Pain Expression and the Metabolic Syndrome - David R. Seaman
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Pain Expression and the Metabolic Syndrome by David R. Seaman, DC, MS, DABCN

Pain Expression and the Metabolic Syndrome by David R. Seaman, DC, MS, DABCN

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  • 1. Pain expression and themetabolic syndrome David R. Seaman, DC, MS, DABCN pain basic Professor, Clinical Sciences National University of Health Sciences St. Petersburg, Florida mechanisms deflame@deflame.com
 Glial cytokine release NTS 3. IL-1, IL-6, TNF, PGE2, ROS 1. IL-1, IL-6, TNF, PGE2, ** 2. IL-1, IL-6, ROS TNF, PGE2, ROS ** Cord glia meditators enhance group IV mediator release & 2nd order neuron excitability© 2005 Dr. David Seaman DAcquisto F, May MJ, Ghosh S. Inhibition of Nuclear Factor Kappa B (NF-B): An Emerging Theme in Anti- Inflammatory Therapies. Mol Interv. 2002 ;2(1):22-35 1
  • 2. NF-kB and Pain •  Pro-inflammatory cytokines such as tumor necrosis NF-kB and Pain & chronic disease factor-–3 Recently, it was reported that the transcription factor nuclear factor-kappa B plays a crucial role in Nuclear factor-kappa B is, thus, regulating pro-inflammatory cytokine gene expression and the transfer of nociceptive information. regarded to be one of the most •  Nuclear factor-kappa B decoy was conveyed and important targets for therapeutic transduced into dorsal root ganglion both in vivo and in intervention against inflammatory vitro. Additionally, nuclear factor-kappa B decoy reduced mechanical allodynia and thermal hyperalgesia in the rat diseases, such as rheumatoid inflammatory pain model, that inhibition of nuclear factor- kappa B with nuclear factor-kappa B decoy may represent arthritis, asthma, or inflammatory a key mechanism for mediating inflammation or reducing bowel disease. inflammatory pain.Inoue G et al. Injection of nuclear factor-kappa B decoy into the sciatic nerve Inoue G et al. Injection of nuclear factor-kappa B decoy into the sciatic nervesuppresses mechanical allodynia and thermal hyperalgesia in a rat inflammatory suppresses mechanical allodynia and thermal hyperalgesia in a rat inflammatorypain model. Spine. 2006;31:2904–2908 pain model. Spine. 2006;31:2904–2908 •  PGE2 (via PLA2 & COX) •  PGE2 (via PLA2 & COX) •  LTB4 (via PLA2 & LOX) •  LTB4 (via PLA2 & LOX) •  VEGF •  VEGF •  IL-1, IL-6, TNF •  IL-1, IL-6, TNF •  PLA2 •  PLA2 (corticosteroids) •  COX •  COX (NSAID, COX2 inhib, Tylenol) •  LOX •  LOX (Singulair) •  GFs: VEGF •  GFs: VEGF (Lucentis, Avastin) •  TNF •  TNF (Remicade etc.) •  IL-1 •  IL-1 (Kineret) •  IL-6 •  IL-6 (Actmera) •  CAM (cell adhesion molecules) •  CAM (cell adhesion molecules) •  MMPs (matrix metalloproteinases) •  MMPs (matrix metalloproteinases) Evans JL, Goldfine ID, Maddux BA, Grodsky Evans JL, Goldfine ID, Maddux BA, Grodsky GM. Oxidative stress and stress-activated GM. Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of signaling pathways: a unifying hypothesis of type 2 diabetes.Endocr Rev. 2002 ;23:599-622 type 2 diabetes.Endocr Rev. 2002 ;23:599-622 A self-perpetuating, •  PGE2 • IL-1, IL-6, TNFpro-inflammatory cycle •  LTB4 •  VEGF Excite group IV afferents and other local cells that release mediators. •  PLA2 (corticosteroids) •  COX (aspirin, NSAIDs, Tylenol) •  LOX (Singulair) •  VEGF (Avastin, Lucentis) •  TNF (Enbrel, Remicade, Humira) Nucleus ron α-motoneu © 2005 Dr. David Seaman γ-moto neuron 2
  • 3. •  Bradykinin •  Hydrogen ions •  Glutamate •  Prostaglandin E2 (E1,3) •  GABA •  Leukotriene B4 (B5) •  Acetylcholine •  Resolvins, lipoxins, NPs •  Norepinephrie •  Serotonin •  Adenosine Syndrome X basics •  Histamine •  Potassium •  Interleukin-1 •  ATP •  Interleukin-6 •  Estrogen •  Tumor necrosis factor •  Glucocorticoids •  Interleukin-10, [IL-4] •  CRF •  Endorphin •  Substance P •  Enkephalin •  Neurokinin A •  Dynorphin •  Cholecystokinin •  Nerve growth factor •  Somatostatin •  Brain-derived neurotrophic factor •  Bombesin •  Glial-derived neurotrophic factor •  Angiotensin II •  FGF, PDGF, VEGF •  Neuropeptide Y •  Substance P •  CGRP •  Glutamate •  Glycine •  GABA •  Acetylcholine •  Serotonin •  Bombesin •  Neuropeptide Y •  Neurotrophins •  TNF •  VIP ron α-motoneu© 2005 Dr. David Seaman γ-moto neuron Extent of syndrome X plus: •  40 million (1), 75 million (2) Americans have Syn X •  63% of men and 55% of women over age 25 in the United States are either overweight or obese (3) •  >60 million Americans have one or more types of St-Onge MP, Janssen I, cardiovascular disease Heymsfield SB. •  50 million Americans are hypertensive Metabolic syndrome in •  10 million Americans have type 2 diabetes normal-weight •  72 million American adults maintain total cholesterol/ Americans; new high-density lipoprotein (HDL) cholesterol ratios of 4.5 or definition of the metabolically obese, greater (2 to 3 best, want <4) normal weight individual. Diabetes Care 2004;27: 2222–8 If patients have three or more of the following risk factors, they are said to be suffering from syndrome X: 1. Fasting glucose of ≥110 (100) mg/dL 2. Triglycerides of ≥150 mg/dL 3. HDL cholesterol <40 mg/dL for men and <50 mg/dL for women 4. Blood pressure of ≥130/85 mmHg 5. Waist circumference of >40 inches for men and >35 inches for women Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the Third National Health and Nutrition Wilson PW, Grundy SM. The metabolic syndrome: practical guide to origins and treatment: Examination Survey. JAMA 2002;287:356–9. Part I. Circulation. 2003; 108:1422-24 3
  • 4. The evolution of man? The evolution of man? Jönsson T et al. A Paleolithic diet confers higher insulin sensitivity, lower C- reactive protein and lower blood pressure than a cereal-based diet in domestic pigs. Nutr Metab. 2006 3:39The evolution of man? 4
