The research, led by Melissa Bowerman of Keele University’s School of Medicine together with colleagues at the University of Hertfordshire and the Wolfson Centre for Inherited Neuromuscular Disease, builds on earlier work from the same laboratory that combined bioinformatics with drug repositioning strategies to identify compounds capable of correcting metabolic defects in SMA. Rather than starting from scratch with novel molecules, the team deliberately focused on drugs that are already approved for human use, an approach that could shorten the path from bench to bedside considerably. The three candidates that emerged—pioglitazone, a thiazolidinedione used to treat type 2 diabetes; melatonin, a hormone that regulates circadian rhythms; and insulin, the classic metabolic hormone—each target a different facet of cellular energy handling.

The experimental system at the heart of the study is the Smn2B/- mouse, a well-established model of SMA that carries a deletion of the mouse Smn gene alongside a human SMN2 transgene. This model recapitulates many features of the human disease, including motor dysfunction, muscle atrophy, shortened lifespan and systemic metabolic abnormalities. The researchers treated these mice with each of the three compounds and assessed a battery of behavioural, molecular and histological endpoints. Alongside the mouse work, they used the nematode worm Caenorhabditis elegans as a complementary in vivo platform, allowing rapid evaluation of the compounds’ effects in a second organism with conserved metabolic pathways.

The results, the team reports, were encouraging across the board, albeit to different degrees for each compound. All three drugs improved various pathological features in the SMA mice and worms, including survival, body weight, motor function, muscle size, the health of the spinal cord and the accumulation of lipids in the liver. Hepatic steatosis—the abnormal build-up of fat in liver tissue—is one of the metabolic pathologies increasingly recognised in SMA patients and models, and its improvement following treatment suggests that the compounds were acting on genuine disease-relevant biology rather than producing non-specific effects. Improvements in muscle size and spinal cord health point to benefits that extend beyond the liver into tissues central to neuromuscular function.

Of the three interventions, melatonin produced the most significant effect on survival, the endpoint that carries the greatest weight in preclinical SMA research. This finding is particularly striking because melatonin is not typically thought of as a metabolic drug; its best-known role is as a circadian signal produced by the pineal gland. Yet the study found that melatonin’s activity in SMA mice extended across several tissues, influencing molecular effectors involved in circadian rhythm regulation, glucose metabolism, mitochondrial biogenesis and the browning of white adipose tissue. Browning—the conversion of energy-storing white fat into energy-burning beige or brown fat—is a process with profound implications for systemic energy balance, and its disruption has been implicated in the metabolic dysfunction seen in SMA.

The involvement of mitochondria is another thread worth unpacking. Mitochondria are the power plants of the cell, and their biogenesis—the generation of new mitochondrial material—is governed by molecular pathways that respond to metabolic stress. In SMA, mitochondrial defects have been observed in multiple tissues, and the ability of melatonin to influence mitochondrial biogenesis suggests a mechanism by which the hormone could restore cellular energy capacity in vulnerable tissues such as muscle and liver. Similarly, its effects on glucose metabolism echo the insulin resistance and dyslipidaemia documented in SMA patients, abnormalities that current disease-modifying therapies do not adequately address.

That last point is crucial to understanding why the study matters. The last several years have seen a remarkable transformation in SMA care, with the arrival of nusinersen, an antisense oligonucleotide that modifies SMN2 splicing; onasemnogene abeparvovec, a gene therapy that delivers a functional copy of the SMN1 gene; and risdiplam, an oral SMN2 splicing modifier. These therapies have delivered dramatic gains in survival and motor function, particularly when treatment begins early. Yet they share a common limitation: they are designed to raise SMN levels, primarily benefiting the neuromuscular system, and they leave the peripheral and metabolic pathologies of the disease largely untouched. Patients treated with these drugs still exhibit metabolic abnormalities, and the peripheral tissues—skeletal muscle, liver, pancreas and adipose tissue—remain sites of ongoing dysfunction. The new study argues that this therapeutic gap is precisely where metabolism-targeted interventions could make a difference.

