In vivo expression of GLP-1/IgG-Fc fusion protein enhances beta-cell mass and protects against streptozotocin-induced diabetes.
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 beta 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.
Soltani
N
N
Department of Medicine, University of Toronto, Ontario, Canada.
Kumar
M
M
Glinka
Y
Y
Prud'homme
G J
GJ
Wang
Q
Q
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D048429:Cell Size; D003921:Diabetes Mellitus, Experimental; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000473:pathology / Q000628:therapy*; D018274:Electroporation; D000077270:Exenatide; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D052216:Glucagon-Like Peptide 1 / Q000097:blood / Q000235:genetics*; D005951:Glucose Tolerance Test; D007141:Immunoglobulin Fc Fragments / Q000235:genetics*; D007074:Immunoglobulin G / Q000235:genetics; D007273:Injections, Intramuscular; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000473:pathology*; D051379:Mice; D008815:Mice, Inbred Strains; D010455:Peptides / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000235:genetics; D014688:Venoms / Q000235:genetics
D001786:Blood Glucose; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D007328:Insulin; D010455:Peptides; D011993:Recombinant Fusion Proteins; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide