U.S. patent application number 15/664468 was filed with the patent office on 2018-01-18 for devices and methods for managing insulin resistance.
This patent application is currently assigned to Gludone Inc.. The applicant listed for this patent is Gludone Inc.. Invention is credited to Li Qiang.
Application Number | 20180014968 15/664468 |
Document ID | / |
Family ID | 59653642 |
Filed Date | 2018-01-18 |
United States Patent
Application |
20180014968 |
Kind Code |
A1 |
Qiang; Li |
January 18, 2018 |
DEVICES AND METHODS FOR MANAGING INSULIN RESISTANCE
Abstract
Disclosed are devices and methods for mitigating insulin
resistance in a human subject by contacting one or more regions of
the neck, the supraclavicular, and the interscapular regions of the
human subject with a part of a cooling device, wherein the part of
the cooling device has a temperature at about 15 or less Celsius
degrees; cooling the one or more regions of the neck, the
supraclavicular, and the interscapular regions of the human subject
for a cooling period of at least 15 minutes; and performing
previous two steps daily for about 14 or more days. The devices and
methods may also be used to preventing, delaying or treating type 2
diabetes in a human subject or activating brown fat without
incurring a sympathetic nerve-mediated cold feeling in a human
subject.
Inventors: |
Qiang; Li; (Fort Lee,
NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Gludone Inc. |
San Jose |
CA |
US |
|
|
Assignee: |
Gludone Inc.
|
Family ID: |
59653642 |
Appl. No.: |
15/664468 |
Filed: |
July 31, 2017 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
15465259 |
Mar 21, 2017 |
9744072 |
|
|
15664468 |
|
|
|
|
62362629 |
Jul 15, 2016 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61F 2007/0234 20130101;
A61H 2201/1619 20130101; A61H 2201/5038 20130101; A61H 2201/0242
20130101; A61F 2007/0018 20130101; A61F 2007/0011 20130101; A61H
2230/06 20130101; A61H 2201/165 20130101; A61F 7/0085 20130101;
A61H 2201/50 20130101; A61H 2230/50 20130101; A61F 2007/0233
20130101; A61H 2201/10 20130101; A61H 39/08 20130101; A61H 39/002
20130101; A61F 2007/0075 20130101; A61H 2230/202 20130101; A61F
2007/0056 20130101; A61H 2201/0214 20130101; A61H 2201/1623
20130101; A61H 2201/1614 20130101 |
International
Class: |
A61F 7/00 20060101
A61F007/00; A61H 39/00 20060101 A61H039/00 |
Claims
1. A method for mitigating insulin resistance in a human subject
without activating brown fat, comprising: a. contacting one or more
regions of neck, supraclavicular, and interscapular regions of the
human subject with a part of a cooling device, wherein the part of
the cooling device has a temperature at about 15 or less Celsius
degrees; b. cooling the one or more regions of neck,
supraclavicular, and interscapular regions of the human subject for
a cooling period of at least 15 minutes; and c. performing steps a
and b for one or more times daily for about 14 or more days.
2. The method of claim 1, wherein the part of the cooling device
has a temperature ranging from about 4 to about 15 Celsius
degrees.
3. The method of claim 1, wherein the part of the cooling device
has a temperature ranging from about -15 to about 4 Celsius
degrees.
4. The method of claim 1, wherein the cooling period ranges from
about 15 to about 30 minutes.
5. The method of claim 1, wherein the cooling period ranges from
about 30 minutes to about 2 hours.
6. The method of claim 1, wherein the cooling period ranges from
about 2 to about 4 hours.
7. The method of claim 1, wherein the cooling device has a
temperature controller that can be used to adjust the temperature
of the part of the cooling device that contacts the human
subject.
8. The method of claim 1, further comprising the step of applying
electroacupuncture to one or more regions selected from the group
consisting of the neck, the supraclavicular and the interscapular
regions in step b.
9. The method of claim 8, wherein the electroacupuncture is applied
simultaneously during the cooling period.
10. The method of claim 8, wherein the electroacupuncture is
applied prior to the cooling period.
11. The method of claim 8, wherein the electroacupuncture is
applied in a period that overlaps the cooling period.
12. The method of claim 1, wherein in the step c, the steps a and b
are performed once daily for 14 or more days.
13. The method of claim 1, wherein in the step c, the steps a and b
are performed twice daily for 14 or more days.
14. The method of claim 1, wherein in the step c, the steps a and b
are performed thrice daily for 14 or more days.
15. A method for preventing, delaying or treating type 2 diabetes
in a human subject without activating brown fat, comprising: a.
contacting one or more regions of neck, supraclavicular, and
interscapular regions of the human subject with a part of a cooling
device, wherein the part of the cooling device has a temperature at
about 15 or less Celsius degrees; b. cooling the one or more
regions of the neck, the supraclavicular, and the interscapular
regions of the human subject for a cooling period of at least 15
minutes; and c. performing steps a and b for one or more times
daily for about 14 or more days.
16. The method of claim 15, wherein the part of the cooling device
has a temperature ranging from about 4 to about 15 Celsius
degrees.
17. The method of claim 15, wherein the part of the cooling device
has a temperature ranging from about -15 to about 4 Celsius
degrees.
18. The method of claim 15, wherein the cooling period ranges from
about 15 to about 30 minutes.
19. The method of claim 15, wherein the cooling period ranges from
about 30 minutes to about 2 hours.
20. The method of claim 15, wherein the cooling period ranges from
about 2 to about 4 hours.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. Non-provisional
patent application Ser. No. 15/465,259, filed on Mar. 21, 2017,
which in inturn claims the benefit of priority of earlier-filed
U.S. Provisional Patent Application No. 62/362,629, filed on Jul.
15, 2016, the disclosure of which applications are incorporated
herein by reference.
FIELD OF INVENTION
[0002] The invention relates generally to the field of medical
devices, specifically devices for managing diabetes, more
specifically for managing insulin resistance, and methods for
managing physiological conditions, specically diabetes, more
specifically insulin resitance.
BACKGROUND
[0003] Easy access to calorie and sedentary life styles have led to
the pandemics of Type 2 diabetes to affect over one billion adults
and a lot more in the prediabetic insulin resistance stage (1, 2).
Currently, in the United States alone, there are over 29 million
people diagnosed with type 2 diabetes, which cost $245 billion
annually (3).
[0004] Type 2 diabetes is characterized by insulin resistance,
which may be combined with relatively reduced insulin secretion.
Type 2 diabetes is a chronic disease, for which there is no known
cure except in very specific situations. Type 2 Diabetes management
concentrates on keeping blood sugar levels as close to normal,
without causing low blood sugar. The current methods of type 2
diabetes management include a healthy diet, exercise, weight loss,
and use of appropriate medications. Those medications include,
among others, Metformin, as well as possibly insulin.
[0005] Current medications for treating Type 2 diabetes can cause
deleterious effects to various extents. For example,
thiazolidinedione (TZDs, Actos, Avandia), an insulin sensitizer for
treating type 2 diabetes, can cause body weight gain, heart
failure, fracture and certain types of cancer (4, 5). Therefore,
there is an urgent need to develop more effective and safer
treatments for Type 2 diabetes.
