title: Self-assembling glucagon-like peptide 1-mimetic peptide amphiphiles for enhanced activity and proliferation of insulin-secreting cells.
abstract: Current treatment for type 1 diabetes mellitus requires daily insulin injections that fail to produce physiological glycemic control. Islet cell transplantation has been proposed as a permanent cure but is limited by loss of β-cell viability and function. These limitations could potentially be overcome by relying on the activity of glucagon-like peptide 1 (GLP-1), which acts on β-cells to promote insulin release, proliferation and survival. We have developed a peptide amphiphile (PA) molecule incorporating a peptide mimetic for GLP-1. This GLP-1-mimetic PA self-assembles into one-dimensional nanofibers that stabilize the active secondary structure of GLP-1 and can be cross-linked by calcium ions to form a macroscopic gel capable of cell encapsulation and three-dimensional culture. The GLP-1-mimetic PA nanofibers were found to stimulate insulin secretion from rat insulinoma (RINm5f) cells to a significantly greater extent than the mimetic peptide alone and to a level equivalent to that of the clinically used agonist exendin-4. The activity of the GLP-1-mimetic PA is glucose-dependent, lipid-raft dependent and partially PKA-dependent consistent with native GLP-1. The GLP-1-mimetic PA also completely abrogates inflammatory cytokine-induced cell death to the level of untreated controls. When used as a PA gel to encapsulate RINm5f cells, the GLP-1-mimetic PA stimulates insulin secretion and proliferation in a cytokine-resistant manner that is significantly greater than a non-bioactive PA gel containing exendin-4. Due to its self-assembling property and bioactivity, the GLP-1-mimetic PA can be incorporated into previously developed islet cell transplantation protocols with the potential for significant enhancement of β-cell viability and function.
authors.affiliation: Institute for BioNanotechnology in Medicine, Northwestern University, Chicago, IL 60611, USA. saahir-khan@northwestern.edu
authors.forename: Saahir
authors.initials: S
authors.lastname: Khan
authors.forename: Shantanu
authors.initials: S
authors.lastname: Sur
authors.forename: Christina J
authors.initials: CJ
authors.lastname: Newcomb
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Appelt
authors.forename: Samuel I
authors.initials: SI
authors.lastname: Stupp
mesh_terms: D000818:Animals; D061249:Batch Cell Culture Techniques / Q000379:methods; D040761:Biomimetic Materials / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004763:Glucagon-Like Peptides / Q000737:chemistry / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats
chemical_list: D007328:Insulin; D004763:Glucagon-Like Peptides; D052216:Glucagon-Like Peptide 1