Background: Preventing diabetic foot ulcer (DFU) recurrence after healing is a major challenge in the remission phase. In this context, remission is not synonymous with healed; it refers to a confirmed post-healing state in which the ulcer is closed, but the individual remains at high risk of recurrence and requires ongoing preventive care. Armstrong, Boulton, and Bus suggested that DFU recurrence is about 40% at 1 year, 60% at 3 years, and 65% at 5 years and argued that limb preservation should follow a long-term “survivorship” model similar to cancer care. However, these estimates combine heterogeneous follow-up intervals and definitions, and there is limited work focusing specifically on the first 12 months after confirmed remission. Methods: This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement. Searches of PubMed/MEDLINE, Scopus, ScienceDirect, and the Cochrane Library were performed on 16 December 2025. Eligible studies enrolled adults with diabetes in confirmed remission after a healed DFU and reported an exact 12-month recurrence outcome (n/N or Kaplan–Meier estimate). Risk of bias was assessed using the Critical Appraisal Skills Program and Joanna Briggs Institute tools, and certainty of evidence was evaluated using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. Twelve-month recurrence proportions were pooled using a random-effects model on the logit scale, and results were interpreted cautiously due to the limited number of eligible cohorts. Results: Across three cohorts with confirmed remission at baseline (total n = 469) and an exact 12-month outcome, the pooled 12-month recurrence proportion was 29.3% (random-effects; 95% CI 24.9–34.1), i.e., about one in three. Although this estimate is lower than the widely cited ~40% 1-year recurrence benchmark, it reflects a strictly defined remission population and a fixed 12-month timepoint, rather than mixed follow-up intervals or less precise definitions. Conclusions: Approximately one in three adults in remission after a healed DFU develop a recurrent ulcer within 12 months. Because this estimate is based on a small number of cohorts and on strictly confirmed remission, it should be interpreted cautiously and should not be generalized to all individuals with a healed DFU. These findings support prevention-focused surveillance and ongoing risk management during remission. Larger, preregistered multicenter cohorts with standardized remission and recurrence definitions are needed to refine short-term recurrence estimates and inform survivorship-style models of care.

Reactive oxygen species (ROS) are an essential component for the maintenance of cellular function. However, if produced in excess, ROS can drive cellular dysfunction and compromise cell viability. Indeed, uncontrolled ROS production plays a pivotal role in the pathogenesis of type 2 diabetes (T2D), contributing to the loss of β-cell function and the impairment in insulin signalling, as well as driving the development of diabetic complications, which can severely compromise quality of life. T2D is characterised by persistent hyperglycaemia, which is a leading contributor to ROS overproduction in this disease state. This enhanced, almost uncontrolled, increase in glucose metabolism upregulates several ROS-producing pathways, including the hexosamine pathway, protein kinase C, NADPH oxidase and the mitochondrial electron transport chain. There is accumulating evidence to suggest that in a bid to preserve redox homeostasis, ROS acts to suppress glucose metabolism by inactivating several enzymes involved in the regulation of glycolytic flux, including glucokinase, glyceraldehyde 3-phosphate dehydrogenase, phosphofructokinase-1 and pyruvate kinase. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a multi-faceted transcription factor, with a central role in ROS signalling and redox homeostasis. Whilst NF-κB mediates the transcriptional regulation of many pro-oxidants, NF-κB activity is also regulated by the oxidative status, with ROS having both inhibitory and stimulatory roles in these signalling pathways. Interestingly, NF-κB is also involved in controlling the delicate balance between glycolytic flux and mitochondrial respiration. This review will summarise the interplay linking hyperglycaemia with ROS formation, emphasising the role of glucose metabolism in the process, and the crosstalk of these pathways with NF-κB.

