Prof. K.M. PrasannaKumar
Prof & Head,
- Dept Of Endocrinology & Metabolism,
M S Ramiah Medical college,
( Bangalore)


INTRODUCTION

Coronary artery disease is the leading cause of death among adult diabetics and accounts for about three times as many deaths among diabetics as among non-diabetics.

· One of the preventable disease prevalent worldwide is coronary artery disease, which has assumed epidemic proportions in India and all over the world. The prevalence has increased from 1.05% in 1960 to about 8 - 9.6% in 1990 in the urban population of India ^1,2 The only major risk factor which seems to be more prevalent in Asian Indians is diabetes mellitus whereas 3 other major risk factors - hypertension, raised cholesterol and cigarette smoking are less among Asian Indians. The comparative study of various risk factors carried out in USA among Asian Indians and local population revealed that Asian Indians had higher prevalence of diabetes mellitus, low HDL and high triglycerides levels. Another important risk factor in Asian Indians is association of diabetes mellitus with insulin resistance, hyper insulinemia and central obesity. Hence one may conclude that higher prevalence of insulin resistance syndrome amongst Asian Indians seems to be the most plausible mechanisms responsible for the metabolic and lipoprotein abnormalities resulting in high prevalence and high mortality from CAD in Asian Indians3.

Pathogenesis Of Coronary Artery Disease In Diabetes

• Macrovascular complications are the most important causes of morbidity, mortality and disability in people with type 2 diabetes mellitus. Diabetes itself is a strong risk factor for CAD. Increased incidence of hypertension, insulin resistance and adverse lipid profile in diabetic patients predisposes to coronary artery disease. This is because of multiple risk factors and complex metabolic disorders characterized by abnormalities in glucose and fat metabolism.
  
  ¨ Hyperglycemia, hyperinsulinemia and insulin resistance may each play a major role in the onset and development of atherosclerosis, which causes arterial wall dysfunction, hematological disturbances and lipid abnormalities through two mechanisms - oxidative stress and non-enzymatic glycation.
  
  ¨ Type 2 Diabetes mellitus begins probably a decade before diagnosis is made and macroangiopathy is the secret and silent killer of type 2 diabetic patients. At diagnosis already about 50% of patients show hypertension or macroangiopathy.
  
  ¨ Phases in the development of type 2 DM - insulin resistance, impaired B cell function, macroangiopathy.
  

  Insulin Sensitivity	Insulin Secretion	Development of Type 2 DM	Macrovascular Disease
  30%	50%	Type 2 DM	50%
  50%	70 - 100%	IGT	40%
  70%	150%	Impaired glucose metabolism	10%
  100%	100%	Normal glucose metabolism	-

  
  

  ¨ Insulin Resistance:
  
  · A condition in which insulin is no longer able to exert a normal biological effect on its target tissues eg: skeletal muscle, adipose tissues and liver. Insulin resistance involves metabolism of three major substrates - glucose, free fatty acid and protein. Skeletal muscles consume most of the energy produced in the body so insulin resistance could be more at this site.
  
  · Hepatic and peripheral insulin resistance and impaired B cell function contribute to hyperglycemia in patients with type 2 DM. Hyperglycemia leads to impaired insulin sensitivity, b cell function. A vicious cycle sets up and maintain a stage of hyperglycemia.
  
  Insulin Resistance Syndrome:
  
  · Characterised by hyperinsulinemia, CAD, dyslipidemia, abdominal obesity, type 2 DM, hypertension, micro albuminuria.
  
  · The sequence of events by which insulin resistance would cause these abnormalities is not clear but the association of these conditions with insulin resistance markedly increased the risk of CAD.
  
  ¨ New Risk Factors:
  
  · In the recent past new risk factors contributed to the pathogenesis of CAD in diabetics.
  
  1) Plasminogen Activator Inhibitor (PAI - 1): It is a fast acting inhibitor of fibrinolysis which alters the balance between thrombosis and fibrinolysis in favour of vascular occlusion. Young survivors of myocardial infarction shows increased level of PAI - 1. It also predicts the recurrence of infarction. Type 2 diabetics have elevated levels of PAI -1 which may increase the risk of thrombosis. Increased PAI - 1 in diabetic patients may not only be a risk factor for myocardial infarction, but also a predictor for poor course during the acute phase. Plasminogen activator inhibitor is synthesized by vascular endothelium and by liver. Hepatic synthesis of PAI - 1 is stimulated by hyper insulinemia. So impaired fibrinolysis may be one of the features of insulin resistance syndrome.
  
