The Mechanism of Metabolic Influences on the Endogenous GLP-1 by Oral Antidiabetic Medications in Type 2 Diabetes Mellitus

Abstract

Incretin-based therapy is now a prevalent treatment option for patients with type 2 diabetes mellitus (T2DM). It has been associated with considerably good results in the management of hyperglycemia with cardiac or nephron-benefits. For this reason, it is recommended for individuals with cardiovascular diseases in many clinical guidelines. As an incretin hormone, glucagon-like peptide-1 (GLP-1) possesses multiple metabolic benefits such as optimizing energy usage, maintaining body weight, β cell preservation, and suppressing neurodegeneration. However, recent studies indicate that oral antidiabetic medications interact with endogenous or exogenous GLP-1. Since these drugs are transported to distal intestine portions, there are concerns whether these oral drugs directly stimulate intestinal L cells which release GLP-1, or whether they do so via indirect inhibition of the activity of dipeptidyl peptidase-IV (DPP-IV). In this review, we discuss the metabolic relationships between oral antihyperglycemic drugs from the aspect of gut, microbiota, hormones, β cell function, central nervous system, and other cellular mechanisms.

In vitro dipeptidyl peptidase IV inhibitory activity and in situ insulinotropic activity of milk and egg white protein digests

“…Therefore, DPP-IV inhibitors (known as gliptins) are commonly used as antidiabetic drugs. 2 Activation of incretin receptors on pancreatic β-cells leads to an increase in cAMP and intracellular calcium, followed by insulin exocytosis in a glucose-dependent manner. 3 While proteins and carbohydrates are strong stimuli for the promotion of GLP-1 secretion, the release of GIP is attributed mainly by dietary lipids and carbohydrates.…”

Insights into a possible role of glucagon-like peptide-1 receptor agonists in the treatment of depression

“…Recent data have indicated that such an effect may depend on the influence on metabolic processes because in chronic unpredictable mild stress (CUMS) in mice, the decreased GLP-1 level in the hippocampus was increased with metformin treatment [ 46 ]. Metformin has been found to produce antidepressive effects by enhancing the responsiveness of the serotoninergic neurons in the dorsal raphe [ 47 ], but the main impact of GLP-1 is exerted by AMP-activated protein kinase (AMPK), a major cellular regulator of lipid and glucose metabolism [ 48 ]. Liraglutide administration weakened depressive- and anxiety-like behaviors in a depression mouse model of chronic administration of corticosterone and attenuated hyperactivity induced by this steroid.…”

Identification of Novel Alkaloids from Portulaca oleracea L. and Characterization of Their Pharmacokinetics and GLP-1 Secretion-Promoting Activity in STC-1 Cells

“…In both cells, the K ATP channel is composed of an inward rectifier potassium channel (Kir6.2) and SUR1. The closure of the K ATP channels will cause an influx of Ca 2+ in the intestinal L cells, which will then secrete glucagon-like peptide-1 (GLP-1) to promote insulin secretion and enhance insulin sensitivity . We previously used molecular docking to examine the interaction of certain purslane alkaloids with SUR1.…”

“…The closure of the K ATP channels will cause an influx of Ca 2+ in the intestinal L cells, which will then secrete glucagon-like peptide-1 (GLP-1) to promote insulin secretion and enhance insulin sensitivity. 19 We previously used molecular docking to examine the interaction of certain purslane alkaloids with SUR1. These alkaloids are also phenylalanine derivatives, and they can bind to SUR1 at a site similar to or the same as the binding site for nateglinide but with a lower binding energy (unpublished data).…”