[0006] In a recent study, a human being who stayed in
climate-controlled rooms at 19.degree. C. for one month, or
14-15.degree. C. for 10 days, had significantly increased insulin
sensitivity (6, 7). However, these current approaches are not
practically operational for clinical utilizations, nor are
preferred by patients because of the uncomfortableness of cold.
[0007] Acupuncture is considered to be an effective therapy for
regulating pain and managing many other functions of the body, for
example chronic muscle spasm and neurological dysfunctions. More
recently, electroacupuncture (EA) was developed and shown to
significantly enhance traditional acupuncture treatments. EA are
similar to traditional acupuncture except that the needles are
attached to a device that sends electrical currents or pulses into
the body.
BRIEF SUMMARY OF THE INVENTION
[0008] In one aspect, the disclosed invention is directed to a
method for mitigating insulin resistance in a human subject by
contacting one or more regions of the neck, the supraclavicular,
and the interscapular regions of the human subject with a part of a
cooling device, wherein the part of the cooling device has a
temperature at about 15 or less Celsius degrees; cooling the one or
more regions of the neck, the supraclavicular, and the
interscapular regions of the human subject for a cooling period of
at least 15 minutes; and performing the above two steps for one or
more times daily for about 14 or more days.
[0009] In some embodiments of the method for mitigating insulin
resistance in a human subject, the part of the cooling device has a
temperature ranging from about 4 to about 15 Celsius degrees. In
other embodiments, the part of the cooling device has a temperature
ranging from about -15 to about 4 Celsius degrees. In some
embodiments, the cooling period ranges from about 15 to about 30
minutes. In other embodiments, the cooling period ranges from about
30 minutes to about 2 hours. In still other embodiments, the
cooling period ranges from about 2 to about 4 hours. In some
embodiments, the cooling device has a temperature controller that
can be used to adjust the temperature of the part of the cooling
device that contacts the human subject.
[0010] In some embodiments, the method for mitigating insulin
resistance in a human subject further comprises the step of
applying electroacupuncture to one or more regions selected from
the group consisting of the neck, the supraclavicular and the
interscapular regions in the second step. In some instances, the
electroacupuncture is applied simultaneously during the cooling
period. In other instances, the electroacupuncture is applied prior
to the cooling period. In still other instances, the
electroacupuncture is applied in a period that overlaps the cooling
period.
[0011] In some embodiments of the method for mitigating insulin
resistance in a human subject, the cooling treatment is performed
once daily for 14 or more days. In other embodiments, the cooling
treatment is performed twice daily for 14 or more days. In still
other embodiments, the cooling treatment is performed thrice daily
for 14 or more days.
[0012] In another aspect, the disclosed invention is directed to a
method for preventing, delaying or treating type 2 diabetes in a
human subject by contacting one or more regions of the neck, the
supraclavicular, and the interscapular regions of the human subject
with a part of a cooling device, wherein the part of the cooling
device has a temperature at about 15 or less Celsius degrees;
cooling the one or more regions of the neck, the supraclavicular,
and the interscapular regions of the human subject for a cooling
period of at least 15 minutes; and performing the above two steps
one or more times daily for about 14 or more days.
[0013] In some embodiments of the method for preventing, delaying
or treating type 2 diabetes in a human subject, the part of the
cooling device has a temperature ranging from about 4 to about 15
Celsius degrees. In other embodiments, the part of the cooling
device has a temperature ranging from about -15 to about 4 Celsius
degrees. In some embodiments, the cooling period ranges from about
15 to about 30 minutes. In other embodiments, the cooling period
ranges from about 30 minutes to about 2 hours. In still other
embodiments, the cooling period ranges from about 2 to about 4
hours. In some embodiments, the cooling device has a temperature
controller that can be used to adjust the temperature of the part
of the cooling device that contacts the human subject.
[0014] In some embodiments, the method for preventing, delaying or
treating type 2 diabetes in a human subject further comprises the
step of applying electroacupuncture to one or more regions selected
from the group consisting of the neck, the supraclavicular and the
interscapular regions in the second step. In some instances, the
electroacupuncture is applied simultaneously during the cooling
period. In other instances, the electroacupuncture is applied prior
to the cooling period. In still other instances, the
electroacupuncture is applied in a period that overlaps the cooling
period.
[0015] In some embodiments of the method for preventing, delaying
or treating type 2 diabetes in a human subject, the cooling
treatment is performed once daily for 14 or more days. In other
embodiments, the cooling treatment is performed twice daily for 14
or more days. In still other embodiments, the cooling treatment is
performed thrice daily for 14 or more days.
[0016] In yet another aspect, the disclosed invention is directed
to a cooling device that comprises a body-contacting vest that
directly contacts one or more regions of the neck, the
supraclavicular and the interscapular regions; a tube that is
filled with cooling media, said tube partially contacts the
body-contacting vest; and a refrigeration part that cools the
cooling media in the tube, said cooling media in turn cools the
body-contacting vest to a specified temperature of 15 Celsius
degree or below.
[0017] In some embodiments of the cooling device, the
body-contacting vest is made of fabric. In other embodiments, the
body-contacting vest is made of carbon fibers. In still other
embodiments, the body-contacting vest is made of metal.
[0018] In some embodiments of the cooling device, the refrigeration
part is a cyclic refrigeration. In other embodiments, the
refrigeration part is a thermoelectric refrigeration. In still
other embodiments, the refrigeration part is an ice bag, or any
other cooling materials that can reduce temperature when in
contact.
[0019] In certain embodiments, the cooling device further comprises
an electroacupuncture unit with at least one pair of electrodes. In
some instances, the at least one pair of electrodes are connected
to a low voltage electricity circuit.
[0020] In some embodiments, the cooling device further comprises a
temperature controller. In other embodiments, the cooling device
further comprises a controller for EA modes. In still other
embodiments, the cooling device further comprises a timer to
pre-set the cooling period.
[0021] In yet another aspect, the disclosed invention is directed
to a method of activating brown fat in a human subject by
contacting one or more regions of the neck, the supraclavicular,
and the interscapular regions of the human subject with a part of a
cooling device, wherein the part of the cooling device has a
temperature at about 15 or less Celsius degrees; cooling the one or
more regions of the neck, the supraclavicular, and the
interscapular regions of the human subject for a cooling period of
at least 15 minutes, thereby activating brown fat in the one or
more regions of the neck, the supraclavicular, and the
interscapular regions of the human subject; and performing the
above two steps daily for about 14 or more days to further activate
or maintain the activation status of the brown fat in the one or
more regions of the neck, the supraclavicular, and the
interscapular regions of the human subject.
[0022] In some embodiments of the method of activating brown fat,
the part of the cooling device has a temperature ranging from about
4 to about 15 Celsius degrees. In other embodiments, the part of
the cooling device has a temperature ranging from about -15 to
about 4 Celsius degrees
[0023] In some embodiments of the method of activating brown fat,
the cooling period ranges from about 15 to about 30 minutes. In
other embodiments, the cooling period ranges from about 30 minutes
to about 2 hours. In still other embodiments, the cooling period
ranges from about 2 to about 4 hours.
