Transcript Metabolic syndrome English (power point)

Dr. James Manos (MD)
September 26, 2015
Overview: METABOLIC SYNDROME
(insulin resistance syndrome, syndrome X)
History
• Although the modern era of what
'metabolic syndrome' or 'insulin resistance
have started less than two decades ago
of syndrome X by G.M. Reaven in the late
this syndrome is much longer.
we now call the
syndrome' seems to
with the description
1980s, the history of
• 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 bodyweight 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 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 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-fatherfield-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 endproduct 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 intimamedia 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
established cardiovascular risk factors and
associated with hypertension.
syndrome are
are frequently
• 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 cerebrocardiovascular 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 2year 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/S10966374(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), IGF1
(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 IGF1, 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
(glitazones) for reducing insulin resistance
thiazolidinediones
Statins
• Statins (simvastastin, atorvastatin, fluvastatin, lovastatin,
pitavastatin, pravastatin & rosuvastatin), also known as HMG-CoA
reductase inhibitors, inhibit HMG-CoA reductase (3-hydroxy-3methylglutaryl 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-tomoderate 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 HDLcholesterol.
• 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
characterized by:
Diet
(MedDiet)
• the abundant consumption
monοunsaturated fatty acid)
of
is
olive
a
oil
nutritional
(oleic
model
acid
as
• 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/indepth/glycemic-index-diet/art-20048478
• http://www.mayoclinic.org/diseases-conditions/diabetes/expertanswers/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.JP
G (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)000293/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