METHOD, SYSTEM AND APPARATUS FOR CONTROL OF PANCREATIC BETA CELL FUNCTION TO IMPROVE GLUCOSE HOMEOSTASIS AND INSULIN PRODUCTION

• US 20120303098A1
• Filed: 03/30/2012
• Published: 11/29/2012
• Est. Priority Date: 12/17/2010
• Status: Active Grant

• Current Assignee: Neural Diabetes, LLC
• Original Assignee: Neural Diabetes Foundation, Inc.
• Inventors: PERRYMAN, Laura Tyler
• Granted Patent: US 8,903,501 B2
• Time in Patent Office: Days
• US Class Current: 607/62
• CPC Class Codes: A61N 1/36057 adapted for stimulating afferent nerves
• CPC Class Codes: A61N 1/36121 Production of neurotransmitters; Modulation of genes expression
• CPC Class Codes: A61N 1/372 Arrangements in connection with the implantation of stimulators
• CPC Class Codes: A61P 5/22 for decreasing, blocking or antagonising the activity of calcitonin

Abstract

The present invention provides methods, systems and apparatuses for effecting excitation or inhibition of small sensory nerve fibers, such as C-afferent fibers, by electrical stimulation of nerves innervating the pancreas in diabetic subjects. In an aspect the methods are directed to effecting insulin production and for the treatment of diabetes. This invention includes a closed or open loop feedback control system in which biomarker levels are monitored in order to direct electrical stimulation. An implantable or external neural stimulation device is also provided.

Claims

1. A method for preserving, restoring, or affecting pancreatic beta cell function in a subject comprising:

(a) electrically stimulating C-afferent sensory nerve fibers innervating pancreatic beta cells in a subject, in which said electrical stimulation serves to modulate secretion of calcitonin gene-related peptide (CGRP) from said C-afferent sensory nerve fibers;

(b) determining a level of a biomarker in said subject; and

(c) repeating said electrical stimulation as a function of the level of said biomarker.

2. The method of claim 1 in which said electrical stimulation is carried out using one or more electrodes or pairs thereof.

3. The method of claim 2 in which said one or more electrodes or pairs thereof are contained in an implantable lead that is positioned in said subject proximal to nerve tissue to be stimulated, including one or more leads positioned proximal to epidural spinal cord column at any vertebral segment from T7 to L1, dorsal root or dorsal root entry zone at any vertebral segments from T7 to L1, spinal nerve bundles leaving at any vertebral segments from T7 to L1, dorsal root ganglia bundles leaving at any vertebral segments from T7 to L1, peripheral nerves innervating endocrine pancreas beta cells, abdominal nerves or their cutaneous branches, a surface of endocrine pancreas, or combinations thereof.

4. The method of claim 3 in which said one or more leads are placed ipsilaterally or bilaterally.

5. The method of claim 2 in which said electrical stimulation is carried out via two or more electrode pairs contained in one or more implantable leads and said stimulation is carried out simultaneously or sequentially.

6. The method of claim 1 in which said electrical stimulation is effected wirelessly.

7. The method of claim 6 in which said electrical stimulation is effected using a wirelessly powered and controlled implanted lead.

8. The method of claim 1 in which the electrical stimulation is carried out at the following parameters:

a pulse width from 20 μ

sec to 1 ms, a frequency from 5 Hertz (Hz) to 10,000 Hz, and a power amplitude from 0.2 to 14 Volts (V) or 0.1 to 20 milliamps (mA).

9. The method of claim 8 in which the frequency of said electrical stimulation is between 5 and 10,000 Hz.

10. The method of claim 8 in which the frequency of said electrical stimulation is between 1 and 50 Hz.

11. The method of claim 10 in which the electrical stimulation is effected as a pulse having a pulse width in the range of about 250 to about 450 microseconds.

12. The method of claim 8 in which the frequency of said electrical stimulation is between 50 and 10,000 Hz.

13. The method of claim 12 in which the pulse width is in the range of about 450 to about 1000 microseconds.

14. The method of claim 1 in which said subject suffers from beta cell dysfunction or impairment.

15. The method of claim 1 in which said subject suffers from diabetes mellitus.

16. The method of claim 1 in which said subject suffers from Type I diabetes.

17. The method of claim 1 in which said subject suffers from Type II diabetes.

18. The method of claim 1 in which said subject suffers from diabetes insipidus.

19. The method of claim 1 in which said subject needs not adopt a lifestyle change.

20. The method of claim 1 in which said subject effects step (c).

21. The method of claim 1 in which step (c) is effected automatically.

22. The method of claim 1 in which said biomarker is selected from the group consisting of insulin, glucose, CGRP, abdominal skin blood flow, abdominal skin temperature and abdominal muscle activity.