[0024] In some embodiments of the method of activating brown fat,
the cooling device has a temperature controller that can be used to
adjust the temperature of the part of the cooling device that
contacts the human subject.
[0025] In some embodiments, the method of activating brown fat
further comprises the step of applying electroacupuncture to one or
more regions selected from the group consisting of the neck, the
supraclavicular and the interscapular regions in the second step.
In some instances, the electroacupuncture is applied simultaneously
during the cooling period. In other instances, the
electroacupuncture is applied prior to the cooling period. In still
other instances, the electroacupuncture is applied in a period that
overlaps the cooling period.
[0026] In some embodiments of the method for activating brown fat
in a human subject, the cooling treatment is performed once daily
for 14 or more days. In other embodiments, the cooling treatment is
performed twice daily for 14 or more days. In still other
embodiments, the cooling treatment is performed thrice daily for 14
or more days.
BRIEF DESCRIPTION OF THE DRAWINGS
[0027] FIG. 1 shows a graph showing the normalization of impaired
blood glucose by Coldia treatment. After two weeks on Coldia
treatment, impaired fasting glucose was decreased to normal range
(below 100 mg/dL). The regions applied ice pad felt cold at the
beginning of treatment (about 10-15 minutes) during the first week
of treatment. Afterwards, skin adapted to the cold and didn't feel
the cold uncomfortableness. At about 2 weeks, the testing subject
felt hungry more often, a typical feeling from increased energy
expenditure due to BAT activation. During the last two weeks on
cold treatment, EA was applied to the treated region. EA
significantly increased the comfort of the treatment, and also
further decreased fasting glucose.
[0028] FIG. 2 shows a plot depicting that the normal blood glucose
levels were maintained after Coldia treatment. Fasting blood
glucose was monitored for three months after stopping Coldia
treatment. The benefit of decreasing fasting glucose from Coldia
treatment was maintained for at least 3 months.
[0029] FIG. 3 shows an exemplary cooling device for the Coldia
treatment. The cooling fluid in the tank is cooled down by
compressor refrigeration, and then pumped to the cooling vest
through a tube by a motor. The cooling fluid takes heat away from
targeted body area and is circulated back to the tank.
[0030] FIG. 4 shows a plot depicting the results of oral glucose
tolerance testing in patient #1 before and after Coldia treatment
for 8 weeks. The x-axis shows the time points when blood glucose
concentration was measured.
[0031] FIG. 5 shows a plot depicting the results of oral glucose
tolerance testing in patient #2 before and after Coldia treatment
for 8 weeks. The x-axis shows the time points when blood glucose
concentration was measured.
[0032] FIG. 6 shows a plot depicting the results of insulin level
testing during the same period of oral glucose tolerance testing as
in FIG. 4 in patient #1 before and after Coldia treatment for 8
weeks. The x-axis shows the time points when blood insulin
concentration was measured.
[0033] FIG. 7 shows a plot depicting the results of insulin level
testing during the same period of oral glucose tolerance testing as
in FIG. 5 in patient #2 before and after Coldia treatment for 8
weeks. The x-axis shows the time points when blood insulin
concentration was measured.
DETAILED DESCRIPTION OF THE INVENTION
[0034] The present disclosure is based, in part, on a new and
surprising discovery that cooling certain parts of the human body
under certain regimes can mitigate insulin resistance and normalize
blood glucose homeostasis. Treatment methods according to the above
discovery herein disclosed in the present application are referred
to as "Coldia" treatments.
[0035] I. Methods for Mitigating Insulin Resistance in a Human
Subject
[0036] In one aspect, the present disclosure is directed to a
method of mitigating insulin resistance in a human subject. In one
embodiment, the method comprises the steps of contacting one or
more regions of the neck, the supraclavicular, and the
interscapular regions of the human subject with a part of a cooling
device with a cooling temperature at about 15 or less Celsius
degrees, cooling the one or more regions of the neck, the
supraclavicular, and the interscapular regions of the human subject
for a cooling period of at least 15 minutes, and performing above
two steps daily for about 14 or more days.
[0037] In the above embodiment, the selective location of the
cooling unit on a human body prevents the unnecessary heat loss
from other body regions, particularly the extremities where most of
the discomfort of cold feeling comes from. Because of the selective
cooling strategy, in some embodiments, the cooling temperature can
go down to about -15.degree. C. to about 4.degree. C. Celsius
degrees so as to improve the cooling efficiency without causing
damage of the skin. In other embodiments, the subjects are more
sensitive to cooling, the cooling temperature ranges from about 4
to about 15 Celsius degrees.
[0038] In some embodiments, the cooling temperature is set at a
specific temperature during the whole treatment period. The
specific temperature can be any specific temperature within the
range, for example the range of about -15 to about 4 Celsius
degrees, the range of about 4 to about 15 Celsius degrees, or other
ranges so long as the up-limit of the temperature of about 15
Celsius degrees.
[0039] In other embodiments, the cooling temperature varies within
a preset range, for example, the range of about -15 to about 4
Celsius degrees or the range of about 4 to about 15 Celsius
degrees, during the treatment period. In some instances, the
variation of temperature with the preset range may follow a preset
program. For example, in a preset range of about -15 to about 4
Celsius degrees for a cooling period or treatment period of 2
hours, the temperature may be about -10 Celsius degree in the first
hour and then zero Celsius degree in the second hour.
[0040] In some embodiments, the cooling temperature is controlled
by a temperature controller that is connected to the cooling device
or integrated in the cooling device. In some instances, the
temperature controller may be manually controlled by a person, who
may be the subject under treatment or may be a caregiver. In other
instances, the temperature controller may be automatically
controlled to adjust the cooling temperature according to a preset
program. The temperature controller maybe digital controller with
0.1 Celsius degree resolution or mechanical controller with broader
set points (1 Celsius degree or low/medium/high) known in the
art.
[0041] The cooling period may vary. In some embodiments, the
cooling period ranges from about 15-30 minutes. In other
embodiments, the cooling period ranges from about 30 minutes to 2
hours. In still other embodiments, the cooling period ranges from
about 2-4 hours.
[0042] In some embodiment, the cooling treatment may be performed
once daily for 1-7 days. In some embodiments, the cooling treatment
may be performed once daily for 7-14 days. In still other
embodiments, the cooling treatment may be performed once daily for
14-21 days. In further embodiments, the cooling treatment may be
performed once daily for more than 21 days. In some embodiments,
the once daily treatment means once every 24 hour treatment. In
other embodiments, the interval between two treatments may vary
between 20-24 hours.
[0043] In some embodiment, the cooling treatment may be performed
twice daily for 1-7 days. In some embodiments, the cooling
treatment may be performed twice daily for 7-14 days. In still
other embodiments, the cooling treatment may be performed twice
daily for 14-21 days. In further embodiments, the cooling treatment
may be performed twice daily for more than 21 days.
