METABOLIC SYNDROME X

Stephen Holt MD, LLD (Hon.) ChB., ND, FRCP (C) ,MRCP (UK), FACP, FACG, FACN, FACAM

Distinguished Professor of Medicine, NYCPM,Scientific Advisor, Natural Clinician LLC

The Most Important Anti-Aging Initiative

SUPER-SIZING AMERICA• Americans exude

complacency abouttheir overweightstatus.

• Obesity is part ofMetabolic SyndromeX

• Syndrome X is underdiagnosed and oftenmistreated by bothconventional andalternative medicine.

FACT• OBESE KIDS BECOME UNHAPPY,

UNHEALTHY OBESE ADULTS

THE UNKNOWN EPIDEMIC

REDEFINING SYNDROME X• Classic Definition: Obesity,

Hypercholesterolemia, HighBlood Pressure, Linked byInsulin Resistance.

• Syndrome X, Y and Z….., anexpanded definitionincorporating a novel unifyingconcept of common diseases

THE PUBLIC HEALTH RISK

• Syndrome X increases risk for : Type II Diabetes Mellitus Cardiovascular Disease Cardiovascular Deaths Deaths from ALL CAUSES

Am.J.Epidemiol, 148, 958, 1998.

INTEGRATIVE MEDICINE FORSYNDROME X

“While proper management of theindividual abnormalities of thissyndrome can reduce morbidity andmortality, it seems unlikely thatmanagement of the individualabnormalities of this syndromeprovides better outcomes than amore integrated strategy”CDC, Atlanta, Ga., JAMA 2002

FACTS

• Obese people die young• Obese people develop premature

disability• Obese people are modern, metabolic

dinosaurs• Obese people are generally

mismanaged in clinical practice

BACKGROUND

• Studies imply that the physically activeperson of normal body weight outlives theoverweight, inactive individual.

• Obesity related disease, most notablyMetabolic Syndrome X, presents unifyingconcepts of premature aging.

• Retention of body functions and survivalare clearly associated with partial foodrestrictions, at least in rodents.

LOOKING AT OBESITY AND RELATEDDISEASE FROM NEW SCIENTIFICPERSPECTIVES CREATES NEWTHERAPEUTICS

A LITANY OF NEW PERSPECTIVES: 2007

• Greater understanding of the epidemiology ofobesity.

• The fat cell regulates energy balance andmetabolism.

• Neuro-hormonal control of appetite.• Incretins: GLP-1 and GLP.• Fuel sensing by the CNS.• Obesitis• Insulin Resistance: The core of Syndrome X• Cancer propagation (colon, prostate, pancreas)• Evidence base for positive lifestyle change.• Drug and nutraceutical approaches to treatment.• The role of bariatric surgery

• Global problem, 1.6b overweight (BMI>25)400m obese (>30)

• 32.9% of U.S. adults (age 20-74y) are obese,17% of teenagers (age 12-19) are overweight.

• Obesity increases risk of death from all causes.• The data support a gene-environment

interaction where the genetically predisposedrespond to increased availability of palatable,energy-dense foods, combined with reductionin energy expenditure. “Farmyard Science”

• Modern accounts of obesity are polite ways oftelling western nations that they are fat and idle.A message that is neither novel nor new!

NEW PERSPECTIVES ON EPIDEMIOLOGY

• New discoveries of circulating factors thatsignal energy reserves which also signal thebrain, adipose tissue, liver, muscle and theimmune system.

• Research surrounding the discovery of leptinled to the discovery of other chemical signals.

• Signaling compounds: leptin, adiponectin,resistin, retinoid binding protein 4, visfatin,visceral adipose-tissue derived serine proteaseinhibitor, plasminogen activator inhibitor 1,adipsin, angiopoientin-like peptide/fastinginduced adipose factor, cytokines andchemokines, adipose production ofcorticosteroids and complex interrelationships.

