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David R. Seaman, DC, MS, DABCN Professor, Clinical Sciences National University of Health Sciences St. Petersburg, Florida

deflame@deflame.com

Pain expression and the metabolic syndrome pain basic

mechanisms

© 2005 Dr. David Seaman

NTS Glial cytokine release

1. IL-1, IL-6, TNF, PGE2, ROS 2. IL-1, IL-6,

TNF, PGE2, ROS

3. IL-1, IL-6, TNF, PGE2, ROS

** Cord glia meditators enhance group IV mediator release & 2nd order neuron excitability

**

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

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•  Pro-inflammatory cytokines such as tumor necrosis factor-–3 Recently, it was reported that the transcription factor nuclear factor-kappa B plays a crucial role in regulating pro-inflammatory cytokine gene expression and the transfer of nociceptive information.

•  Nuclear factor-kappa B decoy was conveyed and transduced into dorsal root ganglion both in vivo and in vitro. Additionally, nuclear factor-kappa B decoy reduced mechanical allodynia and thermal hyperalgesia in the rat inflammatory pain model, that inhibition of nuclear factor-kappa B with nuclear factor-kappa B decoy may represent a key mechanism for mediating inflammation or reducing inflammatory pain.

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 pain model. Spine. 2006;31:2904–2908

NF-kB and Pain

Nuclear factor-kappa B is, thus, regarded to be one of the most important targets for therapeutic intervention against inflammatory diseases, such as rheumatoid arthritis, asthma, or inflammatory bowel disease.

NF-kB and Pain & chronic disease

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 pain model. Spine. 2006;31:2904–2908

Evans JL, Goldfine ID, Maddux BA, Grodsky GM. Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes.Endocr Rev. 2002 ;23:599-622

•  PLA2 •  COX •  LOX •  GFs: VEGF •  TNF •  IL-1 •  IL-6 •  CAM (cell adhesion molecules) •  MMPs (matrix metalloproteinases)

•  PGE2 (via PLA2 & COX) •  LTB4 (via PLA2 & LOX) •  VEGF •  IL-1, IL-6, TNF

Evans JL, Goldfine ID, Maddux BA, Grodsky GM. Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes.Endocr Rev. 2002 ;23:599-622

•  PLA2 (corticosteroids) •  COX (NSAID, COX2 inhib, Tylenol) •  LOX (Singulair) •  GFs: VEGF (Lucentis, Avastin) •  TNF (Remicade etc.) •  IL-1 (Kineret) •  IL-6 (Actmera) •  CAM (cell adhesion molecules) •  MMPs (matrix metalloproteinases)

•  PGE2 (via PLA2 & COX) •  LTB4 (via PLA2 & LOX) •  VEGF •  IL-1, IL-6, TNF

Nucleus

•  PGE2 • IL-1, IL-6, TNF •  LTB4 •  VEGF

•  PLA2 (corticosteroids) •  COX (aspirin, NSAIDs, Tylenol) •  LOX (Singulair) •  VEGF (Avastin, Lucentis) •  TNF (Enbrel, Remicade, Humira)

Excite group IV afferents and other local cells that release mediators.

A self-perpetuating, pro-inflammatory cycle

α-motoneuron

γ-motoneuron © 2005 Dr. David Seaman

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α-motoneuron

γ-motoneuron © 2005 Dr. David Seaman

•  Substance P •  CGRP •  Glutamate •  Glycine •  GABA •  Acetylcholine •  Serotonin •  Bombesin •  Neuropeptide Y •  Neurotrophins •  TNF •  VIP

•  Glutamate •  GABA •  Acetylcholine •  Norepinephrie •  Adenosine •  Potassium •  ATP •  Estrogen •  Glucocorticoids •  CRF •  Substance P •  Neurokinin A •  Cholecystokinin •  Somatostatin •  Bombesin •  Angiotensin II •  Neuropeptide Y

•  Endorphin •  Enkephalin •  Dynorphin •  Nerve growth factor •  Brain-derived neurotrophic factor •  Glial-derived neurotrophic factor •  FGF, PDGF, VEGF

•  Bradykinin •  Hydrogen ions •  Prostaglandin E2 (E1,3) •  Leukotriene B4 (B5) •  Resolvins, lipoxins, NPs •  Serotonin •  Histamine •  Interleukin-1 •  Interleukin-6 •  Tumor necrosis factor •  Interleukin-10, [IL-4]

Syndrome X basics

•  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 cardiovascular disease •  50 million Americans are hypertensive •  10 million Americans have type 2 diabetes •  72 million American adults maintain total cholesterol/high-density lipoprotein (HDL) cholesterol ratios of 4.5 or greater (2 to 3 best, want <4)

Extent of syndrome X plus:

St-Onge MP, Janssen I, Heymsfield SB.

Metabolic syndrome in normal-weight Americans; new definition of the metabolically obese, normal weight individual.

