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Triad 1 and Triad 2 Stacking James LaValle, R.Ph., CCN

The following potential conflict of interest relationships are germane to my presentation.

Equipment: NoneSpeakers Bureau: NoneStock Shareholder: None

Grant/Research Support: NoneConsultant: None

Employment: Integrative Health Resources

Status of FDA devices used for the material being presented: NA/Non‐Clinical

Status of off‐label use of devices, drugs or other materials that constitute the subject of this presentation: NA/Non‐Clinical

Triad 1 and Triad 2 Stacking

Complex Progression in Autoimmunity Induced by

TRIAD 1 and Triad 2 RelationshipsJames B. LaValle

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Copyright © 2012 James B. LaValle, Integrative Health Resources, LLC. All rights reserved. No part of this material may be used or reproduced in any manner whatsoever, stored in a retrieval system, or transmitted in any form, or by any means, electronic, mechanical, photocopying, recording or

otherwise, without prior permission of the author.

This material is provided for educational and informational purposes only to licensed health care professionals. This information is obtained from

sources believed to be reliable, but its accuracy cannot be guaranteed. Herbs and other natural substances are very powerful and can occasionally cause

dangerous allergic reactions in a small percentage of the population. Licensed health care professionals should rely on sound professional

judgment when recommending herbs and natural medicines to specific individuals. Individual use of herbs and natural medicines should be supervised by an appropriate health care professional. The use of any

specific product should always be in accordance with the manufacturer's directions.

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THE INTESTINAL MICROBIOMECOMPOSITION LIES SQUARELY

IN THE INTERSECTION OF DEVELOPING ALLERGIC AND AUTOIMMUNE DISEASES

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GIMicroflora

Factors Affecting our GI Microflora

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How Does Our GI Microflora Affect Us?

ANTICARCINO-

GENIC

IMMUNERESPONSE

VITAMINS &MINERAL

ABSORPTION

DIGESTION&

GUT HEALTH

CHOLEST.ASSIM.

RECOVERYFROM

DIARRHEA

GIMICROFLORA

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Causes of Leaky Gut (dysbiosis)

Destruction of beneficial flora

‐Antibiotics, Xenobiotics, Infections

Inflammation of the Mucosal Barrier

‐NSAIDS, PPI’s esomeprazole, excess EtOH, Meds, Toxins, Stress, Gluten

‐Yeast promoting promoting – Yeast is #1 pathogen in the bowel

– Sugar, processed food, lack of fiber in the diet, excessive carbohydrate

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Chemicals influencing epithelial permeability

• Histmamine

• Leukotrienes

• TNFα

• Inerleukin 4

• Serotonin

• Mast cell proteases

• Platelet activating factor

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Antigen‐Antibody Complexes >Enter vascular circulation >Attach to brain, thyroid, joints, lungs, etc.

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Allergies

• Allergy is an over reaction of the immune system to NON-harmful antigens

• Children with allergies have different bowel flora than kids that don’t.

• Kids with allergies tend to have – higher prevalence of C. difficile and S. aureus

– less Bifidobacteria and Bacteroides

• Breastfeeding increases Bifidobacteria as it contains growth factor for Bifido

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Chain of Events to Trigger Food Allergy• Toxins and allergic material into gut

• Mast cell stimulation

• Histamine response

• Swelling of gut lining/decreased digestion

• Incompetent lining

• Absorption of large molecule/circulation

• Trigger antibody response

• Food allergy

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One Pathway to Acidosis of Connective Tissue

• Mast cell aggravation

• Histamine production and levels increase

• Increased HCI production in stomach

• Depletion of bicarbonate buffer of blood/ connective tissue

• Increased connective tissue acidosis

• Tissue acidification is beginning of many chronic diseases and pathologies

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Acidosis

• Bone demineralization

• Supports anaerobic metabolism

• Reduces energy and increases free radical burden to Krebs cycle

• Best Tests: low intracellular K, Mg, Zn

• Urine ketones

Celiac - Definition

• Celiac disease is a chronic inflammatory erosion of GI villi secondary to gluten allergy

• Wheat, rye, and barley contain gluten

• Gluten is a plant “protein” molecule

• Gluten is a combination of gliadin & glutenin

• Gluten is difficult to digest so = inflammatory

• Genetically modified wheat - 50% more gluten

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Gluten Sensitivity

• Gliadin (a gluten protein) has direct effects on small intestines– Increases permeability of endothelial cells, allowing

food proteins to enter– Proline content of grains in general, forms

prolamines, irritating to gut wall, hard to digest– Blocks protease enzymes so protein unable to be

digested– Binds chemoattractant receptor which causes an

increase in a factor that destroys tight junctions15

Celiac Disease

• Villous atrophy of the small bowel leads to inability to absorb nutrients - wasting

• Genetic predisposition of U.S. population– 30% HLA-DQ2 – are at risk for celiac

– 12% HLA-DQ8

– 57% Less destructive variants (Glut. Sens.)

– <1% HLA-DQ4/4

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Why us? Why now?

