U.S. patent application number 14/540720 was filed with the patent office on 2015-03-12 for method, system and apparatus for control of pancreatic beta cell function to improve glucose homeostasis and insulin production.
The applicant listed for this patent is Neural Diabetes, LLC. Invention is credited to Laura Tyler Perryman.
Application Number | 20150073510 14/540720 |
Document ID | / |
Family ID | 46245408 |
Filed Date | 2015-03-12 |
United States Patent
Application |
20150073510 |
Kind Code |
A1 |
Perryman; Laura Tyler |
March 12, 2015 |
Method, System and Apparatus for Control of Pancreatic Beta Cell
Function to Improve Glucose Homeostasis and Insulin Production
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.
Inventors: |
Perryman; Laura Tyler;
(Miami Beach, FL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Neural Diabetes, LLC |
Miami Beach |
FL |
US |
|
|
Family ID: |
46245408 |
Appl. No.: |
14/540720 |
Filed: |
November 13, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13436293 |
Mar 30, 2012 |
8903501 |
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14540720 |
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PCT/US2011/065653 |
Dec 16, 2011 |
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13436293 |
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61424546 |
Dec 17, 2010 |
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Current U.S.
Class: |
607/62 |
Current CPC
Class: |
A61N 1/372 20130101;
A61P 5/22 20180101; A61N 1/36057 20130101; A61N 1/36121
20130101 |
Class at
Publication: |
607/62 |
International
Class: |
A61N 1/372 20060101
A61N001/372 |
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.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 13/436,293, filed Mar. 30, 2012, which claims benefit of U.S.
provisional Patent Application 61/424,546, filed Dec. 17, 2010, and
is a continuation-in-part of co-pending International Patent
Application No. PCT/US2011/065653, filed Dec. 16, 2011. All of
these prior applications are incorporated by reference in their
entirety.
BACKGROUND OF INVENTION
[0002] The past quarter century has witnessed a dramatic increase
in the prevalence in subjects of a cluster of inter-related
metabolic disease states, primarily caused by obesity and immune
disease states, jeopardizing homeostasis and leading to the
diabetic state. The incidence of diabetes, with or without obesity,
has reached epidemic proportions, bringing with it impaired quality
of life and life span due to serious clinical co-morbidities such
as peripheral vascular and neuropathic disease, with or without
pain, ulcerative skin lesions often leading to infection, gangrene,
and amputation, vision loss, cardiac and renal failure and brain
disorders. Without question, chronic disease associated with
diabetes represents a heavy and growing burden to society in terms
of both direct healthcare costs that have reached catastrophic
levels and mortality rates (American Health Rankings, 2010
edition).
[0003] According to American Diabetes Association, as of 2010, 23.6
million children and adults, approximately 8% of population in the
United States (US) have diabetes, and over 57 million people are
clinically considered pre-diabetic in the US. According to United
HealthCare, based on current trends, 52% of the US adult population
could have pre-diabetes or diabetes by 2020 - up from an estimated
40% in 2010, resulting in costs estimated at $3.4 trillion for
diabetes-related care over the decade from 2010 to 2020. The
incidence of adolescent type 2 diabetes (T2D) has increased 10 fold
from 1982 to 1994 (Pinhas-Hamiel 1996). Over 25% of obese children
are considered glucose intolerant. Insulin resistance is related to
inflammation and obesity induces a state of chronic inflammation.
In obese states, adipose tissue secretes inflammatory agents such
as cytokines. Adipose tissue macrophages alter insulin sensitivity
in animal models. Obesity can be reframed as an inflammatory
disease, with macrophages acting at the junction between over
nutrition and inflammation.
[0004] Insulin is a peptide hormone produced by beta cells
(.beta.-cells) within the islets of Langerhans in the endocrine
pancreas. Insulin promotes glucose utilization, protein synthesis,
and the formation and storage of neutral lipids. Insulin is
generally required for the entry of glucose into muscle. Glucose
stimulates both the secretion and biosynthesis of insulin. Basal
insulin secretion is normally generated to synthesize glycogen from
glucose in the absence of glucose-stimulated insulin secretion.
[0005] Insulin and related insulin-like growth factors (IGF-1) give
trophic support to neural tissue; their receptors are present on
vanilloid transient receptor potential 1 (TRPV1) neurons, which are
essential in serving to maintain neural vitality and to promoting
regeneration of small sensory nerve fibers (Migdalis 1995;
Sathianathan 2003; VanBuren 2005). Moreover, TRPV 1 sensory neurons
appear to be down regulated in pre- and post-diabetic states
whereby they may fail to influence the appropriate release of
calcitonin gene-related peptide (CGRP) and other neuropeptides that
influence production of insulin from the beta cell (Okabayashi
1989). Reports of preclinical and clinical experiments state that
exogenous administration of CGRP or induction of the endogenous
release of CGRP from TRPV 1 sensory neurons by the application of a
TRPV1 antagonist results in the following relevant biological
responses: (1) pain signals conveyed to the central nervous system
(CNS); (2) a neurogenic inflammatory response consisting of
vasodilatation and edema formation, the latter not pronounced in
humans; (3) insulin secretion at appropriate concentrations and (4)
immunosuppression (Nagy 2004, Brain and Grant 2004; Razavi 2006).
In animal models of Type I diabetes (T1D) with insulinopenia,
targeted expression of CGRP to .beta.-cells or local intra-arterial
administration of substance P (SP), which is co-localized with CGRP
in TRPV1 sensory neurons but not as prevalent, has been reported to
prevent or ameliorate diabetes (Khachatryan 1997; Razavi 2006).
[0006] In addition to T1D, .beta.-cell dysfunction with impaired
insulin regulation is also observed in subjects in the early stages
of diabetes development, including impaired glucose tolerance (IGT)
and obesity-related hyperinsulinemia. In obese animals,
capsaicin-sensitive C-fibers containing TRPV1 sensory neurons are
markedly impaired, suggesting that intra-pancreatic neuronal
release of CGRP is reduced, which would further amplify .beta.-cell
dysfunction particularly if the pancreas is maladapted to high
levels of insulin (Ahren 2009). Paradoxically, the deletion or
degeneration of TRPV1 sensory neurons innervating the pancreas has
been reported to result in improved glucose homeostasis and insulin
production (Razavi 2006; Gram 2007).
[0007] Impaired CGRP release due to TRPV 1 sensory neuron pathology
and/or abnormal interaction in the pathway featuring insulin
production and the feedback function of the insulin receptor
exhibit an inflammatory (e.g. autoimmune) state and are seen in
T1D. It has been reported that increased concentrations of CGRP and
other neuropeptides can prevent T1D in experimental animal models
(Khachatryan 1997).
