Syndrome - X or Metabolicsyndrome What is it? Is it important? How common is it? What should be done about it?
What is it? Metabolic syndrome is a combinationof medical disorders that, when occurring together,increase the risk of developing cardiovasculardisease and diabetes. It affects about 20% of the Malaysian populationand prevalence increases with age. There are slight differences in the criteria ofdiagnosis - depending on which authority isquoted. Regardless, the concept of a clustering of risksfactors leading to cardiovascular disease is wellaccepted.
How do we define who has metabolicsyndrome? International Diabetes Federation The IDF consensus worldwide definition of the metabolic syndrome(2006) is: A) Central obesity (defined as waist circumference with ethnicityspecific values) AND B) any two of the following: 1. Raised triglycerides: > 150 mg/dL (1.7 mmol/L), or on treatmentfor this lipid abnormality. 2. Reduced HDL cholesterol: < 40 mg/dL (1.03 mmol/L) in males, <50 mg/dL (1.29 mmol/L) in females, or specific treatment for thislipid abnormality 3. Raised blood pressure: systolic BP > 130 or diastolic BP >85 mmHg, or treatment of previously diagnosed hypertension. 4. Raised fasting plasma glucose :(FPG)>100 mg/dL (5.6 mmol/L),or previously diagnosed type 2 diabetes. (If BMI is >30 kg/m², central obesity can be assumed and waistcircumference does not need to be measured)
The World Health Organization criteria (1999)require presence of one of: Diabetes mellitus / Impaired glucose tolerance /Impaired fasting glucose or Insulin resistance, AND two of the following:1.Blood pressure: ≥ 140/90 mmHg2.Dyslipidemia: triglycerides (TG): ≥ 1.695 mmol/Land high-density lipoprotein cholesterol (HDL-C) ≤0.9 mmol/L (male), ≤ 1.0 mmol/L (female) 3. Central obesity: waist:hip ratio > 0.90 (male); >0.85 (female), or body mass index > 30 kg/m2 4. Microalbuminuria: urinary albumin excretion ratio≥ 20 µg/min or albumin:creatinine ratio ≥ 30 mg/g
The European Group for the Study of InsulinResistance (1999) requires : A) Insulin resistance - defined as the top 25% of thefasting insulin values among non-diabetic individuals, AND two or more of the following: 1. central obesity: waist circumference ≥ 94 cm(male), ≥ 80 cm (female) 2. dyslipidemia: TG ≥ 2.0 mmol/L and/or HDL-C <1.0 mmol/L or treated for dyslipidemia 3. hypertension: blood pressure ≥ 140/90 mmHg orantihypertensive medication 4. treatment for diabetes mellitus
The US National Cholesterol Education ProgramAdult Treatment Panel III (2001) requires atleast three of the following: 1. central obesity: waist circumference ≥ 102 cmor 40 inches (male), ≥ 88 cm or36 inches(female) 2. dyslipidemia: TG ≥ 1.7 mmol/L (150 mg/dl) 3. dyslipidemia: HDL-C < 40 mg/dL (male), <50 mg/dL (female) 4. blood pressure ≥ 130/85 mmHg 5. fasting plasma glucose ≥ 6.1 mmol/L(110 mg/dl)
American Heart Association 1. Elevated waist circumference:◦ Men — greater than 40 inches (102 cm)◦ Women — greater than 35 inches (88 cm) 2. Elevated triglycerides: Equal to or greater than150 mg/dL (1.7 mmol/L) 3. Reduced HDL (―good‖) cholesterol:◦ Men — Less than 40 mg/dL (1.03 mmol/L)◦ Women — Less than 50 mg/dL (1.29 mmol/L) 4. Elevated blood pressure: Equal to or greater than130/85 mm Hg or use of medication for hypertension 5. Elevated fasting glucose: Equal to or greater than100 mg/dL (5.6 mmol/L) or use of medication forhyperglycemia
Ethnic specific values for waistcircumference (IDF) Europids Male ≥ 94 cm Female ≥ 80 cm South Asians Male ≥ 90 cm Female ≥ 80 cm Chinese Male ≥ 90 cm Female ≥ 80 cm Japanese Male ≥ 85 cm Female ≥ 90 cm(Ethnic South and Central Asians Use South Asianrecommendations).