The concept of SMA as a metabolic disease is grounded in the biology of SMN itself. Although the protein is best known for its role in the assembly of spliceosomal ribonucleoproteins, its loss produces detectable abnormalities in tissues far removed from the motor neuron. Insulin resistance, hepatic steatosis, dyslipidaemia and circadian disruption have all been documented in SMA, and these abnormalities are not merely consequences of immobility; they appear to arise from cell-autonomous metabolic defects. Reframing SMA pathology from a neurocentric to a metabolic perspective, as the authors put it, reveals a disease landscape in which energy handling goes wrong in parallel with, and possibly contributes to, neuromuscular degeneration. On this view, correcting metabolic dysfunction is not an afterthought but a legitimate therapeutic goal in its own right.

The translational appeal of the approach lies in the fact that all three compounds are already commercially approved. Pioglitazone is prescribed worldwide for type 2 diabetes and has a well-characterised safety profile, although its use is associated with weight gain and, in some patients, concerns about fluid retention and fracture risk. Melatonin is available over the counter in many countries and is generally well tolerated. Insulin, of course, is a mainstay of diabetes management, though its use in non-diabetic patients would require careful dosing and monitoring. The authors are careful to note that the study was conducted in mouse and worm models, and that the doses, timing and combinations used in animals may not translate directly to humans. Clinical trials would be needed to establish whether these interventions, alone or in combination with existing SMN-restoring therapies, can deliver measurable benefits in patients. Nevertheless, the fact that the compounds are approved means that safety data already exist, potentially accelerating the design of early-phase studies.

The broader significance of the work may lie in the shift it represents in how the field thinks about combination therapy for SMA. Just as oncology moved from single-agent treatments to rational multi-drug regimens that attack different vulnerabilities simultaneously, neuromuscular medicine may be heading toward pairing SMN-restoring therapies with second-generation treatments aimed at specific non-neurological pathologies. The findings position metabolism, as the authors conclude, at the forefront of targets for SMA treatments and provide a strong rationale for exploring metabolism-targeted second-generation therapies to complement currently approved disease-modifying treatments. For a disease that was once considered untreatable, and which now has effective but incomplete therapies, the prospect of adding metabolic correction to the therapeutic arsenal represents a meaningful step forward—one that could matter most for the patients whose peripheral symptoms persist despite the most advanced neuromuscular interventions available today.

Subject of Research: Testing commercially approved metabolism-targeting drugs in a mouse model of spinal muscular atrophy

Article Title: Treating Smn2B/− spinal muscular atrophy (SMA) mice with commercially approved metabolism-targeting interventions leads to improved disease phenotypes

Article References: Çetin, Ö., McCallion, E., Hoolachan, J. M., Sutton, E. R., Cook, J., Al-Mozani, Y., Dhoowooah, A., Varughese, M. S., Velandia Dorta, L. F., Koomson, J., Rashid, S., Pacheco-Torres, P., Dimitriadi, M., & Bowerman, M. (2026). Treating Smn2B/− spinal muscular atrophy (SMA) mice with commercially approved metabolism-targeting interventions leads to improved disease phenotypes. Cellular and Molecular Life Sciences. https://doi.org/10.1007/s00018-026-06461-1

Image Credits: AI Generated

DOI: 10.1007/s00018-026-06461-1

Keywords: spinal muscular atrophy, metabolism, melatonin, pioglitazone, insulin, Smn2B/- mice, drug repositioning, mitochondrial biogenesis, hepatic steatosis, circadian rhythm, adipose tissue browning, combination therapy

The research team analyzed medical records from 240 adults with documented type 2 diabetes who had undergone comprehensive audiological evaluation, alongside 105 normoglycemic control individuals drawn from the same clinical archive. Strict exclusion criteria were applied to sharpen diagnostic specificity: patients with type 1 diabetes, occupational noise exposure, acoustic trauma, conductive middle ear pathology, previous otological surgery, or current use of ototoxic medications were systematically removed from the analysis. Severe renal impairment, hereditary hearing loss, and syndromic deafness were also grounds for exclusion, minimizing confounding from uremia-induced auditory dysfunction and genetic forms of impairment. All participants provided written informed consent in accordance with Declaration of Helsinki principles.

