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Inositol and PCOS - Seminar Presentation

This seminar explores the potential connection between two inositol stereoisomers supplements and improvements in insulin sensitivity and various metabolic parameters.

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Inositol and PCOS - Seminar Presentation

  1. 1. THE EFFECTIVENESS OF INOSITOL SUPPLEMENTATION IN WOMEN WITH POLYCYSTIC OVARY SYNDROME Wendy Thompson Graduate Seminar ANNU 696 March 27th, 2014
  2. 2. Outline • Background • PCOS • Insulin Resistance • Inositol • Objective • Results • Relationship between PCOS and inositol • Possible mechanism of action • Effectiveness of myo-inositol • Compare the effectiveness of inositol isoforms • Conclusions/Implications • Limitations • Questions 2
  3. 3. The Significance of the PCOS 3National Institutes of Health Office of Disease Prevention, 2012 • Complex, Multifactorial • Heterogeneity • Under-diagnosed 4 Billion Dollars!
  4. 4. PathophysiologyofPCOS 4 Rotstein, A., Srinivasan, R., Wong, E. McMaster Pathophysiology Review (MPR), 2013
  5. 5. How is PCOS Diagnosed? NIH 1990 Rotterdam 2003 AE-PCOS Society 2006 • Hyperandrogenism • Chronic Anovulation ---Both criteria needed • Hyperandrogenism • Oligo-and/or anovulation • Polycystic ovaries ---2 of 3 criteria needed • Hyperandrogenism • Ovarian dysfunction ---Both criteria needed First developed and most commonly used criteria today Formulated to expand on NIH diagnostic definition Formulated to provide an evidence-based definition 5 *All possible related disorders must be ruled out NIH Evidenced Based Methodology Workshop on PCOS, 2012
  6. 6. Insulin Resistance and PCOS 6Tony T. Lee; Mary E. Rausch, 2012 Thecal Cells
  7. 7. Inositol Structures 7Croze M, 2013
  8. 8. Where do we get MYO? • Intake • ~900mg per 2500kcal • Range: 300mg to 2,000mg • Absorption • Bioavailability • Free Form ~ 99% • Phytate form ~ 50% • Synthesis • From glucose in kidneys ~4g/day 8Clement R, 1980; Croze M, 2013; Clements R, 1979
  9. 9. Inositol Pathways • Phosphorylated compounds • Component of cell membranes • Signal transduction/cellular signaling • Epimerase activity 9Croze M, 2013
  10. 10. Objective To determine the effectiveness of inositol supplements on improving insulin sensitivity and metabolic parameters in women with PCOS 10
  11. 11. WHAT IS THE CONNECTION BETWEEN PCOS AND INOSITOL? 11 Heimark D, McAllister J, Larner, J. (2014) Decreased myo- inositol to chiro-inositol (M/C) ratios and increased M/C epimerase activity in PCOS theca cells demonstrate increased insulin sensitivity compared to controls. Endocrine Journal. 61(2);111-117.
