ABSTRACT
Research activity in the field of diabetes has increased greatly in recent years. People with diabetes would want this to translate into more effective treatment of diabetes and its complications. Patients with type 1 diabetes would like to be freed from the need to selfinject with insulin. Pancreatic and islet-cell transplantation can achieve this; however, it is unlikely that these techniques will find widespread application in the immediate future. It may prove possible to generate mature β-cells from embryonic stem cells, but many issues need to be resolved before cells derived by these methods can be used in human transplantation. Although experimental gene therapy (with transfer of DNA to somatic cells) has shown promising results, no proposed gene therapy model for the treatment or prevention of diabetes has reached the stage of clinical testing. Technological developments to produce implantable insulin pumps with continuous glucose sensing continue, but are not sufficiently advanced to allow wide uptake. Until sufficient progress in these areas has been achieved, it is likely that most progress will be made through the development of new pharmaceutical products to treat the hyperglycemia of diabetes. Such activity is burgeoning. New insulin analogs continue to appear. Several devices allowing the pulmonary delivery of inhaled insulin have already been developed. Inhaled insulin treatment is being actively investigated as an alternative non-invasive method of insulin delivery and many studies have already attested to its effectiveness in achieving tight glycemic control in both type 1 and type 2 diabetes. Oral insulins have also been developed but are only at a preliminary level of investigation. Perhaps the most exciting
potential therapy area lies in the discovery and evaluation of new drugs to treat type 2 diabetes. Insulin secretion can be stimulated by the incretin gut hormones glucagon-like peptide-1 (GLP-1) and glucosedependent insulinotropic polypeptide (GIP) without leading to hypoglycemia. Stable analogs of these incretins have been developed with a longer half-life. Such an analog, exenatide, Byetta® Amylin pharmaceuticals (exendin-4), when injected subcutaneously has been shown to reduce HbA1c in patients with type 2 diabetes failing to achieve glycemic control on maximal doses of either metformin alone or metformin/sulfonylurea combination. Inhibitors of dipeptidyl peptidase-IV (DPP-IV) which degrades GLP-1 have also been developed and have reached an advanced stage of clinical trial. Amylin, a polypeptide synthesized by the islet β-cells and co-secreted with insulin, appears to act centrally to induce satiety, slow gastric emptying and suppress pancreatic glucagon secretion. Pramlintide is a soluble analog of amylin with amylin-like effects which last for about 3 hours after subcutaneous administration prior to a meal. It has been launched in the USA as Symlin®, Amylin pharmaceuticals and is licensed in both type 1 and 2 diabetes as an adjunct to meal-time insulin therapy in those who have failed to achieve desired glucose control despite optimal insulin therapy. One of its main advantages is that it is not associated with weight gain. Other exciting drugs in development are dual peroxisome proliferator-activated receptor (PPAR)α and γ agonists, which may treat both hyperglycemia and dyslipidemia, and rimonabant which acts on the endocannabinoid system. Endocannabinoids act on
cannabinoid type 1 (CB1) and type 2 (CB2) receptors. The endocannabinoid system plays a key role in the regulation of energy balance and fat accumulation and overactivity of the system is associated with increased food intake and fat accumulation. Rimonabant acts as a selective CB1 blocker inducing weight loss, reducing triglyceride levels and improving glucose tolerance. It presents a novel tool to reduce cardiovascular risk factors of the metabolic syndrome including dyslipidemia and type 2 diabetes (as well as nicotine dependence). Rimonabant (Acomplia®, Sanofi-Aventis), has already obtained regulatory approval as an adjunct to diet and exercise for the treatment of obese patients or overweight patients with associated risk factors.
