ESPE2023 Poster Category 1 Diabetes and Insulin (55 abstracts)
Evaluation of Mitochondrial Bioenergetic Function in Mitochondrial and Type 1 Diabetes
Busra Gurpinar Tosun 1 , Annelise Francisco 2 , Claudia D. C. Navarro 2 , Tuba Seven Menevse 1 , Hamza Polat 3 , Burcu Ozturk Hismi 4 , Ahmet Kahveci 1 , Serap Turan 1 , Belma Haliloglu 1 , Ayse Mine Yilmaz 5 , Betul Karademir Yilmaz 5 , Abdullah Bereket 1 , Roger F. Castilho 2 & Tulay Guran 1
1Marmara University, School of Medicine, Department of Pediatrics, Division of Pediatric Endocrinology, Istanbul, Turkey. 2University of Campinas, School of Medical Sciences, Department of Pathology, Campinas, Brazil. 3Marmara University, School of Medicine, Department of Medical Genetics, Istanbul, Turkey. 4Marmara University, School of Medicine, Department of Pediatrics, Division of Pediatric Metabolism, Istanbul, Turkey. 5Marmara University Faculty of Medicine, Department of Biochemistry, Faculty of Medicine, Genetic and Metabolic Diseases Research Center, Istanbul, Turkey
Background and hypothesis: Mitochondrial disorders are multisystemic conditions associated with sensorineural hearing loss, encephalomyopathy, lactic acidosis, and non-autoimmune diabetes. The majority of molecular etiologies involve mutations in the genes encoding the oxidative phosphorylation system's components. Superoxide generation is significantly increased and causes oxidative damage in the affected tissues in these disorders. The establishment of a definitive diagnosis is challenging due to diverse phenotypical expressions. Assessment of mitochondrial bioenergetic function can be an important functional tool to confirm the molecular diagnosis.
Objective: Assessment of mitochondrial bioenergetic function in patients with mitochondrial diabetes in comparison with type 1 diabetic patients with good and bad metabolic control and healthy control group.
Participants and Method: An 11-year-old girl with mitochondrial diabetes and her non-diabetic mother with a mutation in the MT-CO1 gene (homoplasmic c.795delA, p.(E266Nfs*)) and the control group of healthy individuals (n=5), autoimmune type 1 diabetes (n=8) with good and bad metabolic control was used as a comparison. The mitochondrial bioenergetic function was evaluated by employing peripheral blood mononuclear cells (PBMC). PBMC were isolated from whole blood samples.
Results: Both the patient and her mother presented low basal OCR (oxygen consumption rate) (19 and 32% of healthy control), and low OCR during respiratory complex I-linked oxidative phosphorylation (OXPHOS), using pyruvate and malate (28 and 22% of healthy control) and when glutamate was added as substrates for mitochondrial complex I. The patient with mitochondrial diabetes also showed lower(<2SD) OCR suppression when the complex I inhibitor rotenone was added. Conditions such as the succinate-driven OXPHOS and maximal complex IV-linked OCR sustained were not affected, showing complex II and IV functions are preserved. Autoimmune type 1 diabetic patients did not exhibit any impairment of mitochondrial function, regardless of metabolic control. Western blot analyses suggested an upregulation of complex I expression in the patient. This pattern was not observed in the mother’s sample. Mitochondrial dysfunction was not observed in children with autoimmune type 1 diabetes.
Conclusion: Increased complex I expression due to oxidative stress associated with the presence of diabetes was shown in the case. The further biochemical and functional evaluation may provide insights into the mechanisms of diagnosis and clinical manifestations.
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