Dr. James Manos (MD) September 26, 2015

Overview: METABOLIC SYNDROME (insulin resistance syndrome, syndrome X)

History • Although the modern era of what we now call the

'metabolic syndrome' or 'insulin resistance syndrome' seems to have started less than two decades ago with the description of syndrome X by G.M. Reaven in the late 1980s, the history of this syndrome is much longer.

• A considerable number of scientists, starting as early as almost 90 years ago, have described the very common coexistence of the various components of the syndrome, including hypertension, and some of them gave several names to this clustering.

• In 1988, in his Banting lecture, Gerald M. Reaven proposed insulin resistance as the underlying factor and named the constellation of abnormalities syndrome X. Reaven did not include abdominal obesity, which has also been hypothesized as the underlying factor, as part of the condition.

Prevalence, causes • Prevalence (the number of cases of disease in a

population at a certain time): 20% of the population• USA: 44% of population >50 years; women>men• Causes: interaction of genes & sedentary

overnutrition perpetuated by social norms• Presence of mild inflammation (differentiation from

simple obesity)• There is a 2 –way interaction between depression &

insulin resistance

Etiology – risk factors•Overweight/ obesity – especially central adiposity•Sedentary lifestyle• Increasing age• Insulin resistance (key role)•Lipodystrophy

ΒΜΙ (body mass index)• The body mass index (BMI) (also known as Quetelet index)

is a measure of relative size based on the mass (weight) and height of an individual.• BMI=mass (Kg)/ (height (m))2 or BMI=mass (lb)/ (height

(in))2 x 703• BMI Prime, a simple modification of the BMI system, is the

ratio of actual BMI to upper limit BMI (currently defined at BMI 25). As defined, BMI Prime is also the ratio of body weight to upper body-weight limit, calculated at BMI 25. Since it is the ratio of two separate BMI values, BMI Prime is a dimensionless number without associated units. For example a person with BMI 34 has a BMI Prime of 34/25 = 1.36, and is 36% over his or her upper mass limit. 

Source: http://en.wikipedia.org/wiki/Body_mass_index

Category BMI range – kg/m2 BMI PrimeVery severely underweight less than 15 less than 0.60

Severely underweight from 15.0 to 16.0 from 0.60 to 0.64Underweight from 16.0 to 18.5 from 0.64 to 0.74Normal (healthy weight) from 18.5 to 25 from 0.74 to 1.0Overweight from 25 to 30 from 1.0 to 1.2Obese Class I (Moderately obese) from 30 to 35 from 1.2 to 1.4

Obese Class II (Severely obese) from 35 to 40 from 1.4 to 1.6

Obese Class III (Very severely obese) over 40 over 1.6

Mechanisms• Excess adipose (fat) tissue leads to increased production of pro-inflammatory cytokines• Increased intracellular fatty acid metabolites contribute to insulin resistance by impairing insulin signaling pathways and also accumulation of triglycerides in skeletal & cardiac muscle, while stimulating hepatic glucose & triglyceride production

Characteristics• No specific symptoms. Endothelial dysfunction• Diagnostic criteria: Central obesity or BMI > 30 plus any 2

of:• Hypertension – ΒP> 130/85 mmHg or specific medication• Hyperglycemia/ insulin resistance – Fasting glucose > 100

mg/dL (5.6 mmol/L) or previously diagnosed with type -2 diabetes mellitus (DM) or specific medication• Dyslipidaemia: increased triglycerides > 150 mg/dL or >1.7

mmol/L) or specific treatment for hypertriglyceridemia; decreased HDL (‘good’) - cholesterol < 40 mg/dL or <1.03 mmol/L in males and < 50 mg/dL or <1.29 mmol/L in females; or specific treatment

Associated conditions with metabolic syndrome• Cardiovascular disease• Type 2 diabetes mellitus• Non – alcoholic fatty liver disease (liver steatosis)• Hyperuricemia/ gout• Polycystic ovary syndrome (PCOS)• Obstructive sleep apnea (snoring with episodes of apnea; relation with increased neck mass and abdominal adiposity)

Central (visceral) obesity & waist circumference

• Europe: men>_ 94 cm, women >_ 80 cm• South Asia: men >_90 cm, women >_80 cm• China: men >_90 cm, women >_80 cm• Japan: men >_85 cm, women >_90 cm• South & Central America: use South Asian pro tem

(for the time being)• African & Middle East: use European pro tem

Central (visceral) obesity on a teenager

Insulin resistance & diabetes mellitus (DM)• Insulin resistance is as a decreased ability of insulin to mediate the metabolic actions on glucose uptake, glucose production, and/or lipolysis. • Prevalence of DM is increasing, parallel with the epidemic of obesity – it touches the 8.4% of the USA population – but a significant portion of the population is undiagnosed. 5th leading cause of death

• Diagnostic criteria for DM: • fasting plasma glucose >_126 mg/dL (>_7 mmol/L)• Symptoms of diabetes & a random blood glucose >_ 200

mg/dL (>_ 11.1 mmol/L)• 2 hour plasma glucose >_200 mg/dL (>_11.1 mmol/L)

during a 75 g oral glucose tolerance test• Hemoglobin A1c > 6.5%

Oral glucose tolerance test (OGTT)

• The glucose tolerance test is a medical test in which glucose (also known as dextrose) is given orally and blood samples for plasma glucose are taken afterward to determine how quickly it is cleared from the blood,

• The test is usually used to test for insulin resistance, diabetes mellitus, impaired beta cell function of the pancreas (that secrete insulin) and sometimes for reactive hypoglycemia, acromegaly and rarer disorders of carbohydrate metabolism.

• In the most commonly performed version of the test, an oral glucose tolerance test (OGTT), a standard dose of glucose is ingested by mouth and glucose blood levels are checked two hours later. Many variations of the GTT have been devised over the years for various purposes. The WHO recommendation is for a 75g oral dose of glucose in all adults. The dose is adjusted for weight only in children. The dose should be drunk within 5 minutes.

