Let's Get Clinical

10/21/19

Let’s Get Clinical: Addressing Metabolic Disease Functionally

Melody L. Hartzler, PharmD, BCACP, BC-ADM Clinical Pharmacist, Western Medicine Family Physicians CEO, PharmToTable, LLC Associate Professor of Pharmacy Practice, Cedarville University School of Pharmacy

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Disclosure

There are no relevant financial relationships with ACCME- defined commercial interests for anyone who was in control of the content of the activity.

Pharmacist and Pharmacy Technician Learning Objectives

• Summarize the relationship between gut health and metabolic disease • Outline important supplements for consideration in diabetic and pre-diabetic populations • Identify the role of stress in diabetes and adrenal dysregulation

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THIS SESSION WILL BE UTILIZING AUDIENCE POLLING SOFTWARE

Please go to MEET.PS/CLINICAL to answer poll questions

Case: Mary

• Mary is a 55 year old Caucasian female presenting to your pharmacist-run metabolic syndrome clinic • Here today to discuss her “diagnosis” of prediabetes • Past medical history • Sepsis 12 months ago (hospitalized for 2 weeks) • HTN • born via C-section • bottle fed with formula • frequent infections as a child

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Case: Mary

• Current History of Present Illness • Fatigue • Frequent yeast infections • Sedentary Lifestyle (works 8-10 hour days at a desk) • High stress job • Typically follows a moderate intake of carbohydrate diet due to family history of diabetes • Constipation/Flatulence/Periodic Abdominal Pain

Case: Mary

• Discuss with the person next to you what your approach for Mary would be today.

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WHAT IS FUNCTIONAL MEDICINE?

Functional Medicine

•Functional Medicine is a personalized, systems- oriented model that empowers patients and practitioners to achieve the highest expression of health by working in collaboration to address the underlying causes of disease.

Jones D, Quinn S. Introduction to FM. 2014

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7 Core Principles of FM

• Acknowledging the biochemical individuality of each human being, based on concepts of genetic and environmental uniqueness • Incorporating a patient-centered approach to treatment • Seeking a dynamic balance among the internal and external factors in a patient’s body, mind, and spirit • Addressing the web-like interconnections of internal physiological factors

Jones D, Quinn S. Introduction to FM. 2014

7 Core Principles of FM

• Identifying health as a positive vitality—not merely the absence of disease—and emphasizing those factors that encourage a vigorous physiology • Promoting organ reserve as a means of enhancing the health span • Functional Medicine is a science-using profession

Jones D, Quinn S. Introduction to FM. 2014

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Nutrition

Sedentary Aging Population Lifestyles

Chronic Indoor Living Chronic Stress (Vitamin D) Disease Epidemic

Fragmented Families & Poverty Communities Environmental Toxicity

Adapted from Jones D, Quinn S. Introduction to FM. 2014

One Condition Many Imbalances

Inflammation

Hormones Genetics and Epigenetics Diet and Exercise

Mood Disorders Obesity

Adapted from Jones D, Quinn S. Introduction to FM. 2014

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One Imbalance Heart Disease Many Conditions

Diabetes Depression

Inflammation

Cancer Arthritis

Adapted from Jones D, Quinn S. Introduction to FM. 2014 15

Functional Strategies for Improving Cardiometabolic Resilience

• Decrease central adiposity • Improve peripheral insulin sensitivity • Reduce inflammatory signaling • Reduce circulating free fatty acids • Improve appropriate incretin signaling • Modulate inappropriate HPA-axis regulation & cortisol burden • Maintain/improve kidney metabolic capacity • Maintain circadian alignment

Guilliams, T. Cardiometabolic Risk Management: A Functional and Lifestyle Approach. The Standard Road Map Series. Pointe Institute 2018.

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Functional Strategies for Improving Cardiometabolic Resilience • Protect/improve pancreatic beta cell function • Reduce post-prandial hyperinsulinemia (reduce meal impact) • Reduce lipoprotein atherogenicity • Improve endothelial function • Reduce glycation and formation of accumulation AGEs • Modulate/balance coagulation capacity • Improve mitochondrial efficiency • Reduce oxidative burden • Restore metabolically-favorable gut microbiota

Guilliams, T. Cardiometabolic Risk Management: A Functional and Lifestyle Approach. The Standard Road Map Series. Pointe Institute 2018.

