Chapter 32 - Insulin Resistance and the Metabolic Syndrome · ald Reaven, MD, an endocrinologist at...

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DEFINING METABOLIC SYNDROME

The terms “syndrome of insulin resistance (IR)” and “the metabolic syndrome” were coined in the 1980s by Ger-ald Reaven, MD, an endocrinologist at Stanford Medical School in California. Other names used to describe the condition include syndrome X, prediabetes, dysmetabolic syndrome, and cardiometabolic syndrome.1

Metabolic syndrome is associated with a constellation of risk factors for atherosclerosis and type 2 diabetes mel-litus (DM) including2:• Elevatedfastingglucose• Elevatedtriglycerides• Reducedhigh-densitylipoprotein(HDL)cholesterol• Hypertension• Centralobesity

The presence of three or more of these risk factors defines the metabolic syndrome. Following a joint sci-entific statement by several major organizations, a set of defined cut off values were determined for all compo-nents, with the exception of waist circumference (Table 32.1).3 According to the National Cholesterol Education Program Adult Treatment Panel III, a waist circumfer-ence of more than 40 inches (101 cm) in men and more than 35 inches (89 cm) in women is a defining criteria for metabolic syndrome.4 These values apply to West-ern cultures only. For information regarding other ethnic groups,readersshouldrefertothe2010articlebyLearet al.5 that outlines existing and proposed waist circum-ference and waist-to-hip ratios.

Additional abnormalities posited to define the meta-bolic syndrome include endothelial dysfunction, and pro-coagulant and proinflammatory states.6

IR is the most common clinical finding associated with metabolic syndrome and is thought by many investigators to represent the predominant mechanism underlying the pathogenesis of this condition. IR is defined as decreased cellular sensitivity to insulin and varies according to cell type, organ, and particular metabolic pathway.1 Research suggests that IR is associated with an inflammatory state and the activation of inflammatory pathways sustains IR and ulti-mately leads to the development of metabolic syndrome.7

PREVALENCE

The incidence of metabolic syndrome has reached epi-demic proportions, with nearly 35% of all U.S. adults and 50% of those aged 60 years and older estimated to

have metabolic syndrome in a 2015 report. Data from theNationalHealthandNutritionExaminationSurvey(NHANES)2003to2012reportedaprevalenceofmeta-bolic syndrome of 33% (95% confidence interval [CI], 32.5% to 33.5%), with a significantly higher prevalence in women compared with men (35.6% vs 30.3% respec-tively; P < 0.001). When stratified according to ethnicity, the highest prevalence of metabolic syndrome is observed among Hispanics (35.4%; CI, 34.2% to 36.6%), fol-lowed by nonHispanicwhites (33.4%; 95%CI, 32.6%to 34.2%) and blacks (32.7%; 95% CI, 31.5% to 33.9%). Overall, an increasing prevalence with advancing age has been reported for all ethnic groups. The prevalence of metabolic syndrome was reported as 18.3% among indi-viduals aged 20 to 39 years and to be significantly higher at 46.7% among individuals aged 60 years or older.8

The increased prevalence of IR, metabolic syndrome, and type 2 DM is thought to be attributable to the global rise in the prevalence of obesity. Visceral fat is now con-sidered to be involved in a number of metabolic, endo-crine, and immune functions, all of which have been shown to increase risk of cardiovascular disorders.11 Metabolic syndrome is reportedly associated with a two-fold increased risk of cardiovascular disease (CVD) and a four-fold increased risk of type 2 DM compared to indi-viduals without the condition4 (Table 32.2).

PATHOPHYSIOLOGY

The etiology of IR and the metabolic syndrome is multi-factorial and encompasses genetics, nutrient deficiencies, and metabolic defects in addition to lifestyle and envi-ronmental factors. The pathophysiology of the metabolic syndrome involves a complex cascade of events that occur intracellularly. Insulin is a major hormone whose action is required for proper tissue development, growth, and maintenance of glucose homeostasis.12 Insulin also affects lipid metabolism by increasing hepatic and adipose lipid synthesis. IR is characterized by decreased responsiveness in the tissues to appropriate circulating levels of insulin and is considered the major contributor to the pathogen-esis of metabolic syndrome (Fig. 32.1). Accordingly, IR in muscle tissues causes reduced glucose disposal from the bloodstream, and hepatic IR causes increased glucose production. Impairment of insulin secretion by pancreatic beta cells is a critical feature of the metabolic syndrome that leads to hyperglycemia due to defective insulin secre-tion and timing of the insulin response to glucose.13

CHAPTER 3 2

InsulIn ResIstance and the MetabolIc syndRoMeEdward (Lev) Linkner, MD • Corene Humphreys, ND

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32 InsulIn ResIstance and the MetabolIc syndRoMe 321

The key targets of insulin action are predominantly skeletal muscle (75%), followed by cardiac muscle, adi-pose tissue, and the liver. In the liver, insulin inhibits the production and release of glucose in healthy subjects by inhibiting gluconeogenesis and glycogenolysis. Defects in glucose transport or in the hexokinase II pathway may represent the principle mechanism underlying the inhibi-tion of muscle glycogen synthesis. In vivo studies using nuclear magnetic resonance spectroscopy have demon-strated defects in muscle glycogen synthesis are caused by a defect in muscle glucose itself.14 The glucose trans-porter 4 (GLUT4) is themajor carrier of glucose intothe cell. Stimuli, such as insulin and exercise, promote GLUT4activitybyembeddingitintothecellmembrane.Peroxisome proliferator–activator receptors (PPARs) are nuclear hormone receptor transcription factors that cause target genes to be expressed and play essential roles as regulators of insulin action13 (Fig. 32.2).

Previous definitions of IR generally considered the condition exclusively in terms of the negative effects on glucose metabolism. Such effects include hypergly-cemia following a high carbohydrate meal and over-stimulation of pancreatic beta cells to produce more insulin. Eventually, pancreatic beta cells become unable to produce sufficient insulin to maintain normal blood glucose levels. This inability of beta cells to produce sufficient insulin underlies the transition from IR to type 2 DM.15 It is important to emphasize that IR

TABLE 32.2 Abnormalities Associated With Insulin Resistance9,10

Some Degree of Glucose Intolerance

• Impairedfastingglucose• Impairedglucosetolerance

Abnormal Uric Acid Metabolism• ↑Plasmauricacidconcentration• ↓Renaluricacidclearance

Dyslipidemia• ↑Triglycerides• ↓High-densitylipoproteincholesterol• ↓Low-densitylipoproteinparticlediameter• ↑Postprandiallipemia

Hemodynamic Changes• ↑Sympatheticnervoussystemactivity• ↑Renalsodiumretention• ↑Bloodpressure(50%ofpatientswithhypertensionhaveinsulinresistance)

Hemostatic Changes• ↑Plasminogenactivatorinhibitor-1• ↑Fibrinogen

Endothelial Dysfunction• ↑Mononuclearcelladhesion• ↑Plasmaconcentrationofcellularadhesionmolecules• ↑Plasmaconcentrationofasymmetricdimethylarginine• ↓Endothelial-dependentvasodilatation

Reproductive• Polycysticovariansyndrome• Lowtestosteroneinmen

Data from Corona G, Monami M, Rastrelli G, et al. Testosterone and metabolic syndrome: a meta-analysis study. J Sex Med. 2011;8:272-283 and Reaven G. Metabolic syndrome: patho-physiology and implications for management of cardiovascular disease. Circulation. 2002;106:286-288.