  • 5. 4972 kcal 4075 kcalAt the end of the study in the Paleolithic group:•  weight was 22% less Paleolithic Cereal (n=11) (n=12)•  subcutaneous fat thickness at mid sternum was 43% lower Weight (kg) 129 ± 16 166 ± 28•  dynamic insulin sensitivity was significantly higher (p =0.004) Length (cm) 159 ± 6 170 ± 9•  insulin response was significantly lower in the Paleolithic Subcutaneous 1.9 ± 0.4 3.3 ± 0.9group (p = 0.001) fat (cm)•  geometric mean of C-reactive protein was 82% lower (p = Body temp (°C) 37.7± 1.5 37.6 ± 0.50.0007) CRP (mcg/mL) 4.0 21.7•  intra-arterial diastolic blood pressure was 13% lower in the Systolic BP 140 ± 18 150 ± 9Paleolithic group (p = 0.007) Diasystolic BP 108 ± 12 123 ± 12•  no significant difference was seen in fasting glucosebetween groups Jönsson T et al. A Paleolithic diet confers higher insulin sensitivity,Jönsson T et al. A Paleolithic diet confers higher insulin sensitivity,lower C-reactive protein and lower blood pressure than a cereal-based lower C-reactive protein and lower blood pressure than a cereal-baseddiet in domestic pigs. Nutr Metab. 2006 3:39 diet in domestic pigs. Nutr Metab. 2006 3:39 Food Calories Fiber Mag++ K+ (mg) David before (grams) (mg) visiting 1.5 Glazed cousins in donuts 270 1.5 0* 0* 1 cup millet America. 280 3.2 100 150 2 cups oatmeal 290 8.0 112 262 3 piece white bread 240 2.1 21 108 4 piece whole wheat bread 280 7.6 96 284 6 cups st broccoli 264 27.6 228 3036 35 cups romaine 280 35 105 5670 Hands ES. Nutrients in food. Philadelphia: Lippincott Williams & Wilkins; 2000 5
  • 6. Food Cal Fiber (g) Mg (mg) K (mg) Soda & insulin sensitivity & wt gain1.5 glazed donut 270 1.5 0 0 •  Researchers recently concluded that whether it was diet or regular soda, consumption of 1 soft drink per day was1 cup millet 280 3.2 100 150 associated with increased odds of developing obesity,2 cups oatmeal 290 8.0 112 262 increased waist circumference, impaired fasting glucose, higher blood pressure, high triglycerides, and low high-3 pc white bread 240 2.1 21 108 density lipoprotein cholesterol (HDL – the good cholesterol), and the metabolic syndrome (pre-diabetes).4 pc whole wheat 280 7.6 96 284 •  The mechanism by which diet soda makes us fat is not6 c steam broccol 264 27.6 228 3036 directly related to calories. The caramel of soda is a35 c romaine let 280 35.0 105 5670 source of advanced glycation end products, which are pro-inflammatory and may lead to insulin resistance,4 Gold Delic Aps 240 10.0 24 400 which is associated with higher levels of insulin, greater fat synthesis, and less fat breakdown.3 navel oranges 240 12.0 48 900 Dhingra R, Sullivan L, Jacques PF et al. Soft drink consumption and risk ofZone Perfect Bar 210 3.0 35 90 developing cardiometabolic risk factors and the metabolic syndrome in middle- aged adult community. Circulation. 2007;116:480-88 ….. 1 year later. Suganami
T,
Ogawa
Y.
Adipose
8ssue
macrophages:
their
role
in
 adipose
8ssue
remodeling.
J
Leukoc
Biol.
2010;
88(1):33‐9.
Suganami
T,
Ogawa
Y.
Adipose
8ssue
macrophages:
their
role
in
 Axelsson J, Heimburger O, Lindholm B, Stenvinkel P. Adipose tissue and itsadipose
8ssue
remodeling.
J
Leukoc
Biol.
2010;
88(1):33‐9.
 relation to inflammation: The role of adipokines. J Ren Nutr. 2005; 15(1):131-6 6
  • 7. •  Insulin resistance •  Hyperinsulinemia (& hyperglycemia*) •  Increased triglycerides Cordain L, Eades MR, Eades MD. •  Decreased HDL Hyperinsulinemic diseases of civilization: more than just •  Increased LDL syndrome X. Compar Biochem Physiol 2003; 136:95-112 •  Reduced fibrinolysis •  Hyperuricemia •  Classically associated diseases - Type 2 diabetes, coronary artery disease, hypertension, α-motoneu ron obesity© 2005 Dr. David Seaman γ-moto neuron Barclay AW, Petocz P et al. Glycemic index, glycemic load, and chronic disease risk--a meta-analysis of observational studies. Am J Clin Nutr. 2008; 87(3): 627-37 •  These results suggest that adherence to a low glycemic index or low glycemic load diet may be Outcome of syndrome X associated with a reduced risk of certain chronic diseases. •  The authors point out that the reduced risk of type 2 diabetes and heart disease associated with these diets is comparable to the reduced risk associated with whole grain consumption and high fiber intakes. •  The authors conclude, ”the findings support the hypothesis that higher postprandial glycemia is a universal mechanism for disease progression.” •  208 apparently healthy, nonobese subjects were evaluated 4-11 •  Epithelial carncinomas (breast, prostate, colon) years after baseline measurements of insulin resistance were made to determine the incidence of various clinical events •  Acne including hypertension, coronary heart disease, stroke, cancer, and type 2 diabetes. •  Reduced age of menarche •  The subjects divided into tertiles of insulin resistance at baseline, development of clinical events were compared •  Trend of increased stature 40 clinical events occurred among 37 subjects, including 12 •  Myopia hypertension, 3 hypertension and type 2 diabetes, 9 cancer, 7 coronary heart disease, 4 stroke, and 2 type 2 diabetes. •  Cutaneous pappillomas (skin tags) •  28/40 clinical events in 25 individuals (36%) in the most insulin- resistant tertile; other 12 in the group with an intermediate IR. •  Acanthosis nigricans •  No events in the insulin-sensitive tertile, which according to •  Polycystic ovary syndrome the authors “seems to be truly remarkable.” •  Male vertex balding Facchini FS, Hua N, Abbasi F, Reaven GM. Insulin resistance as a predictor of age-related disease. J Clin Endocrinol Metab 2001; 86:3574-78 7
  • 8. Cowy S, Hardy RW. The metabolic syndrome: A high- risk state for cancer? Am J Pathol. 2006; 169(5):1505-22 Blaha M, Elasy TA. Clinical use of the metabolic syndrome: why the confusion? Clin Diabetes. 2006; 24(3):125-31 The
prevalence
of
MetS
was
33%
in
males
and
29%
in
females.
 Neck
pain
was
present
in
11%
(N
=
42)
of
males
and
19%
(N
=
93)
 of
females
(P
<
0.001).