Functional medicine approaches to address the underlying causes of metabolic disease • Address gut dysfunction • Improve insulin sensitivity • Supplements • Exercise (Enhances uptake of glucose by Dr. Hartzler’s peripheral tissues, DPP Trial) DM Protocol! • Diet • Address stress • Consider anti-inflammatory/cardiac risk reduction supplementation

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Toxicities Related to Diabetes

•Mercury exposure1 •Persistent organic pollutants2

1. He K, et al. Diabetes Care. 2013 Jun;36(6):1584-9 2. Lee D, et al. Diabetes Care. 2006;29(7):1638-1644

Egregious Eleven: defects present in diabetes and prediabetes

AGI, alpha glucosidase inhibitor; GLP-1, glucagon-like peptide 1; QR, quick release; TZDs, thiazolidinediones

© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. Schwartz SS, Epstein S, Corkey BE, et al. The Time Is Right for a New Classification System for Diabetes: Rationale and Implications of the β-Cell–Centric Classification Schema. Diabetes Care Feb 2016, 39 (2) 179-186; DOI: 10.2337/dc15- 1585

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Case: Mary

• Mary is a 55 year old Caucasian female presenting to your pharmacist-run metabolic syndrome clinic • She is here today to discuss her “diagnosis” of prediabetes • Past medical history • sepsis 12 months ago (hospitalized for 2 weeks) • HTN • born via C-section • bottle fed with formula • frequent infections as a child

Case: Mary

• Current HPI • Fatigue • Frequent yeast infections • Sedentary Lifestyle (works 8-10 hour days at a desk) • High stress job • Typically follows a moderate intake of carbohydrate diet due to family history of diabetes • Constipation/Flatulence/Periodic Abdominal Pain

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Please go to MEET.PS/CLINICAL to answer poll questions!

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"All Disease Begins In The Gut." -Hippocrates

METABOLIC DISEASE & THE GUT

Metabolic Syndrome

• Metabolic syndrome is 3 of the following: • Increased waist circumference (>40 inches men, 35 women) • Elevated TG (>150 mg/dL) • Elevated BP (>130/80) • Elevated glucose • Low HDL-C (<40 mg/dL in men, <50 mg/dL in women)

NCEP IV 2018

J Am Coll Cardiol. Nov 2018; DOI: 10.1016/j.jacc.2018.11.003

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Metabolic Continuum & Type 2 Diabetes

Reprinted with permission: Figure 25. Guilliams, T. Cardiometabolic Risk Management: A Functional and Lifestyle Approach. The Standard Road Map Series. Pointe Institute 2018.

Insulin Resistance & CVD

Reprinted with permission: Figure 4. Guilliams, T. Cardiometabolic Risk Management: A Functional and Lifestyle Approach. The Standard Road Map Series. Pointe Institute 2018.

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GIT Microbiome… an endocrine organ? Roles: Food - Carbohydrate digestion Intake - Hormone synthesis - Neurotransmitter production - Vitamin synthesis - Immune response modulation - Inflammatory response modulation Metabolism Energy GUT-BRAIN Homeostasis AXIS

Galland L. J Med Food. 2014;17(12):1261-1272 Brown JM, et al. Annu Rev Med. 2015;66:343–359.

Metabolic Disease and the Gut- SCFAs

• Short-chain fatty acids (SCFAs) are produced by the fermentation of bacteria, when the bacteria in the colon metabolize proteins and complex carbohydrates. • These SCFAs may decrease the risk of developing metabolic disorders due to the increasing demand of cholesterol for de novo synthesis of bile acids • SCFA provide a direct energy source for colonocytes and as signaling molecules that influence epigenetics

Yoo JY et al. Nutrients. 2016 Mar; 8(3): 173.

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Metabolic Disease and the Gut- SCFAs

• SCFAs also are signaling molecules that produce metabolic and satiety signaling compounds such as: • Glucogon-like-peptide-1 (GLP-1) • Peptide YY • SCFA can modulate insulin-signaling in adipose tissue, preventing fat accumulation.

1. Samuel BS et al. Pro Natl Acad Sci USA. 2008 Oct 28;105(43):16767-72. 2. Bolognini D, et al. Mol Pharmacol. 2016 Mar;89(3):388-98. 3. KimuraI et al. Nat Commun. 2013; 4:1829.

Metabolic Disease and the Gut- Microbiome Composition

• Many persons with diabetes may be deficient in a specific gut microbe, bifidobacteria.1 • Having an imbalance of gut microbes can increase gut permeability and allow for infiltration of inflammatory signals which can cause damage to the pancreas and contribute to the development of diabetes.

