Diabetes management in maternally inherited diabetes and deafness (MIDD): A review and a proposed treatment algorithm

Maternally inherited diabetes and deafness (MIDD) is a mitochondrial disorder usually caused by the variant m.3243A>G in the MT-TL1 gene. We have proposed that diabetes in MIDD arises from a combination of insulin resistance and impaired β-cell function that is more likely to occur in the presence of high skeletal muscle heteroplasmy and moderate β-cell heteroplasmy for m.3243A>G and to be driven by oxidative stress as a major pathophysiologic mechanism. There are no randomised trials specifically on the management of MIDD. An approach to MIDD informed by its pathophysiology could optimise management and be a framework for future trials. In this narrative review, we discuss the effects of existing anti-hyperglycaemic medications on oxidative stress, mitochondrial function, and cardiorenal protection. We also review the published case reports and series on the management of diabetes associated with MIDD, and the safety of insulin and non-insulin medications in MIDD. We found that glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors have favourable properties in addressing oxidative stress and mitochondrial function. They also harbour cardiorenal protection properties independent from their effect on glucose control that are fully relevant in MIDD, making them ideal candidates as first-line agents for the management of MIDD. Accordingly, we share our perspective on a disease-specific algorithm for the management of MIDD diabetes that could delay or prevent the development of cardiovascular and renal complications associated with this mitochondrial disease.