ENERGY BALANCE AND METABOLISM: REGULATED BY ADIPOCYTES

LEPTIN PRODUCTION IN ADIPOCYTES

GUT HORMONES AND APPETITE

• Gut hormones influence eating behavior.• Ghrelin: “The Hunger Hormone” increases food

intake and body weight (OREXIGENIC).• In contrast, all other peripheral factors that

regulate energy balance act to restrain eating.• These Satiety Signals include: CCK, PYY, PP,

Oxyntomodulin, GLP-1(Incretin).• These gut hormones may be safe, logical drug

or nutraceutical targets for changing eatingbehavior.

• Ghrelin secretion is promoted by insomnia. The“Nocturnal Fridge Raiding Syndrome”.

INCRETINS: GLP-1 AND GLP

• Incretin peptides include glucose-dependentinsulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GL).

• Secreted within minutes of oral nutrient intake.• Incretin receptor activation leads to glucose-

dependent insulin secretion, and a variety ofother metabolic consequences.

• GLP-1 and GAP integrate nutrient-derivedsignals to control food intake, energyabsorption and assimilation.

• GLP-1 and GIP actions are a basis forinnovative treatments of Syndrome X and TypeII Diabetes Mellitus.

PERIPHERAL ACTIONS OF GLP-1

FUEL SENSING BY THE CNS

• Highly complex neurohormonal controlsunderpin hunger, appetite, satiety andeating behavior. Socio-behavioral factorsmay operate with dominance.

• Lipostatic, Glucostatic and Aminostatictheories of appetite control.

• A function of the hypothalamus: thepromise of Hoodia gordonii, Caralluma etc.

HOODIA GORDONII

OBESITIS

• Epidemiological links between obesity andinflammation have been proposed for >40y.

• Glucose and fat intake induce inflammation byoxidative stress or the activation of transcriptionfactors.

• Reductions in macronutrient intake in obesesubjects reduces oxidative stress and theproduction of inflammatory mediators(1000kcal/day, 4 weeks or 48 hr fast).

• Managing weight control without managinginflammation may be malpractice?

: Fat tissue, normal weight mouse

:Fat tissue, from fat mouse (ob/ob)

INSULIN RESISTANCE

• New concepts of inflammation-induced insulinresistance.

• Two pathways: the NF-kB pathway and thec-Jun NH2-terminal kinase (JNK) pathwaywhich are transcription factor signalingpathways that are linked to the pro-inflammatory effects of obesity and insulinresistance.

• Pathways are activated by pro-inflammatorystimuli e.g. cytokines (TNF-alpha).

• Potential mediators of insulin resistance includeIL-6, IL-10, TNF-alpha, CRP, IL-8, PAI-1 etc.

POTENTIAL MECHANISMS OF OBESITIS

OBESITIS

• Obesity is an inflammatory disorder• 30% of blood cytokine IL-6 from

adipose tissue, decrease CRP and IL-18 with weight loss

• Naïve “Zones”, but EPA valuable• Adipocytokines [leptin, adiponectin and

visfatin], adiponectin lowers TNF-alpha• Final common pathway oxidative stress

OBESITIS

CANCER: OBESITY AND SYNDROME X• Obesity and Syndrome X increase mortality from

several cancers e.g. colon, prostate, breast andpancreas.

• Consistent risk factors for colon cancer (or adenoma)include obesity, inactivity, pot-belly, hyperglycemiaand hyperinsulinemia (Syndrome X)

• Obesity linked to fatal prostate cancer.

• Type II diabetes increases risk of pancreatic cancer byapproximately 50%.

• Hyperinsulinemia or oxidative stress initiated byhyperglycemia appear to be the mechanism.

CANCER: OBESITY AND SYNDROME XPUTATIVE MECHANISMS

LIFESTYLE CHANGE AND NUTRITION:FIRST LINE OPTION

• Randomized controlled trials on the use of lifestyle ordiet changes for inducing and maintaining weight lossare few and far between: The Banting, Yudkin, AtkinsDiets and others involve restriction of simple sugar.This “fits the bill”- at least in the short term.