  12. 12. Methods Ovarian Theca Cells From size-matched follicles from age-matched subjects Age: 28-40 PCOS: Oligoovulation Hyperandrogenism (n=5+) Control: Normal Ovulation/Fertile Normal Insulin Sensitivity (n=5+) 12 Cells were cultured, scraped, processed and analyzed
  13. 13. MYO to CI Epimerase Values 130.006 ± 0.002 (n=10) vs. 0.017 ± 0.003 (n=11)
  14. 14. MYO to CI Ratio 14 18 ± 3 (n=6) vs. 5 ± 2 (n=7)
  15. 15. Conclusions/Limitations • Conclusions: • CI is overproduced and there is an implied deficiency of MYO in PCOS theca cells • MYO/CI ratios and epimerase activity are likely associated with insulin resistance • Limitations: • Small sample size • Used cultured cells • Reasons for hysterectomy • dysfunctional uterine bleeding, endometrial cancer, pelvic pain 15
  16. 16. PathophysiologyofPCOS 16 Alex Rotstein, Raginin Srinivasan, Erin Wong McMaster Pathophysiology Review (MPR), 2013
  17. 17. MECHANISM Relationship of the insulin pathway to phosphatidylinositols Phosphatidylinositol Synthase Myo-Inositol CMP Phosphatidylinositol CDP-DAG cytidine- diphosphate diacylglycerol M.L. Croze, C.O. Soulage (2013)
  18. 18. 18Coustan D.,2013  myo-inositol may increase insulin sensitivity by making more phosphatidylinositol available  glucose transport (GLUT4),  glycogen synthesis  glycogen synthesis,  gluconeogenesis  glucose transport (GLUT4) IRSs - insulin receptor substrates P13K - phosphatidyl inositol 3-kinase PDK1 - phosphoinositide-dependent kinase 1 PKB - protein kinase B p85 - regulatory subunit p110 - catalytic subunit
  19. 19. DOES MYO SUPPLEMENTATION IMPROVE INSULIN SENSITIVITY IN WOMEN WITH PCOS? 19 Gerli S, Mignosa M, DI Renzo GC. (2003) Effects of inositol on ovarian function and metabolic factors in women with PCOS: a randomized double blind placebo-controlled trial. Euro Rev Med Pharmacol Sci. 7; 151-159.
  20. 20. Methods Women with PCOS Age: ≤35 years MYO: 100mg 2x/day (n=136) Control: placebo (n=147) 20 • Not taking any medications that could influence hormonal profiles • No significant differences between groups at baseline Study Design: Randomized Double-blind Placebo-controlled Length: 16-weeks
  21. 21. Effects of Myo-Inositol 21 No significant change recorded for fasting insulin, insulin AUC in response to the glucose challenge, or fasting glucose
  22. 22. Subgroup Analysis 22 Morbidly Obese BMI ≥ 37 BMI • No significant Δ • Pre: 42.5 • Post: 42.3 HDL • No significant Δ • Pre: 0.95 mmol/L • Post: 0.95 mmol/L Leaner BMI < 37 BMI • P = 0.01 • Pre: 29.4 • Post 28.5 HDL • P = 0.02 • Pre: 1.21 mmol/L • Post: 1.32 mmol/L
  23. 23. Conclusion • Not effective in improving glucose or insulin parameters • May have a beneficial side effect of weight loss with an associated increase in HDL • Had no effect on BMI or HDL in morbidly obese women 23 200mg MYO 12-16 weeks
  24. 24. Limitations • Inconsistent timing of measurements • 12-16 weeks • High drop out rate • 30% of treatment group • Compliance • Lifestyle changes • Did not report CI for post-treatment • Mean BMI = 35 24
  25. 25. WOULD WE SEE AN IMPROVEMENT IN INSULIN SENSITIVITY WITH AN INCREASED DOSE? 25 Costantino D, Minozzi G, Minozzi F, Guaraldi C. (2009) Metabolic and hormonal effects of myo-inositol in women with polycystic ovary syndrome: a double blind trial. Euro Rev Med Pharmacol Sci. 13; 105-110.
