Glucolipotoxicity and beta cells in type 2 diabetes mellitus: target for durable therapy?

Type 2 diabetes mellitus (T2DM) is characterised by beta-cell failure in the setting of obesity-related insulin resistance. Progressive beta-cell dysfunction determines the course of the disease, regardless of the treatment used. There is mounting evidence that chronically elevated circulating levels of glucose and fatty acids contribute to relentless beta-cell function decline, by endorsing processes commonly referred to as glucolipotoxicity. Mechanisms related to glucolipotoxicity include endoplasmic reticulum (ER) stress, oxidative stress, mitochondrial dysfunction and islet inflammation. The most commonly prescribed blood-glucose lowering agents, metformin and sul-fonylurea, may temporarily improve glycaemic control, however, these drugs do not alter the continuous decline in beta-cell function in T2DM patients. Evidence exists that novel classes of drugs, the thiazolidinediones (TZDs) and incretin-based therapies, may be able to preserve beta-cell function and functional beta-cell mass, amongst others by reducing glucolipotoxicity in the beta cell. The durability of the effects of TZDs and incretin-based therapies on beta-cell function, whether given as monotherapy or combined with other treatment, should be addressed in future, long-term clinical studies.