blandino-Rosano M, Sure VN, Yu S, Zhang R, Münzberg H, Jacobson DA, Katakam PV, Hodson DJ, Bernal-Mizrachi E, Zsombok A, Mauvais-Jarvis F (2018) JCI Insight 3(12)
    › Primary publication · 29925687 (PubMed) · PMC6124401 (PubMed Central)
  19. Cystic fibrosis-related diabetes is caused by islet loss and inflammation. Hart NJ, Aramandla R, Poffenberger G, Fayolle C, Thames AH, Bautista A, Spigelman AF, Babon JAB, DeNicola ME, Dadi PK, Bush WS, Balamurugan AN, Brissova M, Dai C, Prasad N, Bottino R, Jacobson DA, Drumm ML, Kent SC, MacDonald PE, Powers AC (2018) JCI Insight 3(8)
    › Primary publication · 29669939 (PubMed) · PMC5931120 (PubMed Central)
  20. Synaptotagmin 4 Regulates Pancreatic β Cell Maturation by Modulating the Ca Sensitivity of Insulin Secretion Vesicles. Huang C, Walker EM, Dadi PK, Hu R, Xu Y, Zhang W, Sanavia T, Mun J, Liu J, Nair GG, Tan HYA, Wang S, Magnuson MA, Stoeckert CJ, Hebrok M, Gannon M, Han W, Stein R, Jacobson DA, Gu G (2018) Dev Cell 45(3): 347-361.e5
    › Primary publication · 29656931 (PubMed) · PMC5962294 (PubMed Central)
  21. TALK-1 reduces delta-cell endoplasmic reticulum and cytoplasmic calcium levels limiting somatostatin secretion. Vierra NC, Dickerson MT, Jordan KL, Dadi PK, Katdare KA, Altman MK, Milian SC, Jacobson DA (2018) Mol Metab : 84-97
    › Primary publication · 29402588 (PubMed) · PMC5870147 (PubMed Central)
  22. Cytokine-mediated changes in K channel activity promotes an adaptive Ca response that sustains β-cell insulin secretion during inflammation. Dickerson MT, Bogart AM, Altman MK, Milian SC, Jordan KL, Dadi PK, Jacobson DA (2018) Sci Rep 8(1): 1158
    › Primary publication · 29348619 (PubMed) · PMC5773563 (PubMed Central)
  23. Glucocorticoids Reprogram β-Cell Signaling to Preserve Insulin Secretion. Fine NHF, Doig CL, Elhassan YS, Vierra NC, Marchetti P, Bugliani M, Nano R, Piemonti L, Rutter GA, Jacobson DA, Lavery GG, Hodson DJ (2018) Diabetes 67(2): 278-290
    › Primary publication · 29203512 (PubMed) · PMC5780059 (PubMed Central)
  24. Simultaneous Real-Time Measurement of the β-Cell Membrane Potential and Ca 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) · PMC5927608 (PubMed Central)
  25. TALK-1 channels control β cell endoplasmic reticulum Ca 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)
  26. A novel mechanism for Ca/calmodulin-dependent protein kinase II targeting to L-type Ca 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)
  27. Chronic β-Cell Depolarization Impairs β-Cell Identity by Disrupting a Network of Ca-Regulated Genes. Stancill JS, Cartailler JP, Clayton HW, O'Connor JT, Dickerson MT, Dadi PK, Osipovich AB, Jacobson DA, Magnuson MA (2017) Diabetes 66(8): 2175-2187
    › Primary publication · 28550109 (PubMed) · PMC5521870 (PubMed Central)
  28. 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)
  29. 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)
  30. 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) · PMC5901755 (PubMed Central)
  31. 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)
  32. 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)
  33. 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)
  34. 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)
  35. 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)
  36. 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)
  37. 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)
  38. 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)
  39. 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)
  40. 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)
  41. 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)
  42. 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)
  43. 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)
  44. 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)
  45. 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)
  46. 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)
  47. 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)
  48. 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)
  49. 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)
  50. 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) · PMC5878925 (PubMed Central)
  51. 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)
  52. 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)
  53. TRP channels of the pancreatic beta cell. Jacobson DA, Philipson LH (2007) Handb Exp Pharmacol (179): 409-24
    › Primary publication · 17217070 (PubMed)
  54. 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)
  55. 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)