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Diabetes is probably the greatest hazard associated with moderate obesity because of the long-term damage it causes to the cardiovascular system, kidneys and eyes. The risk of diabetes increases exponentially with increasing BMI. Indeed most individuals with a BMI greater than 35 will become diabetic. The risk of insulin resistance, which is an underlying pathology in the causation of diabetes and cardiovascular disease, also increases with increasing BMI. In the next section the metabolic basis for the relationship between obesity, insulin resistance and diabetes will be discussed.
n 9.2 TYPE II DIABETES

This form of diabetes is probably a consequence of inappropriate storage of fat in tissues such as muscle and liver which impairs the action of insulin. The consequence of a lack of the action of insulin is that blood glucose concentrations rise. This deprives tissues of glucose and in the longer term glucose can react with proteins to cause the formation of glycosylated proteins that can lead to damage to the microcirculation, particularly in the retina, kidney and nervous system. To compensate for the lack of effect of insulin, the body produces more insulin and high levels of insulin in the blood have damaging effects on the circulatory system, itself resulting in raised blood pressure and damage to the vascular endothelium (an early event in atherosclerosis). Many people are not aware that they have Type II diabetes until it becomes severe. The presenting symptoms are usually tiredness, excessive thirst and frequent urination. If the concentration of blood glucose exceeds the renal threshold, glucose will spill over into the urine and so diabetes can be diagnosed by measuring glucose in the urine. However, a more accurate test is to measure the fasting plasma glucose concentration which should be below 7 mmol/l. About 23 per cent of the UK middle-aged population have Type II diabetes and in the USA the prevalence is higher, about 6 per cent. At least twice as many people have impaired glucose tolerance, a condition that usually precedes Type II diabetes. Impaired glucose tolerance can be determined by measuring the change in blood glucose concentration following a standard 75 g glucose load. In the normal state, plasma glucose concentration will rise to a peak approximately 45 mins following the glucose load and then fall back to fasting value by 2 h. In subjects with glucose intolerance, plasma glucose will remain elevated at 2 h. Plasma insulin concentrations are greatly elevated in subjects with glucose intolerance following a glucose load, which indicates that there is resistance to the action of insulin. Insulin resistance, which is dened as resistance to the glucoregulatory actions of insulin, is now believed to be the underlying cause of Type II diabetes and also contributes directly to causing cardiovascular disease. A fundamental consequence of insulin resistance is that fasting and postprandial concentrations of insulin in the blood are elevated. Insulin resistance prevents the inhibition of lipolysis as well as the uptake of glucose by cells. Insulin resistance is characterized by the accumulation of visceral fat and is accompanied by a number of metabolic abnormalities (hypertension, Type IV hyperlipidaemia, gout and decreased brinolytic activity) that all confer increased risk of cardiovascular disease. This is sometimes referred to as syndrome X or metabolic syndrome but the term insulin resistance syndrome is preferred.

A high proportion of Type II diabetes goes undiagnosed and can cause long-term damage to the cardiovascular system

Insulin resistance is the key feature predisposing to and causing Type II diabetes

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Insulin resistance results in raised blood pressure, low HDL and small dense LDL which increase risk of heart disease