  26. 26. Methods Women with PCOS Age: 18 - 40 years Treatment: 4g MYO + 400mcg FA (n=23) Control: 400mcg FA (n=19) 26 • Instructed to not change usual habits of food, sport, and lifestyle • No significant differences between groups at baseline Study Design: Randomized Double-blind Placebo-controlled Length: 12-16 weeks
  27. 27. Changes in Metabolic Parameters 27 Plasma triglycerides decreased by 52%
  28. 28. Glucose and Insulin Measurements 28 Plasma insulin AUC decreased by 36% ISIcomp increased by 84%
  29. 29. Conclusions • Improved glucose tolerance and glucose handling • Reduced the amount of insulin secreted in response to a meal • Provided minor benefits to cardiovascular health independent from weight loss • BP, Triglycerides, Cholesterol 29 4g MYO 12-16 weeks
  30. 30. Limitations • Small sample size (N=42) • Inconsistent timing of measurements • 6-8 weeks: OGTT • Compliance was not measured or reported • ~30% taking medications during the 2 months before the study • High variation in the glucose AUC 30
  31. 31. WHICH IS MORE EFFECTIVE – MYO OR DCI IN WOMEN WITH PCOS? 31 Pizzo A, Laganà AS, Barbaro L. (2014) Comparison between effects of myo-inositol and d-chiro-inositol on ovarian function and metabolic factors in women with PCOS. Gynecol Endocrinol. 30(3); 205-208
  32. 32. Methods Women with PCOS 4g MYO + 400mcg FA (n=25) 1g DCI + 400mcg FA (n=25) 32 • No medication during the previous 6 months or during the study • No significant differences between groups at baseline Study Design: Randomized Double-blind Length: 6 months
  33. 33. Effects of MYO and DCI MYO pre MYO post Δ% DCI pre DCI post Δ% BMI 25.1 ± 5.2 24.7 ± 4.6 - 24.37 ± 5.3 23.87 ± 4.5 - Glic/IRI Ratio 5.52 ± 1.7 9.72 ± 3.8 +43.2% 5.83 ± 1.5 10.56 ± 3.7 +44.8% HOMA 3.51 ± 1.7 1.75 ± 0.8 -100.6% 3.14 ± 1.1 1.61 ± 0.7 -95.0% SBP (mmHg) 104.5 ± 14.0 96 ± 6.6 -8.9% 103.75 ± 14.3 96.25 ± 6.9 -7.8% DBP (mmHg) 68.5 ± 8.2 64.5 ± 6.0 -6.2% 68.12 ± 9.3 64.37 ± 6.2 - 33 Glucose/Immunoreactive Insulin Ratio (Glic/IRI ratio) Homeostasis Model Assessment (HOMA)
  34. 34. Comparative Analysis of MYO and DCI Δ% with MYO post-treatment Δ% with DCI post-treatment Δ% between MYO and DCI P- value Glic/IRI Ratio +43.21 +44.79% 1.58% 0.174 HOMA -100.57% -95.03% 5.54% 0.032 Systolic BP (mmHg) -8.85% -7.79% 1.06% 0.204 34 Glucose/Immunoreactive Insulin Ratio (Glic/IRI ratio) Homeostasis Model Assessment (HOMA)
  35. 35. Conclusion/Limitations • Conclusions: • Both effective in improving insulin sensitivity and SBP • MYO had a greater decrease on DBP and insulin resistance • Limitations: • 4g of MYO vs. 1g of DCI • Physiological ratio 40:1 • Small sample size (N=50) • Did not control for lifestyle changes • Compliance was not measured or reported 35 4g MYO vs 1g DCI 6 months
  36. 36. Summary of Effectiveness 100mg MYO 4g MYO + 400mcg FA 4g MYO + 400mcg FA 1g DCI + 400mc FA Length 3-4 months <2 months 6 months N* 238 42 50 Age at Baseline 28.6 ± 1.7 28.8 ± 1.5 20.25 ± 4.47 19.25 ± 3.47 BMI (kg/m2) at Baseline 34.2 ± 2.5 22.8 ± 0.3 25.1 ± 5.2 24.37 ± 5.31 Metabolic Parameters Measured BMI, WHR, Triglycerides, VLDL, LDL, HDL BMI, WHR, Triglycerides, Cholesterol, BP BMI, BP Insulin/Glucos e Measured Fasting glu/ins, AUC glu/ins Fasting glu/ins, AUC glu/ins, ISIcomp Glic/IRI ratio, HOMA Significant Results BMI, Leptin, HDL SBP/DBP Triglycerides Cholest. Glu AUC Ins AUC SBP/DBP Glic/IRI ratio  HOMA SBP Glic/IRI ratio  HOMA Conclusions Not Effective/Effective Effective Effective Effective 36
  37. 37. Safety of Inositol • Very well tolerated • Dosage of 4g/day • Minimal to no side effects • Doses or 12-30g/day • Mild GI Distributions: • Nausea • Flatus • Diarrhea • Considered safe • 18g/day for 3 months • 2g/day for 1 year 37Carlomagno G, Unfer V. Inositol Safety: Clinical Evidences. (2011) Euro Rev Med Pharmacol Sci. 15; 931-936.