• Βlood is drawn at intervals for measurement of glucose (blood sugar), and sometimes insulin levels. The intervals and number of samples vary according to the purpose of the test. For simple diabetes screening, the most important sample is the 2 hour sample and the 0 and 2 hour samples may be the only ones collected. A laboratory may continue to collect blood for up to 6 hours depending on the protocol requested by the physician.• A variant is often used in pregnancy to screen

for gestational diabetes with a screening test of plasma glycose over 1 hour after the oral administration of 50 grams of glycose. If elevated, this is followed with a test of 100 grams of administered glucose and the plasma glucose check over three hours.• Usually the OGTT is performed in the morning as glucose

tolerance can exhibit a diurnal rhythm variation with a significant decrease in the afternoon. The patient is instructed to fast for 8 – 12 hours prior to the tests.

Impaired fasting glycaemia (IFG) & Impaired glucose tolerance (IGT)• Impaired fasting glycaemia (IFG): fasting plasma glucose

level 100 – 125 mg/dL (5.6 – 6.9 mg/dL) (American Diabetes Association ADA) or 110 – 125 mg/dL (6.1 – 6.9 mg/dL) (WHO); or 2 hour glucose <140mg/dL (<7.8 mmol/L) on the 75 g oral glucose tolerance test• Impaired glucose tolerance (IGT): 2 hour glucose levels

140 – 199 mg/dL (7.8 – 11.1 mmol/L) on the 75 g oral glucose tolerance test. Prevalence: 10 – 15% of adults in USA • People with IFG or IGT do not have DM, but are at

substantial risk for developing type 2 DM and cardiovascular disease in the future

Mechanisms of insulin resistance•Obesity causes insulin resistance by increasing the rate of release of non-esterified fatty acids causing post – receptor defects in insulin’s action•Mutation of genes encoding insulin receptors• Circulating of autoantibodies to the extracellular domain of insulin receptor

• Diabetes mellitus results when the beta pancreatic cell function is insufficient to overcome the insulin resistance. In type 1 diabetes, beta cell function is destroyed. In type 2 diabetes, beta cell function cannot overcome the insulin resistance• Young women with the insulin – resistant form of

polycystic ovary syndrome (PCOS) are as insulin resistant as newly presenting middle – aged patients with type 2 diabetes, but they have high beta – cell activity and, hence, normal glucose homeostasis.

Metabolic hyperglycemia• Metabolic hyperglycemia arises from a

combination of a reduction in the efficiency with which the insulin can move glucose into tissues and by a reduction in the number of functioning beta cells of the pancreas. This results in a surplus of glucose in the bloodstream

Advanced glycation end products (AGEs) and diabetes mellitus (DM)• Advanced glycation end products (AGEs), are substances

that can be a factor in the development or worsening of many degenerative diseases such as diabetes mellitus, atherosclerosis, chronic kidney failure, and Alzheimer's disease. They also contribute to aging. • They are also believed to play a causative role in the blood

- vessel complications of DM. AGEs are seen as speeding up oxidative damage to cells and in altering their normal behavior.

• AGEs are formed both outside and inside the body. Specifically, they stem from glycation reaction, which refers to the addition of a carbohydrate to a protein, without the involvement of an enzyme. Glucose can bind with proteins in a process called glycation, making cells stiffer, less pliable and more subject to damage and premature aging. • AGEs have a range of pathological effects, such as

increasing vascular permeability; increasing arterial stiffness; inhibiting vascular dilation by interfering with nitric oxide (NO); oxidizing LDL; binding to various cells (including macrophage, endothelial and mesangial (in the kidney) cells) to induce the secretion of a variety of cytokines; and enhancing oxidative stress.

Increased insulin resistance –causes (1) • DM (diabetes mellitus type 2)• Metabolic syndrome• Obesity• Asian race• TB drugs• SSRIs (medications for depression)

Increased insulin resistance –causes (2) • Pregnancy• Acromegaly• Cushing syndrome• Renal failure• Polycystic ovary syndrome (PCOS)• Werner’s syndrome (progeria, precocious aging

after puberty)

Drugs that may cause insulin resistance• Thiazides (diuretics)• Beta – blockers• Statins (!)• Steroids• Antipsychotics including atypical• Immunosuppressive medications (e.g. tacrolimus & cyclosporin)• Protease inhibitors (for AIDS)• Nicotinic acid (used as a lipid – lowering agent)• Pentamidine (used to treat Pneumocystis jirovecii pneumonia)

Statin therapy & insulin resistance• An overview on the published data about statin therapy (used

as lipid – lowering agents) and its correlation with insulin showed that clinical evidence suggests a worsening effect of statins on insulin resistance and secretion, anyway basic science studies did not find a clear molecular explanation, providing conflicting evidence regarding both the beneficial and the adverse effects of statin therapy on insulin sensitivity.

• The overview concluded that although most of the clinical studies suggest a worsening of insulin resistance and secretion, the cardiovascular benefits of statin therapy outweigh the risk of developing insulin resistance, thus the data suggest the need to treat dyslipidemia and to make patients aware of the possible risk of developing type 2 diabetes or, if they already are diabetic, of worsening their metabolic control.

• Source: http://www.ncbi.nlm.nih.gov/pubmed/25208056

Primary hyperlipidemias – Fredrickson classification Source: http://www.bcmj.org/articles/dr-ds-fredrickson-founding-father-field-lipidology

Secondary causes of hyperlipidaemia• Hypothyroidism • Excessive alcohol consumption• Obesity• High energy diet, especially saturated diet• Type 2 diabetes (less common in type 1)• Metabolic syndrome• Renal disease, especially with proteinuria – nephrotic syndrome• Cholestatic liver disease – biliary obstruction• Other (anorexia nervosa, paraproteinaemia, lipodystrophy,

autoimmune, pancreatitis etc.)

