Corneal confocal microscopy is a valuable technique for assessing neuropathy; however, whether it can distinguish painful from painless neuropathy remains uncertain and existing evidence is based on the results of smaller studies. This study assessed the association of corneal nerve parameters with abnormalities identified by electromyography (EMG) and neuropathic pain in a large population with and without (pre)diabetes. In this study we included cross-sectional data for 3425 participants from the Maastricht Study. Wide-field corneal confocal microscopy (WF-CCM) was performed using fully automated analysis of three corneal nerve parameters: corneal nerve branch density (CNBD), corneal nerve fibre density (CNFD) and corneal nerve fibre length (CNFL). An axonal degeneration composite score comprising compound muscle action potential amplitudes (peroneal and tibial) and the sensory nerve action potential amplitude of the sural nerve was created by categorising EMG amplitudes as normal or indicating minor (≤10th percentile), moderate (≤5th percentile) or severe (≤2.5th percentile) abnormalities. Neuropathic pain was determined as a modified Douleur Neuropathique en 4 Questions (DN4) interview score ≥3. The mean age of the participants was 59.2 years; 51.6

Background:Type 2 diabetes mellitus, a public health challenge, disproportionately impacts low- and middle-income countries (LMICs), accounting for 73% of global cases. Due to resource constraints, these nations have adopted task-shifting strategies using community health workers (CHWs). However, evidence on the effectiveness of training CHWs in diabetes management is limited and, at most, indirect due to the limited studies, variable training methods, and complex interventions that make it difficult to isolate training effects. Objective:A systematic review was conducted to answer the question: Does training CHWs in type 2 diabetes improve the efficacy of diabetes screening and management at the community level in LMICs? Methods:A total of 2 reviewers, supervised by 2 supervisors, conducted the review following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 guidelines. They searched databases, including PubMed, MEDLINE Ovid, Scopus, EBMR, and CINAHL, for studies published between January 2000 and April 2024, including randomized and nonrandomized controlled trials and observational studies assessing CHW training in diabetes management in LMICs. The primary outcome was the mean change in glycated hemoglobin (HbA1c) percentage levels. Data were narratively synthesized for training characteristics and study outcomes, and quality was assessed using the Risk of Bias 2 and ROBINS-I tools. Results:A total of 3387 studies were screened; 69 were eligible for full-text review, and 4 studies (3 randomized controlled trials [RCTs] and 1 observational stepped-wedge study, ~1000 patients) were included for narrative analysis. One of the 3 RCTs reported a statistically significant mean HbA1c reduction of -0.24% (P=.001), but HbA1c was not the primary outcome, and most patients were normoglycemic, prediabetic, or had diabetes. Other studies reported nonsignificant HbA1c reductions. The risk of bias among RCTs was moderate (some concerns, 1 trial at high risk), and the observational study had a serious risk of bias. No meta-analysis was performed due to the limited number of RCTs. Conclusions:Training CHWs in type 2 diabetes management has shown limited and, at most, indirect effects in improving glycemic control in LMIC settings. These findings are constrained by the small number of eligible studies, heterogeneity in training methodologies, and the multicomponent nature of the included interventions, with 1 trial demonstrating a statistically significant yet small reduction in HbA1c (-0.24%). Our review included only 4 eligible studies with a small representation of CHWs and multicomponent interventions. Considering the limited number of eligible studies, the heterogeneity in training methodologies and study designs, and the multicomponent nature of the included interventions, the existing evidence remains inadequate to definitively conclude whether CHW training significantly improves diabetes management across LMICs. Therefore, strengthening and standardizing CHW training might be an effective strategy to enhance diabetes care in underserved settings. Future larger trials and implementation research can help maximize the impact of CHWs against the growing diabetes burden.

