The Skinny on Insulin March 2012 George Gillson MD PhD

Meet Jane 42 years old Teacher Married 3 children 30 lbs overweight I just feel old Hot flashes at night Anxiety Breast tenderness, puffy ankles, migraines Menses regular but heavier Some hair growth on upper lip Weight gain at waist and hips Heartburn Poor muscle tone: Im mushy Low sex drive Runs out of gas by midmorning Complains her hair is prematurely grey I think my hormones are out of balance. Couch potato Terrible diet Avoids sun exposure

Jane: Objective Data 185 lbs 56 BMI 30 Waist 40 (102 cM) Hips 45 BP 135/87 Skin tags 7 mercury fillings Triglycerides (TG) high Total cholesterol: high HDL cholesterol: low Chem: slightly increased GGT, uric acid Fasting glucose: normal Skin Tags

Typical MD Approach to Jane Patient is treated as a collection of problems, and given pathway-blocking drugs to solve the problems Your blood pressure and cholesterol are too high. Statin drug for cholesterol ACE inhibitor for blood pressure Lose weight +/- Proton pump inhibitor for acid reflux +/- SSRI for anxiety and vasomotor symptoms Can we do any better than this? Yes, but we need an integrating framework

Metabolic Syndrome Elevated Insulin Insulin Resistance Half of the North American population > 45 yrs old ! Visceral Obesity NCEP* CRITERIA Three or more of : Abdominal obesity Elevated triglycerides Low HDL Hypertension Elevated fasting glucose * NCEP: National Cholesterol Education Program

Why is it called Metabolic Syndrome? Metabolic Syndrome is an increasingly well- understood collection of all or many of the following metabolic abnormalities: Borderline/High blood pressure High insulin, insulin resistance Problems regulating blood sugar Abnormal lipids (low HDL and high triglycerides) Impaired vasodilation Evidence of inflammation on blood tests Abnormal steroid hormone levels (some high, some low) High serum uric acid Abnormal liver function tests Abnormal appestat: endorphins, -MSH, leptin

MetS Prognosis Economic crisis of Biblical proportions Decreased quality of life Shortened lifespan/accelerated aging Degeneration/metabolic decompensation Diabetes Cardio/cerebrovascular disease Arthritis Osteoporosis Cancer Dementia?

(Reuters) - More than half of Americans will have diabetes or be prediabetic by 2020 at a cost to the U.S. health care system of $3.35 trillion if current trends go on unabated, according to analysis of a new report released on Tuesday by health insurer UnitedHealth Group Inc. By Bill Berkrot NEW YORK Tue Nov 23, 2010 12:11am EST http://www.reuters.com/article/idUSTRE6AM0NH20101123 MetS and College Football Players Prevalence of MetS was 19% ( 1 in 5) in 2010 paper looking at University of Tennessee NCAA Div. 1 football players J Athl Train 2010;45:67-74. Identification of cardiometabolic risk among collegiate football players. Wilkerson GB, Bullard JT, Bartal DW. The football players are not alone: Pre-MetS in Prepuberty Mauras N et al.. J Clin Endocrinol Metab 2010 ;95:1060-1068. Obese children with normal lipids, normal fasting glucose and normal blood pressure were found to have: Insulin resistance IL-6 PAI-1 (plasminogen activator inhibitor -1) hs CRP fibrinogen

Obesity/MetS Determinants Genetics, ethnicity Prenatal history Lifestyle Diet Sleep pattern Activity pattern Stress management (or lack thereof) Colonic flora Environment e.g. EM pollution, endocrine disruptors

Genetics MetS is strongly inherited Harsh environments select for fat storage genes which promote survival in times of famine These same genes dont serve us well when food is abundant (thrifty gene hypothesis) Mutations involving insulin signaling, vitamin D, thyroid hormone, gut hormones, fat metabolism, muscle development are linked to MetS Song Q, Wang S, Zafari M. Genetics of the Metabolic Syndrome. Hosp Physician 2006. http://www.turner- white.com/pdf/hp_oct06_genetic.pdf

Prenatal History Intrauterine malnutrition Premature birth Low birth weight Maternal smoking All can predispose to MetS in adulthood Infant is programmed to accumulate fat Epigenetic modification, hard wiring of HPA axis

Take up nutrients/utilize some Store nutrients not used immediately Build muscle/prevent muscle breakdown Metabolic Switch must flip between fasted and fed states multiple times throughout 24 hours Burn fat Build muscle/prevent muscle breakdown Provide glucose for brain HOW IS JANES SWITCH WORKING? Fast Eat FASTED FED

High Average GH Energy Fat Muscle Enter Growth Hormone Utz A et al. J Clin Endocrinol Metab 2008;93: 4033-4040 Obesity = Low Growth Hormone 25-35 yo women Low Average GH Fat Muscle Energy

Pituitary gland GH Target tissues: Bone Fat Muscle GHR IGFR Paracrine IGF-1 Endocrine IGF-1 IGF-1 What is Growth Hormone (GH)? Peptide hormone: 191 amino acids Blocks muscle uptake of glucose Stimulates lipolysis ( releases fatty acids) Stimulates fat burning in muscle Promotes liver synthesis of glucose Promotes growth of muscle tissue Prevents breakdown of muscle High blood glucose suppresses GH release IGF-1 Insulin-Like Growth Factor-1 -same basic actions as insulin -longer half-life than insulin due to protein binding -free IGF-1 rises then falls after meals -helps dispose of amino acids after initial work of insulin is done

When do you make Growth Hormone? Stage III Sleep GH Age During and after Exercise ! When youre young When youre asleep -Increased core temperature (sweating) -Increased lactic acid (anaerobic respiration) -Muscle damage (amino acids released into blood) Godfrey RJ, Madgwick Z, Whyte GP. Sports Med 2003;33:599-613. The exercise- induced growth hormone response in athletes. When youre hungry! hunger ghrelin GH

Why does Jane have low GH? Overweight: obesity low GH Age-related decline Lifestyle choices/habits: Eating pattern high blood sugar due to snacking in late evening suppresses sleep- onset GH release Snacking on refined carbs and saturated fats during the day Sleep Not enough sleep Doesnt initiate sleep well Exercise She hardly does any, and what she does is low intensity

What can Jane do about her low GH? Change what she eats and when she eats it Improve her sleep (quality and quantity) Hot bath/sauna before bed Progesterone supplementation at bedtime * DHEA supplementation** Start an exercise program and gradually bring in a high intensity component Growth hormone secretagogues GH injections? * Oral DHEA administration increases GH in women Genazzani AD et al. Fertil Steril 2001;76:241-248 Von Muhlen D et al. Osteoporos Int 2008;19:699-707 ** Progesterone stimulates GH release Clin Endocrinol (Oxf) 2009 ;71:535-542. A potential role of endogenous progesterone in modulation of GH, prolactin and thyrotrophin secretion during normal menstrual cycle. Caufriez A, Leproult R, L'Hermite-Balriaux M, Moreno- Reyes R, Copinschi G.

