Review Article
(Syndrome X/ Insulin Resistance Syndrome)
Dr.ISHRAT ALI SIDDIQUI . PROF.J FEELY.
TRINITY COLLEGE RESEARCH CENTRE
PHARMACOLOGY AND THEAPEUTIC
ST ;JAMES HOSPITAL ,
DUBLIN 8 , IRELAND
Definition: Metabolic Syndrome is a cluster of disorders of the body metabolism. Its characteristic including, glucose intolerance hyperinsulinemia hypertriglycermia hypertensin reduced concentration of HDL-cholesterol, and central Obesity are the predominant components.1
This is a review study on metabolic syndrome (MS), with the following objectives:
Study objectives:
1- To assess the utility of clinical definitions of metabolic syndrome (MS)
2 - To identify individuals with increased cardiovascular risk.
3 - To assess the association between MS and arterial stiffness
1. Utility of clinical definitions of MS
For MS definition, the two most commonly used criteria: Are the ATP III (ADULT TREATMENT PANEL III), and the WHO (WORLD HEALTH ORGANIZATION) criteria. 1 At the outset, a brief background into MS (both epidemiological and clinico-pathological profile) is given.
ATP III (Adult Treatment Panel III):
The ATP IIII criterion describes MS, if any three of the following five criteria is present: 3
1 - Hypertension
2 - Excessive Waist Circumference.
3 - High fasting glucose
4 - Hypertriglyceridemia
5 - Low HDL
WHO clinical criteria:
Insulin resistance is identified by 1 of the following criteria:,4
1- Type II D.M
2 - Impaired fasting glucose
3 - Impaired Glucose tolerance.
4 - For those with normal fasting glucose levels (< 110 mg/dl). For back ground population under investigation under hyperinsulinemic, euglycemic conditions.
Plus any 2 of the following criteria:
1 - Antihypertensive medication and / or high blood pressure
(=>140 mmHg systolic or =>90mmHg diastolic)
2 - Plasma triglycerides (=>150mg/dl/=>1.7mmol/l)
3 - HDL Cholesterol (< 35 mg/dl / < 0.9 mmol/l in Men
Or < 39 mg / dl /1.0 mmol/l in Women)
4 - BMI (> 30 Kg /msquare and / or Waist hip ratio > 0.9 in Men or > 0.85 in Women)
5 - Urinary albumin excretion rate (=> 20 μg / min) or albumin: creatinine ratio (=> 30 mg /g/)
0r
WHO.
1 - Diabetes.IFG, or HOMA – IR
2 - Blood pressure (=> 160 systolic or=> 90 diastolic mmHg).
3 - Hypertriglyceridemia (=> 150 mg/dl )
4 - Low HDL ( Men < 35: Women < 39 mg/dl )
5 - Obesity (waist to hip ratio: Men >0.9, Women >0.85 )5
NCEP ATP III clinical criteria for MS:
Risk factors, such as:
1 - Abdominal obesity (waist circumference:
Men > 102 cm (> 40 inches Women > 88 cm (> 35 inches)
2 - Triglycerides (=> 150 mg /dl/=>1.7 mmol/l)
3 - HDL Cholesterol;
Men < 40 mg /dl (< 1.0 mmol/l) Women < 50 mg/dl (< 1.3mmol/l)
4 - Blood pressure (=> 130 mmHg systolic or => 85 mmHg diastolic)
5 - Fasting Glucose (=> 110 mg/dl /=>6.1 mmol/l )
Incidence of MS:
In America, the incidence of MS is increasing over the past ten years, and has reached 61%. One in four adults below the age of forty years has MS.6
Definition of MS: 7
1 - This is the association of insulin resistance in tissues, with hyperinsulinaemia (fasting insulin > 89.4 pmol/L)
2 - Abdominal obesity or central obesity; Waist measure,
Men = 40inches or more (102cm) Women=35inches or more (88 cm).
