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Transcript
The Skinny on Insulin March 2012 George Gillson MD PhD Meet Jane • • • • 42 years old Teacher Married 3 children • 30 lbs overweight Couch potato Terrible diet • • • • • • • • • • • • “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: “I’m mushy” Low sex drive “Runs out of gas” by midmorning Complains her hair is prematurely grey Avoids sun exposure “I think my hormones are out of balance.” Jane: Objective Data • • • • • • • • 185 lbs 5’6” 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 Visceral Obesity Elevated Insulin Metabolic Syndrome NCEP* CRITERIA Three or more of : Half of the North American population > 45 yrs old ! Insulin Resistance 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 wellunderstood 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, α-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? 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 By Bill Berkrot NEW YORK Tue Nov 23, 2010 12:11am EST (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. 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 http://www.reuters.com/article/idUSTRE6AM0NH20101123 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 don’t 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.turnerwhite.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 Fast Eat Burn fat Take up nutrients/utilize some Build muscle/prevent muscle breakdown Store nutrients not used immediately Provide glucose for brain Build muscle/prevent muscle breakdown FASTED FED Metabolic Switch must flip between fasted and fed states multiple times throughout 24 hours HOW IS JANE”S SWITCH WORKING? Enter Growth Hormone… High Average GH Muscle Low Average GH Muscle Energy Energy Fat Fat Obesity = Low Growth Hormone Utz A et al. J Clin Endocrinol Metab 2008;93: 4033-4040 25-35 yo women What is Growth Hormone (GH)? High blood glucose suppresses GH release Pituitary gland 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 GH Endocrine IGF-1 IGF-1 Insulin-Like Growth Factor-1 -same basic actions as insulin GHR Target tissues: Bone IGFR Fat Muscle IGF-1 Paracrine IGF-1 -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? When you’re asleep Stage III Sleep GH Age When you’re young During and after Exercise ! When you’re hungry! hunger ghrelin GH -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 exerciseinduced growth hormone response in athletes. 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 sleeponset GH release – Snacking on refined carbs and saturated fats during the day • Sleep – Not enough sleep – Doesn’t 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-Balériaux M, MorenoReyes R, Copinschi G. Sleep and Weight • People who sleep less weigh more • Increased sleep promotes weight loss • If you’re 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/729995 Jane: Sleep history • 5-6 ½ hours/night on week nights • Sleeps in on weekends • Many nights, sleep is unrefreshing; hot flashes wake her up frequently • Can’t get to sleep some nights (her brain just won’t switch off) Salivary Cortisol (ng/ml) Jane's Salivary Cortisol Profile 20 18 16 14 12 10 8 6 4 2 0 600 1000 1400 1800 Time (hours) 2200 Jane tells us she “crashes” before lunch, has low energy during the middle part of the day, and can’t sleep at night Her symptoms fit her cortisol pattern 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 sedativehypnotic) • 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) Growth Hormone Enhancing Workout 168 beats/min 52 yrs old 220 – Age = 168 www.mercola.com http://www.youtube.com/watch?v=OKczVO37cEw&feature=related 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 Brain GH release Protein sparing (Endogenous) Exogenous amino acids Fast Eat Burn fat Take up nutrients/utilize some Build muscle/prevent muscle breakdown Store nutrients not used immediately Provide glucose for brain Build muscle/prevent muscle breakdown FED FASTED Growth hormone X Metabolic Switch JANE’S SWITCH ISN”T FLIPPING TO THE GH SIDE! Jane isn’t 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 Triglyceride (TG) glycerol Monounsaturated fat Monounsaturated fat or Polyunsaturated fat Glycerol Glucose Kreb’s Cycle Acetyl CoA Fatty Acids Dietary fat Triglycerides (TG) Stored fat (TG) Insulin regulates the amount of fuel in circulation Insulin promotes uptake of macronutrients