Hearing function was assessed using standardized pure-tone audiometry performed with a clinical audiometer in a soundproof room. Micro-otoscopy ruled out middle ear pathology and active infection, while tympanometry confirmed stable middle ear mechanics. The primary outcome was the pure-tone average at speech frequencies, known as PTA-mean, calculated as the arithmetic mean of air-conduction thresholds at 0.5, 1, 2, and 4 kilohertz, the frequencies most critical for speech intelligibility. Lower PTA-mean values indicate better-preserved hearing, while higher values reflect greater impairment. For participants with asymmetric loss, thresholds from each ear were averaged to provide a representative global estimate, reducing ear-specific variability.

When the researchers compared diabetic and non-diabetic participants using analysis of covariance, adjusting for age, biological sex, body mass index, and smoking status, the presence of type 2 diabetes emerged as a statistically significant predictor of worse hearing thresholds. On average, diabetic patients showed PTA-mean values approximately 8 decibels higher than controls, a difference the authors describe as clinically meaningful, since a 10 decibel rise in auditory threshold is perceptually equivalent to halving perceived loudness. Notably, none of the demographic covariates, including age, reached statistical significance in the adjusted model, a result the authors attribute to the fact that the entire cohort consisted of individuals already diagnosed with sensorineural hearing loss, which compressed the natural variation in auditory function across ages.

The most provocative portion of the study examined whether specific antidiabetic treatments were associated with different auditory outcomes within the diabetic subgroup. Using multivariable linear regression adjusted for age and BMI, the team found that several agents stood out. Semaglutide and dulaglutide, two widely prescribed GLP-1 receptor agonists, were associated with substantially lower PTA-mean values, with large regression coefficients reflecting more favorable hearing thresholds. Metformin, the first-line biguanide used by 55 percent of the cohort, was also linked to better thresholds, and pioglitazone, a thiazolidinedione, showed a similar individual-level association. The remaining drug classes, including sulfonylureas, DPP-4 inhibitors, SGLT2 inhibitors, and glinides, showed no statistically significant connections to hearing outcomes.

When medications were grouped into pharmacological classes, GLP-1RAs again showed the strongest association, with roughly a 9.95 decibel reduction in PTA-mean compared with the reference category, and biguanides were associated with a smaller but significant reduction of about 4.05 decibels. Glinides showed a quantitatively relevant trend that narrowly missed statistical significance, while thiazolidinediones did not reach significance at the class level, likely because only 11 patients in the cohort were taking them. The overall drug-class model explained just over 5 percent of the variance in hearing thresholds, a modest figure consistent with the multifactorial nature of hearing loss, but the medication-related associations persisted even after adjustment for age and BMI, neither of which remained a significant predictor once drug class entered the model.

Why might GLP-1 receptor agonists and metformin be linked to healthier cochleae? The authors point to a convergence of plausible biological mechanisms. Diabetes-related hearing loss is thought to arise from cochlear microangiopathy that compromises blood flow to the stria vascularis, the metabolically demanding tissue that maintains the ionic gradients needed for sound transduction. Chronic hyperglycemia also floods the cochlea with reactive oxygen species, damaging the vulnerable outer hair cells, while advanced glycation end products, mitochondrial dysfunction, low-grade inflammation, and disruption of potassium and calcium homeostasis further erode cochlear and neural function. GLP-1RAs, in this framework, are appealing candidates for auditory protection because they enhance mitochondrial function, suppress inflammasome activation and pro-inflammatory cytokine production, reduce oxidative stress, and improve endothelial function, all of which may preserve the delicate microvascular perfusion the cochlea depends upon.