  2) Elevated level of proinsulin: Insulin is synthesized from its precursor proinsulin by clevage at two sites followed by removal of pairs of basic amino acid with end product of insulin and 'C' peptide. The intermediate steps in this pathway comprises 65, 66 split and des 64, 65 pro insulin and 32, 33 split and des 31, 32 pro insulin. Actual true insulin comprises much smaller proportion of all molecules being measured as insulin, thus type 2 DM patients are much more deficient in insulin than previously measured. High levels of des 31, 32 pro insulin correlate with cardio vascular risk factors in type 2 DM patients. In patients with acute myocardial infarction, PAI - 1 activity concentrated more closely with those of pro insulin like molecules than with insulin. The recent findings that pro insulin can stimulate PAI - 1 synthesis by aortic endothelium supports the view that pro insulin may be involved in the control of fibrinolysis.
  
  3) Micro Albuminuria as a risk factor in diabetes: Microalbuminuria was identified long back as a predictor of clinical diabetic nephropathy but is increasingly recognized as an important predictor of cardiovascular disease in both diabetics and non-diabetics. Many adverse changes in CVS risk factors have been demonstrated in microalbuminuric diabetic patients such as high blood pressure, triglycerides and fibrinogen. Microalbuminuria may be a manifestation of a more generalized vasculopathy, endothelial damage in arteries contribute to the process of atherothrombotic vascular disease. Elevated levels of von Willebrand factor, a marker of endothelial dysfunction, parallels the development of microalbuminuria in diabetic patients.
  
  ¨ Hyperglycemia and Macrovascular disease:
  
  · Hyperglycemia may reduce the onset and development of macrovascular disease, by affecting the three determinants of atherosclerosis -
  
  Ø Arterial wall dysfunction
  Ø Hematological disturbances
  Ø Lipid abnormalities
  · - by two mechanisms -
  Ø oxidative stress and
  Ø non-enzymatic glycation
  · Arterial wall dysfunction:
  
  Ø Hyperglycemia produces changes in the endothelium, smooth muscle matrix. Endothelium has a major role in the regulation of blood flow and blood pressure, regulation of vascular architecture, regulation of haemostasis and fibrinolysis and regulation of lipoprotein concentration. Endothelial dysfunction is diagnosed at the earliest by the increased levels of markers like - endothelin - 1 and von Willebrand factors - seen in diabetic patients with micro vascular complications.
  
  Ø Endothelium also has important function in regulating the arterial wall tone with secretion of both vasodialatory substances like nitric oxide and vasoconstrictive substances like elastin - 1, thromboxane A2. In normal subjects balance between these substances ensures the maintenance of normal vessel tone, while in diabetes the balance is shifted towards vasoconstriction because of reduced vasodialatory and increased vasoconstrictive secretions.
  
  · In hyperglycemic conditions endothelin affects platelet functions by production of different substances that modulate platelet activity such as prostacyclin, nitric oxide and P-selectin. Vascular smooth muscle cell participate in atherogenesis in two ways - (1) Cellular proliferation with successive migration from media to intima. (2) cholesterol engorgement with transformation into foam cells.
  
  · Reduced vascular distensibility associated with increased wall thickness is characteristic of arterial wall disturbance in diabetic microvascular disease.
  
  ¨ Hematological Disturbances:
  
  · Hyperglycemia is associated with shifts in coagulation towards thrombophilia due to enhanced coagulation and impaired fibrinolysis.
  
  ¨ Lipid Abnormalities:
  
  · Lipid abnormalities in type 2 diabetes mellitus is often associated with increased VLDL and LDL - cholesterol, decreased HDL
  
  - cholesterol and increased triglyceride content in LDL and HDL. The high levels of triglycerides disturbs the metabolism of VLDL and LDL with increased levels of highly atherogenic VLDL. The oxidized LDL plays an important role in the development of atherosclerosis through increased expression of endothelial adhesion molecules such as ICAM - 1.
  
  · Hyperglycemia has several modes of action which involve many metabolic pathways and microvascular complications can be prevented by restoring blood glucose near physiological levels. In diabetes insulin resistance with syndrome - X plays an important role in the pathogenesis of coronary artery disease.
  