Glucose + Free fatty acids Glycogen + Stored fat - - Free triglycerides Eat food Amino acids Glucose Free fatty acids Free triglycerides + Protein - Amino acids Insulin Insulin blocks release of stored energy and protein Lipoprotein Lipase Dietary TGs GUT Chylomicrons Capillary LPL VLDL Liver Free fatty acids bound to albumin Free fatty acids Adipose Insulin upregulates LPL If insulin is too low, fatty acids won’t be available for uptake into muscle Fatty acid transport proteins Muscle Jane’s Insulin/TG Paradox • Insulin 21.6 μU/ml (150 pmol/L) : Borderline High • Fasting triglycerides: High • How can Jane’s TG’s be high? Insulin should suppress TG’s and her insulin is high… • How can Jane’s insulin be high? Insulin goes up after you eat. She didn’t eat anything while she was sleeping … β cell Fatty acids Fats determine basal insulin secretion Jane’s Insulin/TG Paradox • Jane’s fat cells are leaking TG’s 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 • Jane’s adipocytes are resistant to the effect of insulin • Jane has: – high fasting insulin – insulin resistant visceral fat - - Insulin Pituitary gland ↓GH Liver ↓ IGF-1 High Fasting Insulin = Low GH 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. 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) Fast Eat Burn fat Take up nutrients/utilize some Build muscle/prevent muscle breakdown Store nutrients not used immediately Provide glucose for brain Build muscle/prevent muscle breakdown FASTED FED Growth hormone Insulin X X Metabolic Switch JANE’S METABOLIC SWITCH IS STUCK! Enough is Enough • There is another way to look at insulin • Insulin is both a satiety signal and an adiposity signal • Satiety: “I’ve had enough to eat for now.” • Adiposity: “I’ve got lots of stored energy” Obese people are resistant to leptin. High leptin levels don’t result in reduced appetite Leptin is proportional to fat mass Inhibit insulin release Shrink fat cells Leptin Eat less Adipocytes Eat less Make bigger fat cells Insulin -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 Neurochemistry of Appetite/Satiety First order neurons Serotonin Serotonin Second-order neurons Brake Gas pedal Increased outflow here results in appetite suppression Decreased outflow here results in appetite suppression Clin Pharmacol Ther. 2007 May;81(5):748-52. New targets for obesity pharmacotherapy. Aronne LJ, Thornton-Jones ZD. MSH and serotonin are important signaling molecules wrt appetite HOMA-IR Homeostatic Model for Metabolic Assessment of Insulin Resistance • Go to: http://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. JANE’S HOMA-IR • 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%) • Jane’s 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 Write talks on Metabolic Syndrome Perform physical work Insulin sensitive liver Insulin sensitive Don’t make glucose if insulin is hi skeletal muscle burn FA’s & glucose ENERGY Store glycogen (FA’s, glucose) Store glycogen Make TGs Generate heat Converts glucose to TG Insulin sensitive visceral adipose tissue absorbs excess energy Stores TGs imported from blood Appropriately releases TG and fatty acids to circulation Adipose Insulin Resistance: Failure to Store Energy Atherosclerosis “Metastatic Fat” Blood Increased cholesterol synthesis vessels Inflammation* Fat cells Marbling Impaired fat burning Muscle Fatty liver Increased liver enzymes Liver Increased serum triglycerides/free fatty acids Epicardial fat * Increase in adipocyte size/macrophage recruitment/secretion of inflammatory cytokines e.g. TNFα, IL-6 Insulin and Cholesterol Glucose Acetyl CoA Triglycerides + Kreb’s Cycle HMG CoA Reductase Insulin Cholesterol ↑ 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) 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).” This person’s adipocytes are quite insulin sensitive! These guys have insulin resistant adipocytes She is able to continuously gain fat They have stopped gaining fat High glycemic load ↑ Insulin ↑ Fat storage Energy is overflowing into other places it shouldn’t be! + feedback Fat mass Insulin sensitive Insulin resistant Insulin Hepatic synthesis of glucose from various substrates Gluconeogenesis 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 doesn’t 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 Insulin Sensitive Liver Insulin Fed Glucagon X Fasted Fat Liver Glucose cells Liver Insulin X Glucose Lipid