Diabetes Care 2004;27: 2222–8

Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the Third National Health and Nutrition Examination Survey. JAMA 2002;287:356–9.

If patients have three or more of the following risk factors, they are said to be

suffering from syndrome X:

Wilson PW, Grundy SM. The metabolic syndrome: practical guide to origins and treatment: Part I. Circulation. 2003; 108:1422-24

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

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The evolution of man?

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

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4075 kcal

4972 kcal

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

•  weight was 22% less

•  subcutaneous fat thickness at mid sternum was 43% lower

•  dynamic insulin sensitivity was significantly higher (p = 0.004)

•  insulin response was significantly lower in the Paleolithic group (p = 0.001)

•  geometric mean of C-reactive protein was 82% lower (p = 0.0007)

•  intra-arterial diastolic blood pressure was 13% lower in the Paleolithic group (p = 0.007)

•  no significant difference was seen in fasting glucose between groups

At the end of the study in the Paleolithic group:

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

Weight (kg) 129 ± 16 166 ± 28

Length (cm) 159 ± 6 170 ± 9

Subcutaneous 1.9 ± 0.4 3.3 ± 0.9 fat (cm)

Body temp (°C) 37.7± 1.5 37.6 ± 0.5

CRP (mcg/mL) 4.0 21.7

Systolic BP 140 ± 18 150 ± 9

Diasystolic BP 108 ± 12 123 ± 12

Paleolithic Cereal (n=11) (n=12)

David before visiting cousins in America.

Hands ES. Nutrients in food. Philadelphia: Lippincott Williams & Wilkins; 2000

Food Calories Fiber (grams)

Mag++ (mg)

K+ (mg)

1.5 Glazed donuts 270 1.5 0* 0* 1 cup millet 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

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Food Cal Fiber (g) Mg (mg) K (mg)

1.5 glazed donut 270 1.5 0 0 1 cup millet 280 3.2 100 150 2 cups oatmeal 290 8.0 112 262 3 pc white bread 240 2.1 21 108 4 pc whole wheat 280 7.6 96 284 6 c steam broccol 264 27.6 228 3036 35 c romaine let 280 35.0 105 5670 4 Gold Delic Aps 240 10.0 24 400 3 navel oranges 240 12.0 48 900 Zone Perfect Bar 210 3.0 35 90 Dhingra R, Sullivan L, Jacques PF et al. Soft drink consumption and risk of

developing cardiometabolic risk factors and the metabolic syndrome in middle-aged adult community. Circulation. 2007;116:480-88

•  Researchers recently concluded that whether it was diet or regular soda, consumption of 1 soft drink per day was associated with increased odds of developing obesity, increased waist circumference, impaired fasting glucose, higher blood pressure, high triglycerides, and low high-density lipoprotein cholesterol (HDL – the good cholesterol), and the metabolic syndrome (pre-diabetes). •  The mechanism by which diet soda makes us fat is not directly related to calories. The caramel of soda is a source of advanced glycation end products, which are pro-inflammatory and may lead to insulin resistance, which is associated with higher levels of insulin, greater fat synthesis, and less fat breakdown.

Soda & insulin sensitivity & wt gain

….. 1 year later.

SuganamiT,OgawaY.Adipose8ssuemacrophages:theirroleinadipose8ssueremodeling.JLeukocBiol.2010;88(1):33‐9.

SuganamiT,OgawaY.Adipose8ssuemacrophages:theirroleinadipose8ssueremodeling.JLeukocBiol.2010;88(1):33‐9.

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

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α-motoneuron

γ-motoneuron © 2005 Dr. David Seaman

•  Insulin resistance

•  Hyperinsulinemia (& hyperglycemia*)

•  Increased triglycerides

•  Decreased HDL

•  Increased LDL

•  Reduced fibrinolysis

•  Hyperuricemia

•  Classically associated diseases - Type 2 diabetes, coronary artery disease, hypertension, obesity

Cordain L, Eades MR, Eades MD. Hyperinsulinemic diseases of civilization: more than just syndrome X. Compar Biochem Physiol 2003; 136:95-112

Outcome of syndrome X •  These results suggest that adherence to a low glycemic index or low glycemic load diet may be 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.”

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

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

•  208 apparently healthy, nonobese subjects were evaluated 4-11 years after baseline measurements of insulin resistance were made to determine the incidence of various clinical events including hypertension, coronary heart disease, stroke, cancer, and type 2 diabetes. •  The subjects divided into tertiles of insulin resistance at baseline, development of clinical events were compared 40 clinical events occurred among 37 subjects, including 12 hypertension, 3 hypertension and type 2 diabetes, 9 cancer, 7 coronary heart disease, 4 stroke, and 2 type 2 diabetes. •  28/40 clinical events in 25 individuals (36%) in the most insulin-resistant tertile; other 12 in the group with an intermediate IR. •  No events in the insulin-sensitive tertile, which according to the authors “seems to be truly remarkable.”