Type 2 diabetes mellitus (T2DM) and obesity affect hundreds of millions of adults worldwide and represent leading drivers of cardiovascular disease, chronic kidney disease, and escalating healthcare expenditures. Incretin-based therapies have fundamentally reshaped cardiometabolic disease management, with dual- and triple-receptor agonists extending the benefits of traditional glucagon-like peptide-1 (GLP-1) receptor agonism. By synthesizing clinical, mechanistic, and real-world data, this review examines the evolving therapeutic landscape of GLP-1-based multi-agonists. Dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonists demonstrate superior metabolic efficacy compared with GLP-1 receptor agonists alone, achieving greater reductions in body weight and glycemic indices across diverse patient populations. Emerging triple agonists targeting GLP-1, GIP, and glucagon receptors further enhance metabolic outcomes, with weight loss approaching that observed following bariatric surgery in late-phase clinical trials. Mechanistically, multi-receptor co- agonism produces synergistic effects through complementary pathways, including appetite suppression, glucose-dependent insulin secretion, improved adipose tissue metabolism, increased energy expenditure, enhanced hepatic lipid oxidation, and reductions in hepatic steatosis. Beyond glycemic and weight endpoints, GLP-1-based therapies confer clinically meaningful cardiovascular and renal protection. Trials consistently demonstrate reductions in major adverse cardiovascular events across populations with and without T2DM, while kidney-specific trials show significant slowing of disease progression. However, gastrointestinal adverse events remain common and contribute to substantial treatment discontinuation, particularly in real-world settings. Despite their transformative efficacy, the population-level impact of these therapies is constrained by significant implementation barriers, including high drug costs, limited insurance coverage, restrictive utilization management policies, and pronounced racial and socioeconomic disparities in access. Emerging innovations including oral formulations, longer-acting injectables, and novel peptide combinations look to improve tolerability, adherence, and scalability, while therapeutic indications continue to expand to conditions such as metabolic dysfunction-associated steatohepatitis, chronic kidney disease, obstructive sleep apnea, and neurodegenerative disease. This review provides a comprehensive framework for understanding the clinical potential, mechanistic basis, and real-world challenges of GLP-1-based multi-agonists and outlines key priorities for optimizing implementation and maximizing their impact on global cardiometabolic health.

Background/Objectives: An increasing proportion of patients with Type 2 diabetes mellitus (T2DM) are classified as high risk, often presenting with multimorbidity, functional vulnerability, and complex treatments. This study compared the sociodemographic, functional, clinical, therapeutic, and healthcare utilization profiles of high-risk chronic patients with and without T2DM in primary health care. Methods: A cross-sectional study included adults classified as high-risk chronic patients in primary health care electronic health records in the Madrid Region (30 April 2021). Sociodemographic, functional, clinical, lifestyle, pharmacological variables, and primary health care services utilization were analyzed. Multivariate logistic regression identified factors independently associated with T2DM. Results: Among 163,188 high-risk chronic patients, 41.5% had T2DM. Patients with T2DM were older, more often male, and had a comparable deprivation index values to non-diabetic patients. They showed higher functional dependency and greater need for informal caregiving. Clinically, patients with T2DM had a higher burden of chronic conditions and a predominance of cardiometabolic, hematological and renal comorbidities, whereas non-diabetic patients exhibited more neuropsychiatric, chronic infectious, oncological and respiratory profiles. Polypharmacy was more frequent in T2DM patients, who also showed lower medication adherence. In the explanatory model, older age (OR 1.02/year), cardiometabolic comorbidities (ORs ~1.2–1.6), highest quartile of morbidity complexity (OR 1.27), polypharmacy (OR 1.34), and concern about medications (OR 1.08) were associated with T2DM, while female sex (OR 0.660), depression (OR 0.888), COPD (0.704), neoplasms (0.688), and higher medication adherence (OR 0.53) were associated with not having T2DM. Conclusions: High-risk chronic patients with T2DM exhibit distinct sociodemographic, functional, and clinical profiles compared with those without T2DM, characterized by greater complexity, cardiometabolic burden, therapeutic intensity and use of healthcare services, supporting the need for tailored, integrated primary health care strategies.

Background: Diabetes is associated with an increased risk of oral health complications, yet adults with diabetes remain less likely to obtain dental care in the United States. Objective: To examine socioeconomic, demographic, and insurance-related determinants of dental spending among adults with and without diabetes using nationally representative 2023 Medical Expenditure Panel Survey (MEPS) data. Materials and Methods: A two-part model was estimated: (1) a logistic regression predicting the likelihood of any dental spending, and (2) a generalized linear model (GLM) with a Gamma distribution and log link for positive spending. Covariates included age, sex, race/ethnicity, education, income, region, and insurance coverage. Results: The MEPS dataset included 15,071 adults (diabetes n = 2104; no diabetes n = 12,967), Adults with diabetes were less likely to have any dental spending than adults without diabetes (38.6% vs. 43.8%). Mean expenditures among users were higher for adults with diabetes but diabetes was not a statistically significant predictor of conditional spending after adjustment. Insurance coverage and preventive care were strong positive predictors of dental spending. Conclusions: Insurance coverage and preventive dental care are major drivers of dental spending and utilization among U.S. adults. Disparities observed among adults with diabetes appear to be driven primarily by reduced access to dental care rather than differences in spending intensity once care is obtained.