  38. 38. Conclusion/Implications • Conclusion: • 4g of MYO/400mcg FA may be beneficial to women with PCOS in improving some metabolic parameters and insulin sensitivity • Implications: • Lifestyle intervention should be the first-line of treatment • Could be beneficial to women who cannot tolerate metformin due to side-effects • More research is needed 38
  39. 39. Limitations • Short study length • Varied diagnostic criteria • Varied baseline measures • Many different phenotypes • No comparison insulin-sensitizing medications • What happens if they stop taking inositol? • Long-term safety • Limited information on effectiveness of morbidly obese women 39
  40. 40. References • ACOG Practice Bulletin No. 108: Polycystic Ovary Syndrome. Obstet Gynecol. 2009;114(4):936–949. • Rotstein, A., Srinivasan, R., Wong, E. (2013) McMaster Pathophysiology Review (MPR) • Clements, R.S . Jr., Diethelm, A.G. (1979). The metabolism of myo-inositol by the human kidney. J. Lab. Clin. Med. 93:210-19 • Clement R. & Darnell, B. (1980) Myo-inositol content of common foods: development of a high-myo-inositol diet. Am J. Clin. Nutr. 33: 1954067 • Croze M. & Soulage C. (2013) Potential role and therapeutic interests of • myo-inositol in metabolic diseases. Biochemie. 95(10);1811-1827 • Coustan D R Dia Care 2013;36:777-779 • Heimark D, McAllister J, Larner, J. (2014) Decreased myo-inositol to chiro-inositol (M/C) ratios and increased M/C epimerase activity in PCOS theca cells demonstrate increased insulin sensitivity compared to controls. Endocrine Journal. 61(2);111-117. • Gerli S, Mignosa M, DI Renzo GC. (2003) Effects of inositol on ovarian function and metabolic factors in women with PCOS: a randomized double blind placebo-controlled trial. Euro Rev Med Pharmacol Sci. 7; 151-159. • Costantino D, Minozzi G, Minozzi F, Guaraldi C. (2009) Metabolic and hormonal effects of myo-inositol in women with polycystic ovary syndrome: a double blind trial. Euro Rev Med Pharmacol Sci. 13; 105-110. • Pizzo A, Laganà AS, Barbaro L. (2014) Comparison between effects of myo-inositol and d- chiro-inositol on ovarian function and metabolic factors in women with PCOS. Gynecol Endocrinol. 30(3); 205-208 • Carlomagno G, Unfer V. Inositol Safety: Clinical Evidences. (2011) Euro Rev Med Pharmacol Sci. 15; 931-936. 40
  41. 41. 41
  42. 42. EXTRA CONTENT
  43. 43. Summary of Baseline Data 100mg MYO 4g MYO + 400mcg FA 4g MYO + 400mcg FA 1g DCI + 400mc FA Length 3-4 months <2 months 6 months 6 months N* 91 23 25 25 Age at Baseline 28.6 ± 1.7 28.8 ± 1.5 20.25 ± 4.47 19.25 ± 3.47 BMI (kg/m2) at Baseline 34.2 ± 2.5 22.8 ± 0.3 25.1 ± 5.2 24.37 ± 5.31 WHR at Baseline 0.88 ± 0.2 0.88 ± 0.2 - - Fasting Insulin mIU/L 16.7 ± 3.7 32.5 ± 4.1 - - PCOS Diagnostic Criteria OO/OA & PCO OO & high serum free T AND/OR hirsutism Rotterdam = 2/3 of the following: HA, OO/OA, PCO Rotterdam = 2/3 of the following: HA, OO/OA, PCO 43OO = oligoovulation; AO = anovulation; HA = hyperandrogenism; PCO = polycystic ovaries