Drugs that may cause hyperlipidaemia• Beta – blockers• Corticosteroids• Oestrogen replacement therapy• Androgen replacement in men• Cyclosporine and other immunosuppressants• Antidopamine agents (antipsychotics, metoclopramide etc)• HIV antiretroviral regimes (HAART)• Isotretinoin analogs (used to treat acne)

Possible consequences of metabolic syndrome• Vascular events: myocardial infarction (MI), stroke•Diabetes mellitus (DM)•Neurodegeneration (e.g. Alzheimer's disease)•Microalbinuria and renal problems•Gallstones (chololithiasis)• Cancer e.g. pancreatic• Fertility and sexual problems (e.g. erectile dysfunction on men with diabetes mellitus)

Metabolic syndrome & increased cardiovascular risk• Intima-media thickness (IMT) is a validated marker of

preclinical atherosclerosis and a predictor of cardiovascular events.• Α study investigated a population of 529 asymptomatic

patients (age 62 ± 12.8 years), divided into two groups of subjects with and without metabolic Syndrome (MetS). All patients, at baseline, have had a carotid ultrasound evaluation and classified in two subgroups: the first one without atherosclerotic lesions and the second one with preclinical atherosclerosis (increased IMT or asymptomatic carotid plaque). Cardiovascular endpoints were investigated in a 20-years follow-up.

• Results. There were 242 cardiovascular events: 144 among patients with metabolic syndrome (57.4%) and 98 among in healthy controls (35.2%). 63 events occurred in patients with normal carotid arteries (31.8%), while 179 events occurred in patients with preclinical atherosclerosis (54.1%). Of the 144 total events occurred in patients with metabolic syndrome, 36 happened in the subgroup with normal carotid arteries (45%) and 108 in the subgroup with preclinical atherosclerosis (63.15%). 98 events occurred in patients without metabolic syndrome, of which 27 in the subgroup with normal carotid arteries (22.88%) and 71 in the subgroup with preclinical atherosclerosis (44.37%). In addition, considering the 63 total events occurred in patients without atherosclerotic lesions, 36 events were recorded in the subgroup with metabolic syndrome (45%) and 27 events in the subgroup without metabolic syndrome (22.88%). Finally, in 179 total events recorded in patients with preclinical carotid atherosclerosis, 108 happened in the subgroup with metabolic syndrome (63.15%) and 71 happened in the subgroup without metabolic syndrome (44.37%). The Kaplan-Meier function showed an improved survival in patients without atherosclerotic lesions compared with patients with carotid ultrasound alterations.

•CONCLUSIONS: The study concluded that preclinical atherosclerosis leads to an increased risk of cardiovascular events, especially if it is associated with metabolic syndrome

• Source: http://www.ncbi.nlm.nih.gov/pubmed/24152423

Underlying mechanism of cardiovascular events on metabolic syndrome: endothelial dysfunction • Metabolic syndrome is associated with increased

risk of both atherothrombotic cardiovascular events and venous thromboembolism. • Endothelial-dependent vasodilatation is impaired.

This is mostly mediated by a reduced expression of vasodilators (nitric oxide (NO) and prostacyclin) with a concomitant increase of vasoconstrictors (endothelin- 1, angiotensin II (AT (II)) and thromboxane A2 (TXA2)). Platelet activity is also enhanced.

• A cross-talk between activated endothelium and platelets results in a pro-thrombotic vicious cycle. Enhanced coagulation together with impaired fibrinolysis is also present, mirrored by high fibrinogen and plasminogen activator inhibitor-1 levels. • Endothelial dysfunction, expressed by high von

Willebrand (vW) factor and tissue plasminogen factor (tPA) levels, also contributes to this abnormality.• Whole blood and plasma viscosity is increased • Source:

http://www.ncbi.nlm.nih.gov/pubmed/24168445

Arterial compliance & atherosclerosis/ cardiovascular risk • Arterial compliance, an index of the elasticity of large

arteries such as the thoracic aorta. Arterial compliance is an important cardiovascular risk factor. Compliance diminishes with age and menopause. Arterial compliance is measured by ultrasound as a pressure (carotid artery) and volume (outflow into aorta) relationship.• Arterial Compliance in simple words is an action in which

an artery yields to pressure or force without disruption. A measure of arterial compliance is used as an indication of arterial stiffening. An increase in age and systolic pressure are accompanied by a decrease of the arterial compliance.

• Protecting the endothelium is a key to reducing cardiovascular (CV) disease risk. Endothelial dysfunction results in reduced compliance or increased arterial stiffness, particularly in the smaller arteries. This abnormality is characteristic of patients with hypertension, but may also be seen in normotensive (with normal blood pressure) patients before the appearance of clinical disease. Reduced arterial compliance is also seen in patients with diabetes and in smokers, and is part of a vicious cycle that further elevates blood pressure, aggravates atherosclerosis (hardening of the arteries), and leads to increased CV risk. 

• Arterial compliance can be measured by several techniques, most of which are invasive or otherwise not clinically appropriate. Pulse contour analysis is a newly developed noninvasive method that allows for easy, in – office measurement of arterial elasticity to identify patients at risk for CV events before disease becomes clinically apparent.

Methods of attenuation of the reduction of arterial compliance• Exercise (aerobic training) such as swimming• Tai Chi (an internal Chinese martial art) •  Ηomocysteine lowering with folic acid and vitamin B6 (pyridoxine)

& vitamin B12• Medications: • Rosiglitazone (for diabetes mellitus type 2)• Amlodipine (for hypertension) and atorvastatin (a statin; a blood

lipid lowering agent) combination• Angiotensin-Converting Enzyme inhibitor (ACEI) and diuretic

combination (both for hypertension and heart failure)• Pravastatin (a statin, blood lipid lowering agent)• ALT-711, a novel non-enzymatic breaker of advanced glycation

end-product crosslinks.

• Herbs & dietary supplements: • n-3 (omega – 3) long-chain polyunsaturate fatty acids/ dietary fish oil

supplementation• alpha-linolenic acid (ALA; an omega – 3 fatty acid)/ flax seed oil• Isoflavones derived from red clover containing genistein, daidzein,

biochanin, and formononetin• Soy isoflavones containing genistein, daidzein• Anthocyanins and flavones (in most herbs/ plants)• Chinese herbal medicine for calming Gan and suppressing hyperactive

yang (CGSHY)• Korean red ginseng (KRG) in ginsenoside and polysaccharide fractions• American ginseng (Panax quinquefolius L.) • Vitamin E supplementation

Metabolic syndrome and coronary plaque - atheromatosis • In a study, the authors sought to characterize coronary plaques in

patients with metabolic syndrome by using optical coherence tomography.