Some other factors High-sensitivity C-reactive protein (hs-CRP) hasbeen developed and used as a marker to predictcoronary vascular diseases in metabolicsyndrome and it was recently used as apredictor for non-alcoholic fatty liver disease . Lahey Clinic Study— 50-60% of Patients <45 years old, whosuffered MI had Metabolic Syndrome, a meanBMI of approximately 32.(The Framingham Risk scores of these patients is typically verylow—because age is low)
Note ―Until much needed research is completed,clinicians should evaluate and treat allCVD risk factors without regard to whethera patient meets the criteria for diagnosisof the ‗metabolic syndrome‘.‖Joint Statement from the AmericanDiabetes Association and the EuropeanAssociation for the Study of Diabetes.
Risk Factors Several associated risk factors include: 1. Genetic Factors: (inherited component):◦ Family history of type 2 diabetes;◦ Being Black, Hispanic, American Indian or Asian. South Asians in urban and migrant environmentsmay be at a higher risk of CHD due to theconfluence of1. genetic factors that predispose to highercholesterol levels, and a possible "thrifty gene"effect, with2. environmental influences that lead to weightgain
2. Particular physiological conditionsand environmental factors:◦ > 40–45 years of age;◦ obesity◦ your body storing fat predominantly inthe abdomen, as opposed to storing it inhips and thighs.◦ sedentary lifestyle, lack of physicalexercise◦ hypertension
◦ 3. Pre-diabetes, your sugar levels inblood have been too high in the past, i.e.your body has previously shown slightproblems with its production and usage ofinsulin ("previous evidence of impairedglucose homeostasis");◦ having developed gestational diabetesduring past pregnancies;◦ giving birth to a baby weighing more than9 pounds (a bit over 4 kilograms).
More risk factors• Urban populations have higher levels of CVDrisk factors related to diet and physicalactivity (overweight, hypertension,dyslipidaemia and diabetes)• Tobacco consumption is more widelyprevalent in rural population• The social gradient will reverse as theepidemic populations mature. The poor willbecome progressively vulnerable to theravages of these diseases.
History The term "metabolic syndrome" datesback to at least the late 1950s, but cameinto common usage in the late 1970s todescribe various associations of riskfactors with diabetes that had been notedas early as the 1920s. The Marseilles physician Dr. Jean Vague,in 1947, observed that upper body obesityappeared to predispose to diabetes,atherosclerosis, gout and renal calculi.
In 1988, in his Banting lecture, Gerald M.Reaven proposed insulin resistance as theunderlying factor and named theconstellation of abnormalities Syndrome X.
INSULIN RESISTANCE IS THE MAINPATHOLOGY BEHIND SYNDROME X
How Insulin Acts• Any food or drink containing glucose (or thedigestible carbohydrates that contain it, suchas sucrose, starch, etc.) causes blood glucoselevels to increase.• In normal metabolism, the elevated bloodglucose level makes beta (β) cells inthe Islets of Langerhans, located inthe pancreas, release insulin into the blood.
Insulin attaches toglucose-insulin receptorson cell membranes toallow glucose to be takeninto the cell. GLUT4 is the insulin-regulated glucosetransporter foundin adipose tissuesand striatedmuscle (skeletal andcardiac) that is responsiblefor insulin-regulatedglucose translocation intothe cell.
Glucose Transporter 4 Receptor The GLUT4 protein is expressed primarily inmuscle and fat cells, the major tissues in thebody that respond to insulin. Under conditions of low insulin, GLUT4 issequestered in intracellular vesicles in muscleand fat cells. Insulin induces the translocation of GLUT4from these vesicles to the plasma membrane. As the vesicles fuse with the plasmamembrane, GLUT4 transporters are insertedand become available for transportingglucose, and glucose absorption increases.