Sleep and Weight People who sleep less weigh more Increased sleep promotes weight loss If youre trying to lose weight, skimping on sleep causes you to lose less fat Eur J Endocrinol 2008;159 Suppl 1:S59-66. Sleep and the epidemic of obesity in children and adults. Van Cauter E, Knutson KL. http://www.medscape.com/viewarticle/729995http://www.medscape.com/viewarticle/729995

Jane: Sleep history Jane tells us she crashes before lunch, has low energy during the middle part of the day, and cant sleep at night Her symptoms fit her cortisol pattern 5-6 hours/night on week nights Sleeps in on weekends Many nights, sleep is unrefreshing; hot flashes wake her up frequently Cant get to sleep some nights (her brain just wont switch off)

What can Jane do about her sleep? Make a conscious decision to get more sleep! Determine whether she has sleep apnea Severe OSA is 6-7 times more likely in MetS patients Eur Heart J 2004;25:735-741. Obstructive sleep apnoea is independently associated with an increased prevalence of metabolic syndrome. Coughlin SR, Mawdsley L, Mugarza JA, Calverley PM, Wilding JP. J Endocrinol Invest 2010;33:192-196. Growth hormone/insulin-like growth factor-I axis in obstructive sleep apnea syndrome: an update. Lanfranco F et al. Oral progesterone at bedtime (metabolites are sedative- hypnotic) Supplement with melatonin (0.5 1 mg hs to start) Promote melatonin synthesis (5-HTP, B6 and magnesium) Magnesium glycinate (100 300 mg at hs)

168 beats/min 220 Age = 168 www.mercola.com http://www.youtube.com/watch?v=OKczVO37cEw&feature=related Growth Hormone Enhancing Workout 52 yrs old

Growth Hormone Secretagogues (1) Nutrients which support pituitary synthesis of GH (2) Peptides which encourage release of GH - ghrelin analogues (3) Amino acids (arginine, lysine, ornithine, glutamine) Muscle Damage Free amino acids (Endogenous) Brain GH release Protein sparing Exogenous amino acids

Take up nutrients/utilize some Store nutrients not used immediately Build muscle/prevent muscle breakdown Burn fat Build muscle/prevent muscle breakdown Provide glucose for brain Fast Eat FASTED Growth hormone FED X Metabolic Switch JANES SWITCH ISNT FLIPPING TO THE GH SIDE!

Jane isnt hungry when she wakes up Jane has high fasting triglycerides and high normal glucose Jane is waking up with too much fuel in her tank Saturated fat Monounsaturated fat Monounsaturated fat or Polyunsaturated fat Triglyceride (TG) glycerol Glucose Acetyl CoA Fatty Acids Triglycerides (TG) Glycerol Dietary fat Krebs Cycle Stored fat (TG)

Insulin regulates the amount of fuel in circulation Glycogen Glucose Insulin blocks release of stored energy and protein Glucose Stored fat Free fatty acids Free triglycerides Free fatty acids Free triglycerides ProteinAmino acids Eat food Insulin + + + - - - Insulin promotes uptake of macronutrients

Lipoprotein Lipase GUT Liver Adipose Chylomicrons VLDL Free fatty acids bound to albumin Capillary LPL Muscle Insulin upregulates LPL If insulin is too low, fatty acids wont be available for uptake into muscle Free fatty acids Fatty acid transport proteins Dietary TGs

Janes Insulin/TG Paradox Insulin 21.6 U/ml (150 pmol/L) : Borderline High Fasting triglycerides: High How can Janes TGs be high? Insulin should suppress TGs and her insulin is high How can Janes insulin be high? Insulin goes up after you eat. She didnt eat anything while she was sleeping Fatty acids cell Insulin Fats determine basal insulin secretion

Janes Insulin/TG Paradox Janes fat cells are leaking TGs and fatty acids at night These fatty acids are driving her pancreas to make more insulin (to clear the fatty acids) That extra insulin is still not able to suppress lipolysis and the fat cells are resisting uptake of the fatty acids in the first place Janes adipocytes are resistant to the effect of insulin Jane has: high fasting insulin insulin resistant visceral fat

Pituitary gland GH Liver IGF-1 Insulin - - Insulin suppresses GH and IGF-1 High fasting insulin = low fasting IGF-1 Clasey JL, Weltman A, Patrie J et al. Abdominal visceral fat and fasting insulin are important predictors of 24-hour GH release independent of age, gender, and other physiological factors. J Clin Endocrinol Metab 2001;86:3845-3452. High Fasting Insulin = Low GH

Insulin Resistance Must be specific when we use these words Should refer to a specific target tissue: muscle, liver, adipose Should refer to a specific nutrient: glucose, fatty acids Should refer to a timescale: transient/postprandial (hours) vs ongoing (days, months, years)

Take up nutrients/utilize some Store nutrients not used immediately Build muscle/prevent muscle breakdown Burn fat Build muscle/prevent muscle breakdown Provide glucose for brain Fast Eat FASTED Growth hormone FED Insulin X Metabolic Switch JANES METABOLIC SWITCH IS STUCK! X

Enough is Enough There is another way to look at insulin Insulin is both a satiety signal and an adiposity signal Satiety: Ive had enough to eat for now. Adiposity: Ive got lots of stored energy

Adipocytes Leptin Eat less Insulin Shrink fat cells Make bigger fat cells Inhibit insulin release -Amount of insulin you make is also proportional to fat mass -Insulin is a central appetite suppressant -High insulin in AM Lots of stored energy Leptin is proportional to fat mass Obese people are resistant to leptin. High leptin levels dont result in reduced appetite

Clin Pharmacol Ther. 2007 May;81(5):748-52. New targets for obesity pharmacotherapy. Aronne LJ, Thornton-Jones ZD. First order neuronsSecond-order neurons MSH Serotonin Increased outflow here results in appetite suppression Decreased outflow here results in appetite suppression Gas pedal Brake MSH and serotonin are important signaling molecules wrt appetite Neurochemistry of Appetite/Satiety

HOMA-IR Homeostatic Model for Metabolic Assessment of Insulin Resistance Go to: http://www.dtu.ox.ac.ukhttp://www.dtu.ox.ac.uk Click HOMA calculator link on sidebar at left side of page Download a program that installs this desktop calculator Use and abuse of HOMA modeling. Wallace T, Levy J, Matthews D. Diabetes Care 2004;27:1487-1495.

Fasting glucose or fasting insulin in isolation may not tell the whole story Glucose 5.6 mmol/L: Insulin 150 pmol/L % S = 35.6 (Normal = 100%) Janes sensitivity to insulin is only 35.6 % of normal HOMA-IR = 100/ (% S) = 100/35.6 = 2.8 Around 1: normal < 1: better > 2 : increased suspicion of Insulin Resistance % B = 154 (Normal = 100%) Her pancreas is working one and a half times harder than normal JANES HOMA-IR

ENERGY (FAs, glucose) Perform physical work Generate heat Insulin sensitive skeletal muscle burn FAs & glucose Converts glucose to TG Stores TGs imported from blood Appropriately releases TG and fatty acids to circulation Insulin sensitive liver Write talks on Metabolic Syndrome Store glycogen Make TGs Dont make glucose if insulin is hi Insulin sensitive visceral adipose tissue absorbs excess energy

Liver Fat cells Increased cholesterol synthesis Adipose Insulin Resistance: Failure to Store Energy Metastatic Fat Muscle Increased liver enzymes Increased serum triglycerides/free fatty acids * Increase in adipocyte size/macrophage recruitment/secretion of inflammatory cytokines e.g. TNF, IL-6 Blood vessels Atherosclerosis Fatty liver Marbling Impaired fat burning Inflammation* Epicardial fat

Glucose Acetyl CoA Triglycerides Cholesterol Krebs Cycle Insulin HMG CoA Reductase Cholesterol Blocking cholesterol synthesis could backfire in some people and cause them to make more insulin (in an attempt to increase cholesterol) HMG CoA Reductase Insulin + Insulin and Cholesterol

Statins Worsen Insulin Int J Clin Pract 2011;65:1141-1148. Comparison of the effects of simvastatin vs. rosuvastatin vs. simvastatin/ezetimibe on parameters of insulin resistance. Moutzouri E et al 3 month study of 156 patients who did not meet LDL-C targets through diet and exercise modification At week 12, all three treatment regimens were associated with significant increases in HOMA-IR and fasting insulin levels (p < 0.05 compared with baseline).