[0044] In a twice daily regime, the two treatments in a single day
may be consecutive or not consecutive. In some embodiments, the
interval between two non-consecutive treatments may be 5 minutes to
an hour. In other embodiments, the interval between two
non-consecutive treatments may be 1-2 hours. In still other
embodiments, the interval between two non-consecutive treatments
may be 2-4 hours. In still other embodiments, the interval between
two non-consecutive treatments may be 4-6 hours. In still other
embodiments, the interval between two non-consecutive treatments
may be 6-8 hours. In still other embodiments, the interval between
two non-consecutive treatments may be 8-10 hours. In still other
embodiments, the interval between two non-consecutive treatments
may be 10-12 hours.
[0045] In some embodiment, the cooling treatment may be performed
thrice daily for 1-7 days. In some embodiments, the cooling
treatment may be performed thrice daily for 7-14 days. In still
other embodiments, the cooling treatment may be performed thrice
daily for 14-21 days. In further embodiments, the cooling treatment
may be performed thrice daily for more than 21 days. In a thrice
daily regime, the three treatments in a single day may be performed
consecutively or not consecutively. In some embodiment, the
interval between non-consecutive treatments may vary from minutes
to hours.
[0046] In some embodiments, the cooling treatment may be performed
intermittently. In some instance, one may skip the cooling
treatment for one day. In other instances, one may skip the cooling
treatment for two consecutive days. In still other instance, one
may skip the cooling treatment for three consecutive days.
[0047] In some embodiments, the cooling treatment may be performed
every other day. On other embodiments, the cooling treatment may be
performed once every three days. In still other embodiments, the
cooling treatment may be performed once every four days. In further
still other embodiments, the cooling treatment may be performed
once every five days.
[0048] In some embodiments, the cooling period can be automatically
set up by a timer that is connected to the cooling device. In other
embodiments, the cooling period is setup by a manually controlled
timer. In still other embodiments, the cooling period is not set up
by a timer, but instead timed manually. The timer may be digital or
mechanical with 1 minute set point known in the art.
[0049] In other embodiments, an additional step of applying
electroacupuncture to one or more regions selected from the group
consisting of the neck, the supraclavicular and the interscapular
regions is carried out. The application of electroacupuncture may
increase the insulin sensitizing efficiency of Coldia treatments
and improve the comfortableness during Coldia treatments. In some
instances, the additional step may be carried out during the
cooling period. In other instances, the additional step may be
carried out prior to the cooling period. In still other instances,
the additional step may be carried out after the cooling period. In
still other instances, the additional step may be carried out
partially overlapping the cooling period.
[0050] The electroacupuncture may be carried out with a separate
electroacupuncture device that is known in the art. Alternatively,
the electroacupuncture may be integrated within the cooling device.
In some embodiments, the electroacupuncture device may be those as
disclosed in the present disclosure as described below.
[0051] II. Methods for Preventing, Delaying or Treating type 2
diabetes in a Human Subject
[0052] In another aspect, the present disclosure is directed to a
method of preventing, delaying or treating type 2 diabetes in a
human subject. In one embodiment, the method comprises the steps of
contacting one or more regions of the neck, the supraclavicular,
and the interscapular regions of the human subject with a part of a
cooling device with a cooling temperature at about 15 or less
Celsius degrees, cooling the one or more regions of the neck, the
supraclavicular, and the interscapular regions of the human subject
for a cooling period of at least 15 minutes, and performing above
two steps daily for about 14 or more days.
[0053] In the above embodiment, the selective location of the
cooling unit on a human body prevents the unnecessary heat loss
from other body regions, particularly the extremities where most of
the discomfort of cold feeling comes from. Because of the selective
cooling strategy, in some embodiments, the cooling temperature can
go down to about -15.degree. C. to about 4.degree. C. Celsius
degrees so as to improve the cooling efficiency without causing
damage of the skin. In other embodiments, the subjects are more
sensitive to cooling, the cooling temperature ranges from 4 to 15
Celsius degrees.
[0054] In some embodiments, the cooling temperature is set at a
specific temperature during the whole treatment period. The
specific temperature can be any specific temperature within the
range, for example the range of about -15 to about 4 Celsius
degrees, the range of about 4 to about 15 Celsius degrees, or other
ranges so long as the up-limit of the temperature of about 15
Celsius degrees.
[0055] In other embodiments, the cooling temperature varies within
a preset range, for example, for example the range of about -15 to
about 4 Celsius degrees or the range of about 4 to about 15 Celsius
degrees, during the treatment period. In some instances, the
variation of temperature with the preset range may follow a preset
program. For example, in a preset range of about -15 to about 4
Celsius degrees for a cooling period or treatment period of 2
hours, the temperature may be about -10 Celsius degree in the first
hour and then zero Celsius degree in the second hour.
[0056] In some embodiments, the cooling temperature is controlled
by a temperature controller that is connected to the cooling device
or integrated in the cooling device. In some instances, the
temperature controller may be manually controlled by a person, who
may be the subject under treatment or may be a caregiver. In other
instances, the temperature controller may be automatically
controlled to adjust the cooling temperature according to a preset
program. The temperature controller may be a digital controller
with 0.1 Celsius degree resolution or mechanical controller with
broader set points (1 Celsius degree or low/medium/high) known in
the art.
[0057] The cooling period may vary. In some embodiments, the
cooling period ranges from about 15-30 minutes. In other
embodiments, the cooling period ranges from 30 minutes to 2 hours.
In still other embodiments, the cooling period ranges from about
2-4 hours.
[0058] In some embodiment, the cooling treatment may be performed
once daily for 1-7 days. In some embodiments, the cooling treatment
may be performed once daily for 7-14 days. In still other
embodiments, the cooling treatment may be performed once daily for
14-21 days. In further embodiments, the cooling treatment may be
performed once daily for more than 21 days. In some embodiments,
the once daily treatment means once every 24 hour treatment. In
other embodiments, the interval between two treatments may vary
between 20-24 hours.
[0059] In some embodiment, the cooling treatment may be performed
twice daily for 1-7 days. In some embodiments, the cooling
treatment may be performed twice daily for 7-14 days. In still
other embodiments, the cooling treatment may be performed twice
daily for 14-21 days. In further embodiments, the cooling treatment
may be performed twice daily for more than 21 days.
[0060] In a twice daily regime, the two treatments in a single day
may be consecutive or not consecutive. In some embodiments, the
interval between two non-consecutive treatments may be 5 minutes to
an hour. In other embodiments, the interval between two
non-consecutive treatments may be 1-2 hours. In still other
embodiments, the interval between two non-consecutive treatments
may be 2-4 hours. In still other embodiments, the interval between
two non-consecutive treatments may be 4-6 hours. In still other
embodiments, the interval between two non-consecutive treatments
may be 6-8 hours. In still other embodiments, the interval between
two non-consecutive treatments may be 8-10 hours. In still other
embodiments, the interval between two non-consecutive treatments
may be 10-12 hours.
[0061] In some embodiment, the cooling treatment may be performed
thrice daily for 1-7 days. In some embodiments, the cooling
treatment may be performed thrice daily for 7-14 days. In still
other embodiments, the cooling treatment may be performed thrice
daily for 14-21 days. In further embodiments, the cooling treatment
may be performed thrice daily for more than 21 days. In a thrice
daily regime, the three treatments in a single day may be performed
consecutively or not consecutively. In some embodiment, the
interval between non-consecutive treatments may vary from minutes
to hours.
