title: Functional plasticity of the human infant β-cell exocytotic phenotype.
abstract: Our understanding of adult human β-cells is advancing, but we know little about the function and plasticity of β-cells from infants. We therefore characterized islets and single islet cells from human infants after isolation and culture. Although islet morphology in pancreas biopsies was similar to that in adults, infant islets after isolation and 24-48 hours of culture had less insulin staining, content, and secretion. The cultured infant islets expressed pancreatic and duodenal homeobox 1 and several (Glut1, Cav1.3, Kir6.2) but not all (syntaxin 1A and synaptosomal-associated protein 25) markers of functional islets, suggesting a loss of secretory phenotype in culture. The activity of key ion channels was maintained in isolated infant β-cells, whereas exocytosis was much lower than in adults. We examined whether a functional exocytotic phenotype could be reestablished under conditions thought to promote β-cell differentiation. After a 24- to 28-day expansion and maturation protocol, we found preservation of endocrine markers and hormone expression, an increased proportion of insulin-positive cells, elevated expression of syntaxin 1A and synaptosomal-associated protein 25, and restoration of exocytosis to levels comparable with that in adult β-cells. Thus, human infant islets are prone to loss of their exocytotic phenotype in culture but amenable to experimental approaches aimed at promoting expansion and functional maturation. Control of exocytotic protein expression may be an important mechanism underlying the plasticity of the secretory machinery, an increased understanding of which may lead to improved regenerative approaches to treat diabetes.
authors: Department of Pharmacology, University of Alberta, and The Alberta Diabetes Institute, Edmonton, Alberta, Canada.
authors: Jocelyn E Manning
authors: JE
authors: Fox
authors: Karen
authors: K
authors: Seeberger
authors: Xiao Qing
authors: XQ
authors: Dai
authors: James
authors: J
authors: Lyon
authors: Aliya F
authors: AF
authors: Spigelman
authors: Jelena
authors: J
authors: Kolic
authors: Catherine
authors: C
authors: Hajmrle
authors: Jamie W
authors: JW
authors: Joseph
authors: Tatsuya
authors: T
authors: Kin
authors: A M James
authors: AM
authors: Shapiro
authors: Gregory
authors: G
authors: Korbutt
authors: Patrick E
authors: PE
authors: MacDonald
mesh_terms: D020746:Calcium Channels, L-Type / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D005089:Exocytosis / Q000502:physiology; D005260:Female; D005934:Glucagon / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006801:Humans; D007223:Infant; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D007515:Islets of Langerhans / Q000254:growth & development / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D018408:Patch-Clamp Techniques; D010641:Phenotype; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050825:Synaptosomal-Associated Protein 25 / Q000378:metabolism; D050827:Syntaxin 1 / Q000378:metabolism; D000099161:Kcnj11 Channel
chemical_list: D020746:Calcium Channels, L-Type; D005934:Glucagon; D051272:Glucose Transporter Type 1; D007328:Insulin; D024661:Potassium Channels, Inwardly Rectifying; D050825:Synaptosomal-Associated Protein 25; D050827:Syntaxin 1; D000099161:Kcnj11 Channel; C495677:SLC2A1 protein, human; C494208:SNAP25 protein, human; C494212:STX1A protein, human