[0008] The release of CGRP to the .beta.-cell has been reported to
improve glucose and insulin homeostasis (see Gram 2005, 2007).
Animal experiments have reported that sensory nerve dysfunction may
contribute to hyperinsulinism, pre-diabetes initiation and
progression of diabetes (Carillo 2005; Leighton and Foot 1995).
Reports indicate that an imbalance in the insulin feedback control
system may be "normalized" through enhancing the local supply of
sufficient neuropeptides, including CORP (Razavi 2006, Khachatryan
1997). Ablation and administration of TRPV1 antagonists have been
reported to improve glucose and insulin homeostasis in subjects
with pre-diabetes or T2D. See Dosch et al., U.S. patent application
Ser. No. 12/478,898, incorporated by reference in its entirety
[0009] TRPV 1 sensory neurons have been shown to act as a central
controller of both .beta.-cell stress and T cell infiltration
(Dosch et. al). Elimination of neurons containing TRPV 1 by
capsaicin or resiniferatoxin (RTX) or transection of sensory nerves
innervating the pancreas and functional normalization of TRPV1
sensory neurons has the same net islet-specific outcomes:
prevention of diabetes, improved glucose; insulin homeostasis,
normalized insulin sensitivity and abrogation of insulitis or T1D
(Szallasi 1999).
[0010] Systemic delivery of pharmaceutical agents has been the
typical treatment for .beta.-cell dysfunction and the hyperglycemia
associated with diabetes; nevertheless, this approach can have
limited dosing and compliance issues, and serious side effects.
While non-insulin and insulin pharmacotherapies have been the
hallmark in controlling hyperglycemia, there are no therapies that
induce immunosuppression, and prevent/attenuate diabetes without
significant risk.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] FIG. 1 shows a diagram of a schematic view of a diabetic
subject (1) with an implanted neural stimulation electrode lead
(22) to stimulate the targeted sensory nerves through epidural
spinal cord (20) stimulation. Also shown is the option for a
receiver (16) at the end of the electrode lead and a typical
wireless pulse generator comprising a programmer (12), a cable (14)
and a antenna (18).
[0012] FIG. 2 shows a diagram of a cross-sectional view of a spinal
column demonstrating a typical implantation position of the distal
end of insulated electrode leads (31, 32), which terminate in
electrodes (33, 34) within the epidural space (41).
[0013] FIG. 3 shows a diagram of a cross-sectional view of a spinal
column demonstrating potential electrode placement at four
locations: dorsal columns (81, 82), dorsal roots and entry zone
(83, 84), dorsal root ganglia (85,86) and spinal nerves
(87,88).
[0014] FIG. 4 is a diagram of a cross sectional pathway overview of
a spinal column segment (201) at which an electrode lead (202) is
placed to stimulate the dorsal root ganglia (203) and/or spinal
nerves (210) from in the dermatome regions from spinal segments T7
to L1, which are sensory nerve fibers (204) that lead to the
pancreas (206).
[0015] FIG. 5 shows a diagram of a cross sectional pathway
overview, as in FIG. 4, but where the electrode lead (302) is
placed to stimulate the splenic nerve.
[0016] FIG. 6 shows a diagram of the various dermatome levels for
nerve fibers to various tissues of the typical body of a subject
(400). The viscera region is innervated by most of the dermatomes
ranging from T7 to L1 (401).
[0017] FIG. 7 shows various configurations for an electrode lead
array. Shown are (a) four electrode leads with 3 mm spacing (501),
(b) four electrode leads with spacing less than 3 mm (502), (c) 8
electrode leads with regular spacing on the lead (503) four
electrode leads with spacing that includes electrodes at the tip,
with remote anodes to create a wide area of volume conduction
(504), (d) electrode pads (505) and embedded paddle electrode leads
(506).
[0018] FIG. 8 shows a neural stimulator device powered by an
implanted pulse generator (IPG).
[0019] FIG. 9 is a schematic diagram of a closed-loop controller,
which includes sensing of physiological parameters and adjusting
stimulation parameters.
[0020] FIG. 10 shows a cartoon of the feedback loop between a small
sensory nerve fiber (SSNF) ending containing TRPV1 sensory neurons
(e.g., C-fibers) secreting neurogenic peptides and beta cells
stimulating insulin action.
[0021] FIG. 11 shows the effect of neural stimulation upon
abdominal blood flow in the rat model: (A, top panel) area under
the curve (AUC) in Zucker Lean (ZL) and Zucker Fatty (ZF) rats at
the indicated frequencies (5 Hz or 100 Hz) and pulse durations (02
ms and 1 ms); (B, bottom panel) time course of spinal cord
stimulation of rats at the indicated frequencies (5 Hz, increase in
blood flow, or 100 Hz, decrease in blood flow) and pulse duration
of 1 ms.
SUMMARY OF THE INVENTION
[0022] Provided herein are methods, systems and apparatuses for
preserving, restoring or affecting pancreatic beta cell function in
a subject. These methods include electrically stimulating
C-afferent sensory nerve fibers innervating pancreatic beta cells
in the diabetic subject, in which the electrical stimulation serves
to modulate a secretion of calcitonin gene-related peptide (CGRP)
from the C-afferent sensory nerve fibers; determining a level of a
biomarker in the subject and repeating the electrical stimulation
as a function of the level of the biomarker.
[0023] The methods, systems and apparatuses include electrical
stimulation carried out via one or more electrodes or pairs thereof
The one or more electrodes or pairs thereof can be contained in an
implantable lead that is positioned in the 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 segment from T7 to L1, spinal nerve bundles leaving at
any vertebral segment from T7 to L1, dorsal root ganglia bundles
leaving at any vertebral segment 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 The one or more electrodes or pairs thereof or
one or more leads are placed ipsilaterally or bilaterally. The
electrical stimulation is carried out simultaneously or
sequentially.
[0024] The methods, systems and apparatuses include electrical
stimulation that is effected wirelessly. For example, the
electrical stimulation is effected using a wirelessly powered and
controlled implanted lead.