•  Epithelial carncinomas (breast, prostate, colon)

•  Acne

•  Reduced age of menarche

•  Trend of increased stature

•  Myopia

•  Cutaneous pappillomas (skin tags)

•  Acanthosis nigricans

•  Polycystic ovary syndrome

•  Male vertex balding

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Blaha M, Elasy TA. Clinical use of the metabolic syndrome: why the confusion? Clin Diabetes. 2006; 24(3):125-31

Cowy S, Hardy RW. The metabolic syndrome: A high-risk state for cancer? Am J Pathol. 2006; 169(5):1505-22

α-motoneuron

γ-motoneuron © 2005 Dr. David Seaman

TheprevalenceofMetSwas33%inmalesand29%infemales.Neckpainwaspresentin11%(N=42)ofmalesand19%(N=93)offemales(P<0.001).

Prevalenceofneckpainwas7.9%amongmalesubjectswithoutMetSand16%amongthosewithMetS.

Therespec8vepropor8onsamongfemaleswere16%and25%.

Widespread pain and glycemic dysregulation Astructuredinterviewandhealthexamina8onstudywith480par8cipantsaged30‐65yrswascarriedoutinLapinlah8municipalityineasternFinland.

Ofthetotalsample,55subjects(11%)haddiabetes.TheprevalenceofCWPwas13%(n=62)inallsubjects.Thecorrespondingpercentagesforsubjectswithnormalglucoseregula8on,IGRanddiabeteswere9,18and28%.

MantyselkaPetal.Glucoseregula8onandchronicpainatmul8plesites.Rheumatology.2008;47(8):1235‐38.

Widespread pain and glycemic dysregulation Astructuredinterviewandhealthexamina8onstudywith480par8cipantsaged30‐65yrswascarriedoutinLapinlah8municipalityineasternFinland.

Chronicpain(dura8onofatleast3months)wasgradedaccordingtofrequency:beingpresentlessocenthandaily,oreverydayorcon8nuously(dailychronicpain,DCP).

Theprevalenceofdailychronicpainwas21%(N=101)inallthesubjects.Inthesubjectswithanormalplasmaglucoselevel,theprevalencewas18%,whileinthosewithanelevatedplasmaglucoselevelitwas38%.Thecorrespondingpercentagesfornon‐diabe8csanddiabe8cswere19%and42%.

MantyselkaPetal.Chronicpain,impairedglucosetoleranceanddiabetes:acommunity‐basedstudy.Pain.2008;137(1):34‐40.

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GaidaJEetal.DyslipidemiainAchillestendinopathyIscharacteris8cofinsulinresistance.MedSciSportsExerc.2009;41(6):1194‐97Althoughoveruseisconsideredamajorcausa8vefactorformidpor8onAchillestendinopathy,uptoonethirdofcasesoccuramongcompletelynonac8veindividuals.Furthermore,midpor8onAchillestendinopathyisocenseenamongoverweightindividualswhoareocentakingmedica8ontotreataspectsofthemetabolicsyndrome.Evenamongelitelevelathletes,aslightlyelevatedwaistcircumference(83cm)drama8callyincreasestheriskoftendonabnormality.

AlthoughincreasedbodyweightdirectlyaffectsAchillestendonloading,itisunlikelythatincreasedtendonloadingadequatelyexplainstheserela8onships.Alternatemechanismslinkingobesityandtendinopathymaybefoundbyexaminingsystemicfactorsthatbecomeincreasinglycommoninthepresenceofobesity.Theseincludedyslipidemia,hypertension,glucoseintolerance,andinsulinresistance.Becauselipiddeposi8onisknowntooccurintendons,highcholesterollevelshavebeenobservedamongindividualswithAchillestendonrupture,andtheesterifiedfrac8onofcholesteroliselevatedinbiopsiesfromAchillestendinopathysubjectswechosetofocusonserumlipidprofiles.

Conclusions:Ourfindingsshowedassocia8onsofabdominalobesity,someothermetabolicfactorsandcaro8din8ma‐mediathicknesswithshoulderpain.Disturbedglucosemetabolismandatherosclerosismaybeunderlyingmechanisms,althoughnotfullysupportedbythefindingsofthisstudy.

Glassman SD, Alegre G, Carreon L, Dimar JR,Johnson JR. Perioperative complications of lumbar instrumentation and fusion in patients with diabetes mellitus. Spine J. 2003;3(6):496-501

Complications of lumbar fusion

Total comps

Major comps

Minor comps

IDDM (n=43)

56% (n=24) 33% (n=14) 23% (n=10)

NIDDM (n=51)

53% (n=27) 24% (n=12) 29%(n=15)

Control (n=43)

21% (n=9) 7% (n=3) 14% (n=6)

•  High GI foods •  Homocysteine •  CRP •  Lack of exercise •  HBP •  Family history •  Oxidative stress •  Smoking •  Obesity and diabetes

German JB, Dillard CJ. Saturated fats: what dietary intake? Am J Clin Nutr 2004; 80:550-59

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Lateral lumbar radiograph, scored 1 for aortic calcifications (both posterior and anterior) in front of the L1 vertebra, 2 for calcifications in front of the L2 vertebra, and 3 for calcifications in front of the L3 and L4 vertebrae. Intervertebral space between the L2 and L3 vertebrae shows Grade 2 disc space narrowing and endplate sclerosis.

