The albumin-exendin-4 recombinant protein E2HSA improves glycemic control and β-cell function in spontaneous diabetic KKAy mice

Abstract

BackgroundE2HSA is a genetic fusion protein that consists of two tandem exendin-4 molecules that are covalently bonded to recombinant human serum albumin via a peptide linker. Previous studies have demonstrated that E2HSA significantly decreased blood glucose levels, improved β-cell function and promoted β-cell proliferation in diabetic db/dB mice. This study aimed to evaluate the benefits of E2HSA on glucose and lipid metabolism in a spontaneous diabetes animal model, KKAy mice.MethodsE2HSA was acutely administered at doses of 1, 3 and 9 mg/kg by subcutaneous injection in diabetic KKAy mice with exendin-4 (2 μg/kg) as a positive reference, and then the non-fasting blood glucose and food intake levels were dynamically monitored. In addition, different doses of E2HSA were injected once daily, as well as with exendin-4 twice daily, for 7 weeks to evaluate the effect on glucose and lipid metabolism, as well as the body weight, food and water intake.ResultsSingle injection of E2HSA decreased non-fasting blood glucose and food intake levels in a dose-dependent manner for 4 days and 2 days, respectively. Repeated injections with E2HSA significantly decreased variations in blood glucose levels with a reduction of HbA1c levels by 1.6% at a 9 mg/kg dose, simultaneously increased fasting blood insulin levels, inhibited fasting blood glucagon levels, improved the impaired oral glucose tolerance and enhanced glucose infusion rate, which is the gold standard for evaluating β-cell function. Moreover, repeated injections with E2HSA also ameliorated the dyslipidemia and reduced body weight, food and water intake in diabetic KKAy mice.ConclusionsE2HSA significantly reduced blood glucose levels over a prolonged duration, enhanced β-cell function, and ameliorated dyslipidemia and obesity in diabetic KKAy mice. Thus, E2HSA may be a new candidate for the treatment of type 2 diabetes.Electronic supplementary materialThe online version of this article (doi:10.1186/s40360-017-0143-8) contains supplementary material, which is available to authorized users.

Terminal differentiation of keratinocytes was damaged in type 2 diabetic mice

“…These results were consistent with those of previous reports on the characteristic features of KKAy mice [12].…”

Effect of miR‑19b on the protective effect of Exendin‑4 on islet cells in non‑obese diabetic mice

“…GLP-1 is one of the most central mediators of glycemic control after gastric bypass in diabetic patients (18). Exendin-4 is a GLP-1 analogue and not inactivated by dipeptidyl peptidase-4, which has an incretin effect, controls blood glucose and protects islet β cells (19,20), but its specific mechanism of action remains unclear. Previous findings have shown that improving pancreatic inflammation and fibrosis and changing microRNA expression level in the pancreatic tissue and blood, Exendin-4 intervention in NOD mice upregulates miR-1 level, downregulates miR-19a, miR-19b and miR-22 levels and inhibits the differentiation and maturation of islet β cells, as well as promotes the recovery of insulin secretion function (21).…”

High salt diet‐induced proximal tubular phenotypic changes and sodium‐glucose cotransporter‐2 expression are coordinated by cold shock Y‐box binding protein‐1

“…Subsequently, the glucose and protein content were determined using NobiStrip U10 test stripes (HI-309-38810601, Hitado) according to the manufacturer's instructions. For determining blood glucose levels, mice were fasted for 4 h 19,20 with water ad libitum, blood samples were taken by puncture of a tail vein and immediately analyzed using Accu-Chek Aviva Connect (PZN 11532906, Roche Diabetes Care). The concentrations of the urinary elecrolytes (sodium, chloride, glucose, and urea) as well as the osmolality were measured according to the manufacturer's instructions (Roche Diagnostics, Cobas c501 module).…”