1. Gomes A, Bueno A, de Souza R, Mota J. Gut microbiota, probiotics and diabetes. Nutr J. 2014;13:60. doi: 10.1186/1475-2891-13-60

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Metabolic Disease and the Gut Microbiome & Immune Activation

• Lipopolysaccharide (LPS) • Highly studied component of gram-negative bacteria • Stimulates immunological responses • Stimulates production of numerous inflammatory mediators • Leads to intestinal permeability & chronic inflammation

Creely SJ, et al. Am J Physiol Endrocrinol Metab. 2007 Mar; 292(3):E740-7.

Metabolic Disease and the Gut Microbiome & Immune Activation

• This deficiency of bifidobacteria has been shown to result in increased translocation of bacterial lipopolysaccharide (LPS)9 which is thought to be a contributor to development of insulin resistance.1 • Supplementation with probiotics that increase bifidobacteria may help to slow progression of insulin resistance and pancreatic damage.2

1. Drewe J, Beglinger C, Fricker G: Effect of ischemia on intestinal permeability of lipopolysaccharides. Eur J Clin Invest. 2001, 31:138–144. doi: 10.1046/j.1365- 2362.2001.00792.x. 2. Firouzi S et al. Eur J Nutr. 2017;56(4):1535-1550. doi:10.1007/s00394-016-1199-8.

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Metabolic Disease and the Gut Bile Acid Metabolism & Signaling • Bi-direction relationship between bile acid production and the gut microbes • Bile can provide a direct antibacterial activity • Indirect effect on host immune response • Gut microbes shape the bile acid pool that is available to recycle to the liver (determine amount and type) • Act as signaling molecules • Bile acid can increase release of GLP-1

Guilliams, T. Cardiometabolic Risk Management: A Functional and Lifestyle Approach. The Standard Road Map Series. 2018; 106-107.

GIT Alteration

Bile Acids SCFAs Metabolic Metabolism Production Endotoximea

DIET Alters activation of Modulates gut Elevates serum ANTIBIOTICS FXR & TGR5 hormones LPS levels GLP-1, leptin, peptide YY Disrupts glucose & Induces (chronic) Affects satiety lipid homeostasis inflammation

Obesity AND Metabolic Syndrome

Tseng CH, Wu CY. The gut microbiome in obesity. J Formos Med Assoc. 2019;118(Suppl. 1):S3-S9.

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Reprinted with permission: Figure 19. Guilliams, T. Cardiometabolic Risk Management: A Functional and Lifestyle Approach. The Standard Road Map Series. Pointe Institute 2018.

NUTRIENTS, SUPPLEMENTS, & LIFESTYLE MODIFICATIONS FOCUSED ON PATIENTS WITH DIABETES & PRE- DIABETES

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Probiotic Data in Diabetes

• Studies have shown… • Reduced glucose levels in postmenopausal women with metabolic syndrome who received Lactobacillus plantarum verses those who did not1 • Improvements in A1C2,3 • Improvements in glucose, and insulin resistance3,4 • Reduction in weight gain4 • Multistrain species may have more impact than single strain5

1. Barreto FM et al. (meta-analysis) 2. Dolatkhah N et al Journal of Health, Population and Nutrition. 2015;33(1):25. 3. Nikbakht E et al. Eur J Nutr. 2016:1-12. (meta-analysis). 4. Dolatkhah N et al Journal of Health, Population and Nutrition. 2015;33(1):25. 5. Nikbakht E et al.. Eur J Nutr. 2016:1-12. (meta-analysis)

Prebiotics

• “a non-digestible food ingredient that beneficially affects the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the colon.” • Examples • Inulin, FOS, lactose, resistant starch, cellulose, hemicellulose, pectins, and gums ( ie guar gum)

Gibson GR et al. J Nutr. 1995 Jun; 125(6):1401-12.

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Prebiotics

• Study of healthy, non-diabetic individuals that received supplementation with prebiotics (derived from chicory roots) for 2 weeks showed: • An increase in plasma GLP-1 and a decrease in postprandial glucose compared to individuals that received the control (dextrin maltose supplementation). • Prebiotic supplementation significantly lowered post-meal hunger scores and improved satiety scores.

Cani P, Lecourt E, Delzenne N, et al. Am J Clin Nutr. 2009;90(5):1236-1243.