Glucose transporter 4, also knownas GLUT4, is a protein receptor that inhumans is encoded by the GLUT4 gene.
• If the cell phospholipid membrane is not ―fluid‖ enough (i.e.its composition does not have enough PUFA), insulinreceptors are disrupted.• The insulin cannot act and glucose cannot enter the cells,and thereby lower the blood glucose level.• The beta cells reduce insulin output only if the bloodglucose level falls, allowing blood glucose to settle at aconstant of approximately 5 mmol/L (90 mg/dL).• In IR states, insulin levels remain high, and this promoteslipogenesis.
When these cells fail to respond adequately tocirculating insulin, blood glucose levels rise. Without insulin, the liver is unable to useglucose, and therefore secretes glucagon,which further increases blood sugar byconverting liver glycogen (stores) into glucose. Glucagon also regulates the rate of glucoseproduction through lipolysis (breakdown ofstored lipids in adipocytes). This raises serum lipid levels.
Insulin keeps the blood sugar and cholesterol incontrol by influencing their intake and output inliver, muscle and fat cells.
Insulin resistance Insulin resistance (IR) is a condition wherethe natural hormone insulin becomes lesseffective at lowering blood sugars. The resulting increase in blood glucose maycause adverse health effects, depending ondietary conditions. Most cell types, especially fat andmuscle cells require insulin to absorbglucose.
Insulin resistant states• In an insulin-resistant person, normal levels ofinsulin do not have the same effect incontrolling blood glucose levels.• During the compensated phase, insulin levelsare higher, and blood glucose levels are stillmaintained.• If compensatory insulin secretion fails, theneither fasting (impaired fasting glucose) orpostprandial (impaired glucose tolerance)glucose concentrations increase.
• Eventually, type 2 diabetes occurs whenglucose levels become higherthroughout the day as the resistanceincreases and compensatory insulinsecretion fails.• The elevated insulin levels haveadditional effects that cause furtherabnormal biological effects throughoutthe body.
More on insulin resistance In IR, reduced muscle glucose uptake, andincreased liver glucose production allcontribute to elevated blood glucose levels. Other functions of insulin can also be affected. Insulin resistance in fat cells reduces thenormal effects of insulin on lipids and resultsin reduced uptake of circulating lipids andincreased hydrolysis of stored triglycerides.
Increased mobilization of stored lipids and reduceduptake in the cells elevates free fatty acids inthe blood . Elevated blood fatty-acid concentrations leads toatherosclerosis and cardiovascular disease.
Diet It is well known that insulin resistance commonlycoexists with obesity. Saturated fat appears to be the most effective atproducing IR. High-fat diet has the tendency to result in caloricintake thats far in excess of our energy needs,resulting in rapid weight gain. Being insensitive to insulin is positively correlatedwith fat intake, and negatively correlated with dietaryfibre intake.
PUFA In the long term, diet has the potential tochange the ratio of polyunsaturated tosaturated phospholipids in cell membranes,correspondingly changing cell membranefluidity. It is hypothesized that increasing cellmembrane fluidity by increasing PUFAconcentration might result in an enhancednumber of insulin receptors and reducedinsulin resistance.
• Recent research is investigating the rolesof adipokines (adiponectin - the inflammatorysubstance produced by adipose tissue) in insulinresistance.• Obese patients tend to have lower adiponectinlevels probably due to feedback inhibition by fataccumulation. Adiponectin levels are also lowerin patients with the metabolic syndrome. Certain foods can increase adiponectin in thebody, eg. Sweet potato.
ADVANCED GLYCATED ENDPRODUCTS AGE: Elevated blood levels of glucose –regardless of cause – lead toincreased glycation of proteins with changesin protein function throughout the body. These are called Advanced Glycated Endproducts and contribute to the end organdamages of T2DM.
