Peripheral and central glucose utilizations modulated by mitochondrial DNA 10398A in bipolar disorder.
Bipolar disorder (BD) is highly heritable and associated with dysregulation of brain glucose utilizations (GU). The mitochondrial DNA (mtDNA) 10398A polymorphism, as a reported BD risk factor, leads to deficient glycolytic energy production by affecting mitochondrial matrix pH and intracellular calcium levels. However, whether mtDNA-10398A has functional effects on the brain and how our body responds remain elusive. We compared peripheral and central glucose-utilizing patterns between mtDNA A10398G polymorphisms in BD and their unaffected siblings (BDsib). Since siblings carry identical mtDNA, we hypothesized that certain characteristics co-segregate in BD families. We recruited twenty-seven pairs of non-diabetic BD patients and their BDsib and 30 well-matched healthy control subjects (HC). The following were investigated: mtDNA, fasting plasma glucose/insulin, cognitive functions including Montreal Cognitive Assessment (MoCA), and brain GU at rest. Insulin resistance was rechecked in sixty-one subjects (19-BD, 18-BDsibib, and 24-HC) six months later. We found that BD-pairs (BD+BDsib) carried more mtDNA-10398A and had higher fasting glucose, even after controlling for many covariates. BD-pairs had abnormally lower dorso-prefrontal-GU and higher cerebellar-GU, but only BD demonstrated lower medio-prefrontal-GU and MoCA. Subjects carrying mtDNA-10398A had significantly lower prefrontal-GU (FWE-corrected p<0.05). An abnormal inverse pattern of insulin-GU and insulin-MoCA correlation was found in BD-pairs. The insulin-MoCA correlation was particularly prominent in those carrying mtDNA-10398A. mtDNA-10398A predicted insulin resistance 6 months later. In conclusion, mtDNA-10398A was associated with impaired prefrontal-GU. An up-regulation of glucose utilizations was found in BD-pairs, probably compensating for mtDNA-10398A-related energy loss.
Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan; Division of Psychiatry, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.
Cheng-Ta
CT
Li
Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan; Division of Psychiatry, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.
Ya-Mei
YM
Bai
Integrated Brain Research Unit, Division of Clinical Research, Department of Medical Research, Taipei Veterans General Hospital, Taiwan; Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan.
Jen-Chuen
JC
Hsieh
Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
Hsin-Chen
HC
Lee
Department of Nuclear Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
Bang-Hung
BH
Yang
Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan; Division of Psychiatry, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.
Mu-Hong
MH
Chen
Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan; Division of Psychiatry, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.
Wei-Chen
WC
Lin
Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan; Division of Psychiatry, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.
Chia-Fen
CF
Tsai
Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan; Division of Psychiatry, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.
Pei-Chi
PC
Tu
Department of Nuclear Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
Shyh-Jen
SJ
Wang
Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan; Division of Psychiatry, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan; Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan. Electronic address: tpsu@vghtpe.gov.tw.
Tung-Ping
TP
Su
D000328:Adult; D001714:Bipolar Disorder / Q000235:genetics* / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism*; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D019788:Fluorodeoxyglucose F18; D020022:Genetic Predisposition to Disease; D006019:Glycolysis / Q000235:genetics*; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D035781:Siblings
D001786:Blood Glucose; D004272:DNA, Mitochondrial; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18
Bipolar disorder; Gene; Glucose homeostasis; Mitochondria; Polymorphism