  ¨ Lipid changes in Type 2 diabetes mellitus:
  
  · Atherosclerotic vascular disease manifesting itself as coronary - artery disease, cerebro-vascular accident and peripheral vascular disease are the major cause of morbidity and mortality in patients with diabetes. Coronary artery disease mortality is 2-4 fold higher in diabetes than in non-diabetic subjects.
  
  · The pathophysiology of dyslipidemia in Type 2 DM results from metabolic disturbances in glucose and lipid metabolism which may be mediated through a common pathophysiological pathway i.e. through resistance to insulin mediated action on both glucose and lipid metabolism.
  
  · An atherogenic pattern of lipoprotein changes is often present for years prior to development of fasting hyperglycemia and diagnosis of type 2 DM. So impaired glucose tolerance, a milder abnormality of glucose metabolism is related to abnormality of lipids and lipoprotein metabolism and since asymtomatic impaired glucose tolerance may last for years, this long exposure to multiple risk factors may explain why the excess of coronary artery disease develops early in the course of type 2 DM.
  
  · The typical lipoprotein profile associated with type 2 diabetes mellitus includes high triglycerides, low HDL and normal LDL levels. The most consistent change is an increase in very low density lipoprotein - triglyceride level.
  
  LIPOPROTEIN ABNORMALITIES IN DIABETES
  
  

  Lipoprotein	Type 2 DM		Atherogenic modification
  	Poor Control	Good Control
  VLDL - TG	Increased	Normal or Increased	Cholesterol ester rich VLDL
  LDL	Normal	Normal	Glycosylation of LDL apoprotein B LDL susceptible to oxidative modification High proportion of small dense LDL particles
  HDL	Decreased	Normal or Decreased	Decreased HDL2 Increased CETP activity Low paroxonase activity

  
  

  ¨ Triglyceride and very low density lipo protein:-
  
  · Type 2 diabetes mellitus is associated with increased amounts of triglycerides and very low density lipo proteins due to -
  
  Ø Increased flow of substrates particularly glucose and free fatty acids.
  
  Ø Defective clearance of very low density lipo proteins and triglycerides due to decrease in lipo protein lipase activity especially those with moderate - severe hyper triglyceridemia who exhibits both insulin deficiency and insulin resistance.
  
  · In diabetes, due to hypertriglyceridemia, large triglyceride rich very low density lipo protein particles are secreted. This compositional changes in very low density lipo protein may have implication for increased propensity for atherosclerosis.
  
  ¨ High Density Lipo protein metabolism in diabetes:
  
  · High density lipo protein levels are decreased in diabetes due to -
  
  Ø Decreased high density lipoprotein production due to decreased lipo protein lipase activity, because the rate of HDL2 formation is dependent upon the rate of flux of surface components from triglyceride rich lipoprotein which is mediated in part by lipoprotein lipase. When LPL mediated VLDL catabolism is efficient, the availability of surface components for transfer to HDL is increased, whereas impaired VLDL lipolysis results in reduced formation of HDL.
  
  Ø Increased catabolism of HDL, because in hyper triglycerdemia a high rate of transfer of triglycerides to HDL2 results in a triglucerides rich HDL2 that is susceptible to catabolism by hepatic triglyceride lipase.
  
  Ø Increased activity of cholesterol - ester transfer proteins (CETP), which pathologically modifies the lipid composition of sub-populations of apoprotein B containing lipoproteins to form atherogenic b - VLDL like particles. Thus increased CETP activity is pro atherogenic.
  
  Ø Low paroxonase activity - Paroxanase an enzyme associated with HDL has the capacity to hydrolyse some of the products of lipid peroxidation. A recent study demonstrated that a polymorphism in the paroxonase gene is associated with coronary artery disease in type 2 DM, although the effect on the capacity of paroxonase to protect against lipid oxidation is unknown.
  
  ¨ Low Density Lipoprotein metabolism in diabetes:
  
  · Patients with diabetes in reasonable metabolic control have normal LDL cholesterol levels. However, although the absolute number of LDL particles is normal, a number of alterations affect their atherogenic properties and increase their atherogenic potential.
  
  · LDL glycosylation.
  
