Multiple pathogenic pathways are able to deregulate glucose homoeostasis leading to diabetes. The 3243A>G mutation in the mtDNA (mitochondrial DNA)-encoded tRNALeu,UUR gene was found by us to be associated with a particular diabetic subtype, designated MIDD (maternally inherited diabetes and deafness). This mutation causes an imbalance in the mitochondrion between proteins encoded by the nuclear and mitochondrial genomes, resulting in a gradual deterioration of glucose homoeostasis during life. Remarkably, carriers of the 3243A>G mutation are generally not obese. The mutation also results in enhanced radical production by mitochondria. We propose that this mutation leads to the development of diabetes due to an inappropriate storage of triacylglycerols within adipocytes. The result is a fatty acid-induced deterioration of pancreatic β-cell function. In combination with an enhanced radical production in the β-cell due to the mutation, this leads to an age-dependent, accelerated decline in insulin production. In common Type 2 (non-insulin-dependent) diabetes, which is generally associated with obesity, a decline in mitochondrial function in adipose cells seems to result in an inappropriate scavenging of fatty acids by β-oxidation. As a consequence, a systemic overload with fatty acids occurs, leading to an enhanced decline in β-cell function due to lipotoxicity.
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October 2006
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Conference Article|
October 25 2006
Mitochondrial diabetes and its lessons for common Type 2 diabetes
J.A. Maassen;
J.A. Maassen
1
*Department of Molecular Cell Biology, Leiden University Medical Centre, 2300 RC Leiden, The Netherlands
1To whom correspondence should be addressed, at Department of Molecular Cell Biology, Leiden University Medical Centre, Room S01-P, P.O. Box 9600, 2300 RC Leiden, The Netherlands (email j.a.maassen@lumc.nl).
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L.M. 't Hart;
L.M. 't Hart
*Department of Molecular Cell Biology, Leiden University Medical Centre, 2300 RC Leiden, The Netherlands
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G.M.C. Janssen;
G.M.C. Janssen
*Department of Molecular Cell Biology, Leiden University Medical Centre, 2300 RC Leiden, The Netherlands
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E. Reiling;
E. Reiling
*Department of Molecular Cell Biology, Leiden University Medical Centre, 2300 RC Leiden, The Netherlands
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J.A. Romijn;
J.A. Romijn
†Department of Endocrinology and Metabolic Diseases, Leiden University Medical Centre, 2300 RC Leiden, The Netherlands
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H.H. Lemkes
H.H. Lemkes
†Department of Endocrinology and Metabolic Diseases, Leiden University Medical Centre, 2300 RC Leiden, The Netherlands
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Publisher: Portland Press Ltd
Received:
June 22 2006
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2006 The Biochemical Society
2006
Biochem Soc Trans (2006) 34 (5): 819–823.
Article history
Received:
June 22 2006
Citation
J.A. Maassen, L.M. 't Hart, G.M.C. Janssen, E. Reiling, J.A. Romijn, H.H. Lemkes; Mitochondrial diabetes and its lessons for common Type 2 diabetes. Biochem Soc Trans 1 October 2006; 34 (5): 819–823. doi: https://doi.org/10.1042/BST0340819
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