DIABETES MELLITUS AND ATHEROSCLEROSIS

Zeljko Metelko, Ivana Pavlic-Renar, Zdravko Babic

Vuk Vrhovac Institute, University Clinic for Diabetes,
Endocrinology and Metabolic Diseases
Dugi dol 4a, HR-10000 Zagreb, Croatia

Received: February 25, 2000

Key words: atherosclerosis, diabetes mellitus

SUMMARY

INTRODUCTION

Atherosclerotic cardiovascular disease (1) is one of the most common complications of diabetes (2,3). It is found in about 75% of diabetic deaths as compared with 30% in diabetes-free patients in North America (2). Diabetic patients are at a 2- to 4-fold risk of coronary artery diseases recorded in diabetes-free individuals (2,4). In diabetes-free individuals, the risk of the development of carotid artery atherosclerosis has been found to increase with hypercholesterolemia associated with an elevated level of low density lipoprotein (LDL) (5) and low level of HDL (6). Similar findings have been reported for hypertriglyceridemia (7,8).

DIABETES MELLITUS

Diabetes mellitus can be simply defined as an absolute or relative insulin deficiency (insulinopenia) with consequential hyperglycemia. Long-term hyperglycemia can result in the development of late complications of diabetes mellitus, involving large and small blood vessels, nerves, and basal membrane of various tissues (9).

The syndrome of diabetes mellitus includes a number of disorders the etiology of which has not yet been fully clarified. Insulin dependent diabetes mellitus (type I) occurs in susceptible individuals, with autoimmune process mediated destruction of islet b -cells, triggered by certain environmental factors. The main features of non-insulin dependent diabetes mellitus (type II) are impaired insulin secretion and peripheral tissue resistance to insulin action, with an even more pronounced role of inheritance (9).

Maintenance of the cellular glucose intake requires about 40 m U insulin/mL, inhibition of lipolysis 15 m U/mL, and inhibition of gluconeogenesis 12 m U/mL, whereas glycogenolysis is inhibited by as little as 6 m U/mL. Thus, lipolysis, gluconeogenesis and glycogenolysis are prevented by 10-20 m U/mL. A hungry man has 3-9 m U insulin/mL blood, and then the processes of lipolysis, gluconeogenesis and glycogenolysis are active. Upon food intake, the concentration of insulin rises, however, it does not happen in diabetic patients. The degree of insulinopenia depends on the metabolic disturbance severity. Glucose transport to muscle and fatty cells is the most delicate step, so hyperglycemia with consequential glucosuria and osmotic diuresis is the first sign of insulin deficiency (Fig. 1).

Figure 1. Changes in type I diabetes mellitus

Figure 2. Changes in type II diabetes mellitus

Type I diabetes mellitus is characterized by marked decrease in the concentration of insulin, which leads to hyperglycemia and osmotic diuresis (Fig. 1). This entails protein and fat breakdown, the patient loses weight, and becomes acidotic and ketotic. The lack of insulin as well as of glucose as a substrate stimulates intracellular glycogenolysis, gluconeogenesis and lipolysis, in addition to hyperglycemia (9).

Lipolysis and free fatty acid oxidation result in acetyl-CoA excess and formation of acetoacetyl-CoA, then of beta hydroxybutyric and acetoacetic acids, and eventually of acetone in amounts that surpass the capacity of utilization. The formation of acetone is one of the compensatory mechanisms by which the liver eliminates excessive acid from the body, therefore ketosis precedes the occurrence of acidosis. The condition may persist for a certain period of time. The process is deteriorated by further insulin decrease. Maximal ketogenesis and impossibility of any further formation of ketones are followed by the accumulation of beta hydroxybutyric acid and acetoacetate, which in turn leads to the occurrence of metabolic acidosis. Hyperglycemia, osmotic diuresis with loss of fluid and electrolytes, dehydration, ketonemia and metabolic acidosis are the features of diabetic ketoacidosis which may exacerbate to coma. In severe hyperosmolar and ketoacidotic states, diminished tissue perfusion increases the concentration of lactic acid due to anaerobic tissue metabolism. Glycolysis only proceeds to pyruvates, because all cytochromes are reduced and Krebs cycle is stopped due to oxygen deficiency. With the formation of lactates from pyruvates, NADH is converted into the indispensable NAD, however, accompanied by the accumulation of lactate. When this mechanism prevails, lactacidosis occurs. This course of events can be seen in type II diabetes mellitus (Fig. 3) (9).

