Work

Mitochondrial heteroplasmy-phenotype correlation and response to glucose lowering therapy in subjects with m.3243A>G mutations

Year: 2025

Type: article

Abstract: 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 1 st 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 38.0 (31.0-44.0) 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/120min, P = 0.002) and insulin sensitivity (OGIS 283.0[209.0-324.0] vs. 437.0 [416.0-524.0]ml min −1 m −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 1/8 subjects transitioned from insulin to SU. Two subjects on SGLT 2 -I 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.

Source: Diabetes & Metabolism

DOI: 10.1016/j.diabet.2025.101678