• Genetically modified wheat– 50% more gluten than 10 years ago

• Eating more wheat/gluten as it is stuffed into many processed foods

• Immunologic challenges (stimulation) from air-water-food-vaccines-toxins-SUGAR

• Abuse of antacids, famotadine, omeprazole, esomeprazole, etc: can’t breakdown food

• Stress is high, weakens the immune system17

Historical Blunder

• Gluten sensitivity and allergy is an immune process producing Antibodies (in the stool)– IgA, endomysial, transglutaminase– Blood tests for these antibody’s horrible insensitive

• Blood tests are not reliably positive until disease is full blown and causing significant problems

• Need to look at stool tests and recommend wheat avoidance. – DASH diet recommends 8 grains per day (4 veggies)

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Blood Tests for Celiacs Dz

• Intestinal villi erosion:

• Blood tests are not sensitive enough, the disease goes undetected until there is significant damage:– Early partial villous atrophy = 30% detection

– Significant erosion and loss of height = 70%

– Complete erosion, total loss of villi = 100%

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Celiac - General Population

• 11% of symptom free population has + gliadinantibodies in the blood– Of these, 45% had measurable intestinal

dysfunction, leaky gut, poor absorption

– 0% had villous atrophy on biopsy, but some showed inflammatory changes

• 30% of this same population had + stool antibodies

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Prior Diagnosis

• + gliadin Ab’s were found in the following:– Chronic diarrhea = 50%

– IBS (Irritable Bowel Syndr.) = 57%

– Crohns or Ulcerative Colitis = 60%

– Autoimmune disease of any kind = 77%

But only 11% of this group had +blood test21

Gluten Sensitivity vs Celiac Disease

• Celiac Disease(CD): Autoimmune enteropathytriggered by intake of gluten

• Gluten Sensitivity: have gluten intolerance and may have similar symptoms as (CD).

• Clinical picture less severe and typically will not have transglutaminase antibodies

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Differences

Celiac Disease

• intestinal permeability

Gluten Sensitivity

• Not associated with Intestinal permeability

• permeability

• Claudin expression

• TLR2

• T Reg cells

• No changes in IL‐6, IL21

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SJOGREN’S SYNDROME AND THE GUT

Gut and Autoimmunity

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Sjogren’s Syndrome

•A chronic autoimmune disorder in which white blood ells attack moisture producing glands in the body. 9 out of 10 patients are women and symptoms usually occur after the age of 40 but can occur to either sex at any age.

• Hallmark symptoms are dry eyes and dry mouth, but other symptoms can include enlarged salivary glands, vaginal dryness, fatigue, fever, joint pain and swelling and dry skin/rashes.

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Symptoms

• Common: dry eyes, dry mouth, burning tongue, cracking tongue, increased dental caries, trouble swallowing, vaginal dryness, chronic dry cough, joint pain, muscle pain, low grade fevers, fatigue, enlarged saliva glands, oral candidiasis

• Less common:Inflammation in lungs, can

cause bronchitis or pneumonia

Inflammation in kidneys and liver leading to decreased kidney function, and hepatitis or cirrhosis

Peripheral neuropathiesVasculitis (inflammation of

the blood vessels)Pancreatitis

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Incidence and co‐morbidities

•2nd most common autoimmune disease affecting at least 4,000,000 Americans

• 50% occur as primary diagnoses

• 50% occur secondarily with other autoimmune disease such as rheumatoid arthritis, Lupus (SLE), Scleroderma, and Polymositis

• 30 ‐ 50% of rheumatoid arthritis patients, 30% of Lupus pts, 4‐5% of scleroderma pts have SS

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Diagnostic Criteria

•Dry mouth• Poor salivary gland production• Dry eyes• Often antinuclear antibodies are present (80% test positive)• Positive rheumatoid factor, with or without rheumatoid symptoms• Often enlarged parotid salivary glands, usually in primary SS (75‐95%).

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Diagnostic Tests

1. Schirmer’s test - measures tear production2. Rose-Bengal staining - determines inflammation

of the cornea3. Salivary gland flow rate - measures saliva

production with a special X-ray called sialogram4. Salivary gland or lip biopsy measure

inflammation of tissue and infiltration of white blood cells

5. Urine tests and blood tests to rule out any kidney and liver involvement

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Other Labs•Elevated sedimentation rates (indicate inflammation)• Mild anemia• Low albumin• Mild leukopenia with elevated eosinophils

• Autoimmune antigens HLA‐B8 and HLA‐DW3 are often present

• SS‐A and SS‐B antibodies • Increases in all classes of immunoglobulins.

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Other conditions commonly associated with Sjogren’s:

• Autoimmune Thyroiditis (Hashimoto’s)

• Gastroesophageal reflux disease (GERD)

•Raynaud’s Disease ‐ occurs in 20% of SS patients

•Gastrointestinal ‐ abdominal pain, nausea, diarrhea

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Prostaglandins

• Lack of PGE 1 is key factor in Sjogren’s

• PGE 1 needed for:

• Lacrimal and salivary gland secretion

• Animal studies show severe atrophy of these gland in linoleic acid deficiency

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Conventional Medical TreatmentConventional Medical Treatment• Salivary aids ‐ artificial saliva preparations

• Saliva stimulant drugs ‐ pilocarpine and cevimeline

• Eye drops ‐ artificial tears, eye lubricant ointments

• Cyclyosporin eye drop

• Hydroxychloroquine ‐ an antimalarial drug which is also used in autoimmune diseases. The mechanism of action for autoimmunity is not known.

• If complications are severe, immunosuppressive drugs may be used.

• Palliative treatment ‐ drinking lots of fluids, using humidifiers, sucking on lemon drops or glycerin swabs, avoiding use of fans and hairdryers, etc.

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Functional Medical Evaluation

• Systems evaluation ‐ symptoms questionnaire

• Toxicity evaluation

• Gastrointestinal evaluation

• Nervous system evaluation

• Hormonal evaluation

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Immune System Review

• Cellular Immunity ‐lymphycytes (small WBC), B cells, T cells and killer cells

• Large WBC = myeloid cells= eosinophils and basophils and phagocytes (monocytes and macrophages).

• Macrophages activate T cells.

• Neutrophils ‐ a type of phagocyte called granulocytes

• T cells ‐ help to coordinate the overall immune response, help the body remember non‐self antigens. Release cytokines.

