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Diabetes and Cardiovascular Disease

Jesús R. Giraudo
Institute of Endocrinology, Diabetes and Nutrition
Córdoba - Argentina

Arterial Hypertension (AH) Abnormal Lipid Profiles
Dislipoproteinemias Endothelial Dysfunction and IRS

Diabetes exerts its greatest impact throughout the vascular system. This effect includes not only the well described consequence of small vessel disease that leads to serious complications -including retinopathy, nephropathy and neuropathy-, but also a substantial predisposition to premature and accelerated disorder of large blood vessels, macrovascular disease.

Coronary, brain and peripherical atherosclerosis is the most important cause of the reduction of the quality of life and even of death of the diabetic patients. There are many factors that contribute to the greater incidence of atherosclerosis in these patients. It is well known that the classic factors of aterogenic risk for the population in general are more frequently associated to diabetes, but by themselves, they are not responsible and do not explain the greater frequency of macrovascular compromise that the diabetic patients of both sexes present. There must exist other factors directly related to the metabolic disease. From this point of view, two main groups of factors of risk can be differentiated: those common to the population in general; and those proper to diabetic patients in particular .

Within the pathogenic theories, macrovasculopathy is considered the response of the vascular wall to the endothelial injury which derives from the interplay of multiple factors such as: mechanical, chemical, toxic, viral and immunologic stimuli.

Qualitatively, there are not major differences in the type of arteriosclerosis between diabetic and non-diabetic, although in the former it tends to be more precocious, more intense and more generalised.

 There is no injury specific of the diabetic but in this case, the fatty streaks, intimal plaques and calcification of vessels tend to be more prominent. Neither is there evidence of the development of atherosclerosis that could explain the diabetic greater susceptibility to it. However, certain characteristics proper to the diabetic can be found. Such is the case of growth factors that stimulate in a different way the spread of smooth muscular cells, the modification of platelet activity with an increase of adhesion and aggregation or the minor resistance of the endothelial barrier that leaves the sub-intimal tissue exposed to platelet adhesion. This last factor increases the stimulus of the function of the smooth muscular cells that raises the capture of LDL lipoproteins.

From the epidemiological point of view, the cardiovascular complication, especially the coronary heart disease (CHD) affects the insulin-dependant diabetes (IDDM) as much as the non-insulin-dependant one (NIDDM), but its prevalence does not seem to be the same. Many of the earlier studies of CHD in diabetic patients did not distinguish IDD from NIDD. The second methodological problem is the definition of CHD. Most studies use mortality as the criterion, but this is often based on the causes of death as registered on death certificates, in which the causes of death are not always carefully researched.

The prevalence of cardiovascular disease in NIDD varies widely between studies, from 9 to 59% because of both, methodological and population differences. There are few data on the prevalence of CHD in IDDM, but it is approximately of 27 %.

Factors of Risk and Diabetes – Etiophysiopathology

The increased prevalence of vascular disease in diabetes is associated to the presence of factors of risk, each of which exerts its own effects. But the greater the number of factors, the greater the risk due to the fact that their consequences are interactive and cumulative. Within these stated that predispose to macroangiopathy there are some that can be regarded as the most important such as:

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Arterial Hypertension (AH)

The prevalence of AH in the diabetic patient is of 30 to 50% approximately, this means 1.5 to 2 times more than in the population in general, thus increasing the risk of death up to 4 times more due to a possible cardiovascular complication.

The AH in IDDM is not generally evident at the moment of diagnosis, but it appears at the beginning of the nephropathy in 80% of the cases, frequency that rises 100% when she is very advanced. The presence of AH is correlated with the duration of the diabetes and the progress of the nephropathy. In NIDD, on the other hand, the AH is diagnosed at the beginning of the metabolic disorder, being closely related to the presence of obesity, hyperinsulinemia and dislipemia but not to kidney disorders.

Essential hypertension is the most frequent form. Pathogenically it is related to the insulin resistance and hyperinsulinism present in Syndrome X, typical of NIDD. Although there are experimental data that support this relationship, it is still not clear why the AH is not more frequent in other chronic hyperinsulinemic states like the insulinoma.

Insulin in isolation or together with other growth factors would act in their receptors placed in the endothelium and in the smooth muscle cells of the arterial wall. The increase of Na-H exchange causes a rise pH values, vascular hypertrophy and hypertension.

The increase of the total and interchangeable body Na –estimated of 10% - together with a decrease of its renal excretion and the alteration of the mechanism of transport of membrane would represent an important pathogenic factor and would be the cause of an increase in the volume of extracellular liquid. Besides, the insulin excess would alter the transmembrane exchange of the potassium and sodium bringing about an increase of the latter within the cells.