Partially Hydrolyzed Guar Gum- Prebiotic

• Administration of 6 g/PHGG with each meal x 12 months1 • Lowered PPG, reduced both the fasting and postprandial insulin (IRI) and triglyceride (TG) levels (p = 0.05). • Low-density lipoprotein (LDL) was lower, whereas high-density lipoprotein (HDL) level was significantly increased (p < 0.01). Plasma leptin, high-sensitive C-reactive protein (hs-CRP) and fasting glucagon like peptide (GLP-1) were also lowered. • Stimulates bifidobacteria and butyrate-producing bacteria in the large intestine2 • Well tolerated compared to other pre-biotics

1. Kapoor M et al. Journal of Functional Foods. 2016; 24:201-220. 2. Ohashi Y et al. Benef Microbes. 20015;6(4):451-5/.

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Zinc

• RCT double-blind, placebo-controlled Phase II clinical trial for a period of 12 months.1,2 • The treatment group received Zinc Sulfate (20mg elemental zinc daily). Patients with pre-diabetes were recruited for the study and randomly assigned into the treatment and control groups (1:1). (N=200) • Mean serum Zinc concentration in both groups prior to the commencement of the trial was below normal. • During the 12 month follow-up period a significantly higher percentage of participants in the Placebo group (25.0%) developed type-2 diabetes in comparison to the Zinc group (11.0%)(p=0.016). • The FPG, OGTT, HOMA-IR, total and LDL cholesterol significantly reduced in the Zinc group, with significant improvement in β-cell function.

1. Ranasinghe P et al. Journal of Diabetes. Accepted Author Manuscript. doi:10.1111/1753-0407.12621 2. Ranasinghe P et al. Trials [serial online]. 2013;14:52.

Zinc

• Another RCT in pre-diabetes with Zinc sulfate 30 mg daily for six months • Reduction in fasting blood glucose concentration. • Improvement in all the HOMA parameters and in lipids and CRP vs. the control group.

Islam M, et al. Diabetes Research And Clinical Practice. May 2016;115:39-46.

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Berberine

• Reduces FBG, fasting serum insulin, HOMA-IR, TC, TG • Improves LFTs • Modulates and stabilizes the LDL receptor, natural PCSK9 inhibitor • Shown to lower LDL, TC, and TG, and raise HDL. • Reduces LDL oxidation and oxidized LDL induced cytotoxicity • Vasodilation

1. Yin et al. Metabolism 2008; 57(5):712-7. 2. Derosa et al. Expert Opin boil Ther. 2013; 13($):475-82. 46

Berberine

• Beneficial effect on gut microbiome (increases akkermansia spp abundance, decreased endotoxemia) • -> similar to metformin’s microbiome effects • Limited studies in HTN have been small but statistically significant improvements Doses & Counseling • 1,000 to 1,500 mg in divided doses (500 mg capsules) • Side Effects: GI Upset • DI: Warfarin

Zang et al. J Clin Endocrinol Metab. 2008;93(7):2559-65.

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Omega-3

• Forms • rTG (re-esterified forms, monoglycerides, etyl esters (EE), free fatty acids (FFA), or phospholipids • Most commonly studied either EE or rTG • Superior bioavailability with rTG > EE forms • DHA >EPA ? • DHA outperforms EPA in nearly every surrogate marker • DHA--> No clinical trails looking at MI, CVD, mortality • 1:1 likely a good ratio based on evidence • Most Pharmaceuticals more EPA • Icosapent ethylà CVOT • Quality 1. Guilliams, T. Cardiometabolic Risk Management: A Functional and Lifestyle Approach. The Standard Road Map Series. Pointe Institute 2018. 2. Bhatt et al. N Engl J Med 2019; 380:11-22

Other Insulin Sensitizing Supplements

Supplement Dose

Lipoic Acid 600-1200 mg/day

Chromium 800-1,000 mcg/day

Vanadium 50-150.day

Cinnamon Extracts Various

1. Guilliams, T. Cardiometabolic Risk Management: A Functional and Lifestyle Approach. The Standard Road Map Series. Pointe Institute 2018. 2. Natural Medicines Comprehensive Database. Natural Medicines [database online]. Stockton, CA: Therapeutic Research Facility; 2019.

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Additional Inflammation Considerations

•Cardiovascular Disease & Inflammation • Curcumin1,2 • Bergamot Flavanoids3,4

1. Jiang, S et al. Pharmacological Research 119 (2017) 373–383 2. Karuppagounder V, et al. Nutrition. 2017 Feb;34:47-54. doi: 10.1016/j.nut.2016.09.005 3. Cappello AR et al., Mini Rev Med Chem. 2016;16(8):619-29 4. Giglio RV, et al. Phytomedicine. 2016 Oct 15;23(11):1175-81.

