Highlight
– Maternally inherited diabetes and deafness (MIDD) is most commonly caused by the mitochondrial m.3243A>G variant and combines insulin secretory failure with insulin resistance influenced by heteroplasmy distribution.
– Oxidative stress and mitochondrial dysfunction are central pathophysiologic drivers, suggesting mitochondria‑targeted benefits from select glucose‑lowering agents.
– GLP‑1 receptor agonists (GLP‑1RAs) and SGLT2 inhibitors offer favourable effects on oxidative stress, mitochondrial biology and cardiorenal protection and therefore are reasonable first‑line agents for many patients with MIDD.
Background and disease burden
Maternally inherited diabetes and deafness (MIDD) is a form of mitochondrial diabetes usually caused by the m.3243A>G point mutation in the mitochondrial tRNALeu (MT‑TL1) gene. Phenotypes range from isolated diabetes with sensorineural hearing loss to multi‑system mitochondrial disease (including cardiomyopathy, nephropathy, macular dystrophy, and stroke‑like episodes). Clinical expressivity depends on heteroplasmy (the proportion of mutant mtDNA) that can vary between tissues and over time, leading to variability in age of onset, severity of hyperglycaemia, and associated organ involvement.
Diabetes in MIDD commonly presents in young‑ to middle‑aged adults, often with progressive β‑cell deficiency that may be compounded by insulin resistance related to high skeletal muscle heteroplasmy and systemic oxidative stress. These features produce glycaemic profiles that can include postprandial hyperglycaemia, progressive fasting hyperglycaemia and the need for escalating therapies. Cardiovascular and renal complications contribute importantly to morbidity and mortality in mitochondrial disease, underscoring the need for therapies that address both glycaemia and extra‑pancreatic risks.
Study design (scope of evidence reviewed)
This narrative synthesis is anchored on the recent review and proposed algorithm by Chaudhry and colleagues (2025) and integrates mechanistic literature on mitochondrial dysfunction, observational series and case reports of diabetes treatment in MIDD, and outcomes data from trials of glucose‑lowering drug classes with known mitochondrial or cardiorenal effects. There are no randomized controlled trials (RCTs) designed specifically for MIDD; recommendations are therefore evidence‑informed rather than evidence‑proven.
Key findings and evidence synthesis
Pathophysiology: heteroplasmy, β‑cell failure, insulin resistance and oxidative stress
Mitochondria are central to glucose‑stimulated insulin secretion and to skeletal muscle insulin sensitivity. The m.3243A>G mutation interferes with mitochondrial protein synthesis, reducing oxidative phosphorylation efficiency and increasing reactive oxygen species (ROS). In pancreatic β cells, this diminishes ATP generation and impairs glucose‑stimulated insulin secretion. In skeletal muscle, high heteroplasmy promotes energetic insufficiency and insulin resistance. Net result: mixed pathophysiology—both reduced β‑cell mass/function and peripheral insulin resistance—which often necessitates combination therapy and sometimes early insulin therapy.
Pharmacologic implications: mechanism‑based selection
Given oxidative stress and mitochondrial dysfunction as core mechanisms, agents with favourable mitochondrial effects or those that mitigate downstream cardiovascular and renal risk are attractive in MIDD.
GLP‑1 receptor agonists (GLP‑1RAs)
Clinical outcome trials in type 2 diabetes show that several GLP‑1RAs reduce major adverse cardiovascular events and slow progression of kidney disease (predominantly albuminuric outcomes). Mechanistic studies demonstrate that GLP‑1RAs have anti‑inflammatory and antioxidant effects, improve endothelial function, and in preclinical models reduce mitochondrial ROS and preserve mitochondrial integrity. These properties are mechanistically congruent with addressing MIDD pathophysiology. Case reports and small series indicate GLP‑1RAs can improve glycaemia and promote weight loss in mitochondrial diabetes, with tolerability patterns similar to those in type 2 diabetes.
SGLT2 inhibitors
Sodium‑glucose cotransporter‑2 inhibitors (SGLT2i) provide robust cardiorenal benefits that are partly independent of glucose lowering. Emerging preclinical and translational data suggest SGLT2i favourably affect mitochondrial dynamics, reduce oxidative stress, and improve myocardial energetics. Because heart and kidney disease are clinically relevant in MIDD, SGLT2i are appealing for dual glycaemic and organ‑protective effects. Practical limitations include reduced efficacy at low eGFR and the need for careful volume and infection risk monitoring.
Metformin and mitochondrial disease
Metformin is the cornerstone of type 2 diabetes therapy and improves insulin resistance and cardiovascular outcomes in large populations. However, metformin’s complex mitochondrial effects (including inhibition of complex I at high concentrations) raise theoretical concerns in patients with primary mitochondrial dysfunction. Historically, fear of lactic acidosis has led clinicians to avoid metformin in mitochondrial disease, although population data suggest lactic acidosis with metformin is rare when used appropriately. In MIDD, especially with significant muscle or hepatic involvement, or renal impairment, cautious use or avoidance is reasonable. If used, monitor renal function, lactate levels when clinically indicated, and start at low doses.
Sulfonylureas, insulin secretagogues, thiazolidinediones
Sulfonylureas may transiently augment insulin secretion but carry hypoglycaemia risk and may accelerate β‑cell exhaustion. Thiazolidinediones (PPARγ agonists) can worsen heart failure—an important concern because cardiomyopathy is common in mitochondrial disease. Therefore these agents are generally lower‑priority choices in MIDD and require individualized risk‑benefit assessment.
