Dr. James Manos (MD)
September 18, 2015Overview of the Metabolic Syndrome
Note: in this text, the writer expresses his point of view. Some advice is empirical, so you should consult your family doctor beforehand.
Metabolic syndrome is also known as Insulin Resistance Syndrome and 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 common coexistence of the various components of the syndrome, including hypertension, and some 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 the disease in a population at a particular time): 20% of the population
A considerable number of scientists, starting as early as almost 90 years ago, have described the common coexistence of the various components of the syndrome, including hypertension, and some 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 the disease in a population at a particular time): 20% of the population
-USA: 44% of people>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.
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 (principal role)
-Lipodystrophy
-Sedentary lifestyle
-Increasing age
-Insulin resistance (principal 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 body weight ratio to the 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 a BMI of 34 has a BMI Prime of 34/25 = 1.36 and is 36% over his or her upper mass limit.
Table (1)
Category
|
BMI range – kg/m2
|
BMI Prime
|
Very severely underweight
|
less than 15
|
less than 0.60
|
Severely underweight
|
from 15.0 to 16.0
|
from 0.60 to 0.64
|
Underweight
|
from 16.0 to 18.5
|
from 0.64 to 0.74
|
Normal (healthy weight)
|
from 18.5 to 25
|
from 0.74 to 1.0
|
Overweight
|
from 25 to 30
|
from 1.0 to 1.2
|
Obese 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 accumulation of triglycerides in skeletal & cardiac muscle while stimulating hepatic glucose & triglyceride production.
-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 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:
-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
-Dyslipidemia:
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.
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 (increased blood uric acid)/ gout
-Polycystic ovary syndrome (PCOS)
-Obstructive sleep apnea (snoring with apnea episodes; relation with an increased neck mass and abdominal adiposity).
-Cardiovascular Disease - Type 2 diabetes mellitus-Non
– alcoholic fatty liver disease (liver steatosis)
-Hyperuricemia (increased blood uric acid)/ gout
-Polycystic ovary syndrome (PCOS)
-Obstructive sleep apnea (snoring with apnea episodes; relation with an 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
Insulin resistance & diabetes mellitus (DM)
-Insulin resistance is a decreased ability of insulin to mediate the metabolic actions on glucose uptake, glucose production, and/or lipolysis.
The prevalence of DM is increasing, parallel with the epidemic of obesity
– it touches 8.4% of the USA population
– but a significant percentage 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 (dextrose) is given orally. 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, and 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 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 recommends 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.
-Blood is drawn at intervals to measure glucose (blood sugar) and sometimes insulin levels. The intervals and number of samples vary according to the test's purpose. For simple diabetes screening, the most critical sample is the 2-hour sample; 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 glucose over 1 hour after the oral administration of 50 grams of glucose. If elevated, this is followed by an examination 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 before the tests.
Impaired fasting glycemia (IFG) and impaired glucose tolerance (IGT)
-Impaired fasting glycemia (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 the USA
-People with IFG or IGT do not have DM but are at substantial risk of developing type 2 DM and cardiovascular disease.
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 autoantibodies to the extracellular domain of the insulin receptor.
Diabetes mellitus results when the beta pancreatic cell function is insufficient to overcome insulin resistance. In type 1 diabetes, the beta-cell function is destroyed. In type 2 diabetes, the beta-cell function cannot overcome insulin resistance. Young women with the insulin–resistant form of polycystic ovary syndrome (PCOS) may also present with type 2 diabetes. However, they have high beta–cell activity and 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 a decrease in the number of functioning beta cells in 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) can be a factor in developing or worsening 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 speeding up oxidative damage to cells and altering their normal behavior.
-AGEs are formed both outside and inside the body. Specifically, they stem from the glycation reaction, which refers to adding a carbohydrate to a protein without the involvement of an enzyme. Glucose can bind with proteins in glycation, making cells stiffer, less pliable, and more subject to damage and premature aging.
-AGEs have a range of pathological effects, such as increased 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
-DM (diabetes mellitus type 2
-Metabolic syndrome
-Obesity
-Asian race
-Tuberculosis (TB) drugs
-SSRIs (medications for depression)
-Pregnancy
-Acromegaly
-Cushing syndrome
-Renal failure
-Polycystic ovary syndrome (PCOS)
-Werner’s syndrome (progeria, precocious aging after puberty).