[0025] The methods, systems and apparatuses include electrical
stimulation that is carried out at the following parameters: a
pulse width from 20 .mu.sec to 1 ms, a frequency from 1 Hertz (Hz)
to 10,000 Hz, and power amplitude from 0.2 to 14 Volts (V) or 0.1
to 20 milliamps (mA). The frequency of the electrical stimulation
is between 5 and 10,000 Hz. The frequency of said electrical
stimulation is between 1 and 50 Hz resulting in enhancement of
secretion and, optionally, the pulse width is in the range of 200
to about 450 microseconds. The frequency of the electrical
stimulation is between 60 and 10,000 Hz resulting in the inhibition
of the secretion and, optionally, the pulse width is in the range
of about 450 to about 1000 microseconds.
[0026] The methods are directed to a subject who suffers from beta
cell dysfunction or impairment from diabetes mellitus states,
specifically T1D T2D, or diabetes insipidus.
[0027] The methods are performed in which the subject needs not
adopt a lifestyle change.
[0028] The methods are performed in which the subject effects the
step of repeating the electrical stimulation as a function of the
level of a biomarker or where the step can be effected
automatically. The biomarker includes, but is not limited to, any
one or more of insulin, glucose, CGRP, abdominal skin blood flow,
abdominal skin temperature and abdominal muscle activity. Other
biomarkers may include, but are not limited to, H1Ac and
inflammatory cytokines.
[0029] The method is performed in which the biomarker is insulin
and the subject is a male subject and the level is below about 8.8
.mu.IU/mL or the subject is a female subject and the level is below
about 8.4 .mu.IU/mL; and the electrical stimulation is carried out
to excite the C-afferent sensory nerve fibers innervating
pancreatic beta cells. The method is performed in which the
biomarker is insulin and the subject is a male subject and the
level is above about 8.8 .mu.IU/mL or the subject is a female
subject and the level is above about 8.4 .mu.IU/mL; and said
electrical stimulation is carried out to inhibit the C-afferent
sensory nerve fibers innervating pancreatic beta cells. The method
is performed in which the biomarker is glucose and the level is
above about 120 mg/dL and the electrical stimulation is carried out
to excite the C-afferent sensory nerve fibers innervating
pancreatic beta cells. The method is performed in which the
biomarker is glucose and the level is below about 100 mg/dL and the
electrical stimulation is carried out to inhibit said C-afferent
sensory nerve fibers innervating pancreatic beta cells.
[0030] A system is provided 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. The means for applying the electrical stimulation may
be positioned at or near dorsal root ganglion, splenic nerve, or
dorsal column. The means for producing may perform electrical
stimulation in an open loop format and at predetermined intervals.
Preferably the means for producing performs electrical stimulation
in a manner to maintain hormone levels at a predetermined
concentration. The open loop format may include alerting the
subject to a change in glucose homeostasis. The subject may also be
alerted when the biomarker level achieves a threshold level.
Accordingly the electrical stimulation may be initiated by the
subject.
[0031] Alternatively the means for producing may perform electrical
stimulation in a closed loop format. Preferably, 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.
As well the means for producing may be further configured to
initiate adjustments to parameter settings of the electrical
stimulation, to evaluate the efficacy of the electrical stimulation
so that the parameter settings can be adjusted, or to compare the
biomarker level to an historic or normative level and adjusts the
electrical stimulation based on the comparison. Various aspects of
the system may be implantable in the subject, including but not
limited to the means for applying or the means for producing. The
system may further comprise a means for receiving incoming signals
from an external programmer. The means for producing preferably
electrically processes the incoming signals and produces the
electrical stimulation sequentially without the aid of a battery.
Moreover the electrical stimulation is preferably charge-balanced
and is effected automatically.
[0032] An apparatus is likewise provided 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 the electrical stimulation
modulates a secretion of CGRP from said C-afferent sensory nerve
fibers. Preferably the electrode lead or multiple electrode lead
array is positioned at or near dorsal root ganglion, splenic nerve,
or dorsal column and is implantable in the subject, along with the
pulse generator.
[0033] The apparatus may further comprise a radio frequency antenna
for receiving incoming signals from an external programmer.
Preferably the pulse generator electrically processes the incoming
signals and produces the electrical stimulation sequentially
without the aid of a battery.
[0034] "C-afferent sensory nerve fibers" means unmyelinated
postganglionic fibers of the autonomic nervous system, also the
unmyelinated fibers at the dorsal roots and at free nerve endings,
that convey sensory impulses from the periphery to the central
nervous system.
[0035] "Subject" means any animal, such as a human, with an
insulin-producing organ, such as an endocrine pancreas, who is
diabetic.
[0036] "Pancreatic beta cells" means insulin-producing cells
situated in the islets of Langerhans.
[0037] "Electrical stimulation" means the application of electrical
current to stimulate nerves.
[0038] "Biomarker" means any physiological indicating species
produced by a diabetic subject. Examples of biomarkers include, but
are not limited to, insulin, glucose, CGRP, abdominal skin blood
flow, abdominal skin temperature, and abdominal muscle electrical
activity.
[0039] "Electrode" means an electrical conductor used to make
contact with a nonmetallic part of a circuit. An electrode can be
an anode or a cathode. An electrode pair means two electrodes: one
anode and one cathode. Configurations of multiple electrodes can be
multiple electrode pairs or one or more anode or cathode with any
number of electrodes of the reverse polarity.
[0040] "Epidural spinal cord column" means the space superficial to
the dura matter that exists between it and the internal surfaces of
the vertebral bones and their supporting ligamentous structures of
the spine.
[0041] "Dorsal root or dorsal root entry zone" means the posterior
root that is the afferent sensory root of a spinal nerve.
[0042] "Dorsal ganglia" means the nerve structure at the distal end
of the dorsal root, which contains the neuron cell bodies of the
nerve fibers conveyed by the root.
[0043] "Spinal nerve bundles" means nerves within the spinal cord,
which are grouped together.
[0044] "Peripheral nerves" means nerves and ganglia outside of the
brain and spinal cord.
[0045] "Diabetes mellitus" means diabetic states that include T1D,
T2D and gestational diabetes.
[0046] "Type I diabetes (T1D)" means a condition characterized by
loss of the insulin-producing beta cells of the islets of
Langerhans in the pancreas leading to insulin deficiency This type
of diabetes can be further classified as immune-mediated or
idiopathic. T1D can affect children or adults but was traditionally
termed "juvenile diabetes" because it represents a majority of the
diabetes cases in children.
[0047] "Diabetes insipidus" means a condition characterized by
excessive thirst and excretion of large amounts of severely diluted
urine, with reduction of fluid intake having no effect on the
latter.
[0048] "Type II diabetes (T2D)" means a condition characterized by
insulin resistance, which may be combined with relatively reduced
insulin secretion.
[0049] "Lifestyle change" means changes in diet, exercise,
nutraceutical and pharmaceutical regimens.