GLUCOSE

Pancreas

Liver

Peripheral tissues (skeletal muscle)

X

Insufficient glucosedisposal

INSULIN RESISTANCE:Receptor and Postreceptor Defects

Increased glucoseproduction

Impaired insulin secretion

FIG. 32.1 □ Sites of the Three Major Pathogenic Defects That Lead to Type 2 Diabetes Mellitus. Insulinresistanceinmusclecauses reduced glucose disposal from the bloodstream, andhepaticinsulinresistancecausesincreasedglucoseproduction.Impairmentofinsulinsecretionbypancreaticbetacellsisacriti-calfeaturethatleadstohyperglycemiawheninsulinsecretionandthetimingoftheinsulinresponsetoglucosearedefective.

TABLE 32.1 Criteria for the Clinical Diagnosis of the Metabolic Syndrome3,6

Measure Categorical Cut Points

Elevatedwaistcircumference

Greaterthan40inches(102cm)inmenorgreaterthan 35inches(88cm)inwomen

Elevatedtriglycerides(drugtreatmentforelevatedtriglyceridesisanalternateindicator)

150mg/dLorgreater

ReducedHDLcholesterol(drugtreatmentforreducedHDLcholesterolisanalternateindicator)

Lessthan40mg/dLformalesandlessthan50mg/dLforfemales

Elevatedbloodpressure(drugtreatmentforhypertensionisanalternateindicator)

Systolic130mmHgorgreaterand/ordiastolic85mmHg

Elevatedfastingglucose(drugtreatmentfordiabetesmellitusisanalternateindicator)

100mg/dLorgreater

Modified from Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome: a joint interim statement of the Inter-national Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Athero-sclerosis Society; and International Association for the Study of Obesity. Circulation. 120(16):1640-1645, 2009 and Aguilar M, Bhuket T, Torres S, Liu B, Wong RJ. Prevalence of the metabolic syndrome in the United States, 2003-2012. JAMA. 313(19):1973-1974, 2015.

HDL, high density lipoprotein.


PART II IntegratIve approach to DIsease322

occurs at the cellular level despite pancreatic beta cell dysfunction (Fig. 32.3).

As further studies of the pathophysiology of IR have been reported, the traditional glucocentric view of IR has evolved to include the “lipocentric” concept. Scientists have discovered that abnormalities in fatty acid metabo-lism cause inappropriate build-up of fat in muscle tissue, theliver,andotherorgans.Lipotoxicity,associatedwithincreased plasma free fatty acid levels, is a hallmark of IR. Subsequently, these lipids are associated with not only an abnormal accumulation but also increased fat oxidation with further damage to the cell.16,17

IR may involve the insulin receptor itself. The insulin receptor belongs to the receptor tyrosine kinase family which also includes insulin-like growth factor-1 receptor (IGF-1R) and the insulin receptor-related receptor (IRR). Therefore impairment of insulin-stimulated glucose uptake may also result from the upregulation of inhibitors of these signaling pathways. Furthermore, protein-tyrosine

phosphatases (PTPases) may also have a role as negative regulators of the insulin-signaling cascade. A combination of the downregulation and upregulation of certain recep-tors may be a key element of IR pathophysiology.13

Chronic, low-grade inflammation has also been pos-ited to have a central pathogenic role in IR. Research has shown that proinflammatory cytokines and acute-phase reactants are associated with many features of the meta-bolic syndrome. These inflammatory cytokines promote IR through site-specific serine phosphorylation of insulin substrates.16

Therefore, IR, predominantly in skeletal muscle, man-ifests as a reduction in insulin-stimulated glycogen syn-thesis resulting from decreased glucose transport. Once this occurs, lipid accumulates in many cells, most impor-tantly in the liver and pancreas, causing oxidative stress and deleterious changes to cellular metabolism. These multiple defects in insulin signaling have been posited to underlie downstream impaired glucose metabolism in

Insulin

CELL NUCLEUS

Insulin-

PPAR-gamma PPAR-alpha

responsiveGLUT4-containingvesicle

Cellmembrane Insulin

receptor

ATP

TNF-alpha(also blocks

other cytokines)

Adipocyte differentiationFat deposition

Agonists:troglitazone,

CLA

Tyrosine phosphatase

Vanadate

In adipocytes

NFkappaB(induces

IL-6, fibrinogen,C-reactive protein,

COX-2,vascular adhesion

molecule-1,others?)

Beta oxidation(peroxisomes hold rate-

limiting enzymes forbeta oxidation)

HDLLDL

TriglyceridesGluconeogenesis

GLUT4

Exercise

5 -AMP-activatedkinase

Translocationto cell

membrane

?

Stimulation of glucose transport

Exercise-responsiveGLUT4-containingvesicle

X

X X

X

FIG. 32.2 □ Insulin Signaling Pathways. AMP, adenosinemonophosphate;ATP, adenosine tri-phosphate; CLA, conjugated linoleic acid; cox, cyclooxygenase; glut, glutamine transporter;HDL,high-densitylipoproteincholesterol;LDL,low-densitylipoproteincholesterol;NF-κβ,aBcell–specifictranscriptionfactor;PPAR,peroxisomeproliferator-activatorreceptor;TNF,tumornecrosisfactor.



most tissues13,18 (Table 32.3). These pathways are sum-marized in Fig. 32.4.

Impact of Environmental Toxins on Metabolic Syn-drome and Type 2 Diabetes MellitusNew research points to the role of environmental toxins as etiological factors in the pathogenesis of IR and type 2 DM. The organic compound bisphenol A (BPA) has been found to have an association with IR and type 2 DM. BPA is used to make polycarbonate and epoxy resins and is primarily found in food and beverage containers. BPA has been used com-mercially since 1957, with more than 90% of U.S. resi-dents estimated to have detectable levels in urine. Findings fromthe2003–2008NHANESreportrevealedanasso-ciation between BPA and prediabetes, independent of tra-ditional risk factors.19 Based on experimental studies, BPA appears to affect glucose metabolism through a number of pathways including insulin resistance, pancreatic beta cell dysfunction, adipogenesis, inflammation, and oxida-tive stress.19 Other pollutants, such as air pollution20 and traffic-related pollution,21 have also been implicated in IR and increased risk of mortality attributable to type 2 DM.

Persistent organic pollutants (POPSs) may also play a role in the pathogenesis of the metabolic syndrome and type 2 DM. POPs are a class of compounds characterized by low water and high lipid solubility, an ability to per-sist in the environment, and a cause of biomagnification in the food chain. Pesticides, solvents, and foods from animals, such as seafood, are the main sources of POPs. Because POPs are lipophilic, these substances are highly resistant to degradation and have an estimated half-life of 7 to 10 years.45 Some of the most common POPs found in humans include dioxins, polychlorinated biphenyls, dichlorodiphenyldichloroethylene, transnonachlor, hexa-chlorobenzene, and hexachlorocyclohexanes.46 In the 1999–2002NHANES report, higher concentrations ofPOPs (mainly pesticides and herbicides) were associated with an increased prevalence of type 2 DM. Subjects in the highest category (more than the 90th percentile) of exposure, as compared with the lowest category (less than

the 25th percentile), had a 38-fold (P < 0.001) increased prevalence of type 2 DM. Obesity was not found to be a risk factor for type 2 DM in individuals with undetect-able levels of persistent organic pollutants.47 A year later, the same research group reported a positive correlation between POPs (in particular organochlorine pesticides) and the metabolic syndrome.48 According to a Lancet

Glu

cose

(m

g/dL

) 350

Postmealglucose

Postmealglucose

Years

Fastingglucose

Fastingglucose

Insulin resistance

Compensatedinsulinresistance

Insulin levelBeta-cell failure

Uncontrolleddiabetes

300

250

200

150

100

50

Rel

ativ

e F

unct

ion

(%)

0−10 −5 0 5 10 15 20 25 30

50

100

150

200

250

FIG. 32.3 □ Naturalhistoryofdiabetes,depictingrisingbloodglu-coselevelswithprogressivebetacelldysfunction.