Metformin’s potential benefit rests on a different but complementary foundation. The drug is a pleiotropic agent that activates AMP-activated protein kinase, a cellular metabolic sensor governing mitochondrial biogenesis, oxidative stress defenses, and inflammatory responses. Through AMPK signaling, metformin may counteract the oxidative damage and microvascular dysfunction that characterize diabetic cochlear pathology, and its systemic metabolic and cardiovascular benefits could secondarily nourish ischemia-sensitive auditory tissue. Intriguingly, the authors note that metformin’s association with better hearing persisted after statistical adjustment, hinting that its potential auditory effects may not be mediated by glycemic control alone. The same logic applies across the medication spectrum: because every drug class studied effectively lowers blood glucose, the differential associations observed suggest that auditory preservation, if real, may stem from antioxidant, anti-inflammatory, and microvascular mechanisms rather than glucose lowering per se. Sulfonylureas, which stimulate insulin secretion without meaningful anti-inflammatory or antioxidant effects, fit neatly into this interpretation by showing no auditory association.

The authors are careful to frame these results as hypothesis-generating rather than practice-changing. The retrospective, non-interventional design precludes causal conclusions, and residual confounding from unmeasured variables, including diabetes duration, HbA1c levels, hypertension, renal function, cumulative drug exposure, treatment duration, and adherence, cannot be excluded. Because longitudinal audiometric follow-up was unavailable, hearing preservation was defined operationally as lower thresholds at a single assessment rather than demonstrated slowing of decline. Some treatment subgroups were small, making the large coefficients for individual agents particularly sensitive to sparse-data effects, outliers, and unmeasured clinical differences. The study also relied on pure-tone audiometry, which does not capture retrocochlear or central auditory processing, and included only hearing-impaired patients, which may explain why age failed to predict thresholds. The authors explicitly caution that the evidence is insufficient to support any change in antidiabetic prescribing based on hearing outcomes.

Even with these caveats, the implications are substantial. Diabetes already affects an estimated 589 million adults worldwide, and hearing loss, a historically underappreciated complication that erodes communication, social integration, and psychological well-being, may deserve a firmer place in routine diabetes care. The study’s authors suggest that audiological monitoring could become a useful adjunctive screening component of comprehensive diabetes management, particularly for older patients with long-standing disease or additional microvascular risk factors. If prospective studies confirm that GLP-1RAs and metformin are genuinely associated with slower auditory decline, hearing outcomes could eventually join cardiovascular and renal endpoints as extra-glycemic measures of treatment success, a notable prospect given the enormous clinical attention these drug classes already command. The mechanistic pathways outlined, from oxidative stress and microvascular inflammation to endothelial dysfunction, now await testing in experimental and translational studies that examine cochlear tissue directly, potentially yielding insights relevant to both diabetes-related and age-related hearing loss.

Subject of Research: Associations between antidiabetic pharmacotherapy and hearing thresholds in adults with type 2 diabetes and sensorineural hearing loss

Article Title: Associations Between Antidiabetic Pharmacotherapy and Hearing Thresholds in Adult Hearing‐Impaired Patients With Type 2 Diabetes

Article References: Martines, F., Salvago, P., Vaccaro, F., Vaccaro, D., Malta, G., Plescia, F., Cascioferro, S., Lavanco, G., & Plescia, F. (2026). Associations Between Antidiabetic Pharmacotherapy and Hearing Thresholds in Adult Hearing‐Impaired Patients With Type 2 Diabetes. Pharmacology Research & Perspectives, 14(5), Article e70316. https://doi.org/10.1002/prp2.70316

Image Credits: AI Generated

DOI: 10.1002/prp2.70316

Keywords: type 2 diabetes, hearing loss, GLP-1 receptor agonists, metformin, pure-tone audiometry, sensorineural hearing impairment, cochlear microangiopathy, oxidative stress, semaglutide, pioglitazone, diabetes complications, audiology