Endocrine Abstracts

The dyslipidaemia that commonly accompanies type 2 diabetes is characterised by raised plasma triglyceride, low HDL cholesterol and small, dense LDL particles. This syndrome has been shown to be caused principally by overproduction of large, triglyceride rich VLDL in the liver (VLDL₁).

Recent investigations have revealed further details of the metabolic abnormality underlying diabetic dyslipidemia. Studies using stable isotope tracers of apolipoprotein B and triglyceride turnover have revealed that in type 2 diabetics there is a failure of insulin to suppress VLDL₁ secretion. This feature of central insulin resistance is likely to be included to another i.e. the inability to control effectively hepatic gluconeogenesis. We were able to demonstrate a correlation between plasma fasting insulin and glucose levels and VLDL₁ triglyceride and apoB overproduction in normal and type 2 diabetic subjects. Subsequent studies have shown that excessive VLDL production is associated with the accumulation of visceral adipose tissue and increased fat deposits in the liver.

Given the underlying mechanism responsible for diabetic dyslipidaemia it can be argued that the treatment of choice would lower VLDL production or improve central insulin sensitivity. Diet (weight loss) and exercise have been shown to have the desired effect. PPARα agonists are moderately effective while PPARα agonists (fibrates) lower plasma triglyceride 50–70% mainly by increasing lipolysis. Use of these compounds have been moderately successful in outcome trials but it is the statins that have provided convincing evidence of benefit. The latter drug class lowering all apoB containing lipoproteins by stimulating receptor mediated catabolism.

Newer agents which raise HDL have promise in the treatment of diabetes. These are under intense investigation at present. Cholesteryl ester transfer protein inhibitors are highly effective but apparently carry risk of aggravating hypertension. Others such as LXR agonists promote reverse cholesterol transport but may also increase VLDL synthesis in the liver, an unwanted side effect. The ultimate usefulness of the agents will be learned only in large scale outcome trials.