Kauppila LI, McAlindon T, Evans S, Wilson PW, Kiel D, Felson DT.

Disc degeneration/back pain and calcification of the abdominal aorta: a 25-year follow-up study in Framingham.

Spine 1997; 22:1642-47

Kauppila LI, McAlindon T, Evans S, Wilson PW, Kiel D, Felson DT.

Disc degeneration/back pain and calcification of the abdominal aorta: a 25-year follow-up study in Framingham.

Spine 1997; 22:1642-47

Advanced aortic atherosclerosis, presenting as calcific deposits in the posterior wall of the aorta, increases a person's risk for development of disc degeneration and is associated with the occurrence of back pain.

Kauppila LI et al. Spine 1997; 22:1642-47

Recent postmortem studies suggest that atheromatous lesions in the aorta obliterate orifices of the feeding arteries of the lumbar spine and may result in disc degeneration and long-term back symptoms.

Kauppila LI et al. Spine 1997; 22:1642-47

Kurunlahti M et al.

Association of atherosclerosis with low back pain and the degree of disc degeneration.

Spine. 1999; 24:2080-84

Sixteen (55%) of the 29 patients with low back pain had aortic calcifications, whereas 11 (21%) of the asymptomatic control group had calcifications.

Kurunlahti M et al. Association of atherosclerosis with low back pain and the degree of disc degeneration. Spine. 1999; 24:2080-84

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Aortic calcifications were identified in 48% of the patients aged less than 50 years with low back pain and in only 8% of the control subjects of the same age.

Kurunlahti M et al. Association of atherosclerosis with low back pain and the degree of disc degeneration. Spine. 1999; 24:2080-84

Among the patients more than 50 years of age, 5 (83%) of 6 with low back pain had aortic calcifications, whereas in the control 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 degree of disc degeneration. Spine. 1999; 24:2080-84

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

•  Patients with long-term non-specific lower back pain frequently have occluded lumbar/middle sacral arteries.

•  Occulsion of lumbar/middle sacral arteries is associated with disc degeneration.

•  High serum LDL cholesterol levels are 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

Leino-Arjas P et al.

Serum lipids and low back pain: an association?

Spine 2006; 31:1032-37

1. It has been suggested that atherosclerosis of the lumbar arteries could cause low back pain via interference with the nutrition of the lumbar tissues.

2. High serum cholesterol and triglyceride 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

Key Points

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3. We found that high serum total cholesterol and triglyceride concentrations at baseline were associated with radiating low back pain at follow-up among subjects of the normal working population free of radiating low back pain initially. The analyses controlled for age, gender, occupational class, history of physically strenuous work, body mass index, smoking, and leisure-time physical activity as potential confounders.

4. The subjects with both high total cholesterol and high triglycerides carried an accumulated risk.

5. Serum lipid levels were associated with radiating but not local low back pain.

Leino-Arjas P et al. Serum lipids and low back pain: an association? Spine 2006; 31:1032-37

• Asample(n=902)ofemployeesinanengineeringcompanywasexaminedforserumtotalcholesterolandtriglycerides,bodymassindex(BMI),smoking,exercise,workhistory,andLBPin1973.ByNovember2000,232subjectshaddied.

• In1978,748(84%ofthesurvivors),in1983,654(76%),andin2000,546(81%)respondedtoafollow‐upques8onnaire.

Leino-Arjas P et al. Serum lipids and low back pain: an association? Spine 2006; 31:1032-37

What should we do with these patients?

Of course they are too tired to exercise….

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Representative transmission electron microscopy of longitudinal sections 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 perinuclear distribution of subsarcolemmal mitochondria was measured using image analysis (National Institutes of Health image 1.61) and can be observed to be substantially depleted in type 2 diabetes. Ritov VB et al. Deficiency of subsarcolemmal mitochondria in obesity and type 2 diabetes. Diabetes 2005; 54(1):8-14.

•  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 transport, and insulin signalling. •  Reduced subsarcolemmal mitochondria may play a role in the development of insulin resistance.

Ritov VB, Menshikova EV, He J, Ferrell RE, Goodpaster BH, Kelley DE. Deficiency of subsarcolemmal mitochondria in obesity and type 2 diabetes. Diabetes 2005; 54(1):8-14

Drivers of the metabolic

syndrome X

Impairment of insulin-stimulated glucose transport, is responsible for resistance to insulin-stimulated glycogen synthesis in muscle in subjects with type 2 diabetes.

