The Incretins and Diabetes

 Way back in 1964 investigators found a greater insulin release from pancreas to an oral glucose load than to an intravenous load. This was recently termed 'the Incretin effect' .  This effect is due to two incretin hormones-  glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]. They are  released by intestinal cells in response to a glucose load. They bind to beta cells and increase insulin secretion. The above said Incretin effect is defective in Type 2 diabetics mainly as a consequence of Diabetes than a primary event..as shown in this study from Denmark. 
The physiologic effects of GLP-1 occur by multiple mechanisms, including stimulation of  insulin secretion, reduced inappropriate glucagon secretion, slowing of gastric emptying, induce satiety,positive effects on β-cell prolif-eration, β-cell differentiation, and inhibition of β-cell apoptosis in animal and in vitro models.(Diab,Obesity & Metabolism 2009)
But GLP gets rapidly degraded in the body by Dipeptidyl peptidase-4 (DPP-4), an enzyme secreted from cell surface of lymphocytes..and also by kidneys, liver, bone marrow.
Given this physiology..now we have two types of medications to enhance the Incretin system. 
1. GLP agonists - Exenatide(Byetta), Liraglutide.
2. DPP 4 inhibitors - Sitagliptin(Januvia), Saxagliptin, Vidagliptin.


In AMIGO trials 1,2,&3 ...addition of Exenatide to Metformin, to sulphonylurea, & to combination of metformin and sulphonylurea respectively showed a significant decrease in HbA1C at 30 weeks compared to placebo. Also more people reached HbA1C targets in Exenatide group compared to placebo. Liraglutide has also shown similar effects .Eventhough these drugs increase insulin secretion ..there is no increase in incidence of hypoglycemia, and,they are weight neutral.(Lira has been associated with medullary ca of thyroid in rats)


In studies where Sitagliptin has been added to Metformin or to pioglitazone showed greater number of people reaching HbA1C targets compared to addition of placebo over a period of 6 months.(Diabetes Care 2006 & C Ther)The other DPP4 inhibitors also showed similar results. The main side effects noted were increase in white cell count, nasopharyngeal infections.(likely due to the fact that DPP4 is secreted from lymphocytes)


Based on the above..these 2 types of medications have started to be used widely. As you can see..they are promising..but these are still early days for them...as we would like to know if these reductions in HbA1C with them will turn out into a reduction or delay in micro or macrovascular complications. (we dont want another Rosiglitazone! -  refer to my post on Aug 3rd 2010)