DETAILED DESCRIPTION OF THE EMBODIMENTS
[0050] Provided herein are methods, systems and apparatuses to
provide electrical neural stimulation of neurons containing the
vanilloid transient receptor potential 1 (TRPV 1) receptor, small
sensory nerve fibers of other TRPV sub-families, and autonomic
nerve fibers to control the production of insulin from endocrine
pancreatic beta cells. The disclosed embodiments are related to the
excitation or inhibition of the small sensory nerves,
preferentially C-afferent fibers, by electrical neural stimulation
of the nerve fibers that innervate the endocrine pancreas and act
upon pancreatic beta cells. Such methods, systems and apparatuses
can be used to treat subjects with various diabetic states.
Embodiments of the invention allow stimulation of neurons
containing the TRPV1 receptor, many of which release a
neuropeptide, calcitonin gene-related peptide (CGRP), which in turn
influences the production of insulin from pancreatic beta cells.
Embodiments of the invention further include a closed or open loop
feedback control system in which biomarker levels are monitored and
used to regulate the applied neural stimulation. Embodiments of the
invention also include an implantable or external neural
stimulation device.
[0051] While not wishing to be held by theory, embodiments of the
invention are based on observations that electrical stimulation of
the dorsal root ganglia sensory nerve fiber bundles reverses
insulin resistance. Thus, in insulinopenic states, purportedly due
to immune and/or endocrine dysfunction and associated with
down-regulation of insulin receptors, CGRP (with SP) release
induced by electrical stimulation of specific neural tissue can
serve as insulin "replacement therapy." CGRP can therefore be used
therapeutically in terms of improving the local immunoregulatory
state of the endocrine pancreas, pancreatic neurogenic
vasodilatation (blood flow) and balancing an abnormal functional
circuit comprised of low insulin production-low activation of TRPV1
sensory neurons-low release of CGRP. This concept also supports a
view of a neuro-immune-endocrine link in .beta.-cell function and
the role for insulin-responsive TRPV1 sensory neurons in
.beta.-cell function and diabetes pathoetiology.
[0052] Consequently, there appears to be a local feedback
interaction between .beta.-cells and the TRPV1 sensory neurons
innervating the islets with nerve terminals responding to insulin
by release of neuropeptides that sustain .beta.-cell physiology in
an optimal range. Normally this interaction is in "balance" but in
T1D animal models, as well as in T2D models, hypofunction of TRPV1
unbalances the feedback, with .beta.-cell stress due to
hyperinsulinism, insulin resistance, and infiltration by T-cell
pools independently generated. Removing TRPV1 sensory neurons
(e.g., desensitization) leads to elimination of the unbalanced
pathogenic interaction whereas administering neuropeptides
exogenously (or by sensitization of TRPV1 neurons) may renormalize
the interaction. Consequently, suppressed neuropeptide release due
to impaired TRPV1 sensory neurons and/or to abnormal .beta.-cell
function including down-regulation of insulin receptors on TRPV1
sensory neurons can be addressed by two approaches. One approach is
the desensitization, removal or inhibition of TRPV1 sensory
neurons. Another approach is the sensitization or excitation of
TRPV1 sensory neurons. Both treatment options can re-balance the
interaction between the .beta.-cell and the TRPV1 sensory neuron
depending on the state of the subject's disease state. Further,
improved local insulin production induced by release of CGRP from
TRPV1 sensory neurons can restore function of the normalized
feedback and glucose-insulin homeostasis by promoting
insulinotrophic action on sensory nerves in diabetic subjects where
production of insulin is severely impaired.
[0053] Embodiments of the invention include the control of glucose
homeostasis by stimulation of TRPV1 sensory neurons that innervate
the endocrine pancreas. Electrical neural stimulation can be
performed by directing the electrical stimulation at one or more
anatomical sites including, but not limited to, 1) epidural spinal
cord column, which can include the area at vertebrae segments T7 to
L1 (and can include branches that innervate the endocrine pancreas
beta cells); 2) dorsal root and dorsal root entry zone, which can
include the area at vertebrae segments T7 to L1; 3) spinal nerve
bundles, which can include the area leaving the vertebrae segments
T7 to L1; 4) dorsal root ganglia bundles, which can include the
area leaving the vertebrae segments T7 to L1; 5) peripheral nerves,
such as the splenic nerve which innervate the endocrine pancreas
beta cells; 6) abdominal nerves or their cutaneous branches (which
can be stimulated by TENS or other external stimulation); and 7)
directly at the surface of the endocrine pancreas. Electrical
neural stimulation may be in more than one area simultaneously or
sequentially, ipsilaterally, or bilaterally.
[0054] While not wishing to be held by theory, in an aspect
embodiments of the invention are directed to methods, systems and
apparatuses that activate/deactivate TRPV1 sensory neurons
associated with pancreatic beta cell function by using
charge-balanced voltage or current controlled electrical pulses
originating from the electrical neural stimulation volume
conduction of electrode leads. The TRPV1 sensory neuron can be
stimulated at a frequency range from 1-10 Hz, 1-20 Hz, or 1 to 50
Hz. This frequency range often results in excitation of the TRPV1
sensory neurons. Such excitation can increase .beta.-cell activity
and promote insulin release. The preferred frequency for neural
excitation can be 5 Hz. For inhibition of the TRPV1 sensory neuron,
which can mimic the effects of ablation or receptor blocking, a
frequency of 60 Hz or greater can be applied. Such inhibition can
balance the insulin-dependent TRPV1 neuronal feedback system,
thereby increasing insulin release. The frequency range for neural
inhibition can be from 60 to 10,000 Hz. The preferred frequency for
neural inhibition can be 100 Hz.
[0055] These and other electrical stimulation parameters used to
stimulate TRPV1 sensory neurons can differ from those commonly used
clinically for control of inflammatory and neuropathic pain and
peripheral vascular disease. Stimulation parameters, in addition to
frequency, that can be modulated include, but are not limited to,
duty cycle, duration, waveform shape, amplitude, voltage, and
magnitude. In an embodiment, the pulse width is in the range of 20
microseconds (.mu.sec) to 1 millisecond (ms). The pulse width can
be 250 .mu.sec to 450 .mu.sec, which can result in excitation of
the TRPV1 sensory neuron. The pulse widths can be 500 .mu.sec to 1
ms, which. can result in. inhibition of the sensory neuron. The
power amplitudes can be from 0.2 to 14 Volts, or 0.1 to 20 mA,
depending on whether the power is voltage or current-driven.