Background: Inflammatory biomarkers, including immune cells appear associated with reduced heart rate variability (HRV), an indicator of cardiac autonomic nervous dysfunction. However, the influence of leukocytes on HRV and their relation across sex and glucose metabolism status remains unclear. Hence, we sought to investigate the cross-sectional association between leukocytes and HRV indices and their association across sex and glucose metabolism status in a general population. Methods: We retrieved cross-sectional data of 1888 participants of the Maastricht Study who completed the baseline survey between November 2010 and December 2017. Blood leukocyte numbers (including neutrophils, monocytes, basophils, eosinophils, and lymphocytes) were determined with an automated hematology analyzer. Qualitative changes within lymphocytes were assessed with flow cytometry. HRV indices were assessed using a 24-hour ECG. Time-domain and frequency-domain HRV index average scores were calculated. We regressed HRV average scores on standardized leukocytes and adjusted the models for several covariates. Results: In fully adjusted models, higher neutrophil (-0.07 [-0.11 to -0.03]; false discovery rate (FDR)-corrected P value, P-FDR=0.006) and monocyte (-0.05 [-0.09 to -0.02]; P-FDR=0.020) counts were associated with a lower time-domain average score. Higher neutrophil (-0.07 [-0.11 to -0.03]; P-FDR=0.006) and monocyte (-0.05 [-0.09 to -0.01]; P-FDR=0.020) counts were also associated with a lower frequency-domain HRV index average score. No effect modification by either sex or glucose metabolism status was found (PintFDR>0.05). There were no other associations between immune cells and HRV indices. Conclusions: Higher neutrophil and monocyte counts were associated with lower HRV, irrespective of sex and glucose metabolism status. This suggests a role of these cells reflecting innate immune processes and inflammatory response in cardiac autonomic nervous dysfunction.

OBJECTIVE:Peripheral neuropathy (PN) is a common complication of type 2 diabetes mellitus (T2DM). In this study, we determined the independent and combined associations of T2DM and PN with device-based measures of physical activity levels and sedentary behaviour. MATERIALS AND METHODS:Cross-sectional data from The Maastricht Study were used (N: 6471, age 59.8 ± 8.8). T2DM was determined with an oral glucose tolerance test and PN was, using a neurothesiometer, defined as an impaired vibration perception threshold (iVPT), that is exceeding 25 V in either one or both halluces. Physical activity and sedentary behaviour outcomes were derived through 8 days of activPAL accelerometer measurement, worn 24 h/day. Multiple linear regression analyses were used with adjustment for demographic, lifestyle and health-related indicators. RESULTS:In the fully adjusted model, the combined presence of T2DM and iVPT presented the lowest step count (-1407 steps/day [95% CI: -1851, -963]), and showed the lowest time in light-intensity (-27.2 min/day [-38.6, -15.8]) and moderate-to-vigorous physical activity (-9.5 min/day [-12.6, -6.5]). Moreover, those with both conditions had the highest sedentary time (+33.3 min/day [21.4, 45.2]) and longest sedentary bout durations (+1.0 min/bout [0.6, 1.4) compared with those without these conditions. DISCUSSION:T2DM and PN were both independently associated with lower levels of physical activity and higher levels of sedentary time. The combination of T2DM with PN was associated with particularly low levels of physical activity and higher levels of sedentary time, indicating an additive association. Strategies to improve physical activity in these individuals should address both conditions.

AIM:To investigate the effect of dipeptidyl peptidase-4 inhibitors (DPP4-Is) and glucagon-like peptide-1 receptor agonists (GLP1-RAs) on diabetic foot ulcer (DFU) and DFU-related outcomes (lower limb amputation [LLA], DFU-related hospitalization and mortality). METHODS:We performed a cohort study with data from the Clinical Practice Research Datalink Aurum database with linkage to hospital data. We included people with type 2 diabetes starting treatment with metformin. Then we propensity score matched new users of DPP4-Is and sulphonylureas (N = 98 770), and new users of GLP1-RAs and insulin (N = 25 422). Cox proportional hazards models estimated the hazard ratios (HRs) for the outcomes. RESULTS:We observed a lower risk of DFU with both DPP4-I use versus sulphonylurea use (HR 0.88, 95% confidence interval [CI]: 0.79-0.97) and GLP1-RA use versus insulin use (HR 0.44, 95% CI: 0.32-0.60) for short-term exposure (≤ 400 days) and HR 0.74 (95% CI: 0.60-0.92) for long-term exposure (>400 days). Furthermore, the risks of hospitalization and mortality were lower with both DPP4-I use and GLP1-RA use. The risk of LLA was lower with GLP1-RA use. The results remained consistent across several sensitivity analyses. CONCLUSIONS:Incretin-based therapy was associated with a lower risk of DFU and DFU-related outcomes. This suggests benefits for the use of this treatment in people at risk of DFU.