3 - Hypertension;
Systolic BP = 135 mm Hg
Diastolic BP = 85 mm Hg.
4 - Hyperglycaemia or Fasting Glucose Level = 110 mg/dl or more.
5 - Increase Plasma Triglyceride Level = 150 mg/dl or more
6 - Decrease HDL OR Low HDL [ good ] Cholesterol below;
Men = 40 mg/ dl. Women = 50 mg/ dl.
It has also been argued that MS is not a disease, but a cluster of disorders of our body metabolism. 8 There are five clusters, and the presence of any three will qualify a patient to have MS. These include:
1- High Blood Pressure
2- High Insulin Level
3 -Excessive Body Weight
4-Abnormal Cholesterol Level
5-Low HDL Level and High HDL
Causes of MS:
The exact cause of MS is not known,8 but few factors are associated with MS. They are:9
1 - Obesity
2 - Hypertension.
3 - Pregnancy.
4 - Asian Origin
5 - Acute and Chronic Renal Failure.
6 - Acromegaly
7 - NIDDM
8 - Sympathetic tone Increase
9 - Cystic fibrosis
10-Poly Cystic Ovaries.
11-Ataxia telangiectasia.
Risk factors for MS:
A few risk factors associated with MS have been identified. They are:
Age:
Less than 10% of the patients in their 20s are diagnosed with MS, while 40% are in their 60s.10
Race:
MS is more common in blacks and in Mexican – Americans than among Caucasians.
Also, black women are affected more relative to black men, while white men are relatively more affected.11
Obesity:
1 - Genetically.
2 - Excessive taking fatty meal.
3 - Less Physical work.
4 - Because of Disease.
5 - Excessive Calorie in take 12
History of Diabetes Mellitus (DM):
MS is more common in the following categories of patients:
1 - Family history of type II DM
2 - History of DM during pregnancy (gestational DM)
Others:
1 - Hypertension
2 - Cardiovascular Disease.
3 - PCO.(Polycystic ovary syndrome)
PATHOGENESIS OF MS:
The most of the body glucose is derived from liver and then kidney produce less glucose.13
And this glucose production is used in the brain and all body tissues in the shape of insulin.
Glucocorticoids are also involved in metabolic inflammatory, cardiovascular and in behavioural process. The cause of action in MS has not been appreciated, but clinical findings suggest that glucocorticoids may play an important role.14
Following glucose ingestion, plasma glucose concentration increases, which stimulate Insulin release and may give rise to Hyper-insulinemia and Hyperglycemia.15
Genes may also play role in MS, because MS is reported to be clustered in a family. 16
When insulin hormone is excreted from pancreas, the pancreas loses its ability to absorb glucose from blood. This blood glucose uses body for energy, and because of excessive dietary intake pancreas releases a high level of insulin in the blood stream. However, loss of insulin production may be genetic or secondary to high fat level with fatty deposits in the pancreas.17
2. Studies on the cardiovascular risk pattern for MS
The STRONG HEART STUDY 18
The strong heart study done by Chinali and colleagues in North Dakota in American Indians (USA) between July 1989 and January 1992 used the ATP III criteria .Their main conclusions were .In Women MS is ( p< 0.001 ) more found with similar aged compare with those with out the MS.
After controlling for confounders, the participants with MS had great dimessio, mass and relative wall thickness, and left atrial diameter ( all p < 0.05 ),mid wall shortening ( p < 0.001 ) and mitral E/A ratio ( p< 0.05 ),then participants who did not have the MS.
After different experiment process, high blood pressure ( BP ) and abdominal obesity were the only components of the MS associated with increased LV diameter, only high BP was associated with increased LVmass and prevalence of LV hyper trop( both p < 0.001 ).
The Third National and Nutrition Examination Survey 19- 20
This study was done in Boston (USA) in 2004.