[0056] In another embodiment of the invention, one or more
biomarker levels in the subject are monitored and the information
resulting from such monitoring is used to determine subsequent
delivery of electrical stimulation. The biomarker can be insulin or
glucose. Normal levels of insulin are about 8.8 .mu.IU/mL in male
subjects and about 8.8 .mu.IU/mL in female subjects. Normal levels
of blood glucose are about 100-120 mg/dL. Consequently, in certain
embodiments of the invention, the C-afferent sensory nerve fibers
innervating pancreatic beta cells are either excited or inhibited
to promote glucose homeostasis in response to abnormal biomarker
levels. The biomarker can also be abdominal skin blood flow,
abdominal skin temperature, or abdominal muscle electrical activity
measured by sensors. Abdominal muscle electrical activity can be
monitored by electromyography (EMG). Subsequent delivery of
electrical stimulation can be performed by open loop control,
whereby the subject is notified to begin, end or adjust parameters
of the stimulation. Subsequent delivery of electrical stimulation
can be performed by closed loop control, by an apparatus comparing
sensed physiological values to historic or normative values, and
automatically adjusting the stimulation output accordingly
[0057] In embodiments of the invention, the methods, systems and
apparatuses disclosed herein are used to protect the endocrine
pancreas against abnormal immune-cell accumulation or inflammation
(insulitis, i.e., T1D). Impaired CGRP release due to TRPV1 sensory
neuron pathology and/or abnormal interaction in the pathway
featuring insulin production/insulin receptor function and CGRP
release favor an inflammatory state and, hence, T1D becomes a model
of immune dysregulation, due to the early onset of sensory nerve
impairment leading to inflammatory destruction of insulin-producing
.beta.-cells and to insulin deficiency and hyperglycemia. Increased
concentrations of neuropeptides like CORP have been shown to
prevent T1D in experimental animal models (Ahren, 2000). Endogenous
produced CGRP is therefore used therapeutically in terms of
improving the local immunoregulatory state of the endocrine
pancreas, pancreatic neurogenic vasodilatation (blood flow) and
balancing an abnormal functional circuit comprised of low insulin
production-low activation of TRPV1 sensory neurons-low release of
CORP.
[0058] In embodiments of the invention, the methods, systems and
apparatuses disclosed herein are used for the treatment of
diabetes. Sensitization of TRPV1 neurons stimulates insulin action
and improves glucose and insulin homeostasis. Consequently, in
various embodiments, T1D, T2D, diabetes mellitus, diabetes,
diabetes insipidus and beta cell deficiency syndrome can be
treated.
[0059] Typically, diabetes treatments include lifestyle
modifications. Lifestyle modifications include changes in diet,
exercise, nutraceutical and pharmaceutical regimens. In an
embodiment, the methods of the invention further include lifestyle
modifications. In another embodiment, the methods of the invention
are applied without the need for lifestyle modifications.
[0060] Also provided are systems and apparatuses for stimulation of
TRPV1 sensory neurons that innervate the endocrine pancreas.
[0061] The system can include an electrode lead or a multiple
electrode lead array as disclosed elsewhere in this
application.
[0062] The system can further include means for electrical neural
stimulation in an open loop format. For example, the system can
alert the subject to a change in glucose homeostasis, thereby
allowing the subject to choose whether to initiate another
electrical neural stimulation. The alert can be triggered by a
sensor that detects a biomarker level achieving a specified
threshold. In another embodiment, the device can be programmed to
stimulate certain neural tissues at predetermined intervals, such
as to maintain hormone levels at a certain concentration.
[0063] The system can further include means for electrical neural
stimulation in a closed loop format. The system can include a
feedback sensor. The feedback sensor can collect information on
biomarker levels and transmit to a controller to compare measured
levels to desired ranges. If outside the desired or threshold
range, the feedback controller can initiate adjustments to
parameter settings of the electrical stimulation. The efficacy of
electrical stimulation can be evaluated so that the parameter
settings can be adjusted to improve the response.
[0064] FIG. 1 shows a schematic view of a subject 10 having an
implant of a neural stimulation electrode lead to stimulate the
targeted sensory nerves through epidural spinal cord stimulation.
The system can employ an implantable 15 or external pulse generator
16 to produce a number of independent stimulation pulses which are
sent to the spinal cord 20 by insulated lead 22 or wirelessly which
has two or more electrodes 33 and 34 (FIG. 2). The implantable
pulse generator 15 can have an internal battery and
pulse-generating electrical components. The system can further
comprise a radiofrequency antenna 18, which can be connected to an
external programmer 12 by an extension 14. Alternatively, the pulse
generator 16 can electrically process incoming radiofrequency
signals from the antenna, and produce electrical pulses
sequentially, without aid of a battery.
[0065] Electrodes can be placed near neural tissue. FIG. 2 is a
diagram of a cross-sectional view of a subject spinal column 20 of
a subject showing an embodiment where the implantation position of
the distal end of insulated electrode leads 31 and 32, which
terminate in electrodes 33 and 34 within the epidural space 41.
Electrodes can be made of a platinum/iridium compound. The
electrodes are shown relative to the subdural space 60 filled with
cerebrospinal fluid (CSF), bony vertebral body 70, vertebral arch
42, and dura mater 43. The spinal cord includes gray matter 56 and
white matter, for example, dorsal columns 40 and dorsolateral
columns 58. At the dorsal tips of the gray matter are the dorsal
roots 50 and 53, which are axons, originating from cell bodies in
the dorsal root ganglia, 52 and 54. These same cell bodies have
sensory endings in tissue, and their axons pass along spinal nerves
44 or 46. Stimulation pulses can be applied to at least one of
electrodes 33 and 34 (which typically are cathodes); while at least
one anode can be used for electrical return paths at other epidural
space 41 locations. Models of electric fields with spinal cord
stimulation (cf. Jan Holsheimer et al.), and clinical experience
suggest that not only are axons in the dorsal columns 40 excited,
but so are axons in the dorsal roots 50 and 53, and possibly also
axons near to dorsal gray matter several millimeters away.