Cause of insulin resistance

Shepard PR, Kahn BB. Glucose transporters and insulin action.1999;341(4):248-57

Exercises8mulatesglucosetransportbypathwaysthatareindependentofphosphoinosi8de‐3kinaseandthatmayinvolve5'‐AMP–ac8vatedkinase.

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Ceriello A. New insights on oxidative stress and diabetic complications may lead to a "causal" antioxidant therapy.Diabetes Care. 2003 May;26(5):1589-96

Magnesium deficiency is associated with diverse clinical manifestations:

•  headaches •  sudden death •  accelerated atherosclerosis •  cardiovascular disease •  hypertension •  stroke •  renal tubular disorders •  osteoporosis •  diabetes mellitus •  asthma •  preeclampsia & eclampsia •  neurologic & psychiatric conditions

•  Ford ES, Mokdad AH. Dietary magnesim intake in a national sample of US adults. J Nutr 2003; 133:2879-82

•  Bar-Dayan Y, Shoenfield Y. Magnesium fortification of water. A possible step forward in preventive medicine? Ann Med Interne (Paris). 1997;148(6):440-4

Drivers of the metabolic syndrome X

The drivers tell us what the treatment is…

Chronic inflammation precedes insulin resistance

•  Insulin resistance and disordering of lipid metabolism occur in obesity, diabetes mellitus, atherosclerosis. This review examines recent research that links inflammation to insulin insensitivity.

•  Recent studies on diseases which involve insulin insensitivity (e.g. obesity, type 2 diabetes and atherosclerosis) also show increased cytokine production and markers of inflammation. Evidence at present favours chronic inflammation as a trigger for chronic insulin insensitivity, rather than the reverse situation.

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•  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

Drivers of hyperinsulinemia:

Undercontrolledfeedingcondi8ons,long‐term(6yr)TFAconsump8onwasanindependentfactorinweightgain.TFAsenhancedintra‐abdominaldeposi8onoffat,evenintheabsenceofcaloricexcess,andwereassociatedwithinsulinresistance,withevidencethatthereisimpairedpost‐insulinreceptorbindingsignaltransduc8on.Kavanagh K, et al. Trans fat diet induces abdominal obesity and changes in insulin sensitivity in monkeys. Obesity. 2007; 15(7):1675-84

In this abdominal MRI scan, it is possible to see subcutaneous fat around the abdomen, surrounding abdominal muscles. Visceral fat is deeper inside the abdomen, surrounding internal organs.It is the visceral fat that secretes IL-6, strongly suggesting a mechanistic link to systemic inflammation.

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

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

Trayhurn P, Bing C, Wood IS. Adipose tissue and adipokines - energy regulation from the human perspective. J. Nutr. 136: 1935S–1939S, 2006.

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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.

GalicSetal.Adipose8ssueasanendocrineorgan.MolCellEndocrinol.2010;316:129‐39.

Obesity‐inducedchangesinmacrophageinfiltra8onandpolarisa8on.Adipose8ssuemacrophages(ATMs)intheleanstateshowcharacteris8csof“alterna8ve”orM2ac8va8onwithincreasedproduc8onofarginaseandthean8‐inflammatorycytokineIL‐10.

Theyarepostulatedtopar8cipatein8ssuerepairandtheamenua8onofinflammatoryresponses.Expansionofadipose8ssueleadstoadipocytehypertrophyandthereleaseofchemokinesthatinduceincreasedrecruitmentofM1macrophagesfromthebloodstream.

M1or“classicallyac8vated”ATMsarecharacterizedbyincreasedproduc8onofthepro‐inflammatorycytokinesTNFαandIL‐6,whichpromotealteredgeneexpressionandinsulinresistanceinadipocytes.Thesechangesresultinalteredadipokinesecre8on,increasedlipolysisandexcessofcircula8ngnonesterifiedfamyacids,whichmayeventuallycontributetosystemicinsulinresistance.

GalicSetal.Adipose8ssueasanendocrineorgan.MolCellEndocrinol.2010;316:129‐39.

Holick MF, Chen TC. Vitamin D deficiency: a worldwide problem with health consequences. Am J Clin Nutr. 2008; 87(4):1080S-86S

* *

Estimated needs of vit D throughout lifecycle 1. Breast-fed infants (800 IU/day)

2. Formula-fed infants (400 IU/day) 3. Toddlers & young children (1000-2000 IU/day) – [when not getting adequate sun, and based on weight*]

4. Lactating women: 7,000 IU/day

5. Adolescents and adults can take between 3000-10000 IU or more depending on vitamin D levels in blood (serum 25(OH)D: 32-100 ng/ml).

6. Pregnant or those thinking of becoming pregnant – get 25(OH)D check every 3-months (get to 40-70 ng/ml*)

Read full text before acting: Cannell JJ, Hollis BW. Use of vitamin D(3) in clinical practice. Alt Med Rev. 2008;13(1):6-20.