The investigators also used ATP III Criteria to determine the prevalence of MS in the American adolescents (12-19 year-olds) across different ethnic groups. They observed variations across ethnic groups. For example, low HDL and Hypertriglyceridemia were more common in the adult non-Hispanic whites, while they are less common in the non-Hispanic blacks. The investigators also noticed that the incidence of MS was 8 % to 12 % in the non-obese adults, while it is 34 % to 41 % in the obese adults. However, the prevalence of MS was comparable for both boys and girls, as well as across older and younger adolescents.
The Health ABC Study 21
The health ABC Study done by Paul Holvoet et al in Belgium between March 1997 and 1998 looked at the elderly People in the Health, Aging, and Body Composition Cohort (ABC).They used ATP III Criteria, and showed that MS was associated with higher levels of oxLDL due to a higher fraction of oxLDL, but not because of higher cholesterol level. The oxLDL was not the lone predictor of total CHD risk, but high oxLDL showed a greater predisposition to myocardial infarction, suggesting atherothrombotic role.
The Arab American Study 22
The Arab American study done in USA in June 2003 investigated into the prevalence of the MS among Arab Americans. They used both the criteria: ATP III and WHO for the diagnosis of prevalence of MS.
According to ATP III ,this study showed that the rates were similar for men and women aged 20 – 40 years, but higher for women aged >/=50years. According to WHO, this study showed that the rate is higher for men then women aged 20- 49 years, but similar for age >/=50years.
The prevalence of MS based on both this criteria was 23 % (ATP III) and 28 % (WHO). The study also indicated that the prevalence of MS increased with age and BMI. The WHO criteria analysis also showed that glucose intolerance or glucose resistance, as well as high blood pressure were the most common abnormalities in both sexes. However, the ATP III criteria-based analysis showed that low HDL cholesterol was higher in both the sexes. This low HDL is danger for blood vessel, because of the potential for atheroma formation, thereby narrowing and causing arterial stiffness. Therefore, this study suggested that low HDL cholesterol and triglyceride are powerful predictors of insulin resistance than obesity, elevated blood pressure or FPG. However, in the presence of obesity, the risk of coronary heart disease is greatly increased.
The ARIC Study 23
The ARIC study was done in North Carolina (USA) between 1987 and 1989 to determine the prevalence of Coronary Heart Disease and Carotid Arterial thickening. The investigators used ATP III criteria, and studied different racial and age groups. The main findings of this ARIC study were that women alone with MS had a significant association with increasing low density lipoprotein cholesterol. CHD prevalence was 7.4 % compared to 3.6 % prevalence in the comparison subjects ( p < 0.0001 ). In other words, MS patients were 2 times as more likely to have CHD as those without MS. The study also indicated that the average intimal–medial wall thickness of carotid arteries was greater among the MS patients versus those with out MS.
The Greenland Study 24
The prevalence of the MS among the Inuit in Greenland.A Comparison b/w two proposed definition .Study by M.J.Jorgensen et all in Denmark in b/w 1999 and 2001.
They used both the criteria, WHO, ATP III. This study compared WHO Syndrome men with NCEP Syndrome, and found higher mean values of waist circumference, BMI and triglycerides and lower mean values of high – density lipoprotein ( HDL ) Cholesterol.among women,triglycerides were higher NCEP Syndrome.
The study also indicated increased prevalence of D.M, because of impaired tolerance and obesity, together with higher physical inactivity levels. All this may have caused increased insulin resistance. According to WHO definition, 37.9 % did not have MS, while according to NCEP Syndrome definition 28.5 % had MS.
The investigators showed that MS is increased with age in men in both the syndrome and women were affected only when they became older. Men with WHO Syndrome had lower waist circumference and triglyceride levels but HDL cholesterol was higher in women. However, the level of risk is same except from HDL cholesterol, which was higher according to WHO Syndrome.