Diet

• Low Carbohydrate Diet • Mediterranean Diet (low-glycemic impact) • Ketogenic Diet • Fasting and Intermittent Fasting

Guilliams, T. Cardiometabolic Risk Management: A Functional and Lifestyle Approach. The Standard Road Map Series. Pointe Institute 2018.

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Exercise

• Regular Exercise • Improves biomarkers for cardiovascular risk • Balances oxidation , with an overall antioxidant effect • Can reduce CRP & inflammation (chronic) • Diabetes Prevention Program • 150 minutes of moderate physical activity OR • 75 minutes of vigorous or intense physical activity

1. Guilliams, T. Cardiometabolic Risk Management: A Functional and Lifestyle Approach. The Standard Road Map Series. Pointe Institute 2018. 2. Diabetes Prevention Program Research Group. N Engl J Med. 2002;346:393-403.

Sleep

• HTN is associated with shorter or longer sleep times (NHANES)1 • < 6 hours and >10 hours/night increased prevalence of HTN • Suboptimal sleep (quantity or quality) is linked to the development of type 2 diabetes2 • <5 hours per night OR > 5 times per month OR waking up too early >5 times/month increased risk of pre-diabetes. • Mechanisms for lack of sleep: • ↑ leptin or ghrelin, ↓ energy expenditure, ↑ SNS, ↑ cytokine production

1. Fang, J. Am J Hypertens. 2012;25(3):355-41. 2. Cappuccio FP, et al. Diabetes Care. 2010;33(2):414-20.

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Exercise

• Aerobic Exercise • Enhanced peripheral glucose uptake (PGU)1 • Reduced glycemic variability and postprandial glucose (PPG)2 • Resistance Exercise • Increased serum adiponectin; reduced insulin resistance, and reduced levels of free fatty acid (FFA), and C-Reactive Protein (CRP)3

1. Winnick, JJ et al. The Journal of Clinical Endocrinology & Metabolism, 2008:93(3), 771-778. 2. Mikus, CR et al. Diabetologia, 2012:55(5), 1417-1423. 3. Brooks, NInt J Med Sci. 2006 Dec 18;4(1):19-27.

Case- Shirley

HPI Labs Initial Meds 40 y/o ● 9/18/18: Ast 66 IU/L, • Albuterol sulfate HFA • Dx - Alt 63 IU/L • Type 2 DM, IBS, HLD, Vit D • Metformin 500 mg BID deficiency, Fatigue ● 9/18/18 : HbA1c 6.5% • NuvaRing • Origin - ● 9/19/18: KUB x ray • Complaints of GI issues showed possible colitis began Aug of 2018 ● 10/09/18: pt had one of diagnosed with IBS by Oct the HLA-DQ variants of 2018 • Diagnosed w/ T2DM Sept associated with celiac of 2018 disease

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Case- Shirley Recommendations & Actions Initial Visit

Initial Visit (10/01/2018) Labs (10/01/18)

• Diarrhea/loose stools: improving with low FODMAP diet. • C-Peptide Serum: 2.5 ng/mL Suspected gut dysbiosis. Experiencing bloating. Restricting to • Free Insulin: 7.3 uU/mL 57 g carbs/day. • Total Insulin: 7.6 uU/mL • Diagnostic Tests Ordered: C-peptide, GAD autoantibodies, Insulin autoantibodies, Zn, Cu, Serum insulin and total insulin • Insulin Antibodies: <5.0 uU/mL • Copper: 188 ug/dL Plan - GI MAP test, SpectraCell test (Nturient) • Zinc: 85 ug/dL • Start berberine 500 mg tid, after GI MAP sample completed • Low carb diet & avoid gluten • Exercise 30 min/day

Case- Shirley Recommendations & Actions Follow-Up 1

Follow-Up 1 (10/22/18) Plan • Berberine 500 mg tid • Spectra Cell Results • B12 functional deficiency • B-complex plus every other day • Borderline: folate, chromium, • Multi-vitamin with phytonutrients once daily (Pack has 15-20 pantothenate, zinc, choline, selenium, mg of zinc) Vit A • Omega 3’s at least 2,000 mg daily (if not 3-4,000mg) • GI MAP test • Positive for H pylori & 2 other • Colostrum Concentrate (Bovine) IGG 2.5/1g per day pathogenic bacteria • GI product containing 500 mg of Vitamin C, 1.5 g DGL, 1 gram mastic gum, 200 mg methylmethionine sulfonium chloride 200 mg(Vitamin U), and 75 mg zinc carnosine per day. (x2 months) • Vitamin D • Exercise • Moderate/Low Carb Diet