TABLE 32.3 Comorbidities of the Metabolic Syndrome

Alzheimer’sdisease22Atrialfibrillation23Baldness24Breastcancer25Cardiovascularrisk30Chronicfatiguesyndrome31Chronickidneydisease32Cognitiveimpairment33

Colorectalcancer(men)26Coronaryarterydisease34Depression35Endometrialcancer27Erectiledysfunction36Gestationaldiabetes37Gout38Hypothyroidandsubclinicalhypothyroidism39

Kidneystones40Nonalcoholicfattyliverdisease41Pancreaticcancer28Peripheralarterydisease42Psoriasis43Sleepapnea44Thyroidcancer29

INFLAMMATION

ATHEROSCLEROSIS

Dyslipidemia

Hypertension

Type II DM

Glucose

Sympatheticactivity

Abnormal Na+

metabolism

Insulin

INSULIN RESISTANCE

FIG. 32.4 □ Summary of Insulin Resistance and Its Effects.DM,diabetesmellitus;Na+,sodium.



editorial,thefindingsfromthestudybyLeeetal.mightimply that “virtually all of the risk of diabetes conferred by obesity is attributable to persistent organic pollutants, and that obesity is only a vehicle for such chemicals.”46 In a 2013 review of the epidemiological evidence of an asso-ciation between POPs and diabetes, Magliano et al.45 con-cluded that there is an independent relationship between POPs exposure and diabetes in the general population as well as occupationally exposed and high-risk populations.

Inorganic arsenic is another environmental toxin that appears to be associated with the metabolic syndrome and type 2 DM. The primary sources of inorganic arsenic are contaminated drinking water due to naturally occur-ring arsenic in rocks and soils, and food.49 Organic arse-nic is predominately derived from the ingestion of fish and shellfish, and is considered nontoxic as it is excreted unchanged in the urine. Results from the 2003–2004 NHANEScross-sectionalstudyrevealedapositiveasso-ciation between increasing levels of total urinary arsenic and type 2 DM. Subjects with type 2 DM had 26% higher total arsenic levels than subjects without DM. In the fully adjusted model comparing the 80th and 20th percentiles of total urine arsenic (16.5 vs 3.0 g/L), the odds ratiofor type 2 DM was 3.58.50 No association was observed between organic arsenic and type 2 DM. The investiga-tors suggested that 8% of public water systems in the United States exceed the U.S. Environmental Protec-tionAgency’sstandardof10mcg/Lfordrinkingwater.50 Wang et al.51 also found an increased prevalence of meta-bolic syndrome in subjects with elevated hair arsenic lev-els. After adjustment for confounding variables, subjects with hair arsenic in the 2nd tertile (0.034 mcg/g) had a statistically significant increased risk of metabolic syn-drome (odds ratio, 2.54; 95% CI, 1.20 to 5.39; P < 0.015). Inorganic arsenic is thought to increase the risk of type 2 DM by stimulating increased expression and secretion of high sensitivity C-reactive protein (hs-CRP), which in turn activates nuclear factor kappa-beta via the Rho-kinase pathway.52

Metabolic syndrome is primarily an environmental pheno-typic disorder (92%) rather than a genotypic disorder (8%).

Nonalcoholic Fatty Liver DiseaseNonalcoholic fatty liver disease (NAFLD) has beendefined as the accumulation of fat in the liver (hepatic accumulation of greater than 5% of liver weight con-firmed by magnetic resonance spectroscopy or liver biopsy) in the absence of other specific causes of liver infiltration, such as recent or significant alcohol inges-tion, hepatic viral infections, or other causes of liver dis-ease.53,54NAFLDisnowthemostcommonchronicliverdisease worldwide, affecting both adults and children with an estimated prevalence of 20% to 35% in the gen-eral population.55

Traditionally NAFLD has been viewed as a his-tological continuum from pure fatty liver (steatosis) throughnonalcoholicsteatohepatitis (NASH)to liverfibrosis, potentially leading to liver cirrhosis associated

with increased risk of hepatocellular carcinoma.53 The histologicalprogressionofNAFLDbeginswithmicro–macro vesicular steatosis, which primarily affects the perivenular regions, and may extend to panacinar dis-tribution.ThediagnosisofNASHisinformedbythepresence of fatty infiltration accompanied by inflam-mation associated with one of three additional features on liver histology: hepatocyte ballooning; Mallory hya-line; or fibrosis.54,56 IR is considered the initial injury to the liver, which leads to increased uptake and syn-thesis of free fatty acids and impaired inhibition of adi-pose tissue lipolysis with resultant steatosis. Following initial fatty infiltration, the liver becomes increasingly vulnerable to multiple hits including gut-derived bac-terial endotoxins, cytokine and adipokine imbalance, mitochondrial dysfunction, oxidative stress, lipid per-oxidation, Kupffer cell activation, and hepatic stellate cell activation.58 These multiple hits are proposed to stimulate hepatocyte injury and the progression from steatosistoNASHandultimatelyfibrosisandcirrhosis(Fig. 32.5).59

Single nucleotide polymorphisms (SNPs) appear to be associated with NASH but not simple steato-sis. NASH confers an increased risk of cirrhosis andsecondary malignancy, partly attributable to genetic predisposition.

Immunological events are believed to play a role in the developmentandprogressionofNASH,andtobeasso-ciated with hepatic apoptosis and fibrogenic responses. Additionally, impaired regeneration of hepatic progeni-tor cells appears to be a unifying pathophysiological path-way for NASH, with resultant dysregulated adipokineproduction and fibrosis.53 In recognizing simple steatosis andNASHastwodiscreteentitieswithdifferentetiolo-gies, clinicians can identify and more closely monitor patients at greatest risk of liver fibrosis and cirrhosis, and individualize therapeutic interventions.

The Interrelationship Between Nonalcoholic Fatty Liver Disease and IRNAFLDisconsideredthehepaticmanifestationofmeta-bolic syndrome, as IR is currently considered the funda-mental underlying pathogenetic mechanism underlying the development of hepatic steatosis. Additionally, all key components of metabolic syndrome (abdominal obe-sity, impaired fasting glucose, dyslipidemia, and elevated blood pressure) have been identified as major risk factors forthedevelopmentandprogressionofNAFLD.55 Based on epidemiological studies, cardiovascular disease is the leadingcauseofdeathinNAFLDpatients,followedbymalignancy and liver disease, respectively. These findings implyNAFLDisastrongrisk factor forcardiovasculardisease and cardiovascular-related mortality.61,62

The prevalence ofNAFLD is estimated to be 50%to 100% in obese and overweight patients, and 30% to 50% in patients with metabolic syndrome.55 NAFLDcombined with metabolic syndrome is reportedly corre-lated with greater severity of liver disease and increased likelihoodofNASH,independentofage,sex,andbodyweight. Given the high prevalence of NAFLD, it has



beenproposedthatNAFLDbeincorporatedintodiag-nostic criteria for the metabolic syndrome.55

