Abstract
Glucagon-like peptide 1 (GLP-1) mimetics have been approved as an adjunct therapy for glycemic control in type 2 diabetic patients for the increased insulin secretion under hyperglycemic conditions. Recently, it is reported that such agents elicit neuroprotective effects against diabetes-associated cognitive decline. However, there is an issue of poor compliance by multiple daily subcutaneous injections for sufficient glycemic control due to their short duration, and neuroprotective actions were not fully studied, yet. In this study, using the prepared exendin-4 fusion protein agent, we investigated the pharmacokinetic profile and the role of this GLP-1 mimetics on memory deficits in a high-fat diet (HFD)/streptozotocin (STZ) mouse model of type 2 diabetic mellitus. After induction of diabetes, mice were administered weekly by intraperitoneal injection of GLP-1 mimetics for 6 weeks. This treatment reversed HFD/STZ-induced metabolic symptoms of increased body weight, hyperglycemia, and hepatic steatosis. Furthermore, the impaired cognitive performance of diabetic mice was significantly reversed by GLP-1 mimetics. GLP-1 mimetic treatment also reversed decreases in GLP-1/GLP-1 receptor expression levels in both the pancreas and hippocampus of diabetic mice; increases in hippocampal inflammation, mitochondrial fission, and calcium-binding protein levels were also reversed. These findings suggest that GLP-1 mimetics are promising agents for both diabetes and neurodegenerative diseases that are associated with increased GLP-1 expression in the brain.
Highlights
Type 2 diabetes mellitus (T2DM) is a widespread, chronic inflammatory disease associated with long-term complications including insulin resistance and cardiovascular diseases
This study introduces the development and in vivo characterization of a novel long-lasting Glucagon-like peptide 1 (GLP-1) mimetic exendin-4 fusion protein (ExA) composed of exendin-4 genetically fused to an albumin binding domain (ABD) and an anti-FcRn affibody
The ExA exhibited a plasma half-life of 5.7 days, and the maximum plasma concentration (4.5 μg/mL on average) of ExA was reached after 2.3 h of post-administration
Summary
Type 2 diabetes mellitus (T2DM) is a widespread, chronic inflammatory disease associated with long-term complications including insulin resistance and cardiovascular diseases. Numerous studies have suggested a close causal association between T2DM and cognitive impairment [1,2]. T2DM has been implicated as a risk factor in vascular dementia and in Alzheimer’s disease (AD) [3]. Insulin resistance in peripheral tissues influences insulin resistance in the brain thereby affecting cognition [4]. Several antidiabetic drugs exert beneficial effects on both systemic and neuronal metabolic processes, which could be clinically significant for the treatment of diabetes-induced complications such as cognitive decline. Diabetes is caused by multiple mechanisms and its etiology is not fully understood
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