Glucose abnormality is also higher in women with WHO Syndrome but in NCEP syndrome 72% of women with IGT and 43% of women with Diabetes were not classified as glucose intolerance. Obesity was much higher with WHO than NCEP. Hypertension was high according to NCEP, because of lower thresholds. The study indicated that prevalence of these two syndromes is equal, while abdominal fat seems to be a greater risk factor than obesity. Blood pressure was higher according to WHO. Microalbuminuria was associated with endothelial dysfunction and with increased risk for CVD, both in diabetic or non-diabetic patients. NCEP Syndrome showed increased IHD mortality, while WHO Syndrome showed increased CVD mortality.
This study is done by Marchesini G et al in 1999 in Bologna, Italy. The investigators employed both WHO and ATP III criteria for the definition of the Metabolic Syndrome in patients with Type 2 diabetes. They found that according to WHO criteria microalbumina has the highest specificity (99 %), while visceral obesity has the highest sensitivity (93 %) for MS.
ATP III criteria showed that hypertension was the most sensitive criterion and low HDL-Cholesterol the most specific (95 %). Positive waist circumference and low HDL Cholesterol were both associated with CHD. Based on the WHO criteria, waist circumference is identified in large proportion of males, while based on ATP III criteria visceral adiposity is more common in females.25
3. METABOLIC SYNDROME CAUSE ARTERIAL STIFFNESS
The mechanisms of development of vascular stiffness is largely unknown. 28
In Metabolic Syndrome, mainly two risk factors are important contributors to the development of atherosclerosis. These are High Density Lipoproteins (HDLs) and Low Density Lipoprotein (LDLs).
The formation of an atherosclerotic plaque is some form of damage to arterial wall, and this damages the endothelial cells of the tunica intima. Other contributing risk factors are: smoking, poor diet (high saturated fatty intake such as cholesterol), stress, lifestyle and social factors.26
Schiffrin has shown that arterial stiffness is increased with advance age and other CV risk factors may role in arterial stiffness, such as Hypertension ,MS,Diabetes,Obesity, Hypercholesterolemia and C-reactive protein.27
Arterial Stiffness is related with Insulin resistance in Non Diebetic Hypertensive Older Adult is done by Sendstock DM,et all in university of Michigan.
They recruited 60 to 80 year age ,and measuring pulse pressure and carotid – femoral pulse wave velocity to find out arterial stiffness ,they say that PWVand PP were negatively correlated with SI,and after multiple regression analysis .PWV and PP remained independtly correlated with SI .( P< 0.005 ).28
TECHNIQUE FOR ARTERIAL STIFFNESS MEASUREMENT
Metabolic Syndrome can be diagnosed with invariable investigation is done by tap measure and a few simple blood test6,and also for to find out the cause of arterial stiffness, we take pulse pressure and carotid – femoral pulse wave velocity and different BP reading ,systolic and diastolic with the help of sphygmomanometer.27
In supine position connect EKG lead and record heart rhythm continuously. Pulse pressures (PP) was calculated by subtracting these measurements. We marked mid point of manubrium to locate maximal impulse of the right common carotid and right common femoral artieries pulses. To approximate the length of the descending aorta, the distance from the midpoint of the manubrium maximal pulse of the right carotid artery was subtracted from the distance from the midpoint of the manubrium to the maximal pulse of the right femoral artery ‘1 aorta (mm)’.A hand –held high-fidelity tometer (SPC-301,Millar instruments, Houston.TX ) placed over the maximal impulse of the carotid artery to achieve a pressure wave contour with a consistent baseline, contour, and amplitude. A twenty – second time span of these carotid pulse contours were recorded ( At Cor version 7.0 ).The average time ‘t C ( msec )’between each R-wave on the EKG and the food of the corresponding carotid pressure waveform was calculated. Similarly, the tonometer was placed over the maximal impulse of the right common femoral artery to calculate ‘tf ( msec )’.PWV ( m / sec) was then calculated by the equation PWV =1 aorta / ( tf-tC).
A measurement was excluded if the pressure contour was of poor quality or if a significant difference (>15%) in the heart rate was found between the carotid and femoral measurements.28
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