Visceral fat Unlike subcutaneous adiposetissue, visceral adipose cellsproduce significant amountsof pro-inflammatorycytokines such as tumournecrosis factor-alpha (TNF-a), Interleukins-1 and -6,etc. In numerous experimentalmodels, these pro-inflammatory cytokinesdisrupt normal insulin actionin fat and muscle cells.
Abdominal obesity increases therisk of developing type 2 diabetes<71 71–75.9 76–81 81.1–86 86.1–91 91.1–96.3 >96.324201612840RelativeriskWaist circumference (cm)
Role of leptin Yet another problem in metabolic syndromeinvolves the phenomenon knownas leptin resistance. Leptin is a hormone that regulates long-termenergy balance in many mammals. Leptin is secreted by fatty tissue. An important role of leptin is long-term inhibitionof appetite in response to formation of body fat.
This mechanism is known to bedisrupted in many obeseindividuals: even though theirleptin levels are commonlyelevated, this does not result inreduction of appetite and caloricintake. Once leptin signalling has beendisrupted, the individual becomesprone to further overeating,weight gain, and insulinresistance. Leptin has recently also beenseen to stimulate the genes forlongevity and have anti-agingproperties.
Glycemic index Integrated blood glucose response to a fixedquantity of carbohydrates in a meal is knownas glycemic index. The rise in blood sugar after a carbohydratemeal depends on how quickly it is absorbed. Complex carbs and foods high in fibercause a slower rise in sugar, and reducedinsulin resistance. Some diets are based on this concept; theyassume that consumption of low-GI foods isless likely to result in insulin resistance andobesity
Sedentary lifestyle Sedentary lifestyle increases the likelihood ofdevelopment of insulin resistance. Its been estimated that each 500 kcal/weekincrement in physical activity related energyexpenditure reduces the lifetime risk of type 2diabetes by 6%. A different study found that vigorous exerciseat least once a week reduced the risk of type 2diabetes in women by 33%.
Signs and symptoms of insulinresistance These depend on poorly understood variations inindividual biology and consequently may not befound with all people diagnosed with insulinresistance. 1. Fatigue. 2. Brain fogginess and inability to focus. 3. High blood sugar. 4. Intestinal bloating – most intestinal gas isproduced from carbohydrates in the diet, mostlythose that humans cannot digest and absorb.
5. Sleepiness, especially after meals. 6. Weight gain, fat storage, difficulty losing weight– for most people, excess weight is from high fatstorage; the fat in IR is generally stored in andaround abdominal organs in both males andfemales. 7. Increased blood triglyceride levels. 8. Increased blood pressure. Many people withhypertension are either diabetic or pre-diabeticand have elevated insulin levels due to insulinresistance. One of insulins effects is to control arterial walltension throughout the body.
9. Increased pro-inflammatory cytokinesassociated with cardiovascular disease. 10. Depression. Due to the deranged metabolismresulting from insulin resistance, psychologicaleffects, including depression, are notuncommon. 11. Acanthosis nigricans. 12. Increased hunger.
Diagnosis Glucose tolerance testing (GTT) During a glucose tolerance test, which may beused to diagnose diabetes mellitus, a fastingpatient takes a 75 gram oral dose of glucose. Blood glucose levels are then measured over thefollowing 2 hours. Interpretation is based on WHO guidelines. After 2 hours a1. Glycemia less than 7.8 mmol/L (140 mg/dl) is considerednormal,2. a glycemia of between 7.8 to 11.0 mmol/dl (140 to197 mg/dl) is considered as Impaired GlucoseTolerance(IGT) and a3. glycemia of greater than or equal to 11.1 mmol/dl(200 mg/dl) is considered Diabetes Mellitus
Multiple risk factor management Goals: Minimize Risk of Type 2Diabetes and Cardiovascular Disease Obesity Glucose Intolerance Insulin Resistance Lipid Disorders Hypertension
The primary treatment for insulinresistance is exercise and weight loss. Low-glycemic index diet has also beenshown to help. Low salt diet helps reduce blood pressureand improves insulin sensitivity. Both metformin and the thiazolidinedionesimprove insulin resistance, but are onlyapproved therapies for type 2 diabetes, notinsulin resistance.
