title: Mitochondrial diabetes and its lessons for common Type 2 diabetes.
abstract: 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 beta-cell function. In combination with an enhanced radical production in the beta-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 beta-oxidation. As a consequence, a systemic overload with fatty acids occurs, leading to an enhanced decline in beta-cell function due to lipotoxicity.
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Centre, 2300 RC Leiden, The Netherlands. j.a.maassen@lumc.nl
authors.forename: J A
authors.initials: JA
authors.lastname: Maassen
authors.forename: L M
authors.initials: LM
authors.lastname: 't Hart
authors.forename: G M C
authors.initials: GM
authors.lastname: Janssen
authors.forename: E
authors.initials: E
authors.lastname: Reiling
authors.forename: J A
authors.initials: JA
authors.lastname: Romijn
authors.forename: H H
authors.initials: HH
authors.lastname: Lemkes
mesh_terms: D004272:DNA, Mitochondrial / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000473:pathology*; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D050417:Insulin-Secreting Cells / Q000473:pathology; D008928:Mitochondria / Q000473:pathology* / Q000502:physiology*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide
chemical_list: D004272:DNA, Mitochondrial; D005947:Glucose