• T cell receptors need major histocompatibility complexes (MHC) to recognize antigens

• CD4 T cells = helper cells ‐promote immune response

• CD8 T cells = suppressor cells ‐ suppress immune response

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TH2 side secretesfactors whichstimulate theproduction ofB‐Cells

An overproduction ofTH2 factorsleads to autoimmuneand allergic conditions

TH1 side secretes factors which stimulate action of CytotoxicT‐cells and NK cells

Natural Killer Cellsdestroy virally infected cells

Cytotoxic T‐cellsidentify andkill infectedhost cells

B‐cells/antibodieskill bacteriaoutside healthycells

TH 1Helper Cell

TH 2Helper Cell

Secrete Secrete

NKCellsInnate

Immunity

CytotoxicT‐Cells

SuppressorCells

B‐CellsAntibodies

IL 2 INF‐� IL 4

IL 10IL 6

TNF

IgE

IgM

IgG

IgA

IgD

Cross Regulate andMaintain balance

THELPERCELLS

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Arbitrary units

Age in years

0 0120 12060 60

NK activity

T ‐cells

B‐cells

IL‐1/6TNFa

IL2

Age in years

AGE‐RELATED TRENDSIN THE IMMUNE SYSTEM

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Toxicity

StressIntestines

Environmental Toxicity

Heavy Metals and Organic Chemicals

• Provoked urine• Packed red blood cell• Fecal metal

• Hair analysis• Electrodermal screening (EDS)

Detoxification Evaluation • Glutathione

• Organic acid urine

• Clearance challenge tests

• Amino acid profiles

Infectious Organisms

– Polymerase Chain Evaluation

– Fecal analysis

– EDS

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Toxicity

Intestines Implicated in autoimmune diseases

Also may explain many of the GI related symptoms of Sjogren’s

Intestinal Integrity

Leaky gut/Dysbiosis are key elements

•Lactulose/Mannitol test

•Food sensitivity and allergy testing

• Hydrogen Breath Test

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Intestinal Integrity and Autoimmunity

• Intestinal permeability seems to precede disease

• Regulation of permeability depends on “tight junctions” which are filled with several protein strands

• Commensal flora positively influence tight junctions

• Cytokines, especially TNF affect mucosal barrier in IBD

• Loss of mucosal barriers is necessary for autoimmunity to develop

• Antigens, ie gliaden, stimulate opening of tight junctions, cytokine production, white blood cell infiltration, and continued increased intestinal permeability

*Fasano A, Shea‐Donohue. Mechanisms of Disease:the role of intestinal barrier function in the pathogenesis of gastrointestinal autoimmune diseases . www.nature.com/clinicalpractice;gasthep, Sept. 20005 2:9.

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Stress

Adrenal

Pancreas

Evaluation:

• Serum cortisol/DHEA

• Salivary neurotransmitter panels

• Urinary neurotransmitter panels

• Blood Test

CRP, Fibrinogen, Uric Acid, Insulin,

ANA, TNF, IL‐6,

•Immune panel (Immunoscience)

Stress and Inflammation

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Primary Nutritional Support in Sjogren’s

• Sterols/Sterolins

• Phosphorylated serine

• Probiotics

• L‐Glutamine

• IgG Powder

• Cat’s Claw

• DGL licorice

• IgG immune globulin

• MMP modulators 42

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Additional Support in Sjogren’s

• Assess Heavy metals ‐ use of appropriate detoxification support

• Determine food allergies and sensitivities

• Assess and implement nutrition strategies for neuro‐endocrine‐immune homeostasis

• Address lifestyle factors ‐ diet, exercise, smoking

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PERVASIVE INFLAMMATION

Gut‐Diabetes Connection

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Intestinal Microbiome and Diabetes

3 Critical Factors that are now recognized

• Aberrant Intestinal Flora

• “leaky”mucosal barrier

• Altered immune responsiveness

• Vaarala,, O., Atkinson, M, Neu,J The “Perfect Storm for Type 1 Diabetes; Diabetes 2008 October 57(10): 255‐2562

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Type 1 Diabetes

• Successful management of diabetes requires insulin management, diet, exercise

– Genetics

–T1D risk stratified 100 fold on basis of HLA DR‐DQ genotype

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Diabetes mellitus

• Islet autoantibodies– High affinity IgG1 class– Over 90% of children w/ T1D have islet autoantibodies– Rarely appear before age 6 months, peaking around 1‐2 yrs

– Antibodies to insulin/proinsulin antigens usually 1st to appear

– Strong association w/HLA‐DR4‐DQ8 w/ pre‐TD1 children

– Immune response thought to occur in Beta cells, particularly ZnT8 cell specific antigen

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Immunoperoxidase stainings for HLA‐DR (A and B) and HLA‐DP (C and D) in jejunal biopsy specimens from a healthy control (Aand C) and from a type 1 diabetic patient with normal jejunal mucosa (B and D). Intensive, positive HLA‐DR staining is seen throughout the epithelial cells of the villi and also in many crypt cells in the type 2 diabetic specimen (B), whereas the control specimen shows only faint HLA‐DR staining in the apical parts of the epithelial cells at the tip of the villi (A). The biopsy specimen from a control patient treated with HLA‐DP antibody shows scattered positive granules in the apical parts of the epithelial cells at the tip of the villi (C), whereas strong positive staining is seen throughout the villous epithelial cells in the specimen from a type 1 diabetic patient (D). No positive staining is seen with either HLA‐DR or HLA‐DP in crypt cells in the control specimen (A and C). AEC‐hematoxylin stain, original magnification ×50. (Please see http://dx.doi.org/10.2337/db08‐0331 for a high‐quality digital representation of this figure.)