  Ø Glycosylation occurs both on the apoprotein B and phospholipid components of LDL, resulting in profound functional alternations in LDL clearance and susceptibility to oxidative modifications
  
  Ø Glycosylation of LDL apoprotein B occurs mainly on lysine, residues in the putative LDL receptor binding domain that are essential for the specific recognition of LDL by the LDL receptor. LDL glycosylation increases in correlation with glucose levels and results in significant impairment of LDL receptor mediated uptake which inturn decreases the invivo clearance of LDL.
  
  Ø Advanced glycosylation of an amine - containing phospho lipid component of LDL is accompanied by the progressive oxidative modification of unsaturated fatty acid residues. Thus glycation confers increased susceptibility of LDL to oxidative modification which is considered to be a critical step in its atherogenicity.
  
  Ø LDL glycosylation enhances its uptake by human aortic intimal cells and monocyte derived macrophages, stimulating the formation of foam cells.
  
  Ø Glycosylation and oxidation are closely related and can mutually accelerate each other. The combined glycation and oxidation of LDL generates a product that is more atherogenic than either glycosylated or oxidized LDL alone.
  
  · LDL composition and Insulin resistance:
  
  Ø In insulin resistant patients with type 2 DM the composition of LDL particles are altered, resulting in a preponderance of small triglyceride enriched and cholesterol depleted particles. Preponderance to small dense LDL is associated with an increased risk of CAD independent of the absolute concentrations of LDL cholesterol presumably because these particles are more susceptible to oxidative modification.
  
  LITERATURE REVIEW
  
  The etiology of atherosclerosis is extraordinarily varied. Of the numerous risk factors of atherosclerosis the disorders of lipid metabolism play a central role. Interest in the role of lipo proteins in the origin of atherosclerosis has intensified over the last three decades. In diabetes, the combination of changes in circulating lipoproteins and a high incidence of atheroma is known. So extensive research into the metabolic interactions between carbohydrates and lipids is on. The clinical manifestation of atherosclerosis whether CAD, peripheral vascular disease or cerebro-vascular accident are responsible for high morbidity and mortality in diabetics. It is therefore reasonable to consider diabetics as subjects at high vascular risk. The following studies show us a glimpse of multiple factors involved in the diabetic patients prone for CAD.
  
  Lipo Proteins and Lipid Changes in Type 2 DM
  
  ¨ LDLC/TC are not found to be elevated but HDLC is decreased and triglicerides values are higher in patients with diabetes and CAD. Thus dyslipidemia played an important role in linking NIDDM with increased incidence of CAD23,24.
  
  ¨ Plasma levels and metabolism of lipoprotein molecules in patients with DM depends on several variables, modulating factors as well as DM. The basic nutritional status of the individuals, levels of plasma insulin and porto-hepatic insulin, state of glycemic control, anthropometric features and coexisting complications have to be assessed prior to interpreting the lipid levels in a subject with DM25,26,27.
  
  ¨ Recently HDLC levels has been found related more to the amount of circulating insulin and insulin sensitivity rather than the severity of diabetes or degree of hyperglycemia. In type 2 diabetics, it was found out that institution of therapy with sulfonyl ureas there occurs rise in portohepatic insulin levels which inturn enhances HDL metabolism and rise in its plasma levels 28,29.
  
  ¨ Recent studies have suggested that the pattern of dyslipidemia in Indians varies from that seen among Europeans. The dyslipidemia pattern in Indians is believed to be combination of normal to high cholesterol level with low HDL cholesterol and elevated serum triglyceride levels 30,31.
  
  ¨ Data on hyperlipidemia in a cohort of south Indian NIDDM patients showed that - hypercholesterolemia is as common if not more common than hypertriglyceredemia among diabetic patients. The serum cholesterol levels tend to be higher in women but they also have higher HDLc levels32.
  
  ¨ It was well established that atherosclerosis is a common complication of diabetes and in number of studies the possible alterations of Lp (a) in individuals with both insulin and non-insulin dependent diabetes mellitus have been examined and found that Lp (a) to be an independent risk factor for CAD patients with type 2 DM 19,33.
  
  ¨ In a study conducted at Mayo clinic it was found out the Lp (a) levels are higher in subjects with type 2 DM and CAD, however do not significantly differ from those without CAD 34.
  
  ¨ Later in 1999, an Indian study found out that high levels of Lp (a) along with high prevalence of type 2 DM and low HDL cholesterol levels may render Asian Indians particularly vulnerable to malignant atherosclerosis at a younger age 21.
  