Chiu KC et al. Hypovitaminosis D is associated with insulin resistance and B-cell dysfuntion. Am J Clin Nutr 2004; 82:820-25

Extrapolation from the observations in the current study suggests that increasing 25(OH)D from 10 to 32 ng/mL can improve insulin sensitivity by 60%. This could potentially eliminate the burden on beta cells and reverse abnormal glucose tolerance.

Furthermore - the 60% improvement in insulin sensitivity from Vit D = more potent than troglitazone or metformin treatment (54% and 13% improvement in insulin sensitivity).

Vitamin D - insulin sensitivity

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CD4 T helper cells

TH1 TH2 T-reg Maintenance of self-tolerance

IL-4, 5, 13, which are associated with IGE responses, and IL-10 which is anti-

Cytokines are pro-inflammatory [i.e., IFN-g] - [IL-1, TNF]. Kill intracellular parasites and perpetuate autoimmunity. Lead to uncontrolled damage and must be balanced by TH2 and T-reg.

Berger A. Science commentary: Th1 and Th2 responses: what are they. BMJ 2000; 321: p.424

inflammatory.

Cantorna MT, Mahon BD.

Mounting evidence for vitamin D as an environmental factor affecting autoimmune disease prevalence.

Exp Biol Med. 2004; 229:1136-42

IFN-g --> IL-1, IL-6, TNF

IL-10

IFN-g --> IL-1, IL-6, TNF

IL-10

Self tolerance

Self tolerance

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

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.

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.

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•  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 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.

Boni-Schnetzler M et al. Insulitis in type 2 diabetes. Diabetes Obesity Metab. 2008;10(suppl 4):201-204.

Hypothalamic inflammation

Experimental interventions that block hypothalamic inflammation (e.g., inhibition of hypothalamic Inhibitor of kappa kinase-b (IKKb) signaling) reduce food intake and lower body weight in animals made obese by high-fat (HF) feeding, but not in controls fed a low-fat (LF) diet.

The mechanism whereby hypothalamic inflammation favors weight gain is strongly linked to the induction of resistance to leptin and other humoral inputs to the hypothalamus, including insulin.

Thaler JP et al. Hypothalamic inflammation and energy homeostasis: Resolving the paradox. Frontiers Neuroendocrinol. 2010;31:79-84.

Hypothalamic inflammation and obesity handout – obesityisassociatedwithapro‐inflammatorystateinkeyneuronalsystemsthatgovernenergyhomeostasis,

.

Diet and supplements

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

Wine (red wine) 32% (23-41)

Fish (n-3 meat, chicken, eggs) 14% (8-19)

Dark chocolate 21% (14-27)

Vegetables & Fruit 21% (14-27)

Garlic (all spices) 25% (21-27)

Almonds (all raw nuts) 12.5% (10.5-13.5)

Combine effect 76% (63-84)

Food choices for

disease prevention and health promotion.

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•  Multivitamin/mineral •  Magnesium •  Fish oil (EPA/DHA) •  Vitamin D •  a-Lipoic acid & acetyl-L-carnitine (ALCAR) •  Fiber

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:

(Seaman additions: CoQ10, anti-inflammatory botantical, glucosamine/chondroitin, hydroxyapatite calcium, proteolytic enzymes, chromium, vitamin K2)

•  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

REVERSE the drivers of hyperinsulinemia:

AnnInternMed.2005;142:323‐32.

Comparedwiththeplacebointerven8on,thelifestyleandmepormininterven8onswerees8matedtodelaythedevelopmentoftype2diabetesby11and3years,andtoreducetheabsoluteincidenceofdia‐betesby20%and8%,respec8vely.

Comparedwiththeplacebointerven8on,thecostperQALY(qualityoflifeadjustedyears)wasapproximately$1100forthelifestyleinterven8onand$31,300forthemepormininterven8on.Fromasocietalperspec8ve,theinterven8onscostapproximately$8800and$29,900perQALY,respec8vely.

Frombothperspec8ves,thelifestyleinterven8ondominatedthemepormininterven8on.

Supplementsforglycemicregula8on:

• Magnesium• VitaminD• Chromium• Lipoicacid• Gymnemasylvestre• Cinnamon• Vanadium

Diabetes.2002;251:2074‐81.

Meporminac8vatesAMPK,whichleadstoGlut4transloca8ontomusclecellmembrane. ShayKP,MoreauRF,SmithEJ,SmithAR,HagenTM.Alpha‐lipoicacidasadietary

supplement:molecularmechanismsandtherapeu8cpoten8al.BiochimBiophysActa.2009;1790(10):1149‐60.

