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
5. 6. Filter bubble concept
-EliPariser
What gets in through the filter?
7. Information
receptor
Information ligands
8. 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 al2009 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
Basal124 nmol/day212 nmol/day
On three mixed meal248 nmol/day447 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