title: Haploid insufficiency of suppressor enhancer Lin12 1-like (SEL1L) protein predisposes mice to high fat diet-induced hyperglycemia.
abstract: Increasing evidence suggests that endoplasmic reticulum (ER) stress plays an important role in the pathogenesis of type 2 diabetes mellitus. SEL1L is an ER membrane protein that is highly expressed in the pancreatic islet and acinar cells. We have recently reported that a deficiency of SEL1L causes systemic ER stress and leads to embryonic lethality in mice. Here we show that mice with one functional allele of Sel1l (Sel1l(+/-)) are more susceptible to high fat diet (HFD)-induced hyperglycemia. Sel1l(+/-) mice have a markedly reduced β-cell mass as a result of decreased β-cell proliferation. Consequently, Sel1l(+/-) mice are severely glucose-intolerant and exhibit significantly retarded glucose-stimulated insulin secretion. Pancreatic islets from Sel1l(+/-) mice stimulated with a high concentration of glucose in vitro express significantly higher levels of unfolded protein response genes than those from wild-type control mice. Furthermore, dominant-negative interference of SEL1L function in insulinoma cell lines severely impairs, whereas overexpression of SEL1L efficiently improves protein secretion. Taken together, our results indicate that haploid insufficiency of SEL1L predispose mice to high fat diet-induced hyperglycemia. Our findings highlight a critical and previously unknown function for SEL1L in regulating adult β-cell function and growth.
authors.affiliation: Department of Animal Science, College of Agriculture and Life Sciences, Cornell University, Ithaca, New York 14850, USA.
authors.forename: Adam B
authors.initials: AB
authors.lastname: Francisco
authors.forename: Rajni
authors.initials: R
authors.lastname: Singh
authors.forename: Haibo
authors.initials: H
authors.lastname: Sha
authors.forename: Xi
authors.initials: X
authors.lastname: Yan
authors.forename: Ling
authors.initials: L
authors.lastname: Qi
authors.forename: Xingen
authors.initials: X
authors.lastname: Lei
authors.forename: Qiaoming
authors.initials: Q
authors.lastname: Long
mesh_terms: D000818:Animals; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D004041:Dietary Fats / Q000009:adverse effects*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000235:genetics / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005947:Glucose / Q000494:pharmacology; D018149:Glucose Intolerance / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D057895:Haploinsufficiency / Q000235:genetics*; D006579:Heterozygote; D006943:Hyperglycemia / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000473:pathology; D058767:Protein Unfolding; D011506:Proteins / Q000235:genetics*
chemical_list: D004041:Dietary Fats; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C492169:Sel1h protein, mouse; D005947:Glucose