Type 2 diabetes (T2D) is a prevalent disease and has been associated with an increased fracture risk despite normal or even higher areal BMD. The aim of this study was to estimate the association between glucose metabolism status (GMS) and measurements of glycemic control with HRpQCT parameters of bone microarchitecture and strength. Participants of the Maastricht study who underwent an HRpQCT scan at the distal radius and tibia were included. GMS was determined by use of an oral glucose tolerance test and grouped into a normal glucose metabolism (NGM), prediabetes, or T2D. Linear regression models were used, stratified by sex with multiple adjustments. This study incorporated cross-sectional data from 1400 (796 [56.9%] NGM, 228 [16.3%] prediabetes, and 376 [26.9%] T2D) men and 1415 (1014 [71.7%] NGM, 211 [14.9%] prediabetes, and 190 [13.4%] T2D) women. The mean age was 59.8 +/- 8.6 and 57.6 +/- 9.0 yr for men and women, respectively. After adjustment, T2D was associated with a higher total BMD measured by HRpQCT and cortical thickness, and a smaller total and trabecular area in men and women compared with NGM. In women, T2D was additionally associated with a higher stiffness and failure load at the radius. Results were more pronounced at the distal radius than at the distal tibia. To conclude, these findings suggest that in this cohort of Maastricht study participants, total and trabecular bone area are smaller, but bone microarchitecture, density, and bone strength assessed by HRpQCT are not impaired in individuals with T2D.

AIMS/HYPOTHESIS:The associations of sitting, standing, physical activity and sleep with cardiometabolic health and glycaemic control markers are interrelated. We aimed to identify 24 h time-use compositions associated with optimal metabolic and glycaemic control and determine whether these varied by diabetes status.METHODS:Thigh-worn activPAL data from 2388 participants aged 40-75 years (48.7% female; mean age 60.1 [SD = 8.1] years; n=684 with type 2 diabetes) in The Maastricht Study were examined. Compositional isometric log ratios were generated from mean 24 h time use (sitting, standing, light-intensity physical activity [LPA], moderate-to-vigorous physical activity [MVPA] and sleeping) and regressed with outcomes of waist circumference, fasting plasma glucose (FPG), 2 h plasma glucose, HbA1c, the Matsuda index expressed as z scores, and with a clustered cardiometabolic risk score. Overall analyses were adjusted for demographics, smoking, dietary intake and diabetes status, and interaction by diabetes status was examined separately. The estimated difference when substituting 30 min of one behaviour with another was determined with isotemporal substitution. To identify optimal time use, all combinations of 24 h compositions possible within the study footprint (1st-99th percentile of each behaviour) were investigated to determine those cross-sectionally associated with the most-optimal outcome (top 5%) for each outcome measure.RESULTS:Compositions lower in sitting time and with greater standing time, physical activity and sleeping had the most beneficial associations with outcomes. Associations were stronger in participants with type 2 diabetes (p<0.05 for interactions), with larger estimated benefits for waist circumference, FPG and HbA1c when sitting was replaced by LPA or MVPA in those with type 2 diabetes vs the overall sample. The mean (range) optimal compositions of 24 h time use, considering all outcomes, were 6 h (range 5 h 40 min-7 h 10 min) for sitting, 5 h 10 min (4 h 10 min-6 h 10 min) for standing, 2 h 10 min (2 h-2 h 20 min) for LPA, 2 h 10 min (1 h 40 min-2 h 20 min) for MVPA and 8 h 20 min (7 h 30 min-9 h) for sleeping.CONCLUSIONS/INTERPRETATION:Shorter sitting time and more time spent standing, undergoing physical activity and sleeping are associated with preferable cardiometabolic health. The substitutions of behavioural time use were significantly stronger in their associations with glycaemic control in those with type 2 diabetes compared with those with normoglycaemic metabolism, especially when sitting time was balanced with greater physical activity.