accumulates in liver Hepatic Insulin Resistance: Failure to Suppress Gluconeogenesis Liver Glucose 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. Skeletal Muscle Insulin Resistance: Failure to Dispose Glucose Glucose Glucose “overflows” into blood Fat cells Skeletal Muscle Glucose Increased TG synthesis Skeletal Muscle Insulin Resistance: Failure to Burn Fat Fatty Acids -Work -Heat Skeletal Muscle Fat deposits intercalate between muscle fibres Fatty Acids “Marbling” GH Insulin Insulin Resistance/Low Growth Hormone “Stuck”Metabolic Switch Fast Progressive failure to manage energy The energy still has to go someplace… Eat Elevated serum glucose, elevated urine glucose Elevated serum triglycerides Elevated free fattyFat acids Fat deposits in liver (fatty liver) Fat deposits in muscle (marbling) Fat deposits in vascular tree Increased epicardial fat 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 Doesn’t 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 Jane’s Diet and Insulin Resistance • • • • • • • • • • • Low antioxidants High trans fats Unbalanced “natural” polyunsaturated fat intake (ω6 vs ω3) 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. Jane’s Oxidative Stress Load • Jane doesn’t eat any highly antioxidant, richly-coloured foods (corn and ketchup don’t count!) • She eats a lot of unsaturated fats (mostly ω6) and a lot of trans fats which are easily damaged by free radicals • Jane’s diet promotes oxidative stress • Inflammation in visceral fat drives MetS JANE’S CHOLESTEROL – Jane’s 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 BRAINSTEM MetS Impaired GH output OSA 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. Quiñones 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 intake Body 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. Sunflower, corn, safflower, soy cottonseed, sesame, various nuts Anti: 13 HODE Nitrated LA Pro: 9 HODE Leukotoxin Leukotoxin diol Omega 6 Linoleic (LA) Essential “Parents” γ-linolenic (GLA) DGLA Arachidonic acid AA n20 Anti-inflammatory: Epoxyeicosatrienoic acids 16-HETE Lipoxins Proinflammatory: PGE2 LTB4 Hemp seeds, fish, flaxseeds, walnuts, green leaves Omega 3 Alpha-linolenic (ALA) 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. Eicosapentaenoic acid EPA Epoxyeicosatetraenoic acids Docosahexaenoic acid DHA Prostaglandins Leukot Essent Fatty Acids 2008 ;79:173-517. Too much linoleic acid promotes inflammation-doesn't it? Fritsche KL. EFA Take Home Points • • • • EFA’s 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) • Jane’s 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! Burn or Store?:Saturated Fat Metabolism Kreb’s Cycle “Shorter-by-two” saturated fat -C-C-(C-C)n-C-C- + Acetyl CoA BURN -C-Cmitochondria Conversion to ketone bodies β-oxidation -C-C-(C-C)n-C-C-C-CSaturated fat desaturation -C=C-(C-C)n-C-C-C-CMonounsaturated fat e.g. oleic acid Incorporation into triglycerides STORE β-oxidation Shorter saturated fat Saturated Fat e.g. stearic acid C18 (animal fat) Stearoyl CoA desaturase (SCD) Desaturation Unsaturated Fat of same chain length e.g. oleic acid C18:1 Excessive activation of SCD leads to obesity SCD -/- mice are obesity resistant *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. How do we avoid excessive upregulation of SCD? Keeping the lid on SCD Saturated Fat e.g. stearic acid C18 (animal fat) Glucose Insulin N-3 fatty acids - + Central appetite suppressant SCD Fructose* + Cortisol + Monounsaturated Fat Oleic acid doesn’t raise postprandial insulin as much as saturated fat Central appetite suppressant Keep fructose intake to “natural” levels Keep cortisol under control, especially at night Adequate intake of N-3 fatty acids and oleic acid Don’t pile refined sugars on top of saturated fats 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. López S, Bermúdez 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 (MCT’s) which are 8-12 carbons -MCT’s don’t raise insulin very much -MCT’s 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 didn’t the Inuit get fat? • They ate a lot of blubber which is higher in monounsaturated fat • They didn’t eat any sugars to excessively raise insulin and redirect their fat intake away from β-oxidation • Their fish oil intake also worked to prevent redirection (n-3 FA’s suppress SCD) • Their mix of fats was appetite suppressant Starch = Polyglucose Some are slower