The editorial draws attention to neuropathy as an early diabetes complication associated with impaired quality of life and elevated mortality. Historical evidence cited by the authors linked neuropathy to subsequent renal impairment, and more recent prospective data have reinforced that relationship. Studies also indicate that cardiac autonomic neuropathy may already be detectable in people with prediabetes or increased prediabetes risk. In a comparison of people with prediabetes, those at increased risk of prediabetes and controls, both prediabetes and increased risk were associated with cardiac autonomic neuropathy independently of age. The authors caution, however, that these findings may point toward broader metabolic influences rather than short-term glycaemic variability alone.

Prospective evidence strengthens the connection between autonomic and somatic nerve involvement. Among people with diabetes who did not have diabetic sensorimotor polyneuropathy at baseline, established cardiac autonomic neuropathy independently predicted its later development under three complementary definitions during an average three-year follow-up. Reduced short-term heart-rate variability also identified people at increased risk and could potentially serve as a practical stratification marker. A separate cross-sectional study of people with type 2 diabetes and diabetic kidney disease found that cardiac autonomic neuropathy was more prevalent in advanced kidney disease and was associated with vitamin D deficiency and impaired heart-rate variability indices. Because that study was cross-sectional, it cannot establish that kidney disease, vitamin D deficiency or autonomic dysfunction caused one another.

Age also emerged as a major influence on the clinical pattern of sensory neuropathy. In a study of 442 patients with type 2 diabetes in a defined metropolitan area, mean age was 65.5 years and mean diabetes duration was 9.6 years. Researchers assessed pressure perception with a 10-g Semmes-Weinstein monofilament, vibration detection with a calibrated 128-Hz tuning fork and symptom reports obtained through three standardized questions about ulcers, persistent pain and lower-limb discomfort. Abnormal results were more frequent with the tuning fork, and the two methods frequently identified different patients. The findings indicate that standard screening tools are not interchangeable and suggest that a simple symptom questionnaire may complement objective testing in routine outpatient care.

Severe neuropathy can also complicate dental diagnosis and treatment, as illustrated by two case reports involving poorly controlled diabetes. A 14-year-old girl with 10 years of poorly controlled type 1 diabetes had marked oral disease, including gingivitis, angular cheilitis, extensive plaque, caries and pericoronaritis, yet showed amplified pain reactions during dental procedures despite adequate local anaesthesia. Quantitative sensory testing documented lower thresholds consistent with generalized sensory hyperexcitability. A 55-year-old man with long-term poor glycaemic control had severe generalized periodontitis, attachment loss, tooth mobility and multiple carious lesions, but reported little or no pain and underestimated the severity of his condition. Testing detected severe, partially maximal hypoesthesia. These cases are not prevalence estimates, but they demonstrate why dental assessment may require individualized strategies and close interdisciplinary cooperation.

Rare causes must also be considered when neuropathy is accompanied by hypoglycaemia. In one case, a 22-year-old woman experienced recurrent hypoglycaemia, numbness, tingling and burning limb pain. Investigations identified multiple radiculopathies and sensorimotor polyneuropathy, followed by a contrast-enhancing tumour near the junction of the body and tail of the pancreas. After laparoscopic distal pancreatectomy, her hypoglycaemia resolved and her neuropathy symptoms improved. The authors identify insulinoma as an uncommon possible cause of neuropathy and argue that early diagnosis is important. The single case does not establish how frequently pancreatic tumours produce this pattern, but it illustrates the value of considering endocrine causes when the clinical presentation is atypical.

Mechanistic research offers potential targets but does not yet amount to proven disease-modifying therapy. One review places oxidative stress at the center of diabetic nerve injury, connecting hyperglycaemia-activated pathways with mitochondrial dysfunction, endoplasmic reticulum stress and chronic inflammatory signaling. Other reviews examine emerging agents for painful diabetic neuropathy, including pilavapadin, an orally administered selective inhibitor of adapter protein-2-associated kinase 1, and vixotrigine, a broad-spectrum voltage-gated sodium-channel inhibitor. Experimental studies suggest possible effects of GLP-1 receptor agonists and SGLT2 inhibitors on neural damage, but the available clinical evidence comes mainly from small, short phase II randomized trials with inconsistent results for clinical and neurophysiological outcomes. Translation review similarly describes distal axon degeneration, impaired regeneration and the continuing absence of an established disease-modifying treatment.

Several studies in the collection examine early detection and risk prediction rather than therapeutic benefit. Current perception threshold testing showed moderate diagnostic accuracy for early C-fiber dysfunction in type 1 diabetes. A random-forest model identified age, diabetes duration, HbA1c, glycated serum protein and 25-hydroxyvitamin D as major predictors of diabetic polyneuropathy. In a propensity score-matched cohort, glycaemic variability was associated with the presence and severity of polyneuropathy independently of HbA1c, with systemic inflammation partly mediating the association. Mendelian randomization produced hypothesis-generating associations between selected phosphatidylcholine species and neuropathy risk. Additional reviews address Schwann-cell injury and potential roles for apoptosis, autophagy, pyroptosis, ferroptosis and necroptosis, as well as the integrated use of metabolic, renal, hepatic, inflammatory, thyroid and vitamin-related laboratory markers.

Interventions beyond medication remain under study. A meta-analysis of seven trials reported improved nerve conduction and glycaemic outcomes with dapagliflozin plus methylcobalamin, although the limited evidence base requires larger, more rigorous and more broadly generalizable trials. In a randomized study, high-intensity interval training and moderate-intensity continuous training both improved metabolic, inflammatory and neurological outcomes, with larger effects reported for high-intensity interval training. A network meta-analysis of antimicrobial dressings for diabetic foot ulcers ranked antibiotic-impregnated bone cement and silver dressings most favorably, while also identifying the need for direct comparative and cost-effectiveness studies. These findings cover different outcomes and interventions, so they should not be read as evidence that one approach universally outperforms the others.

The editorial ultimately argues for precision medicine in diabetic neuropathy because the condition varies in the nerve fibers affected, sensory manifestations, pain burden, mechanisms and individual course. Longitudinal sensory profiling has identified distinct trajectories of dysfunction, while magnetic resonance neurography has associated distinct sciatic-nerve structural patterns with different peripheral sensory phenotypes in type 2 diabetes. Quantitative sensory testing combined with C-fiber-oriented electrical stimulation also revealed that people with markedly impaired heat-pain perception could retain substantial electrically evoked pain responses, showing that loss of a sensory function does not necessarily mean loss of the corresponding excitable axons. The next step is to link mechanistic phenotypes to treatment response through robust prospective studies, targeted therapies and interventions that actually modify the disease rather than only its symptoms.

Subject of Research: Advances in diagnosing, stratifying and treating diabetic sensorimotor polyneuropathy

Article Title: Editorial: Frontiers in diagnostic and therapeutic approaches in diabetic sensorimotor neuropathy, volume II

Article References: Kender, Z., & Kempler, P. (2026). Editorial: Frontiers in diagnostic and therapeutic approaches in diabetic sensorimotor neuropathy, volume II. Frontiers in Endocrinology, 17, Article 2009636. https://doi.org/10.3389/fendo.2026.2009636

Image Credits: AI Generated

DOI: 10.3389/fendo.2026.2009636

Keywords: diabetic neuropathy, sensorimotor polyneuropathy, cardiac autonomic neuropathy, sensory phenotyping, quantitative sensory testing, neuroimaging, neuropathic pain, precision medicine, diabetes complications, Editorial, Frontiers, diagnostic

Diabetic retinopathy is the leading cause of vision loss in working-age adults and develops as chronically elevated blood glucose damages the small vessels of the retina. Clinicians conventionally describe it as a progressive disease, moving from very mild and mild nonproliferative stages through more severe forms and, ultimately, proliferative retinopathy in which abnormal new blood vessels grow. What has been far less documented is regression: the phenomenon in which retinal findings such as microaneurysms and hemorrhages diminish over time and the eye appears to step back to a less severe disease state. Because regression is rarely reported, its true prevalence in early disease has remained uncertain, leaving a gap in how eye care management strategies are designed and communicated.

To address that gap, the research team turned to a uniquely valuable data source: the Indian Health Service teleophthalmology program for diabetic retinopathy evaluation. This program brings retinal imaging to patients in American Indian and Alaska Native communities, many of which face significant barriers to specialty eye care. Trained readers grade the images using standardized scales, creating a longitudinal record of retinal status that is unusually consistent across time. The investigators identified patients who had a baseline retinal examination between 2015 and 2017 and a follow-up examination within three years, then tracked how their retinopathy status changed.

The cohort was substantial. A total of 2,348 patients had very mild nonproliferative diabetic retinopathy at baseline, and 705 had mild disease. Across the full sample, the mean age was 56 years with a standard deviation of 12.8 years, 55 percent were female, the average duration of diabetes was 13.0 years, and the mean hemoglobin A1c, a measure of average blood glucose control over roughly three months, was 8.8 percent. These characteristics describe a population in mid-adulthood with long-standing diabetes and glycemic control well above recommended targets, a profile typical of many patients at risk for retinopathy complications.

