Frontiers in Clinical Diabetes and Healthcare is delighted to present this research topic to highlight the current understanding of complications associated with diabetes. This collection will collate high-quality scholarly papers that highlight current thinking and recent advances in the field, whilst emphasizing important directions and new possibilities for future inquiries. We anticipate that the research presented will promote discussion within the diabetes research community that will translate to best practice applications in clinical, public health and policy settings.

Faculty of Medicine, University of Novi Sad

Life Sciences Institute, University of Michigan

Shupyk National Medical Academy of Postgraduate Education

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Frontiers in Clinical Diabetes and Healthcare

Diabetes Nephropathy

Diabetes Cardiovascular Complications

Diabetes Multiorgan Complications

Current Understanding of Complications Associated with Diabetes

Diabetes mellitus is a chronic metabolic disorder and is caused either by the inability of the pancreas to produce enough insulin or defects in the insulin action on the peripheral tissues, resulting in persistent hyperglycemia. Hyperglycemia is a key outcome of diabetes mellitus and chronic hyperglycemia leads to serious damage to many organs. In 2019, 48% of all mortalities caused by diabetes mellitus were observed in the subjects at or before the age of 70 years (<a href="#B1">1</a>). The clinical data suggests that in 2015, 415 million people were supposed to develop diabetes mellitus and by 2040, this prevalence is estimated to grow to 642 million worldwide (<a href="#B2">2</a>, <a href="#B3">3</a>). By the year 2050, the number of diabetic patients in the United States will increase to 48.3 million (<a href="#B4">4</a>) although 90% to 95% of the diabetes burden is due to type II diabetes (<a href="#B4">4</a>). Diabetes-associated complications including cardiovascular dysfunctions, renal disorders, nerve-related diseases, hepatic disorders, blindness, and organ amputation are key reasons for increased mortality among diabetic patients. Moreover, diabetes-related complexities include microvascular, macrovascular, and nerved-related issues (<a href="#B5">5</a>). Diabetic nephropathy, retinopathy, neuropathy, cardiovascular dysfunctions, and hypertension (<a href="#B5">5</a>) are key microvascular and macrovascular complications. Diabetic nephropathy develops in approximately 40% of diabetic patients and is the main cause of chronic kidney disease worldwide (<a href="#B2">2</a>, <a href="#B6">6</a>). As a result of diabetes mellitus, kidney fibrosis develops which is the leading cause of end-stage renal disease. Diabetes mellitus-related mesenchymal activations observed in the kidneys, heart, and vessels are the critical reason for extracellular matrix (ECM) synthesis, deposition, and fibrogenesis (<a href="#B7">7</a>). Deposition of ECM, collagens, inflammatory cells, and irregulated action of cytokines and chemokine further results in organ fibrosis in diabetes (<a href="#B8">8</a>). There are several drug molecules known for the treatment of diabetes mellitus and related complications; however, developing safe therapeutics is still a challenge. With the development of therapeutic options for diabetes and related complications, diabetic patients have a longer life. This article gives insights into the literature on the background of the complications associated with diabetes.Reducing the levels of oxidative stress, enhancing mitochondrial quality, and regulating the inflammatory and mesenchymal activation in diabetic-related complications have demonstrated desirable results in preclinical settings (<a href="#B9">9</a>–<a href="#B11">11</a>). Such medications show a new therapeutic option for the treatment of diabetes and related complications; however, further research is desirable for better management.Researchers have reported promising activity in flavone, chalcone, and isoflavone as inhibitors against, i.e., phosphotyrosine phosphatase 1B (PTP-1B), α-glucosidase, GLP-1, dipeptidyl peptidase-4 (DPP-4), aldose reductase, and sodium-glucose co-transporter-2 (SGLT-2) in type II diabetes (<a href="#B11">11</a>). These effective molecules have promising antidiabetic activity in preclinical settings and mouse models of diabetes. Recently, tissue-specific angiopoietin-like protein 4 (ANGPTL4), macrophage-stimulating protein 