In the renin angiotensina system a decrease of the plasmatic level of renin and aldosterone is produced and accentuated as the kidney disorder progresses. This disorder is related to: kidney inability in the synthesis or liberation of renin; hyalinisation of the afferent arterioles; more expansion of extravascular volume due to hyperglucemic hyperosmolarity; surplus of Na to the dense macule; etc. It would also contribute to the hypersensitibity to pressor substances – angiotensina II and catecolamines- and an increased response to the rise of the auricular natriuretic factor, which is related to the beginning of the microalbuminuria and the glomerular hyperfiltration.

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Dislipoproteinemias

The qualitative and quantitative alterations of the plasmatic lipoproteins are more frequent in the diabetic patients of both sexes than in the non-diabetic. These disorders are related to the degree of metabolic compensation and can be associated to hyperlipoproteinemia of other origins –genetic, thyroid, alcoholic, renal, medication, etc-

Between the 30 and the 50% of the diabetic patients present some degree of lipid abnormality that is directly connected with the lack of proper metabolic control. Although the dislipemic patterns can be different IDDM and NIDDM, they both share a common lipid disorder caused by insufficiency of insulin, either absolute or relative -associated with IR- respectively.

In no compensated diabetes type I, the lack of insulin produces an increase of triglycerids, chylomicrons and VLDL with a decrease of HDL. These changes are the result of the less activity –insulin dependant- of the LPL that reduces the catabolism of chylomicrons and VLDL. On the other hand, an increased lipolisis triggers the greater offer of NEFA that results from their excessive mobilisation. This process causes an increase in the production and secretion of triglycerids and VLDL. Although cholesterol is an independent variable of diabetes, the level of LDL can rise because of a decrease of its catabolism due to glycosilation of the apo-B100 that reduces the union to its receptor. The inadequate degradation of the VLDL diminishes the production of HDL. All these disorders are corrected or not present when an optimum degree of glycemic compensation is attained.

In diabetes type II, the increase of VLDL and triglycerids is the main consequence of the increase of the synthesis resulting from the surplus of free fatty acids and glucose to the liver and by the less catabolism of the VLDL. Less synthesis and more catabolism reduce the HDL. The level of LDL and cholesterol can be raised due to the less catabolism, but generally it is normal. The less conversion of VLDL into LDL causes the formation of VLDL remanents with greater aterogenic power.

Apart from the quantitative disorders of the lipoproteins, in both types of disbetes qualitative alterations are produced. Among these qualitative changes, the processes of glycosilation and oxidation of the LDL and HDL particles are very significant: they become more cytotoxic for the vascular endothelium and they increase the capacity of stimulating the growth factor of the endothelial cells and of the macrophagic monocytes. The glycolitic LDL is more easily captured by the endothelium, smooth muscular cells and macrophages, also stimulating the platelet aggregation. Glycosilation alters the shape of the LDL that is not recognised by the B-E receptor of the cellular membranes, thus the LDL diminishes its catabolism and increases its circulating levels.

There is a relationship between dislipemia and the alterations in the homeostatic system -with greater aggregation and secretion of platelets-. These changes would play an important role in the developments of the acute events and the instability of the atheromatose plaque. The hypertriglyceridemia stimulates the activity of the Factor VII and increases the trombina. It also raises the synthesis of the PAI-I by the endothelial cells, increases the anti-fibrinolitic activity and inhibits the production of prostaciclina by the endothelium. The Lp(a) increases and competes against the plasmin in the combination with fibrin.

Cigarette Smoking

Of all the factors of risk, cigarette smoking is the easiest to reverse but the hardest to attain. Tobacco has been related to an increase in the risk of developing microangiopathy, but its worst effects lie in the macrovascular morbi-mortality, especially in women. Although the coronary and cerebrovascular events occur more frequently and seriously in diabetic persons that smoke, the arterial perispheric disease is the combination that brings about the most serious problems.

Insulin Resistance Syndrome (IRS)

The IRS described by G. Reaven as Syndrome X -or plurimetabolic- is a group of interrelated abnormalities among which the following are included: insulin resistance (IR), hyperinsulinemia (HI), abdomino-visceral obesity, progressive glucose intolerance, dislipidemia, hemorrheologic changes, hemostatic changes, fibrinolises, arterial hypertension, hyperuricemia, increase of the plasmin inhibitor (PAI-I), hyperandrogenism and endothelial disfunction, being atherosclerosis its final result. It has been estimated a prevalence close to 35% in the population in general and it constitutes a common disorder in patients with miocardic ischemia without any evidence of coronary injuries that can be agiographically proved. These clinical manifestations have been given the name of "Coronary Syndrome X".