They have stopped gaining fat Energy is overflowing into other places it shouldnt be! This persons adipocytes are quite insulin sensitive! She is able to continuously gain fat These guys have insulin resistant adipocytes High glycemic load Insulin Fat storage + feedback Insulin Insulin resistant Insulin sensitive Fat mass

Gluconeogenesis Hepatic synthesis of glucose from various substrates

Insulin suppresses hepatic glucose synthesis One of the roles of insulin is to temporarily shut off glucose production by the liver (since insulin rises after a meal, there will be glucose in circulation from the meal, so the liver doesnt need to make any more) Hepatic insulin resistance refers to the loss of the ability of insulin to suppress gluconeogenesis This has the effect of augmenting the postprandial rise in glucose

Liver Fat cells Hepatic Insulin Resistance: Failure to Suppress Gluconeogenesis Glucose Fasted Liver X Glucose Insulin Fed Liver Glucose Insulin X Lipid accumulates in liver Glucagon Insulin Sensitive Liver

Hepatic before Peripheral Hepatic insulin resistance develops before peripheral resistance Diabetes 2003;52:2453-2460. Primacy of hepatic insulin resistance in the development of the metabolic syndrome induced by an isocaloric moderate-fat diet in the dog. Kim SP et al.

Glucose Skeletal Muscle Fat cells Skeletal Muscle Insulin Resistance: Failure to Dispose Glucose Glucose Glucose overflows into blood Increased TG synthesis

Fatty Acids Skeletal Muscle Skeletal Muscle Insulin Resistance: Failure to Burn Fat Fatty Acids Fat deposits intercalate between muscle fibres -Work -Heat Marbling

Fat StuckMetabolic Switch InsulinGH Insulin Resistance/Low Growth Hormone Progressive failure to manage energy The energy still has to go someplace Elevated serum glucose, elevated urine glucose Elevated serum triglycerides Elevated free fatty acids Fat deposits in liver (fatty liver) Fat deposits in muscle (marbling) Fat deposits in vascular tree Increased epicardial fat Fast Eat

How did what Jane eats get her in this (pun intended) pickle? Skips breakfast (not hungry, too rushed) Coffee & pastry en route to school Lunch in cafeteria (slice pizza, bag of chips) Eats out 1-2 nights/week-fast food Sit-down meals 2-3 nights/week-leans toward packaged food. Few meals from scratch Doesnt eat many whole foods 2-3 diet soda/day Snacks on chips or a chocolate bar, midmorning but especially in evening 4-6 cups coffee with cream/day

Janes Diet and Insulin Resistance Low antioxidants High trans fats Unbalanced natural polyunsaturated fat intake (6 vs 3) Low monounsaturated fat (almonds, olive oil, avocados) High saturated fat High refined carbohydrates (sucrose) High refined fructose intake (high fructose corn syrup) High refined salt Low chromium Low zinc Low magnesium Diabetes Care. 2005 May;28(5):1175-81. Magnesium deficiency is associated with insulin resistance in obese children. Huerta MG, Roemmich JN, Kington ML, Bovbjerg VE, Weltman AL, Holmes VF, Patrie JT, Rogol AD, Nadler JL.

Janes Oxidative Stress Load Jane doesnt eat any highly antioxidant, richly-coloured foods (corn and ketchup dont count!) She eats a lot of unsaturated fats (mostly 6) and a lot of trans fats which are easily damaged by free radicals Janes diet promotes oxidative stress Inflammation in visceral fat drives MetS JANES CHOLESTEROL Janes high cholesterol is not the root cause of her (currently asymptomatic) CAD It is a symptom of widespread metabolic derangements/inflammation High cholesterol (known antioxidant) ? compensatory reaction to oxidative stress

Oxidative Stress and Sleep Apnea Sleep apnea may be caused/worsened by oxidative stress in the brainstem and the tissues of the airway High oxidative stress OSA BRAINSTEM MetS Impaired GH output

Uric Acid Considered to be an antioxidant: elevated UA seen as a compensatory reaction to oxidative stress Elevated insulin causes kidneys to retain both uric acid and sodium Several prospective studies have shown that elevated uric acid is a risk factor for future development of MetS Metabolism 2012;61:281-288. High serum uric acid level and low urine pH as predictors of metabolic syndrome: a retrospective cohort study in a Japanese urban population. Hara S, Tsuji H, Ohmoto Y et al Am J Physiol 1995;268:E1-5. Effect of insulin on uric acid excretion in humans. Quiones G et al. Atherosclerosis 2012;220:525-531. Uric acid level as a risk marker for metabolic syndrome: A Chinese cohort study. Yang T, Chu CH, Bai CH, et al

Fatty Acids and Appetite Jane eats a lot of saturated fat She eats too little monounsaturated fat (oleic acid OA) She eats too little N-3 unsaturated fat (EPA and DHA) Saturated FAs are orexigenic DHA and OA are anorexigenic Int J Obes (Lond). 2011 Mar;35(3):336-44. Epub 2010 Aug 17. Effects of central administration of distinct fatty acids on hypothalamic neuropeptide expression and energy metabolism. Schwinkendorf DR, Tsatsos NG, Gosnell BA, Mashek DG.

Food intakeBody weight Int J Obes (Lond). 2011 Mar;35(3):336-44. Epub 2010 Aug 17. Effects of central administration of distinct fatty acids on hypothalamic neuropeptide expression and energy metabolism. Schwinkendorf DR, Tsatsos NG, Gosnell BA, Mashek DG.

Omega 3 Alpha-linolenic (ALA) Eicosapentaenoic acid EPA Docosahexaenoic acid DHA Omega 6 Linoleic (LA) -linolenic (GLA) DGLA Arachidonic acid AA n20 Hemp seeds, fish, flaxseeds, walnuts, green leaves Sunflower, corn, safflower, soy cottonseed, sesame, various nuts Anti: 13 HODE Nitrated LA Pro: 9 HODE Leukotoxin Leukotoxin diol Proinflammatory: PGE2 LTB4 Anti-inflammatory: Epoxyeicosatrienoic acids 16-HETE Lipoxins Epoxyeicosatetraenoic acids Prostaglandins Leukot Essent Fatty Acids 2008 ;79:173-517. Too much linoleic acid promotes inflammation-doesn't it? Fritsche KL. - Nutr Metab (Lond) 2009 ;6:8. Quantitation of alpha-linolenic acid elongation to eicosapentaenoic and docosahexaenoic acid as affected by the ratio of n6/n3 fatty acids. Harnack K, Andersen G, Somoza V. Essential Parents

EFA Take Home Points EFAs are complicated! We have to have some carbon chains longer than 18 carbons LA is not categorically bad EPA is not categorically good Antithyroid effects, immunosuppression, free radicals http://raypeat.com/articles/articles/unsaturated-oils.shtml A proper LA:ALA balance is essential; this balance is likely somewhere around 1:1 (range 2:1 to 1:2) Janes ratio LA: ALA is likely >10:1 Trans fats are categorically bad, and interfere with the utilization of the parent 6 and 3 fats You are what the animals you eat ate!