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Type 1 DiabetesAltered Microbiota

Altered Mucosal Barrier

Diabetes 2008 October 57(10): 255‐2562

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Microflora

• Infant microbiota important in:

• Growth• Angiogenesis• Nutritional optimization• Help metabolize indigestible compounds, i.e. resistant starches, into energy

• Stimulation of innate and adaptive immunity

Stappenbeck TS, et al. Proc Natl Acad Sci, USA. 2002;99(24):15451‐5.

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Intestinal Microbiota and T1D

• Important interplay between intestinal microbial environment and intestinal mucosal immunity

• Significant role in autoimmune and metabolic conditions including T1D

• Fermentation of complex carbs by microfloraform energy and involved in pathogenesis of T1D

• i.e. butyrate involved in tight junction formation

Roy CC, et al. Njutr Clin Pract. 2006;21(4):351‐66.51

Intestinal Alterations Observed

• Increased absorption of lactulose and mannitol

• Increased ingested lactulose/mannitol in people with β cell autoimmunity

• Serum zonulin elevation

• Enhanced expression: HLA‐DR/DP, ICAM‐1, integrin, IL4, IL‐1α, IFN‐γ IN in the small intestine

• Increased CD3 and CD 25 w/enhanced ICAM‐1 & HLA‐DR expression sm. Intestine biopsy with gliadin

• Increased expression of matrix metalloproteinases52

Targets

• Maintain Flora

• Tightening of the interepithelial junctions

• Retard propagation of inflammatory and autoimmune signaling pathways via nutritional and pharmacologic means

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Food

• Milk and Wheat Gliadin both associated with Type 1 diabetes

• Altered wheat Gliadin expressed HLA‐DR and ICAM‐1.

• Vaarala, O., Klemmetti P, et al. Cellular immune response to cow’s milk beta lactaglobulin in patients with newly diagnosed IDDM Diabetes 1996 Feb;45(2):178

• Klemetti, P, Savilahti E, et.al. T‐cell reactivity to wheat gluten in patients with insulin‐dependent diabetes mellitus, Scand J Immunol 1998 Jan;47(1)48‐53

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Intestinal Microbiota and T1D

• Vitamin D important in mucosal integrity and gut permeability

• Microbial imbalances may disable Vitamin D receptor gene expression

• Zipitis CS, et al. Arch Dis Child. 2008;93(6):512‐7.

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Routine Management of T1DHbA1c

– ADA* • 2‐4 times a year

– NICE** • 2‐6 times a year

Growth (height/weight)‐ ADA

‐ 4 times a year‐ NICE

‐ Every visit

Blood Pressure‐ ADA

– Every physical exam‐ NICE

‐ Every year after age 12

* American Diabetes Association** National Institute for Health and Clinical Excellence 56

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Biochemical Parameters

• Acetaldehyde hypothesis–fungal metabolism pyruvate produced from sugar by glycolysis

–presence of oxygen prevents formation of acetaldehyde

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Acetaldehyde Effects on Chemistry• Reduces microtubules in the liver

• Decreases protein secretion, increases retention in the liver

• Engorgement of Golgi apparatus with VLDL

• Accumulation of lipids and proteins, increases hepatocyte size

• Depresses glutathione in Liver Phase II

• Stimulates hepatic smooth endoplasmic reticulum, increases rate of conversion to secondary toxic metabolites

• Increases collagen deposition in the liver

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Pathways of Formation• Lack of oxygen decarboxylates pyruvate to acetaldehyde and ethanol

• Ethanol conversion by yeast in presence of oxygen and then conversion to acetaldehyde

• Acetaldehyde metabolized in liver and only creates toxicity when high excess formation occurs

• Increases NADH/NAD ratio

• This negatively influences production of ATP60

NADH/NAD Elevated Ratios

• Increases ratio of lactate/pyruvate

• Increases ratio of hydroxysteroids/ ketosteroids

• Decreases galactose tolerance (conversion of galactose to glucose)

• Alters amine metabolism (ie serotonin metabolism)

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NADH/NAD Elevated Ratios• Citric acid cycle changes; inhibition of fatty acid oxidation

– inhibits gluconeogenesis

– amino acids enter for conversion to glycogen, leading to decrease in pyruvate formation, thus increasing deficit of citric acid intermediate oxaloacetate, thereby changing malate/oxaloacetate ratio

• Inhibits glycolysis and ATP production62

NADH/NAD Elevated Ratios

• Elevates blood uric acid levels secondary to increased lactate levels caused by NADH excess; lactate and uric acid compete in tubule for excretion

• Abnormalities in prophyrin metabolism, pooling of coporphyrin

• Inhibits phosphorylation

• Decreases protein synthesis

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Dysbiosis

Poor Diet Antibiotics Glandular Insufficiency Others

Fungal Overgrowth

General Disturbances

• Absorption Problems

• Bowel Disorders

• Auto‐intoxication

• Digestive Disturbances

– Heartburn/Gas

• Nutrients

– Vitamins B12 and E

– Magnesium

– Copper

– Zinc and Selenium

Allergic Manifestations

• Crohn’s

• Neurodermatitis

• Migraine

• General Unwellness

• Flushing

• Dizziness

• Neuraesthenic

• Toxic

– Fermentation � Alcohol

– Liver burden 64

Key Points onDysbiotic Evolution

• History of tetracycline (or other antibiotics) for 2 months or longer for acne

• History of broad spectrum antibiotics for respiratory, urinary or other infections for a period of 2 months or longer

• Regular exposure to pesticides

• History of prednisone‐type drugs

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Key Points onDysbiotic Evolution

• Exposure to perfumes, insecticides, fabric odors, and other chemicals causes a reaction