In the hepatic IR state, fatty infiltration is character-ized by an increase in free fatty acids (FFAs) from sources including diet, adipose tissue, and de novo lipogenesis. Persistently increased glucose and hyperinsulinemia stimulate de novo lipogenesis by upregulating a num-ber of transcription factors, which increase the activity of lipogenic enzymes. Fructose and high-fructose corn syrup have been identified as sugars that stimulate lipo-genesis more profoundly that glucose. Ordinarily, FFAs are transported to the mitochondria for beta-oxidation orundergoesterificationforexcretioninVLDLorstor-age as fat droplets. IR-induced upregulation of FFAs causes direct hepatotoxicity via a number of intracellular responses. Excess FFAs activate the endoplasmic reticu-lum stress response, cause leakage during mitochondrial beta-oxidation, and lipid peroxidation in mitochondria (primarily), microsomes, and peroxisomes leading to reduced intracellular antioxidant capacity and increased oxidative stress. These mechanisms promote cellular apoptosis, a self-protective cellular response and key pathogenic event inNAFLD.Prolonged and increasedlevels of reactive oxygen species generated from mito-chondrial dysfunction ultimately lead to steatosis and hepatic fibrosis.58

DIAGNOSIS

Metabolic syndrome can be diagnosed using the criteria described in Table 32.1. Outside a research laboratory, standard of practice for the diagnosis of the metabolic syndrome is to conduct a 2-hour glucose and insulin tol-erance test (GITT), which can easily be ordered through any outpatient laboratory. The protocol is as follows: (1) 2 days of carbohydrate loading, (2) blood sampling for fasting glucose and insulin measurements, and (3) consumption of a 75-g glucose drink. Thereafter, blood specimens for glucose and insulin measurements are obtained (but not always necessarily) at half-hour inter-vals for the first hour, followed by a final specimen 2 hours later. In the majority of patients, fasting and 2-hour mea-surements are sufficient. Essentially, this protocol is the standard glucose tolerance test (GTT) with concomitant insulin testing. A caveat of this approach is that clini-cians should ensure the laboratory used is familiar with diagnostic procedures involving insulin, which is a very unstable hormone in vitro. False-negative diagnoses are possible if only a fasting insulin specimen is obtained. Regular drawing of blood specimens for the measure-ment of insulin is required to maintain test functionality. Clinician are required to understand the effect of insu-lin on managing blood glucose levels following glucose

Altered VLDL secretion Insulin resistance

Inflammation

Fibrosis/cirrhosis

Apoptosis

Lysosomal permeabilitySteatosis >5%

liver fat

Mitochondriadysfunction

Necrosis andneuroapoptosis

ER stressresponse

Fat dropletand ER injury

Accumulation of fat droplet; ERand cytoskeleton injury

Mitochondrialpermeability andcytochrome leak

Excessive lipids

Stellate cell activation

IL-6IL-8NF-κBJNK

Ductalreaction

Caspases

Systemic factors• Gut endotoxin• Adipokines• Adrenergic tone

Inadequate β oxidation

Systemic factors

Genetic risks

Lipid peroxidation

Lowered ATP and production of ROS

FIG. 32.5 □ Illustration of Molecular Events Involved in the Pathogenesis of Nonalcoholic Fatty Liver Disease.ATP,adenosinetriphosphate;ER,endoplasmicreticulum;IL,interleukin;JNK,c-Jun-N-ter-minalkinase;NF-κβ,nuclearfactorkappabeta,aBcell–specifictranscriptionfactor;ROS,reactiveoxygenspecies.(Reprinted with permission from Xiao J, Fai So K, Liong EC, Tipoe GL. Recent advances in the herbal treatment of non-alcoholic fatty liver disease. J Tradit Complement Med. 2013;3(2):88-94.)



consumption. Baseline fasting insulin levels should nor-mally be less than 15microunits/mL and less than 30microunits/mL at 2 hours following consumption of a75-g glucose load.

Although the 2-hour GITT is considered the most accurate and functional test, other methods for the diag-nosis of the metabolic syndrome include the following:• Triglyceride-to-HDL cholesterol ratio (TG:HDL-

C)—a healthy ratio is less than 2.• Glycosylatedhemoglobin(HbA1c):valuesforpatients

with IR are between 5.7 and 6.4 as per the 2010 Amer-ican Diabetes Association guidelines.63

• Fasting insulin:When assessed in isolation, normalvalues should be less than 15 microunits/mL (140pmol/L);however,anormalfastinginsulinresultdoesnot rule out IR. Reference ranges are laboratory spe-cific, so clinicians must check with the clinical labora-tories for specific values. In addition, what is “normal” and what is “healthy” can be vastly different.Other markers of importance include elevated hs-

CRP, uric acid, small dense low-density cholesterol (sd LDL-C), and inflammatory markers such as IL-6 andIL-8, TNF-alpha, PAF-1, and adiponectin. BecauseNAFLDishypothesizedtorepresentthehepaticmani-festation of IR, the measurement of gamma-glutamyl transpeptidase (GGT) levels should also be considered as this transaminase enzyme is the most sensitive in detect-ing liver toxicity.

For the majority of clinicians, the 2-hour GITT is the most valuable in terms of diagnosis and patient educa-tion, particularly for normal-weight individuals suspected to have metabolic syndrome and women with polycystic ovarian syndrome.

INTEGRATIVE THERAPY

Lifestyle intervention offers the greatest promise for theprevention and management of the metabolic syndrome.

Lifestyle FactorsAlthough the pathogenesis of IR is multifactorial, life-style factors are known to have a profound effect on blood glucose homeostasis. According to statistics reported in 2009, at least 92% of type 2 DM cases are related to lifestyle choices.64 Lack of exercise, centraladiposity, and a diet high in refined carbohydrates and saturated fats and low in fiber represent key lifestyle char-acteristics associated with IR and type 2 DM. Knowler et al.,65 researchers in the Diabetes Prevention Program, compared lifestyle modification with diet and medication in more than 3000 patients with prediabetes. The inves-tigators assigned patients to three groups who received one of the following: (1) metformin 850 mg twice daily, (2) a lifestyle modification program with goals of at least 7% weight loss, or (3) placebo. After 3 years of follow-up, the metformin group contained 31% fewer diabetics, and the lifestyle modification group contained 58% fewer subjects with diabetes compared with the placebo group.

Exercise, weight loss, and a healthy diet are key lifestyle interventions for reducing IR and the risk of developing type 2 DM.7

Exercise

Regular exercise is a vital component of a holistic med-ical treatment plan and has been shown to reduce the incidence of IR by half.66 Patients with IR and meta-bolic syndrome are recommended to partake in 30 to 60 minutes of moderate-intensity aerobic workouts (e.g., brisk walking) at least five times per week. Resis-tance training should also be encouraged up to twice weekly.7 Exercise offers a number of physiological and mental/emotional benefits. One physiological benefit isthatexerciseenhancesGLUT4transporteractivity,which in turn facilitates glucose entry into cells while bypassing the need for insulin.67 This effect has been demonstrated both in healthy individuals and those with IR or T2DM. Preliminary research also suggests that exercise has utility in improving the inflammatory state associated with IR by reducing levels of proin-flammatory chemokines.68 Yoga is another modality proven to help reduce oxidative stress in patients with type 2 DM. Yoga combined with standard care report-edly improves glycemic control and reduces body mass index.69 Other benefits of regular workouts include increased lean muscle mass and reduced body fat (see Chapter 91).