 Prevalence
of
neck
pain
was
7.9%
among
male
subjects
without
 MetS
and
16%
among
those
with
MetS.

 ron α-motoneu© 2005 Dr. David Seaman neuron The
respec8ve
propor8ons
among
females
were
16%
and
25%.
 γ-moto Widespread pain and glycemic dysregulation Widespread pain and glycemic dysregulation A
structured
interview
and
health
examina8on
study
with
480
par8cipants
aged
30‐65
yrs
 A
structured
interview
and
health
examina8on
 was
carried
out
in
Lapinlah8
municipality
in
eastern
Finland.
 study
with
480
par8cipants
aged
30‐65
yrs
was
 Chronic
pain
(dura8on
of
at
least
3
months)
was
graded
 carried
out
in
Lapinlah8
municipality
in
eastern
 according
to
frequency:
being
present
less
ocen
than
 Finland.
 daily,
or
every
day
or
con8nuously
(daily
chronic
pain,
 DCP).
 Of
the
total
sample,
55
subjects
(11%)
had
 The
prevalence
of
daily
chronic
pain
was
21%
(N
=
101)
in
 diabetes.
The
prevalence
of
CWP
was
13%
(n
=
62)
 all
the
subjects.
In
the
subjects
with
a
normal
plasma
 in
all
subjects.
The
corresponding
percentages
for
 glucose
level,
the
prevalence
was
18%,
while
in
those
 subjects
with
normal
glucose
regula8on,
IGR
and
 with
an
elevated
plasma
glucose
level
it
was
38%.
The
 corresponding
percentages
for
non‐diabe8cs
and
 diabetes
were
9,
18
and
28%.
 diabe8cs
were
19%
and
42%.
 Mantyselka
P
et
al.
Glucose
regula8on
and
chronic
pain
at
mul8ple
 Mantyselka
P
et
al.
Chronic
pain,
impaired
glucose
tolerance
and
 sites.
Rheumatology.
2008;47(8):1235‐38.
 diabetes:
a
community‐based
study.
Pain.
2008;137(1):34‐40.
 8
  • 9. Gaida
JE
et
al.
Dyslipidemia
in
Achilles
tendinopathy
Is
characteris8c
of
insulin
resistance.
Med
Sci
Sports
Exerc.
2009;41(6):1194‐97
Although
overuse
is
considered
a
major
causa8ve
factor
for
midpor8on
Achilles
tendinopathy,
up
to
one
third
of
cases
occur
among
completely
nonac8ve
individuals.
Furthermore,
midpor8on
Achilles
tendinopathy
is
ocen
seen
among
overweight
individuals

who
are
ocen
taking
medica8on
to
treat
aspects
of
the
metabolic
syndrome.
Even
among
elite
level
athletes,
a
slightly
elevated
waist
circumference
(83
cm)
drama8cally
increases
the
risk
of
tendon
abnormality.
Although
increased
body
weight
directly
affects
Achilles
tendon
loading,
it
is
unlikely
that
increased
tendon
loading
adequately
explains
these
rela8onships.
Alternate
mechanisms
linking
obesity
and
tendinopathy
may
be
found
by
examining
systemic
factors
that
become
increasingly
common
in
the
presence
of
obesity.
These
include
dyslipidemia,
hypertension,
glucose
intolerance,
and
insulin
resistance.
Because
lipid
deposi8on
is
 Conclusions:
Our
findings
showed
associa8ons
of
abdominal
obesity,
known
to
occur
in
tendons,
high
cholesterol
levels
have
been
observed
 some
other
metabolic
factors
and
caro8d
in8ma‐media
thickness
with
among
individuals
with
Achilles
tendon
rupture,
and
the
esterified
frac8on
 shoulder
pain.
Disturbed
glucose
metabolism
and
atherosclerosis
may
of
cholesterol
is
elevated
in
biopsies
from
Achilles
tendinopathy
subjects
 be
underlying
mechanisms,
although
not
fully
supported
by
the
we
chose
to
focus
on
serum
lipid
profiles.
 findings
of
this
study.