Type 2 diabetes (T2DM) presents an enormous global healthcare challenge, especially among rural communities due to limited access. To overcome this, many low- and middle-income countries are resorting to task shifting, using community health workers (CHWs) for diabetes management. However, its successful implementation depends on the practice behaviours and knowledge of these workers. This cross-sectional study from rural South India aimed to evaluate the proficiency of 275 CHWs in diabetes screening and management. A customized questionnaire, developed through experts and government was used to evaluate the practice behaviours and knowledge. Analytical methodologies consisted of descriptive statistics, logistic regression, and mosaic plots for comprehensive data interpretation. Results showed significant deficiencies of mean correct practice behaviours at 48 and 50% respectively. The identified gaps included diabetes diagnosis, HbA1c testing, diet, self-management, complications screening and risk assessment. In several areas, correct practice behaviour was reported by a relatively large number of CHWs despite incorrect answers to the related knowledge questions such as referral to the health centres, self-management and calculation of diabetes risk assessment. Addressing these deficiencies requires a thorough needs assessment and tailored training for improved diabetes management by CHWs. Training of CHWs, should not only identify prior knowledge and/or behaviour but also their interrelationship to help create a robust and flexible set of practice behaviours.

Few diseases globally require treatment from so many different disciplines as diabetes-related foot disease. At least 25 different professionals may be involved: casting technicians, dermatologists, diabetes (educator) nurses, diabetologists, dieticians, endocrinologists, general practitioners, human movement scientists, infectious diseases experts, microbiologists, nuclear medicine physicians, orthopaedic surgeons, orthotists, pedorthists, physical therapists, plastic surgeons, podiatric surgeons, podiatrists, prosthetists, psychologists, radiologists, social workers, tissue viability physicians, vascular surgeons, and wound care nurses. A shared vocabulary and shared treatment goals and recommendations are then essential. The International Working Group on the Diabetic Foot (IWGDF) has produced guidelines and supporting documents to stimulate and support shared and multidisciplinary evidence-based treatment in diabetes-related foot disease. In this special virtual issue of Diabetes/Metabolism Research and Reviews, all 21 documents of the 2023 update of the IWGDF Guidelines are bundled, added with a further 6 reviews from multidisciplinary experts to drive future research and clinical innovations, based on their contributions to the International Symposium on the Diabetic Foot. We hope the readers will enjoy this special virtual issue, and widely implement the knowledge shared here in their daily clinical practice and research endeavours with the goal to improve the care for people with diabetes-related foot disease.

Background Diabetes is a growing concern worldwide, particularly in low- and middle-income countries (LMICs). Type 2 diabetes mellitus constitutes a significant proportion of cases and is associated with debilitating microvascular complications. Type 2 diabetes mellitus is steadily increasing among the LMICs where many barriers to health care exist. Thus, task shifting to community health workers (CHWs) has been proposed as a solution to improve diabetes management in these settings. However, CHWs often lack the necessary training to manage diabetes effectively. Thus, a systematic review is required to present evidence of the highest degree for this intervention. Objective This study aims to establish the protocols for a systemic review. Methods Using the Participants Intervention Comparator Outcome Time Study Design (PICOTS) framework, this study outlines a systematic review aiming to evaluate the impact of training programs for CHWs in diabetes management in LMICs. Quantitative studies focusing on CHWs, diabetes training, focusing on diabetes management outcomes like hemoglobin A1c levels and fasting blood glucose levels, between January 2000 and December 2023 and found on databases such as PubMed, Ovid MEDLINE, Evidence Based Medicine Reviews, BASE, Google Scholar, and Web of Science will be included. We will include randomized controlled trials but will also include observational studies if we find less than 5 randomized controlled trials. An author committee consisting of 3 reviewers will be formed, where 2 reviewers will conduct the review independently while the third will resolve all disputes. The Cochrane Methods Risk of Bias Tool 2 will be used for assessing the risk of bias and the Grading of Recommendations, Assessment, Development and Evaluation approach for the meta-analysis and narrative synthesis analysis will be used. The results will be presented in a PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) diagram. Results The review will begin in May 2024 and conclude in 3 months. Conclusions The review will synthesize existing evidence and provide insights into the effectiveness of such programs, informing future research and practice in diabetes care in LMICs. Trial Registration PROSPERO CRD42022341717; https://tinyurl.com/jva2hpdr International Registered Report Identifier (IRRID) PRR1-10.2196/57313