1 (MST-1) inhibitors, and SGLT-2 inhibitors have been found to have tremendous activity in controlling diabetes and related complications. Recently, we have observed that enzyme catechol-o-methyl transferase (COMT) deficiency is involved in metabolic disorders and pre-eclampsia-associated phenotypes in mice (<a href="#B12">12</a>). COMT by-product 2-methoxy estradiol (2-ME) treatment suppressed the phenotype of metabolic disorders and pre-eclampsia in the mouse models; however, a randomized clinical trial is needed in diabetic patients for the development of 2-ME into the usable form as a medicine (<a href="#B12">12</a>).Endothelial cell dysfunction is a critical feature of diabetes-related complications (<a href="#B13">13</a>). Endothelial-to-mesenchymal transition (EndMT) is the process through which endothelial cells lose the endothelial characteristics and gain the features of mesenchymal cells (<a href="#B14">14</a>). Conversion of endothelial cells into the EndMT phenotype is the crucial process to accelerate fibrosis-associated pathways resulting in the deposition of ECM and fibrogenesis-associated proteins (<a href="#B15">15</a>, <a href="#B16">16</a>). Our research group identified three key endogenous molecules that are associated to cellular stability and regulation of mesenchymal cells and fibrogenesis, and these are 1) endothelial glucocorticoid receptors (GR), 2) endothelial fibroblast growth factor receptor 1 (FGFR1), and 3) endothelial sirtuin 3 (SIRT3). Deficiency of either GR, FGFR1, or SIRT3 protein levels causes significantly diminished levels of fatty acid oxidation and activation of the inflammatory cascade in the endothelial cells itself and also to tubules in diabetic conditions, resulting in severe fibrotic responses in the diabetic kidneys and heart (<a href="#B17">17</a>–<a href="#B22">22</a>). Defective fatty acid metabolism is critical in renal fibrosis (<a href="#B23">23</a>). GR regulates canonical Wnt signaling and IL-6 levels. FGFR1 signaling is important for restoring antifibrotic microRNAs such as miR-29s and miR-let-7s, whereas SIRT3 regulates metabolic flux by targeting pyruvate kinase M2 tetramer-to-dimer formation (<a href="#B10">10</a>, <a href="#B24">24</a>). The cumulative effects lead to cellular leakage, defects in the permeability, EndMT activations, and related fibrosis in the kidneys and heart in the diabetic condition (<a href="#B24">24</a>, <a href="#B25">25</a>). Podocyte GR plays a critical role in regulating fibrosis in the diabetic glomeruli. Podocyte GR mitigates the Wnt signaling and elevates the levels of fatty acid oxidation and, therefore, is associated with the reduction in the levels of EndMT in glomerular endothelial cells, suggesting that GR loss in podocytes disrupts the important crosstalk between podocytes and endothelial cells in diabetes (<a href="#B17">17</a>).In this Research Topic, <a href="https://doi.org/10.3389/fcdhc.2022.831128">Huang et&nbsp;al.</a> demonstrated the crucial role of angiotensin-converting enzyme (ACE) in diabetic nephropathy and retinopathies. The authors demonstrated that elevated levels of serum ACE are related to DN progression or retina impairment in diabetic patients. This study will facilitate the identification of biomarkers for the management of diabetes-related complications. In another study, the authors discussed how hand manifestations reflect a systemic profibrotic state and are key clinical biomarkers of current or future internal organ fibrosis (<a href="https://doi.org/10.3389/fcdhc.2023.1198782">Phatak et&nbsp;al.</a>). A study by <a href="https://doi.org/10.3389/fcdhc.2023.1167852">Sacareau et&nbsp;al.</a> demonstrated the screening of CKD patients among diabetic subjects in French Guiana. This study links diabetes and hypertension, the two most obvious risk factors for developing CKD, in human subjects.This Research Topic highlights new cellular mechanisms in diabetes-related complications and identifies new molecules for the treatment of organ fibrosis, neuropathies, and foot ulcers. We speculate that this Research Topic will provide valuable information that could be used in the management of diabetes-related complications.SS: Conceptualization, Investigation, Software, Supervision, Validation, Writing &#x2013; original draft, Writing &#x2013; review &amp; editing.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Editorial: Current understanding of complications associated with diabetes