In a normal healthy subject, the release of fatty acids from adipose tissue is inhibited by insulin following a carbohydrate containing meal. Where there is insulin resistance, insulin fails to inhibit lipolysis which means that the release of fatty acids from adipose tissue remains uncontrolled and plasma concentrations of non-esteried fatty acids (NEFA) are increased. This has two major effects. Firstly, the elevated NEFA concentrations stimulate triacylglycerol (TAG) synthesis within the liver and the secretion of TAG-rich very low density lipoproteins (VLDLs). Prolonged elevations of plasma TAG results in a fall in plasma high density lipoprotein (HDL) concentration and an increase in the concentration of small, dense low density lipoproteins (LDLs) by the action of cholesterol ester transfer protein (CETP). CETP exchanges cholesteryl esters in exchange for TAG and the resulting TAG enriched LDLs and HDLs become substrates for hepatic lipase which decreases their density. Secondly, elevated NEFA further aggravates insulin resistance because of their inhibitory effects on both glucose transport and glucose metabolism in skeletal muscle. Elevated plasma concentrations of insulin also result in an increase in blood pressure probably by increasing sympathetic nervous system activity and by causing damage to the vascular system. A major new development has been the recognition that adipose tissue is not an inert organ but produces chemical mediators such as leptin, acylation-stimulating protein (ASP) and adiponectin. Leptin acts as a physiological signal to decrease appetite and increase energy expenditure. Patients with leptin deciency become obese at an early age, primarily from an insatiable appetite. Treatment of such children with leptin results in decreased appetite and weight loss. Leptin production is mainly regulated by insulininduced changes of adipocyte metabolism and plasma leptin concentrations are higher in obese subjects than lean subjects. ASP increases the efciency of triacylglycerol synthesis in adipocytes from TAG-rich lipoproteins such as chylomicrons and VLDL. Effective fatty acid trapping by adipose tissue may prevent some of the undesirable effects resulting from elevated plasma NEFA concentrations. Adiponectin increases insulin sensitivity in adipose tissue and its production is stimulated by agonists of peroxisome proliferator-activated receptor-gamma (PPAR). Plasma levels of adiponectin have been found to be lower in obese people who go on to develop diabetes. As mentioned previously, there is some evidence to suggest that it is the inability to store fat in appropriate sites that causes insulin resistance. Lipodystrophies are characterized by selective but variable loss of body fat with the consequences that fat is stored in muscles and the liver. Lipodystrophies have become increasingly important as they can result from the use of anti-viral drugs used to treat patients with HIV. Patients with lipodystrophies exhibit many of the metabolic abnormalities associated with insulin resistance even though they are not obese. It seems that visceral fat within the abdominal cavity plays an important role in insulin resistance. With increasing obesity, the size of abdominal fat stores increases. Fat stored within the abdominal cavity appears to be a greater contributor to plasma NEFA than fat stored elsewhere. This may also explain why the apple pattern of obesity is more strongly associated with insulin resistance than the female pear shape pattern. The visceral fat pool which is typically 4 5 kg is the rst to be mobilized. It has been observed that sensitivity to insulin increases as this pool is reduced. Several trials have shown that it is

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possible to prevent overweight and obese individuals who are glucose intolerant from developing diabetes by losing moderate amounts of weight (5 kg) and taking regular exercise (e.g. brisk walking for about 30 mins daily).
n 9.3 CARDIOVASCULAR DISEASE

Cerebrovascular disease (stroke) and coronary heart disease (CHD) are leading causes of death worldwide. The risk of both is greater in men than women and increases greatly with age. Stroke is dened by the WHO as Rapidly developing clinical signs of focal (or global) disturbances of cerebral function, with symptoms lasting 24 h or longer or leading to death, with no apparent cause other than of vascular origin. Stroke can result either from the rupture of an artery (cerebral haemorrhage) or blockage of an artery supplying the brain (cerebral infarction). The incidence of stroke resulting from cerebral haemorrhage is strongly linked to raised blood pressure. CHD results from the blockage of one of the coronary arteries supplying the heart muscle and this results in a heart attack which is characterized by severe chest pain (angina) and damage to the heart muscle (myocardial infarction). Cerebral infarction and CHD share a common pathology which is atherosclerosis of the large arteries. Atherosclerosis is a process by which nodular cholesterol enriched plaques are laid down in the intima of large to medium arteries. This is a chronic process that develops silently over 20 30 years. Rupture of an atherosclerotic plaque triggering the formation
Figure 9.3 Relationship of atherosclerosis with coronary heart disease and stroke

Atherosclerosis is a major risk factor for coronary heart disease and occlusive stroke and develops over a 20 30 year period

ARTERIAL FATTY STREAK

INCREASING AGE

ATHEROSCLEROTIC PLAQUE

PLAQUE RUPTURE AND THROMBOSIS

Coronary arteries

Carotid or basillar arteries

HEART ATTACK

STROKE

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