Calcium signaling and diabetes

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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

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Calcium signaling and diabetes

  1. 1. Calcium signaling in the islets<br />Md. Shahidul Islam<br />Karolinska Institutet<br />Stockholm, Sweden<br />shaisl@ki.se<br />
  2. 2. Ca++ homeostasome<br />Schwaller B 2011 Adv Exp Med Biol. (in press)<br />
  3. 3. Ca++ signaling is a productive area of research <br />Exponential technology<br />Fluorescent Ca++ probes<br />Cameleons<br />Lasers<br />Confocal and multiphoton microscopy<br />Information technology<br />Rodent islets, and insulinoma cell lines<br />Molecular techniques, and knockout models<br />Publish of perish atmosphere<br />
  4. 4. LocalCa++Signaling: Ca++puffs, Ca++ sparks, Ca++ quarks<br />
  5. 5.
  6. 6. Filter bubble concept<br />-EliPariser<br />What gets in through the filter?<br />
  7. 7. Information<br />receptor<br />Information ligands<br />
  8. 8.
  9. 9. Mouse beta cells are bursting<br />Henquin J.C. et al 1994<br />
  10. 10. A growing list of ion channels dictate electrical activity<br />KATP channel<br />L-Type voltage-gated Ca++ channel<br />T-Type voltage-gated Ca++ channel<br />P/Q Type voltage-gated Ca++ channel<br />Voltage-gated Na+ channels<br />“Leak current” channels<br />Voltage-gated K+ channels<br />SK4 Ca++-activated K+ channels<br />BK Ca++-activated K+ channels<br />HERG channels<br />volume-sensitiveanioncurrents<br />
  11. 11. Model simulation of bursting, Ca++ changes, and ATP/ADP ratio <br />Bertram R et al, Adv. Exp. Med. Biol. 2010, 654:261<br />
  12. 12. The beta-cell electrophysiology<br />is a state of an<br />interacting complex network<br />of components rather than<br />a sequence of events leading to the<br />burst phenomenon. <br />
  13. 13. Lancet 2011 online<br />The number of people with diabetes increased from 153 million in 1980, <br />to 347 million in 2008<br />
  14. 14. “There is nothing more pointless, <br />or common, <br />than doing the same things, <br />and expecting different results” <br />-Gordon Livingstone<br />
  15. 15. Human islets live here,<br />not here,<br />
  16. 16. Human beta cells live in an environment of about 5-8 mM glucose<br />Tsukuda K et al 2009 Diabetes Technol.Ther. 11:499<br />
  17. 17. 15 mM<br />12 mM<br />6 mM<br />6 mM<br />3 mM<br />3 mM<br />3 mM<br />3 mM<br />Glucose stimuli<br />
  18. 18. I nMOrexin A does not signal through IP3R<br />100 nM does<br />Peltonen H M 2009, BBRC, 385:408<br />
  19. 19. Human beta cells are in a READY mode <br />6 mM Glucose<br />Braun M et al, 2008, Diabetes 57:1618<br />
  20. 20. Human Beta cells are in a READY mode <br />Insulin secretionNormalObese<br />Basal 124 nmol/day 212 nmol/day<br />On three mixed meal 248 nmol/day 447 nmol/day<br />Polonsky K. S. et al, 1988, J Clin Invest. 81:435<br />
  21. 21. Yin and yang of initial membrane<br />potential of beta cells<br />Na+<br />K+<br />Ca++<br />
  22. 22. KATP channels tune the beta cells<br />
  23. 23. Ashcroft and Rorsman 2004, Hum Mol Genet, 13:R21<br />
  24. 24. With glibenclamide<br />Without glibenclamide<br />(OFF mode)<br />Effect of Glibenclamide on insulin secretion in <br />subjects with activating mutation in the KCNJ11<br />gene encoding the Kir6.2 subunit of the KATP channel<br />Pearson,E.R. et al 2006. NEJM 355:467<br />
  25. 25. Degree of READINESS<br />Of the B eta Cells<br />Fasting P-Glucose<br />91-99 mg/dl<br />87-90 mg/dl<br /><86 mg/dl<br />
  26. 26. Fasting Plasma Glucose and Risk for Developing Diabetes<br />Tirosh A et al, 2005. NEJM 353:14<br />
  27. 27. Lancet 2011<br />Worldwide, mean fasting plasma glucose concentrations have risen on average by 0·08 mmol/L per decade (standard ised for age).<br />
  28. 28. The highly tuned beta cells<br />Makes people fat over the years<br />Die of overwork over the years<br />
  29. 29. Overwork over years lead to organ failure<br />Heart fails when it overworks<br />Kidney fails when it overworks<br />Islets fail when they overwork<br />
  30. 30. Mean relative beta cell volume in non-diabetic and diabetic subjects<br />Butler AE 2003 Diabetes 52:102<br />
  31. 31. Ashcroft and Rorsman 2004, Hum Mol Genet, 13:R21<br />
  32. 32. Transient Receptor Potential<br />From: Minke, B. & Cook, B. Physiol Rev.82, 429-472 (2002). <br />
  33. 33.
  34. 34. 1997<br />TRPM2<br />2009<br />Bari M R et al, 2009, <br />J Cell Mol. Med. 13:3260<br />
  35. 35. 1986<br />Marigo V 2009, Mol Cell Endocrinol 299: 194<br />
  36. 36. Plasma insulin response and Ca++ signaling in the islets<br />in TRPM5 knockout mice<br />Colsoul B et al, 2010, PNAS, 107:5208<br />
  37. 37. http://tinyurl.com/pdftrp<br />http://bit.ly/calsig<br />
  38. 38. Effect of Glibenclamide on insulin secretion in <br />subjects with activating mutation in the KCNJ11<br />gene encoding the Kir6.2 subunit of the KATP channel<br />Pearson,E.R. et al 2006. NEJM 355:467<br />
  39. 39. Islam MS 98 Diabetologia41:A37<br />
  40. 40. Islam MS 98 Diabetologia41:A37<br />
  41. 41. Voltage-gated Ca2+ channels<br />Ca2+-gated Ca2+ channels<br />IP3 receptor<br />RyanodineRecpror<br />
  42. 42. CICR is the language<br />of channel chatter<br />
  43. 43. Gustafsson AJ et al Läkartidningen 2005, 102:3214-9<br />
  44. 44.
  45. 45. Beyond the KATP channel<br />Beyond the ATP/ADP ratio<br />Beyond the voltage-gated Ca++ channels<br />Beyond the mouse beta cells<br />Beyond the existing models<br />Beyond the insulinoma cells<br />Beyond the non-physiological resting state<br />Beyond the mathematical simulations<br />Beyond all that<br />It´s different out there<br />
  46. 46. “I may be wrong”<br />Kathryn Schulz<br />“Wrongologist<br />

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