Weight Management

Excessive food consumption, particularly dietary fat and foods with a high glycemic index, is a key contribu-tor to the pathogenesis of IR and metabolic syndrome.2 Although the majority of patients with IR are over-weight, a small subgroup of patients has a normal body mass index. These patients are termed metabolically obese, normal-weight individuals and share the same risks of developing type 2 DM and cardiovascular disease due to increased visceral fat.70 Increased visceral fat is associated with increased release of free fatty acids and initiates a self-perpetuating cycle leading to the development of increased IR. Affected patients are said to be “bathed in cortisol” and have the appearance of Cushing syndrome. As previously mentioned, this type of fat affects other organs by causing dysfunction and increasing inflamma-tion. Adipose cells are not, as previously believed, pas-sive depots for energy but are rather hormonally active by secreting adipokines. Adipose cells have also been shown to secrete TNF-alpha, adiponectin, resistin, leptin, and other inflammatory mediators, all of which are involved in the promotion and exacerbation of IR. Hu et al.71 reported sedentary behaviors (particularly watching tele-vision) are associated with significantly elevated risks of visceral adiposity, irrespective of exercise levels. Stud-ies have reported that even small percentages of weight loss (6 to 10%) can significantly improve IR and reduce the risk of developing type 2 DM by 58%.65,72 Weight reduction (coupled with exercise) has also been shown to improve histological disease activity in patients with NAFLD.58



As little as 10% weight loss can reverse fatty infiltration of the liver.

The speed of chewing has also been shown to have an impact on diabetes risk. Fast eating is reported asso-ciated with a more than two-fold increased risk of type 2 DM compared with slower eating.73 Eating quickly has also been positively associated with body mass index, increased body weight, and weight gain based in a nation-wide survey of middle-aged women.74

NutritionFor patients with insulin resistance, the focus should be on diets rich in whole grains rather than refined grains, fish and white meat instead of red meat, and plenty of fruits and vegetables along with nuts, legumes, and soy. In2002,researchersfromtheHarvardSchoolofPublicHealthpublishedasetofnutritionalguidelinesknownastheAlternativeHealthyEatingIndex(AHEI)withanemphasis on the foods listed previously. Results from the Whitehall II Prospective Cohort Study showed that adherencetotheAHEIinamiddle-agedpopulationwasassociated with a reversal of the metabolic syndrome after 5 years (odds ratio 1.88; 95% CI, 1.04 to 3.41). This effect was more pronounced in subjects with cen-tral obesity and elevated serum triglycerides.75

The Mediterranean and low glycemic index/load diets are considered the most effective nutritional regimens for the treatment of metabolic syndrome, insulin resistance, and NAFLD.

Mediterranean Diet

Much has been written about the Mediterranean diet, which is rich in vegetables, legumes, soy products, fish, and essential fatty acids. This type of diet is also low in refined carbohydrates and “junk foods,” as well as in red meat, which is rich in saturated fats.55 The beneficial effects asso-ciated with adherence to the Mediterranean diet relate to the nutrient-dense properties of the foods (i.e., vitamins, minerals, phytochemicals, and fiber).55 In a randomized trial, Esposito et al.76 compared a Mediterranean diet with a standard diet in 180 patients with metabolic syndrome. After 2 years, only 40 out of 90 subjects on the Mediter-ranean diet still had features of metabolic syndrome com-pared with 78 out of 90 participants in the standard diet group. A recent paper by Salas-Salvadó et al.77 also dem-onstrated a significant reduction in the incidence of type 2 DM with adherence to a Mediterranean diet. In this trial, nondiabetic subjects aged 55 to 80 years old were ran-domly assigned to either a low fat diet (control group), a Mediterraneandiet supplementedwith1L/weekof freevirgin olive oil, or a Mediterranean diet supplemented with 30 g/day of nuts. All diets were ad libitum. After 4 years, the incidence of type 2 DM was 18% in the control group, 10% in the Mediterranean plus olive oil group, and 11%

in the Mediterranean plus nuts group. When pooling the Mediterranean diet groups, there was a 52% reduction in the incidence of type 2 DM when compared with the control group. Of particular interest was the fact that the reduced incidence of type 2 DM occurred in the absence of any significant alterations in body weight or physical activity. Adherence to the Mediterranean diet has also been associated with reduced risk of metabolic syndrome inNAFLDpatients55 (see Chapter 88).

Low-Glycemic Index Foods

The glycemic-index is a system for classifying carbo-hydrate-containing foods based on glycemic response. Carbohydrates range from simple sugars to starches and can all be converted to glucose. The rate at which con-version occurs is determined by saccharide chain length, with longer chains constituting complex carbohydrates. The glycemic index value for carbohydrates can vary by more than fivefold, with starchy foods having a higher glycemic index than nonstarchy foods such as fruits, vegetables, and legumes. Diets that favor high-glycemic index foods are associated with increased 24-hour glu-cose and insulin levels in addition to higher levels of C-peptide and glycosylated hemoglobin. These effects have been demonstrated in both nondiabetic and dia-betic individuals.78

Research has shown that a combination of exercise and a low-glycemic index diet in obese subjects with predia-betes not only improves postprandial hyperinsulinemia but also reduces pancreatic beta cell stress. Conversely, exercise in combination with a high-glycemic index diet impairs beta and intestinal K cell function despite a simi-lar reduction in weight loss. These findings emphasize the importance of diets rich in low-glycemic index foods that support beta cell preservation, a key factor in the prevention of type 2 DM79 (see Chapter 87).

Fiber

Dietary fiber, either from whole foods or dietary supple-ments, is a vital component of the treatment plan for IR and metabolic syndrome. Fiber helps reduce blood pres-sure aswell as total andLDLcholesterol levels, and itmodifies inflammatory markers. When taken with meals, soluble fibers, such as psyllium, have been shown to improve postprandial glycemic index and increase insulin sensitivity. Psyllium appears to work by reducing glucose absorption from the intestine and increasingGLUT-4protein expression in muscles. Regular consumption of dietary fiber also promotes weight reduction by enhanc-ing satiety. Oats and barley are other examples of solu-ble fiber that have U.S. Food and Drug Administration (FDA)-approved health claims for reducing the risk of heart disease.4

Cooking Techniques

Cooking methods can also have an impact on biochemi-cal markers associated with IR and metabolic syndrome. High-heat-treatedfoodstypicallyfoundintheWesterndiet generate harmful compounds known as Maillard



reaction products. These compounds have been found to reduce insulin sensitivity and increase plasma choles-terol and triglycerides.80 Mild cooking techniques such as steaming, poaching, and stewing are recommended instead of roasting, barbecuing, broiling, or frying.

Therapeutic Foods

Blueberries are rich in phenolic compounds and anthocya-nins and have been demonstrated to have certain health benefits, including improved cognition and reduced car-diovascular and cancer risk. Preliminary research sug-gests blueberries may also exhibit antidiabetic effects. In a double-blind, placebo-controlled randomized trial, consuming the equivalent of two cups of fresh blueberries a day improved IR in nondiabetic and obese insulin-resis-tant individuals.81 Consuming this quantity of blueberries has also been shown to reduce blood pressure, oxidized LDLcholesterol,andlipidperoxidationinpatientswithmetabolic syndrome.82

Apple cider vinegar (20 g diluted in 40 g of water) has been shown to reduce postprandial fluxes in glucose and insulin following a carbohydrate-rich meal. Acetic acid in vinegar acts similarly to medications such as acarbose and metformin by suppressing disaccharidase activity and increasing glucose-6-phosphate concentrations in skeletal muscle.83 Other forms of vinegar, such as white vinegar in a vinaigrette sauce, can also be used to lower post-prandial glucose (20 to 28 g white vinegar mixed with 8 g olive oil).84,85 Another first step would be to promote the patient’s own acid production by stopping unnecessary chronic usage of antacid medications if possible.

Foods and Substances to Avoid or Consume in Moderation

Table 32.4 provides a list of foods and substances that should be avoided, given their direct or indirect role in affecting glucose and insulin metabolism.