Background: Type 2 diabetes (T2DM) poses an enormous global health care challenge, especially among rural communities. Healthcare in these areas can be inadequate and inaccessible due to socio-demographic barriers. To overcome this situation, many low- and middle-income countries are resorting to task shifting, using community health workers (CHWs) for diabetes management. However, its successful implementation depends on the practice behaviours and knowledge of these workers. Objective: This cross-sectional study aimed to evaluate the proficiency of CHWs involved in diabetes screening and management in rural South India by identifying the existing practice behaviours and knowledge gaps. Methods: Employing a customised questionnaire, developed through inputs from experts and government officials, we assessed practice behaviours and the corresponding knowledge base of 275 CHWs. Analytical methodologies consisted of descriptive statistics, logistic regression, and mosaic plots for comprehensive data interpretation. Results: The study showcased significant deficiencies in both practice behaviours (97%) and knowledge (95%) with current mean levels ranging from 48 to 50%, respectively, among the participants. The identified areas of insufficiency were broadly representative of the core competencies required for effective diabetes management, encompassing diabetes diagnosis and referral, HbA1c testing, diabetes diet, diabetes type and self-management, microvascular complications and their screening, peripheral neuropathy management, and diabetes risk assessment. In several areas, correct practice behaviour was reported by a relatively large number of CHWs despite incorrect answers to the related knowledge questions such as referral to the health centres, self-management, and calculation of diabetes risk assessment. Conclusion: This study highlights widespread deficiencies (97% CHWs) in diabetes management practices and knowledge (95% CHWs). To overcome these deficiencies, a thorough needs assessments is vital for effective CHW training. Training of CHWs should not only identify prior knowledge and/or behaviour but also their interrelationship to help create a robust and flexible set of practice behaviours.

BackgroundDetrimental associations of sedentary behaviour (time spent sitting) with musculoskeletal pain (MSP) conditions have been observed. However, findings on those with, or at risk of, type 2 diabetes (T2D) have not been reported. We examined the linear and non-linear associations of device-measured daily sitting time with MSP outcomes according to glucose metabolism status (GMS). MethodsCross-sectional data from 2827 participants aged 40-75 years in the Maastricht Study (1728 with normal glucose metabolism (NGM); 441 with prediabetes; 658 with T2D), for whom valid data were available on activPAL-derived daily sitting time, MSP [neck, shoulder, low back, and knee pain], and GMS. Associations were examined by logistic regression analyses, adjusted serially for relevant confounders, including moderate-to-vigorous intensity physical activity (MVPA) and body mass index (BMI). Restricted cubic splines were used to further examine non-linear relationships. ResultsThe fully adjusted model (including BMI, MVPA, and history of cardiovascular disease) showed daily sitting time to be significantly associated with knee pain in the overall sample (OR = 1.07, 95%CI: 1.01-1.12) and in those with T2D (OR = 1.11, 95%CI: 1.00-1.22); this was not statistically significant in those with prediabetes (OR = 1.04, 95%CI: 0.91-1.18) or NGM (OR = 1.05, 95%CI: 0.98-1.13). There were no statistically significant associations between daily sitting time and neck, shoulder, or low back pain in any of the models. Furthermore, the non-linear relationships were statistically non-significant. ConclusionAmong middle-aged and older adults with T2D, daily sitting time was significantly associated with higher odds of knee pain, but not with neck, shoulder, or low back pain. No significant association was observed in those without T2D for neck, shoulder, low back, or knee pain. Future studies, preferably those utilising prospective designs, could examine additional attributes of daily sitting (e.g., sitting bouts and domain-specific sitting time) and the potential relationships of knee pain with mobility limitations.

