Beta cell preservation
Not only the pathogenesis of type 2 diabetes but also disease progression is characterized by continuous decline of beta-cell function. Therefore, preservation of existing beta-cell function and protection from ''toxic'' processes is highly desirable for both prevention and chronic treatment. In principle, any lowering of prevailing glycaemia will protect the beta-cell by removing glucose toxicity.

In addition, any improvement in insulin resistance will diminish the allostatic load on the glucoregulatory system captured by the ''hyperbolic'' relationship between insulin sensitivity and beta-cell function. The key question is whether any therapy goes beyond these two general mechanisms and can specifically protect the beta-cell. Among the commonly used oral antidiabetic agents metformin is beta-cell neutral and sulphonylureas/meglitinides appear to accelerate beta-cell deterioration.

In contrast, GLP-1 based therapies (DPP IV inhibitors and GLP-analogues) and thiazolidinediones have been shown to improve beta-cell function. GLP-1 has been shown to stimulate beta-cell proliferation and inhibit beta-cell apoptosis in vitro but it is unclear how this translates into long-term clinical scenarios.

Thiazolidinediones have also been shown to preserve beta-cell mass through a number of mechanisms. For example, rosiglitazone reduces beta-cell death in ZDF rats and pioglitazone protects beta-cells from glucose and IL1-b induced apoptosis. In humans, a significant improvement in the acute insulin response to IV glucose was observed after 6 months of therapy with rosiglitazone which was independent of reduced glucose toxicity because the control group (insulin treatment) had a similar reduction in HbA1c. Moreover, a decrease in the proinsulin:insulin ratio seen after 6 months of rosiglitazone therapy in patients with type 2 diabetes indicates an improvement in insulin granule maturation. Furthermore, a key component of thiazolidinedione action is redistribution of fatty acid fluxes which may alleviate beta-cell lipotoxicity. In the American Diabetes Prevention Program in patients with IGT, evaluation of the 1-year troglitazone arm demonstrated an even greater effect on reduction of diabetes risk than metformin or lifestyle intervention, a finding well compatible with a beta-cell protective effect. Independent evidence for a beta-cell protective effect of rosiglitazone comes from studies in renal transplant patients treated with beta-cell-toxic immunosuppressants.

In 18 out of 22 patients, adequate glycaemic control was achieved with rosiglitazone suggesting a dramatic amelioration of beta-cell toxicity. In conclusion, both GLP-1 based therapies and thiazolidinediones have potential for chronic beta-cell protection but clinical data in support of this concept are only available for thiazolidinediones. Both direct and indirect mechanisms are likely to be involved.