Figure 3. Cellular metabolism

Beside genetic factors, environmental factors are of utmost importance in diabetes mellitus (Fig. 4).

Figure 4. Risk factors for diabetes

The main goals in the treatment of diabetes mellitus include elimination of disturbances and prevention of the development of late complications by the achievement of normal metabolic balance in the body. The objective is to provide 'conditional health', to establish working capacity, and to resocialize the patient; in children, to allow for normal physical and mental development.

Five mutually overlapping modes of treatment are currently used in the practical management of diabetes mellitus:

1. training of diabetic patients through education in self-monitoring and self-care – needed in all diabetic patients;
2. dietary therapy – needed in all diabetic patients;
3. exercise therapy– needed in all diabetic patients;
4. therapy with oral antidiabetic agents – needed in some more than one fourth of diabetic patients; and
5. insulin therapy – needed in some less than one fourth of diabetic patients.

The management of diabetes by education in self-monitoring and self-care, dietary regimen, and regular exercise is required in every diabetic patient. This approach to treatment implies preparation of the patient to adopt dynamic methods of treatment. These three methods of treatment are of paramount importance, they actually constitute the very backbone of the management of diabetes mellitus in all diabetic patients, while in some 50% of them this is the only mode of treatment used (9).

An individual with type II diabetes mellitus should be properly informed on the role of diabetic diet and exercise in the treatment of diabetes mellitus, and on the prevention of diabetic complications. The treatment results achieved should thereby be continually evaluted via self-control measures (which also requires proper patient education). Consistent use of these basic principles of the modern management of diabetes mellitus will help avoid two therapeutic errors attributable to the physician, i.e. 'abuse' of oral hypoglycemics (in fully unjustifiable indications), and 'abuse' of too high insulin doses (Fig. 5).

Figure 5. Step-wise strategy combined with continuous education in the treatment of type II diabetes mellitus

The pronounced dynamics of 24-hour blood glucose oscillations in diabetic patients treated with diet, oral hypoglycemic agents or insulin enhances the physician's uncertainty in daily management of the disease (Fig. 6).

Figure 6. Blood glucose variations during 24 hours

These marked variations of all factors involved, and consequentially of blood glucose during 24 hours, are all responsible for the development of late complications of diabetes (Fig. 7).

Figure 7. Prevalence of diabetes mellitus and diabetes complications in Croatia (March 1996)

For the sake of convenience, let us compare the management of diabetes mellitus with driving a car (Fig. 8).

Figure 8. Strategy for life without complications

ATHEROSCLEROSIS

Atherosclerosis is the most common arterial lesion characterized by local intimal thickenings that consist of multiplied and modified smooth muscle cells, macrophages, lipids from intra- and pericellular serum lipoprotein deposits, and multiplied connective tissue (collagen, elastin, mucopolysaccharides) (11).

Atherosclerosis is considered to be a lesion that begins with endothelial cell injury. Endothelial injury can be induced chemically, due to hypercholesterolemia or increased LDL in blood and cigarette smoking, or mechanically, e.g., due to hypertension, or diagnostic and therapeutic manipulation with intravascular catheters. Chemical injury to endothelial cells, when they are permanently exposed to excessive LDL amounts, occurs due to the precipitated cholesterol turnover leading to minimal changes in the membrane viscosity. Mechanical causes, hypertension being most important of them, lead to the occurrence of atherosclerosis at the sites where blood stream bumps against the vascular wall, forming whirlpools. Among other potential causes, initial atherosclerotic changes can be due to arterial spasms or immune mechanisms. The formation of microthrombi and alteration in the vascular wall architecture entail cholesterol accumulation in the macrophages and their activation (foam cells) as well as in smooth muscle cells, and the formation of fatty spots and streaks on the vascular wall. Prolonged presence of a large amount of cholesterol from LDL in the vessel intima stimulates the synthesis of collagen, elastin and mucopolysaccharides at the site of lesion. Thus, an atheroma or a plaque is formed from lipids. The vascular lumen is narrowed, while thinning of the plaque sheath may cause its rupture, which results in the formation of an aneurysm. Further in the course of events, calcium accumulation may ensue, which results in vascular wall rigidity (11).