• Damp, muggy days provoke a response

• Persistent athlete’s foot, “jock itch” or infections of the skin and nails

• Cravings for sugar, bread, and alcohol

• Smoke bothers the individual

• History of allergies, asthma, or sinusitis66

DysbiosisA Short List of Primary Symptoms

• Confusion

• Brain fog

• Poor concentration

• Depression

• Aggressive behavior

• Vertigo/dizziness

• Poor learning

• ADD/autism

• Dry mouth, especially during sleep

• Dry eyes

• Blurred vision

• Tinnitus

• Periodontal disease

• Caries

• Sinusitis/allergies

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DysbiosisA Short List of Primary Symptoms

• Respiratory disturbances

• Cardiac arrhythmias/palpitations

• Belching/bloating

• Constipation/diarrhea/colitis/irritable bowel

• Cystitis/urethritis/pruritis

• Eczema

• Menopausal/PMS

• CFS68

Genetics Miasm Birth Trauma

Inadequate Nutrition Nutrient Sparse Toxic

SkewedPoorly

Digested

Toxic Exposure Exotoxin •Air •H20 • Food Dental Fillings Electromagnetic Smoking Medication

Poor EliminationLow Fiber Pulmonary Vent Exercise Poor Water

Accumulated Toxicity (r) + Imbalanced pH

Inactivation of Cellular Function

(Decreased Oxidation)/(Decreased Oxygenation)

�Cancer �Tissue Damage �Endogenic Infection

Tissue Peroxidation

Irreversible Damage

In face of inadequate antioxidant

protective system

< ‐ 371945 ‐ 23Now ‐ 9

ATM PO2

Routine Management of T1DLipid Profile

ADA*

• Adults: at diagnosis then every 1‐2 yr

• Child (low risk): age > 10 yr; then every 1‐5yr

• Child (high risk): after age 2y, then every 1‐5yr

NICE**

• Adult: every year

• Child: not recommended

Foot Examination

‐ ADA *

‐ Every year

‐ ‐ NICE**

‐ Every year

‐ AACE***

‐ Every year

* American Diabetes Association

** National Institute for Health and Clinical Excellence

***American Association of Clinical Endocrinologists 69

Routine Management of T1DNephropathy

– ADA*

• Albumin/Creatinine Ratio

– Every year once diabetes duration > 5yr and age > 10yr

• Serum creatinine

– Every year (adults only)

– NICE**

• Albumin/Creaqtinine Ratio

– Every year after age 12

• Serum creatinine

– Every year from age 12

– AACE***

• Albumin/Creatinine Ratio

– Every year after 5 yr duration

• Serum Creatinine

– Every year after 5 yr duration



***American Association of Clinical Endocrinologists70

Routine Management of T1DRetinopathy

– ADA*

• Adults: W/in 5 yr of diagnosis, then every yr

• Children: 10yr of age and 3‐5 yr duration, then every year

– NICE**

• Every year from age 12

– AACE***

• Every year after 5 yr duration

Dental Examination

‐ NICE**

‐ Every 2 years



***American Association of Clinical Endocrinologists 71

Routine Management of T1DNeuropathy

– ADA*

• Distal symmetric polyneuropathy: Every year

• Autonomic Neuropathy: After 5 yr duration

– NICE**

• Adults: Every year

• Children: Not indicated

– AACE***

• Every year after 5 yr duration



***American Association of Clinical Endocrinologists72

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Routine Management of T1DThyroid Disease

– ADA*

• TSH; TPO and TG Abs – After metabolic control achieved, then every 1‐2yr; antibodies at diagnosis

– NICE**

• TSH – at diagnosis, then every year

Celiac Disease

‐ ADA*‐ TTG or EMA, IgG and serum IgA – After diagnosis, then periodically

‐ NICE**‐ EMA, IgA and serum IgA – at diagnosis, then every 3 years


** National Institute for Health and Clinical Excellence73

THYROID & ASSOCIATED TRIAD 2 SHIFTS

Thyroid‐Gut‐Immune Brain Connection

(Triad 1 stacking 2)

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Thyroid Antibody Formation and the GUT

• Thyroid imbalances and antibody formation are intimately connected to the GUT and the enteric nervous system

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Thyroid Antibody Formationand the GUT

• Gastrointestinal manifestations of thyroid disease generally due to:

– Reduced motility in hypothyroidism

– Increased motility in hyperthyroidism,

– Autoimmune gastritis, or esophageal compression by a thyroid process

– Symptoms usually resolve with treatment of the thyroid disease.

» Ebert EC. J Clin Gastroenterol. 2010; 76

Thyroid and the Gut

• Celiac cases have 10 times the rate of autoimmune thyroiditis

• Approximately 26%

• Mycotoxins and Molecular mimicry

• Mycotoxins as destructive forces

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Thyroid Antibody Formation and the GUT – Celiac Disease

• Celiac disease associated with thyroid imbalances• Autoimmune thyroid diseases (AITDs) are most evident.

• Development of AITDs in CD is modulated by:– Genetics – Gluten intake – Selenium deficiency– Environmental factors (i.e. heavy metals, POPs, BPA)

• Leads to overexpression of inflammatory cytokines

– Stazi AV, et al. Ann 1st Super Sanita. 2010;46(4):389‐99. 78

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– Selenoproteins significant in biosyntheis and activity of thyroid hormones.

– Selenoproteins serve as glutathione peroxidases and involved in apoptosis inhibition.

– Selenium malabsorption in CD key factor directly leading to thyroid imbalances and intestinal damage

– Stazi AV, et al. Ann 1st Super Sanita. 2010;46(4):389‐99.

