title: SORCS1 is necessary for normal insulin secretory granule biogenesis in metabolically stressed β cells.
abstract: We previously positionally cloned Sorcs1 as a diabetes quantitative trait locus. Sorcs1 belongs to the Vacuolar protein sorting-10 (Vps10) gene family. In yeast, Vps10 transports enzymes from the trans-Golgi network (TGN) to the vacuole. Whole-body Sorcs1 KO mice, when made obese with the leptin(ob) mutation (ob/ob), developed diabetes. β Cells from these mice had a severe deficiency of secretory granules (SGs) and insulin. Interestingly, a single secretagogue challenge failed to consistently elicit an insulin secretory dysfunction. However, multiple challenges of the Sorcs1 KO ob/ob islets consistently revealed an insulin secretion defect. The luminal domain of SORCS1 (Lum-Sorcs1), when expressed in a β cell line, acted as a dominant-negative, leading to SG and insulin deficiency. Using syncollin-dsRed5TIMER adenovirus, we found that the loss of Sorcs1 function greatly impairs the rapid replenishment of SGs following secretagogue challenge. Chronic exposure of islets from lean Sorcs1 KO mice to high glucose and palmitate depleted insulin content and evoked an insulin secretion defect. Thus, in metabolically stressed mice, Sorcs1 is important for SG replenishment, and under chronic challenge by insulin secretagogues, loss of Sorcs1 leads to diabetes. Overexpression of full-length SORCS1 led to a 2-fold increase in SG content, suggesting that SORCS1 is sufficient to promote SG biogenesis.
authors.forename: Melkam A
authors.initials: MA
authors.lastname: Kebede
authors.forename: Angie T
authors.initials: AT
authors.lastname: Oler
authors.forename: Trillian
authors.initials: T
authors.lastname: Gregg
authors.forename: Allison J
authors.initials: AJ
authors.lastname: Balloon
authors.forename: Adam
authors.initials: A
authors.lastname: Johnson
authors.forename: Kelly
authors.initials: K
authors.lastname: Mitok
authors.forename: Mary
authors.initials: M
authors.lastname: Rabaglia
authors.forename: Kathryn
authors.initials: K
authors.lastname: Schueler
authors.forename: Donald
authors.initials: D
authors.lastname: Stapleton
authors.forename: Candice
authors.initials: C
authors.lastname: Thorstenson
authors.forename: Lindsay
authors.initials: L
authors.lastname: Wrighton
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Floyd
authors.forename: Oliver
authors.initials: O
authors.lastname: Richards
authors.forename: Summer
authors.initials: S
authors.lastname: Raines
authors.forename: Kevin
authors.initials: K
authors.lastname: Eliceiri
authors.forename: Nabil G
authors.initials: NG
authors.lastname: Seidah
authors.forename: Christopher
authors.initials: C
authors.lastname: Rhodes
authors.forename: Mark P
authors.initials: MP
authors.lastname: Keller
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Coon
authors.forename: Anjon
authors.initials: A
authors.lastname: Audhya
authors.forename: Alan D
authors.initials: AD
authors.lastname: Attie
mesh_terms: D000818:Animals; D003920:Diabetes Mellitus / Q000235:genetics*; D017353:Gene Deletion; D005838:Genotype; D005947:Glucose / Q000737:chemistry; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000166:cytology*; D051379:Mice; D018345:Mice, Knockout; D019308:Palmitic Acid / Q000737:chemistry; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000502:physiology; D022142:Secretory Vesicles / Q000378:metabolism*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D007328:Insulin; D011956:Receptors, Cell Surface; C000595029:SORCS1 protein, mouse; D019308:Palmitic Acid; D005947:Glucose