title: The Hypoglycemic Phenotype Is Islet Cell-Autonomous in Short-Chain Hydroxyacyl-CoA Dehydrogenase-Deficient Mice.
abstract: Congenital hyperinsulinism of infancy (CHI) can be caused by inactivating mutations in the gene encoding short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD), a ubiquitously expressed enzyme involved in fatty acid oxidation. The hypersecretion of insulin may be explained by a loss of interaction between SCHAD and glutamate dehydrogenase in the pancreatic β-cells. However, there is also a general accumulation of metabolites specific for the enzymatic defect in affected individuals. It remains to be explored whether hypoglycemia in SCHAD CHI can be uncoupled from the systemic effect on fatty acid oxidation. We therefore transplanted islets from global SCHAD knockout (SCHADKO) mice into mice with streptozotocin-induced diabetes. After transplantation, SCHADKO islet recipients exhibited significantly lower random and fasting blood glucose compared with mice transplanted with normal islets or nondiabetic, nontransplanted controls. Furthermore, intraperitoneal glucose tolerance was improved in animals receiving SCHADKO islets compared with those receiving normal islets. Graft β-cell proliferation and apoptosis rates were similar in the two transplantation groups. We conclude that hypoglycemia in SCHAD-CHI is islet cell-autonomous.
authors.affiliation: Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway Department of Pathology, Haukeland University Hospital, Bergen, Norway anders.molven@uib.no.
authors.forename: Anders
authors.initials: A
authors.lastname: Molven
authors.affiliation: Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hollister-Lock
authors.affiliation: Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA.
authors.forename: Jiang
authors.initials: J
authors.lastname: Hu
authors.affiliation: Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA.
authors.forename: Rachael
authors.initials: R
authors.lastname: Martinez
authors.affiliation: KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway Department of Pediatrics, Haukeland University Hospital, Bergen, Norway.
authors.forename: Pål R
authors.initials: PR
authors.lastname: Njølstad
authors.affiliation: Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL.
authors.forename: Chong Wee
authors.initials: CW
authors.lastname: Liew
authors.affiliation: Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA.
authors.forename: Gordon
authors.initials: G
authors.lastname: Weir
authors.affiliation: Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA Harvard Stem Cell Institute, Boston, MA.
authors.forename: Rohit N
authors.initials: RN
authors.lastname: Kulkarni
mesh_terms: D063988:3-Hydroxyacyl-CoA Dehydrogenase / Q000172:deficiency*; D000818:Animals; D044903:Congenital Hyperinsulinism / Q000201:enzymology* / Q000235:genetics; D005969:Glutamate Dehydrogenase / Q000378:metabolism; D007003:Hypoglycemia / Q000201:enzymology* / Q000235:genetics; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype
chemical_list: D007328:Insulin; D063988:3-Hydroxyacyl-CoA Dehydrogenase; D005969:Glutamate Dehydrogenase