[0066] Electrodes can be placed at one or more sites. FIG. 3 is a
diagram of a cross-sectional view of a spinal column showing
embodiments of electrode placement at different implantation sites
to stimulate dorsal columns, dorsal roots and entry zone, dorsal
root ganglia and/or spinal nerves. The diagram shows the spinal
cord 20 of the subject relative to implantation sites of the
electrodes which are useful to therapeutically control TRPV 1
sensory neurons: 1) electrodes 81 and 82 for epidural spinal cord
stimulation at segments T7 to L1 (sites with relatively significant
proportions of branches of TRPV1 neurons innervating the pancreas);
2) electrodes 83 and 84 for dorsal root and dorsal root entry zone
stimulation at segments T7 to L1; 3) electrodes 85 and 86 spinal
nerve stimulation of nerves T7 to L1); 4) electrodes 87 and 88 for
dorsal root ganglia stimulation of T7 to L1. Electrodes for
therapeutic stimulation can also be placed at: 5) peripheral nerves
innervating the pancreas; 6) abdominal nerves or their cutaneous
branches; and/or 7) the surface of the pancreas. Two or more
electrodes can be used, at least one of which is a cathode
(negative) and at least one of which is an anode (positive). One or
more of the electrodes used can be at spinal levels. In the case of
anode(s), the electrode can be distant. Pulses may be current or
voltage controlled. The pulses can be charge-balanced for safety.
Electrodes can be placed in the epidural space, outside the dura,
or subdurally. Electrodes may be placed nearby, outside the
perineural sheath, or inside and along the nerve fibers of
peripheral nerves.
[0067] The electrodes can be placed near the dorsal root ganglia
and/or the spinal nerves. FIG. 4 is a diagram of a cross sectional
pathway overview 200 of an exemplary spinal column segment 201
showing positioning electrode lead 202 to stimulate the dorsal root
ganglia 203 and/or spinal nerves 210 by placement perpendicularly
with the nerve bundle leaving the particular dermatome. The
electrode lead placement in FIG. 4 can stimulate TRPV1 sensory
neurons via the dorsal root ganglia in the dermatome regions from
spinal segments T7 to L1, which are sensory nerve fibers 204 that
lead to the pancreas 206. Electrodes can also be placed at the: 1)
peripheral nerves innervating the pancreas 204; 2) abdominal nerves
or their cutaneous branches; and/or 3) the surface of the pancreas
206. While pairs of electrodes 202 are shown in FIG. 4, stimulation
can be effected with two or more electrodes, at least one of which
is a cathode (negative) and at least one of which is an anode
(positive). One or more of the electrode leads used can be placed
at different spinal levels or even distant in the case of anode(s).
The sensory nerve terminals 208 contain TRPV1 and insulin receptors
209 that act on the release of certain neuropeptides, i.e. CGRP or
respond to the presence of insulin 212. The neuropeptides act on
the beta cell 211 and modulate the release or inhibition of insulin
from the beta cell.
[0068] The splenic nerve can be a site of electrode placement. FIG.
5 is an overview 300 of a subject spinal column segment 301 showing
an electrode lead 302 placed to stimulate the splenic nerve 303 by
placement in parallel with the nerve bundle 304.
[0069] FIG. 6 shows the various dermatome levels for nerve fibers
to various tissue of the typical subject 400. The viscera region is
innervated by most of the dermatomes ranging from T7 to L1 401.
[0070] Electrode types and electrode spacing can be modified in
suitable embodiments. FIG. 7 shows various optional configurations
for the electrode lead array that can be placed in the epidural
space, directly on the dorsal root ganglia, in the region of the
splenic nerve, or other location along the neuronal pathway from
the dorsal column to the pancreas originating from dermatomes in
the region of T7 to L1. Typically, four electrode leads are
sufficient for peripheral nerve stimulation placements 501. The
spacing of these electrodes can be about 3 mm, as shown 501,
however studies have shown that targeting of the nerve bundle can
be improved by electrode spacing that is less than 3 mm 502. In
other embodiments, such as for greater range of coverage in
epidural space placements, leads with 8 electrodes 503 or more can
be used to cross over multiple dermatome levels. In other
embodiments 504, spacing can include electrodes at the tip, with
remote anodes to create a wide area of volume conduction. In yet
another embodiment, the electrode pads can be placed in a
configuration that eliminates the 360 degree electrode wrapping
around the lead 503 and places the electrodes embedded in a lead
assembly where placement must be manually inserted to lie against
the spinal column within the lead unilateral volume conduction area
505. Embedded paddle electrode leads can have a multitude of
electrode pads 506.
[0071] In some embodiments, the invention further comprises an
implanted pulse generator (IPG) that can be used for open- or
closed-loop feedback. FIG. 8 is a diagram showing an IPG and an
external pulse generator system. The IPG can be located
subcutaneously in the abdomen or lower back region and tunneled by
extension wire to the electrode lead at the therapeutic treatment
area. Alternatively, pulse information can be received for this
treatment protocol by an external pulse generator sending
information to an imbedded antenna receiver which interprets and.
correlates the instruction set to provide the electrode lead with
the appropriate therapeutic parameter sets.
[0072] The system and apparatus can further include a controller.
The controller can generate excitatory or inhibitory electrical
stimulation to TRPV1 sensory neurons to alleviate the imbalance
between insulin production from the .beta.-cell-CGRP release. The
controller can communicate with one or more sensors to detect
biomarker levels as disclosed herein.
[0073] The controller can comprise one or more transmitters and
receivers in communication with sensors and the electrical
stimulation device such as the pulse generator. The controller can
send the signals to increase or decrease stimulation until glucose
homeostasis is achieved. The stimulus parameters include, without
limitation, amplitude, pulse duration, duty cycle, pulse
width/frequency, and polarity of electrodes on the lead. The
controller can include a microprocessor that can instruct the
system to produce an exciting or inhibiting stimulation signal or
to cease electrical stimulation. The microprocessor can be
programmed with pre-selected stimulus parameters. The receivers
receive signals from the sensors, process signals to be analyzed by
the controller and store the signals in a data storage and/or
pre-processor area, such as a dynamic random access memory (DRAM).
Sensors sense various biomarker levels to determine, for example,
whether there has been sufficient glucose homeostasis control in
the neuroendocrine system.
[0074] The controller can be an external device or an implantable
device. In certain embodiments, it can provide signals to a subject
who is experiencing an unexpected event. The controller can be
programmed for either automatic or manual operation. The controller
can have one or more conventional glucose sensors. Upon detection
of a hormonal irregularity, the controller can automatically begin
treatment of the subject by regulating hormone levels through
electrical stimulation. In another embodiment, the subject can
manually activate the controller. The activation can begin or
adjust regulation of CGRP levels. The activation can regulate
insulin homeostasis. A positive physiological response, e.g. a
physiological response that trends to the "normal" range, can be
used as an indication that the electrical stimulation is effective
in producing glucose homeostasis.