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Keytoinsulinsignalingmolecules:

• AMPK:adenosinemonophosphate‐ac8vatedproteinkinase

• IRS‐1: insulinreceptorsubstrate1(IRS1)protein

• PTP1B:proteintyrosinephosphatase

• PI3K:phosphoinosi8de3‐kinase

• PDK1:PtdIns‐dependentkinase1(phosphoinosi8des)

• Akt:serine/threonineproteinkinase

• AS160:Aktsubstrateof160kDa

IRS‐1PI3K Akt

AS160

I

Glut4

Cr

Apo‐chromodulin

BLOOD GLUCOSE LEVELS RISE

IRS‐1PI3K Akt

AS160

I

Glut4

Cr

Apo‐chromodulin

BLOOD GLUCOSE LEVELS RISE

Cr

IRS‐1PI3K Akt

Chromodulin

Cr

I

AS160

Glut4

BLOOD GLUCOSE

Cr

IRS‐1PI3K Akt

AS160

Chromodulin

Cr

I BLOOD GLUCOSE

Cr

AMPK

α‐LA

Glut4

Musclecontrac8on

IRS‐1PI3K Akt

AS160

Chromodulin

Cr

I BLOOD GLUCOSE

Cr

AMPK

α‐LA

Glut4

Musclecontrac8on

21

• Supplementaldosesofchromiumthatbenefitglycemicregula8on,whichrangefrom200to1000mcg,arenotthelevelsfoundinfood.

• Adequateintakeofchromiumforadultsrangesfromonly20to45micrograms(mcg)perday.Theprogressionofmetabolicsyndromeisnotlikelycausedbyachromiumdeficiency.

• Func8onofhighdosechromium:TopushinternalsignalingthatleadstoGlut4transloca8on.

• Takewith/withoutfood.

Chromiumsupplementa8on VincentJB.Chromium:celebra8ng50yearsasanessen8alelement?DaltonTrans.2010;39:3787‐94.

VincentJB.Thebiochemistyofchromium.JNutr.2000;130:715‐18.

AndersonRA.Chromiumandinsulinresistance.NutrResRev.2003;16:267‐75.

Dietarysupplementfactsheet.Na8onalIns8tutesofHealth.hmp://ods.od.nih.gov/factsheets/chromium/

AndersonRA.Chromium,glucoseintoleranceanddiabetes.JAmCollNutr.1998;17(6):548‐55.

CefaluWT,RoodJPatriciaPinsonatPetal.Characteriza8onofthemetabolicandphysiologicresponsetochromiumsupplementa8oninsubjectswithtype2diabetesmellitus.MetabClinExper.2010;59:755‐62.

HeimbachJT,AndersonRA.Chromium:recentstudiesregardingnutri8onalrolesandsafety.NutrToday.2005;40(4):18095.

AndersonRA,BrydenNA,PolanskyMM.Serumchromiumofhumanssubjects:effectsofchromiumsupplmenta8onandglucose.AmJClinNutr.1985;41:571‐77.

AndersonRA,PolanskyMM,BrydenNA.Stabilityandabsorp8onofchromiumandabsorp8onofchromiumhis8dinatecomplexesbyhumans.BioTraceElemRes.2004;101:211‐18.

DiSilvestroRA,DyE.Comparisonofacuteabsorp8onofcommerciallyavailablechromiumsupplements.JTraceElementMedBiol.2007;21:120‐24.

Humanstudiesusing1000mcgperdayfor8monthshavebeenshowntobesafeandanimalmodelsusingsignificantlymorearenotassociatedwithtoxicologicalconsequences.

• AndersonRA.Chromiumandinsulinresistance.NutrResRev.2003;16:267‐75.

• HeimbachJT,AndersonRA.Chromium:recentstudiesregardingnutri8onalrolesandsafety.NutrToday.2005;40(4):18095.

Chromium supplementation safety

Wisetoregularlymonitorbloodsugar.

• Thefoodsrichestinα‐lipoicacidareanimal8ssueswithextensivemetabolicac8vitysuchasheart,liver,andkidney,whicharerarelyconsumed.Theplantsourcesofα‐lipoicacid,listedfromhighesttolowest,arespinach,broccoli,tomatoes,gardenpeas,brusselsprouts,andricebran.Whilethesefoodsarenotconsumedinlargeamounts,theresultantreducedconsump8onoflipoicisnotalikelypromoterofinsulinresistance.

• Thisisbecausethesupplementalamountsofα‐lipoicacidusedinthetreatmentofdiabetes(300‐600mg)arelikelytobeasmuchas10008mesgreaterthantheamountsthatcouldbeobtainedfromthediet.

• Supplementalα‐lipoicacidhasbeenusedextensivelyinpa8entssufferingfrominsulinresistantrelatedcondi8ons.

alpha‐lipoicacidsupplementa8on

SinghU,JialalI.Alpha‐lipoicacidsupplementa8onanddiabetes.NutrRev.2008;66(11):646‐57.

