In vivo expression of GLP-1/IgG-Fc fusion protein enhances beta-cell mass and protects against streptozotocin-induced diabetes

Abstract

Glucagon-like peptide 1 (GLP-1) and its analogue exendin-4 (Ex4) have displayed potent glucose homeostasis-modulating characteristics in type 2 diabetes (T2D). However, there are few reports of effectiveness in type 1 diabetes (T1D) therapy, where there is massive loss of b cells. We previously described a novel GLP-1 analogue consisting of the fusion of active GLP-1 and IgG heavy chain constant regions (GLP-1/IgG-Fc), and showed that in vivo expression of the protein, via electroporation-enhanced intramuscular plasmid-based gene transfer, normalized blood glucose levels in T2D-prone db/db mice. In the present study, GLP-1/IgG-Fc and Ex4/IgG-Fc were independently tested in multiple low-dose streptozotocin-induced T1D. Both GLP-1/ IgG-Fc and Ex4/IgG-Fc effectively reduced fed blood glucose levels in treated mice and ameliorated diabetes symptoms, where as control IgG-Fc had no effect. Treatment with GLP-1/IgG-Fc or Ex4/IgG-Fc improved glucose tolerance and increased circulating insulin and GLP-1 levels. It also significantly enhanced islet beta-cell mass, which is likely a major factor in the amelioration of diabetes. This suggests that GLP-1/IgG-Fc gene therapy may be applicable to diseases where there is either acute or chronic beta-cell injury.

DsAAV8-mediated expression of glucagon-like peptide-1 in pancreatic beta-cells ameliorates streptozotocin-induced diabetes

“…[53][54][55] Others have fused GLP-1 to various proteins such as IgG or albumin to improve circulating half-lives. 18,56 In each of these studies, the therapeutic effects of GLP-1 were achieved following systemic increase in GLP-1 levels. Although continuous infusion of GLP-1 in humans has not been associated with decreased receptor activation, the effects associated with chronic and continuous high levels of circulating GLP-1 are likely not yet fully appreciated.…”

“…17 In animal models of type-1 diabetes, administration of GLP-1-receptor agonists has been shown to improve glycemia, in part due to increases in beta-cell mass. 5,18,19 Native GLP-1, as well as currently available GLP-1-receptor agonists, have short biological half-lives. [20][21][22][23] Native GLP-1 is degraded within minutes by dipeptidylpeptidase (DPP)-IV, 20,21 rendering it unfit for use as a subcutaneously administered therapeutic.…”

Ectopic expression of glucagon receptor in skeletal muscles improves glucose homeostasis in a mouse model of diabetes

“…Radioimmunoassay and enzyme-linked immunosorbent assay Serum glucagon and C-peptide, insulin or glucagonlike peptide-1 (GLP-1) concentrations were determined [20] using corresponding RIA kits (Linco, St Charles, MO, USA). Plasma adrenalin (epinephrine) levels were determined using an ELISA kit (IBL, Hamburg, Germany).…”

“…Animal care Mice were housed under a 12 h light-dark cycle with free access to standard rodent chow and water except where noted. An intraperitoneal glucose tolerance test (IPGTT), insulin tolerance test (ITT) and glucagon tolerance test (GcgTT) were performed as described previously [20]. Insulin-induced hypoglycaemia was performed in randomly fed mice by intraperitoneal insulin injection (2.0 U/kg) and blood glucose levels were monitored at the indicated times.…”

“…Insulin-induced hypoglycaemia was performed in randomly fed mice by intraperitoneal insulin injection (2.0 U/kg) and blood glucose levels were monitored at the indicated times. Diabetic hyperglycaemia was induced by multiple low-dose STZ injection as described previously [20]. Metabolic cages were used in some groups of mice before termination of the experiments.…”