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Background: The diagnosis of neonatal diabetes can be problematic in preterm infants with fetal growth restriction (FGR). Growth restricted fetuses may have impaired insulin production and secretion; low birthweight infants may have a reduced response to insulin. We report a novel missense ABCC8 variant associated with a clinical phenotype compatible with transient neonatal diabetes mellitus (TNDM) in a fetal growth restricted preterm infant., Methods and Results: A preterm growth restricted infant experienced hyperglycemia from the first day of life, requiring insulin therapy on the 13th and 15th day of life and leading to the diagnosis of TNDM. Glycemic values normalized from the 35th day of life onwards. Genetic screening was performed by next generation sequencing, using a Clinical Exon panel of 4800 genes, filtered for those associated with the clinical presentation and by means of methylation-specific multiplex ligation-dependent probe amplification analysis to identify chromosomal aberrations at 6q24. Genetic tests excluded defects at 6q24 and were negative for KCNJ11, SLC2A2 (GLUT-2) and HNF1B, but revealed the presence of the heterozygous missense variant c.2959T > C (p.Ser987Pro) in ABCC8 gene. The presence of the variant was excluded in parents' DNA and the proband variant was then considered de novo., Conclusions: In our infant, the persistence of hyperglycemia beyond 3 weeks of life led us to the diagnosis of TNDM and to hypothesize a possible genetic cause. The genetic variant we found could be, most likely, the main cause of both FGR and TNDM., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Lower-extremity endovascular revascularization (LER) is often required for diabetic patients with chronic limb threatening ischemia (CLTI). During the post-revascularization period patients may unpredictably experience major adverse cardiac events (MACE) and major adverse limb events (MALE). Several families of cytokines are involved in the inflammatory process that underlies the progression of atherosclerosis. According to current evidence, we have identified a panel of possible biomarkers related with the risk of developing MACE and MALE after LER. The aim was to study the relationship between a panel of biomarkers - Interleukin-1 (IL-1) and 6 (IL-6), C-Reactive Protein (CRP), Tumor Necrosis Factor-α (TNF-α), High-Mobility Group Box-1 (HMGB-1), Osteoprotegerin (OPG), Sortilin and Omentin-1- at baseline, with cardiovascular outcomes (MACE and MALE) after LER in diabetic patients with CLTI., Methods: In this prospective non-randomized study, 264 diabetic patients with CLTI undergoing endovascular revascularization were enrolled. Serum levels of each biomarker were collected before revascularization and outcomes' incidence was evaluated after 1, 3, 6 and 12 months., Results: During the follow-up period, 42 cases of MACE and 81 cases of MALE occurred. There was a linear association for each biomarker at baseline and incident MACE and MALE, except Omentin-1 levels that were inversely related to the presence of MACE or MALE. After adjusting for traditional cardiovascular risk factors, the association between each biomarker baseline level and outcomes remained significant in multivariable analysis. Receiver operating characteristics (ROC) models were constructed using traditional clinical and laboratory risk factors and the inclusion of biomarkers significantly improved the prediction of incident events., Conclusions: Elevated IL-1, IL-6, CRP, TNF-α, HMGB-1, OPG and Sortilin levels and low Omentin-1 levels at baseline correlate with worse vascular outcomes in diabetic patients with CLTI undergoing LER. Assessment of the inflammatory state with this panel of biomarkers may support physicians to identify a subset of patients more susceptible to the procedure failure and to develop cardiovascular adverse events after LER., (© 2023. The Author(s).)

Cardiovascular complications after lower extremity revascularization (LER) are common in diabetic patients with peripheral arterial disease (PAD) and chronic limb threatening ischemia (CLTI). The Klotho-fibroblast growth factor 23 (FGF23) axis is associated with endothelial injury and cardiovascular risk. We aimed to analyze the relationship between Klotho and FGF23 serum levels and the incidence of major adverse cardiovascular events (MACE) and major adverse limb events (MALE) after LER in diabetic patients with PAD and CLTI. Baseline levels of Klotho and FGF23, and their association with subsequent incidence of MACE and MALE were analyzed in a prospective, non-randomized study in a population of diabetic patients with PAD and CLTI requiring LER. A total of 220 patients were followed for 12 months after LER. Sixty-three MACE and 122 MALE were recorded during follow-up period. Baseline lower Klotho serum levels (295.3 ± 151.3 pg/mL vs. 446.4 ± 171.7 pg/mL, p < 0.01), whereas increased serum levels FGF23 (75.0 ± 11.8 pg/mL vs. 53.2 ± 15.4 pg/mL, p < 0.01) were significantly associated with the development of MACE. Receiver operating characteristic (ROC) analysis confirmed the predictive power of Klotho and FGF23 baseline levels. Furthermore, decreased Klotho levels were associated with the occurrence of MALE after LER (329.1 ± 136.8 pg/mL vs 495.4 ± 183.9 pg/mL, p < 0.01). We found that Klotho and FGF23 baseline levels are a potential biomarker for increased cardiovascular risk after LER in diabetic patients with PAD and CLTI., (© 2023. The Author(s).)