 Complications of lumbar fusion Total Major Minor comps comps comps •  High GI foods IDDM 56% (n=24) 33% (n=14) 23% (n=10) •  Homocysteine (n=43) •  CRP NIDDM 53% (n=27) 24% (n=12) 29%(n=15) •  Lack of exercise (n=51) •  HBP Control 21% (n=9) 7% (n=3) 14% (n=6) •  Family history (n=43) •  Oxidative stress Glassman SD, Alegre G, Carreon L, Dimar JR,Johnson •  Smoking JR. Perioperative complications of lumbar •  Obesity and diabetes instrumentation and fusion in patients with diabetes mellitus. Spine J. 2003;3(6):496-501 German JB, Dillard CJ. Saturated fats: what dietary intake? Am J Clin Nutr 2004; 80:550-59 9
  • 10. Lateral lumbar radiograph, scored 1 for aortic calcifications (both Kauppila LI, McAlindon T, Evans posterior and anterior) in front of the L1 vertebra, 2 for calcifications S, Wilson PW, Kiel D, Felson DT. in front of the L2 vertebra, and 3 for calcifications in front of the L3 and L4 vertebrae. Intervertebral Disc degeneration/back pain space between the L2 and L3 and calcification of the vertebrae shows Grade 2 disc space narrowing and endplate abdominal aorta: a 25-year sclerosis. follow-up study in Framingham. Kauppila LI, McAlindon T, Evans S, Wilson PW, Kiel D, Felson DT. Disc degeneration/back pain and Spine 1997; 22:1642-47 calcification of the abdominal aorta: a 25-year follow-up study in Framingham. Spine 1997; 22:1642-47 Kauppila LI et al. Spine 1997; 22:1642-47 Kauppila LI et al. Spine 1997; 22:1642-47Advanced aortic Recent postmortem studiesatherosclerosis, presenting ascalcific deposits in the suggest that atheromatousposterior wall of the aorta, lesions in the aortaincreases a persons risk for obliterate orifices of thedevelopment of disc feeding arteries of thedegeneration and is lumbar spine and may resultassociated with the in disc degeneration andoccurrence of back pain. long-term back symptoms.Kurunlahti M et al. Sixteen (55%) of the 29 patients with low back painAssociation of atherosclerosis had aortic calcifications,with low back pain and the whereas 11 (21%) of thedegree of disc degeneration. asymptomatic control groupSpine. 1999; 24:2080-84 had calcifications. Kurunlahti M et al. Association of atherosclerosis with low back pain and the degree of disc degeneration. Spine. 1999; 24:2080-84 10
  • 11. Aortic calcifications were Among the patients moreidentified in 48% of the than 50 years of age, 5 (83%)patients aged less than 50 of 6 with low back pain hadyears with low back pain and aortic calcifications,in only 8% of the control whereas in the controlsubjects of the same age. group, calcifications were identified in 8 (50%) of 16 in the same age group.Kurunlahti M et al. Association of atherosclerosis with low back pain and the Kurunlahti M et al. Association of atherosclerosis with low back pain and thedegree of disc degeneration. Spine. 1999; 24:2080-84 degree of disc degeneration. Spine. 1999; 24:2080-84 Key PointsKauppila LI et al. •  Patients with long-term non-specific lower back pain frequently have occludedMR aortography and serum lumbar/middle sacral arteries.cholesterol levels in patients •  Occulsion of lumbar/middle sacralwith long-term non-specific arteries is associated with disclower back pain. degeneration. •  High serum LDL cholesterol levels areSpine. 2004; 29:2347-52 associated with severe neurogenic symptoms of back pain. Kauppila LI et al. MR aortography and serum cholesterol levels in patients with long-term non-specific lower back pain. Spine. 2004; 29:2347-52 Key Points 1. It has been suggested thatLeino-Arjas P et al. atherosclerosis of the lumbar arteries could cause low back pain viaSerum lipids and low back interference with the nutrition of the lumbar tissues.pain: an association? 2. High serum cholesterol and triglycerideSpine 2006; 31:1032-37 concentrations are common risk factors of atherosclerosis. Their associations with low back pain have been little studied. Leino-Arjas P et al. Serum lipids and low back pain: an association? Spine 2006; 31:1032-37 11
  • 12. 3. We found that high serum total cholesterol and triglyceride 4. The subjects with both concentrations at baseline were high total cholesterol and associated with radiating low back high triglycerides carried an pain at follow-up among subjects of the normal working population free of accumulated risk. radiating low back pain initially. 5. Serum lipid levels were The analyses controlled for age, gender, occupational class, history of physically associated with radiating strenuous work, body mass index, smoking, but not local low back pain. and leisure-time physical activity as Leino-Arjas P et al. Serum lipids and low back pain: an association? potential confounders. Spine 2006; 31:1032-37Leino-Arjas P et al. Serum lipids and low back pain: an association?Spine 2006; 31:1032-37• 
A
sample
(n=902)
of
employees
in
an
engineering
company
was
examined
for
serum
total
cholesterol
and
triglycerides,
body
mass
index
(BMI),
smoking,
exercise,
work
history,
and
LBP
in
1973.
By
November
2000,
232
subjects
had
died.