-C-C-(C-C) n -C-C-C-C- -C-C-(C-C) n -C-C- + Acetyl CoA -oxidation Krebs Cycle mitochondria -C=C-(C-C) n -C-C-C-C- desaturation Incorporation into triglycerides Saturated fat Burn or Store?:Saturated Fat Metabolism -C-C--C-C- STORE BURN Conversion to ketone bodies Monounsaturated fat e.g. oleic acid Shorter-by-two saturated fat

Saturated Fat e.g. stearic acid C18 (animal fat) Unsaturated Fat of same chain length e.g. oleic acid C18:1 Desaturation -oxidation Stearoyl CoA desaturase (SCD) Excessive activation of SCD leads to obesity SCD -/- mice are obesity resistant How do we avoid excessive upregulation of SCD? Shorter saturated fat *J Biol Chem. 1994 Nov 4;269(44):27773-7. Insulin and dietary fructose induce stearoyl-CoA desaturase 1 gene expression of diabetic mice. Waters KM, Ntambi JM.

Saturated Fat e.g. stearic acid C18 (animal fat) Monounsaturated Fat SCD Insulin Keeping the lid on SCD Fructose* + Cortisol + N-3 fatty acids Central appetite suppressant - Glucose + + Keep fructose intake to natural levels Keep cortisol under control, especially at night Adequate intake of N-3 fatty acids and oleic acid Dont pile refined sugars on top of saturated fats Oleic acid doesnt raise postprandial insulin as much as saturated fat Central appetite suppressant Avocados, olive oil, almonds

Am J Clin Nutr. 2008;88:638-644. Distinctive postprandial modulation of beta cell function and insulin sensitivity by dietary fats: monounsaturated compared with saturated fatty acids. Lpez S, Bermdez B, Pacheco YM, Villar J, Abia R, Muriana FJ. Isocaloric combinations of various types of fats layered over a basic carb meal Avoid combining excessive carbs and excessive saturated fats -Coconut oil contains medium-chain triglycerides (MCTs) which are 8-12 carbons -MCTs dont raise insulin very much -MCTs bypass the liver, so they can provide immediate energy -They burn fast like carbs but they are not carbs! ROO: olive oil | HPSO: high palmitic sunflower oil VEFO: vegetable/fish oil

Why didnt the Inuit get fat? They ate a lot of blubber which is higher in monounsaturated fat They didnt eat any sugars to excessively raise insulin and redirect their fat intake away from -oxidation Their fish oil intake also worked to prevent redirection (n-3 FAs suppress SCD) Their mix of fats was appetite suppressant

Sugars and Insulin Resistance/Obesity (Glucose fructose disaccharide) Sucrose FructoseHigh fructose corn syrup Fruit juice Fruit Fructose Starch = Polyglucose Glucose Fructose Slower release (in general) Glucose Some are slower release Faster release Fructose does not raise insulin Fructose creates other issues ! Increased need for nutrients needed to metabolize the sugars: Mg, lipoic acid, riboflavin, niacin, thiamine, pantothenic acid

Fructose aka Corn sugar Fructose raises uric acid; uric acid may be causative in MetS Am J Physiol Renal Physiol. 2006 Mar;290(3):F625-31. Epub 2005 Oct 18. A causal role for uric acid in fructose-induced metabolic syndrome. Nakagawa T, Hu H, Zharikov S et al Fructose is associated with systolic hypertension J Am Soc Nephrol. 2010 Sep;21(9):1543-9. Increased fructose associates with elevated blood pressure. Jalal DI, Smits G, Johnson RJ, Chonchol M. Fructose is preferentially metabolized to triglycerides in the liver J Nutr. 2008 Jun;138(6):1039-46. Dietary sugars stimulate fatty acid synthesis in adults. Parks EJ, Skokan LE, Timlin MT, Dingfelder CS.

A SEA OF FRUCTOSE NHANES 2004: 95th percentile > 100 g/day Elliott S et al. Am J Clin Nutr 2002;76:911-922

Artificial Sweeteners Consumption of low-cal diet foods can lead people to overeat high calorie foods (people think they have headroom because of the diet food) Consumption of sweet-tasting foods devoid of calories can result in uncoupling of normal responses to ingestion of sugars, e.g. heat-generating response Behav Neurosci 2009;123:772-780. General and persistent effects of high-intensity sweeteners on body weight gain and caloric compensation in rats. Swithers SE, Baker CR, Davidson TL.

Obesity and Endorphins Obesity and MetS are accompanied by - endorphinemia Int J Obes Relat Metab Disord. 1998 Feb;22(2):143-8. Relationship between insulin sensitivity, obesity, body fat distribution and beta-endorphinaemia in obese women. Percheron C, Colette C, Mariano-Goulart D et al. Eur Surg Res. 1998;30(6):409-13. Serum beta-endorphin levels in morbidly obese patients: the effect of vertical banded gastroplasty. Karayiannakis AJ, Zbar A, Makri GG et al.

Endorphins and Sugar High endorphin exposure is associated with increased sugar intake/preference for high-sugar foods J Opioid Manag 2010:445-452. The relationship between opioid and sugar intake: review of evidence and clinical applications. Mysels DJ, Sullivan MA. Sugar indirectly activates and sensitizes brain reward pathways Neuroreport 2001;12:3549-3552. Excessive sugar intake alters binding to dopamine and mu-opioid receptors in the brain. Colantuoni C et al. Anesth Analg. 2005 Jul;101(1):64-8, table of contents. Sugar solution analgesia: the effects of glucose on expressed mu opioid receptors. Kracke GR, Uthoff KA, Tobias JD.

