Incretins: Their physiology and application in the treatment of diabetes mellitus

Abstract

Therapies targeting the action of incretin hormones have been under close scrutiny in recent years. The incretin effect has been defined as postprandial enhancement of insulin secretion by gut-derived factors. Likewise, incretin mimetics and incretin effect amplifiers are the two different incretin-based treatment strategies developed for the treatment of diabetes. Although, incretin mimetics produce effects very similar to those of natural incretin hormones, incretin effect amplifiers act by inhibiting dipeptidyl peptidase-4 (DPP-4) enzyme to increase plasma concentration of incretins and their biologic effects. Because glucagon-like peptide-1 (GLP-1) is an incretin hormone with various anti-diabetic actions including stimulation of glucose-induced insulin secretion, inhibition of glucagon secretion, hepatic glucose production and gastric emptying, it has been evaluated as a novel therapeutic agent for the treatment of type 2 diabetes mellitus (T2DM). GLP-1 also manifests trophic effects on pancreas such as pancreatic beta cell growth and differentiation. Because DPP-4 is the enzyme responsible for the inactivation of GLP-1, DPP-4 inhibition represents another potential strategy to increase plasma concentration of GLP-1 to enhance the incretin effect. Thus, anti-diabetic properties of these two classes of drugs have stimulated substantial clinical interest in the potential of incretin-based therapeutic agents as a means to control glucose homeostasis in T2DM patients. Despite this fact, clinical use of GLP-1 mimetics and DPP-4 inhibitors have raised substantial concerns owing to possible side effects of the treatments involving increased risk for pancreatitis, and C-cell adenoma/carcinoma. Thus, controversial issues in incretin-based therapies under development are reviewed and discussed in this manuscript.

Effect of GLP‐1 and GIP on C‐peptide secretion after glucagon or mixed meal tests: Significance in assessing B‐cell function in diabetes

“…The relationship between Cmax and AUC of C‐peptide in the MMTT but not in GST was previously studied in people with T1D, so we could compare the 2 tests between normal people and people with diabetes. The peak of C‐peptide with MMTT was reached earlier ( t = 35‐40 minutes) in healthy people compared to what reported in patients with T1D ( t = 90 minutes), and this difference can be explained by the slower B‐cell secretion observed in T1D. Despite this difference, we believe that the relationship between Cmax and iAUC of C‐peptide is of great interest in clinical practice.…”

Pancreatic hyperplasia after gastric bypass surgery in a GK rat model of non-obese type 2 diabetes

“…Many studies have addressed the effects of gut hormones on pancreatic hypertrophy and hyperplasia. Cholecystokinin (CCK) (Miyasaka et al 1998, Saillan-Barreau et al 1999 and GLP-1 (Tasyurek et al 2014) exert clear trophic effects on the pancreas. The effect of GLP-1 is presumably related to its impact on b-cell growth (Xu et al 2006).…”

Diabetes pharmacotherapy and effects on the musculoskeletal system

“…Current FDA‐approved DPP‐4 inhibitor medications include Sitagliptin (the first DPP‐4 inhibitor to be approved for therapeutic use in T2D, approved in 2006), Saxagliptin (2009), Linagliptin (2011), and Alogliptin (2013). Vildagliptin, a newer DPP‐4 inhibitor marketed in the European Union, has been shown to increase the ability of both α and β cells to sense and respond to glucose and induce peripheral insulin sensitivity . DPP‐4 inhibitors are effective and well tolerated when used as monotherapy, although when used in combination with other oral antidiabetic agents, such as metformin and SUs, their efficacy is improved .…”

“…Vildagliptin, a newer DPP‐4 inhibitor marketed in the European Union, has been shown to increase the ability of both α and β cells to sense and respond to glucose and induce peripheral insulin sensitivity . DPP‐4 inhibitors are effective and well tolerated when used as monotherapy, although when used in combination with other oral antidiabetic agents, such as metformin and SUs, their efficacy is improved . Their mechanism of action on bone is still largely undiscovered but due to their effect on prolonging endogenous GLP‐1 and GIP action, improved glucose tolerance and enhanced GLP‐1 and GIP action on bone are two of the proposed mechanisms .…”