• 
In
1978,
748
(84%
of
the
survivors),
in
1983,
654
(76%),
and
in
2000,
546
 What should we do(81%)
responded
to
a
follow‐up
ques8onnaire.
 with these patients? Of course they are too tired to exercise…. 12
  • 13. •  Energy generated by oxidative phosphorylation for muscle contraction is generated by intermyofibular mitochondria (along Z-line). Smaller in type II diabetes. •  Subsarcolemmal mitochondria generate ATP for energy-requiring processes at cell surface: ion exchange, substrate transport, cell signalling, and protein synthesis - fatty acid oxidation, glucoseRepresentative transmission electron microscopy of longitudinal sections transport, and insulin signalling.of human skeletal muscle from a lean (T) and a type 2 diabetic (DM)research volunteer are shown (bar = 2.5 µm). The thickness of the •  Reduced subsarcolemmal mitochondria may play aperinuclear distribution of subsarcolemmal mitochondria was measured role in the development of insulin resistance.using image analysis (National Institutes of Health image 1.61) and can beobserved to be substantially depleted in type 2 diabetes. Ritov VB, Menshikova EV, He J, Ferrell RE, Goodpaster BH, Kelley DE.Ritov VB et al. Deficiency of subsarcolemmal mitochondria in obesity and Deficiency of subsarcolemmal mitochondria in obesity and type 2type 2 diabetes. Diabetes 2005; 54(1):8-14. diabetes. Diabetes 2005; 54(1):8-14 Cause of insulin resistance Drivers of the Impairment of insulin- stimulated glucose transport, metabolic is responsible for resistance to insulin-stimulated syndrome X glycogen synthesis in muscle in subjects with type 2 diabetes. Shepard PR, Kahn BB. Glucose transporters and insulin action.1999;341(4):248-57 Exercise
s8mulates
glucose
transport
by
pathways
that
are
 independent
of
phosphoinosi8de‐3
kinase
and
that
may
 involve
5‐AMP–ac8vated
kinase.
 13
  • 14. Magnesium deficiency is associated with diverse clinical manifestations: •  headaches •  sudden death •  accelerated atherosclerosis •  cardiovascular disease •  Ford ES, Mokdad AH. Dietary magnesim intake in a national •  hypertension sample of US adults. J Nutr •  stroke 2003; 133:2879-82 •  renal tubular disorders •  Bar-Dayan Y, Shoenfield Y. Magnesium fortification of •  osteoporosis water. A possible step forward •  diabetes mellitus in preventive medicine? Ann Med Interne (Paris). •  asthma 1997;148(6):440-4 •  preeclampsia & eclampsiaCeriello A. New insights on oxidative stress and diabetic complications may •  neurologic & psychiatric conditionslead to a "causal" antioxidant therapy.Diabetes Care. 2003 May;26(5):1589-96 Drivers of the metabolic Chronic inflammation precedes insulin resistance syndrome X •  Insulin resistance and disordering of lipid metabolism occur in obesity, diabetes mellitus, atherosclerosis. This review examines recent research that links inflammation to insulin The drivers tell insensitivity. •  Recent studies on diseases which involve insulin insensitivity (e.g. obesity, type 2 diabetes and us what the atherosclerosis) also show increased cytokine production and markers of inflammation. Evidence treatment is… at present favours chronic inflammation as a trigger for chronic insulin insensitivity, rather than the reverse situation. 14
  • 15. Drivers of hyperinsulinemia: •  High GI foods (Cordain) •  High GL foods (Cordain) •  Low potassium intake (1) •  Low magnesium intake (2) •  High omega-6 fatty acids (3) •  Excess body fat - incr TNF (4) •  Vitamin D (>32 ng/mL) impr insulin sens 1. Demigne C, Sabboh H, Remesy C, Meneton P. Protective effects of high dietary potassium: nutritional and metabolic aspects. J Nutr. 2004; 134:2903-06 2. Lopez-Ridaura R, Willett WC, Rimm EB, Liu S, Stampfer MJ, Manson JE, Hu FB. Magnesium intake and risk of type 2 diabetes in men and women. Diabetes Care. 2004; 27:134-40 3. Simopoulos AP. Essential fatty acids in health and chronic disease. Am J Clin Nutr 1999; 70(3 Suppl):560S-569S 4. Grimble RF. Inflammatory status and insulin resistance. Curr Opin Clin Nutr Metab Care 2002; 5:551-559 Fontana L, Eagon JC, Trujillo ME, Scherer PE, Klein S. Visceral fat adipokine secretion is associated with systemic inflammation in obese humans. Diabetes, 2007;56(4):1010-3Under
controlled
feeding
condi8ons,
long‐term
(6
yr)
TFA
consump8on
was
an
independent
factor
in
weight
gain.
TFAs
 In this abdominal MRI scan, it is possible to seeenhanced
intra‐abdominal
deposi8on
of
fat,
even
in
the
absence
of
 subcutaneous fat around the abdomen, surroundingcaloric
excess,
and
were
associated
with
insulin
resistance,
with
 abdominal muscles. Visceral fat is deeper inside theevidence
that
there
is
impaired
post‐insulin
receptor
binding
signal
 abdomen, surrounding internal organs.It is thetransduc8on.
 visceral fat that secretes IL-6, strongly suggesting aKavanagh K, et al. Trans fat diet induces abdominal obesity and changes ininsulin sensitivity in monkeys. Obesity. 2007; 15(7):1675-84 mechanistic link to systemic inflammation. Axelsson J, Heimburger O, Lindholm B, Stenvinkel P. Adipose tissue and its Trayhurn P, Bing C, Wood IS. Adipose tissue and adipokines - energy relation to inflammation: The role of adipokines. J Ren Nutr. 2005; 15(1):131-6 regulation from the human perspective. J. Nutr. 136: 1935S–1939S, 2006. 15
  • 16. Interleukin (IL)-10 is a centrally operating anti- inflammatory cytokine that plays a crucial role in the regulation of the innate immune system. It has strong deactivating properties on the inflammatory host response mediated by macrophages and lymphocytes, and potently inhibits the production of pro- inflammatory cytokines such as IL-6 and TNF-a. IL-10 is produced by T-cells, B-cells, monocytes, and macrophages, and is under tight genetic control, with heritability estimates as high as 75%. We therefore propose that low IL-10 production capacity is associated with the metabolic syndrome and type 2 diabetes. Galic
S
et
al.
Adipose
8ssue
as
an
endocrine
 organ.
Mol
Cell
Endocrinol.
2010;316:129‐39.
Obesity‐induced
changes
in
macrophage
infiltra8on
and
polarisa8on.
Adipose
8ssue
macrophages
(ATMs)
in
the
lean
state
show
characteris8cs
of
“alterna8ve”
or
M2
ac8va8on
with
increased
 * *produc8on
of
arginase
and
the
an8‐inflammatory
cytokine
IL‐10.

They
are
postulated
to
par8cipate
in
8ssue
repair
and
the
amenua8on
of
inflammatory
responses.
Expansion
of
adipose
8ssue
leads
to
adipocyte
hypertrophy
and
the
release
of
chemokines
that
induce
increased
recruitment
of
M1
macrophages
from
the
blood
stream.

M1
or
“classically
ac8vated”
ATMs
are
characterized
by
increased
produc8on
of
the
pro‐inflammatory
cytokines
TNFα
and
IL‐6,
which
promote
altered
gene
expression
and
insulin
resistance
in
adipocytes.
These
changes
result
in
altered
adipokine
secre8on,
increased
lipolysis
and
excess
of
circula8ng
nonesterified
famy
acids,
which
may
eventually
contribute
to
systemic
insulin
resistance.