Initiating factor or factors circulating endorphins mu opiod receptor expression effect of mu opioids pleasure from sweets Loss of negative feedback sensitivity for endogenous opioids craving for sweets -There is a lot of literature on the role of -endorphin in regulating the pancreatic insulin response to glucose -The pancreas may make its own endorphins for local regulation of insulin -High endorphin may represent failure of negative feedback Loss of negative feedback on pancreas insulin

Self Injection MetS patients with -endorphinemia are self-injecting opioids This suggests a way to intervene Well get to this in a few slides

Insulin and Zinc Secretion of insulin cannot take place without sufficient zinc Biochem Biophys Res Commun. 2006 ;351:165-170. Epub 2006 Oct 11. Oral administration of a zinc complex improves type 2 diabetes and metabolic syndromes. Adachi Y et al Biol Trace Elem Res. 2006;112:109-118. Effect of zinc supplementation on serum leptin levels and insulin resistance of obese women. Marreiro N et al. Indian J Exp Biol 2006;44:705-718. Long term excessive Zn- supplementation promotes metabolic syndrome-X in Wistar rats fed sucrose and fat rich semisynthetic diet. Taneja SK, Mandal R, Girhotra S. Insulin-Zn-Zn-Insulin Insulin Insulin is stored as a hexamer in the pancreas

Insulin and Chromium Insulin (Ins) Insulin receptor (IR) Ins-IR Complex Ins-IR Complex Cr Activation by chromium Downstream signalling more effective with Cr Cr deficiency: more insulin will be required to deliver the same message chromium polynicotinate 1000 ug/drop 1-10 drops per meal

Vanadium Vanadium can inhibit some of the anabolic effects of insulin, such as amino acid uptake and cell growth Mol Cell Biochem. 1998 May;182(1-2):109-19. Multifunctional actions of vanadium compounds on insulin signaling pathways: evidence for preferential enhancement of metabolic versus mitogenic effects. Fantus IG, Tsiani E. Vanadium is not found in significant amounts in food, compared to chromium: supplementation with mg amounts of vanadium may not be a good long term option Insulin (Ins) Insulin receptor (IR) Ins-IR Complex Ins-IR Complex V V VV Vanadylated insulin signaling complex is slower to break down more prolonged signaling

Other Contributors to Insulin Resistance Bad adipose tissue/inflammation in visceral fat Vitamin D deficiency Things getting in the way of insulin: Too much anti-insulin activity Loss of muscle mass/thyroid hormone issues

http://www.uchsc.edu/sm/ch s/research/ctscan_read.html Visceral Fat Pinchable fat Visceral Fat is directly proportional to Waist Circumference Obes Res 2003;11:1488-1494. Methods of estimation of visceral fat: advantages of ultrasonography. Ribeiro-Filho FF, Faria AN, Azjen S et al.

Inflammation and MetS (Fat is not just a storage depot!) Adipocytes Adipokines IL-6 ACP TNF PAI-1 VEGF Brain -satiety -appetite Adrenals -steroidogenesis Muscle Vascular tree -endothelial dysfunction -hypercoagulability + FA metabolites J Atheroscler Thromb2010;17:332-341. Adipose tissue, inflammation and atherosclerosis. Gustafson B. Am J Biomed Sci 2009;1:133-142. Regulation of Microvascular Function by Adipose Tissue in Obesity and Type 2 Diabetes: Evidence of an Adipose-Vascular Loop. Zhang H, Zhang C.

NF kappa B, Obesity and POMC Nat Med 2011;17:883-837. Uncoupling the mechanisms of obesity and hypertension by targeting hypothalamic IKK- and NF-B. Purkayastha S, Zhang G, Cai D. NF kappa B pathway drives obesity-related hypertension in mice Inhibition of NF kappa B signaling reversed hypertension Inflammation in hypothalamus interferes with central appetite regulation

Jane the Cave Dweller If Jane doesnt get outside much, and if she wears sunscreen when she does, what is her Vitamin D status? Her serum 25-hydroxyvitamin D level is low (< 25 nmol/L) What does Vitamin D have to do with insulin resistance and MetS?

Vitamin D and Insulin Low Vitamin D is associated with MetS in North American adults Horm Metab Res 2011;43:72-74. Low vitamin D levels in Northern American adults with the metabolic syndrome. Devaraj S et al Low Vitamin D is associated with insulin resistance Kayaniyil S et al. Association of vitamin D with insulin resistance and beta-cell dysfunction in subjects at risk for type 2 diabetes. Diabetes Care 2010;33:1379- 1381. Vitamin D supplementation improves insulin sensitivity Borissova AM et al. The effect of vitamin D3 on insulin secretion and peripheral insulin sensitivity in type 2 diabetic patients. Int J Clin Pract 2003;57:258-261.

How much Vitamin D does Jane need? The accepted standard to assess Vitamin D is serum 25-hydroxyvitamin D: Deficiency: 0-25 nmol/L Insufficiency: 25-40 nmol/L Sufficiency: 40-100 nmol/L Desirable: 75-160 nmol/L (minimum needed for fracture prevention) Toxic: >220 nmol/L JANE We would like to raise Janes 25-hydroxyvitamin D level by 100 nmol/L Long-term intake of 1000 IU/d cholecalciferol (Vitamin D3) will raise serum 25(OH)Vitamin D by 25 nmol/L* She needs around 4000 IU per day. (4000/1000 x 25) * Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Vieth R. Am J Clin Nutr. 1999 May;69:842-856.

Ins GH EpiC Ins Overproduction of cortisol and epinephrine, plus low GH leads to increased need for insulin Adequate growth hormone/non obese Insufficient growth hormone Excess cortisol and epinephrine Epi C C C Things Getting in the Way of Insulin JANE Profession: Teacher Stress level: High Stress type: Sandwich stress Jane has had years of over-secretion of cortisol and epinephrine due to stress, lack of sleep and excess caffeine As she has gained weight, her GH has dropped

What is the relationship between sleep deficit and cortisol? Sleep deprivation causes elevated cortisol in the latter half of the following day Elevated bedtime cortisol and sleep deprivation. Spiegel K, Leproult R, Van Cauter E. Lancet 1999;354:1435- 1439.

What is the eventual price of over- secretion of epinephrine? norepinephrine PNMT epinephrine methyl donor Continual stress methyl donor depletion Continual stress copper depletion Cu CH 3

Methyl Donors CH 3 S -- CH 3 O = MSM or dimethylsulfone Betaine SAMe Methyl donor precursors: Folate: green leafy vegetables, legumes, citrus fruits, berries, nuts B12 (cyanocobalamin): animal products (milk, meat, cheese, eggs) Choline: liver, egg yolks, wheat germ, green leafy vegetables, cauliflower, cucumber, soybeans, legumes Methyl donors: MSM: supposedly found in all fresh food Betaine: legumes, beets, shrimp, fish, wheat germ, wheat bran, spinach

Methyl Donors and Gastric Acid Histamine Methylated Histamine Gastric acid secretion Does not promote acid secretion Methyl donor Methyl donor deficiency could lead to prolonged gastric acid output Acid reflux (heartburn) is probably a symptom of methyl donor deficiency Jane is using up her methyl donors trying to keep up with epinephrine synthesis in her adrenal glands CH 3

MetS and H. Pylori Patients with H.Pylori infection had higher HOMA-IR, higher TGs, lower HDL compared to controls Eradication of H.Pylori led to improvements in these parameters whereas failure to eradicate infection did not lead to improvement South Med J 2010 Feb 3. [Epub ahead of print] Effect of Helicobacter pylori Eradication on Insulin Resistance, Serum Lipids and Low-Grade Inflammation. Gen R, Demir M, Ataseven H.

Copper and Vascular Disease Menkes Disease:genetic disorder involving copper transport: increased incidence of aortic aneurysm Copper Lysyl oxidase Elastin + Supple aorta Stiff aorta Hypertension Aortic aneurysm Copper depletion Hypercholesterolemia* *Atherosclerosis. 1978 Jan;29(1):81-93. Cholesterolemia and cardiovascular abnormalities in rats caused by copper deficiency. Allen KG, Klevay LM.