[0075] In some embodiments, the invention further comprises a
closed-loop controller. FIG. 9 is a schematic diagram of a
closed-loop controller, which includes sensing of biomarker levels
and adjusting stimulation parameters. The closed-loop controller
generates excitatory or inhibitory electrical stimulation to TRPV1
neurons alleviating the imbalance between insulin production from
the .beta.-cell and CGRP production. The controller utilizes one or
more sensors to detect the biomarker level. The controller compares
sensed biomarker levels (data) 102 to stored historic or normative
levels 104, and adjusts the stimulation output accordingly.
Physiological normative data, past data from this subject, and
ranges of stimulation parameters can be saved in storage element
100. Once sensed data is acquired 102, a decision can be made 105,
optionally based on priorities, whether stimulation must be
initiated or altered to affect this parameter. The controller can
effect changes to parameters or to anatomical locations of
stimulation as required 103. The controller can effect these
changes independent of altering the timing element 101 of the
electrical stimulation. If the decision to change a parameter or
location of stimulation is negative, the timer will be checked 106,
and either the timer will be reset, or parameters of stimulation in
general can be reduced 107, but not below a priori limits The
controller can consult with two or more sensed physiological values
before making decisions.
Example 1
The Biological Feedback Loop Between SSNF And Beta Cells
[0076] The biological feedback loop between a small sensory nerve
fiber (SSNF) ending containing TRPV1 sensory neurons (e.g.
C-fibers) secreting neuropeptides and beta cells stimulating
insulin action can be controlled by electrical stimulation. FIG. 10
shows a feedback diagram of a SSNF ending containing TRPV1 sensory
neurons (e.g., C-fibers) when modulated by electrical neural
stimulation techniques by methods described in this invention act
on the nerve bundles dorsal root ganglia through volume conduction
from a dorsal column placement of an electrode lead, or other
methods of sensory nerve stimulation described herein. The
neuropeptide CGRP, among others, are released from the activated
TRPV1 sensory neuron terminal. The released neuropeptides act on
the beta cell stimulating insulin action through an inflammatory
response action.
[0077] Subjects treated with spinal cord stimulation using
excitatory protocols described herein show a marked effect (i.e.,
an increase in) on insulin production. This closed loop system can
also be inhibited to cut off the production of insulin from the
beta cell. Insulin released from the beta cell acts on the insulin
receptor located on the TRPV1 sensory neuron terminal. The influx
of insulin into the sensory nerve cells up regulates the TRPV1
receptor channel and an influx of calcium enters the cell, which
leads to the release of CGRP neuropeptide from the cell, closing
the loop to act on the beta cell invoking insulin release.
Electrical neural stimulation parameters are set in this invention
to both stimulate the cycle of release of insulin and/or inhibit
the cycle with blocking parameter settings.
Example 2
Placement of Epidural Neural Stimulator
[0078] A spinal cord stimulator (SCS) is a medical device typically
used for the treatment of chronic pain, which usually includes an
implantable lead, a pulse generator (implanted or external) and a
power source as shown in FIG. 1. Wired SCS devices introduce an
implantable lead containing a number of electrodes into the
epidural space, as well as an extension cord to an implantable
pulse generator (IPG). These IPGs can either contain a battery pack
or a radio frequency (RF) receiver and are typically placed under
the skin around the buttocks or hip area. The diabetic subject
would have SCS leads placed at a medical facility bilaterally. The
subject lays down on a flat surface with their back facing upwards.
Typically, a 14-gauge Tuohy needle (2.1 mm diameter or less) is
inserted into the back and is carefully navigated upwards into the
epidural space of the spinal cord with the aid of a fluoroscope or
other imaging device. Once the Tuohy needle is located properly, a
guide wire is pushed through the lumen of the needle in order to
safely move tissue to the side creating a pathway for the lead. The
guide wire is removed, and then the SCS lead is advanced through
the interior of the needle. The lead is advanced up into the
epidural space until the electrodes are near the nerve branches
that correspond to the location of the dermatomes that innervate
the pancreas small sensory nerve fibers.
[0079] Stimulating electrodes incorporated into a lead can be
placed at the 9th to 11th thoracic (T9-T11) vertebrae directly
through various implantation orthopedic techniques. The implantable
stimulation electrodes are made of inert materials, such as
platinum-iridium. The leads are made from a biocompatible
polyurethane or silicone and may contain a silicon microelectronic
chip. When energized, the implanted device produces small waveform
pulses of a current to excite or inhibit a release of neural
transmitters, depending on the parameter settings of frequency and
pulse width. The lead can be secured in place with a steristrip or
a monofilament absorbable (Monocryl) suture to anchor device.
[0080] SCS can be applied at the epidural surface of T9-T11
vertebrae spinal location in the center of the cord for example, or
bilaterally on either side of the cord. SCS has been shown to
increase vasodilation in the skin through release of CGRP from the
afferent fibers in the dorsal roots (Tanaka 2004). Muscle twitch
threshold and threshold under epidural stimulation was determined.
Continuous epidural electrical stimulation can be delivered at 5
Hz, for insulin production or 100 Hz, for insulin inhibition at
various pulse durations. The stimulation intensity ranges from 100
.mu.A to a maximum of 10 mA.
Example 3
Electrical Stimulation Regulates Insulin Activity in Diabetics
[0081] SCS-induced modulation of SSNFs leads to enhanced insulin
action and release. This can occur as a result of improved SSNF
function and restoration of insulin receptor regulation. Outcome
measures include the Oral Glucose Tolerance Test (OGTT) and a
Homeostasis Model Assessment of Insulin Sensitivity (HOMA)
analysis. Oral Glucose Tolerance Test (OGTT) is a widely used
procedure that was originally developed to classify carbohydrate
tolerance. The OGTT requires the subject to be fasting overnight. A
plasma sample is then drawn to determine baseline values for
glucose and insulin. Following an oral glucose load (usually by
swallowing 75 grams of dextrose), the glucose and insulin in blood
plasma samples are measured at specific times, such as 30 minutes
and 120 minutes (Weyer 1999). The test indicates the ability (also
called tolerance) of pancreatic .beta.-cells to respond to glucose
stimulation by secreting sufficient amounts of insulin to maintain
glucose homeostasis.