Introduction: Recurrent hypoglycemia occurring prior to the initiation of insulin therapy is an uncommon finding at the onset of pediatric type 1 diabetes mellitus (T1D). Aim: The aim of this study was to describe an unusual presentation of T1D onset characterized by recurrent hypoglycemia in a pediatric patient and to provide an updated review of the literature on hypoglycemic episodes occurring before insulin initiation in children with new-onset T1D. Case report: We present the case of a child who exhibited recurrent fasting hypoglycemia and postprandial hyperglycemia at the onset of T1D. Clinical findings also included persistently elevated glucagon levels (66–93 pmol/L; normal values [n.v.] 3–60); markedly elevated glycated hemoglobin (98 mmol/moL); low C-peptide levels (0.05 nmol/L); and a slight positivity for antibodies to glutamic acid decarboxylase (38.3 KUI/L; n.v. < 10). Review of the literature: A narrative review of the literature was conducted using the PubMed (MEDLINE) database to identify studies reporting hypoglycemia at the onset of T1D in pediatric patients prior to insulin initiation. The search included combinations of the terms hypoglycemia, new-onset, type 1 diabetes, child, and adolescent, with an exclusion of insulin-treated cases. We also explore potential pathogenetic mechanisms underlying this unusual presentation, including alpha-cell acute damage or dysregulation and loss of intra-islet paracrine signaling. Conclusions: Among individuals with T1D onset, episodes of recurrent hypoglycemia before the initiation of insulin therapy have been reported in a few studies. The presented case expands the clinical spectrum of early T1D and suggests that early alpha-cell dysfunction may contribute to atypical glycemic patterns during disease onset.

Background/Objectives: Gestational diabetes mellitus (GDM) affects approximately 12.7% of pregnant women in South Korea. While breastfeeding provides critical health benefits for mothers with GDM and their infants, including improved insulin resistance and reduced Type 2 diabetes risk, no validated GDM-specific breastfeeding knowledge instrument exists. This study aimed to develop and validate a breastfeeding knowledge instrument for women with GDM. Methods: This methodological study employed systematic procedures for the development and validation of knowledge test. Initial item generation yielded 30 items across three domains: postpartum physical characteristics, breastfeeding barriers, and breastfeeding benefits. Content validity was evaluated by six clinical experts and ten experiential experts (women with GDM). An online survey was conducted in October 2022 with 220 women diagnosed with GDM who were either pregnant or within six months postpartum. Item analysis, exploratory factor analysis, and reliability testing were performed. Convergent validity was assessed by calculating the Pearson correlation coefficient with an established breastfeeding knowledge scale. Results: Following expert review and psychometric analysis, the final instrument comprised 14 items across three factors: postpartum physical characteristics (3 items), breastfeeding barriers (2 items), and breastfeeding benefits (9 items). The Kaiser–Meyer–Olkin measure was 0.884, Bartlett’s test was significant (χ2 = 838.835, p < 0.001), and factor loadings were satisfactory. The KR-20 reliability coefficient was 0.826, and criterion validity was confirmed. Conclusions: This first validated GDM-specific breastfeeding knowledge instrument enables the identification of knowledge gaps and the development of targeted educational interventions to improve maternal-child health outcomes.

Diabetes mellitus remains a major global health burden, and many patients do not achieve durable glycemic control despite modern pharmacotherapy. This narrative review synthesizes evidence on plant-derived strategies that may complement standard care, focusing on two clinically aligned domains: glucose-lowering medicinal plants and plant-based sugar substitutes that reduce dietary glycemic load. We summarize key mechanistic pathways, including inhibition of α-amylase/α-glucosidase, reduced intestinal glucose entry and absorption kinetics, glucose-dependent insulinotropic effects, improved insulin signaling, suppression of hepatic gluconeogenesis, and microbiota-linked effects. We critically appraise human evidence for selected botanicals (cinnamon, fenugreek, mulberry, gymnema, gynura, rosehip, and Jerusalem artichoke) and plant sweeteners (stevia and monk fruit). Overall, clinical effects are modest and heterogeneous; the most reproducible signals are observed for mulberry leaf in blunting postprandial glucose excursions, and for cinnamon, fenugreek, and gymnema, where meta-analyses suggest modest improvements in glycemic markers. Stevia and monk fruit are best supported as glycemically neutral sucrose substitutes, while inulin-type fructans show small-to-moderate benefits with sustained intake, limited by gastrointestinal tolerability at higher doses. Key gaps include a shortage of long-term randomized trials using standardized preparations and durable endpoints such as glycated hemoglobin. Plant-derived interventions are therefore best positioned as adjuncts within individualized, evidence-based glycemic management.

Diabetic ketoacidosis (DKA) remains a life-threatening complication of diabetes mellitus with suboptimal outcomes despite standard management. Emerging evidence suggests that thiamine (vitamin B1) deficiency may play an under-recognized role in DKA pathophysiology and clinical course. This narrative review synthesizes current evidence regarding thiamine deficiency in diabetes and DKA, examining molecular mechanisms, clinical implications, and the rationale for thiamine supplementation as adjunctive therapy. Thiamine deficiency is highly prevalent in diabetes, with plasma concentrations reduced by approximately 75% compared to healthy controls. In DKA specifically, 25–35% of patients present with thiamine deficiency, which often worsens during insulin therapy. The primary mechanism involves hyperglycemia-induced downregulation of renal thiamine transporters (THTR-1 and THTR-2), resulting in 16–24-fold increased renal clearance and massive urinary losses. Thiamine pyrophosphate serves as an essential cofactor for three critical enzymes in glucose metabolism: pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, and transketolase. Deficiency impairs these pathways, causing pyruvate accumulation with conversion to lactate (resulting in lactic acidosis), compromised TCA cycle function (reducing ATP production by 40–48%), and decreased NADPH generation (increasing oxidative stress). Clinical manifestations include persistent metabolic acidosis despite standard therapy, myocardial dysfunction with elevated cardiac biomarkers, neurological impairment, and prolonged recovery times. Cellular studies demonstrate that thiamine supplementation significantly improves mitochondrial oxygen consumption in DKA patients. The high prevalence of thiamine deficiency in DKA, compelling biochemical rationale, excellent safety profile, and preliminary mechanistic evidence support the urgent need for large-scale randomized controlled trials examining thiamine supplementation to definitively establish efficacy, optimal dosing, and patient selection criteria.

Background/Objectives: Inflammation may play a critical role in the pathogenesis of gestational diabetes mellitus (GDM). However, evidence linking early-pregnancy cytokines to subsequent GDM risk remains inconsistent, with most prior research focusing only on CRP, IL6, and TNFα. In this study, we expand on prior work by evaluating a broader range of immune markers and assessing sociodemographic factors as potential moderators. Methods: Data from a prospective U.S. pregnancy cohort (n = 308) were analyzed. Twenty cytokines were quantified in maternal first-trimester plasma using the MILLIPLEX High-Sensitivity Human Cytokine Magnetic Bead Panel. One-hour oral glucose (50 g) tolerance test (OGTT) values assessed at an average gestational age of 27.7 weeks (SD = 2.9) and GDM diagnosis were abstracted from medical records. Multivariable linear and logistic regression models were used to examine associations between cytokines and 1 h 50 g OGTT levels or GDM diagnosis, adjusting for key sociodemographic factors. Interactions terms were included to evaluate whether sociodemographic factors moderated cytokine–GDM relationships. Results: Sixteen women (5.1%) were diagnosed with GDM. Higher first-trimester high-sensitivity-IL6 levels were significantly associated with increased 1 h 50 g OGTT values (b = 3.76; 95% CI: 0.21, 7.32; p = 0.04) and greater odds of GDM (OR = 2.36; 95% CI: 1.17, 4.77; p = 0.02). These associations were more pronounced among Non-Hispanic White women compared to Non-Hispanic Black women (p for interaction = 0.03) and potentially those with normal weight or underweight during early pregnancy compared to overweight or obese women (p for interaction = 0.08). Conclusions: Elevated inflammatory markers, particularly high-sensitivity IL6, in early pregnancy are linked to impaired glucose metabolism and increased GDM risk later in pregnancy. These relationships appeared stronger in Non-Hispanic White women and women with normal weight or underweight during early pregnancy, underscoring the potential to develop serology-based early identification and prevention strategies.