[0062] In some embodiments, the cooling treatment may be performed
intermittently. In some instance, one may skip the cooling
treatment for one day. In other instances, one may skip the cooling
treatment for two consecutive days. In still other instance, one
may skip the cooling treatment for three consecutive days.
[0063] In some embodiments, the cooling treatment may be performed
every other day. On other embodiments, the cooling treatment may be
performed once every three days. In still other embodiments, the
cooling treatment may be performed once every four days. In further
still other embodiments, the cooling treatment may be performed
once every five days.
[0064] In some embodiments, the cooling period can be automatically
set up by a timer that is connected to the cooling device. In other
embodiments, the cooling period is setup by a manually controlled
timer. In still other embodiments, the cooling period is not set up
by a timer, but instead timed manually. The timer may be digital or
mechanical with 1 minute set point known in the art.
[0065] In other embodiments, an additional step of applying
electroacupuncture to one or more regions selected from the group
consisting of the neck, the supraclavicular and the interscapular
regions is carried out. The application of electroacupuncture may
increase the insulin sensitizing efficiency of Coldia treatments
and improve the comfortableness during Coldia treatments. In some
instances, the additional step may be carried out during the
cooling period. In other instances, the additional step may be
carried out prior to the cooling period. In still other instances,
the additional step may be carried out after the cooling period. In
still other instances, the additional step may be carried out
partially overlapping the cooling period.
[0066] The electroacupuncture may be carried out with a separate
electroacupuncture device that is known in the art. Alternatively,
the electroacupuncture may be integrated within the cooling device.
In some embodiments, the electroacupuncture device may be those as
disclosed in the present disclosure as described below.
[0067] III. Methods for Activating Brown Fat without Incurring a
Sympathetic Nerve-Mediated Cold Feeling in a Human Subject
[0068] In another aspect, the present disclosure is directed to a
method of activating brown fat without incurring a sympathetic
nerve-mediated cold feeling in a human subject.
[0069] Coldness is the classic activator of BAT and the nature of
BAT is to generate heat to defend body temperature during cold
environment. It involves multiple processes coordinated with
different organs: skin sensing of the cold, sympathetic neuronal
stimulation, brown adipocyte activation, blood flow increase to the
activated region (8-10). Coldness activates the whole spectrum of
pathways in multiple types of cells, including brown adipocytes
themselves, endothelial cells for vascularization, neurons for
innervation and immune cells (11-13).
[0070] The alternatives to activate BAT is by pharmacological
reagents that the scientific community and pharmaceutical industry
spend billions of dollars on (14). There are some potent browning
candidates identified over the past decade from in vitro screening
or rodent studies, however their effectiveness in humans and safety
concerns restrict their clinical applications (15). For example,
the major class of BAT activators, .beta.-adrenergic receptor
agonists, robustly activates BAT in mice but works poorly in humans
(16, 17). Thyroid hormones activate BAT efficiently and it is
naturally synthesized in humans, however, its safety should be
closely watched due to overdosing lethality (18, 19). The
insulin-sensitizing FGF21 and TZDs induces BAT activity but also
cause bone loss (4, 20). The angiongenic factor VEGF-A is able to
induce browning in mice (21) but its obvious cancer risks dampen
its therapeutic potential (22).
[0071] Comparing to all of these pharmacological reagents, coldness
has a unique advantage, the safety. It decreases heart rate and
blood pressure rather than the increase of cardiovascular risks,
improves bone and muscle health rather than fracture, and has no
risks for cancer. Moreover, any chemical or biological reagent to
activate BAT has to consider dose and clearance time to treat
humans, but these problems do not exist for coldness-induced BAT
activation. Therefore, coldness represents the most efficient but
least expensive, natural and safe approach to activate BAT.
[0072] Cold approaches to humans presently include immersing a limb
into icy water, staying in climate-controlled rooms or
water-circulating incubator. These approaches are completely
dependent on cold feeling-stimulated sympathetic nerve activity.
However, none of these approaches can be applied to free-living
individuals or is practically operational. And it is unrealistic to
treat patients with coldness because of the uncomfortableness
although cold prescription has been suggested to treat obesity and
diabetes (13).
[0073] The Coldia treatment is different from the traditional way
of activating BAT, which depends on the sympathetic nerve mediated
cold feeling. Adipocyte can directly sense the coldness and
activate thermogenic response (23). The Coldia treatment disclosed
in the present application directly stimulates the BAT around one
or more regions of neck, supraclavicular and interscapular regions
without causing the unnecessary cold feeling from non-BAT regions,
particularly the extremities where most of the uncomfortableness
come from.
[0074] In one embodiment, the method comprises the steps of
contacting one or more regions of the neck, the supraclavicular,
and the interscapular regions of the human subject with a part of a
cooling device with a cooling temperature at about 15 or less
Celsius degrees, cooling the one or more regions of the neck, the
supraclavicular, and the interscapular regions of the human subject
for a cooling period of at least 15 minutes, and performing above
two steps daily for about 14 or more days.
[0075] In the above embodiment, the selective location of the
cooling unit on a human body prevents the unnecessary heat loss
from other body regions, particularly the extremities where most of
the discomfort of cold feeling comes from. Because of the selective
cooling strategy, in some embodiments, the cooling temperature can
go down to about -15.degree. C. to about 4.degree. C. Celsius
degrees so as to improve the cooling efficiency without causing
damage of the skin. In other embodiments, the subjects are more
sensitive to cooling, the cooling temperature ranges from about 4
to about 15 Celsius degrees.
[0076] In some embodiments, the cooling temperature is set at a
specific temperature during the whole treatment period. The
specific temperature can be any specific temperature within the
range, for example the range of about -15 to about 4 Celsius
degrees, the range of about 4 to about 15 Celsius degrees, or other
ranges so long as the up-limit of the temperature of about 15
Celsius degrees.
[0077] In other embodiments, the cooling temperature varies within
a preset range, for example, for example the range of about -15 to
about 4 Celsius degrees or the range of about 4 to about 15 Celsius
degrees, during the treatment period. In some instances, the
variation of temperature with the preset range may follow a preset
program. For example, in a preset range of about -15 to about 4
Celsius degrees for a cooling period or treatment period of 2
hours, the temperature may be about -10 Celsius degree in the first
hour and then zero Celsius degree in the second hour.
[0078] In some embodiments, the cooling temperature is controlled
by a temperature controller that is connected to the cooling device
or integrated in the cooling device. In some instances, the
temperature controller may be manually controlled by a person, who
may be the subject under treatment or may be a caregiver. In other
instances, the temperature controller may be automatically
controlled to adjust the cooling temperature according to a preset
program. The temperature controller may be a digital controller
with 0.1 Celsius degree resolution or mechanical controller with
broader set points (1 Celsius degree or low/medium/high) known in
the art.