Diabetes control For every 1% rise in Hgb A1c there is an 18%rise in risk of cardiovascular events & a 28%increase in peripheral arterial disease Evidence is accumulating to show that tight bloodsugar control in both Type 1 and Type 2 diabetesreduces risk of CVD Goals: FBS - premeal 90-130, postmeal<180. Hgb A1c <7%
Hypertension controlBP >130/85 or on Rx for previouslydiagnosed hypertension. Goal: BP.<130/85 MRFIT and Framingham Heart Studies:◦ Conclusively proved the increased risk of CVDwith long-term sustained hypertension◦ Demonstrated a 10 year risk of cardiovasculardisease in treated patients vs non-treatedpatients to be 0.40.◦ 40% reduction in stroke with control of HTN
DYSLIPIDEMIA Goals: HDL >40 mg% (>1.1 mmol /l) LDL <100 mg/dL (<3.0 mmol /l) TG <150 mg% (<1.7 mmol /l) Multiple major studies show 24 - 37% reductionsin cardiovascular disease risk with the control ofhyperlipidemia. Increased HDL cholesterol can be achieved withincrease in marine omega 3 fats intake.
SURGERY? Recent research has shown that weight reducingsurgeries like gastric banding and roux-en-ygastric bypass can cure T2DM and IR,irrespective of associated weight loss. The mechanisms of this effect are still beingstudied.
Type 2 diabetes has long been regardedas inevitably progressive, requiringincreasing numbers of oral hypoglycemicagents and eventually insulin, but it isnow certain that the disease process canbe halted with restoration of normalcarbohydrate and fat metabolism. Type 2 diabetes can be understood as apotentially reversible metabolic stateprecipitated by the single cause of chronicexcess intraorgan fat.
Reversal of type 2 diabetes to normalmetabolic control by either bariatricsurgery or hypocaloric diet allows for thetime sequence of underlyingpathophysiologic mechanisms to beobserved. In reverse order, the same mechanismsare likely to determine the events leadingto the onset of hyperglycemia and permitinsight into the etiology of type 2diabetes. Roy Taylor, MD, FRCP, DiabetesCare. 2013;36(4):1047-1055.
Within 7 days of instituting a substantialnegative calorie balance by either dietaryintervention or bariatric surgery, fastingplasma glucose levels can normalize. Thisrelates to a substantial fall in liver fatcontent and return of normal hepaticinsulin sensitivity. Over 8 weeks, insulin secretion steadilyreturn to normal, and this change is instep with steadily decreasing pancreaticfat content.
New Perspectives on the β-cell Defect Chronic exposure of β-cells to triacylglycerolor fatty acids decreases β-cell capacity torespond to an acute increase in glucoselevels. The cellular process of insulin secretion inresponse to an increase in glucose supplydepends on ATP generation by glucoseoxidation. However, in the context of anoversupply of fatty acids, such chronicnutrient surfeit prevents further increases inATP production.
Fatty acids have been shown to inhibit β-cell proliferation, and this effect ismagnified by increased glucoseconcentration. Histological studies of the pancreas intype 2 diabetes consistently show an~50% reduction in number of β-cellscompared with normal subjects. β-Cell loss appears to increase asduration of diabetes increases.
In light of new knowledge about β-cellapoptosis and rates of turnover duringadult life, it is conceivable that removal ofadverse factors could result in restorationof normal β-cell number, even late in thedisease. Regeneration of β-cells is seen aftersuccessful bariatric surgery or Incretinbased therapies.
The twin cycle hypothesis of the etiology oftype 2 diabetes.