Copper and the Skin Synthesis of melanin depends on copper and methyl donors Jane doesnt tan well; she burns Janes failure to tan and her gray hair might be symptoms that she is methyl donor and copper deficient Her low antioxidant intake is another reason why she doesnt tan well (poor protection against free radicals) Melatonin Melanin EpinephrineCopper and methyl donors Hair pigmentation Tanning

Janes Aldosterone Janes fluid retention (puffy ankles) and hypertension suggest she is retaining sodium Hypertension 2004;43:358-563. * Epoxy-keto derivative of linoleic acid stimulates aldosterone secretion. Goodfriend TL et al. Hypertension 2006;48:239-245. Plasma aldosterone is independently associated with the metabolic syndrome. Bochud M et al. MetS Altered fatty acid metabolites (visceral fat) Paradoxical hyperaldosteronemia and sodium retention in the face of excess sodium intake Adrenals * Increased aldosterone Increased insulin Kidneys remain insulin sensitive Sodium retention

Glucose WorkHeat Skeletal Muscle Skeletal muscle is a significant glucose and fatty acid sink Well muscled individual: -High resting consumption of fuel -Highly insulin sensitive Muscle and Energy Disposal Insulin sensitivity Muscle mass Im mushy Sarcopenia: loss of muscle She is telling us she is low on Growth Hormone Sarcopenia is also a clue that she isnt getting enough T3 in muscle Janes Muscles Fatty acids

Cortisol T3 Skeletal muscle mitochondria ATP Mitochondria with beefier cell membranes More electron transport chains More ATP Iron Check ferritin !

T4 + T3 Deiodinase Copper ATP Iron Iodine Prevents loss of muscle T4 X T3 Deiodinase Low protein intake ATP Iron Iodine Muscle Copper reverse T3 (inactive) High Cortisol Zinc ? Most active form of thyroid hormone Selenium Growth Hormone Bromine Cadmium Mercury Low growth hormone X Often takes place in target tissue

Is there a link between T3 and Insulin Resistance? Clin Endocrinol (Oxf) 2007;67:265-269. Free triiodothyronine and thyroid stimulating hormone are directly associated with waist circumference, independently of insulin resistance, metabolic parameters and blood pressure in overweight and obese women. De Pergola G, Ciampolillo A, Paolotti S, Trerotoli P, Giorgino R. Mutation in skeletal muscle deiodinase has been associated with degree of insulin resistance in diabetic patients: J Clin Endocrinol Metab 2005;90:3472-3478. The type 2 deiodinase A/G (Thr92Ala) polymorphism is associated with decreased enzyme velocity and increased insulin resistance in patients with type 2 diabetes mellitus. Canani LH, Capp C, Dora JM et al. Curr Opin Clin Nutr Metab Care 2010 Aug 4. [Epub ahead of print] Adipocyte-myocyte crosstalk in skeletal muscle insulin resistance; is there a role for thyroid hormone? Havekes B, Sauerwein HP.

Is there a link between T3 and Insulin Resistance? Clin Endocrinol (Oxf) 2007;67:265-269. Free triiodothyronine and thyroid stimulating hormone are directly associated with waist circumference, independently of insulin resistance, metabolic parameters and blood pressure in overweight and obese women. De Pergola G, Ciampolillo A, Paolotti S, Trerotoli P, Giorgino R. 201 euthyroid, apparently healthy women Serum fT3 in the higher end of the normal range is independently associated with visceral obesity, but not insulin resistance High normal serum fT3 does not reflect tissue stores!

Metabolic Issues: Summary Growth hormone: low growth hormone Insulin: hyperinsulinemia, insulin resistance Failure to manage energy Inflammation originating in visceral fat Thyroid axis: poor tissue activity of T3 Mineralocorticoids: hyperaldosteronemia -endorphinemia Vitamin D: insufficiency

Janes Mustache From her history, we already know Jane has elevated androgens, but we can measure them just to check Salivary Testosterone 63 pg/ml (15-45 pg/ml) : Hi Salivary DHEAS 18 ng/ml (2-11 ng/ml) : Hi Salivary estradiol 15 pg/ml (1-9 pg/ml) : Hi Salivary progesterone 22 pg/ml (50-250 pg/ml) : Low Whats going on?

High insulin upregulates several key enzymes in the steroidogenic pathways in the ovaries and adrenals With high insulin, progesterone is diverted to androstenedione and pregnenolone is diverted to DHEA. The net result is increased DHEA and androstenedione (leading to higher testosterone and estradiol) Abnormal fatty acid metabolites

Eur J Endocrinol. 2011 Feb;164(2):197-203. Epub 2010 Nov 8. Insulin enhances ACTH-stimulated androgen and glucocorticoid metabolism in hyperandrogenic women. Tosi F, Negri C, Brun E et al. Insulin enhances the response to ACTH So what if insulin is too low??

Gynecol Endocrinol. 2009 Jul;25(7):423-6. Hyperandrogenism in oligomenorrhoea with minimal or nil 'unwanted hair growth'. Bhattacharya SM. Women in Groups A and B had fewer than 7 cycles per year Women in Group B had significant hirsutism Group C were controls Group B women had the same fasting insulin, the same SHBG, the same serum total testo and the same BMI, but much higher hirsutism scores than Group A Leads to concept of ovarian hyperandrogenicity i.e. enough excess androgens production in ovary to mess up folliculogenesis, but not enough to manifest systemically (Group A)

Impact of High Insulin in Women High DHEAS High Testosterone These imbalances contribute to Janes irritability and increased facial hair growth Low Progesterone High Estradiol These imbalances contribute to Janes symptoms of estrogen dominance: breast tenderness, fluid retention, and irritability, as well as heavier menses

PCOS and MetS The majority of patients with PCOS are insulin resistant and PCOS is characterized by an increased inflammatory state with abdominal obesity and increased secretion of interleukins, chemokines, and adipokines. PCOS is therefore associated with an increased risk of the metabolic syndrome and type 2 diabetes Gynecol Endocrinol 2010;26:281-296. An update on the pathogenesis, inflammation, and metabolism in hirsutism and polycystic ovary syndrome. Glintborg D, Andersen M.

Adrenal gland DHEA Adipose tissue Androstenedione Testosterone Estrone aromatization Why does Jane have high estradiol? aromatization Estradiol Upregulation of aromatization Increased androgens Increased adiposity Upregulation of aromatization Same story for males: J Androl 2010;31:155-162. Estradiol and metabolic syndrome in older italian men: The InCHIANTI Study. Maggio M et al.

pancreas Insulin glucose cell -Cheng CM et al. Estrogen augments glucose transporter and IGF1 expression in primate cerebral cortex. FASEB J 2001;15:907-915. -Nadal A et al. Rapid insulinotropic effect of 17beta- estradiol via a plasma membrane receptor. FASEB J 1998;12:1341-1348 Estradiol Potentiates Insulin E2 + + Is high E2 an attempt to compensate for insulin resistance?