INTRODUCTION Peripheral artery disease (PAD) is associated with an increased likelihood of delayed or non-healing of a diabetes-related foot ulcer, gangrene, and amputation. The selection of the most effective surgical technique for revascularisation of the lower limb in this population is challenging and there is a lack of conclusive evidence to support the choice of intervention. This systematic review aimed to determine, in people with diabetes and tissue loss, if direct revascularisation is superior to indirect revascularisation and if endovascular revascularisation is superior to open revascularisation for the outcomes of wound healing, minor or major amputation, and adverse events including mortality. METHODS Title and abstract searches of Medline, Embase, PubMed, and EBSCO were conducted from 1980 to 30th November 2022. Cohort and case-control studies and randomised controlled trials reporting comparative outcomes of direct (angiosome) revascularisation (DR) and indirect revascularisation (IR) or the comparative outcomes of endovascular revascularisation and open or hybrid revascularisation for the outcomes of healing, minor amputation, and major amputation in people with diabetes, PAD and tissue loss (including foot ulcer and/or gangrene) were eligible. Methodological quality was assessed using the Cochrane risk-of-bias tool for randomised trials, the ROBINS-I tool for non-randomised studies, and Newcastle-Ottawa Scale for observational and cohort studies where details regarding the allocation to intervention groups were not provided. RESULTS From a total 7086 abstracts retrieved, 26 studies met the inclusion criteria for the comparison of direct angiosome revascularisation (DR) and indirect revascularisation (IR), and 11 studies met the inclusion criteria for the comparison of endovascular and open revascularisation. One study was included in both comparisons. Of the included studies, 35 were observational (31 retrospective and 4 prospective cohorts) and 1 was a randomised controlled trial. Cohort study quality was variable and generally low, with common sources of bias related to heterogeneous participant populations and interventions and lack of reporting of or adjusting for confounding factors. The randomised controlled trial had a low risk of bias. For studies of DR and IR, results were variable, and it is uncertain if one technique is superior to the other for healing, prevention of minor or major amputation, or mortality. However, the majority of studies reported that a greater proportion of participants receiving DR healed compared with IR, and that IR with collaterals may have similar outcomes to DR for wound healing. For patients with diabetes, infrainguinal PAD, and an adequate great saphenous vein available for use as a bypass conduit who were deemed suitable for either surgical procedure, an open revascularisation first approach was superior to endovascular therapy to prevent a major adverse limb event or death (Hazard Ratio: 0.72; 95% CI 0.61-0.86). For other studies of open and endovascular approaches, there was generally no difference in outcomes between the interventions. CONCLUSIONS The majority of available evidence for the effectiveness of DR and IR and open and endovascular revascularisation for wound healing and prevention of minor and major amputation and adverse events including mortality in people with diabetes, PAD and tissue loss is inconclusive, and the certainty of evidence is very low. Data from one high quality randomised controlled trial supports the use of open over endovascular revascularisation to prevent a major limb event and death in people with diabetes, infrainguinal disease and tissue loss who have an adequate great saphenous vein available and who are deemed suitable for either approach.

Background: If retinal indices of neurodegeneration are to be biomarkers for the monitoring of cerebral neurodegeneration, it is important to establish whether potentially modifiable risk factors for dementia are associated with retinal neurodegenerative changes. Objective: To study associations of dementia risk factors with retinal sensitivity, an index of retinal neural function, and retinal nerve fiber layer (RNFL) thickness, an index of retinal neural structure. Methods: We used cross-sectional data from The Maastricht Study (up to 5,666 participants, 50.5% men, mean age 59.7), and investigated associations with regression analyses (adjusted for potential confounders). Results: Most risk factors under study (i.e., hyperglycemia, unhealthy diet, lower cardiorespiratory fitness, smoking, alcohol consumption, and hypertension) were significantly associated with lower retinal sensitivity and lower RNFL thickness. Conclusion: Findings of this population-based study support the concept that retinal neural indices may be biomarkers for the monitoring of therapeutic strategies that aim to prevent early-stage cerebral neurodegeneration and, ultimately, dementia.