IntroductionWith over half of the population living under the poverty threshold, the social and health context in French Guiana is more difficult than in mainland France. The prevalence of diabetes is twice as great and end-stage renal failure is 45% higher than in mainland France.</sec>ObjectiveOur objective was to describe the profile of diabetic patients with chronic kidney disease in French Guiana and search for possible risk factors.</sec>MethodWe conducted a multicenter cross-sectional observational study based on the CODIAM cohort (Cohort of Diabetes in French Amazonia). We analyzed 1,287 patients followed up between May 2019 and June 2021 at Cayenne Hospital, Saint Laurent Hospital, and delocalized health centers.</sec>ResultsIn our cohort, chronic kidney disease was present after an average of 12 years of diabetes. Compared with the French population, 41% of diabetic patients had chronic kidney disease (i.e., 12% more), and had an average age of 56 years (i.e., 10 years younger). Forty-eight per cent of these patients were obese (i.e., 7% more). Seventy-four per cent of patients were precarious and 45% were foreigners but neither was associated with chronic kidney disease, contrary to countries where the health system is not universal.</sec>ConclusionScreening of patients with chronic kidney disease among diabetics in French Guiana remains a real challenge. Patients were younger and more obese than in other French territories. In this cohort, precariousness and immigration were not associated with the presence of chronic kidney disease. However, particular attention should be paid to hypertensive patients and those over 65 years of age, which are, with diabetes itself, the two most obvious risk factors for developing chronic kidney disease among diabetic patients in our territory.</sec>

Introduction: With over half of the population living under the poverty threshold, the social and health context in French Guiana is more difficult than in mainland France. The prevalence of diabetes is twice as great and end-stage renal failure is 45% higher than in mainland France.Objective: Our objective was to describe the profile of diabetic patients with chronic kidney disease in French Guiana and search for possible risk factors.Method: We conducted a multicenter cross-sectional observational study based on the CODIAM cohort (Cohort of Diabetes in French Amazonia). We analyzed 1,287 patients followed up between May 2019 and June 2021 at Cayenne Hospital, Saint Laurent Hospital, and delocalized health centers.Results: In our cohort, chronic kidney disease was present after an average of 12 years of diabetes. Compared with the French population, 41% of diabetic patients had chronic kidney disease (i.e., 12% more), and had an average age of 56 years (i.e., 10 years younger). Forty-eight per cent of these patients were obese (i.e., 7% more). Seventy-four per cent of patients were precarious and 45% were foreigners but neither was associated with chronic kidney disease, contrary to countries where the health system is not universal.Conclusion: Screening of patients with chronic kidney disease among diabetics in French Guiana remains a real challenge. Patients were younger and more obese than in other French territories. In this cohort, precariousness and immigration were not associated with the presence of chronic kidney disease. However, particular attention should be paid to hypertensive patients and those over 65 years of age, which are, with diabetes itself, the two most obvious risk factors for developing chronic kidney disease among diabetic patients in our territory.

Factors associated with chronic kidney disease in patients with diabetes in French Guiana