 Holick MF, Chen TC. Vitamin D Galic
S
et
al.
Adipose
8ssue
as
an
endocrine
organ.
Mol
Cell
 deficiency: a worldwide problem with health consequences. Am J Clin Nutr. Endocrinol.
2010;316:129‐39.
 2008; 87(4):1080S-86S Estimated needs of vit D throughout lifecycle Vitamin D - insulin sensitivity 1. Breast-fed infants (800 IU/day) Extrapolation from the observations in the 2. Formula-fed infants (400 IU/day) current study suggests that increasing 3. Toddlers & young children (1000-2000 IU/day) – 25(OH)D from 10 to 32 ng/mL can improve [when not getting adequate sun, and based on weight*] insulin sensitivity by 60%. This could potentially eliminate the burden on beta cells 4. Lactating women: 7,000 IU/day and reverse abnormal glucose tolerance. 5. Adolescents and adults can take between 3000-10000 IU or more depending on vitamin D levels in Furthermore - the 60% improvement in insulin blood (serum 25(OH)D: 32-100 ng/ml). sensitivity from Vit D = more potent than 6. Pregnant or those thinking of becoming pregnant – troglitazone or metformin treatment (54% and get 25(OH)D check every 3-months (get to 40-70 ng/ml*) 13% improvement in insulin sensitivity).Read full text before acting: Cannell JJ, Hollis BW. Use of vitamin D(3) in Chiu KC et al. Hypovitaminosis D is associated with insulin resistance and B-cellclinical practice. Alt Med Rev. 2008;13(1):6-20. dysfuntion. Am J Clin Nutr 2004; 82:820-25 16
  • 17. CD4 T helper cells TH1 TH2 T-regCytokines are pro-inflammatory [i.e., IL-4, 5, 13, MaintenanceIFN-g] - [IL-1, TNF]. which are of self-Kill intracellular associated with toleranceparasites and IGE responses, Cantorna MT, Mahon BD.perpetuate and IL-10 whichautoimmunity. Lead is anti-inflammatory. Mounting evidence for vitamin D as anto uncontrolled environmental factor affecting autoimmunedamage and must Berger A. Science commentary: Th1be balanced by TH2 and Th2 responses: what are they. disease prevalence.and T-reg. BMJ 2000; 321: p.424 Exp Biol Med. 2004; 229:1136-42 IFN-g --> IL-1, IL-6, TNF Self tolerance IL-10 IFN-g --> IL-1, IL-6, TNF Self tolerance IL-10 Axelsson J, Heimburger O, Lindholm B, Stenvinkel P. Adipose tissue and its relation to inflammation: The role of adipokines. J Ren Nutr. 2005; 15(1):131-6 Increased number of islet macrophages in type 2 diabetic islets. Pancreatic section from a nondiabetic patient (A) and a patient with type 2 diabetes (B) displaying increased numbers of islet-associated macrophages detected by double immunostaining for CD68 in brown (arrows) and insulin in red. Insulitis – Beta cell inflammation Donath MY, Schumann DM, Faulenbach M, Ellingsgaard H, Perren A, Ehses JA. Islet inflammation in type 2 diabetes: from metabolic stress to therapy. Diabetes Care. 2008:31 (Suppl. 2):S161-64. 17
  • 18. Boni-Schnetzler M et al. Insulitis in type 2 diabetes. Diabetes ObesityMetab. 2008;10(suppl 4):201-204. •  Islets of patients with type 2 diabetes have the feature of an inflammatory process reflected by the presence of cytokines, immune cells, b-cell apoptosis, amyloid deposits Hypothalamic inflammation and fibrosis. Beta-cells from patients with type 2 diabetes display inflammatory markers, including increased interleukin (IL)-1b expression. •  Increased islet-associated macrophages are observed in human type 2 diabetic patients and in most animal models of diabetes. •  Increased numbers of macrophages are detectable very early in high fat–fed mice islets, before the onset of diabetes. •  These immune cells are most likely attracted by islet- derived chemokines, produced in response to metabolic stress, and under the control of IL-1b.Thaler JP et al. Hypothalamic inflammation andenergy homeostasis: Resolving the paradox. Hypothalamic inflammation andFrontiers Neuroendocrinol. 2010;31:79-84. obesity handout – obesity
is
 Experimental interventions that block hypothalamic inflammation (e.g., inhibition of associated
with
a
pro‐ hypothalamic Inhibitor of kappa kinase-b (IKKb) signaling) reduce food intake and lower body inflammatory
state
in
key
 weight in animals made obese by high-fat (HF) feeding, but not in controls fed a low-fat (LF) diet. neuronal
systems
that
govern
 The mechanism whereby hypothalamic energy
homeostasis,
 inflammation favors weight gain is strongly linked to the induction of resistance to leptin and other humoral inputs to the hypothalamus, including .
 insulin. Wine (red wine) 32% (23-41) Diet and Fish (n-3 meat, chicken, eggs) 14% (8-19) Dark chocolate Food choices for 21% (14-27) disease supplements Vegetables & Fruit Garlic (all spices) prevention 21% (14-27) and health 25% (21-27) promotion. Almonds (all raw nuts) 12.5% (10.5-13.5) Combine effect 76% (63-84) Franco OH et al. The Polymeal: a more natural, safer, and probably tastier (than the Polypill) strategy to reduce cardiovascular disease by more than 75%. BMJ. 2004; 329:1447-50 18
  • 19. Ames BN. Low micronutrient intake may accelerate the REVERSE the drivers of hyperinsulinemia:degenerative diseases of aging through allocation of scarce •  High GI foods (Cordain)micronutrients by triage. PNAS. 2006;103(47):17589-94. •  High GL foods (Cordain)Ames presents argument for eating more fruits/ •  Low potassium intake (1)vegetables and taking key supplements: •  Low magnesium intake (2) •  High omega-6 fatty acids (3) •  Multivitamin/mineral •  Excess body fat - incr TNF (4) •  Vitamin D (>32 ng/mL) impr insulin sens •  Magnesium 1. Demigne C, Sabboh H, Remesy C, Meneton P. Protective effects of high dietary potassium: nutritional and metabolic aspects. J Nutr. 2004; 134:2903-06 •  Fish oil (EPA/DHA) 2. Lopez-Ridaura R, Willett WC, Rimm EB, Liu S, Stampfer MJ, Manson JE, Hu •  Vitamin D FB. Magnesium intake and risk of type 2 diabetes in men and women. Diabetes Care. 2004; 27:134-40 •  a-Lipoic acid & acetyl-L-carnitine (ALCAR) 3. Simopoulos AP. Essential fatty acids in health and chronic disease. Am J Clin Nutr 1999; 70(3 Suppl):560S-569S (Seaman additions: CoQ10, anti-inflammatory botantical, •  Fiber glucosamine/chondroitin, hydroxyapatite calcium, 4. Grimble RF. Inflammatory status and insulin resistance. Curr Opin Clin Nutr Metab Care 2002; 5:551-559 proteolytic enzymes, chromium, vitamin K2) Supplements
for
glycemic
regula8on:
 Ann
Intern
Med.
2005;142:323‐32.

 • 
Magnesium
Compared
with
the
placebo
interven8on,
the
lifestyle
and
mepormin
interven8ons
were
es8mated
to
delay
the
development
of
type
2
 • 
Vitamin
D
diabetes
by
11
and
3
years,
and
to
reduce
the
absolute
incidence
of
dia‐
betes
by
20%
and
8%,
respec8vely.
 • 
Chromium
Compared
with
the
placebo
interven8on,
the
cost
per
QALY
(quality
 • 
Lipoic
acid
of
life
adjusted
years)
was
approximately
$1100
for
the
lifestyle
interven8on
and
$31,300
for
the
mepormin
interven8on.
From
a
 • 
Gymnema
sylvestre
societal
perspec8ve,
the
interven8ons
cost
approximately
$8800
and
$29,
900
per
QALY,
respec8vely.