Research has shown that low to moderate alcohol con-sumption (one to two standard drinks per day) increases insulin sensitivity and reduces insulin concentrations in nondiabetic postmenopausal women. However, regularconsumption in this cohort also increased levels of the ste-roidogenichormonesDHEA-Sandestronesulfate,whichare possible risk factors for breast cancer.86 Alcohol appears to have a U-shaped relationship with metabolic syndrome, with nondrinkers and heavy drinkers having a similar risk profile. This curious finding may be attributable to increased levelsofHDLcholesterolobservedinheavydrinkers.87 As the potential risks may outweigh the benefits, teetotalers should not be encouraged to start drinking to reduce their risk of developing type 2 DM. Smoking should be avoided as it is a known health hazard and shown to be associated with an increased risk for type 2 DM.88

Mind BodyStress Management

Relaxation techniques are valuable in the treatment of IR because they promote stabilization of adrenal gland

function. Stress management lowers both cortisol levels and blood pressure, increasesDHEA, improves immu-nity, and reduces anxiety and depression. Patients are therefore less likely to abuse their bodies and tend to feel better about themselves following the use of relax-ation techniques. A prescription with an individualized approach involving meditation, relaxation techniques, prayer, visualization, and other stress-reducing modali-ties is indicated in patients with IR or type 2 DM.92

Stress management and exercise are key components of ther-apies for IR and type 2 DM.

Depression

The results of a 2009 study by Takeuchi et al.93 indicate the metabolic syndrome may be a predictive factor for the development of depression but not anxiety. Multivariate analysis indicated that an increase in waist circumference was the main factor influencing the relationship between metabolic syndrome and new-onset depression. Skilton et al.35 also found a positive association between depres-sion (versus anxiety) and metabolic syndrome. In light of their research, the investigators posited screening for depression in patients with the metabolic syndrome.

SupplementsNumerous nutritional supplements have demonstrated a beneficial effect on glucose and insulin metabo-lism. Patients with IR and metabolic syndrome should

TABLE 32.4 Foods to Avoid in Patients With Insulin Resistance and the Metabolic Syndrome

Food/Substance Metabolic Effect

RefinedStarchyFoods

Instantrice,potatoes,whitebreads,pasta,cerealssuchasRiceKrispiesandcornflakes,cornchips,andcannedfoodshaveahighglycemicindexandareknowntoimpairglucosemetabolismandincreaseinsulinsecretion.78

FastFoods Thesefoodsarecalorierich,giventheirhighsugarandfatcontent,andcontributetoweightgain,insulinresistance,andhyperlipidemia.2

SugarSweetenedBeverages

Softdrinks,fruitdrinks,icedtea,andenergyandvitaminwaterdrinksareoftenrichinfructosecornsyrupandareassociatedwithweightgainandanincreasedriskofIRandtype2DM.89Consumingonetotwodrinks/dayisassociatedwitha26%increasedriskofdevelopingtype2DM.90

ArtificialSweeteners

Artificialsweeteners,suchasaspartame,saccharin,andsucralose,areassociatedwithobesityandatwofoldincreasedriskoftype2DM.91

DM, diabetes mellitus.



include a multivitamin as a core component of their health regime. Certain nutrients, including antioxi-dants, may be required in therapeutic doses to ensure a physiological effect in the management of IR and meta-bolic syndrome.94-96 Supplementation with the follow-ing nutraceuticals should be guided by overall health and dietary habits along with laboratory parameters and current IR status.

Vitamin B6

A deficiency in vitamin B6 is associated with a decrease in several important enzymes that contribute to gluco-neogenesis (the generation of glucose from nonsugar substrates).97 In patients taking metformin for poly-cystic ovarian syndrome, vitamin B6 and folate have been shown to counteract increases in homocysteine levels.98

DosageThe recommended dose of vitamin B6 is 50 mg to 100 mg/day.99

PrecautionsNonehavebeenreportedattherecommendeddose.Higherdoses (>150 mg) may cause reversible neuropathy.

Folic Acid

The combination of IR and elevated plasma homocyste-ine levels is associated with cardiovascular risk. Research has shown that patients with this combination of risk factors also have altered or reduced folate levels, which are thought to lead to the progression of hyperten-sion.100High dose supplementationwith folic acid hasbeen shown to protect against microvascular complica-tions associated with metabolic syndrome101 and improve metabolic profiles in women with polycystic ovarian syn-drome.102 Patients heterozygous or homozygous for the methylenetetrahydrofolate reductase single nucleotide polymorphism(MTHFRC677T)maybenefitfromsup-plementation with L-5-Methyltetrahydrofolate ratherthan folic acid.

DosageThe recommended dose of folate is 500 mcg to 5 mg/day.99-102

PrecautionsNone have been reported. The administration of high doses of folic acid to patients with a concomitant vitamin B12 de-ficiency may correct megaloblastic anemia but increase the risk of irreversible neurological damage.103

Vitamin B12

Research has demonstrated a negative correlation between B12 status and body mass index.104 In patients with metabolic syndrome, the administration of folate

and vitamin B12 reportedly decreases IR and improves endothelial function. Homocysteine levels have alsobeen shown to improve with folate and vitamin B12, affirming the beneficial effect of these treatments on cardiovascular disease risk factors.105 Because metfor-min has been shown to impair vitamin B12 status, prac-titioners should assess and monitor B12 levels in patients receiving metformin.106

DosageThe recommended dose of vitamin B12 is 500 mcg/day.107

PrecautionsNone have been reported at the recommended dose.

Vitamin C

Individuals with metabolic syndrome have been found to have significantly lower levels of vitamin C compared to healthy individuals.108,109 A deficiency of vitamin C is thought to be associated with a greater resistance to fat mass loss.110HighdosesofvitaminChavealsobeenfound to reverse the adverse effects of free fatty acids on vascular function.111,112

DosageThe recommended dose of vitamin C is 1000 to 2000 mg/day.113

PrecautionsTake with food to reduce the risk of diarrhea.

Vitamin D

Supplemental (and dietary) vitamin D has been shown to reduce the development of metabolic syndrome.114 In a study of young adults, an inverse relationship between bloodglucose,IR,andserum25-hydroxy(OH)vitaminD was demonstrated.115 Other research has confirmed that serum 25(OH) D levels positively correlate withinsulin sensitivity.116,117 Ford et al.118 also reported sig-nificant inverse relationships between serum vitamin D levels and abdominal obesity, elevated triglycerides, and hyperglycemia. Visceral fat reduces the absorption of vitamin D from the skin.

DosageThe recommended dose of vitamin D is 300 to 2000 IU/day.119,120 Dosing may also be guided by the season of the yearandserum25(OH)Dlevels(thepreferredrangeis30to60ng/mLor75to150nmol/L).121

PrecautionsMonitor serum calcium levels in patients taking thiazide di-uretics and vitamin D supplements, as this combination may cause hypercalcemia.122



Vitamin E

Vitamin E supplementation has demonstrated hepato-protective effects in patients diagnosed with NAFLD(including those with NASH when accompanied withpharmacological medications).58,123

DosageThe recommended dose is 400 IU per day (or 200 IU twice daily) of alpha tocopherol or 400 mg of mixed tocotrienols.123-125

PrecautionsExercise caution in patients taking anticoagulants, as chronic high dosing may affect blood clotting and induce symptoms of muscular weakness and fatigue (reported at doses of 720 mg alpha tocopherol per day).126

Biotin

High-dose biotin is considered an important vitamin forpreventing and treating IR and obesity.127 When given in quantities 10 times greater than the physiological range, biotin directly activates an enzyme that mimics the action of nitric oxide. Biotin has also been shown to improve glyce-mic control by reducing excessive hepatic glucose output.128

DosageThe recommended dose of biotin is 3 mg three times a day.127

PrecautionsNone have been reported.

