title: Glucose metabolism derangements in adults with the MELAS m.3243A>G mutation.
abstract: The m.3243A>G mutation in the mitochondrial gene MT-TL1 leads to a wide clinical spectrum ranging from asymptomatic carriers to MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) at the severe end. Diabetes mellitus (DM) occurs in mitochondrial diseases, with the m.3243A>G mutation being the most common mutation associated with mitochondrial DM. The pathogenesis of mitochondrial DM remains largely unknown, with previous studies suggesting that impaired insulin secretion is the major factor. In this study we used stable isotope infusion techniques to assess glucose metabolism in vivo and under physiological conditions in 5 diabetic and 11 non-diabetic adults with the m.3243A>G mutation and 10 healthy adult controls. Our results revealed increased glucose production due to increased gluconeogenesis in both diabetic and non-diabetic subjects with the m.3243A>G mutation. In addition, diabetic subjects demonstrated insulin resistance and relative insulin deficiency, resulting in an inability to increase glucose oxidation which can explain the development of DM in these subjects. Non-diabetic subjects showed normal insulin sensitivity; and therefore, they were able to increase their glucose oxidation rate. The ability to increase glucose utilization can act as a compensatory mechanism that explains why these subjects do not have DM despite the higher rate of glucose production. These results suggest that increased gluconeogenesis is not enough to cause DM and the occurrence of combined insulin resistance and relative insulin deficiency are needed to develop DM in individuals with the m.3243A>G mutation. Therefore, multiple defects in insulin and glucose metabolism are required for DM to occur in individuals with mitochondrial diseases. The results of this study uncover previously undocumented alterations in glucose metabolism in individuals with the m.3243A>G mutation that contribute significantly to our understanding of the pathogenesis of mitochondrial DM and can have significant implications for its management.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Division of Clinical Genetics and Metabolic Disorders, Department of Pediatrics, Tawam Hospital, Al-Ain, United Arab Emirates.
authors.forename: Ayman W
authors.initials: AW
authors.lastname: El-Hattab
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA.
authors.forename: Lisa T
authors.initials: LT
authors.lastname: Emrick
authors.affiliation: Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Jean W
authors.initials: JW
authors.lastname: Hsu
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA.
authors.forename: Sirisak
authors.initials: S
authors.lastname: Chanprasert
authors.affiliation: Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Farook
authors.initials: F
authors.lastname: Jahoor
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA. Electronic address: fscaglia@bcm.edu.
authors.forename: Fernando
authors.initials: F
authors.lastname: Scaglia
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Craigen
mesh_terms: D000328:Adult; D003920:Diabetes Mellitus / Q000235:genetics / Q000503:physiopathology*; D005260:Female; D050259:Genes, Mitochondrial; D005943:Gluconeogenesis; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000172:deficiency; D007333:Insulin Resistance; D007553:Isotope Labeling; D017241:MELAS Syndrome / Q000235:genetics / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D017354:Point Mutation; D012356:RNA, Transfer, Leu / Q000235:genetics*
chemical_list: D007328:Insulin; D012356:RNA, Transfer, Leu; D005947:Glucose
keywords: Diabetes; Gluconeogenesis; Insulin resistance; Mitochondrial diseases; Stable isotope infusion
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