**3. Contribution of incretin system in the pathogenesis of diabetes**

Diabetes is the state of compromised insulin secretion which resulted with hyperglycemia. Incretin effect is reduced or almost absent in T2 DM [63]. Although the secretion of GIP is nearly normal, its insulinotropic effect has been shown to be lost in T2 DM [27]. Secretion of GLP-1 is decreased in contrast to GIP, but its favorable effects on endocrine pancreas and extrapanceratic sites are preserved in T2 DM [20, 64]. In conclusion, detoriation of both the effect and secretion of incretin hormones are involved in the pathogenesis of T2 DM. It is not clear wheter the detoriation of incretin effect is a primary defect in the pathogenesis of diabetes or not. Studies suggest that incretin hormone detoriation is a secondary defect during pro‐ gression of diabetes. Another important fact is the restoration of insulin secretion with GLP-1 replacement is possible and improve hyperglycemia [65, 66].

There are several mechanisms of action of GLP-1 in T2 DM. The first one is the augmentation of glucose induced insulin secretion, resulting with improvement in hyperglycemia. Nearnormal improvement in β-cell response to glucose, improvement in the first phase insulin secretion and completely normalisation of second phase insulin secretion by GLP-1 has been exactly defined [67]. Although the induction of insulin secretion is lost during chronic GLP-1 administration, glucose lowering action with maintained insulin levels tend do persist. Reduction in glucagon secretion is another mechanism of antiglycemic effect of GLP-1 [68]. Administration of GLP-1 delays gastric emptying significantly, and results with reduced postprandial glucose levels [69, 70]. The latter mechanism seems to be lost in chronic fashion. Based upon these mentioned antiglycemic effects of GLP-1, several pharmacological agents are developed for the treatment of diabetes, which will be talked about elswhere in this chapter.