Chromium

The trace element chromium is an important nutrient that helps prevent IR and dyslipidemia associated with obesity.129 Chromium also appears to have important effects on skeletal muscle IR.128 Chromium has been found to improve insulin sensitivity and increase glucose disposal in women with polycystic ovarian syndrome.130

DosageThe recommended dose of chromium is 200 to 1000 mcg/day.130-132

PrecautionsTake chromium supplements half an hour before or 3 to 4 hours after thyroid or levothyroxine medications, as chromi-um may bind to these medications and reduce absorption.133

Magnesium

Intracellular magnesium plays a vital role in regulat-ing insulin action, insulin-mediated glucose uptake and vascular tone.134 Higher intakes of magnesium

are associated with increased insulin sensitivity and a reduced risk of developing metabolic syndrome.135-137 Conversely, low dietary intake of magnesium is associ-ated with an increased risk of developing IR and type 2 DM.138,139

DosageA dose of 100 mg/day is recommended to reduce the risk of developing type 2 DM.140 A dose of 382 mg/day is required to improve metabolic profiles and blood pressure.134,141 Dosing can also be guided by assessing red blood cell mag-nesium levels.

PrecautionsHigh-dose magnesium may cause gastric irritation anddiarrhea.142

Zinc

Recent research has reported an inverse relationship between serum zinc concentrations and insulin resis-tance.143 The antioxidant capacity of zinc is thought to underlie its valuable effects on IR.144 Two ran-domized controlled trials reported a reduction in fast-ing glucose and insulin in addition to other markers of IR in obese prepubescent children following zinc supplementation.145,146

DosageThe recommended dose of zinc is 20 mg/day.146

PrecautionsNone reported at the recommended dose.

Alpha lipoic acid

Alpha lipoic acid (ALA) is a potent antioxidant that isconsidered important for the treatment of metabolic syn-drome.ThemechanismsbywhichALAexertsitseffectsinclude protection against oxidative stress-induced IR, inhibition of hepatic gluconeogenesis, and increased peripheral glucose use.147 ALA may also exert modestreductions in plasma nonesterified fatty acid concentra-tions.148 When administered solely or in combination with the angiotensin receptor blocker irbesartan, ALAhas been shown to improve endothelial function and reduceIL-6andPAF-1levelsinsubjectswithmetabolicsyndrome.149

DosageTherecommendeddoseofALAis100mgthreetimesdailybefore each meal.149

PrecautionsNone reported.



Coenzyme Q10

Coenzyme Q10 (CoQ10) is required for adenosine triphosphate (ATP) synthesis and is therefore impor-tant for the conversion of carbohydrates to energy.150 By enhancing the functioning of the mitochondrial enzyme glycerol-3-phosphate dehydrogenase, CoQ10 helps with glycemic control.128 A study by Singh et al.151 reported reductions in systolic and diastolic blood pressure, fasting and 2-hour plasma insulin, and triglycerides with the use of CoQ10 supplemen-tation. Markers of oxidation, such as lipid peroxides, malondialdehyde, and diene conjugates, were also lowered by CoQ10, indicating a decrease in oxidative stress. Many patients with IR and metabolic syndrome are treated with statin drugs, and these medications have been found to lower plasma and tissue levels of CoQ10.152

DosageThe recommended dose of CoQ10 is 120 mg/day (or 60 mg twice daily).151

PrecautionsCoQ10 may decrease the anticoagulant effect of warfarin. Monitor clotting time regularly, particularly within the first 2 weeks of taking CoQ10.153

Acetyl-L-Carnitine

The amino acid, carnitine, plays an important role in energy metabolism, largely through its effects on fatty acid oxidation. Carnitine deficiency has been associated with various conditions, including obe-sity and type 2 DM.154 When fatty acids are unable to enter the cell, triglycerides accumulate in the cytosol; an important contributor to the pathogen-esis of IR. The administration of acetyl-L-carnitineto patients with type 2 DM and to healthy persons have been shown to improve insulin-mediated glucose disposal.155

DosageThe recommended dose of carnitine is 1 to 2 g/day between meals.156

PrecautionsNone have been documented at the dose recommended.156

Omega-3 Fatty Acids

Longtermsupplementationwithomega-3fattyacidshasbeen shown to improve postprandial lipoprotein metab-olismby decreasing triglycerides and increasingHDL-cholesterol.2 Omega-3 fatty acids have also demonstrated improvements in endothelial function and arterial stiff-ness, with an accompanying reduction of the proinflam-matorycytokine,IL-6.157

DosageThe recommended dose is 1 g/day of eicosapentaenoic acid and docosahexaenoic acid (EPA and DHA). For patients with elevated triglycerides, the dose is 2 to 4 g/day of EPA andDHA.157-159

PrecautionsNone have been reported at the recommended dose.

BotanicalsGinseng (Panax ginseng)

The herb Panax ginseng has numerous medicinal effects, including antiinflammatory and antioxidant properties, and has also been used in the treatment of type 2 DM. Ginseng is thought to control and prevent type 2 DM by increasing insulin sensitivity and enhancing insulin secretion.160 Another proposed mechanism of action lies in the herb’s ability to mod-ulate glucose activity by increasing GLUT-4 trans-porter activity.161

DosageThe recommended dose is 100 to 200 mg/day (standardized to contain 4% ginsenosides).162,163

PrecautionsGinseng may decrease the effectiveness of warfarin.164

Green Tea (Camellia sinensis)

Green tea supplementation has been shown to improve whole blood glutathione and plasma antioxidant capac-ity and reduce plasma iron in adults with metabolic syndrome.165 Based on the research by Basu et al.,166 sup-plemental green tea in patients with metabolic syndrome is thought to reduce serum amyloid alpha, an indepen-dent cardiovascular disease risk factor. Green tea may also maintain normal body composition by stimulating thermogenesis and enhancing fat oxidation.167

DosageGreen tea extract (270 mg to 460 mg/day of epigallocatechin gallate).165-167

PrecautionsGreen tea may decrease the effectiveness of warfarin.168 Do not combine with ephedrine or other stimulants.169

Milk Thistle (Silybum marianum)

Milk thistle is considered an important herb in the treat-ment of hepatic disorders and also appears to play a



beneficial role in maintaining normal glucose and lipid metabolism.Liverdysfunction impairs theefficiencyofpostprandial hepatic glucose storage and is thought to trigger hyperinsulinemia due to reduced liver clearance of insulin.170 Phase III clinical trials have determined sily-marin (the active component of milk thistle) to be the bestmedicationforNAFLDduetoitseffectsinloweringaminotransferase levels and reducing steatosis severity, liver ballooning, and fibrosis. Milk thistle has also been shown to act as an insulin sensitizer in studies of patients withNAFLD.171

DosageGive 420 to 600 mg/day (standardized to contain 70%–80% silymarin).172,173

PrecautionsExercise caution in patients taking drugs metabolized by cytochrome, the P-450 isoenzymes CYP3A4 and CYP2C9, because the silibinin content of milk thistle may inhibit these hepatic isoenzymes.174

PharmaceuticalsWhile lifestyle modification is the preferred approach to managing IR and metabolic syndrome, at times pre-scription drugs are necessary. The problem with such medications is that they do not correct underlying nutri-ent deficiencies. Medications often merely “treat” the results of the disease; that is, they reduce high serum lipid or glucose levels or high blood pressure but do not treat the overall patient. Although no FDA-approved prescription drugs exist for IR, many of the medications used for type 2 DM have studied as treatment of meta-bolic syndrome. Some of these medications may not spe-cifically address IR or may have unhealthy side effects. For example, 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA)reductaseinhibitors(statins)lowerserumCoQ10, and metformin reduces folic acid and vitamin B12 levels but may increase homocysteine levels. Statin administration is also associated with a dose-dependent increase in insulin resistance.175 Of importance is the fact that pharmaceutical drugs do not correct diet and lifestyle issues. Pharmaceuticals can be an appropriate complementary option when required. Following is a list of medications grouped according to their physi-ological action. There are a number of brands in each category, and many can be used in combination with each other. Even though these medications are usually used for type 2 DM, they are often prescribed for IR (although they may need to be prescribed “off-label”). It should be noted that medications approved for type 2 DM are the main medications being investigated for the treatmentofNAFLD.58

Oral Medications

Insulin Sensitizers. Biguanides (e.g., metformin) are the most commonly used front-line medications.

