Calcium signaling in the islets, roles of the ATP-sensitive potassium channels (KATP-channels) and the TRP channels in the context of the pathogenesis of diabetes. The ready mode, off mode and the on mode of the beta cells; the role of the KATP channels in tuning the beta cells and fate of the highly tuned beta cells

1. Calcium signaling in the islets Md. Shahidul Islam Karolinska Institutet Stockholm, Sweden shaisl@ki.se

2. Ca++ homeostasome Schwaller B 2011 Adv Exp Med Biol. (in press)

3. Ca++ signaling is a productive area of research Exponential technology Fluorescent Ca++ probes Cameleons Lasers Confocal and multiphoton microscopy Information technology Rodent islets, and insulinoma cell lines Molecular techniques, and knockout models Publish of perish atmosphere

4. LocalCa++Signaling: Ca++puffs, Ca++ sparks, Ca++ quarks

6. Filter bubble concept -EliPariser What gets in through the filter?

7. Information receptor Information ligands

9. Mouse beta cells are bursting Henquin J.C. et al 1994

10. A growing list of ion channels dictate electrical activity KATP channel L-Type voltage-gated Ca++ channel T-Type voltage-gated Ca++ channel P/Q Type voltage-gated Ca++ channel Voltage-gated Na+ channels “Leak current” channels Voltage-gated K+ channels SK4 Ca++-activated K+ channels BK Ca++-activated K+ channels HERG channels volume-sensitiveanioncurrents

11. Model simulation of bursting, Ca++ changes, and ATP/ADP ratio Bertram R et al, Adv. Exp. Med. Biol. 2010, 654:261

12. The beta-cell electrophysiology is a state of an interacting complex network of components rather than a sequence of events leading to the burst phenomenon.

13. Lancet 2011 online The number of people with diabetes increased from 153 million in 1980, to 347 million in 2008

14. “There is nothing more pointless, or common, than doing the same things, and expecting different results” -Gordon Livingstone

15. Human islets live here, not here,

16. Human beta cells live in an environment of about 5-8 mM glucose Tsukuda K et al 2009 Diabetes Technol.Ther. 11:499

17. 15 mM 12 mM 6 mM 6 mM 3 mM 3 mM 3 mM 3 mM Glucose stimuli

18. I nMOrexin A does not signal through IP3R 100 nM does Peltonen H M 2009, BBRC, 385:408

19. Human beta cells are in a READY mode 6 mM Glucose Braun M et al, 2008, Diabetes 57:1618

20. Human Beta cells are in a READY mode Insulin secretionNormalObese Basal 124 nmol/day 212 nmol/day On three mixed meal 248 nmol/day 447 nmol/day Polonsky K. S. et al, 1988, J Clin Invest. 81:435

21. Yin and yang of initial membrane potential of beta cells Na+ K+ Ca++

22. KATP channels tune the beta cells

23. Ashcroft and Rorsman 2004, Hum Mol Genet, 13:R21

24. With glibenclamide Without glibenclamide (OFF mode) Effect of Glibenclamide on insulin secretion in subjects with activating mutation in the KCNJ11 gene encoding the Kir6.2 subunit of the KATP channel Pearson,E.R. et al 2006. NEJM 355:467

25. Degree of READINESS Of the B eta Cells Fasting P-Glucose 91-99 mg/dl 87-90 mg/dl <86 mg/dl

26. Fasting Plasma Glucose and Risk for Developing Diabetes Tirosh A et al, 2005. NEJM 353:14

27. Lancet 2011 Worldwide, mean fasting plasma glucose concentrations have risen on average by 0·08 mmol/L per decade (standard ised for age).

28. The highly tuned beta cells Makes people fat over the years Die of overwork over the years

29. Overwork over years lead to organ failure Heart fails when it overworks Kidney fails when it overworks Islets fail when they overwork

30. Mean relative beta cell volume in non-diabetic and diabetic subjects Butler AE 2003 Diabetes 52:102

31. Ashcroft and Rorsman 2004, Hum Mol Genet, 13:R21

32. Transient Receptor Potential From: Minke, B. & Cook, B. Physiol Rev.82, 429-472 (2002).

34. 1997 TRPM2 2009 Bari M R et al, 2009, J Cell Mol. Med. 13:3260

35. 1986 Marigo V 2009, Mol Cell Endocrinol 299: 194

36. Plasma insulin response and Ca++ signaling in the islets in TRPM5 knockout mice Colsoul B et al, 2010, PNAS, 107:5208

37. http://tinyurl.com/pdftrp http://bit.ly/calsig

38. Effect of Glibenclamide on insulin secretion in subjects with activating mutation in the KCNJ11 gene encoding the Kir6.2 subunit of the KATP channel Pearson,E.R. et al 2006. NEJM 355:467

39. Islam MS 98 Diabetologia41:A37

40. Islam MS 98 Diabetologia41:A37

41. Voltage-gated Ca2+ channels Ca2+-gated Ca2+ channels IP3 receptor RyanodineRecpror

42. CICR is the language of channel chatter

43. Gustafsson AJ et al Läkartidningen 2005, 102:3214-9

45. Beyond the KATP channel Beyond the ATP/ADP ratio Beyond the voltage-gated Ca++ channels Beyond the mouse beta cells Beyond the existing models Beyond the insulinoma cells Beyond the non-physiological resting state Beyond the mathematical simulations Beyond all that It´s different out there

46. “I may be wrong” Kathryn Schulz “Wrongologist