Author(s): Miao Chen aff1 , Cheng Hu aff1 aff2 , Weiping Jia [*] aff1
glinides; mitiglinide; nateglinide; pharmacogenomics; repaglinide; T2DM
Type 2 diabetes mellitus (T2DM) is a worldwide epidemic and a chronic disease that is characterized by hyperglycemia. T2DM occurs when insulin secretion can no longer overcome an individual's level of insulin resistance [ 1 ]. Under normal conditions, the insulin secretion response, which is initiated by oral or intravenous glucose, consists of two phases. The early phase of insulin release peaks at 3-5 min after the glucose stimulus and ends within 10 min. In the second phase of the insulin response, the insulin concentrations rise steadily to a much lower peak [2,3 ]. The appropriate timing and magnitude of the early phase of insulin release is very important for maintaining normal glucose tolerance. This initial phase of insulin secretion is attenuated or lost in T2DM patients [ 2,4 ]. This loss or attenuation of insulin secretion leads to inadequate insulin-mediated suppression of hepatic glucose production, resulting in postprandial hyperglycemias. The importance of postprandial glycemia in the management of hyperglycemia has been well established [5-7 ]. Postprandial glycemia greatly contributes to the mean glucose and HbA1c levels [8,9 ]. Furthermore, it has been clearly demonstrated that postprandial hyperglycemia is associated with the development and progression of diabetic complications [10-12 ]. Alleviating postprandial hyperglycemia in patients suffering from T2DM or impaired glucose tolerance (IGT) may delay or prevent the progression of cardiovascular disease [7 ]. Therefore, the appropriate control of postprandial glycemia is very crucial for the treatment of T2DM.
Glinides, including repaglinide, nateglinide and mitiglinide, are a type of fasting insulin secretagogue that could help to mimic early-phase insulin release, thus providing improved control of the postprandial glucose (PPG) levels [13-15 ]. Acting as nonsulphonylurea [beta]-cell-activating insulinotropic compounds, glinides bind to distinct sites on the [beta]-cell membrane and display insulinotropic activity that is more rapid and shorter than that of sulfonylureas [14,15 ]. Clinical trials have demonstrated that glinides are effective in lowering the PPG and HbA1c levels as a monotherapy or a combination therapy in patients suffering from T2DM [14,16 ]. Nateglinide and repaglinide are effective in reducing the PPG and HbA1c levels by 0.8-1% in T2DM [14 ]. There are very few clinical trials using mitiglinide to date. A current study shows that mitiglinide can be expected to reduce the HbA1c levels by 0.17-1.1% [17 ]. In addition to improving glycemic control, homeostasis model assessment of [beta]-cell function (HOMA-B) and the homeostasis model assessment of insulin resistance (HOMA-IR) were significantly improved after repaglinide or nateglinide treatment in clinical trials, indicating that [beta]-cell function and insulin resistance might be improved [18-20 ]. Moreover, it has been demonstrated that glinides also affect the gastrointestinal incretin system by inhibiting dipeptidyl peptidase-IV (DPP-IV) [21,22 ]. These studies showed that nateglinide exerts an inhibitory effect on the activity of DPP-IV or a stimulatory effect on glucagon-like peptide-1 (GLP-1) secretion. Thus, glinides could improve the glucose-lowering and insulin-releasing activity of GLP-1 in T2DM. Glinides display a large...