• The authors identified 451 coronary plaques from 171 subjects who underwent optical coherence tomographic imaging in 3 coronary arteries. Subjects were divided into 3 groups: diabetes mellitus (DM, n=77), metabolic syndrome (n=35) and a control group (C group-n=59) without DM or metabolic syndrome.

• CONCLUSIONS: the study concluded that compared with control subjects, coronary plaques in metabolic syndrome contain larger lipid. However, the metabolic syndrome criteria used in this study could not distinguish the vulnerable features such as thin-cap fibro-atheroma, suggesting the necessity of complementary information to identify patients at high risk for cardiovascular events.

• Source: http://www.ncbi.nlm.nih.gov/pubmed/23922003

Metabolic syndrome and early carotid atherosclerosis • A study investigated whether metabolic syndrome can

predict the new onset of carotid plaque or the progression of carotid intima-media thickness (C-IMT) and identify other associated factors in an elderly population without evidence of early carotid atherosclerosis.• B-mode carotid ultrasonography was used to assess the

presence of carotid plaque and the C-IMT at baseline and follow-up. Participants with carotid plaque or an increased C-IMT(≥1.0mm) at baseline were excluded from the study. The new occurrence of carotid plaque, defined as early carotid atherosclerosis and the progression of C-IMT, was evaluated.

• A total of 370 participants over 60 years of age(median age=66 years, 34.1% men) were enrolled. After a median follow-up period of 25 months, 64 participants (17.3%) had newly developed carotid plaque. After adjusting for variables determined to be statistically significant in univariate analyses, a multivariable regression analysis showed that predictors of newly developed carotid plaque were metabolic, white blood cell, and vitamin B12, and total levels. A multiple linear regression analysis showed that the rate of change for C-IMT tended to be associated with the development of metabolic syndrome.

• CONCLUSIONS: the study concluded that metabolic syndrome is associated with the progression of early carotid atherosclerosis in the general population, suggesting that metabolic syndrome plays an important role in initiating the atherosclerotic process.

• Source: http://www.ncbi.nlm.nih.gov/pubmed/24477027

Metabolic syndrome and impaired kidney function/ chronic kidney disease (CKD)• Metabolic syndrome has been clearly associated with chronic

kidney disease markers including reduced glomerular filtration rate (GFR), proteinuria and/or microalbuminuria and histopathological markers such as tubular atrophy and interstitial fibrosis.

• Possible mechanisms of renal injury include insulin resistance and oxidative stress, increased proinflammatory cytokine production, increased connective tissue growth and profibrotic factor production, increased microvascular injury, and renal ischemia.

• Metabolic syndrome also portends a higher cardiovascular disease (CVD) risk at all stages of CKD (chronic kidney diseased) from early renal insufficiency to end-stage renal disease.

• Source: http://www.ncbi.nlm.nih.gov/pubmed/25374814

Metabolic syndrome and increased homocysteine levels• Hyperhomocysteinemia and the metabolic syndrome are

established cardiovascular risk factors and are frequently associated with hypertension. • Α study investigated the association of homocysteine with

the metabolic syndrome and cerebro- cardiovascular events in hypertension. • In the study 562 essential hypertensive patients who

underwent accurate assessment of fasting and postload glucose metabolism, insulin sensitivity, and renal function, the authors measured plasma levels of homocysteine, vitamin B12, folate, and fibrinogen and assessed the prevalence of the metabolic syndrome and of coronary heart disease (CHD) and cerebrovascular disease (CVD).

• The results showed that patients with the metabolic syndrome had significantly higher plasma homocysteine levels and its increasing levels were associated with an increasing prevalence of the metabolic syndrome, coronary heart disease, and CVD. Plasma homocysteine was directly correlated with age, waist circumference, fasting glucose, triglyceride, uric acid, and fibrinogen levels, and homeostatic model assessment index and inversely correlated with creatinine clearance and high-density lipoprotein cholesterol (HDL), vitamin B12, and folate levels. Logistic regression analysis showed an independent association of homocysteine levels with age, male gender, vitamin B12 and folate levels, and the metabolic syndrome, and indicated also an independent association with cerebro-cardiovascular disease that was independent of the metabolic syndrome.

• CONCLUSION: the study concluded that elevated plasma homocysteine is associated with the metabolic syndrome in hypertensive patients. Prevalence of events increases with increasing plasma homocysteine levels suggesting its contribution to cerebro-cardiovascular diseases in these patients.

• Source: http://www.ncbi.nlm.nih.gov/pubmed/25498997

Obesity, metabolic syndrome and androgen levels on men & women• The presence of obesity and metabolic syndrome in men

and women is associated with increased risk of cardiovascular disease and hypertension.

• In men, obesity and metabolic syndrome are associated with reductions in testosterone levels. In men, reductions in androgen levels are associated with inflammation, and androgen supplements reduce inflammation.

• In women, obesity and metabolic syndrome are associated with increases in androgen levels. In women, increases in androgens are associated with increases in inflammatory cytokines, and reducing androgens reduces inflammation.

• Source: http://www.ncbi.nlm.nih.gov/pubmed/21274756

Metabolic syndrome and androgen levels on older men• A study sought to examine the cross-sectional, longitudinal,

and predictive associations between reproductive hormones and SHBG (Sex hormone-binding globulin, a glycoprotein that binds to the sex hormones, androgen and estrogen) and metabolic syndrome in older men. Men ages 70 years and older from the Concord Health and Ageing in Men Project study (n = 1705 subjects) were assessed at baseline and 2-year follow-up.

• RESULTS: In cross-sectional data, significant associations between each of T (testosterone), SHBG, DHT (dihydrotestosterone) and calculated free testosterone (cFT) with the metabolic syndrome remained significant after multivariate adjustment. In longitudinal analyses, however, only lower SHBG was significantly associated with incident metabolic syndrome over the 2-year follow-up.