release Glucose Increased need for nutrients needed to metabolize the sugars: Sucrose (Glucose – fructose disaccharide) Glucose Fructose Faster release High fructose corn syrup Fructose Mg, lipoic acid, riboflavin, niacin, thiamine, pantothenic acid Fructose does not raise insulin Fruit juice Slower release Fruit Fructose Fructose creates other issues ! (in general) Sugars and Insulin Resistance/Obesity 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 βendorphinemia – 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. Loss of negative feedback on pancreas Initiating factor or factors ↑ circulating endorphins ↑ insulin ↓ mu opiod receptor expression ↓ effect of mu opioids ↑ craving for sweets ↓ pleasure from sweets Loss of negative feedback sensitivity for endogenous opioids -There is a lot of literature on the role of β-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 Self Injection • MetS patients with β-endorphinemia are self-injecting opioids • This suggests a way to intervene… • We’ll get to this in a few slides… Insulin and Zinc Insulin Insulin Insulin-Zn-Zn-Insulin Insulin is stored as a hexamer in the pancreas Insulin Insulin • 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 Znsupplementation promotes metabolic syndrome-X in Wistar rats fed sucrose and fat rich semisynthetic diet. Taneja SK, Mandal R, Girhotra S. Insulin and Chromium Activation by chromium Insulin (Ins) Insulin receptor Ins-IR Cr Ins-IR Cr (IR) Complex Complex Cr Cr deficiency: – more insulin will be required to deliver the same message – chromium polynicotinate 1000 ug/drop – 1-10 drops per meal Cr Downstream signalling more effective with Cr Vanadium Insulin (Ins) Insulin receptor Ins-IR (IR) Complex V V Ins-IR V Complex V Vanadylated insulin signaling complex is slower to break down more prolonged signaling • 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 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 Visceral Fat “Pinchable” fat http://www.uchsc.edu/sm/ch s/research/ctscan_read.html Obes Res 2003;11:1488-1494. Methods of estimation of visceral fat: advantages of ultrasonography. Ribeiro-Filho FF, Faria AN, Azjen S et al. Visceral Fat is directly proportional to Waist Circumference Inflammation and MetS (Fat is not just a storage depot!) Adipocytes Adipokines + FA metabolites IL-6 ACP TNFά PAI-1 Adrenals VEGF -steroidogenesis Vascular tree -endothelial dysfunction -hypercoagulability Brain -satiety -appetite Muscle 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-β and NF-κB. 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 doesn’t 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;33:13791381. • 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? JANE 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 We would like to raise Jane’s 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. Things “Getting in the Way” of Insulin JANE Profession: Teacher Stress level: High Stress type: Sandwich stress Adequate growth hormone/non obese Ins Ins Ins GH C Epi 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 Overproduction of cortisol and epinephrine, plus low GH leads to increased need for insulin Ins Ins Ins Epi C Epi Ins Ins Ins C Epi C Insufficient growth hormone Excess cortisol and epinephrine 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;354:14351439. Salivary Cortisol (pg/ml) Diurnal Salivary Cortisol Profile 12 11 10 9 8 7 6 5 4 3 2 1 0 600 1000 1400 1800 Time (hours) 2200 What is the eventual price of oversecretion of epinephrine? PNMT norepinephrine epinephrine CH3 Cu CH3 methyl donor Continual stress methyl donor depletion Continual stress copper depletion Methyl Donors O= SAMe O= CH3 – S -- CH3 MSM or dimethylsulfone 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 Betaine Methyl Donors and Gastric Acid Histamine Gastric acid secretion Methyl donor CH3 CH3 Methylated Histamine Does not promote acid secretion 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 MetS and H. Pylori • Patients with H.Pylori infection had higher HOMA-IR, higher TG’s, 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 Copper + Elastin Supple Lysyl oxidase aorta Hypertension Stiff aorta Menke’s Disease:genetic disorder involving copper transport: increased incidence of aortic aneurysm 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 Tanning Melatonin Melanin Hair pigmentation Epinephrine Copper