Aims/hypothesis To assess the associations between glucose metabolism status and a range of continuous measures of glycaemia with corneal nerve fibre measures, as assessed using corneal confocal microscopy. Methods We used population-based observational cross-sectional data from the Maastricht Study of N =3471 participants (mean age 59.4 years, 48.4% men, 14.7% with prediabetes, 21.0% with type 2 diabetes) to study the associations, after adjustment for demographic, cardiovascular risk and lifestyle factors, between glucose metabolism status (prediabetes and type 2 diabetes vs normal glucose metabolism) plus measures of glycaemia (fasting plasma glucose, 2 h post-load glucose, HbA 1c , skin autofluorescence [SAF] and duration of diabetes) and composite Z -scores of corneal nerve fibre measures or individual corneal nerve fibre measures (corneal nerve bifurcation density, corneal nerve density, corneal nerve length and fractal dimension). We used linear regression analysis, and, for glucose metabolism status, performed a linear trend analysis. Results After full adjustment, a more adverse glucose metabolism status was associated with a lower composite Z -score for corneal nerve fibre measures ( β coefficients [95% CI], prediabetes vs normal glucose metabolism −0.08 [−0.17, 0.03], type 2 diabetes vs normal glucose metabolism −0.14 [−0.25, −0.04]; linear trend analysis showed a p value of 0.001), and higher levels of measures of glycaemia (fasting plasma glucose, 2 h post-load glucose, HbA 1c , SAF and duration of diabetes) were all significantly associated with a lower composite Z -score for corneal nerve fibre measures (per SD: −0.09 [−0.13, −0.05], −0.07 [−0.11, −0.03], −0.08 [−0.11, −0.04], −0.05 [−0.08, −0.01], −0.09 [−0.17, −0.001], respectively). In general, directionally similar associations were observed for individual corneal nerve fibre measures. Conclusions/interpretation To our knowledge, this is the first population-based study to show that a more adverse glucose metabolism status and higher levels of glycaemic measures were all linearly associated with corneal neurodegeneration after adjustment for an extensive set of potential confounders. Our results indicate that glycaemia-associated corneal neurodegeneration is a continuous process that starts before the onset of type 2 diabetes. Further research is needed to investigate whether early reduction of hyperglycaemia can prevent corneal neurodegeneration. Graphical Abstract

Aims: The aim of this study was to assess patient perspectives and experiences of the impact of neuropathic pain, painful diabetic neuropathy (pDPN) diagnosis and treatment, and the patient-healthcare professional (HCP) relationship.Methods: We conducted a quantitative online survey in Germany, the Netherlands, Spain, and the UK among adults with diabetes who responded "yes" to at least four of ten questions of in the Douleur Neuropathique en 4 Questions (DN4) questionnaire.Results: Of 3626 respondents, 576 met the eligibility criteria. Daily pain was rated as moderate or severe by 79 % of respondents. Most participants reported a negative impact of their pain on sleep (74 %), mood (71 %), exercise (69 %), concentration (64 %) and daily activities (62 %), and 75 % of those in employment had missed work because of their pain in the past year. Overall, 22 % of respondents avoided discussing pain with their HCP, 50 % had not received formal pDPN diagnosis, and 56 % had not used prescribed pain medications. Although two-thirds (67 %) of respondents reported feeling satisfied or very satisfied with treatment, 82 % of these patients still experienced daily moderate or severe pain.Conclusions: Neuropathic pain in people with diabetes affects daily life and remains underdiagnosed and undertreated in clinical practice.

Foot disease is a devastating complication of diabetes. For almost 3 decades, the mission of the International Working Group on the Diabetic Foot (IWGDF) is to produce evidence-based guidelines to inform health care providers worldwide on strategies for the prevention and management of diabetes-related foot disease. In this publication, we aim to better inform the reader about 'the story behind' the IWGDF Guidelines and thus facilitate improved uptake of the recommendations described in the guidelines. The first IWGDF Guidelines were published in 1999, and these have been successfully updated every 4 years since. With each update, IWGDF has improved the methodological rigour and extended the topics covered. This has been possible thanks to the involvement of > 100 experts from > 60 countries, all voluntarily dedicating their time. We estimate that the 2023 update of the IWGDF Guidelines required a total 10 years of full-time work, which would have cost 2 million euros if the voluntary work had been financially compensated. The IWGDF Guidelines are not only published in English but also translated to support local implementation. Currently available translations serve 2.9 billion people globally in their native language. As an independent and multidisciplinary organisation, IWGDF hopes that the 2023 update will continue to stimulate clinicians from all different disciplines to deliver the best care possible for these patients, will motivate researchers to undertake the high-quality trials needed to deliver the new evidence to advance the field further, and collectively will support people with diabetes-related foot disease to minimize their disease burdens.