The central result was striking. Among patients starting with very mild nonproliferative diabetic retinopathy, 47 percent, with a confidence interval of 45 to 50 percent, showed regression on follow-up imaging, while only 27 percent progressed. Among those starting with mild disease, 36 percent regressed, with a confidence interval of 33 to 40 percent, compared with 34 percent who progressed. In other words, for the very mildest form of retinopathy, improvement was nearly twice as likely as worsening over the follow-up window. Even in the mild stage, regression matched or exceeded progression. The findings directly challenge the assumption that early diabetic retinopathy inevitably advances.

Beyond simply counting transitions, the researchers used multivariable analyses to untangle which factors were associated with the odds of regression, accounting simultaneously for other patient characteristics. Three variables emerged as significant. Lower hemoglobin A1c levels were associated with greater odds of regression in patients with either very mild or mild baseline disease, reinforcing the central role of glycemic control. Insulin use, by contrast, was associated with lower odds of regression, likely reflecting that patients requiring insulin tend to have more severe or longer-standing diabetes. Shorter diabetes duration was associated with greater odds of regression, but only among patients who began with very mild disease, suggesting that the window for spontaneous or treatment-supported reversal narrows as diabetes persists.

These associations carry mechanistic weight. Sustained hyperglycemia damages retinal capillaries through well-characterized pathways, including the accumulation of advanced glycation end products, increased vascular permeability, and chronic low-grade inflammation. When average glucose levels fall, the metabolic drivers of vascular injury weaken, and the retina’s supporting cells and vessels can partially recover. Clinical trials have long shown that intensive glycemic control slows retinopathy progression, but the new study extends that principle in a different direction: better control is not merely protective against worsening, it is statistically linked to measurable improvement in early disease. Behavioral modifications such as increased physical activity and weight loss, which lower hemoglobin A1c and thereby reduce the risk of progression, are important to emphasize in diabetic eye care, the authors conclude.

The population context matters as much as the biology. American Indian and Alaska Native communities experience among the highest rates of type 2 diabetes in the United States, and geographic isolation often delays access to ophthalmologists. The Indian Health Service teleophthalmology program was built to close that gap by bringing fundus photography and standardized grading directly into primary care settings. Because the same imaging and grading protocols are applied across sites and years, the program produces longitudinal data of a consistency that is difficult to achieve in fragmented private health systems. That infrastructure is what made it possible to observe thousands of transitions in retinal status over a defined three-year window, and it demonstrates how teleophthalmology can serve simultaneously as a care delivery mechanism and a surveillance engine for population eye health.

For clinicians, the practical implications are immediate. Patients told that they have very mild or mild diabetic retinopathy often assume that vision-threatening disease is inevitable, a message that can foster fatalism and disengagement from self-care. The new evidence supports a different framing: early retinopathy is a warning sign, but it is also a stage at which improvement is common, particularly when glucose control improves, diabetes is caught early, and the disease has not yet required insulin therapy. That message could strengthen motivation for the very behaviors, diet, exercise, adherence to glucose-lowering treatment, and regular monitoring, that the data link to better retinal outcomes. It also argues for continued regular retinal screening even after regression is documented, since the underlying metabolic disease persists and the risk of future progression remains.

The study also leaves open questions that future research must address. As a retrospective cohort analysis, it can identify associations but cannot prove that lowering hemoglobin A1c causes regression; randomized or prospective designs would be needed to establish causation. The three-year follow-up window captures short-term dynamics but not the longer arc of disease. And the findings, drawn from a specific population served by a single national program, may not generalize identically to all populations with diabetes. Nevertheless, the scale and consistency of the results make a compelling case that the earliest stages of diabetic retinopathy deserve to be described to patients not as a one-way slide toward vision loss but as a reversible crossroads, one at which the choices a patient makes about glucose control, activity, and weight can measurably tilt the odds toward a healthier retina.

Subject of Research: Rates of nonproliferative diabetic retinopathy (NPDR) regression among patients with very mild or mild NPDR in an Indian Health Service teleophthalmology program, 2015 – 2020

Article Title: Rates of nonproliferative diabetic retinopathy (NPDR) regression among patients with very mild or mild NPDR in an Indian Health Service teleophthalmology program, 2015 – 2020

Article References: Bursell, S.-E., Fonda, S. J., Borik, K., Stainback, J., & Shahon, D. (2026). Rates of nonproliferative diabetic retinopathy (NPDR) regression among patients with very mild or mild NPDR in an Indian Health Service teleophthalmology program, 2015 – 2020. PLOS One, 21(10), e0361052. https://doi.org/10.1371/journal.pone.0361052

Image Credits: AI Generated

DOI: 10.1371/journal.pone.0361052

Keywords: diabetic retinopathy, regression, Indian Health Service, teleophthalmology, nonproliferative diabetic retinopathy, HbA1c, glycemic control, retinal screening, diabetes complications, eye disease, Rates, nonproliferative

The core problem with diabetic foot ulcers is that they are not single diseases. They arise from a convergence of peripheral neuropathy, ischemia and hypoxia, and recurrent infection, all superimposed on a metabolic environment warped by chronic hyperglycemia. Sensory neuropathy strips patients of the protective pain reflexes that warn of minor trauma, while motor neuropathy deforms the foot and redistributes pressure onto vulnerable tissue. Autonomic dysfunction dries the skin, cracking the protective barrier and inviting bacterial entry. Meanwhile, prolonged high blood sugar drives atherosclerosis in the large vessels of the leg and damages the microcirculation, starving tissue of oxygen and nutrients. The result is a wound microenvironment in which matrix metalloproteinases run rampant, collagen synthesis lags, advanced glycation end products accumulate, and inflammation refuses to resolve. Conventional diagnostic tools, from the Ankle-Brachial Index to MRI and transcutaneous oxygen pressure measurement, capture the macroscopic consequences of this cascade but say little about the cellular actors driving it.

This is where single-cell RNA sequencing enters the picture. Unlike bulk transcriptomic methods, which measure average gene expression across thousands of mixed cells and thereby mask the contributions of rare subpopulations, scRNA-seq profiles each cell individually. The review’s authors explain that this resolution allows researchers to identify distinct cellular subtypes, map ligand-receptor interactions between cell populations using computational tools such as CellChat and iCELLNET, and reconstruct the pathological evolution of a wound at unprecedented depth. When integrated with spatial transcriptomics, which preserves the physical location of cells within tissue, and proteomics, which validates transcriptomic predictions at the protein level, the approach yields a multidimensional picture that bulk sequencing simply cannot match. The technology has already proven its worth in oncology, where it uncovered exhausted CD8-positive T cell signatures in hepatocellular carcinoma and identified macrophages and dendritic cells as key mediators in colorectal cancer, insights that have guided immunotherapy development.

Applied to diabetic foot ulcers, single-cell sequencing has produced its most striking findings in the immune compartment. Macrophages, the versatile scavengers and regulators of tissue repair, emerge as central players whose behavior is fundamentally corrupted in the diabetic wound. In healthy healing, pro-inflammatory macrophages dominate early to fight infection and clear debris, then give way to pro-resolving counterparts that secrete anti-inflammatory mediators such as C1QA, C1QB, C1QC and CD163, promoting tissue remodeling and angiogenesis. In diabetic wounds, this transition stalls. The review highlights that the histone demethylase JMJD3, an epigenetic regulator, activates the JAK1/3-STAT3 signaling axis and amplifies NF-kappa-B-mediated release of inflammatory cytokines including tumor necrosis factor and interleukins, effectively trapping macrophages in a pro-inflammatory state. Inhibition of JMJD3 in macrophages has been shown to alleviate inflammation and improve wound repair in both streptozotocin-induced type 1 and db/db type 2 diabetic mouse models, positioning the enzyme as a promising immunomodulatory target.

Beyond macrophages, single-cell atlases have exposed the heterogeneity of T lymphocytes in diabetic foot ulcers. Vu and colleagues found marked increases in naive T cells and CD8-positive T cells, resolving them into ten and seven distinct subclusters respectively. Cheng and colleagues reported upregulation of IL-17 signaling genes in CD8-positive T cells, alongside reduced expression of regulatory genes such as TSC22D3 and PIK3IP1, driving excessive activation and local inflammation. Regulatory T cells, which normally suppress inflammation through IL-10 and TGF-beta secretion, are significantly depleted in diabetic ulcers compared with normal wounds, weakening a critical brake on Th1 and Th17-driven immune responses. Natural killer T cells and gamma-delta T cells are enriched, contributing to a self-reinforcing cycle of infection, inflammation and impaired repair. Neutrophils, too, display remarkable diversity, with Retnlg-positive, Lcn2-positive, Wfdc21-positive and Mmp8-positive subsets identified, some of which peak during early ulcer formation and decline during healing, suggesting distinct roles in initiating versus resolving inflammation.