Medications that may cause insulin resistance
-Thiazides (diuretics)-Beta-blockers
-Statins (!)
-Steroids
-Antipsychotics, including atypical
-Immunosuppressive medications (e.g., tacrolimus & cyclosporine)
-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 of 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. 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 indicate 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.
Primary hyperlipidemia – Fredrickson classification
Secondary causes of hyperlipidemia
-Hypothyroidism
-Excessive alcohol consumption
-Obesity
-High-energy diet, especially saturated fat-rich 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, paraproteinemia, lipodystrophy, autoimmune, pancreatitis, etc.).
Medications that may cause hyperlipidemia
-Beta-blockers
-Corticosteroids
-Estrogen replacement therapy
-Androgen replacement in men
-Cyclosporine and other immunosuppressants
-Antidopamine agents (antipsychotics, metoclopramide, etc.)
-HIV antiretroviral regimens (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)
-Microalbuminuria and renal problems
-Gallstones (cholelithiasis)
-Cancer, e.g., pancreatic
-Fertility and sexual problems (e.g., erectile dysfunction in 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 are classified into two subgroups: the first without atherosclerotic lesions and the second with preclinical atherosclerosis (increased IMT or asymptomatic carotid plaque). Cardiovascular endpoints were investigated in a 20-year follow-up. The study concluded that preclinical atherosclerosis leads to an increased risk of cardiovascular events, mainly if it is associated with metabolic syndrome.
The underlying mechanism of cardiovascular events on the metabolic syndrome: endothelial dysfunction
-Metabolic syndrome is associated with an increased risk of atherothrombotic cardiovascular events and venous thromboembolism.
-Endothelial-dependent vasodilation 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.
-An interaction between activated endothelium and platelets results in a pro-thrombotic vicious cycle. Enhanced coagulation and impaired fibrinolysis are also 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
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 the 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 is accompanied by decreased arterial compliance. Protecting the endothelium is key to reducing cardiovascular (CV) disease risk.
Endothelial dysfunction reduces compliance or increases 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 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 the 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) -Homocysteine 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 polyunsaturated 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.
The study concluded that compared with control subjects, coronary plaques in metabolic syndrome contain larger lipids. 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 elevated risk for cardiovascular events.
Metabolic syndrome and early carotid atherosclerosis
A study investigated whether metabolic syndrome could 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 a carotid plaque or an increased C-IMT (≥1.0mm) at baseline were excluded from the study. The new occurrence of carotid plaque (early carotid atherosclerosis) and the progression of C-IMT were evaluated.
A total of 370 participants aged over 60 (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, vitamin B12, and total levels. Multiple linear regression analysis showed that the rate of change for C-IMT tended to be associated with the development of metabolic syndrome.
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 essential role in initiating the atherosclerotic process.
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 damage, and renal ischemia.
-Metabolic syndrome also portends a higher risk of cardiovascular disease (CVD) at all stages of CKD (chronic kidney disease), from early renal insufficiency to end-stage renal disease.
Metabolic syndrome and increased homocysteine levels
Hyperhomocysteinemia and metabolic syndrome are established cardiovascular risk factors and are frequently associated with hypertension.
Α study investigated the association of homocysteine with metabolic syndrome and stroke & heart attack events in hypertension.
In a study of 562 essential hypertensive patients who underwent an accurate assessment of fasting and post-load glucose metabolism, insulin sensitivity, and renal function, the authors measured plasma levels of homocysteine, vitamin B12, folate, and fibrinogen. They assessed the prevalence of metabolic syndrome, coronary heart disease (CHD), and cerebrovascular disease (CVD). The study concluded that elevated plasma homocysteine is associated with metabolic syndrome in hypertensive patients. The prevalence of events increases with increasing plasma homocysteine levels, suggesting its contribution to cerebrovascular (stroke) and cardiovascular (heart attack) diseases in these patients.
Obesity, metabolic syndrome and androgen levels in men and women
-The presence of obesity and metabolic syndrome in men and women is associated with an increased risk of cardiovascular disease and hypertension.