 • 
Cinnamon
From
both
perspec8ves,
the
lifestyle
interven8on
dominated
the
mepormin
interven8on.

 • 
Vanadium
 Diabetes.
2002;251:2074‐81. 
 Mepormin
ac8vates
AMPK,
which
 leads
to
Glut
4
transloca8on
to
 muscle
cell
membrane.
 Shay
KP,
Moreau
RF,
Smith
EJ,
Smith
AR,
Hagen
TM.
Alpha‐lipoic
acid
as
a
dietary
 supplement:
molecular
mechanisms
and
therapeu8c
poten8al.
Biochim
Biophys
 Acta.
2009;1790(10):1149‐60.
 19
  • 20. Key
to
insulin
signaling
molecules:
 I Cr 
 BLOOD GLUCOSE LEVELS RISE • 
AMPK:
adenosine
monophosphate‐ac8vated
protein
kinase
 • 
IRS‐1:
 insulin
receptor
substrate
1
(IRS1)
protein
 PI3K
 Akt
 IRS‐1
 • 
PTP1B:
protein
tyrosine
phosphatase
 • 
PI3K:
phosphoinosi8de
3‐kinase
 • 
PDK1:
PtdIns‐dependent
kinase
1
(phosphoinosi8des)
 Apo‐ 
 chromodulin
 AS160
 • 
Akt:
serine/threonine
protein
kinase
 Glut
4
 • 
AS160:
Akt
substrate
of
160
kDa
 Cr
 I BLOOD GLUCOSE LEVELS RISE BLOOD GLUCOSE I Glut
4
 PI3K
 Akt
 PI3K
 Akt
 IRS‐1
 IRS‐1
 Cr
 Chromodulin
 Apo‐ 
chromodulin
 AS160
 AS160
 Glut
4
 Cr 
 Cr
 BLOOD GLUCOSE BLOOD GLUCOSE I I Glut
4
 Glut
4
 PI3K
 Akt
 PI3K
 Akt
 IRS‐1
 IRS‐1
 Cr
 Cr
 Cr
 Cr
 Chromodulin
 α‐LA
 Chromodulin
 α‐LA
 AMPK
 AMPK
 AS160
 AS160
 Muscle
 Muscle
 contrac8on
 contrac8on
 20
  • 21. Vincent
JB.
Chromium:
celebra8ng
50
years
as
an
essen8al
element?
Dalton
Trans.
Chromium
supplementa8on
 2010;39:3787‐94.
 Vincent
JB.
The
biochemisty
of
chromium.
J
Nutr.
2000;130:715‐18.
 • 
Supplemental
doses
of
chromium
that
benefit
 Anderson
RA.
Chromium
and
insulin
resistance.
Nutr
Res
Rev.
2003;16:267‐75.
 glycemic
regula8on,
which
range
from
200
to
1000
 Dietary
supplement
fact
sheet.
Na8onal
Ins8tutes
of
Health.
hmp://ods.od.nih.gov/ factsheets/chromium/
 mcg,
are
not
the
levels
found
in
food.

 Anderson
RA.
Chromium,
glucose
intolerance
and
diabetes.
J
Am
Coll
Nutr.
1998;17(6):548‐55.
 • 
Adequate
intake
of
chromium
for
adults
ranges
 Cefalu
WT,
Rood
J
Patricia
Pinsonat
P
et
al.
Characteriza8on
of
the
metabolic
and
physiologic
 from
only
20
to
45
micrograms
(mcg)
per
day.
The
 response
to
chromium
supplementa8on
in
subjects
with
type
2
diabetes
mellitus.
Metab
Clin
 Exper.
2010;59:755‐62.
 progression
of
metabolic
syndrome
is
not
likely
 Heimbach
JT,
Anderson
RA.
Chromium:
recent
studies
regarding
nutri8onal
roles
and
safety.
 caused
by
a
chromium
deficiency.
 Nutr
Today.
2005;40(4):18095.
 Anderson
RA,
Bryden
NA,
Polansky
MM.
Serum
chromium
of
humans
subjects:
effects
of
 • 
Func8on
of
high
dose
chromium:
To
push
internal
 chromium
supplmenta8on
and
glucose.
Am
J
Clin
Nutr.
1985;41:571‐77.
 signaling
that
leads
to
Glut
4
transloca8on.
 Anderson
RA,
Polansky
MM,
Bryden
NA.
Stability
and
absorp8on
of
chromium
and
absorp8on
 of
chromium
his8dinate
complexes
by
humans.
Bio
Trace
Elem
Res.
2004;101:211‐18.
 • 
Take
with/without
food.
 DiSilvestro
RA,
Dy
E.
Comparison
of
acute
absorp8on
of
commercially
available
chromium
 supplements.
J
Trace
Element
Med
Biol.
2007;21:120‐24.
 Chromium supplementation safety alpha‐lipoic
acid
supplementa8on
 • 
The
foods
richest
in
α‐lipoic
acid
are
animal
8ssues
with
extensive
 Human
studies
using
1000
mcg
per
day
 metabolic
ac8vity
such
as
heart,
liver,
and
kidney,
which
are
rarely
 consumed.
The
plant
sources
of
α‐lipoic
acid,
listed
from
highest
to
 for
8
months
have
been
shown
to
be
 lowest,
are
spinach,
broccoli,
tomatoes,
garden
peas,
brussel
 safe
and
animal
models
using
 sprouts,
and
rice
bran.
While
these
foods
are
not
consumed
in
large
 amounts,
the
resultant
reduced
consump8on
of
lipoic
is
not
a
likely
 significantly
more
are
not
associated
 promoter
of
insulin
resistance.

 with
toxicological
consequences.

 • 
This
is
because
the
supplemental
amounts
of
α‐lipoic
acid
used
in
 • 
Anderson
RA.
Chromium
and
insulin
resistance.
Nutr
Res
Rev.
 the
treatment
of
diabetes
(300‐600
mg)
are
likely
to
be
as
much
as
 2003;16:267‐75.
 1000
8mes
greater
than
the
amounts
that
could
be
obtained
from
 the
diet.

