title: Investigating the link of ACAD10 deficiency to type 2 diabetes mellitus.
abstract: The Native American Pima population has the highest incidence of insulin resistance (IR) and type 2 diabetes mellitus (T2DM) of any reported population, but the pathophysiologic mechanism is unknown. Genetic studies in Pima Indians have linked acyl-CoA dehydrogenase 10 (ACAD10) gene polymorphisms, among others, to this predisposition. The gene codes for a protein with a C-terminus region that is structurally similar to members of a family of flavoenzymes-the acyl-CoA dehydrogenases (ACADs)-that catalyze α,β-dehydrogenation reactions, including the first step in mitochondrial FAO (FAO), and intermediary reactions in amino acids catabolism. Dysregulation of FAO and an increase in plasma acylcarnitines are recognized as important in the pathophysiology of IR and T2DM. To investigate the deficiency of ACAD10 as a monogenic risk factor for T2DM in human, an Acad-deficient mouse was generated and characterized. The deficient mice exhibit an abnormal glucose tolerance test and elevated insulin levels. Blood acylcarnitine analysis shows an increase in long-chain species in the older mice. Nonspecific variable pattern of elevated short-terminal branch-chain acylcarnitines in a variety of tissues was also observed. Acad10 mice accumulate excess abdominal adipose tissue, develop an early inflammatory liver process, exhibit fasting rhabdomyolysis, and have abnormal skeletal muscle mitochondria. Our results identify Acad10 as a genetic determinant of T2DM in mice and provide a model to further investigate genetic determinants for insulin resistance in humans.
authors.affiliation: Department of Pediatrics, School of Medicine, University of Pittsburgh, 4401 Penn Avenue, Pittsburgh, PA, 15224, USA.|Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Kaitlyn
authors.initials: K
authors.lastname: Bloom
authors.affiliation: Department of Pediatrics, School of Medicine, University of Pittsburgh, 4401 Penn Avenue, Pittsburgh, PA, 15224, USA.
authors.forename: Al-Walid
authors.initials: AW
authors.lastname: Mohsen
authors.affiliation: Department of Pediatrics, School of Medicine, University of Pittsburgh, 4401 Penn Avenue, Pittsburgh, PA, 15224, USA.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Karunanidhi
authors.affiliation: Department of Pediatrics, School of Medicine, University of Pittsburgh, 4401 Penn Avenue, Pittsburgh, PA, 15224, USA.
authors.forename: Dina
authors.initials: D
authors.lastname: El Demellawy
authors.affiliation: Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Miguel
authors.initials: M
authors.lastname: Reyes-Múgica
authors.affiliation: Department of Pediatrics, School of Medicine, University of Pittsburgh, 4401 Penn Avenue, Pittsburgh, PA, 15224, USA.
authors.forename: Yudong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, School of Medicine, University of Pittsburgh, 4401 Penn Avenue, Pittsburgh, PA, 15224, USA.
authors.forename: Lina
authors.initials: L
authors.lastname: Ghaloul-Gonzalez
authors.affiliation: Department of Pediatrics, School of Medicine, University of Pittsburgh, 4401 Penn Avenue, Pittsburgh, PA, 15224, USA.
authors.forename: Chikara
authors.initials: C
authors.lastname: Otsubo
authors.affiliation: Department of Pediatrics, School of Medicine, University of Pittsburgh, 4401 Penn Avenue, Pittsburgh, PA, 15224, USA.
authors.forename: Kimi
authors.initials: K
authors.lastname: Tobita
authors.affiliation: Department of Pediatrics, School of Medicine, University of Pittsburgh, 4401 Penn Avenue, Pittsburgh, PA, 15224, USA.
authors.forename: Radhika
authors.initials: R
authors.lastname: Muzumdar
authors.affiliation: Department of Pediatrics, School of Medicine, University of Pittsburgh, 4401 Penn Avenue, Pittsburgh, PA, 15224, USA.
authors.forename: Zhenwei
authors.initials: Z
authors.lastname: Gong
authors.affiliation: Department of Pediatrics, School of Medicine, University of Pittsburgh, 4401 Penn Avenue, Pittsburgh, PA, 15224, USA.
authors.forename: Emir
authors.initials: E
authors.lastname: Tas
authors.affiliation: Department of Pediatrics, School of Medicine, University of Pittsburgh, 4401 Penn Avenue, Pittsburgh, PA, 15224, USA.
authors.forename: Shrabani
authors.initials: S
authors.lastname: Basu
authors.affiliation: Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.affiliation: Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Bennett
authors.affiliation: School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Hoppel
authors.affiliation: Department of Pediatrics, School of Medicine, University of Pittsburgh, 4401 Penn Avenue, Pittsburgh, PA, 15224, USA. gerard.vockley@chp.edu.|Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA. gerard.vockley@chp.edu.
authors.forename: Jerry
authors.identifier: 0000-0002-8180-6457
authors.initials: J
authors.lastname: Vockley
mesh_terms: D050153:Abdominal Fat / Q000201:enzymology / Q000503:physiopathology; D042964:Acyl-CoA Dehydrogenase / Q000235:genetics* / Q000172:deficiency; D050154:Adiposity; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics; D008052:Lipid Metabolism, Inborn Errors / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D008099:Liver / Q000201:enzymology / Q000473:pathology; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008931:Mitochondria, Muscle / Q000201:enzymology / Q000473:pathology; D018482:Muscle, Skeletal / Q000201:enzymology / Q000473:pathology; D065626:Non-alcoholic Fatty Liver Disease / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D056128:Obesity, Abdominal / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D010641:Phenotype; D012206:Rhabdomyolysis / Q000201:enzymology / Q000235:genetics / Q000473:pathology
chemical_list: D001786:Blood Glucose; D007328:Insulin; D042964:Acyl-CoA Dehydrogenase; C000629365:Acad10 protein, mouse