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 in | Journal of inherited metabolic disease Vol. 41; no. 1; pp. 49 - 57 |
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Main Authors | , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Dordrecht
Springer Netherlands
01.01.2018
Blackwell Publishing Ltd |
Subjects | |
Online Access | Get full text |
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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. |
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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. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 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 |