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.
Highlights
E2HSA 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
Large fluctuations in blood glucose levels has been identified as the biggest culprit in causing diabetic complications, and strictly restraining blood glucose levels by keeping glycated hemoglobin (HbA1c) levels < 7.0% has been the main outcome for diabetes treatment [1]
Repeated treatments with exendin-4 (2 μg/kg) controlled the non-fasting blood glucose levels during the first 3 weeks and the fasting blood glucose levels during the first 2 weeks, but the (Glycated hemoglobin) (HbA1c) levels were only decreased by 0.7%
Summary
E2HSA 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. Type 2 diabetes mellitus (T2DM) has become a global epidemic disease that is associated with both increased economic and clinical burdens, which causes high mortality rates due to related micro- and macro-vascular complications, such as cardiovascular disease, kidney failure, amputations and blindness. GLP-1 performs a hypoglycemic function by simultaneously enhancing insulin secretion and inhibiting glucagon secretion. Unlike the aforementioned anti-diabetic drugs, GLP-1 has an advantage in inducing weight loss and only rarely causing hypoglycemia [2]. GLP-1 provides evident protection for pancreatic islet β cells that suppresses or delays progressive failure and improves the homeostasis of glucose metabolism [3]. Liraglutide, a GLP-1 analog, has been reported to increase β-cell mass by directly regulating cell kinetics and suppressing both oxidative and endoplasmic reticulum stresses [4]
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