The stromal side of the wound tells an equally compelling story. Fibroblasts, the workhorses of extracellular matrix production and wound contraction, exhibit profound heterogeneity in diabetic ulcers. Buechler and colleagues generated a single-cell fibroblast atlas classifying lineages into general steady-state cells, specialized steady-state cells, and disturbance-specific activated cells. Januszyk and colleagues compared fibroblasts from diabetic and non-diabetic ulcers across ethnic groups, uncovering subpopulations with varied fibrotic potentials. A key mechanistic discovery came from Ku and colleagues, who showed that dysregulation of the IGF-1-SP1-CD248 pathway impairs fibroblast migration and delays healing. Healing-associated fibroblasts characterized by high expression of MMP1, MMP3, MMP11, HIF1A, CHI3L1 and TNFAIP6 concentrate in the central granulation bed, where they drive matrix remodeling and angiogenesis. Senescent, pro-inflammatory fibroblasts accumulate at the wound margin and avascular base, sustaining chronic inflammation and blocking closure. Spatial transcriptomics confirms that this dysfunctional spatial distribution, rather than transcriptional change alone, is a core determinant of refractory ulcer progression.

Vascular endothelial cells fare no better. Single-cell profiling of the public dataset GSE165816 revealed that core genes including CCND1, ENO1, HIF1A and SERPINE1 are significantly downregulated in endothelial cells of diabetic foot ulcers, undermining cell cycle regulation, hypoxic response and microcirculatory homeostasis. Two characteristic subsets emerge: functionally reparative endothelial cells marked by SLCO2A1 and CYP1A1, which are enriched in granulation tissue with healing potential, and senescent dysfunctional cells that predominate in refractory wounds, secreting anti-angiogenic factors such as thrombospondin-1 and pigment epithelium-derived factor. Hyperglycemia and hypoxia jointly suppress the Nrf2 antioxidant pathway while persistent NF-kappa-B activation floods the wound with pro-inflammatory mediators, creating a vicious cycle of endothelial injury, ischemia and senescence. Even keratinocytes are implicated, with quiescent BC-2 subsets failing to support re-epithelialization and senescent epidermal cells expressing p16INK4a and p21Cip1 losing proliferative and migratory capacity.

Perhaps most surprisingly, the review highlights the role of sensory neurons in coordinating repair. Lu and colleagues demonstrated that nociceptive neurons expressing calcitonin gene-related peptide engage RAMP1 receptors on neutrophils, monocytes and macrophages, reducing immune cell recruitment, accelerating apoptosis, enhancing phagocytosis and polarizing macrophages toward pro-resolving phenotypes. Loss of NaV1.8-positive sensory neurons impairs skin closure and muscle regeneration, providing a cellular-level explanation for why neuropathy and poor healing are so tightly linked. This neuroimmune axis, invisible to conventional bulk analyses, exemplifies the kind of mechanistic insight that single-cell approaches are uniquely positioned to deliver.

The translational implications are substantial. The review identifies MMP1, MMP3, MMP11, JMJD3 and HIF1A as valuable biomarkers and therapeutic targets, validated across multiple independent human cohorts and animal models. Computational drug-target network analysis has yielded seven potential core therapeutic targets and twenty candidate small-molecule drugs with translational potential. Single-cell signatures may eventually allow diabetic foot ulcers to be classified into inflammation-dominant, angiogenesis-deficient and matrix repair-impaired molecular subtypes, guiding individualized anti-inflammatory, pro-angiogenic or matrix-remodeling strategies. Yet significant barriers remain. Most studies rely on small, cross-sectional samples; db/db and streptozotocin mouse models cannot fully replicate the neuropathy, arterial occlusion and mixed infections characteristic of human disease; and sequencing costs, lack of standardized pipelines and insufficient prospective validation continue to limit clinical adoption. The authors argue that future progress will require stratified, longitudinal human cohorts, multi-omics integration combining spatial transcriptomics, proteomics and epigenomics, and rigorous preclinical validation of targets such as JMJD3 and STING. If those challenges can be met, single-cell technology may finally convert one of diabetes’ most intractable complications from a clinical guessing game into a data-driven precision discipline.

Subject of Research: Application of single-cell RNA sequencing to diabetic foot ulcer pathogenesis, biomarker discovery and translational research

Article Title: Single-cell RNA sequencing in diabetic foot ulcers: pathogenesis, biomarkers, and translational potential

Article References: Yang, S., Wang, S., Yang, R., Xu, K., Yang, X., & Zhao, Y. (2026). Single-cell RNA sequencing in diabetic foot ulcers: pathogenesis, biomarkers, and translational potential. Frontiers in Clinical Diabetes and Healthcare, 7, Article 1833678. https://doi.org/10.3389/fcdhc.2026.1833678

Image Credits: AI Generated

DOI: 10.3389/fcdhc.2026.1833678

Keywords: diabetic foot ulcer, single-cell RNA sequencing, macrophage polarization, wound healing, JMJD3, biomarkers, angiogenesis, fibroblasts, spatial transcriptomics, precision medicine, diabetes complications, IGF-1-SP1-CD248 pathway

The research, published in the journal Diabetes Therapy, examined the International Working Group on the Diabetic Foot (IWGDF) risk stratification system, a framework that sorts people with diabetes into four categories — very low, low, moderate, and high risk — based on whether they have lost protective sensation in their feet, whether they have peripheral artery disease, whether their feet are deformed, and whether they have ever had an ulcer or amputation before. The system is the backbone of diabetic foot screening worldwide, yet its real-world performance in specialist clinics, particularly in the Middle East, had remained thinly documented.

The team, led by Fatimah Z. Alenazi of Qassim University, analyzed clinical records from consecutive adults attending the diabetic foot service of the Abdullah Al-Othaim Diabetes Center in Buraydah between November 2025 and June 2026. The cohort comprised 373 men and 340 women, overwhelmingly with type 2 diabetes, with a mean age of 57.6 years and an average glycated hemoglobin (HbA1c) of 7.82 percent. Because every patient under follow-up at the center is routinely scheduled for foot screening regardless of symptoms, the researchers argue the sample reflects ordinary specialist practice rather than a cherry-picked group of problem feet.

The headline result is a gradient so steep it borders on dramatic. Not a single active ulcer was found among the 335 patients classified as very low risk. Prevalence crept up to 0.8 percent in the low-risk group, 4.8 percent in the moderate-risk group, and then leapt to 38.5 percent among the 39 patients in the high-risk category — more than one in three. The trend across ordered categories was highly significant, with a Cochran–Armitage test statistic of 10.02 and a p value below 0.001, meaning the probability of such a smooth staircase arising by chance is vanishingly small.

Quantified as a single number, the system’s cross-sectional discrimination for detecting a prevalent active ulcer was a c-statistic of 0.938, a value approaching the theoretical ceiling of 1.0. At the moderate/high-risk threshold, the classification caught 90.5 percent of all active ulcers while carrying a negative predictive value of 99.7 percent — in plain terms, if a patient was told their risk was low, the odds they had a hidden ulcer at that moment were roughly one in three hundred. Tightening the criterion to the high-risk category alone pushed specificity to 96.5 percent and the positive predictive value to 38.5 percent, at the cost of sensitivity dropping to 71.4 percent, a trade-off clinicians can calibrate depending on available resources.

Overall, 2.9 percent of the cohort — 21 patients — arrived with an active diabetic foot ulcer, a figure consistent with the lower range reported in specialist clinics and below the global pooled point prevalence of roughly 6.3 percent. Men carried a numerically higher burden, at 3.8 percent versus 2.1 percent in women, echoing international cohorts in which male sex is repeatedly linked to ulceration and amputation. But the difference did not reach statistical significance, and the study’s 21 ulcer events leave limited power to rule out a real gap.

The more provocative finding emerged from the multivariable logistic regression. After adjusting for age, sex, and diabetes type, each additional year of age raised the odds of moderate/high IWGDF risk by about 4 percent, and each 1 percent rise in HbA1c raised those odds by 13.2 percent. Gender, by contrast, was statistically invisible: the adjusted odds ratio for women was 1.048, with a confidence interval spanning unity and a p value of 0.819. In a region where sex differences in care-seeking and footwear habits are often invoked to explain foot disease patterns, the data suggest the risk machinery itself does not discriminate by sex — age and glycemic control do the heavy lifting.

The biology behind the HbA1c signal is well understood. Chronic hyperglycemia drives the formation of advanced glycation end-products, fuels oxidative stress, and degrades both nerves and microvessels. The result is a foot that cannot feel a pebble in a shoe and cannot perfuse a wound once it forms — the classic pairing of neuropathy and peripheral artery disease that turns minor trauma into a non-healing ulcer. Elevated plantar pressures from obesity add a further mechanical insult, though body mass index was not systematically recorded in this registry and could not be modeled.

The study’s authors and independent commentators alike are careful about what the numbers do and do not prove. Because the design is cross-sectional, the c-statistic quantifies how well the system identifies ulcers that already exist, not how well it predicts ulcers that will appear next year — although prior external validation studies have shown the IWGDF categories do forecast future ulceration and amputation, with risk rising progressively across categories. The exploratory model for active ulceration itself, with only 21 events, yielded directionally similar associations for age and HbA1c but nothing statistically significant, and the researchers flag it as underpowered and vulnerable to overfitting.

Even with those caveats, the practical implications are immediate. Vascular assessment with ankle–brachial index or pulse-volume recording was documented in 90.2 percent of patients, demonstrating that structured screening can be nearly complete in routine care. The findings support concentrating specialist podiatry and vascular resources on the 17.3 percent of patients classified at moderate or high risk — a subgroup that accounted for a disproportionate share of prevalent disease — while reassuring the majority that their short-term ulcer risk is minimal. For national diabetes programs in Saudi Arabia and beyond, where amputation rates remain among the highest regionally, the message is that a monofilament, a Doppler probe, and a disciplined scoring habit may be the cheapest amputation-prevention technology medicine has.

Subject of Research: Clinical Performance of the IWGDF Risk Stratification System for Diabetic Foot Ulceration: A Gender-Disaggregated Study of 713 Patients

Article Title: Clinical Performance of the IWGDF Risk Stratification System for Diabetic Foot Ulceration: A Gender-Disaggregated Study of 713 Patients

Article References: Alenazi, F. Z., Alslamah, T., Alharbi, B., Alotaibi, W. I., Algeffari, M., Alsalamah, Y. S., Almohaileb, F. I., Fawaz, M. A., & Raposo, A. (2026). Clinical Performance of the IWGDF Risk Stratification System for Diabetic Foot Ulceration: A Gender-Disaggregated Study of 713 Patients. Diabetes Therapy. https://doi.org/10.1007/s13300-026-01925-w

Image Credits: AI Generated

DOI: 10.1007/s13300-026-01925-w

Keywords: diabetic foot ulcer, IWGDF risk stratification, diabetes complications, HbA1c, peripheral neuropathy, Saudi Arabia, foot screening, peripheral artery disease, Clinical, Performance, IWGDF, Risk

The peptide, known as MOTS-c, is transcribed from the mitochondrial open-reading-frame of the 12S rRNA-c region. Since its discovery, MOTS-c has attracted intense interest as one of a handful of mitochondrial-derived peptides that can act as signaling molecules, influencing metabolism, stress responses and aging far beyond the organelle where they are made. What the Nanjing-led team has done is to trace its role in the eye with unusual precision. Using retinal tissue, they showed that MOTS-c is predominantly localized in retinal endothelial cells, the thin, tightly connected cells that form the inner lining of blood vessels and constitute the blood-retinal barrier, the critical interface that keeps the light-sensitive tissue protected and properly nourished.

That localization matters because the earliest events in diabetic retinopathy are vascular. Chronically high blood sugar injures endothelial cells, weakens the junctions between them, and allows fluid and blood components to leak into the retina. It also damages mitochondria within the endothelial cells themselves, promoting the accumulation of reactive lipid peroxides that attack cellular membranes. To test whether MOTS-c is a casualty of this process, the researchers exposed human retinal endothelial cells to high glucose concentrations and studied a streptozotocin-induced diabetic mouse model, a standard experimental system in which the drug destroys insulin-producing cells and produces sustained hyperglycemia. In both settings, high glucose reduced the expression of MOTS-c in the retinal vasculature, suggesting that the loss of this mitochondrial signal is part of the injury program that diabetes unleashes on the eye.

The therapeutic logic followed directly. When the team supplied MOTS-c to human retinal endothelial cells suffering high-glucose-induced injury, the peptide protected the endothelial barrier and ameliorated mitochondrial dysfunction. The same benefit appeared in the diabetic mice: MOTS-c treatment rescued vascular endothelial damage in the retina. These genetic and pharmacological approaches, applied both in cell culture and in living animals, established that the peptide’s dysregulation is not merely a byproduct of disease but a mechanistically meaningful contributor to the vascular breakdown that drives diabetic retinopathy.

The deeper question was how a 16-amino-acid peptide could accomplish this. To find out, the researchers turned to unbiased molecular profiling. Transcriptomic analyses, which survey changes in gene expression across the whole genome, and lipidomic analyses, which map the constellation of fats and phospholipids inside the cells, converged on a surprising pathway: MOTS-c increased the activity of phospholipase A2, a family of enzymes that cleave phospholipids, the molecules that form the backbone of every cellular membrane, and thereby regulated phospholipid metabolism. In other words, the mitochondrial peptide appears to reprogram how endothelial cells maintain and remodel their own membranes under diabetic stress.

Among the differentially expressed genes associated with this upregulated phospholipase A2 activity, one stood out. Phospholipase A2 group VI, known as PLA2G6, showed the most significant upregulation following MOTS-c treatment. PLA2G6, an intracellular calcium-independent phospholipase, is best known in other contexts for its role in lipid homeostasis and, when mutated, in neurodegenerative disease. In the diabetic retina, the new work assigns it a protective job: PLA2G6-mediated degradation of lipid peroxides served as a primary mediator of the endothelial barrier protection seen during MOTS-c treatment. Lipid peroxides are the corrosive products of unsaturated fatty acid oxidation, and their accumulation is a hallmark of ferroptosis and related forms of oxidative cell death. By accelerating their breakdown, PLA2G6 effectively detoxifies the membrane environment of stressed endothelial cells.

The causal chain was then tested in the most demanding way, by removing the link. When the researchers knocked down PLA2G6, the protective effect of MOTS-c against vascular endothelial damage collapsed, both in vitro and in vivo. The peptide could no longer defend the endothelial barrier without its enzymatic partner. This loss-of-function result elevates the finding from correlation to mechanism: MOTS-c acts upstream, PLA2G6 acts downstream, and the degradation of lipid peroxides is the functional bridge between them. It also suggests that patients or experimental systems with insufficient PLA2G6 activity might respond poorly to MOTS-c-based interventions, a consideration that could shape future strategies for patient selection.

Taken together, the study identifies a novel role for MOTS-c dysregulation in mediating vascular endothelial damage in diabetic retinopathy and proposes MOTS-c supplementation as a potential therapeutic approach, one that works by regulating phospholipid homeostasis and protecting the endothelial barrier through PLA2G6. The conceptual appeal is considerable. Rather than blocking a single growth factor after the vasculature has already begun to fail, a MOTS-c-based strategy would aim to reinforce the fundamental resilience of endothelial membranes early in the disease, when intervention could still prevent the cascade of leakage, inflammation and pathological vessel growth that ultimately destroys vision. It also adds to a growing appreciation that mitochondrial-derived peptides are not metabolic footnotes but active hormones with tissue-specific protective functions.

Substantial work remains before this biology reaches the clinic. The findings, published as an open-access article in Cell Death Discovery on 10 October 2026, were obtained in cell culture and in a mouse model of diabetes, and translating a mitochondrial peptide into a safe, durable therapy for human eyes will require solving questions of delivery, dosing, stability and long-term safety that the current study did not address. Human diabetic retinas, exposed to years of metabolic fluctuation, may behave differently from acute experimental hyperglycemia. Yet the study offers something the field has lacked: a defined molecular axis, running from a mitochondrial genome-encoded peptide through phospholipase A2 activity and lipid peroxide clearance to the integrity of the blood-retinal barrier. If that axis holds up in further preclinical and clinical testing, the smallest genome in our cells may turn out to hold one of the larger answers to diabetic blindness.

Subject of Research: The role of the mitochondrial-derived peptide MOTS-c and phospholipase A2 group VI in protecting retinal endothelial cells in diabetic retinopathy

Article Title: Mitochondrial-derived peptide MOTS-c rescues vascular endothelial damage via PLA2G6 in diabetic retinopathy

Article References: Liao, Y., Xiang, J., Xia, Y., Liu, C., He, C., Tong, J., Chen, Y., Yao, G., & Xie, Z. (2026). Mitochondrial-derived peptide MOTS-c rescues vascular endothelial damage via PLA2G6 in diabetic retinopathy. Cell Death Discovery. https://doi.org/10.1038/s41420-026-03384-5

Image Credits: AI Generated

DOI: 10.1038/s41420-026-03384-5

Keywords: MOTS-c, mitochondrial-derived peptide, diabetic retinopathy, retinal endothelial cells, PLA2G6, phospholipase A2, lipid peroxides, endothelial barrier, mitochondrial dysfunction, phospholipid metabolism, blood-retinal barrier, diabetes complications

The study, led by Fatimah Z. Alenazi of Qassim University together with colleagues in Saudi Arabia, Lebanon, South Africa, and Portugal, set out to answer a deceptively simple question: which factors independently predict whether a patient’s feet fall into the danger zone, and whether they have already developed an active ulcer? The team focused on three candidate variables with strong clinical plausibility: glycated hemoglobin (HbA1c), the standard laboratory marker of average blood sugar over the preceding two to three months; age; and sex. Using a census sampling approach, they extracted every eligible record with a confirmed diabetes diagnosis and a documented foot assessment between January 2022 and December 2024, excluding only nine records with missing or non-numeric HbA1c values.

The technical backbone of the analysis was a pair of multivariable binary logistic regression models, one for each outcome. The primary outcome was at-risk diabetic foot status, defined as an IWGDF risk category of 1 or higher under the 2019 stratification system, which grades patients from category 0 (no loss of protective sensation or arterial disease) up to category 3 (previous ulceration or amputation). The secondary outcome was active foot ulceration, defined as a full-thickness wound distal to the ankle identified by the treating clinician during the same visit. Age and HbA1c were entered as continuous variables, with the HbA1c estimate expressed per 1% increase, and the models were assessed for calibration using the Hosmer–Lemeshow test and for explanatory power using the Nagelkerke R-squared statistic.

The results delivered a clear verdict on two of the three variables. Older age emerged as the strongest predictor of at-risk foot status, with each additional year of life raising the odds by 2.8% (odds ratio 1.028; 95% confidence interval 1.016–1.039; P < 0.001). The descriptive data traced the same gradient: at-risk status affected 39.6% of patients under 50, 55.3% of those aged 50 to 65, and 62.1% of those over 65. Male sex carried an independent 40% increase in the odds of at-risk status (OR 1.403; 95% CI 1.036–1.901; P = 0.029), with 58.3% of men classified as at risk compared with 48.4% of women. Both findings align with established biology: aging brings cumulative microvascular and macrovascular damage, progressive peripheral neuropathy, worsening peripheral arterial disease, thinner skin, slower tissue repair, and a heavier comorbidity burden, while men in many cohorts show higher rates of arterial disease and less favorable cardiovascular risk profiles.

The surprise came from HbA1c. Despite its reputation as the master metric of diabetes control, the glycemic marker showed no independent association with at-risk foot status (OR 1.037; P = 0.422) and fell short of statistical significance for active ulceration (OR 1.224; P = 0.077). Yet the raw descriptive numbers told a more suggestive story. Foot ulcer prevalence climbed steadily across HbA1c categories, from 1.9% among patients with HbA1c below 7.0% to 2.6% in the 7.0–9.0% band and 6.3% among those exceeding 9.0%. The authors argue that this gradient is biologically plausible and consistent with the known pathophysiology of wound breakdown, which involves chronic inflammation, immune dysfunction, endothelial impairment, and delayed repair, all of which are sensitive to current metabolic state.

Why might a single HbA1c reading fail to predict foot risk while still tracking ulceration descriptively? The researchers offer a mechanistic explanation rooted in the different time scales of the two outcomes. The IWGDF classification is built on structural, cumulative risk factors, including peripheral neuropathy, peripheral arterial disease, foot deformity, previous ulceration, and amputation, which develop over years or decades of glycemic exposure and vascular injury. A single recent HbA1c measurement captures only a snapshot of that long arc. Active ulceration, by contrast, represents acute tissue breakdown and impaired healing, processes that may respond more directly to current metabolic control. In other words, the foot risk category reflects the accumulated damage of the past, while the open wound may reflect the metabolic environment of the present.

The authors are careful, however, not to overstate what their data can support. The dataset lacked a long list of variables that any foot specialist would consider essential: diabetes duration, severity of neuropathy and peripheral arterial disease, renal function and chronic kidney disease, diabetic retinopathy, body mass index, smoking status, medication use, nationality, and socioeconomic status. Because these potential confounders could not be adjusted for, residual confounding cannot be excluded, and the independent role of HbA1c in diabetic foot risk cannot be confirmed or ruled out on the basis of this study alone. The team also notes that the most recent HbA1c value may not correspond in time to the foot assessment, introducing possible exposure misclassification, and that a single measurement may poorly represent long-term glycemic variability.

Several other quirks in the data deserve cautious reading. Active ulceration was recorded in only 21 patients, or 3.0% of the cohort, and its distribution across subgroups was uneven in ways that resist simple interpretation. Ulcer prevalence peaked in the 50-to-65 age group at 4.4% rather than among the over-65s at 2.6%, a pattern the authors attribute plausibly to survivor bias, more intensive surveillance of older patients, and reduced mobility in the oldest group, which may limit the repetitive mechanical trauma that drives skin breakdown even as structural risk rises. Similarly, although men carried higher at-risk status, active ulcers were actually more frequent in women, 3.7% versus 2.0%, a discrepancy that could reflect differences in healthcare utilization, footwear, mobility, or wound healing rather than biology. With so few ulcer events, the statistical models had limited precision, and the authors emphasize that their age–sex–HbA1c models were never intended as comprehensive risk-prediction tools.

The study’s strengths lie in its design discipline. The census approach avoided discretionary subsampling, the standardized IWGDF framework allowed comparison with international benchmarks, and reporting followed the STROBE guidelines for observational research. Its limitations are equally clear: the single tertiary center limits generalizability to primary care and community settings, the cross-sectional design forbids any causal inference, and the absence of the total number of diabetic patients seen at the center means the completeness of screening coverage could not be determined. A history of lower-extremity amputation was documented in only four patients and was deliberately excluded from the models, partly because amputation history is itself a defining criterion of IWGDF category 3, which would make its inclusion circular.

The practical message for clinicians and health systems is nonetheless concrete. With more than half of specialist-attending patients already in an at-risk category, the authors argue that foot screening and preventive care should be tailored to demographic profiles, with intensified surveillance for older patients and men, and delivered through multidisciplinary teams spanning podiatry, vascular assessment, endocrinology, and patient education. Glycemic optimization remains a cornerstone of diabetic foot prevention, but the study suggests that blood sugar control alone cannot identify who is in danger. What is needed next, the researchers conclude, are prospective, multicenter, longitudinal studies that capture the full spectrum of clinical, laboratory, and behavioral variables, so that risk-prediction models can be built and validated for Saudi Arabia and the wider Middle East and North Africa region, where the diabetes epidemic is still gathering force.

Subject of Research: Associations of glycemic control, age, and sex with diabetic foot risk and active foot ulceration in patients with diabetes in Saudi Arabia

Article Title: Associations of Glycemic Control, Age, and Sex with Diabetic Foot Risk and Active Foot Ulceration among Patients with Diabetes in Saudi Arabia: A Cross-Sectional Study

Article References: Alenazi, F. Z., Alslamah, T., Alharbi, B., Alotaibi, W. I., Fawaz, M., Algeffari, M., Alsalamah, Y. S., & Raposo, A. (2026). Associations of Glycemic Control, Age, and Sex with Diabetic Foot Risk and Active Foot Ulceration among Patients with Diabetes in Saudi Arabia: A Cross-Sectional Study. Diabetes Therapy. https://doi.org/10.1007/s13300-026-01923-y

Image Credits: AI Generated

DOI: 10.1007/s13300-026-01923-y

Keywords: diabetic foot, foot ulceration, HbA1c, glycemic control, IWGDF risk stratification, type 2 diabetes, peripheral neuropathy, peripheral arterial disease, Saudi Arabia, cross-sectional study, logistic regression, diabetes complications

Diabetes-related foot ulcers, often abbreviated as DFUs, are among the most feared complications of diabetes mellitus. They arise when prolonged high blood sugar damages nerves and blood vessels in the lower limbs, leaving the foot insensitive, poorly perfused, and vulnerable to wounds that refuse to heal. Globally, they affect a substantial share of the diabetic population, and their consequences are grim: infection, hospitalisation, amputation, and elevated mortality. Yet in recent years, clinicians have noticed something else. Patients with DFUs appear to perform worse on cognitive tests than their peers with diabetes but no ulcers, and the review’s authors cite emerging evidence of a potential association between these lower-extremity complications and declining brain function.

The connection is biologically plausible. Diabetes is already a recognised risk factor for vascular dementia and Alzheimer-type pathology, operating through chronic hyperglycaemia, inflammation, endothelial dysfunction, and recurrent hypoglycaemic episodes. A foot ulcer may act as both a marker and an amplifier of this systemic damage. It signals long-standing, poorly controlled disease, and it can itself trigger inflammatory cascades, pain, sleep disruption, depression, and social isolation, all of which have been linked to cognitive decline. Understanding which factors drive cognitive impairment in this population could therefore reshape how clinicians screen, monitor, and support patients whose wounds and minds deteriorate together.

To find those factors, the team followed the PRISMA guidelines, the international standard for conducting and reporting systematic reviews. They searched five major databases, MEDLINE via EBSCOhost, PubMed, CINAHL, EMBASE, and PsycINFO, from their inception to June 2025, looking for observational studies that assessed cognition in people with DFUs. Two reviewers independently screened the results for eligibility, a safeguard against individual bias. Methodological quality was appraised with the Mixed Methods Appraisal Tool, a validated instrument for judging the rigour of diverse study designs, and data were extracted using a customised template by two independent reviewers. The search initially identified 460 records, of which 317 were screened, and just four studies survived the process.

That number is striking. Four studies, all conducted at single centres, represent the entire quantitative evidence base on factors associated with cognitive impairment in a complication that affects tens of millions of people worldwide. Three of the four were case-control studies, which compare people with and without a condition retrospectively, and the remaining two were cross-sectional studies, which capture a snapshot of a population at a single point in time. No cohort studies, which follow patients forward in time and can establish temporal sequences, were available. Crucially, none of the included studies was designed to identify risk factors for cognitive impairment, meaning the review could describe associations but not causation.

Despite these constraints, the review identified fourteen factors that remained statistically significant in multivariate analyses, the statistical technique that adjusts for the influence of other variables, in at least one of the included studies. The factors clustered into five domains. Sociodemographic characteristics included older age, male sex, and lower educational attainment, all well-established correlates of cognitive performance in the general population. Lifestyle factors encompassed smoking, body mass index, and depression, the latter being both a common companion of chronic wounds and a recognised contributor to cognitive difficulties. Diabetes-specific factors included glycated haemoglobin, or HbA1c, the standard measure of long-term blood sugar control, and the duration of diabetes itself, both proxies for cumulative metabolic injury.

The remaining two domains point directly to the burden of advanced disease. Comorbidities associated with cognitive impairment included cardiovascular disease, cerebrovascular disease, nephropathy, and retinopathy, conditions that share vascular pathology with both diabetes and dementia. Foot-related complications, meanwhile, included peripheral neuropathy, the nerve damage that often precedes ulceration, and amputation, the most drastic outcome of a non-healing wound. The pattern is coherent: the more organ systems damaged by diabetes, and the more severe the lower-limb involvement, the more likely a patient is to show measurable cognitive deficits. This supports the hypothesis that DFUs and cognitive impairment are parallel manifestations of systemic vascular and metabolic deterioration rather than coincidental neighbours.

The methodological details of the underlying studies matter for interpreting these findings. Cognitive assessment in the included research relied on standard screening instruments such as the Mini-Mental State Examination and the Montreal Cognitive Assessment, alongside tests like the Trail Making Test, which probes executive function and processing speed. Such tools are sensitive to education and language, which complicates comparisons across populations. The authors judged the studies with the Mixed Methods Appraisal Tool but found the evidence too heterogeneous, in design, measures, and populations, to pool statistically. No meta-analysis was possible, and the single-centre designs limit generalisability. Bivariate associations that failed to hold up under multivariate adjustment were excluded, which strengthens confidence in the fourteen surviving factors but also underscores how much depends on small samples.

The clinical implications are nonetheless significant. If cognitive impairment is common among DFU patients, it has direct consequences for wound care. Self-management of a foot ulcer demands vigilance: daily inspection of the feet, dressing changes, offloading pressure, glycaemic control, and prompt reporting of deterioration. A patient with impaired memory, attention, or executive function may struggle with every one of these tasks, creating a vicious cycle in which cognitive decline worsens the ulcer and the ulcer’s systemic effects worsen cognition. The review’s findings suggest that clinicians should consider cognitive screening when assessing DFU patients, particularly those who are older, less educated, depressed, smokers, or carrying multiple diabetic complications, and that caregivers may need to be involved in treatment plans.

The authors are careful about what their review cannot claim. Because no study was designed to identify risk factors, the temporal relationship between ulcer onset and cognitive decline remains unresolved: poor cognition may contribute to ulcer development through neglected self-care, or the ulcer’s inflammatory and psychological burden may accelerate cognitive deterioration, or both. The review concludes that these associated factors, spanning sociodemographic, lifestyle, diabetes-related, comorbid, and foot-related domains, must be explicitly considered in future research to establish a robust relationship between cognition and DFUs. More rigorous cohort studies, the authors argue, are warranted to identify true risk factors for cognitive impairment in this population. Until such studies exist, the review stands as both a synthesis of what is known and a pointed indictment of how little has been studied at the intersection of a wound and a mind.

Subject of Research: Cognitive impairment and its associated factors in people with diabetes-related foot ulcers

Article Title: Factors associated with cognitive impairment in people with diabetes-related foot ulcers: a systematic review

Article References: Karunathilaka, N., Lokeesan, V., & Rathnayake, S. (2026). Factors associated with cognitive impairment in people with diabetes-related foot ulcers: a systematic review. BMC Endocrine Disorders. https://doi.org/10.1186/s12902-026-02561-y

Image Credits: AI Generated

DOI: 10.1186/s12902-026-02561-y

Keywords: diabetes-related foot ulcers, cognitive impairment, systematic review, diabetes complications, peripheral neuropathy, HbA1c, depression, vascular disease, amputation, PRISMA, MMSE, cohort studies

The study drew on the PHDA Diabetes Complications Data Set maintained by the National Population Health Science Data Center in China. The investigators, Bin Yang of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, and Penglu Yang of the same institution’s First Clinical School, assembled records from patients treated between January 1, 2018, and December 31, 2022. Crucially, they used a predefined 1:1 matching structure: exactly 1,500 patients with diabetic retinopathy and 1,500 without. This balanced design gives the comparison considerable statistical power, because the two groups contribute equally to every estimate and the analysis is not skewed by an overabundance of one type of patient.

The physiological logic behind the findings rests on the shared vulnerability of small blood vessels to chronic hyperglycemia. Diabetic retinopathy develops when persistently elevated blood glucose damages the delicate capillaries that nourish the retina, causing them to leak, become blocked, and eventually grow abnormally. The kidneys contain similarly fine capillary networks in their filtering units, the glomeruli, and the nerves and arteries of the lower limbs are also exposed to the same metabolic assault. Because the retina is the only place in the body where capillaries can be directly visualized noninvasively, ophthalmologists have long speculated that the eye might serve as a window onto the systemic state of the vasculature. The new data lend quantitative weight to that idea.

The numbers are striking. Diabetic nephropathy was present in 60.07 percent of patients with retinopathy but only 24.93 percent of those without, a nearly two-and-a-half-fold difference in raw prevalence. Chronic kidney disease, defined by sustained impairment of kidney filtration function, affected 10.60 percent of the retinopathy group compared with just 1.60 percent of the comparison group, roughly a six-fold gap. Lower extremity artery disease, a manifestation of atherosclerosis in the vessels supplying the legs, was found in 23.73 percent of retinopathy patients versus 7.93 percent of the others. All three differences were highly statistically significant, with p values below 0.001, meaning the probability that they arose by chance alone is vanishingly small.

Beyond categorical diagnoses, the study revealed measurable differences in basic clinical chemistry. Patients with retinopathy had higher glycated hemoglobin, reflecting poorer long-term glucose control, as well as elevated blood pressure, higher serum creatinine, and higher blood urea levels. Most telling was the estimated glomerular filtration rate, or eGFR, a standard index of kidney function calculated from age, sex, and serum creatinine. The retinopathy group averaged 78.95 milliliters per minute per 1.73 square meters of body surface area, compared with 93.05 in the non-retinopathy group. That fifteen-point difference indicates substantially reduced kidney filtration capacity and was statistically significant at the p < 0.001 level.

To move from raw prevalence to adjusted risk, the researchers employed multivariable logistic regression, a statistical technique that estimates the association between an exposure and an outcome while accounting for other variables that could confound the relationship. Here, the models adjusted for age, sex, fasting blood glucose, and HbA1c, the two most important glycemic measures. After adjustment, diabetic retinopathy remained independently associated with lower extremity artery disease with an odds ratio of 3.914, meaning retinopathy patients had nearly four times the odds of leg artery disease. The odds ratio for chronic kidney disease was 2.131, and for diabetic nephropathy it was 1.952. In each case the 95 percent confidence intervals, which ranged from roughly 1.26 to 5.09 across the three outcomes, excluded the null value of 1, indicating statistically robust associations.

One result stands out as counterintuitive: the study found an inverse association between diabetic retinopathy and coronary heart disease, with an odds ratio of 0.507. In other words, patients with retinopathy were about half as likely to have documented coronary heart disease as those without. This is surprising because both conditions are linked to diabetic vascular injury, and much prior literature has posited that retinopathy marks generalized atherosclerotic risk. The authors of the study themselves urge caution in interpreting this finding, noting that the cross-sectional design, the predefined sampling structure of the dataset, and the absence of certain important confounder variables all limit the strength of any causal or directional inference. The inverse coronary signal may reflect selection effects, differences in diagnostic workup between groups, or genuine pathophysiological divergence between microvascular and macrovascular disease, and it will require confirmation in longitudinal cohorts.

The methodological caveats deserve emphasis for readers weighing the clinical implications. A cross-sectional study captures a single moment in time, so it can establish that retinopathy and kidney or leg artery disease co-occur more often than expected, but it cannot prove that one causes the other or even establish the temporal sequence. It is biologically plausible that shared exposure to hyperglycemia, hypertension, and dyslipidemia drives all three conditions in parallel rather than retinopathy somehow triggering renal or peripheral arterial damage. Furthermore, the 1:1 sampling design, while statistically efficient, means the prevalence figures within the dataset do not represent the true prevalence in the general diabetic population, since equal numbers of retinopathy and non-retinopathy patients were deliberately selected. The authors also acknowledge that key confounders such as diabetes duration, smoking status, and medication use were unavailable in the dataset.

Despite these limitations, the study carries a practical message that clinicians and patients can act on today. Diabetic retinopathy is typically diagnosed during routine dilated eye examinations, which many patients with type 2 diabetes already undergo annually. If the presence of retinopathy meaningfully raises the probability of undetected nephropathy or lower extremity artery disease, then an eye clinic finding could serve as an efficient triage signal, prompting intensified screening of kidney function through urine protein measurements and eGFR monitoring, and of leg circulation through ankle-brachial index testing. Early detection of diabetic nephropathy allows interventions such as renin-angiotensin system blockers and newer agents like SGLT2 inhibitors to slow progression, while identifying peripheral artery disease early can prevent the catastrophic outcomes of foot ulcers and amputations.

The broader significance of the work lies in its contribution to a growing body of evidence that diabetic complications should be understood as a systemic syndrome rather than a collection of organ-specific diseases. With more than 140 million people living with diabetes in China and hundreds of millions worldwide, tools that help stratify risk cheaply and early have enormous public health value. The retinal examination, already a cornerstone of diabetes care, may deserve recognition as one of the most informative single data points in the entire clinical assessment. Future longitudinal studies, ideally with repeated retinal imaging and serial kidney and vascular measurements, will be needed to confirm whether the eye truly functions as a predictive sentinel for the rest of the diabetic body, and whether the unexpected inverse coronary finding holds up under scrutiny.

Subject of Research: Associations between diabetic retinopathy and systemic complications in type 2 diabetes

Article Title: Associations between diabetic retinopathy and systemic complications in patients with type 2 diabetes mellitus: a retrospective cross-sectional analysis of the PHDA diabetes complications data set in China

Article References: Yang, B., & Yang, P. (2026). Associations between diabetic retinopathy and systemic complications in patients with type 2 diabetes mellitus: a retrospective cross-sectional analysis of the PHDA diabetes complications data set in China. BMC Endocrine Disorders. https://doi.org/10.1186/s12902-026-02644-w

Image Credits: AI Generated

DOI: 10.1186/s12902-026-02644-w

Keywords: diabetic retinopathy, type 2 diabetes, diabetic nephropathy, chronic kidney disease, lower extremity artery disease, coronary heart disease, eGFR, HbA1c, cross-sectional study, diabetes complications, microvascular disease, China

Type 1 diabetes is an autoimmune condition in which the pancreas produces little or no insulin, requiring people to manage their glucose through external insulin for life. More than 121,000 Australians live with the condition, and roughly 3000 new cases are diagnosed each year. Over decades, persistently elevated glucose damages small blood vessels, driving complications such as retinopathy, neuropathy, and kidney disease. Recent Australian data estimate average annual direct healthcare costs of AUD 7084 per person with type 1 diabetes, more than two and a half times the AUD 2789 spent on people without diabetes, and the 2022 Australian National Diabetes Audit identified peripheral neuropathy and retinopathy as the most frequently reported complications, with rates climbing as the duration of disease lengthens.

Automated insulin delivery systems represent the newest generation of diabetes technology. These hybrid closed-loop devices link a continuous glucose monitor to an insulin pump via a control algorithm that adjusts insulin dosing every few minutes, mimicking some of the feedback function of a healthy pancreas. A 2024 consensus statement convened and endorsed by Diabetes Australia and numerous other societies declared automated insulin delivery the standard of care and recommended that all Australians with type 1 diabetes should have access to it. Yet fewer than 20 percent of people with the condition in Australia currently use such systems, largely because of cost and the limited funding arrangements available to adults outside top-tier private health insurance.

The new analysis focused on the MiniMed 780G advanced hybrid closed-loop system and compared it with the combination of multiple daily injections and continuous glucose monitoring. Clinical inputs came from the ADAPT randomized controlled trial, a European study in adults with type 1 diabetes and baseline HbA1c of at least 8.0 percent. In that trial, participants using the MiniMed 780G achieved a mean reduction in HbA1c of 1.54 percentage points from a baseline of 9.04 percent, while those on injections plus glucose monitoring achieved only a 0.20 percentage point reduction. The researchers assumed that intermittently scanned and real-time continuous glucose monitors had equivalent HbA1c efficacy, an assumption supported by published meta-analyses, though the modeling restricted treatment effects to HbA1c differences alone.

The simulation used the IQVIA Core Diabetes Model, an established platform for projecting long-term outcomes in diabetes. The model consists of multiple interdependent Markov sub-models covering both acute events and chronic complications, run through patient-level Monte Carlo simulations with tracker variables allowing the sub-models to interact. Physiological parameters such as HbA1c drive individual event risks and progress naturally over time based on long-term epidemiological studies. The simulated cohort reflected Australian registry data, with a mean baseline age of 43.3 years and a mean diabetes duration of 20.3 years. The base case analysis took a public healthcare payer perspective, captured only direct costs, ran over a 50-year horizon, and applied the 5 percent annual discount rate that Australian health economic guidance requires for future costs and outcomes.

The base case results showed that long-term use of the MiniMed 780G was projected to yield 13.32 quality-adjusted life years compared with 11.81 for injections plus monitoring, a difference of 1.51 quality-adjusted life years. Lifetime direct costs were higher with the technology, at AUD 367,341 versus AUD 317,819, driven mainly by device acquisition and consumable expenses. However, complication costs ran in the opposite direction, falling for users of the automated system because fewer people progressed to diabetes-related damage. The resulting incremental cost-effectiveness ratio was AUD 32,840 per quality-adjusted life year gained, well below the AUD 50,000 per quality-adjusted life year threshold that more than 60 percent of Australian cost-utility analyses published between 1992 and 2022 have assumed, even though Australia has no official willingness-to-pay threshold.

The projected clinical benefits extended across nearly every complication category. Simulated users of the automated system spent 1.15 years longer free of any diabetes-related complication, a 128 percent increase, with the largest gains seen in microvascular outcomes: 9.67 additional years free of macular edema, 8.20 years free of proliferative retinopathy, 7.58 years free of microalbuminuria, 6.25 years free of neuropathy, and 5.78 years free of severe vision loss. These delays translated into meaningful savings, including AUD 18,882 less in ulcer, amputation, and neuropathy costs, AUD 15,323 less in eye complication costs, AUD 8150 less in cardiovascular costs, and AUD 5428 less in renal costs over a lifetime.

Sensitivity analyses underscored how strongly the result depends on the long view. Over shorter horizons of 10 to 15 years, the incremental cost-effectiveness ratio exceeded AUD 50,000 per quality-adjusted life year, likely because many diabetes complications take decades to develop, so the savings and quality-of-life gains from preventing them only accumulate late. The analysis was also sensitive to the inclusion of hypoglycemic event rates and to the quality-of-life benefit associated with reduced fear of hypoglycemia, which the ADAPT trial had quantified. When that fear-related utility benefit of 0.0544 annually for the automated system was removed entirely, the ratio rose to AUD 55,976 per quality-adjusted life year, pushing the result above the conventional threshold. Conversely, adding severe hypoglycemic events and diabetic ketoacidosis lowered the ratio to AUD 19,234 per quality-adjusted life year, since preventing these acute crises avoids expensive emergency care.

A secondary analysis from the societal perspective, which incorporated indirect costs such as lost productivity from absenteeism using the human capital approach, made the case for the technology even stronger. Without hypoglycemia and ketoacidosis included, the societal-perspective ratio was AUD 23,378 per quality-adjusted life year; with those events included, it fell to just AUD 9446. Previous research has shown that even non-severe hypoglycemic episodes impair workplace productivity, and Australian users of advanced glucose technologies report in community surveys that the devices ease limitations on eating, sleeping, exercising, and socializing while improving emotional well-being. Severe hypoglycemic events causing loss of consciousness can also trigger temporary suspension of a person’s driving license in Australia, a consequence that compounds the personal burden beyond anything a cost model can capture.

The authors acknowledge limitations, including the reliance on a European trial, the assumption of equivalent HbA1c efficacy between glucose monitor types, the exclusion of complications not captured in the model such as oral, hearing, and autonomic effects, and the restriction to people with baseline HbA1c above 8.0 percent. Even so, real-world Australian studies, including a multicenter Queensland evaluation showing that starting automated insulin delivery improved time in range and HbA1c, particularly for those with higher baseline levels, support the generalizability of the findings. With the Australian Government’s Insulin Pump Program currently means-tested for people under 21, and Diabetes Australia and a 2024 parliamentary committee report both calling for stepwise expansion of access, the analysis concludes that broader funding of automated insulin delivery for adults with above-target HbA1c would improve long-term outcomes and likely represent an efficient use of healthcare resources.

Subject of Research: Long-term cost-effectiveness of advanced hybrid closed-loop automated insulin delivery versus multiple daily injections with continuous glucose monitoring in Australian adults with type 1 diabetes

Article Title: Long-Term Cost-Effectiveness of an Advanced Hybrid Closed-Loop Automated Insulin Delivery System Versus Multiple Daily Insulin Injections Plus Continuous Glucose Monitoring in Adults with Type 1 Diabetes in Australia

Article References: Glastras, S., Read, M., Ozdemir Saltik, A. Z., Huynh, M., Challis, G., Hill, M., Field, M., Pollock, R., & de Portu, S. (2026). Long-Term Cost-Effectiveness of an Advanced Hybrid Closed-Loop Automated Insulin Delivery System Versus Multiple Daily Insulin Injections Plus Continuous Glucose Monitoring in Adults with Type 1 Diabetes in Australia. Advances in Therapy. https://doi.org/10.1007/s12325-026-03752-8

Image Credits: AI Generated

DOI: 10.1007/s12325-026-03752-8

Keywords: type 1 diabetes, automated insulin delivery, hybrid closed-loop, MiniMed 780G, cost-effectiveness, continuous glucose monitoring, health economics, Australia, HbA1c, quality-adjusted life years, diabetes complications, IQVIA Core Diabetes Model

The research, conducted at Loghman Hakim Hospital, a tertiary referral centre affiliated with Shahid Beheshti University of Medical Sciences in Tehran, was published in Health Science Reports. It followed the Standards for Reporting of Diagnostic Accuracy Studies (STARD 2015) and enrolled 127 adults with diabetes and clinically suspected foot infection, each of whom underwent both ultrasound and magnetic resonance imaging (MRI) as part of routine care. The stakes are considerable: diabetic foot ulcers affect an estimated 19 to 34 percent of diabetic patients over their lifetime, and people with these ulcers face roughly an eight-fold higher risk of lower extremity amputation compared with non-diabetics. Osteomyelitis is present in 10 to 15 percent of moderate infections and in about half of severe ones, making early and reliable detection a decisive factor in whether a limb is saved.

The technical logic of the study is straightforward but demanding. MRI, performed on a 1.5 Tesla scanner with a full protocol of T1-weighted, T2-weighted, proton-density fat-saturated, diffusion-weighted and contrast-enhanced sequences, served as the reference standard for osteomyelitis and deep abscess, in line with Infectious Diseases Society of America and International Working Group on the Diabetic Foot guidance. On MRI, osteomyelitis was defined by bone marrow oedema appearing dark on T1-weighted images and bright on fluid-sensitive sequences, restricted diffusion, and cortical destruction adjacent to the ulcer. Ultrasound criteria included periosteal elevation or thickening, subperiosteal abscess, and cortical erosion with fluid in direct contact with bone. Ultrasound was always performed first, and each modality was interpreted by a different experienced radiologist blinded to the other’s findings, preserving the independence of the two readings.

The headline result is stark. MRI identified osteomyelitis in 106 of the 127 participants, or 83.5 percent, yet ultrasound detected only 17.9 percent of those MRI-positive cases, with a confidence interval of 11.2 to 26.6 percent. In other words, more than four out of five bone infections visible on MRI were invisible to ultrasound. Specificity was high, at 95.2 percent, meaning that when ultrasound did suggest bone infection it was usually right, with a positive predictive value of 95 percent. But the negative predictive value collapsed to just 18.7 percent overall, and in severe ulcers it fell to an almost meaningless 1.1 percent. A clean ultrasound scan in a severely affected foot, the data show, provides almost no reassurance whatsoever that the underlying bone is healthy.

The severity subgroup analysis sharpens the clinical message. Among the 19 patients with moderate ulcers, classified as Wagner grades 1 and 2, MRI found no osteomyelitis at all, and ultrasound correctly agreed in every case. But among the 108 patients with severe ulcers, grades 3 through 5, MRI confirmed bone infection in 98.1 percent, and ultrasound missed the overwhelming majority of them. Overall accuracy for osteomyelitis detection in severe ulcers was a mere 18.5 percent. The authors argue that these figures quantify the danger of false reassurance: a clinician who relies on a negative ultrasound to exclude bone infection in a severely ulcerated foot risks delayed diagnosis, inadequate surgical debridement, and ultimately amputation.

The picture changes dramatically when the target shifts from bone to soft tissue. For abscess detection, ultrasound achieved perfect sensitivity of 100 percent in both moderate and severe ulcers, meaning a negative scan reliably rules out a drainable collection. Specificity, however, was poor, at 30.4 percent overall and as low as 22.6 percent in severe ulcers, producing a flood of false positives and a positive predictive value of only 46.6 percent overall. The practical implication is that ultrasound works well as a rule-out tool for abscess but should not be used alone to confirm one before committing a patient to surgical drainage. For cellulitis, ultrasound identified the condition in 126 of 127 cases, agreeing with both the clinical diagnosis and MRI in 99.2 percent of participants, although the authors caution that because every participant had clinically diagnosed cellulitis, these concordance figures describe detection rather than true discriminative accuracy.

Why does ultrasound fail so badly at bone? The physics and anatomy offer an explanation. Ultrasound sound waves reflect strongly at soft tissue interfaces and cannot penetrate cortical bone, so the modality can only infer infection from secondary signs at the bone surface, such as periosteal reaction or cortical irregularity. Early marrow infection, which MRI captures through signal changes deep within the bone, produces no visible surface change for the ultrasound probe to detect. The study’s authors also note operator dependence and probe quality as limiting factors, and they contrast their findings with earlier literature: a 1999 study by Enderle and colleagues reported ultrasound sensitivity of 78.6 percent for chronic osteomyelitis, and paediatric studies have shown better performance in acute haematogenous osteomyelitis, where accessible affected areas and different disease biology may favour surface detection.

The study is candid about its limitations. Bone biopsy with histopathology and microbiology remains the definitive gold standard for osteomyelitis, but subjecting every participant to an invasive bone procedure was not ethically justifiable, so MRI served as the reference standard, and MRI itself is imperfect. Charcot neuroarthropathy, with its reactive marrow oedema, can mimic infection on MRI and may have inflated apparent disease in some cases. Each modality was read by a single radiologist, so interobserver reproducibility could not be assessed. Requiring contrast-enhanced MRI excluded patients with advanced kidney disease, a group in whom chronic renal impairment is common and in whom ultrasound may in practice be the only feasible option. Patients with indeterminate MRI bone findings, described as osteitis without confluent marrow replacement, were excluded rather than adjudicated, a recognised source of optimistic bias in diagnostic accuracy studies. The predominance of severe ulcers in the cohort also introduces spectrum bias toward the very patients in whom ultrasound performed worst.

Microbiological data from the cohort add epidemiological texture. Staphylococcus aureus was the most prevalent pathogen at 25.2 percent, followed by Escherichia coli at 18.1 percent, Staphylococcus epidermidis at 14.2 percent, Enterococcus species at 13.4 percent, Pseudomonas aeruginosa at 9.4 percent, Klebsiella pneumoniae at 8.7 percent and Acinetobacter baumannii at 7.9 percent. Most ulcers were severe: 37 percent were Wagner grade 3, 31.5 percent grade 4 and 16.5 percent grade 5, with the forefoot the most commonly involved region at 48 percent and the plantar surface the most frequent site of surface involvement at 40.9 percent. No imaging-related complications were recorded for either modality.

The authors propose a tiered diagnostic protocol as the study’s practical takeaway. Ultrasound, cheap, portable and radiation-free, earns its place as a first-line triage tool for soft-tissue complications, rapidly identifying abscesses that need drainage and confirming cellulitis at the bedside. But its diagnostic ceiling at the bone surface is now quantified, and it is low. Where osteomyelitis is clinically suspected and ultrasound is negative, MRI remains a mandatory next step, consistent with current IWGDF guidance that recommends plain radiography first, followed by MRI when suspicion persists. In a condition where every day of delay narrows the window between debridement and amputation, the message for clinicians is unambiguous: trust ultrasound to map the soft tissues, but never let a negative scan silence suspicion of infection in the bone.

Subject of Research: Diagnostic accuracy of ultrasonography versus MRI for detecting osteomyelitis and soft-tissue infections in diabetic foot ulcers

Article Title: Ultrasonography Cannot Exclude Osteomyelitis in Diabetic Foot Ulcers: A Cross‐Sectional Diagnostic Accuracy Study Against Magnetic Resonance Imaging

Article References: Haghighi‐Morad, M., Vahedi, H., Fard, A. Y., Pordanjani, B. M., & Mahmoudi, S. T. S. (2026). Ultrasonography Cannot Exclude Osteomyelitis in Diabetic Foot Ulcers: A Cross‐Sectional Diagnostic Accuracy Study Against Magnetic Resonance Imaging. Endocrinology, Diabetes &amp; Metabolism, 9(5), Article e70320. https://doi.org/10.1002/edm2.70320

Image Credits: AI Generated

DOI: 10.1002/edm2.70320

Keywords: diabetic foot ulcer, osteomyelitis, ultrasonography, MRI, diagnostic accuracy, amputation, abscess, cellulitis, diabetes complications, medical imaging, Wagner classification, IWGDF guidelines