 • 
Heimbach
JT,
Anderson
RA.
Chromium:
recent
studies
regarding
 nutri8onal
roles
and
safety.
Nutr
Today.
2005;40(4):18095.
 • 
Supplemental
α‐lipoic
acid
has
been
used
extensively
in
pa8ents
 suffering
from
insulin
resistant
related
condi8ons.

 Wise
to
regularly
monitor
blood
sugar.
 Singh
U,
Jialal
I.
Alpha‐lipoic
acid
supplementa8on
and
diabetes.
Nutr
Rev.
2008;66(11): 646‐57.

alpha‐lipoic
acid
supplementa8on
(600
mg/day)
 Leach, Matthew J. Gymnema sylvestre for diabetes mellitus: a systematic review. J Altern Comp Med. 2007;13(9):977-83. Food
intake
is
reported
to
reduce
the
bioavailability
of
 supplemental
α‐lipoic
acid,
which
is
why
it
is
generally
 Given
that
G.
sylvestre
targets
several
of
the
e0ological
 recommended
to
be
taken
up
on
an
empty
stomach
(1
hour
 factors
connected
with
diabetes
(Fig.
1),
including
chronic
 before
or
2
hours
acer
ea8ng)
(1).

 inflamma8on,
obesity,
enzyma8c
defects,
and
pancrea8c
 beta‐cell
func8on,
and
no
single
oral
hypoglycemic
drug
 In
general,
α‐lipoic
acid
supplementa8on
has
been
found
to
 presently
exerts
such
a
diverse
range
of
effects,
suggests
that
 have
few
serious
side
effects.
In
a
five
week
study,
pa8ents
 gymnema
may
be
useful
in
the
management
of
diabetes
and
 with
diabe8c
polyneuropathy
were
supplemented
with
 the
preven8on
of
associated
pathological
changes.

 either
a
placebo
(n=43)
or
α‐lipoic
acid
at
600
mg
(n=45),
 1200
mg
(n=47),
or
1800
mg
(n=46).
Side
effects
were
similar
 However,
as
this
systema8c
review
shows,
the
clinical
 in
the
placebo
and
600
mg
group
(2).
 efficacy
of
gymnema
has
only
been
supported
by
a
small
1.  Singh
U,
Jialal
I.
Alpha‐lipoic
acid
supplementa8on
and
diabetes.
Nutr
Rev.
2008;66(11): number
of
nonrandomized,
open‐label
trials.
Hence,
further
 646‐57.

 inves8ga8on
into
the
clinical
effect
of
G.
sylvestre
on
both
2.  Ziegler
D,
Ametov
A,
Barinov
A,
et
al.
Oral
treatment
with
alpha‐lipoic
acid
improves
 symptoma8c
diabe8c
polyneuropathy:
the
SYDNEY
2
trial.
Diabetes
Care.
 diabetes
and
its
associated
complica8ons
is
urgently
needed.
 2006;29:2365‐70.

 21
  • 22. Gymnema - Dosage and Toxicity The
typical
therapeu8c
dose
of
an
extract,
 standardized
to
contain
24‐percent
gymnemic
 acids,
is
400‐600
mg
daily.
It
is
not
clear
from
 examining
the
studies
whether
divided
doses
is
 ideal
but,
because
it
is
being
used
to
regulate
blood
 sugar,
three
divided
doses
with
meals
would
seem
 ideal.
 Conclusions
Intake
of
2g
of
cinnamon
for
12
weeks
significantly
 reduces
the
HbA1c,
SBP
and
DBP
among
poorly
controlled
 No
significant
adverse
effects
have
been
reported,
 type
2
diabetes
pa8ents.
Cinnamon
supplementa8on
could
be
 aside
from
the
expected
hypoglycemia.
Safety
in
 considered
as
an
addi8onal
dietary
supplement
op8on
to
regulate
 pregnancy
has
not
been
established.
 blood
glucose
and
blood
pressure
levels
along
with
conven8onal
 medica8ons
to
treat
type
2
diabetes
mellitus.
 Alternative Medicine Review Volume 4, Number 1 1999 
 
 
 







Diabet.
Med.
27,
1159–1167
(2010) 
 Vanadium VanadiumVanadium
is
a
poorly
understood
trace
element
that
is
ubiquitous
in
 Vanadium
is
a
poorly
nature
and
believed
to
have
many
func8ons
in
human
physiology.
In
 understood
trace
element
that
vitro
and
animal
studies
have
demonstrated
its
insulinomime8c
 is
ubiquitous
in
nature
and
effects
mediated
by
inhibi8on
of
phosphotyrosine
phosphatase
enzymes
that
affect
the
insulin
receptor.
 believed
to
have
many
 func8ons
in
human
physiology.
A
recent
meta‐analysis
iden8fied
5
uncontrolled
trials
(N
=
48)
in
 In
vitro
and
animal
studies
have
which
50
to
300
mg
of
vanadium
was
administered
for
3
to
6
weeks.
 demonstrated
its
Vanadyl
sulfate
was
used
in
4
trials
and
sodium
metavanadate
was
 insulinomime8c
used
in
1
trial.
All
5
trials
reported
reduc8ons
in
FBG
levels,
but
 effects
mediated
by
inhibi8on
these
were
of
short
dura8on;
none
of
the
trials
included
controls.
 of
phosphotyrosine
Commonly
reported
side
effects
included
gastrointes8nal
 phosphatase
upset,
bloa8ng,
and
nausea.
There
is
insufficient
evidence
to
 enzymes
that
affect
the
insulin
support
the
use
of
vanadium
in
the
treatment
of
type
2
DM.
 receptor.
Nahas R et al. Complementary and alternative medicine for the treatment of type2 diabetes. Can Fam Physician. 2009;55:591-96.Ames BN. Low micronutrient intake may accelerate thedegenerative diseases of aging through allocation of scarcemicronutrients by triage. PNAS. 2006;103(47):17589-94.Ames presents argument for eating more fruits/vegetables and taking key supplements: •  Multivitamin/mineral •  Magnesium •  Fish oil (EPA/DHA) •  Vitamin D •  a-Lipoic acid & acetyl-L-carnitine (ALCAR) (Seaman additions: CoQ10, anti-inflammatory botantical, •  Fiber glucosamine/chondroitin, hydroxyapatite calcium, proteolytic enzymes, chromium, vitamin K2) 22