Betatrophin Researchers at Harvard University discoveredthat the hormone, called betatrophin, promotesthe growth of Beta cells in the pancreas in mice. The scientists found the hormone caused miceto produce these cells at 30 times the normalrate. Rather than having to take daily injections ofinsulin to control the amount of sugar in theirblood, patients would need to take this newhormone just weekly or even monthly,according to the researchers. Dr Melton added, however, that the work wasstill in the early stages and it would be severalyears before a treatment using the hormonecould be used by humans. From the Telegraph, 26 Apr 2013
Testostorone Testosterone replacement reverses insulinresistance in hypogonadal men with type 2diabetes, preliminary data suggest. Thefindings, from a randomized trial in 81 men,were reported by Paresh Dandona, MD, PhD,head of the division of endocrinology,diabetes, and metabolism at the University ofBuffalo, State University of New York. American Association of Clinical Endocrinologists2013 Scientific & Clinical Congress Abstract 280,presented May 2, 2013.
Prevention There is an urgent need to increase awarenessof the CVD burden, and develop preventivestrategies. Prevention and treatment strategies that havebeen proven to be effective in developedcountries should be adapted for developingcountries. Prevention is the best option as an approachto reduce CVD burden.
Screening 1. Public Education 2. Screening for at risk individuals:◦ Blood Sugar/ HbA1c◦ Lipids◦ Blood pressure◦ Tobacco use◦ Body habitus◦ Family history
Calculating Mortality Risk in T2DM Gargano Mortality Risk ScoreAll-cause 2-year mortality risk score inpatients with type 2 diabetes mellitus. Using variables like age, body mass index(BMI), diastolic blood pressure, LDLcholesterol, triglycerides, HDLcholesterol, urine albumin-to-creatinine ratio, antihypertensivetreatment, and insulin therapy — aphysician can quickly determine whether apatient has a high risk for death. http://www.operapadrepio.it/rcalc/rcalc.php
DIET Carbohydrates:1.Eat according to energy requirements and as perenergy expended.2.Eat complex carbohydrates and fibre. Proteins1.Choose a wide variety of sources, bothVegetarian and Non-vegetarian over the week2.Restrict intake to 30 gms per meal (size of adeck of cards) Fats1.Choose vegetable fats2.Eat 1 helping of oily fish at least 2 -3 days aweek3.Snack on nuts
Life-Style Modification Exercise◦ Improves CV fitness, weight control,sensitivity to insulin, reduces incidence ofdiabetes◦ Goal: Brisk walking - 30 min./day Weight loss◦ Improves lipids, insulin sensitivity, BPlevels, reduces incidence of diabetes◦ Goal: 10% reduction in body wt.
Basic recommendations are1.3 days a week = aerobics 20 mins +weight training (anaerobics) 10 mins2.2 days a week = aerobics 20 mins +flexibility and core exercises 10 mins.3.Saturday and Sunday = games or outdooractivities you enjoy WITH family andfriends , 20 – 30 mins. Even walking willdo!
SMOKING CESSATION Both passive and active exposure harmful A major risk factor for:◦ insulin resistance and metabolicsyndrome◦ Macro-vascular disease (PVD, MI,Stroke)◦ Micro-vascular complications of diabetes◦ pulmonary disease, etc.
SLEEP People who go to bed late and sleep in latetypically have a greater degree of "circadianmisalignment" between their actual sleep-wake pattern and their natural body clock. Studies have linked such misalignment with ahost of ailments, including coronary arterydisease, metabolic syndrome, and impairedglucose tolerance. The implications of the study are that peoplewith type 2 diabetes might do well to get tobed earlier, wake up earlier, and try to keepas regular a schedule as possible. Diabetes Care. Published online May 1, 2013.
Key Points• There is an urgent need to increaseawareness of the CVD and T2DM burden, anddevelop preventive strategies.• Prevention and treatment strategies thathave been proven to be effective indeveloped countries should be adapted fordeveloping countries.• Prevention is the best option as an approachto reduce CVD and T2DM burden.