• CONCLUSIONS: The study concluded that although low serum T (testosterone), SHBG, DHT (dihydrotestosterone) and calculated free testosterone (cFT) were associated cross-sectionally with metabolic syndrome among community-dwelling older men, over a 2-year follow-up period only SHBG remained significant after multivariate adjustment.• This suggests that lowered

circulating androgens (testosterone (T) and dihydrotestosterone (DHT)) may be biomarkers rather than causally related to incident metabolic syndrome.

• Source: http://www.ncbi.nlm.nih.gov/pubmed/25259909

Metabolic syndrome & Polycystic ovary syndrome (PCOS) • Polycystic ovary syndrome (PCOS; also known as Stein–

Leventhal syndrome) is the most common endocrine and metabolic disorder affecting women in reproductive age. • Women with PCOS have higher lifetime risk for

cardiovascular disease (CVR) than healthy women at the same age and tend to display insulin resistance (IR). This results in a requirement for increased amounts of insulin to achieve a given metabolic action. • It has been recently suggested that women with

metabolic syndrome show increased circulating androgens. • Source: http://www.ncbi.nlm.nih.gov/pubmed/25245380

• Polycystic ovary syndrome (PCOS) and metabolic syndrome share many similarities, including abdominal obesity and insulin resistance (IR), and PCOS is regarded by some as the ovarian manifestation of metabolic syndrome. • A prospective study in 1 223 Caucasian women with

PCOS and 277 women without PCOS, matched for BMI, was performed. The presence/absence of metabolic syndrome in PCOS+ and PCOS- women was recorded and comparisons among the resulting four groups were performed.• CONCLUSIONS. Even though metabolic syndrome

and PCOS have many similarities, they are distinct disorders. PCOS does not appear to simply represent the ovarian manifestation of metabolic syndrome. Further studies are required to assess the contribution of hyperandrogenism to the pathogenesis of insulin resistance (IR) in PCOS.• Source: http://

www.ncbi.nlm.nih.gov/pubmed/23315058

Metabolic syndrome & reduced growth hormone (GH) levels• Like growth hormone-deficient (GHD) adults, abdominally

obese individuals have increased visceral adipose tissue (VAT), insulin resistance, and growth hormone (GH) levels that are below normal during continuous 24-h monitoring.

• These similarities have prompted a number of recent investigations in abdominally obese adults that reported significant reductions in truncal and visceral fat and an improvement in insulin sensitivity following prolonged GH administration.

• However, other studies have shown that insulin resistance and glucose concentrations transiently worsen during the first few weeks of GH treatment and that these deleterious effects can persist even after VAT reduction has occurred.

• Source: http://www.growthhormoneigfresearch.com/article/S1096-6374(06)00029-3/abstract?cc=y

IGF – 1 (Insulin-like growth factor 1)• Insulin-like growth factor 1 (IGF-1), also called somatomedin C, is

a protein that in humans is encoded by the IGF gene. IGF-1 is a hormone similar in molecular structure to insulin. It plays an important role in childhood growth and continues to have anabolic effects in adults.

• A synthetic analog of IGF-1, mecasermin, is used for the treatment of growth failure (failure to thrive, i.e., inadequate weight gain or inappropriate weight loss, in paediatric patients).

• IGF-1 is a primary mediator of the effects of growth hormone (GH). • Growth hormone is made in the anterior pituitary gland, is released

into the blood stream, and then stimulates the liver to produce IGF-1. • IGF-1 then stimulates systemic body growth, and has growth-

promoting effects on almost every cell in the body, especially skeletal muscle, cartilage, bone, liver, nerves, skin, hematopoietic cells and lung.

Metabolic syndrome & low levels of Vitamin D and IGF -1 (insulin like growth factor - 1)• Hypovitaminosis D (Vitamin D deficiency) and

reduced IGF-1 (insulin like growth factor - 1) are associated, individually, with metabolic syndrome.

• In a study, data on 25-hydroxyvitamin D (25(OH)D), IGF-1 (insulin like growth factor - 1), and metabolic syndrome abnormalities (abdominal obesity; raised HbA1C, blood pressure, and triglycerides; and low HDL cholesterol) were collected from 6 810 British white subjects in the 1958 cohort, surveyed during 2002-2004 (age 45 years).

• RESULTS: IGF-1 concentrations increased with 25(OH)D up to approximately 75 – 85 nmol/l but not thereafter. Both 25(OH)D and IGF-1 were inversely associated with metabolic syndrome. There was an interaction between 25(OH)D and IGF-1 on metabolic syndrome prevalence: IGF-1 was not significantly associated with metabolic syndrome among those with the lowest levels of 25(OH)D, whereas higher 25(OH)D was associated with metabolic syndrome at all IGF-1 concentrations. Metabolic syndrome prevalence was lowest for participants with the highest concentrations of both 25(OH)D and IGF-1. 25(OH)D was associated with the prevalence of high ΗbA1C, blood pressure, and triglycerides after adjustment for IGF-1, obesity, and social and lifestyle variations.

• CONCLUSIONS: The study concluded that serum 25(OH)D (vitamin D) is inversely associated with metabolic syndrome, whereas the inverse association with IGF-1 (insulin like growth factor - 1) was found only among those without hypovitaminosis D. These results suggest that metabolic syndrome prevalence is the lowest when both 25(OH)D and IGF-1 are high.

• Source: http://www.ncbi.nlm.nih.gov/pubmed/18003755

Metabolic syndrome & decreased IGF – 1 levels; implications on life span• In human, defects in insulin receptor signaling cause insulin

resistance and diabetes, and IGF-1 (insulin like growth factor – 1 ) deficiency is associated with an increased risk of cardiovascular disease and atherosclerosis.

• Interestingly, insulin sensitivity normally decreases during aging; however, centenarians were reported to maintain greatly increased insulin sensitivity and had a lower prevalence of the metabolic syndrome as compared to younger subjects.

