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1. Introduction
2. KATP channels and insulin secretion (1)
3. Structure of the KATP channel
4. Expression of Kir6.2 and SUR1
5. KATP channels link metabolism to electrical activity
6. Functional roles of the KATP channel
7. KATP channels are regulated by metabolism (1)
8. KATP channels are regulated by metabolism (2)
9. Metabolic regulation involves both subunits
10. Molecular model of the Kir6.2 tetramer
11. KATP channels are inhibited by ATP
12. Mg-nucleotides open channels via SUR NBDs (1)
13. Mg-nucleotides open channels via SUR NBDs (2)
14. Mg-nucleotides open channels via SUR NBDs (3)
15. SUR1 modulates Kir6.2
16. ATP blocks channels by binding to Kir6.2
17. ATP sensitivity lowers in open-cell configuration
18. KATP channels are activated by PIP2
19. KATP channels and insulin secretion (2)
20. Insulin is important in blood glucose homeostasis
21. Insulin is not a cure
22. Several types of diabetes
23. KATP channels and insulin secretion (2)
24. Therapeutic drugs regulate KATP channels
25. KATP channels and insulin secretion (3)
26. Familial hyperinsulinaemia
27. The KATP current is reduced in hyperinsulinism
28. Mechanism of action of HI mutations
29. SUR1 HI mutations change membrane expression
30. Some HI mutations are not activated by MgATP/ADP
31. Location of HI mutations in Kir6.2 model
32. Some HI mutations impair activation by PIP2
33. KATP channels and insulin secretion (4)
34. Neonatal diabetes
35. Location of ND mutations in Kir6.2 model (1)
36. Location of ND mutations in Kir6.2 model (2)
37. Increased KATP current in neonatal diabetes
38. Increased current in ND via different mechanisms
39. Mutations in the ATP-binding site
40. R50P is blocked less by ATP
41. Mutations that alter gating and ATP sensitivity (1)
42. I296L is less sensitive to ATP
43. Gating mutations increase intrinsic Po
44. I296 may form a cytosolic gate
45. Disease severity-KATP current correlation (Kir6.2)
46. Location of ND mutations in SUR1
47. Mutations that alters gating and ATP sensitivity (2)
48. Mutations altering MgATP hydrolysis (1)
49. Mutations altering MgATP hydrolysis (2)
50. Disease severity-KATP current correlation (SUR1)
51. KATP channels and diabetes
52. Implications for therapy
53. Sulphonylureas close KATP channels (1)
54. Sulphonylureas close most mutant KATP channels
55. Glucose control is improved on sulphonylureas
56. Oral glucose is more effective than IV glucose
57. Incretin response restored after treatment with SU
58. Can SU improve extra-pancreatic symptoms?
59. Glibenclamide enhances brain blood flow
60. Summary-KATP mutations and ND
61. NOT lost in translation
62. Kir6.2 mutations relevant to type 2 diabetes
63. Further reading
64. Acknowledgements

Topics Covered

• KATP channels and insulin secretion
• Structure of the KATP channel
• Functional roles
• Regulation by metabolism, nucleotides and lipids
• Overview of insulin secretion and diabetes
• Effects of loss-of-function KATP channel mutations
• Effects of gain-of-function KATP channel mutations
• Implications for the treatment of neonatal diabetes

Links

Series:

• Ion Channels

Categories:

• Biochemistry
• Cell Biology
• Metabolism & Nutrition

Therapeutic Areas:

• Cardiovascular & Metabolic

Talk Citation

Publication History

• Published on July 3, 2012

Financial Disclosures

• Prof. Frances Mary Ashcroft has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.