Effects of E2HSA, a Long-Acting Glucagon Like Peptide-1 Receptor Agonist, on Glycemic Control and Beta Cell Function in Spontaneous Diabetic db/db Mice.

Shaocong Hou,Qian Jiang,Sujuan Sun,Shuainan Liu,Caina Li,Chunming Jia,Quan Liu,Yi Huan,Zhufang Shen

doi:10.1155/2015/817839

Abstract

Glucagon like peptide-1 (GLP-1) receptor agonists such as exendin-4 have been widely used but their short half-life limits their therapeutic value. The recombinant protein, E2HSA, is a novel, long-acting GLP-1 receptor agonist generated by the fusion of exendin-4 with human serum albumin. In mouse pancreatic NIT-1 cells, E2HSA activated GLP-1 receptor with similar efficacy as exendin-4. After single-dose administration in ICR mice, E2HSA showed prolonged glucose lowering effects which lasted up to four days and extended inhibition on gastric emptying for at least 72 hours. Chronic E2HSA treatment in db/db mice significantly improved glucose tolerance, reduced elevated nonfasting and fasting plasma glucose levels, and also decreased HbA1c levels. E2HSA also increased insulin secretion and decreased body weight and appetite. Furthermore, immunofluorescence analysis showed that E2HSA increased β-cell area, improved islet morphology, and reduced β-cell apoptosis. In accordance with the promotion of β-cell function and survival, E2HSA upregulated genes such as Irs2, Pdx-1, Nkx6.1, and MafA and downregulated the expression levels of FoxO1 and proapoptotic Bcl-2 family proteins. In conclusion, with prolonged glucose lowering effects and promoting β-cell function and survival, the fusion protein, E2HSA, is a promising new therapeutic for once weekly treatment of type 2 diabetes.

Highlights

Type 2 diabetes mellitus (T2DM) has two major characteristics: reduced insulin sensitivity linked to obesity and impaired insulin secretion due to β-cell dysfunction [1]. β-cell dysfunction occurs when the demand for insulin overwhelms the capacity of the β-cell to respond [2], which results in severely reduced insulin secretion [3] and β-cell death [4]
GLP-1 receptor (GLP-1R) agonists have the advantage of simultaneously stimulating insulin secretion while inhibiting gastric emptying, which eventually leads to effective blood glucose control and weight loss [6]
Utilizing luciferase reporter gene expression assays, we demonstrated that E2HSA retained the ability of exendin-4 to activate GLP-1R and showed the same efficacy as exendin-4, suggesting that altered peptide conformation did not prevent exendin-4 from recognizing and activating the Glucagon like peptide-1 (GLP-1) receptor

Summary

Introduction

Type 2 diabetes mellitus (T2DM) has two major characteristics: reduced insulin sensitivity linked to obesity and impaired insulin secretion due to β-cell dysfunction [1]. β-cell dysfunction occurs when the demand for insulin overwhelms the capacity of the β-cell to respond [2], which results in severely reduced insulin secretion [3] and β-cell death [4]. Type 2 diabetes mellitus (T2DM) has two major characteristics: reduced insulin sensitivity linked to obesity and impaired insulin secretion due to β-cell dysfunction [1]. Β-cell dysfunction occurs when the demand for insulin overwhelms the capacity of the β-cell to respond [2], which results in severely reduced insulin secretion [3] and β-cell death [4]. Few available drugs can enhance β-cell viability and restore their ability to synthesize and secrete insulin without side effects such as hypoglycemia or weight gain. After binding to GLP1 receptor, GLP-1 stimulates insulin secretion in a glucose dependent manner, which means there is no or little risk of hypoglycemia [7]. Other effects include suppression of glucagon secretion, delayed gastric emptying, and increased satiety [6]. Through multiple signal transduction pathways, GLP-1 promotes the proliferation and neogenesis of islet β-cells while at the same time reducing their apoptosis [8]

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