and methyl donors • Synthesis of melanin depends on copper and methyl donors • Jane doesn’t tan well; she burns • Jane’s 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 doesn’t tan well (poor protection against free radicals) Jane’s Aldosterone Jane’s fluid retention (puffy ankles) and hypertension suggest she is retaining sodium Altered fatty acid metabolites (visceral fat) Adrenals * Increased aldosterone MetS Increased insulin Kidneys remain insulin sensitive Sodium retention Paradoxical hyperaldosteronemia and sodium retention in the face of excess sodium intake 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. Work Heat Fatty acids Glucose Muscle and Energy Disposal Skeletal Skeletal muscle is a significant glucose and fatty acid “sink” Muscle Well muscled individual: Insulin sensitivity -High resting consumption of fuel -Highly insulin sensitive Jane’s Muscles Muscle mass “I’m mushy” Sarcopenia: loss of muscle She is telling us she is low on Growth Hormone Sarcopenia is also a clue that she isn’t getting enough T3 in muscle Cortisol T3 Skeletal muscle mitochondria ATP Check ferritin ! Iron Mitochondria with beefier cell membranes More electron transport chains More ATP Often takes place in target tissue Most active form of thyroid hormone Iodine Deiodinase T4 Zinc ? + T3 ATP Selenium Copper Growth Hormone Prevents loss of muscle Iron ↑Bromine ↓Iodine ↓Copper Deiodinase ↓T4 X Cadmium X ↓T3 ↓ATP Mercury Low protein intake Low growth hormone High Cortisol reverse T3 (inactive) ↓Iron ↓Muscle 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 β-endorphinemia Vitamin D: insufficiency Jane’s 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 • What’s going on? High insulin upregulates several key enzymes in the steroidogenic pathways in the ovaries and adrenals Abnormal fatty acid metabolites 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) Insulin enhances the response to ACTH So what if insulin is too low?? 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. 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 Jane’s irritability and increased facial hair growth • Low Progesterone • High Estradiol – These imbalances contribute to Jane’s 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 Increased adiposity Why does Jane have high estradiol? Adipose Upregulation of aromatization tissue Increased androgens Androstenedione aromatization Testosterone Estrone aromatization Estradiol 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 Estradiol Potentiates Insulin E2 Insulin + glucose cell + Is high E2 an attempt to compensate for insulin resistance? -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 17betaestradiol via a plasma membrane receptor. FASEB J 1998;12:1341-1348 Zn 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 Methyl Donors and Estrogens Estradiol Estrone hydroxyestradiols R-Me methoxyestradiols Estrone Sulphate (E1S) 4-OH estrone Associated with breast cancer hydroxyestrones R-Me methoxyestrones Proper breakdown of estrogens demands an adequate supply of methyl donors. Adrenal gland DHEA cell membrane receptor ? DHEA DHT Am J Physiol Endocrinol Metab 2008;294:E961-968. Testosterone and DHEA activate the glucose metabolismrelated signaling pathway in skeletal muscle. Sato K et al. 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. 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 longterm naltrexone treatment on endocrine profile, clinical features, and insulin sensitivity in obese women with polycystic ovary syndrome. AUC after OGTT Insulin AUC Plasma insulin OGTT Plasma 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. Premenopausal PCOS patients given 6 weeks of naltrexone (50 mg orally qd) 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 Naltrexone Increased hepatic extraction of insulin -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 ↑ Androgens 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 Lipotropins Liberate stored fat from adipocytes and in bone marrow, helps create hematopoietic factors Enkephalins are small peptides which replicate part of the endorphin molecule They don’t come from POMC 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 POMC MSH β-endorphin Appetite suppression Satiety ↓ food intake ↓ food intake • “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. Estradiol and POMC expression Estradiol -Insulin -Leptin + POMC gene ↑ POMC expression ↑ MSH + ↑ Appetite suppression 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 Eur J Pharmacol 2011;660:181-187. The estrogen receptor α colocalizes with proopiomelanocortin in hypothalamic neurons and binds to a conserved motif present in the neuron-specific enhancer nPE2. de Souza FS, Nasif S, López-Leal R et al. Progesterone and Insulin • Progesterone acts on the pancreatic beta cells to decrease insulin production – Progesterone inhibits insulin secretion by a membrane delimited, nongenomic action. Straub SG et al. Biosci Rep 2001;21:653-666. • Patients in Helene Leonetti’s 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 Why does Jane have increased aromatase activity? Androgens Cortisol - Aromatase Adipose tissue Enzyme DNA Adipose tissue Estrogens Pg* *Schmidt M, Renner C, Loffler G. J Endocrinol 1998;158:401-407 (1) Cortisol trapping in visceral fat (2) Low progesterone (3) Zinc deficiency Obesity and Cortisol • Must distinguish between what we can measure and what we can’t measure • Obese people don’t have high serum or salivary cortisol. (They have high 24 hour urinary cortisol.) Morning Cortisol (ng/mL) Salivary First Morning Cortisol vs Waist Circumference 10 9 8 7 6 5 4 3 2 1 0 y = -0.0201x + 8.0658 R2 = 0.4708 60 70 80 90 100 Waist Circumference (cM) 110 120 We have to look at what is going on with cortisol in places we can’t directly measure What is Cortisol Trapping? Cortisone (inactive) Many fresh hits on PubMed for this enzyme Cortisol (active) 11 βHSD Type 1 GH/IGF-1 + TNFα Obese Lean Cortisone Cortisol Cortisone Cortisol ↓11 βHSD1 High GH ↑11 βHSD1 Low GH Low TNFα High TNFα Serotonin Depletion & Cortisol Trapping 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 + Carbohydrate Ingestion + Hepatic TP Tryptophan TP: tryptophan pyrolase ↑Kynurenine + Serotonin Blood glucose Stress Depletion Failure of appetite suppression GH Suppression Cortisol More cortisol trapping due to low GH Increased visceral fat Metabolism 1995;44(2 Suppl 2):38-41. Neuroendocrine abnormalities in human obesity. Björntorp P. Tryptophan and Niacinamide (B3) B3 Tryptophan TP Kynurenine B3 supplementation 5 HTP Tryptophan 5 HTP X Serotonin TP Kynurenine B3 supplementation “steers” tryptophan toward serotonin and away from kynurenine Serotonin 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 SHBG SHBG Insulin Ingestion of glucose and fructose lowers liver synthesis of SHBG SHBG SHBG Estrogens Sugar intake T3 Mol Cell Endocrinol 2010;316:53-59. Sex hormonebinding globulin gene expression in the liver: drugs and the metabolic syndrome. Pugeat M, Nader N, Hogeveen K et al. 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 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 Jane’s 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 Salivary Cortisol (ng/ml) Jane's Salivary Cortisol Profile 20 18 16 14 12 10 8 6 4 2 0 600 1000 1400 1800 Time (hours) 2200 Jane’s risk of Breast Cancer • Iodine/seaweed – Asia Pac J Clin Nutr 2009;18:145-154. Could dietary seaweed reverse the metabolic syndrome? Teas J, Baldeón ME, Chiriboga DE, Davis JR, Sarriés 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 proliferatoractivated receptor type gamma may mediate the antineoplastic effect of iodine in mammary cancer. Nuñez-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 ↓ SHBG ↓ GH IGF-1: ↓ , normal or ↑ ↑ serum fT3 ?low in skeletal muscle ↑ Cortisol in abdominal fat ↓ Vitamin D ↑ Aldosterone ↑ β endorphins WOMEN MEN • • • • • • ↑ T (not always) ↑ DHEAS (as inflammation gets out of control, this may decrease DHEAS) ↑ E2, ↓Pg ¥ Eur ↓Testosterone ↑ DHEAS ¥ (associated with fatty liver*) ↑ E2 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. Völzke H et al. Hormonal Do’s and Don’ts • Don’t 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. • Don’t 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 Do’s and Don’ts • 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 • Don’t 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 ω-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.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 don’t identify metabolic syndrome patients up front, you will never get very far with basic HRT • Practice what you preach • Don’t blame the patient • Everything is related to everything else “It’s amazing that any of us are even alive.” Davis Lamson MSc ND