Long-term insulinotropic activity of glucagon-like peptide-1/polymer conjugate on islet microcapsules.
The biohybrid artificial pancreas (BAP), a promising therapy for type 1 diabetes, faces several obstacles such as the need for a large implantation volume of encapsulated islets because of low functionality. To address such problems, in this study we examined long-term insulinotropic activity of glucagon-like peptide-1 (GLP-1)/polymer conjugate [VAPG: poly(N-vinylpyrrolidone-co-acrylic acid-g-PEG) (VAP)-GLP-1] as well as GLP-1/Zn(2+) crystal by coencapsulation with islets. Microcapsules with VAPG or crystal produced round-shaped beads whereas free GLP-1 showed poor capsule morphology. A perfusion experiment suggested that VAPG showed higher bioactivity than did microcapsules with GLP-1/Zn(2+). In long-term culture (200 mg of glucose/dL [G]), VAPG also enhanced insulinotropic activity over 5 weeks compared with the crystal form of GLP-1. However, maintenance of the high bioactivity of VAPG suddenly declined after week 5, possibly because of degradation, metabolism, and overstimulation. Basal (50 G) and glucose-stimulated (300 G) levels of insulin secretion confirmed a see-saw pattern in which the VAPG gradually decreased insulin secretion from encapsulated islets and then fell below the insulin level secreted from microcapsules containing GLP-1/Zn(2+) crystal. Viability of the microcapsulated islets of each group was not significantly different. Consequently, the coencapsulation of VAPG or GLP-1/Zn(2+) crystal can be a potential approach to reducing BAP volume with further optimization of activity duration.
Kim
Sungwon
S
Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, Utah, USA.
Bae
You Han
YH
D000818:Animals; D018929:Cell Culture Techniques / Q000379:methods*; D002470:Cell Survival; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism; D005934:Glucagon / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1; D004763:Glucagon-Like Peptides; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D019397:Pancreas, Artificial; D010446:Peptide Fragments / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D011108:Polymers / Q000737:chemistry; D011498:Protein Precursors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D023822:Tissue Engineering / Q000379:methods*
D007328:Insulin; D010446:Peptide Fragments; D010455:Peptides; D011108:Polymers; D011498:Protein Precursors; D005749:Gastric Inhibitory Polypeptide; D004763:Glucagon-Like Peptides; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D005947:Glucose; C051322:glucagon-like peptide 1 (7-37)