23. The method of claim 1 in which said biomarker is selected from the group consisting of H1Ac and inflammatory cytokines.

24. The method of claim 22 in which:

(a) said biomarker is insulin and,

(i) said subject is a male subject and said level is below about 8.8 μ

IU/mL or said subject is a female subject and said level is below about 8.4 μ

IU/mL; and

said electrical stimulation is carried out to excite said C-afferent sensory nerve fibers innervating pancreatic beta cells;

or

(ii) said subject is a male subject and said level is above about 8.8 μ

IU/mL or said subject is a female subject and said level is above about 8.4 μ

IU/mL; and

said electrical stimulation is carried out to inhibit said C-afferent sensory nerve fibers innervating pancreatic beta cells;

Or,

(b) said biomarker is glucose; and

(i) said level is above about 120 mg/dL and said electrical stimulation is carried out to excite said C-afferent sensory nerve fibers innervating pancreatic beta cells;

or

(ii) said level is below about 100 mg/dL and said electrical stimulation is carried out to inhibit said C-afferent sensory nerve fibers innervating pancreatic beta cells.

26. The system of claim 23 in which the means for applying the electrical stimulation is positioned at or near dorsal root ganglion, splenic nerve, or dorsal column.

25. A system for preserving, restoring, or affecting pancreatic beta cell function in a subject, comprising:

means for detecting a biomarker level;

means for producing electrical stimulation as a function of the biomarker level; and

means for applying the electrical stimulation to stimulate C-afferent sensory nerve fibers innervating pancreatic beta cells in a subject, in which said electrical stimulation modulates a secretion of calcitonin gene-related peptide (CGRP) from said C-afferent sensory nerve fibers.

27. The system of claim 25 in which the means for producing performs electrical stimulation in an open loop format.

28. The system of claim 27 in which the means for producing performs electrical stimulation at predetermined intervals.

29. The system of claim 27 in which the means for producing performs electrical stimulation in a manner to maintain hormone levels at a predetermined concentration.

30. The system of claim 27 in which the open loop format comprises alerting the subject to a change in glucose homeostasis.

31. The system of claim 30 in which the subject is alerted when the biomarker level achieves a threshold level.

32. The system of claim 30 in which the electrical stimulation is initiated by the subject.

33. The system of claim 25 in which the means for producing performs electrical stimulation in a closed loop format.

34. The system of claim 33 in which the means for producing compares detected biomarker levels to at least one predetermined range, and the means for detecting transmits information about the biomarker level to the means for producing.

35. The system of claim 34 in which the means for producing is further configured to initiate adjustments to parameter settings of the electrical stimulation.

36. The system of claim 35 in which the means for producing is further configured to evaluate the efficacy of the electrical stimulation so that the parameter settings can be adjusted.

37. The system of claim 34 in which the means for producing compares the biomarker level to an historic or normative level and adjusts the electrical stimulation based on the comparison.

38. The system of claim 25 in which the means for applying is implantable in the subject.

39. The system of claim 35 in which the means for producing is implantable in the subject.

40. The system of claim 25 in which the system further comprises a means for receiving incoming signals from an external programmer.

41. The system of claim 40 in which the means for producing electrically processes the incoming signals and produces the electrical stimulation sequentially without the aid of a battery.

42. The system of claim 25 in which the electrical stimulation is charge-balanced.

43. The system of claim 25 in which the electrical stimulation is effected automatically.

44. An apparatus for preserving, restoring, or affecting pancreatic beta cell function in a subject, comprising:

a sensor that detects a biomarker level;

a pulse generator to produce electrical stimulation as a function of the biomarker level; and

an electrode lead or a multiple electrode lead array;

in which the pulse generator applies the electrical stimulation to the electrode lead or multiple electrode lead array;

in which the electrode lead or multiple electrode lead array comprises an electrode for applying the electrical stimulation to stimulate C-afferent sensory nerve fibers innervating pancreatic beta cells in a subject, in which said electrical stimulation modulates a secretion of CGRP from said C-afferent sensory nerve fibers.

45. The apparatus of claim 44 in which the electrode lead or multiple electrode lead array is positioned at or near dorsal root ganglion, splenic nerve, or dorsal column.

46. The apparatus of claim 44 in which the pulse generator is implantable in the subject.

47. The apparatus of claim 44 in which the apparatus further comprises a radio frequency antenna for receiving incoming signals from an external programmer.

48. The apparatus of claim 44 in which the biomarker is any one or more of insulin, glucose, calcitonin gene-related peptide, abdominal skin blood flow, abdominal skin temperature and abdominal muscle electrical activity.