[0082] Using the OGTT, other indices of .beta.-cell function can be
measured: .DELTA.Ins/.DELTA.Gluc at 30 minutes is reduced
.about.6-fold in early diabetes and the glucose area under the
curve (AUC) is raised .about.2-fold in early diabetes, reflecting
impaired modulation of glucose after a glucose load or glucose
intolerance. The gold standard test for Insulin Resistance (IR) is
the euglycemic hyperinsulinemic clamp, a procedure that is
technically complex and not practical for clinical research
particularly with large population samples. The Homeostasis Model
Assessment of Insulin Sensitivity (HOMA) is used to analyze the
results (Stumvoll et al, 2000; Haffner et al, 1997). It is derived
from the OGTT and is calculated as [fasting insulin
(.mu.U/ml).times.[fasting glucose (mmol/L)]/22.5. The HOMA has a
range of .about.0.2-15. The correlation coefficient with the clamp
is about 0.75, suggesting a strong correlation. Higher scores are
associated with glucose intolerance, progression to diabetes, the
metabolic syndrome, and cardiovascular disease. For the HOMA scale,
the highest quartile for IR among a non-diabetic population is 3.0;
thus we will use>3.0 values to depict IR in our population.
[0083] Subjects that are treated with SCS use the system a minimum
of three times daily to elicit changes in pancreatic function. The
treatment time intervals are determined by each individual
subject's use of the device and eating patterns. Durations for each
treatment session are at least 15 minutes of SCS 3 times daily. The
subject uses the stimulator for a prescribed period of time each
day, for example 15 minutes three times daily, or 30 minutes six
times daily. As much as possible these three `treatments` should
occur at the same times each day. A Daily Stimulation Log is used
to record treatment times and length for the stimulation. After ten
days of treatment, subject logs are reviewed by the endocrinologist
along with the HOMA analysis to mark the impact of the SCS
treatment on the subject's overall systemic glucose levels.
[0084] Before the end of the first month of SCS treatment, the
subject fasts 9-12 hours overnight before a final office for a
series of blood draws to determine the effects of the SCS
treatment. At start, in a fasting state a blood sample is taken for
baseline glucose and insulin values for OGTT. The subject is given
75 g of dextrose mixture to ingest (glucose load). At 30 minutes a
second blood sample is taken for glucose and insulin values. At 120
minutes a third blood sample is taken for glucose and insulin
values. Two weeks later the subject will fast overnight before a
visit to the site for about 3 hours during which they will again
have 3 blood draws. At start, in a fasting state a blood sample is
taken for Fructosamine and baseline glucose and insulin values for
OGTT. The subject then ingests 75 g dextrose mixture (glucose
load). At 30 minutes a second blood sample is taken for glucose and
insulin values. At 120 minutes a third blood sample is taken for
glucose and insulin values.
[0085] Again after at least two weeks, the subject will fast
overnight before a visit for about 3 hours during which they will
again have 3 blood draws, plus the LDF abdominal blood flow
analysis. At start, in a fasting state a blood sample is taken for
Fructosamine and baseline glucose and insulin values for OGTT. The
subject then ingests 75 g dextrose mixture (glucose load). At 30
minutes a second blood sample is taken for glucose and insulin
values. At 120 minutes a third blood sample is taken for glucose
and insulin values. LDF Abdominal blood flow is again recorded. SCS
treatment is shown to elicit an insulin action from the beta cell
after treatments of 15-minute duration.
Example 4
Electrical Stimulation Regulates Abdominal Blood Flow
[0086] Zucker Lean and Zucker Fatty rats are subjected to
intermediate 90 second 5 Hz (exciting) and 100 Hz (blocking)
stimulation at 0.2 microseconds or one millisecond pulse durations
as indicated in FIG. 11. Top panel, the four left bars are 5 Hz and
the right four bars are 100 Hz. Abdominal blood flow is analyzed by
a laser Doppler (Moor Instruments) measuring the area under the
curve (AUC) FIG. 11. The following observations are made: (1)
spinal cord stimulation causes higher abdominal skin blood flow at
5 Hz rather than 100 Hz and (2) Zucker fatty rats do not exhibit
negative blood flow at inhibitory frequencies of 100 Hz suggesting
that these animals do in fact have a serious impairment of
sympathetic nerve fibers. The magnitude of blood flow in the obese
rats is only minimally decreased, perhaps due to the relatively
young age of the rats and/or to residual vasodilatory molecules
that are released by spinal cord stimulation.
[0087] Abdominal Blood Flow (ABF) tests are used to compare
different pulse durations in order to select the one that maximizes
blood flow. To optimize the stimulation, blood flow is used as an
output measure at the abdomen because the same sensory nerve fibers
innervate both the pancreas and the abdomen. The SCS system for
example would be turned on twice for a certain period of time at
least 2 to 3 hours after a meal, i.e., for 15 minutes with a
15-minute rest interval between treatments. During the stimulation
session, changes in abdominal blood values at the abdomen will be
recorded using a surface Laser Doppler Flowmetry (LDF) (Moor Inst
Co. Devon, England). The stimulation parameters typically will be
set at a frequency of 5 Hz and a pulse duration at 0.2 ms.
Intensity at or near motor threshold of the abdominal muscles will
be assessed by recording surface electromyography (SEMG) signals of
less than 200 .mu.V from the upper abdominal muscles. Blood flow
response output measurements include peak values, area under curve,
and correlation curves to EMG recordings of voltage levels required
to generate a muscle action potential. Successful treatment
candidates will exhibit an increase of at least 10% or more (above
baseline resting values) in blood flow measured 60 seconds prior to
stimulation on at least one side of the abdomen.
[0088] Local blood flow can be measured in the dorsal skin with a
laser Doppler blood flow meter as a diagnostic tool to ensure
vasodilation is being achieved by the stimulation protocols Skin
sites were marked out on the dorsal skin according to a balanced
site pattern with two sites for each measurement on the right side
of the abdomen corresponding to the location of the pancreas. Laser
probes are adhered to the skin with an adhesive attached via a
laser probe holder perpendicular to the abdomen skin. The laser
Doppler flow meter is set at 5 Hz at a gain of 10. The blood flow
readings can be taken sequentially at each site at 2-second
intervals. Both ipsilateral and contralateral data can be
analyzed.
[0089] The raw blood flow flux measurement data and the area under
the curve can be calculated to express results as a percentage of
change in blood flow as observed from the abdomen skin innervated
by SCS. Measurements to be evaluated include the percent change
from baseline blood flow values. The system measures (1)
dose-dependent abdominal blood flow and vascular resistance
responses during SCS with current patterns blood flow at the two
sites; (2) sustained blood flow at a selected sub-threshold. level
80-90% of motor threshold for the abdominal muscles as activated by
SCS prior to and following multiple epochs of stimulation; and (3)
testing timelines till the depletion of CGRP by blood flow.
* * * * *