Bullous pemphigoid (BP) is the most common autoimmune bullous skin disease that affects primarily patients older than 60 years. The majority of BP cases are spontaneous, but BP can also be triggered by certain drugs' exposures. Since 2011, a growing number of observations has been reporting cases of BP in Type 2 diabetic patients. These forms have been linked to the use of a new category of anti-diabetic drugs called dipeptidyl peptidase inhibitors (DPP-4i) or gliptins, but to date, the exact pathophysiological mechanisms underlying this association are not completely elucidated. Although conventional and gliptin-associated BP are thought to share similar clinical and histopathological features, our thorough review of the most recent literature, shows that these 2 forms are quite distinct: DPP-4-i-associated BP seems to appear at an earlier age than spontaneous BP, it may manifest either as a noninflammatory or inflammatory phenotype, while the conventional form presents with a typical inflammatory phenotype. Additionally, an important distinctive histological feature was recently shown in Gliptin-associated BP: these forms may present a less significant eosinophils infiltrate in the upper dermis of peri-blister lesions compared to the skin of patients with spontaneous BP, and this seems a specific feature of the clinically non-inflammatory forms. In accordance with previous literature, we found that the direct immunofluorescence (DIF) gives identical findings in both DPP-4i-associated and conventional forms of BP which is an IgG and complement C3 deposition as a linear band at the dermal-epidermal junction in perilesional skin. Indirect immunofluorescence shows the presence of IgG circulating autoantibodies in the patient's serum which titer does not differ between spontaneous and DPP-4i-associated BP, while the specificity of these autoantibodies, may be different in spontaneous, induced non-inflammatory and induced inflammatory forms, epitope spreading phenomenon seems to play a role in determining these specificities. Further research, based on integrated epidemiological, clinical, histo-immunological and pharmacogenomic approaches, may give more insight into these forms of BP. This combined approach will allow to better define BP endotypes and to unveil the mechanism of spontaneous or drug-induced breakage of the immunotolerance to skin self-antigens., (© 2021. The Author(s).)

Objective: The aim of this study was to evaluate clinical and functional outcomes in diabetic patients undergoing tibiocalcaneal arthrodesis using a retrograde nail., Methods: A total of 12 diabetic patients [8 men and 4 women; mean age at intervention: 56.8 years (range: 27-76 years)] who underwent tibiocalcaneal arthrodesis by a retrograde nail were enrolled in this study. The indication for surgery was massive talar osteonecrosis in four patients, Charcot arthropathy in another four patients, and various severe ankle/hindfoot derangements in four patients. All surgeries were performed by the same surgeon. All patients were evaluated by their American Orthopedic Foot and Ankle Score (AOFAS) score, and radiographic follow-up was performed., Results: The mean follow-up time was 59.5 months (range: 27-121 months). Ten patients (83.3%) healed and were able to walk with full weight bearing without crutches. Among them, nine patients (75%) achieved union with solid bone healing. The mean overall improvement in the AOFAS score was 72.5% (preoperatively: 40 points vs postoperatively: 69 points; p<0.001). We observe a complication in 50% of our patients. Minor complications included two cases of dehiscence of the surgical wound, one case of soft tissue irritation owing to hardware protrusion, and one cause of lymphedema. Two patients had deep infection and underwent surgical removal of hardware, debridement, and antibiotic treatment: one healed after the treatment but never recovered full weight bearing and the other one died from other complications. These two deep infections occurred after 23 months of follow-up., Conclusion: Tibiocalcaneal arthrodesis using retrograde nails is a salvage technique extremely effective in ankle and hindfoot disorders in a diabetic patient. This procedure allows good functional outcomes and pain relief. When correctly indicated, it is a safe procedure with good clinical outcomes and low risk of below-knee amputation., Level of Evidence: Level IV, Therapeutic study.

Objective: Peripheral artery disease (PAD) is one of the most relevant complications of diabetes. Although several pharmacological and revascularization approaches are available for treating patients with diabetes and PAD, an endovascular approach is often associated with postprocedural complications that can increase the risk for acute limb ischemia or amputation. However, no definitive molecular associations have been described that could explain the difference in outcomes after endovascular treatment in patients with diabetes, PAD, and chronic limb-threatening ischemia (CLTI)., Research Design and Methods: We evaluated the relationship between the levels of the main cytokines associated with diabetic atherosclerosis and the outcomes after endovascular procedures in patients with diabetes, PAD, and CLTI., Results: A total of 299 patients with below-the-knee occlusive disease who were undergoing an angioplasty procedure were enrolled. The levels of key cytokines-osteoprotegerin (OPG), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and C-reactive protein (CRP)-were measured, and major adverse limb events (MALE) and major adverse cardiovascular events (MACE) were assessed 1, 3, 6, and 12 months after the procedure. There was a linear trend from the lowest to the highest quartile for each cytokine at baseline and incident MALE. A linear association was also observed between increasing levels of each cytokine and incident MACE. Receiver operating characteristics models were constructed using clinical and laboratory risk factors, and the inclusion of cytokines significantly improved the prediction of incident events., Conclusions: We demonstrated that elevated OPG, TNF-α, IL-6, and CRP levels at baseline correlate with worse vascular outcomes in patients with diabetes, PAD, and CLTI undergoing an endovascular procedure., (© 2019 by the American Diabetes Association.)