As a progressive disease process, early diagnosis and ongoing monitoring and treatment of lower limb peripheral artery disease (PAD) is critical to reduce the risk of diabetes-related foot ulcer (DFU) development, non-healing of wounds, infection and amputation, in addition to cardiovascular complications. There are a variety of non-invasive tests available to diagnose PAD at the bedside, but there is no consensus as to the most diagnostically accurate of these bedside investigations or their reliability for use as a method of ongoing monitoring. Therefore, the aim of this systematic review was to first determine the diagnostic accuracy of non-invasive bedside tests for identifying PAD compared to an imaging reference test and second to determine the intra- and inter-rater reliability of non-invasive bedside tests in adults with diabetes. A database search of Medline and Embase was conducted from 1980 to 30 November 2022. Prospective and retrospective investigations of the diagnostic accuracy of bedside testing in people with diabetes using an imaging reference standard and reliability studies of bedside testing techniques conducted in people with diabetes were eligible. Included studies of diagnostic accuracy were required to report adequate data to calculate the positive likelihood ratio (PLR) and negative likelihood ratio (NLR) which were the primary endpoints. The quality appraisal was conducted using the Quality Assessment of Diagnostic Accuracy Studies and Quality Appraisal of Reliability quality appraisal tools. From a total of 8517 abstracts retrieved, 40 studies met the inclusion criteria for the diagnostic accuracy component of the review and seven studies met the inclusion criteria for the reliability component of the review. Most studies investigated the diagnostic accuracy of ankle -brachial index (ABI) (N = 38). In people with and without DFU, PLRs ranged from 1.69 to 19.9 and NLRs from 0.29 to 0.84 indicating an ABI <0.9 increases the likelihood of disease (but the extent of the increase ranges from a small to large amount) and an ABI within the normal range (≥0.90 and <1.3) does not exclude PAD. For toe-brachial index (TBI), a threshold of <0.70 has a moderate ability to rule PAD in and out; however, this is based on limited evidence. Similarly, a small number of studies indicate that one or more monophasic Doppler waveforms in the pedal arteries is associated with the presence of PAD, whereas tri- or biphasic waveform suggests that PAD is less likely. Several forms of bedside testing may also be useful as adjunct tests and 7 studies were identified that investigated the reliability of bedside tests including ABI, toe pressure, TBI, transcutaneous oxygen pressure (TcPO2 ) and pulse palpation. Inter-rater reliability was poor for pulse palpation and moderate for TcPO2. The ABI, toe pressure and TBI may have good inter- and intra-rater reliability, but margins of error are wide, requiring a large change in the measurement for it to be considered a true change rather than error. There is currently no single bedside test or a combination of bedside tests that has been shown to have superior diagnostic accuracy for PAD in people with diabetes with or without DFU. However, an ABI <0.9 or >1.3, TBI of <0.70, and absent or monophasic pedal Doppler waveforms are useful to identify the presence of disease. The ability of the tests to exclude disease is variable and although reliability may be acceptable, evidence of error in the measurements means test results that are within normal limits should be considered with caution and in the context of other vascular assessment findings (e.g., pedal pulse palpation and clinical signs) and progress of DFU healing.

Background and aims: Drugs for diabetes are required to demonstrate cardiovascular safety through CV outcome trials (CVOT). The pre-defined end-points for cardiovascular outcome studies may not be sufficient to capture all clinically relevant atherosclerotic cardio vascular disease (ASCVD) events particularly peripheral arterial disease (PAD).Methods: We planned a scoping review and searched database to identify CVOT conducted in population with diabetes measuring lower limb events due to PAD as the primary outcome measure. We also searched CVOT for reported differential cardiovascular outcomes in population with PAD.Results: We identified that CV outcomes are measured as 3 point major adverse cardiovascular outcomes (3P MACE) that includes nonfatal MI and nonfatal stroke or 4P-MACE that included additional unstable angina which is further expanded to 5P-MACE by the inclusion of hospitalization for heart failure (HHF). These CV end points are captured as surrogate for CV mortality based on the biological plausibility of relation between the surrogate and final outcome from pathophysiological studies. We found the prevalence of PAD is no lesser than other CV events in people with diabetes. Moreover, PAD contributes to the significant morbidity associated with diabetes as a surrogate for mortality. However, none of the CVOT with anti-diabetic drugs include PAD events as primary outcome measure despite the inclusion of 6-25 % participants with PAD in major CVOT. PAD outcomes are objectively measurable with tibial arterial waveforms and clinical end-point as lower extremity amputation. PAD outcomes do improve with treatment including intensive glycemic control and novel oral anticoagulants. We suggest the inclusion of PAD to MACE as a pre-specified outcome for a comprehensive capture of major adverse vascular event in future studies for people with diabetes.Conclusions: MACE should be expanded to include PAD event as major adverse vascular event in cardiovascular outcome studies since PAD is clinically relevant and objectively measurable in diabetes.