Until recently, the question of which comes first in type-2 diabetes - loss of pancreatic function or development of insulin resistance - was only of academic importance, since there was no effective treatment for insulin resistance.

Type-2 diabetes patients relied largely on:

Sulphonylureas such as glibenclamide, which stimulate the pancreatic beta cells to produce higher-than-normal insulin levels in an effort to combat tissue resistance.

Metformin, which inhibits release of glucose from the liver and improves insulin-dependent glucose uptake into muscle and fat.

A combination of the two treatments if glucose could not be controlled with one approach alone.

The addition of insulin if combination treatment failed.

The first drug to tackle insulin resistance was troglitazone (Romozin) which was withdrawn at the end of 1997, two months after launch, after reports linking it to liver problems.

Extensive clinical experience with the chemically related rosiglitazone has demonstrated that the drug is better tolerated, though patients do require liver function tests every two months in the first year and periodically thereafter.

Rosiglitazone makes fat and muscle more sensitive to insulin and reduces glucose output from the liver.

SmithKline Beecham also presented data at a recent international diabetes conference suggesting that rosiglitazone has a protective effect on pancreatic beta cells.

Last month's launch of pioglitazone (Actos) brought almost immediate competition for rosiglitazone. With the same indications and effects on insulin resistance and beta cell function, Takeda is stressing the additional benefits of pioglitazone on lipid levels, notably the triglycerides and HDL-cholesterol levels which are frequently abnormal in diabetes. On price, rosiglitazone and pioglitazone cost the same at low dose, but a 28-day supply of the higher-dose 30mg tablet of pioglitazone costs£36.96, compared with£54.60 for a month's supply of the 8mg dose of rosiglitazone.

The arrival of rosiglitazone and pioglitazone has kept insulin resistance in the limelight this year, but 2001 could see the focus shift back to pancreatic beta cell dysfunction with the introduction of nateglinide (Starlix).

This amino acid derivative developed by Novartis reduces the sharp increases in glucose levels seen in patients with diabetes after meals, owing to a loss of early-phase insulin production from their failing beta cells.

Since post-prandial glucose peaks have been linked to increased risk of heart attacks and strokes, Novartis hopes nateglinide will have a beneficial impact on cardiovascular complications of diabetes, but this has yet to be demonstrated in intervention studies. Clinical trials with nateglinide as monotherapy have demonstrated comparable effects on glucose control to those seen with metformi, and additional benefits when the two drugs are used in combination.