Improving the anti-diabetic activity of GLP-1 by fusion with globular adiponectin

Abstract

Glucagon-like peptide-1 (GLP-1) as an endogenous glucose-lowering peptide has great potential in diabetes therapy, but its clinical utility is compromised by its limited activity in vivo. Herein to improve the anti-diabetic activity of GLP-1, we constructed a fusion protein (GLP-1-globular adiponectin, GAD) using this peptide and the globular adiponectin. Using recombinant expression, we prepared the GAD fusion protein with a purity of above 95%. In normal mice, we validated the acute glucose-lowering activity of GAD by performing intraperitoneal glucose tolerance test (IPGTT). After that, we evaluated the anti-diabetic activity of this fusion protein in a multiple-low-dose streptozotocin (STZ)-induced diabetic mice model. In this diabetic mice model, GAD treatment greatly reduced the elevated fasting glucose and improved their impaired glucose homeostasis as judged by oral glucose tolerance test (OGTT). After treatment, the fasting glucose was 15.34 ± 2.07 mmol/L and 9.47 ± 1.08 mmol/L for GLP-1-treated and GAD-treated diabetic mice, respectively. Moreover, GLP-1 treatment and GAD treatment improved the pancreas function of the diabetic mice by ~1.5-fold and ~4.2-fold, respectively. Furthermore, GAD treatment greatly reduced the tissue damage in the pancreas of the diabetic mice. These data suggest that GAD possesses an improved anti-diabetic activity in vivo compared with native GLP-1, and therefore it could be regarded as a potential candidate for the future development of anti-diabetic drugs.

Keywords::

• adiponectin
• diabetes
• glucagon-like peptide-1
• incretin
• protein engineering