• Additionally, a longitudinal study revealed that insulin-sensitizing hormones, including leptin and adiponectin, were significantly associated with the survival of centenarians, indicating that an efficient insulin response may influence human longevity

• Source: http://www.ncbi.nlm.nih.gov/pubmed/18672019

Treatment of metabolic syndrome• Motivational therapy (benefits are more than simply chemical);

Cognitive - Behavioral therapy (CBT); Tai Chi• Weight reduction: increased physical activity/Exercise, caloric

restriction, medications (e.g. orlistat), bariatric surgery on morbid obesity

• Statins for lipid abnormalities. In some cases fibrates or niacin. • Omega – 3 fatty acids (fish oil) for increased triaglycerols• Mediterranean diet (?ketonogenic) • Antihypertensive drugs including ACE inhibitors or ARBs, when

possible• Hypoglycemic drugs e.g. metformin and thiazolidinediones

(glitazones) for reducing insulin resistance

Statins• Statins (simvastastin, atorvastatin, fluvastatin, lovastatin,

pitavastatin, pravastatin & rosuvastatin), also known as HMG-CoA reductase inhibitors, inhibit HMG-CoA reductase (3-hydroxy-3-methylglutaryl coenzyme A reductase) an enzyme involved in the synthesis of cholesterol especially in the liver. Decreased cholesterol production leads to an increase in the number of LDL (low density lipoprotein) membrane receptors, which increases clearance of LDL cholesterol from circulation.• Statins are used to treat hyperlipidemia and are the most

effective drugs in lowering LDL (‘bad’) cholesterol.

• Adverse effects: statins may cause liver problems. Rarely, severe and sometimes fatal liver problems have been reported in patients taking "statin" medicines, including lovastatin. The risk of developing liver problems may be greater if the patient drinks alcohol daily or in large amounts or if he/she has a history of liver problems.  Statins may also cause muscle problems (myopathy),  or even rhabdomyolysis (destruction of muscle cells), which can in turn result in life-threatening kidney injury. • Also as previously referred, statins may increase the risk

for diabetes mellitus.

Coenzyme Q10 & statins • Coenzyme Q10 (CoQ10, ubiquinone) levels are decreased

in statin use, so some suggest coenzyme Q10 supplementation on people taking statins. CoQ10 is often added on multivitamins. • A study concluded that coenzyme Q10 supplementation

(50 mg twice daily) effectively reduced statin-related mild-to-moderate muscular symptoms, causing lower interference of statin-related muscular symptoms with daily activities

(Source http://www.ncbi.nlm.nih.gov/pubmed/25375075 )

Fibrates• The fibrates are a class of ampipathic carboxylic acids.

They are used for a range of metabolic disorders, mainly hypercholesterolemia, and there are hypolipidemic agents. Commonly prescribed fibrates include bezafibrate, ciprofibrate, clifibrate (largely obsolete due to side-effect profile, e.g. gallstones), gemfibrozil & fenofibrate. • Fibrates are used in accessory therapy in many forms

of hypercholesterolaemia, usually in combination with statins. Clinical trials do also support their use as monotherapy agents.

• Although less effective in lowering LDL (‘bad’) – cholesterol & triglyceride levels, by increasing HDL levels and decreasing triglyceride levels, they seem to reduce insulin resistance when the dyslipidemia is  associated with other features of the metabolic syndrome (hypertension, & type 2 DM) and are therefore used in many hyperlipidemias. • Fibrates are not suitable for patients with low HDL –

cholesterol levels. 

• Mechanisms of action: • Ιnduction of lipoprotein lipolysis • Ιnduction of hepatic fatty acid (FA) uptake and reduction of

hepatic triglyceride production• Ιncreased removal of LDL particles• Reduction in neutral lipid (cholesteryl ester and

triglyceride) exchange between VLDL and HDL may result from decreased plasma levels of TRL• Increase in HDL (‘good’) – cholesterol production and

stimulation of reverse cholesterol transport.  

• Adverse effects: fibrates may cause muscle problems (myopathy),  or even rhabdomyolysis (destruction of muscle cells), which can in turn result in life-threatening kidney injury. The risk is increased especially when combined with statins. They may also cause gallstones and acute kidney injury (AKI).

Niacin (Nicotinic acid; vitamin B3)• Niacin is an organic compound, and one of the 20 to

80 essential human nutrients. • A review of niacin did not find that it affected

either cardiovascular disease, or risk of death in those already taking a statin. Niacin alone appears to reduce the risk of cardiovascular disease.• The National Cholesterol Education Program (NCEP) in

2002 recommended niacin alone for cardiovascular and atherogenic dyslipidemia in mild or normal LDL (‘bad’) – cholesterol levels or in combination for higher LDL levels. By lowering VLDL levels, niacin also increases the level of HDL (‘good’) – cholesterol in blood, and therefore it is sometimes prescribed for people with low HDL, who are also at high risk of a heart attack.

• Mechanisms of action: Niacin therapeutic effect is mostly through its binding to G protein coupled receptors, niacin receptor 1 (NIACR1) and niacin receptor 2 (NIACR2) that are highly expressed in adipose (fat) tissue, spleen, immune cells and keratinocytes. 

• NIACR1 inhibits cAMP production and thus fat breakdown in adipose tissue and free fatty acids available for liver to produce triglycerides and VLDL and consequently LDL (‘bad’) – cholesterol.

• Decrease in free fatty acids also suppress hepatic expression of apolipoprotein c3 (APOC3) and PGC-1b, thus increase VLDL turn over and reduce its production.

• It also inhibits diacylglycerol acyltransferase – 2, important on hepatic triglyceride synthesis.

• Side effects include dermatological (skin) conditions such as skin flushing and itching, dry skin, and skin rashes including eczema exacerbation and acanthosis nigricans. Nausea and liver toxicity - even fulminant liver failure have also been reported. Side effects of hyperglycemia, cardiac arrhythmia, birth defects in experimental animals, hyperuricemia and gout have also been reported. • Although high doses of niacin may elevate blood sugar,

thereby worsening diabetes mellitus, recent studies show the actual effect on blood sugar to be only 5–10%. Patients with diabetes who continued to take anti-diabetes drugs containing niacin did not experience major blood glucose changes. Thus overall, niacin continues to be recommended as a drug for preventing cardiovascular disease in patients with diabetes.• Niacin, particularly the time-release variety, at extremely

high doses can cause acute toxic reactions. Extremely high doses of niacin can also cause niacin maculopathy on the macula of the retina of the eye that is reversible after niacin intake ceases.