Foodintakeisreportedtoreducethebioavailabilityofsupplementalα‐lipoicacid,whichiswhyitisgenerallyrecommendedtobetakenuponanemptystomach(1hourbeforeor2hoursacerea8ng)(1).

Ingeneral,α‐lipoicacidsupplementa8onhasbeenfoundtohavefewserioussideeffects.Inafiveweekstudy,pa8entswithdiabe8cpolyneuropathyweresupplementedwitheitheraplacebo(n=43)orα‐lipoicacidat600mg(n=45),1200mg(n=47),or1800mg(n=46).Sideeffectsweresimilarintheplaceboand600mggroup(2).

alpha‐lipoicacidsupplementa8on(600mg/day)

1.  SinghU,JialalI.Alpha‐lipoicacidsupplementa8onanddiabetes.NutrRev.2008;66(11):646‐57.

2.  ZieglerD,AmetovA,BarinovA,etal.Oraltreatmentwithalpha‐lipoicacidimprovessymptoma8cdiabe8cpolyneuropathy:theSYDNEY2trial.DiabetesCare.2006;29:2365‐70.

Leach, Matthew J. Gymnema sylvestre for diabetes mellitus: a systematic review. J Altern Comp Med. 2007;13(9):977-83.

GiventhatG.sylvestretargetsseveralofthee0ologicalfactorsconnectedwithdiabetes(Fig.1),includingchronicinflamma8on,obesity,enzyma8cdefects,andpancrea8cbeta‐cellfunc8on,andnosingleoralhypoglycemicdrugpresentlyexertssuchadiverserangeofeffects,suggeststhatgymnemamaybeusefulinthemanagementofdiabetesandthepreven8onofassociatedpathologicalchanges.

However,asthissystema8creviewshows,theclinicalefficacyofgymnemahasonlybeensupportedbyasmallnumberofnonrandomized,open‐labeltrials.Hence,furtherinves8ga8onintotheclinicaleffectofG.sylvestreonbothdiabetesanditsassociatedcomplica8onsisurgentlyneeded.

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Alternative Medicine Review ◆ Volume 4, Number 1 ◆ 1999

Thetypicaltherapeu8cdoseofanextract,standardizedtocontain24‐percentgymnemicacids,is400‐600mgdaily.Itisnotclearfromexaminingthestudieswhetherdivideddosesisidealbut,becauseitisbeingusedtoregulatebloodsugar,threedivideddoseswithmealswouldseemideal.

Nosignificantadverseeffectshavebeenreported,asidefromtheexpectedhypoglycemia.Safetyinpregnancyhasnotbeenestablished.

Gymnema - Dosage and Toxicity

ConclusionsIntakeof2gofcinnamonfor12weekssignificantlyreducestheHbA1c,SBPandDBPamongpoorlycontrolledtype2diabetespa8ents.Cinnamonsupplementa8oncouldbeconsideredasanaddi8onaldietarysupplementop8ontoregulatebloodglucoseandbloodpressurelevelsalongwithconven8onalmedica8onstotreattype2diabetesmellitus.

Diabet.Med.27,1159–1167(2010)

Vanadiumisapoorlyunderstoodtraceelementthatisubiquitousinnatureandbelievedtohavemanyfunc8onsinhumanphysiology.Invitroandanimalstudieshavedemonstrateditsinsulinomime8ceffectsmediatedbyinhibi8onofphosphotyrosinephosphataseenzymesthataffecttheinsulinreceptor.

Arecentmeta‐analysisiden8fied5uncontrolledtrials(N=48)inwhich50to300mgofvanadiumwasadministeredfor3to6weeks.Vanadylsulfatewasusedin4trialsandsodiummetavanadatewasusedin1trial.All5trialsreportedreduc8onsinFBGlevels,butthesewereofshortdura8on;noneofthetrialsincludedcontrols.

Commonlyreportedsideeffectsincludedgastrointes8nalupset,bloa8ng,andnausea.Thereisinsufficientevidencetosupporttheuseofvanadiuminthetreatmentoftype2DM.

Vanadium

Nahas R et al. Complementary and alternative medicine for the treatment of type 2 diabetes. Can Fam Physician. 2009;55:591-96.

Vanadiumisapoorlyunderstoodtraceelementthatisubiquitousinnatureandbelievedtohavemanyfunc8onsinhumanphysiology.Invitroandanimalstudieshavedemonstrateditsinsulinomime8ceffectsmediatedbyinhibi8onofphosphotyrosinephosphataseenzymesthataffecttheinsulinreceptor.

Vanadium

•  Multivitamin/mineral •  Magnesium •  Fish oil (EPA/DHA) •  Vitamin D •  a-Lipoic acid & acetyl-L-carnitine (ALCAR) •  Fiber

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:

(Seaman additions: CoQ10, anti-inflammatory botantical, glucosamine/chondroitin, hydroxyapatite calcium, proteolytic enzymes, chromium, vitamin K2)