Fibrosis leads to irreversible stiffening of tissue and loss of function, and is a common pathway leading to morbidity and mortality in chronic disease. Diabetes mellitus (both type 1 and type 2 diabetes) are associated with significant fibrosis in internal organs, chiefly the kidney and heart, but also lung, liver and adipose tissue. Diabetes is also associated with the diabetic cheirarthropathies, a collection of clinical manifestations affecting the hand that include limited joint mobility (LJM), flexor tenosynovitis, Duypuytren disease and carpal tunnel syndrome. Histo-morphologically these are profibrotic conditions affecting various soft tissue components in the hand. We hypothesize that these hand manifestations reflect a systemic profibrotic state, and are potential clinical biomarkers of current or future internal organ fibrosis. Epidemiologically, there is evidence that fibrosis in one organ associates with fibrosis with another; the putative exposures that lead to fibrosis in diabetes (advanced glycation end product deposition, microvascular disease and hypoxia, persistent innate inflammation) are ‘systemic’; a common genetic susceptibility to fibrosis has also been hinted at. These data suggest that a subset of the diabetic population is susceptible to multi-organ fibrosis. The hand is an attractive biomarker to clinically detect this susceptibility, owing to its accessibility to physical examination and exposure to repeated mechanical stresses. Testing the hypothesis has a few pre-requisites: being able to measure hand fibrosis in the hand, using clinical scores or imaging based scores, which will facilitate looking for associations with internal organ fibrosis using validated methodologies for each. Longitudinal studies would be essential in delineating fibrosis trajectories in those with hand manifestations. Since therapies reversing fibrosis are few, the onus lies on identification of a susceptible subset for preventative measures. If systematically validated, clinical hand examination could provide a low-cost, universally accessible and easily reproducible screening step in selecting patients for clinical trials for fibrosis in diabetes.

Fibrosis leads to irreversible stiffening of tissue and loss of function, and is a common pathway leading to morbidity and mortality in chronic disease. Diabetes mellitus (both type 1 and type 2 diabetes) are associated with significant fibrosis in internal organs, chiefly the kidney and heart, but also lung, liver and adipose tissue. Diabetes is also associated with the diabetic cheirarthropathies, a collection of clinical manifestations affecting the hand that include limited joint mobility (LJM), flexor tenosynovitis, Duypuytren disease and carpal tunnel syndrome. Histo-morphologically these are profibrotic conditions affecting various soft tissue components in the hand. We hypothesize that these hand manifestations reflect a systemic profibrotic state, and are potential clinical biomarkers of current or future internal organ fibrosis. Epidemiologically, there is evidence that fibrosis in one organ associates with fibrosis with another; the putative exposures that lead to fibrosis in diabetes (advanced glycation end product deposition, microvascular disease and hypoxia, persistent innate inflammation) are &#x2018;systemic&#x2019;; a common genetic susceptibility to fibrosis has also been hinted at. These data suggest that a subset of the diabetic population is susceptible to multi-organ fibrosis. The hand is an attractive biomarker to clinically detect this susceptibility, owing to its accessibility to physical examination and exposure to repeated mechanical stresses. Testing the hypothesis has a few pre-requisites: being able to measure hand fibrosis in the hand, using clinical scores or imaging based scores, which will facilitate looking for associations with internal organ fibrosis using validated methodologies for each. Longitudinal studies would be essential in delineating fibrosis trajectories in those with hand manifestations. Since therapies reversing fibrosis are few, the onus lies on identification of a susceptible subset for preventative measures. If systematically validated, clinical hand examination could provide a low-cost, universally accessible and easily reproducible screening step in selecting patients for clinical trials for fibrosis in diabetes.

Does hand stiffness reflect internal organ fibrosis in diabetes mellitus?

AimTo describe patients’ reported employment challenges associated with diabetic foot ulcers (DFUs).</sec>MethodsFifteen patients from under-resourced communities in Southern Arizona, with a history of DFUs and/or amputations, were recruited from a tertiary referral center from June 2020 to February 2021. Participants consented to an audio-recorded semi-structured phone interview. Interviews were transcribed and thematically analyzed using the Dedoose data analysis platform.</sec>ResultsParticipants shared a common theme around the cyclic challenges of DFU prevention/management and employment. Those employed in manual labor-intensive jobs or jobs requiring them to be on their feet for long durations of time believed working conditions contributed to the development of their DFUs. Patients reported work incapacity due to declines in mobility and the need to offload for DFU management. Many expressed frustration and emotional distress related to these challenges noting that DFUs resulted in lower remuneration as medical expenses increased. Consequently, loss of income and/or medical insurance often hindered participants’ ability to manage DFUs and subsequent complications.</sec>ConclusionThese data illuminate the vicious cycle of DFU and employment challenges that must be addressed through patient-centered prevention strategies. Healthcare providers should consider a person’s contextual factors such as employment type to tailor treatment approaches. Employers should establish inclusive policies that support patients with DFUs returning to work through flexible working hours and adapted work tasks as needed. Policymakers can also mitigate employment challenges by implementing social programs that provide resources for employees who are unable to return to work in their former capacity.</sec>