The IR is a compensatory response to a failure in the use and storage of glucose by the muscular, liver, kidney and adipose tissue. IR is also the consequence of a modification of the insulin action in the mechanisms of muscular perfusion, of antilipolisis, of apoptosis and of transport of cations.

Several clinic states associated to IRS (Table I) have been identified and the biochemical disorders related to it have been defined as well
(Table II).

Associated Pathologies to IR
(Table I)

Central and Generalised Obesity
Dislipidemia
Arterial Hypertension
Diabetes Type II
Glucose intolerance
Arteriosclerosis
Feminine Hyperandrogenism
Dislipemic first degree relatives
NIDM first degree relatives
Normotense relatives of hypertense patients
Sons of essential hypertense patients
Hypercortitism
Somatotrophine excess
Acantosis Nigricans
Breast of endometric cancer

 


Biochemical Disorders Related to IR
(Table 2)

Hyperinsulinemia
Glucose intolerance
Increase of VLDL and decrease of HDL
Increase of LDL
Increase of intracellular Na caused by a deficient contratransport of Na/H
Increase of intracellular C++ by altered transport
Increase of androgens in women
Decrease of androgens in men
Decrease of SHBG
Increase of IGF-1

Abnormal Lipid Profiles

The dislipemia that accompanies IRS is characterised by an increase of triglycerids, a dicrease of HDL and changes in the size and composition of LDL. The IR diminishes the insulin inhibiting effect on the hormonosensitive lipase, enzyme that physiologically limits the mobility of triglycerids from the adipose tissue. This fault leads to a postprandial increase of the flow of the free fatty acids (FFA) to the liver, where together with the triglycerids, are used to form VLDL. This mechanism is more active in the level of intraabdominal adipose tissue since this tissue is less sensitive to the inhibiting action of insulin and more reactive to the lipolitic stimulus of adrenergic origin. At the same time, another mechanism involved in the increase of circutlating triglycerids is the less activity of the lipoprotein lipasa that regulates the hydrolisis from VLDL and chylomicrons that produces a minor clearence.

The hyperglyceridemia is also accompanied by an increased action of the CEPT enzyme (Cholesterol ester transfer protein) which increases the exchange of cholesterol esters from VLDL to LDL and HDL, enriching them with triglycerids, molecules that by the liver lipasa form HDL with low content of cholesterol and smaller and denser LDL. The bigger the IR the shorter the LDL diameter.

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Endothelial Dysfunction and IRS

The initial mechanism of aterosclerosis is the endothelial dysfunction that results from a complex interplay of different factors –i.e: hyperglucemia, dislipidemia, genetics, lifestyle, tobacco, stress, eating habits, free radicals, oxidised lipids, etc.- in which the insulin resistance can be the cause of endothelial damage. There is a hypothesis, however, that supports the idea that endothalial dysfuction can be the cause of IRS rather than its consequence. In this case, the association of IR with arteriosclerosis would have endothelial disorder as the central and unifying pathogenic cause.

The excess of insulin interacts with the cytokines and growth factor in the cross talk among vascular wall cell and a variety of mediators. Insulin can act a specific smooth cell growth factor. It also plays an important role in concert with lipoproteins when they exhibit an abnormal pattern.

Advanced Glycation End Products (AGEs)

It has also been studied the relationship between hyperglicemia and vascular disorders which has a strong effect in diabetes I and II as well. Glucose is able of reducing molecules of oxigen that react with amino-proteic groups to form aldimine of Schiff base, chemically reversible, which get ordered to integrate the most stable products of Amadori. These compounds react with the amino groups to produce biologically abnormal molecules with monovalent links – particularly carbamil compounds, such as the 3 deoxiglucosone, which react with the amino groups to form advanced AGEs.

Many proteins can undergo glycation to form AGEs, such as albumin, fibrinogenic and fibrin, antitrombina II, etc. Three mechanisms are implied in the development of diabetic cardiovascular complications caused by the formation of AGEs in response to the hyperglucemia: interaction with specific receptors, glycation of the proteic matrix and intracellular glycation. The first of them implies the interaction between AGEs and their specific receptors; their union with the receptors of macrophages increases the synthesis of the tumoral necrosis factor and interleucine-1, stimulating the degradation enzymes. There is an increase of cytosines and vascular permeability. The glomerular mesangial as well as the smooth muscular arterial cells are stimulated. This stimulation caused by AGEs leads to the liberation of the growth factor that derives from the platelet, interleucina and growth factor of the insulin type. Thus, AGEs are involved in the cellular proliferation, thrombosis and finally, in the inflammatory and aterogenic changes produced by diabetes.

Correspondence:
Dr. Jesús R. Giraudo- Instituto de Endocrinología
Buenos Aires 787- (5000) – Córdoba – Argentina

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© CETIFAC
Bioengineering

UNER
Update
14/10/1999