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Shirley- Case Recommendations & Actions Follow-Up 2

Plan Follow-Up 2 (1/15/19) • Consider switching probiotics to target strains • HbA1c decreased from 6.5% (09/2018) to 5.8% proven to lower insulin resistance. (HOMA-IR) • Retest to verify H Pylori was eradicated • Add prebiotic fibers as tolerated • GI dysbiosis & abdominal pain - well controlled • Heartburn - improving Labs

• Diarrhea - resolved. Now having well formed stools • 1/15/19: Vitamins within normal range • BG - 110-140 mg/dL 1-2 hours post-eating • 1/29/19: Negative for H Pylori • Patient aimed for <70g carbs/day

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Case- Shirley

Final Supplement List

• Berberine (Health First) - 1 cap tid

• IgG Protect (Health First) - 4 caps qd

• Omega 3 FA 1,000 mg - 2-4 caps qd

• One daily MV w/ minerals - 1 pack/day

• Probiotic 100 billion CFU- 1 cap qd

• B Complex Plus (Health First) - 1 cap every other day

STRESS

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EEKK what if I told you that you had to retake the NAPLEX right now? What would happen in your body?

• Stress would… • Increase heart rate and blood pressure • Hinder release of stomach acid • Delay stomach emptying • Stimulate the colon, increasing movement • Activate changes in the hypothalamic-pituitary adrenal(HPA) axis

Wilson, D. Integrative Medicine 2009.

Over time Stress….

• Leads to increased cholesterol levels • Suppresses the reproductive system • Hinders growth • May lead to increased cancer and autoimmunity • May lead to change in appetite and weight gain • Decreases ability to fight infections • Affects balance of neurotransmitters • Can result in long-term activation of the stress system

Wilson, D. Integrative Medicine 2009.

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Reprinted with permission: Figure 5. Guilliams, T. The Role of Stress and the HPA Axis in Chronic Disease Management. The Standard Road Map Series. Pointe Institute 2018.

Stress and Diabetes

• HPA-axis dysregulation is an important biological link among stress, depression, and diabetes.1 • Patients with diabetes had higher cortisol levels, a flattening of the diurnal cortisol curve, and post stress recovery is also weakened2 • Specific significant differences were seen at 1600-1630, 2000-2030, and on waking (morning).

1. Joseph JJ et al. Ann N Y Acad Sci. 2017;1391(1):20-34. 2. Steptoe A et al. Proceedings of the National Academy of Sciences. 2014;111(44):15693-15698.

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Stress and Diabetes

• Impaired stress response is present in patients with Type 2 diabetes1 • In those with diabetes complications: • Hypothalmic-pituitary-adrenal activity is enhanced • The degree of cortisol secretion is related to the presence and number of diabetes complications.2

1. Carvalho LA, et al. Psychoneuroendocrinology. 2015;51:209-218. 2. Chiodini I, et al. Diabetes Care. 2007;30(1):83-88.

Stress and Diabetes

•Stress Management • Individuals with type 2 diabetes had a flatter cortisol slope throughout the entire day and higher bedtime cortisol levels compared to individuals that did not have type 2 diabetes.1

1. Hackett R, Steptoe A, Kumari M. J Clin Endocrinol Metab. 2014;99(12):4625-4631. doi:10.1210/jc.2014-2459.

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What Makes the Brain Stressed?

Reprinted with permission:. Guilliams, T. The Role of Stress and the HPA Axis in Chronic Disease Management. The Standard Road Map Series. Pointe Institute 2018. p. 80

Diurnal Salivary Cortisol and DHEA(S) Sample Pattern

Reprinted with permission: Guilliams, T. The Role of Stress and the HPA Axis in Chronic Disease Management. The Standard Road Map Series. Pointe Institute 2018. p.68

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Reprinted with permission:. Guilliams, T. The Role of Stress and the HPA Axis in Chronic Disease Management. The Standard Road Map Series. Pointe Institute 2018. p 102.

Please go to MEET.PS/CLINICAL to answer poll questions!

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Stage Theory - “Adrenal Fatigue”

• Stage 1: Alarm • Stage 2: Suppression/Resistance • Stage 3: Exhaustion

• Limitations?

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What is the correct terminology?

• Most appropriate overall term: • HPA Axis Dysfunction • Maladaptation to Stress or Stress-response dysfunction, Adaptation to Stress……with consequences.