  ¨ IGT and lipid changes:
  
  · The highest lipid adnormality found in IGT patients was decreased HDL then increased triglycerides, increased cholesterol, increased LDL in that order35,36.
  
  · Increased Lp (a) levels have also been found in subjects with impaired glucose tolerance37.
  
  FACTORS INFLUENCING LIPID AND LIPOPROTEIN ABNORMALITIES IN CORONARY RISK PATIENTS.
  
  1. Age and Sex Factors:
  
  · It was found that a population attributable risk of 25% for contracting myocardial infarction before 60 years of age in men with an Lp(a) concentration in the top quartile of the population distribution. The population attributable risk fell to 13% for the 60 - 69 years age group38.
  
  · The relative risk of coronary artery disease is 1.9 in diabetic men and 3.3 in diabetic women after adjustment of other risk factors1.
  
  · It was found out that cholesterol and HDL correlate with increased risk of CAD and that Apo-A1 and triglycerides are strong indicators of CAD in men39 while triglyceride and Apo-B correlate with CAD in women having mean age of 60 years40.
  
  2. Smoking and Alcohol:
  
  · It was found that smoking was significantly associated with premature CAD and it emerged as a non-lipid independent risk factor of CAD in both genders39.
  
  · Preliminary recent studies have shown that alcohol consumption might affect the level of Lp(a) in human plasma in addition to its known effects on LDL and HDL.
  
  3. Obesity and poor glycemic control as a risk factor for CAD:
  
  · A WHO multinational study in 1983 found out that serum triglycerides may be a string indicator for CAD than serum cholesterol in obese NIDDM patients41.
  
  · A study conducted in US in 1995 among American and Western Samoan found that an abdominal obesity measured by BMI correlates well with serum lipid parameters as measured by total cholesterol, total HDL cholesterol ratio, Apo-B and negatively with HDL-1 and HDL-2 cholesterol in men. However in women, BMI levels were significantly associated with HDL-2 cholesterol, triglyceride and insulin42.
  
  · In a study conduced at Wisconsin University in 1992 found out that in subjects with well controlled type 2DM, Lp(a) concentration were not increased43 which was contradicted later by a study conducted in Mayo clinic where it was found that there was no significant association between Lp(a) levels and glycemic control34.
  
  4. Role of diet in alteration of serum lipid and lipoprotein profile(a).
  
  · Lp(a) concentrations are unaffected by conventional lipid lowering dietary treatment and are even increased by dietary trans fatty acid44.
  
  · It was found that change in the total cholesterol in response to increase in saturated fats correlated with base line cholesterol ester transferase activity, total cholesterol, triglycerides and Apo-B. Thus the results have relevance to dietary approaches aimed at reducing the lipoprotein mediated risk of CAD45.
  
  · In a Canadian study on pre-menopausal women, it was found that beef, pork, veal, eggs and milk products reduce significantly plasma cholesterol, HDL, LDL levels when compared to the pre-experimental diet. Lean white fish diet when compared to the experimental diet reduced VLDL triglyceride and also the ratio of LDL to Apo-B. Hence the improvement in the lipid profile with the iso-energetic diet46.
  
  5. Role of drugs in the modification of serum lipid and lipoprotein (a):
  
  · It was found out that treatment with niacin & a combination of niacin and neomycin may have a lipid lowering effect. But it should be viewed cautiously in terms of effectiveness and potential toxicity.
  
  · It was also found that neither treatment with bile sequestrants, HMG CoA reductase inhibitors, norfibric acid drugs have resulted in significant lowering of Lp(a) levels44.
  
  · The most effective Lp(a) lowering treatment is LDL-apheresis which can reduce Lp(a) by 50 - 60%.
  
  · Lp(a) concentration may also be decreased by treatment with estrogen, acetyl cysteine, stanozolol.
  
  · In a Hong Kong study in diabetic patients, it was found that, lovastatin was associated with significant reduction of total cholesterol, LDL-C Beneficial effects on serum triglycerides, HDLS were also observed. Renal function as observed by GFR didn't show significant deterioration. However, serum creatinine and 24 hours protein excretion showed a statistically significant increase. Thus they concluded that effective control of hypercholesterolemia may retard the progression of diabetic nephropathy47.
  
  6. Ethnicity:
  
  Key References
  
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