• Face to face lifestyle advice performs about 50% betterthan comprehensive internet-based programs forweight loss. (inference: the same applies to books?)

• Continued patient-practitioner contact, high levels ofphysical activity and the long term use of drugs(supplements?) with positive lifestyle change promotesustained weight control.

• Managing weight loss without managing Syndrome X isnihilistic. Reason for failure of the Atkins Diet, in longterm.

DRUGS AND NUTRACEUTICALS

WEIGHT MANAGEMENT

• Not only a function of diet• Calorie Control• Behavior Modification• Exercise• Management of Syndrome X• Treatment of obesity related disease• Obesitis

HOODIA-PEER REVIEW ARTICLES NOVEMBERAND DECEMBER 2006 TOWNSEND LETTER

UNREALISTICWEIGHT LOSSEXPECTATOIN

WHICH ARE QUICK FIXPROMISES?

• Drugs: Phentermine, Fen-phen,Sibutramine, Orlisat

• OTC: Phenylpropanolamine• Dietary Supplements: Pyruvate,

Chromium Picolinate, ConjugatedLinoleic Acid, Hydroxycritic Acid,Omega 3 Fatty Acids, GLA, HoodiaGordonii etc? [SYNERGY]

ALL OF THE ABOVE!

COMMON CAUSES OFOBESITY

• The Double Whopper Brain• Sedentary Lifestyle• Genetic Tendency• Social Gluttony (Appetite)• Sleeplessness

THE GLYCEMIC INDEX• Calculations of the glycemic index of

food is probably a waste of time.

• Understanding factors that controlgastric emptying rate can result ininference about the glycemic index.

• Slowing gastric emptying slows glucoseabsorption – relevance in acute dosing

GLUCOSE TOLERANCE WITHSOLUBLE FIBER

Holt S, et alEffect ofGel Fiber…Lancet,March 24th,1979.

DIETARY PRINCIPALS

• Calories Count• Watch Macronutrients CHO, Fat

Protein• Healthy Fat (EPA)• Salt Restriction• Fiber Intake

SYNDROME X NUTRITIONAL FACTORS

•OBESITY: Hoodia, fiber, green coffee beanextract, starch blocker, chromium, fat blockers

•HYPERTENSION: fiber, botanicals unpredictable

•OXIDATIVE STRESS: alpha lipoic acid, AGES,redox balanced, hydrophilic and lipophilic

•HOMOCYSTEINE: B6, B12, folate, TMG

•INSULIN RESISTANCE: fish oil(EPA), alphalipoic acid, vitamin and mineral support

•BLOOD LIPID: soy, fish oil, guggul, garlic etc.

•INFLAMMATION: EPA, curcumin, C etc.

SYNDROME X NUTRITIONAL FACTORS

•A healthy blood glucose level

•A healthy blood cholesterol level

•A healthy blood homocysteine level

•Healthy immune function

•Healthy digestive function

•Antioxidant function

•Calorie control by induction of satiety

•Inhibition of fat and sugar absorption

SYNDROME X NUTRITIONAL FACTORS• Soluble fiber e.g. oat beta glucan• Soy Protein 25 g/day• Omega 3 fatty acids (EPA)• Chromium• Alpha lipoic acid• Vanadium• Antioxidants eg ellagic acid, bioflavonoids• Starch blockers• Cinnamon• Maitake• Green coffee bean extract• Hoodia gordonii

CONCLUSIONS• Weight management involves holistic medicine and

education on new perspectives.• There is no successful, sustainable stand alone

intervention for weight control• Failing to manage Metabolic Syndrome X and its

complex pathophysiology in the overweight personis malpractice.

• Sleep, inflammation,nutrition etc. must beaddressed.

• Nutraceuticals are preferred first line adjunctiveoptions: the concept of “Syndrome X NutritionalFactors”.

• The “Integrative Approach” must be favored.