• Specific Terms (where appropriate) • Hypocortisolism/Hypercortisolism • Low DHEA or DHEA-S • High Allostatic Load, or Burnout (properly defined)

Guilliams, T. New Strategies for Understanding the Stress Response…. Beyond the Adrenal Glands. 85

Assessment of Adrenal Hormone Output (Cortisol & DHEA(S))

• Serum, saliva, or urine • Protein bound vs. free fraction • Diurnal rhythm of Cortisol • Convenience of collection • Cost • Salivary free-fraction option: • Correlated with serum free fraction studies • Measures the bioavailable vs. pool or reserves • Easy at home collections throughout day, night or month • Economical • Most commonly used in published clinical trials related to HPA axis dysfunction and stress. Guilliams, T. New Strategies for Understanding the Stress Response…. Beyond the Adrenal Glands.

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Stress Reduction

• Supplements1 • Ashwagandha, Rhodiola rosea, Phosphatidylserine, Eleuthero Root Extract, Skullcap Root Extract, Banaba etc. • Yoga2 • Mindful Relaxation Exercises/Mindfulness Practices3

1. Natural Medicines Comprehensive Database. Natural Medicines [database online]. Stockton, CA: Therapeutic Research Facility; 2017. 2. Thind H et al. Prev Med. 2017 Sep 4;105:116-126. doi: 10.1016/j.ypmed.2017.08.017. 3. Brand S et al. Neuropsychobiology. 2012;65(3):109-18. doi: 10.1159/000330362. Epub 2012 Feb 24.

Adaptogens

• Increases the resistance of the recipient to a variety of physical, chemical, or biological stressors • It has to have a nonspecific effect in that it increases • It has to have normalizing effects in that it counteracts or prevents disturbances brought about by stressors. • It has to be innocuous to the normal functioning of the organism, thus being nontoxic. • Think “partial agonist” in pharmacology • Can down-regulate or up-regulate depending on the physiological need.

1. Altern Med Rev 2009;14(2):114-140; 2. Alternative and Complementary Therapies 2015; 21 (6):242-246.

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Adaptogens

• Most well studied • Eleuthero root (siberian Ginseng)-> 750 mg TID • (beneficial for support cognitive function, overnight jobs) • Rhodiola root • (low doses stimulating, high doses are needed to reduce cortisol) • Schisandra root (studied mostly in combination products) • Ashwaghanda root à 300 mg BID 1. Guilliams, T. The Role of Stress and the HPA Axis in Chronic Disease Management. The Standard Road Map Series. Pointe Institute 2018. 2. Altern Med Rev 2009;14(2):114-140; 3. Alternative and Complementary Therapies 2015; 21 (6):242-246.

Cortisol Modulators

• Phosphatidylserine (400-800mg daily) • Fish Oil (Dose studied was 7.3 g daily) • Plant Sterols and Sterolins • Increased DHEA and decreased cortisol • Alpha-Lipoic Acid • Magnesium • Zinc (25 mg daily)

Altern Med Rev 2009;14(2):114-140

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Anxiolytic/Sedative Botanicals and Plant Extracts

• L-theanine (green or black tea), 200mg (20mg is found in 1 cup of black tea) • Bacopa monniera • Valeriana officinalis (valerian) • Passiflora incarnata (passionflower) extract • Humulus lupulus (hops) • Matricaria chamomilla (German chamomile) • Galphimia glauca (thryallis; rain-of-gold) • Centella asiatica (gotu kola) • Melissa officinalis (lemon balm) • Piper methysticum (kava kava) • Scutellaria lateriflora (blue skullcap) • Ziziphus jujuba (jujabe)

Altern Med Rev 2009;14(2):114-140

Oral Lavandula angustifolia

• Known as Silexan™ • Studied vs. conventional treatment in anxiety • Well tolerated, similar results regarding reduction in HAM-Scores, higher remission rates1 • Superior to conventional approach2 • Significant beneficial influence on quality and duration of sleep and improved general mental and physical health without causing any unwanted sedative effects.3 • Dose 80-160 mg per day

• Side effects <5%:1. GIWoelk upsetH, Schläe S. Phytomedicine 2010;17:94–9. 2. Woelk H, Kapoula O, Lehr S, Schröter K, Weinholz P (1999). Healthnotes Review 6:265–70. 3. Kasper S, Gastpar M, Müller WE, et al. Int Clin Psychopharmacol 2010;25:277–87.

