Improving function and survival of pancreatic islets by endogenous production of glucagon-like peptide 1 (GLP-1).
Glucagon-like peptide 1 (GLP-1) is a hormone that has received significant attention as a therapy for diabetes because of its ability to stimulate insulin biosynthesis and release and to promote growth and survival of insulin-producing beta cells. While GLP-1 is produced from the proglucagon precursor by means of prohormone convertase (PC) 1/3 activity in enteroendocrine L cells, the same precursor is differentially processed by PC2 in pancreatic islet alpha cells to release glucagon, leaving GLP-1 trapped within a larger fragment with no known function. We hypothesized that we could induce GLP-1 production directly within pancreatic islets by means of delivery of PC1/3 and, further, that this intervention would improve the viability and function of islets. Here, we show that adenovirus-mediated expression of PC1/3 in alpha cells increases islet GLP-1 secretion, resulting in improved glucose-stimulated insulin secretion and enhanced survival in response to cytokine treatment. PC1/3 expression in alpha cells also improved performance after islet transplantation in a mouse model of type 1 diabetes, possibly by enhancing nuclear Pdx1 and insulin content of islet beta cells. These results demonstrate a unique strategy for liberating GLP-1 from directly within the target organ and highlight the potential for up-regulating islet GLP-1 production as a means of treating diabetes.
Wideman
Rhonda D
RD
Laboratories of Molecular and Cellular Medicine, Departments of Cellular and Physiological Sciences and Surgery, Life Sciences Institute, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, Canada.
Yu
Irene L Y
IL
Webber
Travis D
TD
Verchere
C Bruce
CB
Johnson
James D
JD
Cheung
Anthony T
AT
Kieffer
Timothy J
TJ
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D018929:Cell Culture Techniques; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D005822:Genetic Vectors; D052216:Glucagon-Like Peptide 1 / Q000096:biosynthesis*; D005947:Glucose / Q000494:pharmacology; D005951:Glucose Tolerance Test; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007375:Interleukin-1 / Q000494:pharmacology; D007515:Islets of Langerhans / Q000166:cytology* / Q000378:metabolism*; D016381:Islets of Langerhans Transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D045664:Proprotein Convertase 1 / Q000378:metabolism; D045706:Proprotein Convertase 2 / Q000378:metabolism; D014161:Transduction, Genetic
D007328:Insulin; D007375:Interleukin-1; D052216:Glucagon-Like Peptide 1; D045664:Proprotein Convertase 1; D045706:Proprotein Convertase 2; D005947:Glucose