Aim: To describe patients’ reported employment challenges associated with diabetic foot ulcers (DFUs).Methods: Fifteen patients from under-resourced communities in Southern Arizona, with a history of DFUs and/or amputations, were recruited from a tertiary referral center from June 2020 to February 2021. Participants consented to an audio-recorded semi-structured phone interview. Interviews were transcribed and thematically analyzed using the Dedoose data analysis platform.Results: Participants shared a common theme around the cyclic challenges of DFU prevention/management and employment. Those employed in manual labor-intensive jobs or jobs requiring them to be on their feet for long durations of time believed working conditions contributed to the development of their DFUs. Patients reported work incapacity due to declines in mobility and the need to offload for DFU management. Many expressed frustration and emotional distress related to these challenges noting that DFUs resulted in lower remuneration as medical expenses increased. Consequently, loss of income and/or medical insurance often hindered participants’ ability to manage DFUs and subsequent complications.Conclusion: These data illuminate the vicious cycle of DFU and employment challenges that must be addressed through patient-centered prevention strategies. Healthcare providers should consider a person’s contextual factors such as employment type to tailor treatment approaches. Employers should establish inclusive policies that support patients with DFUs returning to work through flexible working hours and adapted work tasks as needed. Policymakers can also mitigate employment challenges by implementing social programs that provide resources for employees who are unable to return to work in their former capacity.

A vicious cycle: employment challenges associated with diabetes foot ulcers in an economically marginalized Southwest US sample

BackgroundDiabetic peripheral neuropathy (DPN) is the most common complication of diabetes mellitus (DM). Approximately 50% of diabetic patients are estimated to develop DPN, depending on disease duration and diabetic control. Early diagnosis of DPN will avoid complications, including non-traumatic lower limb amputation, which is considered the most debilitating complication, as well as significant psychological, social, and economical problems. There is a paucity of literature on DPN from rural Uganda. This study aimed to deliver the prevalence and grade of DPN among DM patients in rural Uganda.</sec>MethodsA cross-sectional study that recruited 319 known DM patients was conducted in an outpatient clinic and a diabetic clinic at Kampala International University-Teaching Hospital (KIU-TH), Bushenyi, Uganda, between December 2019 and March 2020. Questionnaires were used to obtain clinical and sociodemographic data, a neurological examination was carried out to assess the DPN, and a blood sample was collected from each participant (for random/fasting blood glucose and glycosylated hemoglobin analyses). Data were analyzed using Stata version 15.0.</sec>ResultsThe sample size was 319 participants. The mean age of study participants was 59.4 ± 14.6 years and there were 197 (61.8%) females. The prevalence of DPN was 65.8% (210/319) (95% CI 60.4% to 70.9%), and 44.8% of participants had mild DPN, 42.4% had moderate DPN, and 12.8% had severe DPN.</sec>ConclusionThe prevalence of DPN at KIU-TH was higher among DM patients and its stage might have a negative impact on the progression of Diabetes Mellitus. Therefore, clinicians should consider neurological examination as a routine during assessment of all DM patients especially in rural areas where resources and facilities are often limited so that complications related to Diabetic mellitus will be prevented.</sec>

Background: Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes mellitus (DM). Approximately 50% of diabetic patients are estimated to develop DPN, depending on disease duration and diabetic control. Early diagnosis of DPN will avoid complications, including non-traumatic lower limb amputation, which is considered the most debilitating complication, as well as significant psychological, social, and economical problems. There is a paucity of literature on DPN from rural Uganda. This study aimed to deliver the prevalence and grade of DPN among DM patients in rural Uganda.Methods: A cross-sectional study that recruited 319 known DM patients was conducted in an outpatient clinic and a diabetic clinic at Kampala International University-Teaching Hospital (KIU-TH), Bushenyi, Uganda, between December 2019 and March 2020. Questionnaires were used to obtain clinical and sociodemographic data, a neurological examination was carried out to assess the DPN, and a blood sample was collected from each participant (for random/fasting blood glucose and glycosylated hemoglobin analyses). Data were analyzed using Stata version 15.0.Results: The sample size was 319 participants. The mean age of study participants was 59.4 ± 14.6 years and there were 197 (61.8%) females. The prevalence of DPN was 65.8% (210/319) (95% CI 60.4% to 70.9%), and 44.8% of participants had mild DPN, 42.4% had moderate DPN, and 12.8% had severe DPN.Conclusion: The prevalence of DPN at KIU-TH was higher among DM patients and its stage might have a negative impact on the progression of Diabetes Mellitus. Therefore, clinicians should consider neurological examination as a routine during assessment of all DM patients especially in rural areas where resources and facilities are often limited so that complications related to Diabetic mellitus will be prevented.

Prevalence and grade of diabetic peripheral neuropathy among known diabetic patients in rural Uganda

ObjectivesRenin-angiotensin-aldosterone system plays important roles in the development of diabetic nephropathy (DN), and angiotensin converting enzyme (ACE) is the key factor in the process from angiotensin I to angiotensin II, but the variation and roles of serum ACE in DN patients are still unclear.</sec>MethodsForty-four type 2 diabetes mellitus (T2DM) patients, 75 DN patients, and 36 age-gender-matched healthy volunteers were recruited who attended Xiangya Hospital of Central South University in this case control study. Serum ACE levels and other indexes were tested with commercial kit.</sec>ResultsACE levels in DN were significantly higher than T2DM and controls (F = 9.66, P < 0.001). Serum ACE levels significantly correlated with UmALB (r = 0.3650, P < 0.001), BUN (r = 0.3102, P < 0.001), HbA1c (r = 0.2046, P = 0.0221), ACR (r = 0.4187, P < 0.001), ALB (r = -0.1885, P = 0.0192), and eGFR (r = -0.3955, P < 0.001), and we got an equation that Y = 2.839 + 0.648X1 + 2.001X2 + 0.003X3 - 6.637X4 +0.416X5 - 0.134X6 (Y: ACE; X1: BUN; X2: HbA1C; X3: UmALB; X4: gender; X5: ALB; X6: eGFR, R2 = 0.655). When DN patients were divided into advanced-stage and early-stage with or without DR, ACE levels would increase when early-stage DN develops into advanced-stage or companied with DR.</sec>ConclusionElevated serum ACE levels may hint DN progression or retina impaired of DN patients.</sec>

Objectives: Renin-angiotensin-aldosterone system plays important roles in the development of diabetic nephropathy (DN), and angiotensin converting enzyme (ACE) is the key factor in the process from angiotensin I to angiotensin II, but the variation and roles of serum ACE in DN patients are still unclear.Methods: Forty-four type 2 diabetes mellitus (T2DM) patients, 75 DN patients, and 36 age-gender-matched healthy volunteers were recruited who attended Xiangya Hospital of Central South University in this case control study. Serum ACE levels and other indexes were tested with commercial kit.Results: ACE levels in DN were significantly higher than T2DM and controls (F = 9.66, P &lt; 0.001). Serum ACE levels significantly correlated with UmALB (r = 0.3650, P &lt; 0.001), BUN (r = 0.3102, P &lt; 0.001), HbA1c (r = 0.2046, P = 0.0221), ACR (r = 0.4187, P &lt; 0.001), ALB (r = -0.1885, P = 0.0192), and eGFR (r = -0.3955, P &lt; 0.001), and we got an equation that Y = 2.839 + 0.648X1 + 2.001X2 + 0.003X3 - 6.637X4 +0.416X5 - 0.134X6 (Y: ACE; X1: BUN; X2: HbA1C; X3: UmALB; X4: gender; X5: ALB; X6: eGFR, R2 = 0.655). When DN patients were divided into advanced-stage and early-stage with or without DR, ACE levels would increase when early-stage DN develops into advanced-stage or companied with DR.Conclusion: Elevated serum ACE levels may hint DN progression or retina impaired of DN patients.