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In the last half of the 20th century, the incidence of type 2 diabetes mellitus (T2DM), previously unrecognized in the Pima Indians, began to rise. Multiple factors were postulated to be responsible including environmental factors, such as diet and resultant obesity, along with a number of genetic determinants. ACAD10 was one of 30 genes further examined after demonstrating a significant signal for diabetes in a genome-wide association study (GWAS). In these studies, a single-nucleotide polymorphism (SNP), rs632650, was found to map within intron 2 of ACAD10.
The hypothetical ACAD10 protein is structurally related to the ACAD family of mitochondrial flavoproteins, which consists of nine enzymes that are similar in structure and function as they catalyze the α, β-dehydrogenation of their corresponding acyl-CoA substrates. Seven of these ACADs, LCAD, medium-chain acyl-CoA dehydrogenase (MCAD), short-chain acyl-CoA dehydrogenase (SCAD), isovaleryl-CoA dehydrogenase (IVD), isobutyryl-CoA dehydrogenase, 2-methyl-branched chain acyl-CoA dehydrogenase, and glutamate dehydrogenase, are homotetramers (~400-aa per monomer) and two, VLCAD and ACAD9, are homodimers (~640-aa per monomer). In addition to their usual location in the mitochondrial matrix, some ACADs, including LCAD, MCAD, and SCAD, have been shown to be associated with cytoplasmic GLUT4-containing vesicles where they interact with two dileucine motifs on insulin-regulated aminopeptidase (IRAP). Mutation of the dileucine motif of IRAP (amino acids 55–82) eliminates this interaction. In cells, glucose equilibrium is maintained by the GLUT4 response to insulin. The GLUT4- and IRAP-containing vesicles respond to insulin stimulation by translocation to the cell surface. The dileucine motif in IRAP plays a critical role in regulating GLUT4 trafficking. While these findings connect some of the ACADs with insulin dependent transportation of glucose within cells, the physiologic role of the ACAD proteins in this setting is unclear.
Skeletal muscle patterns of fatty acid utilization during fasting conditions have been shown to be associated with obesity-related insulin resistance and altered mitochondrial energy metabolism, including fatty acid oxidation. These abnormalities have also been shown to be present in the context of T2DM. We have recently shown that the pattern of acylcarnitines (ACNs), key metabolic intermediates of fatty acid oxidation, in the blood of obese and T2DM participants fall into two distinct patterns. First, the T2DM and obese participants had a similar accumulation of long-chain ACNs that arise from activity in the initial rounds of β-oxidation, consistent with increased flux at entry into mitochondrial β-oxidation. Diabetic participants also displayed a secondary accumulation of various shorter chain ACNs suggestive of inefficient complete fatty acid oxidation or interactions between β-oxidation and ETC. They also showed an inability to efficiently switch from fat metabolism during insulin clamp, as reflected in their inability to lower their ACNs as effectively as either the lean or obese subjects. In contrast, this pattern was not present in obese adolescents, who instead showed metabolic findings suggestive of upregulation of fatty acid oxidation.
To characterize the physiologic role of ACAD10 in intermediary metabolism and its possible link to T2DM, we have characterized an ACAD10 gene trap mouse model. Aging animals become obese on a normal diet and develop insulin-resistant hyperglycemia in response to an intraperitoneal glucose challenge. Tissue and blood ACN profiles are similar to those previously described for adult humans with T2DM. Our findings identify ACAD10 deficiency as new monogenic cause of T2DM in mice, and provide valuable insight into its potential role in the development of T2DM in Pima Indians.
Gerard Vockley, MD, PhD
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One Children’s Hospital Way
4401 Penn Ave.
Pittsburgh, PA 15224
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