[0079] The cooling period may vary. In some embodiments, the
cooling period ranges from 15-30 minutes. In other embodiments, the
cooling period ranges from 30 minutes to 2 hours. In still other
embodiments, the cooling period ranges from 2-4 hours.
[0080] In some embodiment, the cooling treatment may be performed
once daily for 1-7 days. In some embodiments, the cooling treatment
may be performed once daily for 7-14 days. In still other
embodiments, the cooling treatment may be performed once daily for
14-21 days. In further embodiments, the cooling treatment may be
performed once daily for more than 21 days. In some embodiments,
the once daily treatment means once every 24 hour treatment. In
other embodiments, the interval between two treatments may vary
between 20-24 hours.
[0081] In some embodiment, the cooling treatment may be performed
twice daily for 1-7 days. In some embodiments, the cooling
treatment may be performed twice daily for 7-14 days. In still
other embodiments, the cooling treatment may be performed twice
daily for 14-21 days. In further embodiments, the cooling treatment
may be performed twice daily for more than 21 days.
[0082] In a twice daily regime, the two treatments in a single day
may be consecutive or not consecutive. In some embodiments, the
interval between two non-consecutive treatments may be 5 minutes to
an hour. In other embodiments, the interval between two
non-consecutive treatments may be 1-2 hours. In still other
embodiments, the interval between two non-consecutive treatments
may be 2-4 hours. In still other embodiments, the interval between
two non-consecutive treatments may be 4-6 hours. In still other
embodiments, the interval between two non-consecutive treatments
may be 6-8 hours. In still other embodiments, the interval between
two non-consecutive treatments may be 8-10 hours. In still other
embodiments, the interval between two non-consecutive treatments
may be 10-12 hours.
[0083] In some embodiment, the cooling treatment may be performed
thrice daily for 1-7 days. In some embodiments, the cooling
treatment may be performed thrice daily for 7-14 days. In still
other embodiments, the cooling treatment may be performed thrice
daily for 14-21 days. In further embodiments, the cooling treatment
may be performed thrice daily for more than 21 days. In a thrice
daily regime, the three treatments in a single day may be performed
consecutively or not consecutively. In some embodiment, the
interval between non-consecutive treatments may vary from minutes
to hours.
[0084] In some embodiments, the cooling treatment may be performed
intermittently. In some instance, one may skip the cooling
treatment for one day. In other instances, one may skip the cooling
treatment for two consecutive days. In still other instance, one
may skip the cooling treatment for three consecutive days.
[0085] In some embodiments, the cooling treatment may be performed
every other day. On other embodiments, the cooling treatment may be
performed once every three days. In still other embodiments, the
cooling treatment may be performed once every four days. In further
still other embodiments, the cooling treatment may be performed
once every five days.
[0086] In some embodiments, the cooling period can be automatically
set up by a timer that is connected to the cooling device. In other
embodiments, the cooling period is setup by a manually controlled
timer. In still other embodiments, the cooling period is not set up
by a timer, but instead timed manually. The timer may be digital or
mechanical with 1 minute set point known in the art.
[0087] In other embodiments, an addition step of applying
electroacupuncture to one or more regions selected from the group
consisting of the neck, the supraclavicular and the interscapular
regions is carried out. The application of electroacupuncture may
increase the insulin sensitizing efficiency of Coldia treatments
and improve the comfortableness during Coldia treatments. In some
instances, the additional step may be carried out during the
cooling period. In other instances, the additional step may be
carried out prior to the cooling period. In still other instances,
the additional step may be carried out after the cooling period. In
still other instances, the additional step may be carried out
partially overlapping the cooling period.
[0088] The electroacupuncture may be carried out with a separate
electroacupuncture device that is known in the art. Alternatively,
the electroacupuncture may be integrated within the cooling device.
In some embodiments, the electroacupuncture device may be those as
disclosed in the present disclosure as described below.
[0089] IV. Cooling Devices
[0090] In another aspect, the present disclosure is directed to a
cooling device. In some embodiments, the cooling device is an ice
pad or other similar cooling materials, which can be directly
applied to cool desired body regions.
[0091] In other embodiments, the cooling device comprises a
body-contacting vest that directly contacts one or more regions of
the neck, the supraclavicular and the interscapular regions, a tube
that is filled with cooling media and partially contacts the
body-contacting vest, and a refrigeration part that cools the
cooling media in the tube, which cooling media in turn cools the
body-contacting vest to a specified temperature of 15 Celsius
degree or below.
[0092] In some embodiments, the body-contacting vest is made to fit
the neck, the supraclavicular and the interscapular regions. In
other embodiments, the body-contacting vest is made to fit one or
more regions of the neck regions only. In still other embodiments,
the body-contacting vest is made to fit the supraclavicular regions
only. In still other embodiments, the body-contacting vest is made
to fit the interscapular regions only. In still other embodiments,
the body-contacting vest is made to fit the neck and the
supraclavicular regions only. In still other embodiments, the
body-contacting vest is made to fit the neck and the interscapular
regions only. In still other embodiments, the body-contacting vest
is made to fit the supraclavicular and the interscapular regions
only.
[0093] In some embodiments, the body-contacting vest is made of
fabric. The fabric can be a fabric known in the art. In other
embodiments, the body-contacting vest is made of carbon fibers. In
still other embodiments, the body-contacting vest is made of metal.
In the body-contacting vest may be cooled to a temperature range of
about -15 to about 15 Celsius degrees.
[0094] In some embodiments, the refrigeration part is a cyclic
refrigeration. The cyclic refrigeration can be any refrigeration
system with sufficient power to lower the temperature of cooling
media to a designed range. The cooling media or fluid circulates
between refrigeration system and cooling tube. In some instances,
the cooling media or fluid may be salted water, or any other low
melting temperature fluid. The electricity circuit for compressor
may be separated from those used for other parts of the cooling
device.
[0095] In other embodiments, the refrigeration part is a
thermoelectric refrigeration system. In some embodiments, the
cooling side of the thermoelectric refrigeration system may face
the skin and applied directly to the vest without the need for the
tube and cooling media.
[0096] In some embodiments, the cooling device further comprises an
electroacupuncture unit with at least one pair of electrodes. In
some embodiments, the electrodes are implanted in the cooling
device. The electrodes may be low voltage electricity circuit,
which is separated from the circuit for refrigeration system. An
exemplary electroacupuncture device has the parameters shown in
Table 1.
TABLE-US-00001 TABLE 1 Exemplary EA Output: DC 5-9 V Wave form:
Pulse and biphasic Pulse duration: 100 .mu.s Frequency: <70 Hz,
with 0.01-1 Hz modulating frequency Pulse period: 10-850
miliseconds Output current: 0-125 milliamps Output voltage range:
7-85 V (@ 500-10 k.OMEGA.) Wave shape: rectangular
[0097] In some embodiments, the cooling device further comprises a
controller for EA modes. Examples of such controller may be a
digital controller with 0.1 Celsius degree resolution or mechanical
controller with broader set points (1 Celsius degree or
low/medium/high) known in the art.
[0098] In some embodiments, the cooling device further comprises a
timer to pre-set the cooling period. Examples of such timer may be
a digital or mechanical timer with 1 minute set point known in the
art.