The risk factors for atherosclerosis include inappropriate dietary habits, dyslipoproteinemia, obesity, lack of exercise, hypertension, cigarette smoking, psychologic profile and pattern of behavior (12), immune reaction (13), diabetes mellitus (14), male sex, postmenopause and use of contraceptives, and uric arthritis (Fig. 9) (12).

Figure 9. Risk factors for atherosclerosis

The reversible changes of atherosclerosis are only treatable to a certain grade of advancement of the vascular intimal lesion. Modifications in the patient's behavioral pattern, coupled with the use of hypolipemic agents, are advised. Unfortunately, this stage in the development of atherosclerosis usually proceeds unnoticed, and treatment is only considered when the complications of atherosclerosis have already developed (Fig. 10) (11).

Figure 10. Relationship of patient motivation and treatment possibilities

• primary prevention of the occurrence of RISK FACTORS,
• prevention of the occurrence of manifest SYMPTOMS of coronary disease and atherosclerosis involving other blood vessels due to the risk factors, and
• prevention of CORONARY DISEASE, and of atherosclerosis of cerebral and peripheral blood vessels (11).

Figure 11. Risk factors for atherosclerosis and diabetes

Dyslipoproteinemia

A type I diabetic patient has a fat metabolism similar to that found in a non-diabetic individual. However, the lack of insulin in the liver results in a greater formation of apoprotein B-containing lipoproteins, and the clearance of lipoproteins decreases due to the reduced activity of insulin dependent lipoprotein lipase. In poorly regulated diabetes mellitus, cholesterol, triglycerides, very low density lipoproteins (VLDL), and occasionally LDL are increased, while high density lipoproteins (HDL) are decreased. In acidosis, severe hyperlipoproteinemia with chylomicronemia develops. This condition is readily recovered by the action of insulin (16). Poorly regulated, elderly, obese and patients with nephropathy are at a higher risk of hyperlipoproteinemia, even if only associated with microalbuminuria (16).

Qualitative lipoprotein alterations in patients with type I diabetes mellitus include glucosylation of apoproteins, especially apo B. Glycosylated LDL more weakly binds to the hepatic cell receptors (16,17). Such glycosylated LDL does not enter the cells by endocytosis via LDL receptors but binds to the scavenger receptors on macrophages, whereby they become activated and convert to foam cells (18).

Fat metabolism disturbances occur more commonly in patients with type II diabetes mellitus. This especially holds for hypertriglyceridemia, low HDL and HDL-2 in particular, usually with normal total and LDL cholesterol. HDL decrease is generally proportionate to insulin resistance. Small, dense LDL particles, associated with the risk of vascular changes, predominate in type II diabetes mellitus (16,19). They probably are less efficiently catabolized and are prone to oxidation. The patients with this type of diabetes mellitus have pronounced postprandial chylomicronemia (even if fasting triglycerides are normal). The chylomicron remnants more easily bind to hepatic receptors than VLDL, and this is considered to account for the increased accumulation of the potentially atherogenic LDL (20).

Lipoprotein a (Lp(a)) alterations occur in hormonal disorders such as diabetes mellitus (21). The association of Lp(a) with glucosylated hemoglobin (HbA_1c) as a mean glycemia measure has not yet been confirmed (22), whereas its relationship with coronary disease is still being investigated (4,23).

Dyslipoproteinemia in type II diabetes mellitus is closely related with insulin resistance and hyperinsulinemia as part of the insulin resistance syndrome or 'metabolic syndrome', which includes abdominal obesity, hypertension, impaired glucose tolerance, fat metabolism impairment, and accelerated atherosclerosis (16).

The prevalence of coronary heart disease rises in parallel with the cholesterol concentration increase in non-diabetic individuals, with a higher rate of increase in diabetics. The increase in LDL cholesterol correlates with macrovascular disease in diabetic patients, whereas an inverse correlation is found for HDL cholesterol. A similar correlation has been recorded for hypertriglyceridemia (16). An LDL decrease is achieved by a multifactorial program of treatment for hypercholesterolemia, cigarette smoking, and diabetes mellitus (24).

Total cholesterol, total triglycerides and HDL cholesterol should be controlled on a regular basis (16). In diabetes mellitus, beside quantitative lipoprotein changes, due attention should also be paid to their qualitative alterations (glucosylation and oxygenation) (25,26).

