Leader

Insulin resistance and cardiac risk factors

Diabetes mellitus occurs in up to 5% of the elderly in the UK. Although symptomatic treatment of diabetes with diet or, if necessary, a sulphonylurea or biguanide, rarely causes a problem in these patients, a very appreciable increase in the instance of cardiovascular disease leading to both increased morbidity and mortality is observed. The Framingham Heart Study showed that coronary heart disease (CHD) accounts for the death of 25% diabetic patients between the ages of 30-55 years compared with only 8% of men and 4% of women without diabetes. A recent study from Finland shows that asymptomatic hyperglycaemia is associated with an increased instance of CHD in subjects aged 65-74. The cause of this increase, and an explanation of why diabetes should have such a devastating effect on the arterial system, is poorly under- stood but a number of exciting developments within this field have been reported recently.

The cause of NIDDM (Type 2) diabetes is still a mys- tery. Originally, it was thought to be due to a defect in the pancreas but it was then recognised that these patients might have hyperinsulinaemia and it was suggested that insulin resistance in the peripheral tissues was the cause of the diabetes. Present understanding suggests there is both, defect in terms of pancreatic insulin secretion, including the type of insulin released, and insulin resis- tance in the periphery.

Radioimmunoassay for insulin does not distinguish between active and inactive forms of insulin, and a recent study by Professor Hales and his colleagues in Cambridge suggests that much of the hyperinsulinaemia in NIDDM patients is, in fact, pro-insulin which has reduced biologi- cal activity.

These workers have found that reduced growth in early life is strongly associated with impaired glucose tolerance or NIDDM in late middle age. This study was undertaken due to findings that retardation of growth during fetal life and infancy is associated with increased mortality from cardiovascular disease in adult life. Workers examined 468 men who were born between 1920-1930. Of these, 93 had impaired glucose tolerance or hitherto unknown diabetes and there was a strong association between low birth weight and weight at one year in these patients. Another study has shown that low birth weight is strongly related to hypertension, which is known to be more common in dia- betes. Obesity is also very common in NIDDM and is associated with insulin resistance. However, for diabetes to occur in association with insulin resistance, a defect in pancreatic insulin release/and or formation must also be present. Insulin resistance, however, usually improves greatly with weight reduction.

The effect of obesity on insulin resistance can be vari- able. A recent study from Washington University School of Medicine investigated the ratio of waist to hip circum- ference, plasma insulin levels and glucose intolerance as independent predictors of high density lipoprotein (HDL)-cholesterol levels in older adults. HDL levels were inversely correlated with truncal fat, plasma insulin

levels and the presence of glucose intolerance but were not independently associated with gender or total body fat. HDL has a strong protective effect against atherosclerosis and CHD and hence truncal obesity tends to be much more important in insulin resistance and in risk of atherosclerosis than peripheral obesity.

One of the effects of hyperinsulinaemia is stimulation of the ovarian follicle with hyperandrogenism; this may be an important link between diabetes, hyperinsulinaemia and vascular disease and may explain why diabetic women lose their female “protection” against coronary artery dis- ease before the menopause. However, hyperinsulinaemia itself has been shown to be a risk factor for cardiovascular disease in the general population. In the Paris prospective study, a long-term investigation of CHD risk factors in a large population of working men, both fasting and two- hour post-load plasma insulin levels were major indepen- dent predictors of death from CHD. This association is present in both diabetic and non-diabetic patients. We have shown that hyperinsulinaemia by insulin infusion causes potentially atherogenic changes in cellular choles- terol synthesis. Thus, the mechanism may in part be due to the effect of hyperinsulinaemia on lipids.

Hypertriglyceridaemia is another independent risk fac- tor for vascular disease which is often found in poorly con- trolled diabetic patients. It is common in obesity and thereby provides a possible link between hypertrig- lyceridaemia, insulin and cholesterol. Another interesting association occurs between hypertension and hyperin- sulinaemia. Although the mechanism is still disputed, insulin has specific effects on electrolyte excretion in the kidney. Total body sodium content is also increased in obesity as well as in NIDDM patients.

A second mechanism by which insulin can cause hyper- tension involves stimulation of the sympathetic nervous system. These associations are of considerable interest and have definite therapeutic implications. Firstly, since diabetes is so often associated with obesity, the physician should encourage weight reduction in the obese, which will have the effect of both improving glycaemic control and lowering serum insulin levels. Secondly, hypertension should be treated energetically, both in the young and in the old, as there is now good evidence to suggest the benefits in relationship to stroke and to coronary artery morbidity, if not mortality. Thirdly, normoglycaemia should be achieved in the diabetic patient as this should have the effect of increasing sensitivity of insulin receptors and further reduce the serum insulin levels.

In the 1990s, it appears that more and more attention should be paid to treatment of risk factors when treating the diabetic patient. Reducing mortality and, in particu- lar, morbidity, is a worthwhile goal and many studies now confirm the value of aggressive treatment in these patients.

Pmfissor Gemld Tomkin MD, FRCPI FACP FRCP(L0nd) Adelaid Hospital and Department of Medicine

lkinity CoUege Dublin 2

Practical Diabetes March/April Vol9 No 2 41