Drugs for diabetes(1) Metformin • Metformin: • Acts on the liver to reduce gluconeogenesis and causes a

decrease in insulin resistance via increasing AMPK (5' AMP-activated protein kinase) signaling. • It has low risk of hypoglycemia as compared to

alternatives hypoglycemics• Good effect on LDL – cholesterol and also decreases

triglycerides. • Adverse effects include gastrointestinal problems

(2) Sulfonylureas• Sulfonylureas (e.g. glyburide, glipizide & glimepiride): • They stimulate insulin release by pancreatic beta cells by

inhibiting the K ATP channel. • They have increased risk of hypoglycemia. • They do not have effect on LDL – cholesterol. • There have lower risk of gastrointestinal (GI) problems

than with metformin

(3) Thiazolidinediones (TZDs)• Thiazolidinediones (TZDs) (e.g. pioglitazone &

rosiglitazone):• Reduce insulin resistance by activating PPAR - gamma

receptor in fat and muscle. • Have lower risk of hypoglycemia and light increase in HDL-

cholesterol. • Their adverse effects is the increased risk of heart failure,

weight gain, higher risk of oedema & anemia, increase on LDL and also hepatotoxicity.

Antihypertensive drugs:(1) Angiotensin converting enzyme (ACE) Inhibitors • Angiotensin converting enzyme inhibitors (ACE inhibitors;

e.g. perindopril, captopril, enalapril, ramipril & lisinopril) • They are a group of pharmaceuticals that modulate

the renin – angiotensin – aldosterone system. These substances inhibit the Angiotensin converting enzyme (ACE) and thus the block the conversion of angiotensin I (AT-I) to angiotensin II (AT-II), causing vasodilation, reducing the secretion of antidiuretic hormone (ADH, vasopressine) and reduces production and secretion of aldosterone, among other actions. The combined effect reduces blood pressure.

• Their main uses are in the treatment of hypertension, diabetic nephropathy, and congestive heart failure.

• Adverse effects include hyperkalaemia, angioedema and persistent dry cough.

(2) Angiotensin receptor blockers (ARBs)• Angiotensin receptor blockers (ARBs; e.g. valsartan & losartan) are a

group of pharmaceuticals that modulate the renin – angiotensin – aldosterone system.

• These substances are AT1-receptor antagonists, i.e., they block the activation of angiotensin II AT1 receptors causing vasodilation, reducing the secretion of antidiuretic hormone (ADH, vasopressine) and reduces production and secretion of aldosterone, among other actions. The combined effect reduces blood pressure.

• Their main uses are in the treatment of hypertension, diabetic nephropathy, and congestive heart failure.

• ARBs are used primarily for the treatment of hypertension, where the patient is intolerant of ACE inhibitor therapy due to dry cough.

• Adverse effects include hyperkalaemia. • They may also increase longevity.

Dietary changes. The Mediterranean diet • The Mediterranean Diet (MedDiet) is a nutritional model

characterized by: • the abundant consumption of olive oil (oleic acid as

monοunsaturated fatty acid) • high consumption of plant foods (fruits, vegetables,

pulses, cereals, nuts and seeds)• the frequent and moderate intake of wine (mainly with

meals)• the moderate consumption of fish, seafood, yogurt,

cheese, poultry and eggs• and the low consumption of red meat, processed meat

products and seeds.

• Several epidemiological studies have evaluated the effects of a Mediterranean pattern as protective against several diseases associated with chronic low-grade inflammation such as cancer, diabetes, obesity, atherosclerosis, metabolic syndrome and cognition disorders.

• The adoption of this dietary pattern could counter the effects of several inflammatory markers, decreasing, for example, the secretion of circulating and cellular biomarkers involved in the atherosclerotic process.

• Source: http://www.ncbi.nlm.nih.gov/pubmed/25244229

The omega -6 to omega -3 ratio • Excessive amounts of omega-6 polyunsaturated fatty acids

(PUFAs such as various seed oils) and a very high omega-6/omega-3 ratio, as is found in today’s Western diets, promote the pathogenesis of many diseases, including cardiovascular disease, cancer, and inflammatory and autoimmune diseases, whereas increased levels of omega-3 PUFA (a low omega-6/omega-3 ratio) exert suppressive effects. • In the secondary prevention of cardiovascular disease, a

ratio omega-6/omega-3 ratio of 4/1 was associated with a 70% decrease in total mortality.• Source: http://www.ncbi.nlm.nih.gov/pubmed/12442909

Omega – 3 fatty acids – fish oil • Omega-3 fatty acids are beneficial for the heart. Positive effects

include anti-inflammatory and anti-blood clotting actions, lowering cholesterol and triglyceride levels, and reducing blood pressure. They may also reduce the risks and symptoms for other disorders including diabetes, stroke, some cancers, and the age related cognitive decline.

• Omega – 3 fatty acids are contained in fish oil of fatty fish (EPA & DHA) • The linseed oil contains another omega - 3 fatty acid: alpha-linolenic

acid (ALA). The value of ALA has recently emerged, although most companies that sell supplements of omega -3 use fish oil EPA and DHA as sources for omega - 3 polyunsaturated fatty acids, and do not include ALA.

• They are useful at lowering triglycerides in the blood (the only FDA indication).

• They are used in Europe as secondary prevention after cardiovascular events

Plant sterols (phytosterols) & stanol esters • Phytosterol (plant sterol; including beta sitosterol) is plant-

based compound that can compete with dietary cholesterol to be absorbed by the intestines, resulting in lower blood cholesterol levels. • Phytosterols may also have some effect in cancer

prevention. • Patients with hypercholesterolemia (increased blood

cholesterol) can eat phytosterols and stanols found in nuts, seeds, vegetable oils, and fortified food products, such as orange juice, yogurt, margarine spreads, and salad dressing. • Studies show that eating spreads enriched with

phytosterols per day reduced total cholesterol by up to 11% and LDL cholesterol (‘bad’ cholesterol) by up to 15%

Glycaemic index• Foods with low glycemic index should be preferred • The glycaemic index (GI) is a number associated with a

particular type of food that indicates the food’s effect on a person’s blood glucose. The number typically ranges between 50 and 100, where 100 represents the standard, an equivalent amount of pure glucose.