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– Zinc levels important in thyroid hormone balance

– Zinc levels also altered in enteric nervous system imbalances, GI disorders (especially IBD)

– Alkhouri RH, et al. J Pediatr Gastroenterol Nutr.

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Supplements for Thyroid/GUT • Supplements for autoimmunity and GUT imbalances include:

– Probiotic supplement, 1‐15billion CFU 1‐3 times daily; heat stable

– L‐tyrosine is a precursor to neurotransmitter and thyroid hormone production. Thyroid hormone levels may respond to N‐acetyl‐L‐tyrosine, 250‐500mg daily.

• Thomopoulos P. Rev Prat. 1998;48(18):1987‐91.

– Multiple vitamin, 4‐6 capsules daily

– Zinc carnosine, 1‐2 capsules 14 times daily; helps increase

Mahmood A, et al. Gut. 2007;56:168‐175.

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Thyroid Stimulating Hormone Receptor

• TSH‐R G protein receptor anchored on the epithelial cells

• TSH binds to site for production of T4

• TSH‐R is the major target of antigen specific T cells

• Antigen specific T cells and autoantigens:

‐ stimulate leading to hyperthyroid state

‐ block leading to hypothyroid state 82

Importance of TSHR

• Deficient expression or blocking of the receptor leads to

‐ reduction in sodium‐iodine symporter(NIS) activity

‐ Reduction in follicles and gland size

‐ Crucial in neonatal development of function and active thyroid tissue

‐ TSHR function in adipocytes and bone cell modulation

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TSHR • Cysteine rich clusters are necessary for trafficking and confirmation (folding) of receptor

• Leucine is needed in the ectodomain for the binding of TSH

• High affinity TSH binding needs a rich Cysteine environment for disulfide binding

• TSH is highly dependent on Sulfation for receptor activation

• Palmiytolation is critical for cysteine activation, also in lipid disposition

84

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L CARNITINE 2‐4 GRAMS A DAY REGULATES T3 AND T4 ENTRY INTO THE CELL HELPING TO MODULATE HYPERTHYROID STATE .

Clinical Pearl

85

What disrupts the Thyroid Receptor

• Interference with Transport‐Production and metabolism

• Most Significant: Endocrine Disruptors in 3 ways 1. Mimicry of natural hormones with higher binding

affinity creating stronger or extended signaling or alters timing of signals

2. Bind to the receptor and prevent homoeostatic hormone binding and signaling

3. Inhibition or stimulation of the endocrine receptor then increased or decreased hormone production

86

Top Disruptors of the Thyroid• Humans

• PCB’s

• BPA

• Perchlorate

• Dioxin

• Pentachlorphenol

• Tricolsan

• PBDE (flame retardant)

• Animal

• Phthalates

• DEHP

• DnOP

• DIDP

• DBP

• Resorcinol

Patrick L. Thyroid disruption: mechanism and clinical implications in human health. Altern Med Rev. 2009 Dec;14(4):326‐46. Review. Erratum in: Altern Med Rev. 2010 Apr;15(1):58.Zoeller RT. Environmental chemicals targeting thyroid. Hormones (Athens). 2010 Jan‐Mar;9(1):28‐40. 87

Halogens and Thyroid System Damage

Fluoride in as little as 1 ppm

• Iodinase enzyme damage

• G protein stimulation (affects thyroid hormone uptake into the cell)

• TSH release in inhibited (pituitary)

• Competition for TSHR binding with TSH reducing production

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Thyroid – Stress ‐ Brain• Type 2 iodothyronine deiodinase (D2) helps control

thyroid signaling• D2 plays central role in T3 content in developing

brain tissue• D2‐catalyzed T3 production increases thyroid

hormone signaling• Blocking D2 activity or disrupting D2 gene leads to

localized hypothyroidism• D2 critical in T4‐mediated negative feedback of

pituitary and hypothalamus• Important in promoting thermogenesis in brown

adipose tissue– Drigo RA, et al. Biochim Biophys Acta. 2012;[Epub ahead of print].

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Thyroid – Stress ‐ Brain

• Animal studies report high fat diet reported toimbalance D2 signaling

• Leads to hyperactivation of HPA axis• Araujo RL, Endocrinology. 2010;151(7):3460‐9.

• Flaxseed administration reported to helpbalance D1 and D2 activity

• Figuerido MS, et al. Horm Metab Res. 2011;43(6):410‐6.

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Stress and Thyroid Antibodies

• Reduced glucocorticoid activity is associated with an increased prevalence of ThAbspositivity in older ambulatory subjects.

• Terzidis K, et al. Eur J Endocrinol. 2010;162(2):307‐13.

• HPA axis (neuro‐endocrine) imbalances caused by stress‐mediated activation involved in autoimmune thyroid diseases (AITD)

• Klecha AJ, et al. Neuroimmunomodulation. 2008;15(1):68‐75.

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Stress and Thyroid Autoantibodies

• Increased oxidative stress common in obesity

• Oxidative stress key regulator of TSH levels in pre‐pubertal patients

• In obese children oxidative stress markers reported increased significantly in relation to TSH, independently of BMI‐SDS, age and gender.

» D’Adamo E, et al. Free Radic Res. 2012;46(3):303‐9.

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Stress and Thyroid Antibodies

• Reduced glucocorticoid activity is associated with an increased prevalence of ThAbspositivity in older ambulatory subjects.

• Terzidis K, et al. Eur J Endocrinol. 2010;162(2):307‐13.

• HPA axis (neuro‐endocrine) imbalances caused by stress‐mediated activation involved in autoimmune thyroid diseases (AITD)

• Klecha AJ, et al. Neuroimmunomodulation. 2008;15(1):68‐75.