[0099] In some embodiments, the cooling device may be a mobile
device that can be used at home or at work. In some instance, the
power for the mobile cooling device may be supplied via wire
electricity. In other instances, the power may be supplied by a
rechargeable battery. In some instances, the mobile cooling device
may be wearable and thus there is no need for the human subject to
maintain a certain position during the treatment. In some further
instances, the mobile cooling device may also be applied at ambient
temperature room without staying in a cold environment during the
treatment.
[0100] In other embodiments, the cooling device may be a stationary
device. In some instances, the stationary cooling device may
comprise an integrated electricity-powered refrigeration system
together with cooling tubes and cooling vest, which is further
incorporated with EA. In other instances, the stationary cooling
device may further comprise heart monitor system, insulin
sensitivity measuring and entertaining system. Stationary cooling
devices may be preferably used in hospital or rehabilitation
centers.
[0101] As used in this application, including the appended claims,
the term "about," particularly in reference to a given quantity, is
meant to encompass deviations of plus or minus ten percent.
[0102] As used herein, the singular forms "a," "an," and "the"
include plural references, unless the content clearly dictates
otherwise, and are used interchangeably with "at least one" and
"one or more."
[0103] As used herein, the terms "comprises," "comprising,"
"includes," "including," "contains," "containing," and any
variations thereof, are intended to cover a non-exclusive
inclusion, such that a process, method, product-by-process, or
composition of matter that comprises, includes, or contains an
element or list of elements does not include only those elements
but can include other elements not expressly listed or inherent to
such process, method, product-by-process, or composition of
matter.
[0104] As used herein, the term "resistance" as used in insulin
resistance, means that the subject does not show a response to a
substance based on an underlying ability of cells to escape the
effect of the substance. Resistance includes de novo resistance and
acquired resistance. A human subject that exhibit de novo
resistance do not respond to the substance from the start. However,
in acquired resistance, the cells initially respond to a substance
but eventually acquire resistance to it. The cells might also show
cross-resistance to other structurally and mechanistically
unrelated substance--a phenomenon commonly known as multi drug
resistance (MDR). Owing to acquisition of MDR, treatment regimens
that combine multiple agents with different targets are no longer
effective.
EXAMPLES
1. Normalization of Impaired Blood Glucose by Coldia Treatment
[0105] The example describes the use of the Coldia treatment in the
normalization of impaired blood glucose homeostasis in a human
subject with insulin resistance. Specifically, a healthy male who
has insulin resistance and impaired fasting glucose levels
underwent the Coldia treatment. Ice pads were used as a cooling
device in this example. Ice pads were directly applied to the neck,
the supraclavicular, and the interscapular regions of the human
subject for a duration of two hours daily. The treatment lasted for
60 days, during which time the human subject maintained his normal
work-outs and diets. Fasting glucose levels were measured every
morning. Fasting glucose levels are indications for insulin
resistance and the diagnosis of type II diabetes.
[0106] As shown in FIG. 1, when the Coldia treatment started, the
human subject is in a pre-diabetes status with fasting glucose
levels above 100 mg/dl. About 14 days after the Coldia treatment,
the fasting glucose levels fell below 100 mg/dl and stayed below
100 mg/dl during the whole remaining treatment period to day 60.
The Coldia treatment in a human subject with insulin resistance
therefore can result in the normalization of impaired blood glucose
homeostasis, which may improve insulin sensitivity, delay or
prevent the onset of hyperglycemia and diabetes, reduce the
severity or even cure diabetes and the associated co-morbidities,
including dyslipidemia, cardiovascular risks.
2. Maintenance of the Normal Blood Glucose Levels After Coldia
Treatment
[0107] This example describes that the fasting glucose levels stay
in the normal range in a human subject with insulin resistance even
after the Coldia treatment is stopped in the human subject.
Specifically, following the Coldia treatment in Example A, the
fasting glucose was monitored for another three months
post-treatment. As shown in FIG. 2, the fasting glucose from Coldia
treatment was maintained in the normal range for 3 months.
3. A Cooling Device for the Coldia treatment
[0108] This example describes one embodiment of the cooling device
that can be used for the Coldia treatment. As shown in FIG. 3, the
cooling device comprises a refrigerator 1, the tube 2, and the vest
3. The refrigerator 1 comprises a compressor 4, a cooling tank 6,
and a motor 7. The compressor 4 is used for active cooling. The
exemplary compressor has the parameters shown in Table 2. The
cooling media 5 in the cooling tank 6 is cooled down by compressor
refrigeration, and then pumped to the cooling tube 10 via the
inflow tube 8 by the motor 7. The cooling media 5 in the cooling
tube 10 cools the part of the vest 3 that contacts the cooling tube
10. The cooled vest 3 directly contacts the targeted body regions.
As a result, the cooling media takes heat away from the targeted
body regions and is circulated back to the cooling tank 6 through
the outflow tube 9.
TABLE-US-00002 TABLE 2 Parameters of a compressor. Compressor model
CW-5300 Voltage 220 VAC Output watt 0.75 KW Compressor watt 1.67 KW
coolant R-134a Cooling fluid ethylene glycol Fluid volume 9 L
Temperature 5-25.degree. C. Temp. Accurancy .+-.0.3.degree. C.
4. Improved Glucose Homeostasis and Insulin Sensitivity After
Coldia Treatment
[0109] This example describes additional embodiments of Coldia
treatment to improve glucose homeostasis and insulin sensitivity.
Specifically, two newly identified insulin resistant patients (1
male, 1 female) received Coldia treatment (2 hours daily) for 8
weeks. Specifically, in this particular Coldia treatment, a cooling
vest with ice pads was used to cover and cool the neck,
supraclavicular, and interscapular regions once daily for 8 weeks.
Each cooling treatment lasted for about 2 hours. EA was performed
concurrently with the cooling treatment in the first 30 minutes of
each cooling treatment.
[0110] Diabetes-related tests were performed before and after the
treatment. The test results are shown in Table 3 below.
[0111] In both patients, BMIs were slightly decreased after 8-weeks
Coldia treatment, from 25.6 to 24.93 and 24.13 to 23.34
respectively. HOMA-IR was significantly improved, from 5.67 to 3.88
and 8.35 to 5.79 in the two patients, respectively.
[0112] In both patients, glucose intolerance was completely
normalized after the treatment. As shown in FIG. 4, the glucose
level at 2 hours post glucose administration were normalized from
8.53 to 5.45 in patient #1. FIG. 5 shows that the glucose level at
2 hours post glucose administration were normalized from 10.16 to
4.27 in patient #2.
[0113] In addition, the insulin release during oral glucose
tolerance was also significantly decreased in both patients. As
shown in FIG. 6, the 2 hr insulin and 3 hr insulin in patient #1
were reduced from 136.8 to 57.3, and from 99.9 to 24.9,
respectively. As shown in FIG. 7. the 2 hr insulin and 3 hr insulin
in patient #2 were reduced from 171.2 to 25.7, and from 162.2 to
18.3, respectively. These data showed improvement of insulin
sensitivity and beta-cell function in both patients.
