Investigating the link of ACAD10 deficiency to type 2 diabetes mellitus

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,...

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Published inJournal of inherited metabolic disease Vol. 41; no. 1; pp. 49 - 57
Main Authors Bloom, Kaitlyn, Mohsen, Al-Walid, Karunanidhi, Anuradha, El Demellawy, Dina, Reyes-Múgica, Miguel, Wang, Yudong, Ghaloul-Gonzalez, Lina, Otsubo, Chikara, Tobita, Kimi, Muzumdar, Radhika, Gong, Zhenwei, Tas, Emir, Basu, Shrabani, Chen, Jie, Bennett, Michael, Hoppel, Charles, Vockley, Jerry
Format Journal Article
LanguageEnglish
Published Dordrecht Springer Netherlands 01.01.2018
Blackwell Publishing Ltd
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Summary: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.
Bibliography:Communicated by: Eva Morava
Electronic Supplementary Material
The online version of this article (doi:10.1007/s10545‐017‐0013‐y) contains supplementary material, which is available to authorized users.
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Dr. Chen helped with mouse fasting studies.
Dr. Muzumdar, Gong and Tas helped with insulin signalling studies
Dr. Tobita helped with MRI imaging experiments.
Dr. Hoppel performed acylcarnitine studies
Dr. Mohsen participated in experimental design, supervising day to day activities of the project, and writing the manuscript
Ms. Karunanidhi provided technical assistance for immunostaining experiments.
Drs. Ghaloul-Gonzalez and Otsubo helped RNA expression studies.
Drs. Demellawy and Reyes-Múgica performed histology experiments.
Dr. Bennett supervised acyl-CoA studies.
Dr. Bloom performed most of the described experiments as part of her PhD thesis project at the University of Pittsburgh. She wrote the first draft of the manuscript
Ms. Basu provided general technical assistance for enzyme studies
Dr. Vockley served as the project director, outline the experimental design, and in writing the manuscript.
ISSN:0141-8955
1573-2665
DOI:10.1007/s10545-017-0013-y