Objective: The efficacy of antiplatelet drugs may differ in specific patient subgroups. We aimed to assess the efficacy and safety of the P2Y12 inhibitors clopidogrel, ticlopidine, prasugrel, ticagrelor, and cangrelor according to diabetes status, age, gender, body mass index, and body weight., Methods: Randomized clinical trials (RCTs) of P2Y12 inhibitors reporting information on cardiovascular disease (defined as myocardial infarction, stroke, or cardiovascular death) and bleeding (defined as any bleeding) events among the subgroups diabetes and non-diabetes, age ≥65 and <65 year-old, men and women, body mass index ≥30 and <30 kg/m(2), and body weight ≥60 and <60 kg, were identified in Medline, Embase, Web of Science, and Cochrane Library on August 31st, 2014. For each inhibitor, random-effects meta-analyses were used to estimate the ratio of relative risks (rRR) for cardiovascular and bleeding events among patient subgroups., Results: Twenty distinct RCTs (233 285 participants, 21 323 cardiovascular and 5183 bleeding events) were identified. Cardiovascular risk reduction with clopidogrel did not significantly differ according to diabetes (rRR: 1.04; 95% CI: 0.95 to 1.13; p = 0.395), age (0.98; 0.88 to 1.09; p = 0.347), gender (0.97; 0.90 to 1.04; p = 0.382), or body mass index (1.11, 0.95 to 1.31; p = 0.191). Results for other inhibitors were comparable, although available data were sparse. Limited data on bleeding events were available., Conclusion: Data from RCTs did not show a different cardiovascular efficacy of clopidogrel in diabetes mellitus and other clinically relevant subgroups. Limited information was available on the efficacy and safety of other P2Y12 inhibitors in specific subgroups., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Several abnormalities of the respiratory function have been reported in patients with type 1 and type 2 diabetes. These abnormalities concern lung volume, pulmonary diffusing capacity, control of ventilation, bronchomotor tone, and neuroadrenergic bronchial innervation. Many hypotheses have emerged, and characteristic histological changes have been described in the "diabetic lung", which could explain this abnormal respiratory function. Given the specific abnormalities in diabetic patients, the lung could thus be considered as a target organ in diabetes. Although the practical implications of these functional changes are mild, the presence of an associated acute or chronic pulmonary and/or cardiac disease could determine severe respiratory derangements in diabetic patients. Another clinical consequence of the pulmonary involvement in diabetes is the accelerated decline in respiratory function. The rate of decline in respiratory function in diabetics has been found to be two-to-three times faster than in normal non-smoking subjects, as reported in longitudinal studies. This finding, together with the presence of anatomical and biological changes similar to those described in the aging lung, indicates that the "diabetic lung" could even be considered a model of accelerated aging. This review describes and analyses the current insight into the relationship of diabetes and lung disease, and suggests intensifying research into the lung as a possible target organ in diabetes.

Pulmonary delivery of insulin is more than a promise in the treatment of diabetes mellitus. Inhaled insulin seems at least as efficacious as the conventional regimen of subcutaneous insulin and/or oral glucose-lowering agents in both type 1 and type 2 diabetes mellitus. Improved metabolic control and the use of a non-invasive route of administration represent the main benefits of this new treatment. Several physico-chemical factors could reduce the bioavailability of inhaled insulin. Indeed, both deep-lung deposition and adsorption of insulin variously depend on the type of propellants used, speed of air flow, particle size and velocity, drug deposition into the throat and larger bronchial tree. These factors, in turn, depend on the pulmonary delivery systems used and on respiratory mechanics and flows. Furthermore, the pharmacokinetics of inhaled insulin is affected by smoke, which increases its absorption, and by lung diseases, which decrease the available alveolar-capillary surface. Selected abnormalities of respiratory function complicate both type 1 and type 2 diabetes mellitus and a mild depression of carbon monoxide lung transfer after a 6-month period of treatment with inhaled insulin has been reported. Finally, results from some longitudinal studies suggest that diabetes might speed up the age-related decline of lung volumes and probably alter the pharmacokinetics of inhaled insulin, particularly in the elderly. Clarifying these issues is mandatory in order to define the indications and safety of inhaled insulin.