[0114] Coldia treatment did not affect heart functions and liver
lipid metabolism as there is no significant changes of blood
pressure, hear rate, Triglycerides, LDL-C or HDL-C. See Table 3.
This example showed that Coldia treatment for 8 weeks significantly
improved glucose homeostasis and insulin sensitivity, and even
cured early stage type 2 diabetes. Therefore, Coldia treatment can
be an efficient way to manage diabetes.
TABLE-US-00003 TABLE 3 Testing results after Coldia treatment for
eight weeks. Patient #1 Patient #2 Age 55 49 Sex Male Female Normal
Treatment Time Range 0 W 8 W 0 W 8 W Body Weight (kg) 81 79 61 59
Height (m) 1.78 1.78 1.59 1.59 BMI (kg/m.sup.2) 25.6 24.93 24.13
23.34 Waist Circumference 97 97 83 82 (cm) Hip Circumference 104
102 97 100 (cm) Waist-Hip Ratio 0.93 0.95 0.86 0.82 Glucose Control
and Insulin Resistance HOMA-IR (Fasting <2.5 5.67 3.88 8.35 5.79
Glucose .times. Fasting Insulin/22.5) HbA1c (%) 4-6 5.8 6.2 5.9
Fasting Glucose 3.9-6.1 5.32 5.17 5.62 5.61 (mmol/L) 1 hour Oral
Glucose 8.56 8.61 11.83 8.69 Tolerance (mmol/L) 2 hour Oral Glucose
<7.8 8.53 5.45 10.16 4.27 Tolerance (mmol/L) 3 hour Oral Glucose
4.93 4.58 8.82 5.14 Tolerance (mmol/L) Fasting Insulin 5.0-25.0
24.0 16.8 33.3 23.1 (mIU/L) 1 hr Insulin (mIU/L) 81.9 109.1 333.8
118.0 2 hr Insulin (mIU/L) 136.8 57.3 171.2 25.7 3 hr Insulin
(mIU/L) 99.9 24.9 162.2 18.3 Cardiovascular Function Blood Pressure
120/90 132/85 116/78 120/63 Systolic/Diastolic (mmHg) Heart Rate
(bmp) 76 80 60 63 Lipids Triglycerides 0.56-1.47 1.86 1.75 4.40
5.40 (mmol/L) LDL-C (mmol/L) 2.7-3.1 4.02 3.45 2.66 3.22 HDL-C
(mmol/L) 1.29-1.55 1.12 1.06 0.65 0.78
REFERENCE
[0115] 1. WHO. Obesity: preventing and managing the global
epidemic. Report of a WHO consultation. World Health Organization
technical report series. 2000;894:i-xii, 1-253. 2. Stevens G A,
Singh G M, Lu Y, Danaei G, Lin J K, Finucane M M, et al. National,
regional, and global trends in adult overweight and obesity
prevalences. Population health metrics. 2012;10(1):22.
3. CDC. National Diabetes Statistics Report: Estimates of Diabetes
and Its Burden in the United States, 2014. US Department of Health
and Human Services. 2014.
[0116] 4. Ahmadian M, Suh J M, Hah N, Liddle C, Atkins A R, Downes
M, et al. PPARgamma signaling and metabolism: the good, the bad and
the future. Nat Med. 2013;19(5):557-66. 5. Stein S A, Lamos E M,
and Davis S N. A review of the efficacy and safety of oral
antidiabetic drugs. Expert opinion on drug safety. 2013;12(2):
153-75. 6. Lee P, Smith S, Linderman J, Courville A B, Brychta R J,
Dieckmann W, et al. Temperature-acclimated brown adipose tissue
modulates insulin sensitivity in humans. Diabetes.
2014;63(11):3686-98. 7. Hanssen M J, Hoeks J, Brans B, van der Lans
A A, Schaart G, van den Driessche J J, et al. Short-term cold
acclimation improves insulin sensitivity in patients with type 2
diabetes mellitus. Nat Med. 2015;21(8):863-5. 8. Cannon B, and
Nedergaard J. Brown adipose tissue: function and physiological
significance. Physiological reviews. 2004;84(1):277-359. 9. Cannon
B, Houstek J, and Nedergaard J. Brown adipose tissue. More than an
effector of thermogenesis? Ann N Y Acad Sci. 1998;856:171-87. 10.
Cannon B, Shabalina I G, Kramarova T V, Petrovic N, and Nedergaard
J. Uncoupling proteins: a role in protection against reactive
oxygen species--or not? Biochim Biophys Acta.
2006;1757(5-6):449-58. 11. Kajimura S, Seale P, and Spiegelman B M.
Transcriptional control of brown fat development. Cell Metab.
2010;11(4):257-62. 12. Rosen E D, and Spiegelman B M. What we talk
about when we talk about fat. Cell. 2014;156(1-2):20-44. 13. Harms
M, and Seale P. Brown and beige fat: development, function and
therapeutic potential. Nat Med. 2013;19(10):1252-63. 14. Wu J,
Cohen P, and Spiegelman B M. Adaptive thermogenesis in adipocytes:
is beige the new brown? Genes Dev. 2013;27(3):234-50. 15. Cypess A
M, Haft C R, Laughlin M R, and Hu H H. Brown fat in humans:
consensus points and experimental guidelines. Cell Metab.
2014;20(3):408-15. 16. Buemann B, Toubro S, and Astrup A. Effects
of the two beta3-agonists, ZD7114 and ZD2079 on 24 hour energy
expenditure and respiratory quotient in obese subjects. Int J Obes
Relat Metab Disord. 2000;24(12): 1553-60. 17. Arch J R.
beta(3)-Adrenoceptor agonists: potential, pitfalls and progress.
European journal of pharmacology. 2002;440(2-3):99-107. 18. Mullur
R, Liu Y Y, and Brent G A. Thyroid hormone regulation of
metabolism. Physiological reviews. 2014;94(2):355-82. 19. Chen W,
Yang Q, and Roeder R G. Dynamic interactions and cooperative
functions of PGC-1 alpha and MED 1 in TRalpha-mediated activation
of the brown-fat-specific UCP-1 gene. Molecular cell.
2009;35(6):755-68. 20. Wei W, Dutchak P A, Wang X, Ding X, Wang X,
Bookout A L, et al. Fibroblast growth factor 21 promotes bone loss
by potentiating the effects of peroxisome proliferator-activated
receptor gamma. Proc Natl Acad Sci USA. 2012;109(8):3143-8. 21. Sun
K, Kusminski C M, Luby-Phelps K, Spurgin S B, An YA, Wang Q A, et
al. Brown adipose tissue derived VEGF-A modulates cold tolerance
and energy expenditure. Molecular metabolism. 2014;3(4):474-83. 22.
Goel H L, and Mercurio A M. VEGF targets the tumour cell. Nature
reviews Cancer. 2013;13(12):871-82. 23. Ye L, Wu J, Cohen P, Kazak
L, Khandekar M J, Jedrychowski M P, et al. Fat cells directly sense
temperature to activate thermogenesis. Proc Natl Acad Sci USA.
2013;110(30):12480-5.
* * * * *