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

1. Pain expression and the
metabolic 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
D'Acquisto 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 nerve
suppresses mechanical allodynia and thermal hyperalgesia in a rat inflammatory suppresses mechanical allodynia and thermal hyperalgesia in a rat inflammatory
pain 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, TNF
pro-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
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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 3:39
The evolution of man?
4

5. 4972 kcal
4075 kcal
At 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 ± 0.9
group (p = 0.001) fat (cm)
• geometric mean of C-reactive protein was 82% lower (p = Body temp (°C) 37.7± 1.5 37.6 ± 0.5
0.0007) CRP (mcg/mL) 4.0 21.7
• intra-arterial diastolic blood pressure was 13% lower in the
Systolic BP 140 ± 18 150 ± 9
Paleolithic group (p = 0.007)
Diasystolic BP 108 ± 12 123 ± 12
• no significant difference was seen in fasting glucose
between 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-based
diet 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 gain
1.5 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 was
1 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 not
6 c steam broccol 264 27.6 228 3036 directly related to calories. The caramel of soda is a
35 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 of
Zone 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 its
adipose 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.
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© 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; 22:1642-47
Advanced aortic
Recent postmortem studies
atherosclerosis, presenting as
calcific deposits in the
suggest that atheromatous
posterior wall of the aorta, lesions in the aorta
increases a person's risk for obliterate orifices of the
development of disc feeding arteries of the
degeneration and is lumbar spine and may result
associated with the in disc degeneration and
occurrence of back pain. long-term back symptoms.
Kurunlahti M et al.
Sixteen (55%) of the 29
patients with low back pain
Association of atherosclerosis had aortic calcifications,
with low back pain and the whereas 11 (21%) of the
degree of disc degeneration.
asymptomatic control group
Spine. 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 more
identified in 48% of the than 50 years of age, 5 (83%)
patients aged less than 50 of 6 with low back pain had
years with low back pain and aortic calcifications,
in only 8% of the control whereas in the control
subjects 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 the
degree of disc degeneration. Spine. 1999; 24:2080-84 degree of disc degeneration. Spine. 1999; 24:2080-84
Key Points
Kauppila LI et al. • Patients with long-term non-specific
lower back pain frequently have occluded
MR aortography and serum lumbar/middle sacral arteries.
cholesterol levels in patients • Occulsion of lumbar/middle sacral
with long-term non-specific arteries is associated with disc
lower back pain. degeneration.
• High serum LDL cholesterol levels are
Spine. 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 that
Leino-Arjas P et al. atherosclerosis of the lumbar arteries
could cause low back pain via
Serum lipids and low back interference with the nutrition of the
lumbar tissues.
pain: an association?
2. High serum cholesterol and triglyceride
Spine 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; 31:1032-37
Leino-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, glucose
Representative 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 a
perinuclear 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 be
observed 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 2
type 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 & eclampsia
Ceriello A. New insights on oxidative stress and diabetic complications may • neurologic & psychiatric conditions
lead 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):1010-3
Under 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 see
enhanced intra‐abdominal deposi8on of fat, even in the absence of subcutaneous fat around the abdomen, surrounding
caloric excess, and were associated with insulin resistance, with abdominal muscles. Visceral fat is deeper inside the
evidence that there is impaired post‐insulin receptor binding signal abdomen, surrounding internal organs.It is the
transduc8on. visceral fat that secretes IL-6, strongly suggesting a
Kavanagh K, et al. Trans fat diet induces abdominal obesity and changes in
insulin 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-cell
clinical 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-reg
Cytokines are pro-
inflammatory [i.e., IL-4, 5, 13, Maintenance
IFN-g] - [IL-1, TNF]. which are of self-
Kill intracellular associated with tolerance
parasites and IGE responses, Cantorna MT, Mahon BD.
perpetuate and IL-10 which
autoimmunity. Lead is anti-inflammatory. Mounting evidence for vitamin D as an
to uncontrolled environmental factor affecting autoimmune
damage and must Berger A. Science commentary: Th1
be 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 Obesity
Metab. 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 and
energy homeostasis: Resolving the paradox. Hypothalamic inflammation and
Frontiers 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 Vanadium
Vanadium 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 type
2 diabetes. Can Fam Physician. 2009;55:591-96.
Ames BN. Low micronutrient intake may accelerate the
degenerative diseases of aging through allocation of scarce
micronutrients 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