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Updated: Sep 18, 2025
Genotyping Single Nucleotide Polymorphisms in the Mitochondrial Genome by Pyrosequencing
Published on: February 10, 2023
Mitochondrial heteroplasmy-phenotype correlation and response to glucose lowering therapy in subjects with m.3243A>G
N Ng1, B Sanchez-Lechuga2, C J McCarrick2
1Department of Diabetes and Endocrinology, Mater Misericordiae University Hospital, Eccles Street, Dublin 7, Ireland; School of Medicine, University College Dublin, Dublin, Ireland.
Introduction:
There is a paucity of evidence to guide pharmacological treatment for mitochondrial diabetes. Metformin is generally contraindicated due to the high risk of lactic acidosis, Sulphonylurea (SU) therapy has been used as 1st line therapy but most progress to insulin. The aim of this study is to investigate the glucose-insulin secretory response to oral glucose, the response to glucose lowering therapy, and the heteroplasmy phenotype correlation in subjects with a confirmed m.3243A>G mutation.
Methods:
49 subjects were phenotyped in detail. A 2 hr OGTT was performed to establish insulin-secretory response. Heteroplasmy was measured and they had bi-annual clinical follow-up.
Results:
34 of 49 m.3243A>G subjects had diabetes mellitus (DM) with an onset at 38 (31-44) years, 7 had impaired glucose tolerance or impaired fasting glucose, and 8 had normal glucose tolerance (NGT). DM subjects had reduced insulin secretion (AUC C-peptide 2009.0[1710.0-3156.0] vs. 4693.75[3768.25-5609.38] pmol/l/120 min, P = 0.002) and insulin sensitivity (OGIS 283.0[209.0-324.0] vs. 437.0 [416.0-524.0]ml min-1m-2, P < 0.001]) compared to NGT subjects. Heteroplasmy was higher in DM subjects compared to NGT (20[11-26] vs. 6[5-10] %, P = 0.014). 5 of 8 subjects on metformin had raised lactate and 65 % of subjects required insulin to improve glycaemic control. Only 1/6 subjects transitioned from insulin to SU. Two subjects on SGLT2i and GLP-1 agonists progressed to insulin.
Conclusion:
β-cell dysfunction and insulin resistance contribute to mitochondrial diabetes development. 65 % of subjects required insulin to improve glycaemic control. Early insulin initiation may be necessary to improve glycaemic control in the long term.