These drugs work by reducing glucose output from the liver (most likely by decreasing gluconeogenesis).176

Thiazolidinediones help improve body cell sensi-tivity to insulin by stimulating the nuclear receptor, peroxisome proliferator activated receptor (PPAR-gamma). These receptors are primarily found in fat cells and, to a lesser extent, in liver and skeletal muscle.176

Agents That Slow the Digestive/Absorptive Process. Alpha-glucosidase inhibitors help slow down the absorption of carbohydrate into the bloodstream following a meal, thereby reducing postprandial glucose peaks.177

Medications That Increase Insulin Production and Decrease Glucose Production. Dipeptidyl pepdiase-4 (DPP-4) inhibitors are a newer class of drugs that work by inhibiting the breakdown of incretin hormones glucagon-like peptide-1 and glucose dependent insulinotropic peptide. Increased levels of these hormones result in improved glucose-dependent insulin secretion, suppressed glucagon secretion, and reduced gastric emptying.178

Sodium-Glucose Transporter-2 (SGLT-2) Inhibitors. These medications work by a novel insulin-independent mechanism by blocking the reabsorption of glucose in the proximal convoluted tubules of the kidneys, thereby resulting in increased glucosuria and weight loss (due to loss of 300 to 400 kcal/day).179

Bile Acid Sequestrants. Colesevelam is a second-generation bile acid sequestrant and the only drug in this class that is approved for the treatment of hyperlipidemia and type 2 DM.180 Bile acid sequestrants work by binding bile acid in the intestinal lumen, thus impeding bile acid reabsorption in the terminal ileum and increasing fecal bile-acid output.181 A small study reported the efficacy of colesevelam in improving impaired fasting glucose levels.182

SurgeryThe most dramatic, but at times successful, option for the treatment of type 2 DM is bariatric surgery. While the majority of studies have focused on bariat-ric surgery for type 2 DM,183-189 there is research to support the use of this procedure in obese patients. In a nonrandomized, prospective, controlled study, bar-iatric surgery proved to be more efficient than usual care in the prevention of type 2 DM in obese persons. Subjects were divided into patients who underwent bariatric surgery (1658) and obese matched controls (1771). No participants had type 2 DM at baseline. After 15 years, type 2 DM developed in 392 partici-pants in the control group compared with 110 in the bariatric surgery group, corresponding to incident rates of 28.4 cases per 1000 person-years and 6.8 cases per 1000 person-years, respectively (adjusted hazard ratio with bariatric surgery, 0.17; 95% CI, 0.13 to 0.21; P < 0.001).



THERAPEUTIC REVIEW

LABORATORY EVALUATION• 2-hourglucoseandinsulintolerancetesttomeasureglucoseandinsulinlevelsafteraglucoseload.

• Serumlipidmeasurements(lookingforincreasedtriglyceridelevel,decreaseinhigh-densitylipoproteincholesterollevel,andnormalorslightlyincreasedlow-densitylipoproteincholesterollevel).

• Fastingglucosehigherthan100mg/dL.• High-sensitivityC-reactiveprotein,amarkerofinflammation,andgamma-glutamyltranspeptidase,amarkeroflivertoxicity.

LIFESTYLE• Encourageanexerciseroutinethatconsistsofmod-erateintensityworkoutsandresistancetraining.

• Encouragegoalstoachieveappropriateweight.

• Encouragethepatienttostopusingnicotine-contain-ingproducts.

NUTRITION• Low-carbohydrate,Mediterranean-typedietwithafocusonlow-glycemicindexfoods.

• High-fiberdietincludingsolublefibers,suchaspsyl-lium,oats,andbarley.

• Decreasedconsumptionofredmeatandfriedfoods.

MIND-BODY THERAPIES• Encouragelifestylechoicestoreducestressandanxiety.Recommendarelaxationtechniquetailoredtotheindividual.

• Note: Theprecedingrecommendationshighlyout-weighthosethatfollowforthetreatmentofIRandmetabolicsyndrome.

SUPPLEMENTS• High-qualitymultivitaminwithmineralsandB-groupvitamins.

• Omega-3fattyacids(eicosapentaenoicacid/ docosahexaenoicacid)1to4g/daytoreduce inflammation,bloodpressure,andtriglyceride levels.

• Chromiumpicolinate:200to1000mcg/day.

• VitaminC:1000to2000mg/day.

• VitaminD:300to2000IU/day.

• Alpha-lipoicacid:100to300mg/day.

• CoenzymeQ10:60to120mg/day.

• Highriskindividualsmayneedtoconsider additionalsupplementationasoutlinedinthe bodyofthetext.

BOTANICALS• Americanginseng:100to200mg/day.

• Milkthistle:420to600mg/day.

PHARMACEUTICALS• Metformin:500to2500mgeachmorningortwicedaily.

• Pioglitazone:15to45mg/day.

AA 1

AA 1

BB 1

AA 1

BB 1

BB 1

BB 1

BB 1

BB 1

BB 22

BB 22

BB 1

BB 1

BB 22

BB 22

BB 22

AAAA 22

AAAA 22

Key Web Resources

TheNationalDiabetesInformationClearinghouse(NDIC)pro-videsinformationoninsulinresistanceandprediabetes

https://www.niddk.nih.gov/health-information/diabetes/types/prediabetes-insulin-resistance

Myhealthywaist.orgofferseducationandtoolsregardingtheimportanceofreducinglargewaistlines

http://www.myhealthywaist.org

Educationalresourcesonlipidsandhealth https://www.lipid.org/lipidacademy

CalorieneedscalculatorfromtheMayoClinic http://www.mayoclinic.com/health/calorie-calculator/NU00598

Fitdayisawebsitethatprovidesonlineeducation,tools,andrecord-keepingtohelpmeetweightlossandexercisegoals

http://www.fitday.com

PREVENTIONPRESCRIPTION

• Maintainahealthybodyweight.Peoplewithanincreaseinvisceral(truncal)fatareathigherrisk.

• Exerciseof30minutes/dayisrecommendedonmostdaysoftheweekforpatientswithappropri-ateweightand60minutes/dayonmostdaysoftheweekforthoseneedingtoloseweight.

• Managestressandincreasetherelaxation(para-sympathetic)response.

• Followalow-glycemicload,Mediterranean-typediet.

• TakeahighqualitymultivitaminthatincludesmineralsandB-groupvitamins.

REFERENCESReferences are available online at ExpertConsult.com.




http://www.myhealthywaist.org

https://www.lipid.org/lipidacadem

http://www.mayoclinic.com/health/calorie-calculator/NU00598

http://www.fitday.com

http://ExpertConsult.com

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Chapter 32 - Insulin Resistance and the Metabolic Syndrome · ald Reaven, MD, an endocrinologist at...

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