Enhanced Protection against Cytokine- and Fatty Acid-induced Apoptosis in Pancreatic Beta Cells by Combined Treatment with Glucagon-like Peptide-1 Receptor Agonists and Insulin Analogues

Advanced glycation end products (AGEs) might play a pathophysiological role in the development of diabetes and its complications. AGEs negatively affect pancreatic beta-cell function and the expression of transcriptional factors regulating insulin gene. Glucagon-like peptide-1 (GLP-1), an incretin hormone that regulates glucose homeostasis, might counteract the harmful effects of AGEs on the beta cells in culture. The aim of this study was to identify the intracellular mechanisms underlying GLP-1-mediated protection from AGE-induced detrimental activities in pancreatic beta cells. HIT-T15 cells were cultured for 5 days with glycated serum (GS, consisting in a pool of AGEs), in the presence or absence of 10 nmol/L GLP-1. After evaluation of oxidative stress, we determined the expression and subcellular localization of proteins involved in maintaining redox balance and insulin gene expression, such as nuclear factor erythroid-derived 2 (Nrf2), glutathione reductase, PDX-1, and MafA. Then, we investigated proinsulin production. The results showed that GS increased oxidative stress, reduced protein expression of all investigated factors through proteasome activation, and decreased proinsulin content. Furthermore, GS reduced ability of PDX-1 and MafA to bind DNA. Coincubation with GLP-1 reversed these GS-mediated detrimental effects. In conclusion, GLP-1, protecting cells against oxidants, triggers protective intercellular pathways in HIT-T15 cells exposed to GS.

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Lixisenatide – A New Glucagon-like Peptide 1 Receptor Agonist in the Treatment of Type 2 Diabetes

European Endocrinology ◽

10.17925/ee.2013.09.02.76 ◽

2010 ◽

Vol 9 (2) ◽

pp. 76 ◽

Cited By ~ 4

Author(s):

Josep Vidal ◽

Keyword(s):

Type 2 Diabetes ◽

Glycaemic Control ◽

Basal Insulin ◽

Glycated Haemoglobin ◽

Insulin Analogues ◽

Receptor Agonists ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Long Acting

Optimal glycaemic control is essential to managing risks in patients with type 2 diabetes. However, glycaemic control remains poor among type 2 diabetes patients, particularly the control of post-prandial glucose (PPG). Almost half of patients treated with basal insulin and oral anti-diabetic drugs (OADs) do not achieve their glycated haemoglobin (HbA1c) goals, despite achieving fasting plasma glucose (FPG) control. Glycaemic control targets have emphasised FPG targets, but PPG contributes significantly to overall glycaemic control in type 2 diabetes. Glucagon-like peptide 1 (GLP-1) receptor agonists have shown substantial efficacy in improving overall glycaemic control but have differing effects on PPG, which is a result of their different mechanisms of action. Lixisenatide is unique among existing GLP-1 receptor agonists in that it is short acting but given as a once daily dose, and exerts its main effects during the prandial period. It has demonstrated efficacy in an extensive clinical trial programme. In particular, it has shown a beneficial effect on PPG compared with existing GLP-1 receptor agonists, probably a result of its effect on slowing gastric emptying. This has provided a strong rationale for its use as add-on therapy to long-acting basal insulin analogues, in cases where the latter is not providing adequate glycaemic control. The additive effects on glycaemic control may lead to a new treatment approach to manage blood glucose and prevent long-term complications in patients with type 2 diabetes.

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