Insulin therapy
Insulin remains indispensable when β‑cell failure is advanced, during pregnancy, or in severe hyperglycaemia. Insulin corrects hyperglycaemia irrespective of mechanism and should not be withheld due to mitochondrial disease. Careful titration can avoid hypoglycaemia; consider combination with GLP‑1RA to reduce insulin doses and mitigate weight gain.
Safety considerations and monitoring
Key safety issues in MIDD include risk of lactic acidosis (metformin), risk of volume depletion and genitourinary infection (SGLT2i), gastrointestinal side effects (GLP‑1RA), hypoglycaemia with insulin or secretagogues, and heart failure risk with TZDs. Multisystem surveillance (renal function, cardiac imaging, audiology, ophthalmology, lactate in selected cases) is essential. Genetic counselling and family screening are important because of maternal transmission patterns.
Proposed pragmatic treatment algorithm (clinical application)
Below is a concise, practical pathway integrating pathophysiology and available evidence. This is a suggested approach, not a guideline, and should be individualized with specialist input.
1. Confirm diagnosis and baseline assessment
– Confirm m.3243A>G by genetic testing where feasible; consider heteroplasmy quantification in blood and, if clinically indicated, muscle. Document family history and maternal transmission.
– Baseline assessment: HbA1c, fasting glucose, continuous glucose profile if postprandial hyperglycaemia suspected, eGFR, urine albumin‑to‑creatinine ratio, ECG and echocardiography (to assess cardiomyopathy), hearing assessment, ophthalmology, lactate if symptomatic or if considering metformin in high‑risk patients.
2. Lifestyle and multidisciplinary care
– Individualized nutrition with attention to energy needs and mitochondrial disease specialist input when available.
– Early referral to endocrinology, nephrology and cardiology as indicated; involve genetics and audiology.
3. Pharmacologic initiation
– For most patients with MIDD and hyperglycaemia requiring pharmacologic therapy, consider initiating a GLP‑1RA (if no contraindication) or an SGLT2 inhibitor depending on comorbidities and eGFR.
– If a patient has established cardiorenal disease (albuminuria, reduced eGFR but above drug thresholds, heart failure), prioritise an SGLT2i for renal‑cardiac protection, adding a GLP‑1RA where weight loss or further ASCVD risk reduction is desired.
– If eGFR below thresholds for SGLT2 efficacy, GLP‑1RA is a reasonable first agent.
– Consider combination GLP‑1RA + SGLT2i when glycaemic control and organ protection both indicated and tolerated.
– Use metformin with caution: avoid if eGFR <45 mL/min/1.73 m2 depending on local guidance, or if significant hepatic dysfunction, high lactate, or severe myopathy. If used, start low and monitor closely.
4. Escalation
– If glycaemic targets not met, consider adding a long‑acting basal insulin or short‑acting agents depending on postprandial vs fasting hyperglycaemia; GLP‑1RA can reduce insulin requirements.
– Avoid TZDs if cardiomyopathy/heart failure; avoid routine sulfonylureas if hypoglycaemia risk high.
5. Special situations
– Pregnancy: mitochondrial disease raises complex issues; insulin remains the preferred agent. Preconception counselling and specialist care mandatory.
– Acute illness or hospitalization: treat hyperglycaemia per inpatient protocols; temporary insulin may be required.
Expert commentary, limitations and research priorities
Chaudhry et al. synthesize mechanistic rationale and clinical observations to propose GLP‑1RAs and SGLT2 inhibitors as ideal first‑line choices in many patients with MIDD [Chaudhry A et al., 2025]. This recommendation is biologically plausible and congruent with the broader evidence base for cardiovascular and renal protection in type 2 diabetes. Limitations include the absence of RCTs in genetically defined MIDD populations, heterogeneity of heteroplasmy, and variable organ involvement that may alter drug benefit–harm balance.
Priority research questions include: prospective trials (or registry‑based pragmatic trials) of GLP‑1RA and SGLT2i in genetically confirmed MIDD; mechanistic studies of how these agents affect mitochondrial function in human tissues; safety studies of metformin in mitochondrial disease with stratification by heteroplasmy and organ involvement; and long‑term observational data on cardiorenal outcomes in MIDD treated with these agents.
Conclusion and clinical takeaways
MIDD is a distinct, mitochondrially mediated diabetes subtype characterized by combined β‑cell dysfunction and insulin resistance driven in part by mitochondrial dysfunction and oxidative stress. Although randomized trials in MIDD are lacking, mechanistic data and extrapolation from large outcome trials support the use of GLP‑1 receptor agonists and SGLT2 inhibitors as rational first‑line agents for many patients with MIDD because they address both glycaemia and organ‑level risks, and exert favourable actions on oxidative stress and mitochondrial biology. Individualization remains essential—decisions should be informed by heteroplasmy, comorbid organ involvement, renal function, pregnancy considerations, and patient values. Multidisciplinary care and research focused on this genetically defined population are urgently needed.
Funding and clinicaltrials.gov
No dedicated funding declared in this review synthesis. There are currently no registered randomized trials specifically enrolling genetically confirmed MIDD patients comparing GLP‑1RA or SGLT2i as first‑line therapies (clinicaltrials.gov: search recommended for current registrations).
References
1. Chaudhry A, Thompson DM, Chanoine JP. Diabetes management in maternally inherited diabetes and deafness (MIDD): A review and a proposed treatment algorithm. Diabetes Obes Metab. 2025 Oct 27. doi: 10.1111/dom.70240. Epub ahead of print. PMID: 41145374.
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Note: Additional mechanistic and case‑report literature on mitochondrial diabetes, metformin and mitochondrial function, and effects of GLP‑1RAs and SGLT2 inhibitors on mitochondrial biology were reviewed to inform the above synthesis.