  44. 44. 100mg MYO 4g MYO + 400mcg FA 4g MYO + 400mcg FA 1g DCI + 400mc FA BMI  0.9% NS NS NS Triglycerides NS  52% - - HDL  5.6% - - - Total Cholesterol NS  18.6% - - Systolic Blood Pressure -  3.1%  8.1%  7.1% Diastolic Blood Pressure -  6.8%  5.8% NS Fasting Insulin NS NS - - Fasting glucose NS NS - - GTT insulin AUC NS  36% - - GTT Glucose AUC -  15.8% - - ISIcomp -  84% - - Glic/IRI Ratio - -  76.1%  81.1% HOMA - -  50.1%  48.7% 44
  45. 45. 45M.L. Croze, C.O. Soulage/ Ciochimie 95 (2013) 1811 - 1827 Phosphatidylinositol Synthase
  46. 46. Calculation for Whole-Food Consumption • ---Remember this 4g supplement is on top of normal daily consumption, which is estimated to be 900mg in 2,500kcal • ---In theory, you would need to consume 5g to have similar effects: 46
  47. 47. Sample 5g Myo-Inositol Diet • Breakfast: • ½ cantaloupe (710mg) • 1 C milk (10mg) • 1 C bran flakes (110mg) • 3 Walnuts (13g) • ½ C grapefruit juice (456mg) • Snack: • 2 dried prunes (94mg) • 16 almonds (84mg) • 1 Kiwi (136mg) • Lunch: • 1 orange (307mg) • 2 slices of stone ground wheat bread (576mg) • 2 T of Peanut Butter (122mg) • ½ C Kidney Beans (250mg) • Snack: • 1 C Lima beans (300mg) • 1 Mango (99mg) • 1 slice stone ground wheat bread (288 mg) • Dinner: • 1C Great Northern Beans (880mg) • 1/2 C artichoke hearts, canned (116mg) • 1 C tomatoes (54mg) • ¼ C onion, yellow (22mg) • 6 oz. chicken (14mg) • Dessert: • 1 Grapefruit (400mg) Totals: MYO: 5,068mg* kcal: 2,342 47
  48. 48. Inositol Food Sources 48 Clements RS Jr, Darnell B. Myo-inositol content of common foods: development of a high-myo-inositol diet. Am J Clin Nutr. (1980)
  49. 49. 49Croze M. & Soulage C. (2013) Potential role and therapeutic interests of myo-inositol in metabolic diseases. Biochemie. 95(10);1811-1827
  50. 50. Diagnostic Values Diagnosis/Test Criteria Insulin Resistance in Women 3 or more of the following: • Waist Circumference > 88cm • Triglycerides ≥ 150 mg/dL • HDL Cholesterol <50 mg/dL • Blood Pressure ≥ 130/85 mm/Hg • Fasting Glucose ≥ 100 mg/dL Fasting Glucose/Insulin Ratio Insulin Resistance: • <4.5 in obese, euglycemic, non-Hispanic white adult PCOS patients • <7.0 in adolescents 75g Oral Glucose Tolerance Test (at 2- hours) Normal: <140mg/dL Impaired GT: 140-199 mg/dL Diabetes: ≥200 mg/dL Fasting Insulin Hyperinsulinemia: 5 mIU/L (34.73 pmol/LL) Waist to Hip Ratio (WHR) Females: • 0.80 or below = Low Risk • 0.81 to 0.85 = Moderate Risk • 0.85 or above = High Risk 50National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH)

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