B6 deficiency sluggish detachment of estradiol/receptor complex from DNA leads to/may worsen Estrogen Dominance Estrogen supplementation (including OCP) and high endogenous estrogens increased need for B6 leads to eventual B6 depletion Zn

Methyl Donors and Estrogens Estradiol Estrone Estrone Sulphate (E1S) hydroxyestrones methoxyestrones methoxyestradiols hydroxyestradiols Proper breakdown of estrogens demands an adequate supply of methyl donors. R-Me 4-OH estrone Associated with breast cancer

Adrenal gland DHEA DHEA cell membrane receptor ? Moves glucose transporters to adipocyte cell surface uptake DHEA acts like Insulin High DHEA/S in insulin resistance may be viewed as a compensatory response (DHEA can increase glucose uptake independent of insulin) In women with PCOS, higher DHEAS is associated with less insulin resistance: Fertil Steril 2009;91:1848-1852. Dehydroepiandrosterone sulfate and insulin resistance in patients with polycystic ovary syndrome. Brennan K, Huang A, Azziz R. Am J Physiol Endocrinol Metab 2008;294:E961-968. Testosterone and DHEA activate the glucose metabolism- related signaling pathway in skeletal muscle. Sato K et al. DHT

Strategies to lower androgens in women with metabolic syndrome Decrease insulin (diet, pharmaceuticals) Licorice (not DGL!!) Armanini D et al. Licorice reduces serum testosterone in healthy women. Steroids 2004;69:763-764 Armanini D et al. Treatment of polycystic ovary syndrome with spironolactone plus licorice. Eur J Obstet Gynecol Reprod Biol 2007;131:61-67. Cinnamon extract (acts like thiazolidinediones) Progesterone Naltrexone Fruzzetti F et al. Fertil Steril 2002 May; 77: 936-944. Effect of long- term naltrexone treatment on endocrine profile, clinical features, and insulin sensitivity in obese women with polycystic ovary syndrome.

Curr Pharm Des. 2006;12(8):1001-12. Role of opioid antagonists in the treatment of women with glucoregulation abnormalities. Guido M, Romualdi D, Lanzone A. Plasma insulin OGTT Insulin AUC Premenopausal PCOS patients given 6 weeks of naltrexone (50 mg orally qd) Plasma AUC after OGTT

Fertil Steril. 2004 Apr;81(4):1047-54.Use of naltrexone in postmenopausal women with exaggerated insulin secretion: a pilot study. Cucinelli F, Soranna L, Perri C et al. -41 postmenopausal women age 47-57 -Segregated into normoinsulinemic and hyperinsulinemic groups after OGTT -Randomization to naltrexone (50 mg/d oral x 5 weeks) or placebo was then done, resulting in 4 equal study groups

Insulin Adrenals and ovaries Androgens Increased hepatic extraction of insulin Naltrexone -Naltrexone lowers insulin by increasing the hepatic extraction rate of insulin -Lowered circulating insulin decreases the effect on androgen synthesis -Naltrexone did not decrease the pancreatic synthesis of insulin in the foregoing study Naltrexone treatment may also serve to normalize signaling at various mu opioid receptors e.g. brain, by upregulating receptor density

POMC Pro-opiomelanocortin Neuropeptide which is a precursor for multiple signaling daughters called Melanocortins Pituitary, hypothalamus, skin, hair follicles, gut, bone marrow

Enkephalins are small peptides which replicate part of the endorphin molecule They dont come from POMC Lipotropins Liberate stored fat from adipocytes and in bone marrow, helps create hematopoietic factors Melanocyte stimulating hormones: -appetite -energy utilization -blood pressure -anti-inflammatory -immunomodulation -skin and hair pigmentation -tissue differentiation (bone, cartilage) Endorphins -analgesia -immunomodulation -sex hormone regulation via LH -glucoregulation

POMCMSHAppetite suppression food intake -endorphin food intakeSatiety The melanocortin system, as is now known, is far more complex than most of us could have imagined in 1997, and, similarly, the importance of this system for regulating energy homoeostasis in the general human population is much greater than we would have predicted. Of the known factors that can cause human obesity, or protect against it, the melanocortin system is by far the most significant. Biochem J. 2010 May 27;428(3):305-24. Functions for proopiomelanocortin-derived peptides in obesity and diabetes. Mountjoy KG.

POMC gene Estradiol Appetite suppression POMC expression MSH -Insulin -Leptin Estradiol and POMC expression + + Eur J Pharmacol 2011;660:181-187. The estrogen receptor colocalizes with proopiomelanocortin in hypothalamic neurons and binds to a conserved motif present in the neuron-specific enhancer nPE2. de Souza FS, Nasif S, Lpez-Leal R et al. If E2 drops, may be losing a key regulator of appetite and weight control This may in part explain why ERT results in weight loss if done properly

Progesterone and Insulin Progesterone acts on the pancreatic beta cells to decrease insulin production Progesterone inhibits insulin secretion by a membrane delimited, non- genomic action. Straub SG et al. Biosci Rep 2001;21:653-666. Patients in Helene Leonettis study of progesterone cream and vasomotor symptoms who had high triglycerides (TG) at inception, had lower TG after one year of Pg cream, 20 mg qd. There are widespread, but anecdotal reports of improvement in PCOS with topical progesterone (lower androgens, resumption of regular menses) Bottom line: progesterone appears to ameliorate problems associated with increased insulin In reasonable doses, there is no evidence that progesterone causes or worsens insulin resistance

Cortisol DNA Adipose tissue Aromatase Enzyme Androgens Estrogens Why does Jane have increased aromatase activity? Zn - Pg* - (1) Cortisol trapping in visceral fat (2) Low progesterone (3) Zinc deficiency *Schmidt M, Renner C, Loffler G. J Endocrinol 1998;158:401-407 Adipose tissue

Obesity and Cortisol Must distinguish between what we can measure and what we cant measure Obese people dont have high serum or salivary cortisol. (They have high 24 hour urinary cortisol.) We have to look at what is going on with cortisol in places we cant directly measure Salivary

What is Cortisol Trapping? Cortisol (active) Cortisone (inactive) GH/IGF-1 11 HSD Type 1 - Cortisol Cortisone 11 HSD1 High GH Low TNF Cortisol Cortisone 11 HSD1 Low GH High TNF Obese Lean TNF + Many fresh hits on PubMed for this enzyme

Serotonin Depletion & Cortisol Trapping Tryptophan Serotonin Depletion Kynurenine Hepatic TP Cortisol + Carbohydrate Ingestion + Blood glucose GH SuppressionIncreased visceral fat Stress More cortisol trapping due to low GH Metabolism 1995;44(2 Suppl 2):38-41. Neuroendocrine abnormalities in human obesity. Bjrntorp P. Ann N Y Acad Sci 2010;1199:1-14. Metabolic syndrome, age-associated neuroendocrine disorders, and dysregulation of tryptophan-kynurenine metabolism. Oxenkrug GF. Pro-inflammatory cytokines TP: tryptophan pyrolase + Failure of appetite suppression

Tryptophan and Niacinamide (B3) Tryptophan Kynurenine TP 5 HTP Serotonin B3 supplementation B3 supplementation steers tryptophan toward serotonin and away from kynurenine X Tryptophan Kynurenine TP 5 HTP Serotonin B3

SHBG and MetS Low SHBG has been shown to be predictive of MetS in women and men Arch Intern Med. 2008 Jul 28;168(14):1568-75. Menopause and the metabolic syndrome: the Study of Women's Health Across the Nation. Janssen I, Powell LH, Crawford S, Lasley B, Sutton-Tyrrell K. Diabetes Care 2004;27:1036-1041. Testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men. Laaksonen DE et al.