-In men, obesity and metabolic syndrome are related to 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 increased androgen levels. In women, increases in androgens are associated with increases in inflammatory cytokines, and reducing androgens reduces inflammation.
Metabolic Syndrome and androgen levels in 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 aged 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. 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 the incident metabolic syndrome.
Metabolic syndrome and polycystic ovary syndrome (PCOS)
-Polycystic ovary syndrome (PCOS, also known as Stein–Leventhal syndrome) is the most common endocrine and metabolic disorder affecting women of reproductive age.
-Women with PCOS have a 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.
-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 of 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 were recorded, and the resulting four groups were compared.
Even though metabolic syndrome and PCOS have many similarities, they are distinct disorders. PCOS does not appear to merely 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.
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-hour monitoring. -These similarities have prompted several recent investigations in abdominally obese adults that reported significant reductions in truncal and visceral fat and improved insulin sensitivity following prolonged GH administration.
Other studies have shown that insulin resistance and glucose concentrations transiently worsen during the first few weeks of GH treatment. These deleterious effects can persist even after VAT reduction.
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 a vital role in childhood growth and continues to have anabolic effects in adults.
-A synthetic analog of IGF-1, mecasermin, is used to treat growth failure (failure to thrive, i.e., inadequate weight gain or inappropriate weight loss, in pediatric patients).
-IGF-1 is a primary mediator of growth hormone (GH) effects.
-Growth hormone is made in the anterior pituitary gland, is released into the bloodstream, and then stimulates the liver to produce IGF-1.
-IGF-1 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 individually associated 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). The study concluded that serum 25(OH)D (vitamin D) is inversely associated with metabolic syndrome. In contrast, 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.
Metabolic syndrome & decreased IGF – 1 levels; implications on lifespan!
-In humans, 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 decreases typically during aging; however, centenarians were reported to maintain significantly increased insulin sensitivity and had a lower prevalence of metabolic syndrome than 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
Treatment of the metabolic syndrome
-Motivational therapy; 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 triacylglycerols-Mediterranean diet (? ketogenic)
-Antihypertensive drugs, including ACE inhibitors or ARBs, when possible-Hypoglycemic drugs, e.g., metformin and thiazolidinediones (glitazones) for reducing insulin resistance
Statins
-Statins (simvastatin, 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 increases the number of LDL (low-density lipoprotein) membrane receptors, which increases the clearance of LDL cholesterol from circulation. Statins are used to treat hyperlipidemia and are the most effective drugs for lowering LDL (‘bad’) cholesterol.
-Adverse Effects: statins may cause liver problems.
-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 higher if the patient drinks alcohol daily or in substantial 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.
-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 in people taking statins. CoQ10 is often added to 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
Fibrates
-The fibrates are a class of amphipathic carboxylic acids. They are used for various metabolic disorders, mainly hypercholesterolemia, and there are hypolipidemic agents. Commonly prescribed fibrates include bezafibrate, ciprofibrate, clofibrate (mostly obsolete due to side-effect profile, e.g., gallstones), gemfibrozil & fenofibrate.
-Fibrates are used in accessory therapy in many forms of hypercholesterolemia, usually in combination with statins. Clinical trials 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 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:
-Induction of lipoprotein lipolysis
-Induction of hepatic fatty acid (FA) uptake and reduction of hepatic triglyceride Increased 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 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 the 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 the fat breakdown in adipose tissue and free fatty acids available for the liver to produce triglycerides, VLDL, and consequently LDL (‘bad’)-cholesterol.
-The decrease in free fatty acids also suppresses the hepatic expression of apolipoprotein c3 (APOC3) and PGC-1b, thus increasing VLDL turnover and reducing its production. It also inhibits diacylglycerol acyltransferase-2, essential for 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 significant blood glucose changes. Thus, 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 eye's retina, reversible after niacin intake ceases.
-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 eye's retina, reversible after niacin intake ceases.
Medications for diabetes
(1) 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 a low risk of hypoglycemia as compared to the alternative hypoglycemic drugs
-Good effect on LDL-cholesterol and decreases triglycerides.
-Good effect on LDL-cholesterol and decreases triglycerides.