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Thyroid and Brain Development • ↓In thyroid hormone leads to deficiencies in cell migra on in

neocortex, less layering cortical mass, and altered distribution of callosal connections

• Controls differentiation of microglia, dendricytes and astrocytes

• Astrocytes signal uptake of T4 and conversion and delivery of T3 in neurons

• Receptor defects could be significant in behavior TRα1 deficiency can’t forget negative memories, is involved at hippocampus

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TSH and bone

• TSH has a positive influence on bone remodeling • Inhibits osteoclast • Activates osteoblasts

• Animal models in osteopenia have demonstrated ‐ enhanced trabecular and cortical bone

formation

Abe E, Marians RC, Yu W, et al. Bone loss in thyroid disease: the role of low TSH and High thyroid hormone. Ann N Y Acad Sci 2007;1116:338‐91Bassett JH Williams AJ, MurphyE, et al. A lack of thyoid hormones rather than excess thyrotropin casues abnormal skeletal development in hypothyroidismMol Endocrinol 2008;22:501‐12

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Vectors and Autoimmune Thyroiditis

• Yersinia enterocolitica (TSH receptor binding sites on its surface)

• Epstein‐Barr Virus‐ causes mononucleosis or “mono.”• Lyme disease spirochete (Borrelia burgdorferi)‐and co

infections (Baesia, erlichia, baronella, mycoplasm)• Rickettsia‐ bacteria transmitted by biting insects.• Hepatitis C – virus that resides in the liver.• Herpes virus – incurable virus found in the nervous system.• Parvovirus B19 – virus that causes “fifths disease” in

children and can affect adults.• Influenza B – The classic “flu” virus.• Rubella – virus that causes German measles.

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VAGAL TONICITY INFLUENCES ON APPETITE AND GUT HORMONE SIGNALING

Adrenal‐Gut Triad 1 stacking 2

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Gut Hormones in Obesity

• Gut uses an array of humoral factors and vagus nerve stimulation to signal digestion and appetite control

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Gut Hormones in Obesity

• Pancreatic polypeptide‐fold peptides (PP‐fold)

• Comprised of CNS peptide, neuropeptide Y (NPY), pancreatic polypeptide (PP) and peptide tyrosine‐tyrosine (PYY)

• Important in appetite regulation with distinct roles

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Gut Hormones in Obesity‐ PYY

• Peptide tyrosine‐tyrosine (PYY)

• PYY co‐released from L cells in GIT w/ glucagon‐like peptide (GLP)‐1 and oxyntomodulin (OXM)

• PYY immunoreactivity highest in rectum

• PYY also distributed in adrenal medulla

• 2 endogenous circulating forms of PYY synthesized in GUT, PYY1‐36 and PYY3‐36

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Gut Hormones in Obesity ‐ PYY

• PYY secretion important in satiety

• PYY released in circulation in response and proportion to caloric intake

• Humoral factors thought to exist that signal distal portion of GUT to release PYY in response to nutrients in proximal portion

• These include gastrin and cholecystokinin

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Gut Hormones in Obesity ‐ PYY

• Anorectic conditions characterized by increased circulating PYY3‐36

• Gastric bypass associated with elevated basal and postprandial PYY3‐36

• Peripheral administration of PYY3‐36 reported to inhibit food intake in fasted animals

• Tschop M, et al. Nature. 2004;430:1‐3.

• Acts on hypothalamus as satiety signal and delays gastric emptying

• Disturbances in PYY may play role in obesity102

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Gut Hormones in Obesity –Pancreatic polypeptide (PP)

• Major stimulus of PP is food ingestion

• Remains elevated 6 hours post food ingestion

• Various humoral factors also found to stimulate PP release (CCK, ghrelin, motilin, secretin)

• Somatostatin reported to inhibit PP release

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Gut Hormones in Obesity – PP

• Considered part of “ileal brake”

• PP acts to slow transit of food thru GUT

– Delays gastric emptying

– Attenuates pancreatic exocrine secretion

– Inhibits gallbladder contraction• Kojima S, et al. Peptides. 2007;28:459‐63

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• Reduces postprandial secretion of PP associated with obesity

• Elevated levels of PP associated with anorexia• Lassman V, et al. Diabetes. 1980;29:428‐30.

• PP may play role in Prader‐Willi syndrome (PWS)

• Patients with PWS have reduced basal and postprandial PP release

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• Peripheral injection of PP in animals and humans results in reduced food intake

• PP injection in lean humans resulted in reduced food intake by 25% over 24 hrs

• Batterham RL, et al. J Clin EndocrinolMetab.2004;88:3989‐92.

• Produces anorexia via brainstem and vagusintervention mediated by Y4 receptor

• May also act on hypothalamus and reduced ghrelin release

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Gut Hormones in Obesity – (GLP)‐1

• Glucagon‐like peptide‐1 (GLP)‐1

• Secreted and released by L cells of intestine

• GLP‐17‐36amide is major form in circulation

• T1/2 of GLP‐1 is only 2 minutes in blood

• Thought to be component of “ileal brake”

– Plays role in metabolism of ingested carbs

– Inhibits gastric acid secretion

– Delays gastric emptying107


• Also up‐regulates various stages of insulin production

• Significant weight loss reported in animals administered GLP‐1

• Meeran K, et al. Endocrinology 1999;140:244‐50.

• Dose dependent reduction in caloric intake and appetite reduction in humans reported in lean, obese and diabetic individuals

• Naslund E, et al. Br J Nutr. 2004;91:439‐46.