SHBG T3 SHBG Estrogens SHBG Insulin SHBG Sugar intake Mol Cell Endocrinol 2010;316:53-59. Sex hormone- binding globulin gene expression in the liver: drugs and the metabolic syndrome. Pugeat M, Nader N, Hogeveen K et al. Ingestion of glucose and fructose lowers liver synthesis of SHBG

Regulation of SHBG Synthesis HNF-4 SHBG gene promoter SHBG HNF-4: Hepatocyte Nuclear Factor-4: ancient, highly structurally-conserved protein Is a nuclear receptor found in the gut, liver, kidney, intestines and pancreas The HNF-4 receptor is sensitive to the metabolic state of the liver, in particular, the fatty acids and it is also sensitive to T3, Vitamin D, progesterone, bile acids, vitamin E, and xenobiotics Key regulator of growth and development tied to the availability of energy + +

HNF-4 SHBG gene promoter SHBG - - Palmitate 16 carbon fatty acid - Excess glucose and fructose intake lipogenesis Excess glucose and fructose have a suppressive effect on SHBG which occurs independent of insulin SHBG is sensitive to the metabolic disruption in fatty acids caused by overload with simple sugars especially fructose SHBG is also sensitive to genetic factors involving fatty acid metabolism which might predispose to the development of MetS * This is probably why low SHBG is a long lead time marker for risk of MetS * J Clin Invest. 2007 Dec;117(12):3979-87. Monosaccharide-induced lipogenesis regulates the human hepatic sex hormone-binding globulin gene. Selva DM, Hogeveen KN, Innis SM, Hammond GL.

Ways to Raise SHBG Weight loss Restrict simple sugar intake Low/modest saturated fat intake Increased exercise/weight training Increased fibre intake ? (probably indirect effect) Linoleic acid Isoflavones Green tea extract Thyroid hormone supplementation/measures to improve tissue levels of T3 Testosterone/Estrogen supplementation PPAR gamma agonists N-3 fatty acids, cinnamon extracts, thiazolidinediones

Janes risk of Breast Cancer High insulin High bedtime cortisol There is increasing evidence that hyperinsulinemia is associated with increased risk of cancer (e.g. breast and prostate cancer) Cancer cells can only burn glucose; cancer cells are therefore heavily armed with insulin receptors High bedtime cortisol suppresses melatonin Decreased melatonin is associated with increased risk of breast cancer

Janes risk of Breast Cancer Iodine/seaweed Asia Pac J Clin Nutr 2009;18:145-154. Could dietary seaweed reverse the metabolic syndrome? Teas J, Balden ME, Chiriboga DE, Davis JR, Sarris AJ, Braverman LE. J Nutr. 2009;139:939-944. Dietary seaweed modifies estrogen and phytoestrogen metabolism in healthy postmenopausal women. Teas J, Hurley TG, Hebert J et al. Epidemiologic studies and animal models indicate that iodine is protective against breast cancer Iodine is involved in regulating the cell cycle (antiproliferation, apoptosis) Prostaglandins Other Lipid Mediat. 2009;89:34-42. A complex between 6-iodolactone and the peroxisome proliferator- activated receptor type gamma may mediate the antineoplastic effect of iodine in mammary cancer. Nuez-Anita RE et al. Iodine also upregulates p450 enzymes involved in estrogen metabolism and may increase 2-OH estrone

Things to do for High Bedtime Cortisol Phosphatidyl serine, theanine, melatonin, low dose metformin, progesterone, Holy basil Some practitioners report success with: a protein/complex carbohydrate snack at bedtime low glycemic index foods during the day protein snacks between meals Adrenal support might also be indicated

Hormone Patterns in Metabolic Syndrome WOMEN T (not always) DHEAS (as inflammation gets out of control, this may decrease DHEAS) E2, Pg MEN Testosterone DHEAS (associated with fatty liver*) E2 SHBG GH IGF-1: , normal or serum fT3 ?low in skeletal muscle Cortisol in abdominal fat Vitamin D Aldosterone endorphins Eur J Clin Invest 2009 Dec 30. [Epub ahead of print] Elevated serum dehydroepiandrosterone sulphate level correlates with increased risk for metabolic syndrome in the elderly men. Chen YC et al. * Int J Androl 2009 Feb 10. [Epub ahead of print] Hepatic steatosis is associated with low serum testosterone and high serum DHEAS levels in men. Vlzke H et al.

Hormonal Dos and Donts Dont throw estradiol at female patients just because they have hot flashes Do try progesterone (progesterone alleviates VM symptoms) Obstet Gynecol 1999 Aug;94:225-228. Transdermal progesterone cream for vasomotor symptoms and postmenopausal bone loss. Leonetti HB, Longo S, Anasti JN. Dont throw testosterone at women just because they have low libido (many of them already have high testosterone) Do try testosterone supplementation in men with low testosterone, but will need to block aromatase if they have excessive fat accumulation

Hormonal Dos and Donts Consider T3 supplementation/measures to promote T3 formation Work on increasing growth hormone secretion by natural means GH therapy is not a panacea for obesity, and not all obese people are low on GH Fix cortisol if abnormal day curve Treat obesity as an inflammatory illness

Testing Insulin-glucose axis: HOMA-IR Sex hormones (saliva, serum, urine) SHBG Salivary Cortisol 4 point profile Thyroid hormone status 25-hydroxy Vitamin D Fasting amino acids Nutritional analysis: Elements: Zn, Cr, Mg, I, Br, Hg, Cd, Se Other metabolic analysis

Live Long and Prosper: How to Avoid Metabolic Syndrome Choose good parents Avoid being born prematurely Eat a low glycemic index/low glycemic load diet, and a high fibre diet Dont eat high fructose corn syrup or excessive amounts of sugary fruits (bananas, melons) Have a moderate intake of saturated fats and LA, eat fish and -9 fats (olive oil, almonds, avocados) Eat an antioxidant-rich diet (highly coloured foods) Eat methyl donors/supplement with methyl donors Limit sodium intake; eat lots of potassium Optimize tissue conversion of T4 to T3 Iodine, Se, Zn Address heavy metal intoxication

Live Long and Prosper: How to Avoid Metabolic Syndrome Limit aromatization if indicated (Zn, Pg, pharmaceuticals) Increase estrogen excretion where indicated (Ca-D glucarate, fibre intake) De-stress your lifestyle (decrease cortisol and epinephrine) Get lots of sleep Get enough sun/supplement with Vitamin D Boost endogenous GH : sleep, exercise, eating habits Mark Sisson My Blog: www.MarksDailyApple.com My Book: www.PrimalBlueprint.com My Store: www.PrimalNutrition.com Connect with me on: Twitter: http://twitter.com/Mark_Sisson Facebook: http://www.facebook.com/mark.sisson1www.MarksDailyApple.comwww.PrimalBlueprint.comwww.PrimalNutrition.comhttp://twitter.com/Mark_Sissonhttp://www.facebook.com/mark.sisson1

Closing Remarks All the common sense stuff that our species worked out over the eons now makes sense from a biochemical standpoint If you dont identify metabolic syndrome patients up front, you will never get very far with basic HRT Practice what you preach Dont blame the patient Everything is related to everything else Its amazing that any of us are even alive. Davis Lamson MSc ND

Documents

The Skinny on Insulin March 2012 George Gillson MD PhD