• We all need to chose foods with low glycemic index (GI), as foods with high glycemic index may predispose to diabetes and cardiovascular disease

• Common foods such as bananas have high glycemic index, so we should eat them moderate, or less. For a calculator of glycemic index on foods see http://www.glycemicindex.com/foodSearch.php

Herbs & dietary supplements that have been studied for metabolic syndrome

• Coffee• Grapefruit• Black & green tea• Tart cherries• Alpha – lipoic acid• Strawberries, blueberries, cranberries• Beta – glucan (e.g. from oat)• Flavonoids• Black chokeberry• Other (garlic, bilberry, beta – carotene, lycopene, Acai berry etc).

Other herbs & dietary supplements that may prevent cardiovascular disease

• Cinnamon (sugar lowering)• Lecithin• Plant sterol (phytosterols) & stanol esters; including beta - sitosterol• Garlic & kyolic (aged garlic extract) • Pomegranate (pressure lowering effects)• Blueberry• Green and black tea• Milk thistle/ silymarin and also NAC (N- acetyl cysteine) (liver

detoxification)• Valerian, rhodiola, St John's wort, lemon balm (melissa) & passion

flower (relaxing and antidepressive effects, decrease of the overstimulated sympathetic system)

• Hawthorn (blood pressure lowering effects, cardioprotective (protective for the heart), used for heart failure)

• Astaxanthin (krill oil)• Coenzyme Q10 (CoQ10)• Tart cherry• Spirullina & Chlorella (algae)• Wheat grass• Soy protein • Resveratrol (substance in red wine, may offer longevity)• Quercetin• Pterostilbene • Fisetin (e.g. on strawberry) • Flavonoids & polyphenols / OPCs (Oligomeric Proanthocyanidins) from

grape seed extract • Pycnogenol (pine bark extract) etc.

Reference – Bibliography• Longo D.L., Fauci A.S., Kasper D.L., Hauser S.L., Jameson J.L., Loscalzo

J.L., Harrison’s manual of medicine, 18th edition, McGraw – Hill, 2013. • Longmore M., Wilkinson I.B., Davidsnon E.H., Foulkes A., Mafi A.R.,

Oxford Handbook of Clinical Medicine, 8th edition, Oxford University Press, 2010.

• Ahmed N., Clinical Biochemistry, Oxford University Press, 2010.

Reference – Links (Retrieved 01-18-2015)

• http://www.diapedia.org/other-types-of-diabetes-mellitus/drug-induced-diabetes

• http://www.globalusers.com/aboutmedicine_eng/herbs_and_diseases.htm• http://en.wikipedia.org/wiki/Diabetes_mellitus• http://en.wikipedia.org/wiki/Impaired_fasting_glucose• http://en.wikipedia.org/wiki/Impaired_glucose_tolerance• http://en.wikipedia.org/wiki/Metabolic_syndrome• http://www.ncbi.nlm.nih.gov/pubmed/25208056• http://en.wikipedia.org/wiki/Hyperlipidemia• http://www.ncbi.nlm.nih.gov/pubmed/12442909• http://www.ncbi.nlm.nih.gov/pubmed/24168445

• http://www.glycemicindex.com/foodSearch.php•  

http://www.mayoclinic.org/healthy-living/nutrition-and-healthy-eating/in-depth/glycemic-index-diet/art-20048478 

• http://www.mayoclinic.org/diseases-conditions/diabetes/expert-answers/diabetes/faq-20058466

• http://www.bcmj.org/articles/dr-ds-fredrickson-founding-father-field-lipidology (table)

• http://en.wikipedia.org/wiki/Metabolic_syndrome#mediaviewer/File:Obesity6.JPG (free to use picture)

• http://en.wikipedia.org/wiki/Glycemic_index• http://www.ncbi.nlm.nih.gov/pubmed/25374814• http://www.ncbi.nlm.nih.gov/pubmed/25498997• http://www.umm.edu/imres/AmbCareSem/Hyperlipidemia-JLiu0708.pdf • http://www.umm.edu/imagepages/19302.htm

• http://www.ncbi.nlm.nih.gov/pubmed/25244229• http://www.ncbi.nlm.nih.gov/pubmed/23922003• http://www.ncbi.nlm.nih.gov/pubmed/24477027• http://www.ncbi.nlm.nih.gov/pubmed/24152423• http://www.ncbi.nlm.nih.gov/pubmed/25259909• http://www.ncbi.nlm.nih.gov/pubmed/21274756• http://www.ncbi.nlm.nih.gov/pubmed/25245380• http://www.ncbi.nlm.nih.gov/pubmed/23315058• http://

www.growthhormoneigfresearch.com/article/S1096-6374(06)00029-3/abstract?cc=y

• http://www.ncbi.nlm.nih.gov/pubmed/18672019• http://www.ncbi.nlm.nih.gov/pubmed/18003755• http://www.ncbi.nlm.nih.gov/pubmed/16531786

• http://www.drugs.com/drug-class/hmg-coa-reductase-inhibitors.html• http://www.drugs.com/cdi/lovastatin.html• http://en.wikipedia.org/wiki/Statin• http://en.wikipedia.org/wiki/Anti-diabetic_medication• http://en.wikipedia.org/wiki/Angiotensin_II_receptor_antagonist• http://en.wikipedia.org/wiki/ACE_inhibitor• http://en.wikipedia.org/wiki/Body_mass_index (table) • http://en.wikipedia.org/wiki/Glucose_tolerance_test• http://

www.umgcc.org/patient_info/dictionaryEn/definition/phytosterol.htm• http://www.umm.edu/altmed/articles/hypercholesterolemia-000084.htm• http://en.wikipedia.org/wiki/Advanced_glycation_end-product• http://www.globalusers.com/aboutmedicine_eng/herbal_chap8.htm• http://biolexikon.blogspot.gr/2010/09/prevalence.html

• http://en.wikipedia.org/wiki/Insulin-like_growth_factor_1• http://www.ncbi.nlm.nih.gov/pubmed/25375075• http://en.wikipedia.org/wiki/Fibrate• http://en.wikipedia.org/wiki/Niacin