• However, rapid degradation makes unsuitable for obesity tx

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• Exendin‐4 developed as a long‐acting analog of GLP‐1

• FDA approved exenatide in 2004 as 1st incretin‐mimetic agent

• Used as adjunctive Tx in T2DM• Lowers fasting glycemia, postprandial glycemia dn HbA1c

• Meta‐analysis reports exenatide reduces weight by av. Of 1.44kg compared to placebo and 4.76kg compared to insulin

• Amori RE, et al. J Am Med Assoc. 2007;298;194‐206.109

Gut Hormones in Obesity – GLP‐1

• Exenatide SE’s include increased nausea, vomiting, diarrhea compared to placebo or insulin

• SEs mild to moderate during 1st 8wks of therapy, with decreased effects during dose titration

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• Liraglutide also GLP‐1 analog bound to albumin

• Administered SQ

• Studies report weight loss of 1.2kg and decreased HbA1c after 12 wks of SQ injection QD

• Similar SEs to exenatide

• Used in Tx of T2DM 111


• GLP‐1 half‐life also increased by altering DPP‐IV enzyme

• Oral antagonists include sitagliptin and vildagliptin

• However meta analysis reports increased weight gain and altered lipid profile (decreased HDL) when compared to placebo

• Amori RE, et al. J Am Med Assoc. 2007;298;194‐206.

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Gut Hormones in Obesity – OXM

• Oxyntomodulin (OXM)

• 37 amino peptide that displays glucagon‐like activity in liver

• Has entire sequence of glucagon with addition of octapeptide C‐terminal extension (spacerpeptide‐1)

• Co‐released w/ GLP‐1 and PYY from L cells

• Binds to GLP‐1 receptor 113


• OXM possess incretin activity but stimulates insulin release much less than GLP‐1

• Functions as satiety hormone

• Released in circulation following food ingestion and levels reflect caloric intake

– Inhibitor or pentagastrin‐induced gastric acid secretion

– Delays gastric emptying114

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• OXM levels increased after gastric bypass

• Nutrients diverted away from stomach and proximal sm. intestines to regions of high OXM expression (distal sm. Intestines and colon)

• Reports that OXM plays essential role in wt. loss after gastric bypass

• Holst JJ, et al. Scand J Gastroenterol. 1979;14:205‐7.

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• OXM injection results in appetite suppression and weight loss

• Injection in animals resulted in similar potency of GLP‐1 in re: to food intake

• Dakin CL, et al. Endocrinology. 2004;145:2687‐95.

• May lead to weight reduction by increased energy expenditure

• Reported to decrease release of ghrelin in lab animals

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• OXM in humans reported to improve satiety

• Healthy, fasting volunteers experienced significant reduction in hunger and plasma ghrelin levels compared to placebo

• Also reduced energy intake (19.3%) postinfusion when compared to placebo and remained low 12hr post injection

• Cohen MA, et al. J Clin Endocrinol Metab. 2003;88:3989‐92. 117


• OXM potency comparable to GLP‐1, although receptor binding is 2 orders of magnitude less than GLP‐17‐36amide

• Fehmann HC, et al. Peptides.1994;15:453‐6.

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Gut Hormones in Obesity – Ghrelin

• Growth hormone secretagogues (GHS) include (GH)‐releasing peptide‐6 and hexarelin

• GHS‐receptor (GHR‐R) binds and mediates effects of GH secretagogues

• Ghrelin identified as ligand that binds to GHR‐R• Kojima M, et al. Nature. 1999;51(Suppl 3):1‐8.

• GHR‐R expressed in hypothalamus, GIT, myocardium, pituitary, pancreas, adipose tissue, liver, kidney and placenta

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• Ghrelin principally excreted from X/A‐like cells in gastric oxyntic glands

• Gastrectomy reported to decrease ghrelin content by 80%

• Date Y, et al. Endocrinology. 2000;141:4255‐61.

• Remainder of ghrelin secreted from intestine, pancreas, pituitary and colon

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• Ghrelin – Stimulates appetite

– Only gut hormone that stimulates food intake

– Increases gastric motility

– Up‐regulates hypothalamo‐pituitary‐adrenal axis

– Cardiac effects including vasodilation, increased cardiac contractility

• Ghrelin also acts as neurotransmitter ‐expressed w/in hypothalamus

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• Plasma levels of ghrelin correlate inversely with body weight

• Levels significantly higher in lean individuals vs. obese

• Diet‐induced weight loss increases circulating ghrelin levels

• Increases preprandially and decreases postprandially in lean humans and animals

• Hosoda H, et al. J Pharm Sci. 2006;100:398‐410.

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• Food intake fails to suppress plasma ghrelin levels in obese individuals

• Dysregulation of ghrelin thought to play role in obesity

• Circulating levels of ghrelin decreased in gastric bypass

• 28% increase in energy consumption reported during buffet meal

• May help in cachexiaWren AM, et al. J Clin Endocrinol Metab. 2001;86:5992‐5.

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Gut Hormones in Obesity – CKK• Cholecystokinin (CKK)

• 1st gut hormone implicated in appetite regulation

• Peptide hormone expressed in sm. Intestine

• Released rapidly in response to food intake

• CKK:

– stimulates pancreatic and gallbladder exocrine secretions

– Inhibits gastric emptying

– Increases intestinal motility

• Also expressed as neurotransmitter

– Involved in reward behavior

– Anxiety

– Memory• Little TJ, et al. Obes Rev. 2005;6:297‐306.

• CKK infusion reported to fail to have effect on food intake beyond 24hr• Kissileff HR, et al. Am J Physiol Regul Integr Comp Physiol. 2003;285:R992‐8.

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Summary

• Primary concern is to correct immune shift in the gut causing systemic neuro‐endocrine‐immune shifts

• Rebuild nutrient pools

• Reestablish cross‐talk communication between hormones with appropriate negative feedback loops.

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