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Neurotransmitter Treatment

• gamma-Aminobutyric Acid • L-Tryptophan/5-Hydroxytryptophan (5-HTP) • 200-400 mg/day in divided doses • Melatonin • L-Tyrosine

Altern Med Rev 2009;14(2):114-140

Summary of Vitamins & Relationship to Stress Vitamin Function Regarding Stress Doses Studied for response Thiamin (B1) Protective nutrient for the adrenals, decreases stress induced 120mg/day cortisol response. Niacinamide (B3) Improves sleep quality and quantity; shuts tryptophan to serotonin. 500mg BID to 1,000mg TID

Pantethine/Pantothenic Protective nutrient for the adrenals, decreases stress induced Various/Combo Acid (Vitamin B5) cortisol response. Products

Pyridoxal 5’phosphate Cofactor for synthesis of GABA, serotonin, and dopamine. Various/Combo (Vitamin B6) Products Methylcobalamin (Vitamin Resets circadian rhythms for improved sleeping and normalizing Various/Combo B12) cortisol peak. Products

5-Methyltetrahydrofolate Regenerates BH4, essential for neurotransmitter formation. Various/Combo (5-MTHF; active folate) (serotonin, norepinephrine, dopamine, and epinephrine). Products

Ascorbic Acid (Vitamin C) Electron donor in the formation of norepi from dopamine, also aids 200-400 mg daily up in the modulation of NO induced catecholamine release to 3,000 mg. 94

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Other Non-Pharm

• Cognive Behavioral Therapy • HeartMath or other biofeedback systems • hp://www.youtube.com/watch?v=BU5IZlBlRBc&sns=em • Sleep Hygiene Self-Care • Eye Movement Desensizaon and Reprocessing Therapy (EMDR) • Parcularly useful if past trauma cased stress/anxiety • Hypnotherapy • Meditaon & Breathing Exercises

WRAPPING UP

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Wrap-up

• Tell your neighbor 3 big take-aways from this morning’s talk.

How do we communicate/discuss FM with our Patients?

• Explain your approach looks at the root cause • It takes time to heal • Some financial investment in testing/support is needed • Health is not the absence of disease, we want them to thrive • Motivational Interviewing is a must

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Metabolic Syndrome Protocol Take-Aways

• Diet Modifications • Address Gut Dysfunction (likely needs tested) • Weight Loss • Physical Activity (150 min per week) • Stress Management /Sleep Support • Core Supplements (MV, Omega-3, Vitamin D, Probiotic) • Insulin Sensitizing Supplements • Berberine, Lipoic Acid, Chromium, Vanadium, Cinnamon extracts • CVD Supplement Considerations • Consider CQ10, Mg, resveratrol, quercetin, green tea, etc.

Guilliams, T. Cardiometabolic Risk Management: A Functional and Lifestyle Approach. The Standard Road Map Series. Pointe Institute 2018.

Let’s Get Clinical - Handout

• Addressing underlying gut dysfunction is an important step in the functional medicine approach to metabolic syndrome. • 150 minutes of physical activity per week should be recommended to patients with diabetes, this should include cardio and resistance training. • Stress management is a key component of addressing metabolic syndrome, especially in patients with diabetes.

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Melody L. Hartzler

Clinical Pharmacist, Western Medicine Family Physicians CEO, PharmToTable, LLC Associate Professor of Pharmacy Practice, Cedarville University School of Pharmacy

[email protected]

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SUPPLEMENTAL SLIDES

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Low Salivary Cortisol

Low/Flattened Daytime Cortisol Low CAR (only)

Reprinted with permission: Guilliams, T. The Role of Stress and the HPA Axis in Chronic Disease Management. The Standard Road Map Series. Pointe Institute 2018. p.75

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Evening Rise in Salivary Corsol

• All samples within reference range except evening cortisol: (usually flatter overall curve and with less

dynamic CAR) Reprinted with permission: Guilliams, T. The Role of Stress and the HPA • Insomnia (short sleep Axis in Chronic Disease Management. The Standard length night before Road Map Series. Pointe test) Institute 2018. p.72 • Inflammation

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High Salivary CAR (or first morning sample)

High Cortisol Awakening response will usually affect the first morning sample if it is taken between 30-60 minutes after awakening. May not alter rest of the samples throughout the day.

Reprinted with permission: CAR is highly influenced by anticipated Guilliams, T. The Role of Stress and the HPA stress (perceived), and is significantly Axis in Chronic Disease lower on weekends even in patients with Management. The Standard Road Map Series. Pointe stressful jobs. Institute 2018. p.69

Test on Monday, Not Sunday!

Perceived work overload and chronic worrying predict weekend-weekday Psychosom Med. 2004 Mar-Apr;66(2):207-14. differences in the cortisol awakening response. 105

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