-Adverse effects include gastrointestinal problems
(2) Sulfonylureas (e.g., glyburide, glipizide & glimepiride):
-They stimulate insulin release by pancreatic beta cells by inhibiting the K+ /ATP channel.
-They have an increased risk for hypoglycemia.
-They do not influence LDL-cholesterol.
-They have a lower chance of gastrointestinal (GI) problems than with metformin
(3) Thiazolidinediones (TZDs) (e.g., pioglitazone & rosiglitazone):
-Reduce insulin resistance by activating PPAR - gamma receptor in fat and muscle.
-Have a lower risk for hypoglycemia and a slight increase in HDL-cholesterol.
-Their adverse effects include the increased risk of heart failure, weight gain, higher risk of edema & anemia, increased LDL - cholesterol, and hepatotoxicity.
Antihypertensive drugs:
(1) Angiotensin-converting enzyme (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 block the conversion of angiotensin I (AT-I) to angiotensin II (AT-II), causing vasodilation, reducing the secretion of antidiuretic hormone (ADH, vasopressin), and reducing production and secretion of aldosterone, among other actions. The combined effect reduces blood pressure. -Their primary uses are in treating hypertension, diabetic nephropathy, and congestive heart failure.
-Adverse effects include hyperkalemia, angioedema, and persistent dry cough.
(2) 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, vasopressin), and reducing production and secretion of aldosterone, among other actions. The combined effect reduces blood pressure. -Their primary uses are in treating hypertension, diabetic nephropathy, and congestive heart failure.
-ARBs are used primarily for treating hypertension, where the patient is intolerant of ACE inhibitor therapy due to a dry cough.
-Adverse effects include hyperkalemia. 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 monounsaturated fatty acid)
-high consumption of plant foods (fruits, vegetables, pulses, cereals, nuts, and seeds)-the frequent and moderate intake of wine (better consumed 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.
-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.
Adopting 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.
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. In contrast, 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.
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 of other disorders, including diabetes, stroke, some cancers, and age-related cognitive decline.
-Omega – 3 fatty acids are contained in fatty fish (EPA & DHA)
-The linseed oil contains alpha-linolenic acid (ALA), another omega-3 fatty acid. 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 omit 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 a 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 on 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 a low glycemic index should be preferred.
-The glycemic 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 choose foods with a low glycemic index (GI), as foods with a high glycemic index may predispose us to diabetes and cardiovascular disease. Common foods such as bananas have a high glycemic index, so we should eat them moderately or less.
For a calculator of the glycemic index on foods, see http://www.glycemicindex.com/foodSearch.php
Herbs & dietary supplements that have been studied for treating 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 effects)
-Lecithin
-Plant sterol (phytosterols) & stanol esters, including beta-sitosterol
-Garlic & Kyolic™ (aged garlic extract)
-Pomegranate (pressure-lowering effects)
-Blueberry, green tea and black tea
-Milk thistle/ silymarin and NAC (N- acetylcysteine) (liver detoxification)
-Valerian, Rhodiola, St John's wort, lemon balm (Melissa) & passionflower (relaxing and anti-depressive 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
-Spirulina & Chlorella (algae)
-Wheatgrass
-Soy protein (cholesterol-lowering effects)
-Resveratrol (a substance in red wine that may offer longevity)
-Quercetin (e.g., from onions)
-Pterostilbene
-Fisetin (e.g., from strawberry)
-Flavonoids & polyphenols / OPCs (Oligomeric Proanthocyanidins) from grape seed extract or pycnogenol (pine bark extract).
Thanks for reading!
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., Davidson 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)
(Retrieved 01-18-2015)
• http://www.diapedia.org/other-types-of-diabetes-mellitus/drug-induced-diabetes
• http://www.ncbi.nlm.nih.gov/pubmed/25208056
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• http://www.ncbi.nlm.nih.gov/pubmed/24168445
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• 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
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• http://www.umm.edu/imagepages/19302.htm
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• 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://www.umgcc.org/patient_info/dictionaryEn/definition/phytosterol.htm
• http://www.umm.edu/altmed/articles/hypercholesterolemia-000084.htm
• http://biolexikon.blogspot.gr/2010/09/prevalence.html
• http://www.ncbi.nlm.nih.gov/pubmed/25375075
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