The treatment of hyperlipoproteinemia in diabetic patients includes glycemia control and lifestyle modifications such as body weight reduction in obese individuals and regular exercise. The target lipid levels are presented in Table 1.

Table 1. Target lipid levels in diabetic patients

If hyperlipemia persists in spite of lifestyle modifications and satisfactory glycemia control, medicamentous therapy should be introduced. The use of medication for hypercholesterolemia as a prevention of coronary events is especially indicated in high risk groups such as diabetic patients (27). In women, the postmenopause is an additional factor of cardiovascular risk (28). Improvement can be achieved by the hormone replacement therapy (29). In diabetic women, however, this therapy may cause mild triglyceride increase when coadministered with oral conjugated estrogen. Therefore, additional studies are needed, because the greater risk of coronary disease in diabetic women than in diabetic men has just been explained by the higher level of triglyceridemia and lower level of HDL cholesterol. The protective effects of hormone replacement therapy might be less pronounced in diabetic than in other postmenopausal women (30,31).

Abdominal obesity is caused by complex regulatory mechanisms of extrinsic (sympathetic-parasympathetic and endocrine) and intrinsic (enteric nervous system and paracrine secretion) factors that may be involved in the association of diabetes mellitus and atherosclerosis (32). More data on the issue, i.e. whether obesity is a dependent (related to hypertension, dyslipoproteinemia and diabetes mellitus) or an independent (due to compensatory hyperinsulinemia) factor in the genesis of atherosclerosis, will become available from the studies of thiazolidinediones, substances imitating the action of insulin (33). The possible discussion about insulin as a vascular hormone has been postulated (34).

The lack of exercise has been ever more clearly associated with the development of atherosclerosis and diabetes mellitus. The effect of exercise manifests in the increase of HDL cholesterol and decrease of resistance to the action of insulin and estrogens. Their increase, seen in the lack of exercise, is associated with the initiation of a closed circle of the resistance – hyperinsulinemia syndrome (35). Moderate exercise is necessary to reduce the risk of cardiovascular diseases, possibly through reduced lipoprotein glucosylation (36).

In addition to dyslipoproteinemia, hypertension plays a major role in the development of vascular atherosclerotic changes, primarily due to the possible mechanical damage to the endothelium. Beside other signs, hypertension is a significant factor in the metabolic syndrome X (3). Upon the completion of UK Prospective Diabetes Study, the effect of hypertension on the development of late complications of diabetes has been confirmed. In addition to other diabetes complications, the tolerable level of hypertension also changes to below 17/11 kPa in patients with the signs of renal diabetic complications (37).

Vascular microthrombosis is one of the basic atherosclerotic effects of cigarette smoking. Smoking has been postulated to decrease the level of HDL cholesterol, which has a similar effect (3). The problem of hampered oxygen transport in diabetic patients is further compromised by cigarette smoking, thus contributing to the development of late diabetes complications. Giving up smoking should be stimulated even at an older age, since those aged 60 have a life expectancy of more than 20 years (38).

There are clear evidence for the impact of psychological factors on the risk of coronary heart disease and hypertension, pointing to the importance of stress control. Functional recovery after myocardial infarction greatly depends on social help and stress control (39). Numerous psychological factors have been identified as risk factors. Discontent in the treated men with hypertension and marked cardiovascular risk was significantly and independently associated with carotid artery intimal/medial thickening. Positive feelings can influence the process of atherosclerosis (40). The psychological profile of a diabetic patient clearly determines his/her approach to motivation for learning about the treatment of diabetes, self-control and self-care, and about the overall therapeutic success and quality of life (10,17).

CONCLUSION

In conclusion, it should be emphasized that diabetes mellitus is a marked risk factor in the onset of atherosclerosis in its early stages, whereas atherosclerosis is a significant additional factor of exacerbation of late diabetes complications, with a mutual tendency of potentiating alterations. Therefore, the presence of common factors deteriorates the development of late diabetes complications and atherosclerosis which assume some features of independent exacerbation in the late stages of diseases. The recognition of various factors influencing the disease alterations and their dynamic monitoring are the only mode of satisfactory treatment. The higher the patient's motivation for treatment, the more regular the self-control and self-care, and the earlier the beginning of treatment, the better the success of treatment.

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