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Diabetic foot syndrome (DFS) is a major complication of diabetes mellitus. Coronavirus infectious disease 2019 (COVID-19) has created new necessities and priorities in DFS management. These include telemedicine and patient triage to minimise hospitalisation and visits to the clinic. Moreover, new studies will be needed to evaluate whether the lockdown in patients with DFS or in those with high risk of DFS have increased the risk of deteriorating outcomes, including limb loss. Our future challenge will lie in re-organising our world during the pandemic and after its resolution. We need more awareness of the widespread ways of the changes in taking care of patients and to improve education, skills, and behaviour of high-risk patients.

Diabetic foot syndrome (DFS) is a complex disease. The best outcomes are reported with the multi-disciplinary team (MDT) approach, where each member works collaboratively according to his/her expertise. However, which health provider should act as the team leader (TL) has not been determined. The TL should be familiar with the management of diabetes, related complications and comorbidities. He/she should be able to diagnose and manage foot infections, including prompt surgical treatment of local lesions, such as abscesses or phlegmons, in an emergent way in the first meeting with the patient. According to the Organization for Economic Co-operation and Development (OECD) reports, Italy is one of countries with a low amputation rate in diabetic patients. Many factors might have contributed to this result, including 1)the special attention directed to diabetes by the public health system, which has defined diabetes as a "protected disease", and accordingly, offers diabetic patients, at no charge, the best specialist care, including specific devices, and 2)the presence of a network of diabetic foot (DF) clinics managed by diabetologists with medical and surgical expertise. The health care providers all share a "patient centred model" of care, for which they use their internal medicine background and skills in podiatric surgery to manage acute or chronic needs in a timely manner. Therefore, according to Italian experiences, which are fully reported in this document, we believe that only a skilled diabetologist/endocrinologist should act as a TL. Courses and university master's degree programmes focused on DF should guarantee specific training for physicians to become a TL.

The diabetic foot (DF) is one of the most feared conditions among chronic complications of diabetes, which affects a growing number of patients. Although exercise therapy (ET) has always been considered a pillar in the treatment of patients at risk of DF it is not usually used. Several causes can contribute to hindering both the organization of ET protocols for Diabetes Units and the participation in ET programs for patients at different levels of risk of foot ulceration. The risk of favoring the occurrence of ulcers and the absence of clear evidence on the role played by ET in the prevention of ulcers could be considered among the most important causes leading to the low application of ET. The increased availability of new technologies and in particular of systems and devices equipped with sensors can enable the remote monitoring and management of physical activity performed by patients. Consequently, they can become an opportunity for introducing the systematic use of ET for the treatment of patients at risk. Considering the complexity of the clinical conditions that patients at risk or with diabetic foot ulcer can show, the evaluation of how patients perform the ET proposed can consequently be very important. All this can contribute to improving the treatment of patients and avoiding possible adverse effects. The aim of this brief review was to describe that the use of new technologies and the assessment of the execution of the ET proposed allows an important step forward in the management of patients at risk.

Diabetic foot syndrome (DFS) increases the risk for atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), or mortality. The present study aims at ascertaining whether such DFS-related excess risk differs between genders, retrospectively investigating a population with diabetes from Tuscany, Italy, followed-up for 6 years (2011–2016). People with diabetes living in Tuscany on January 1st 2011 identified by administrative databases, were divided by baseline history of prior DFS hospitalizations, stratified by presence/absence of peripheral vascular disease and evaluating, by Cox regression analysis, whether adjusted DFS-related excess risk of incident ASCVD, CKD or mortality differed between genders. In an overall population of 165,650 subjects with diabetes (81,829M/83,821F), basal prevalence of DFS was twice higher among males, who were moreover at a significantly greater risk of all considered outcomes along the 6-year period. On the contrary, baseline DFS significantly increased the hospitalization risk for ASCVD, CKD and mortality equally or at a slightly greater extent in females, while the risk for stroke was significantly associated with DFS only among females (HR: 1.622 (1.314–1.980); p = 0.0001 vs. HR: 1.132 (0.955–1.332); p = NS). This finding was even reinforced in non-vascular DFS, which was associated with a significant raised risk for stroke, heart failure or mortality exclusively in females. In this population, DFS prevalence and overall risk for ASCVD, CKD or mortality were significantly higher among males. Baseline co-presence of DFS, however, conferred a similar adjusted risk for all these outcomes between genders, and in case of non-vascular DFS the risk was significantly increased only among females.

Early reports from Asia suggested that increased serum levels of the muscular enzyme creatine-(phospho)-kinase (CK/CPK) could be associated with a more severe prognosis in COVID-19. The aim of this single-center retrospective cohort study of 331 consecutive COVID-19 patients who were hospitalized during Italy’s “first wave” was to verify this relationship, and to evaluate the role of possible confounding factors (age, body mass index, gender, and comorbidities). We subdivided our cohort in two groups, based on “severe” (n = 99) or “mild” (n = 232) outcomes. “Severe” disease is defined here as death and/or mechanical invasive ventilation, in contrast to “mild” patients, who were discharged alive with no need for invasive ventilation; this latter group could also include those patients who were treated with non-invasive ventilation. The CK levels at admission were higher in those subjects who later experienced more severe outcomes (median, 126; range, 10–1672 U/L, versus median, 82; range, 12–1499 U/L, p = 0.01), and hyperCKemia >200 U/L was associated with a worse prognosis. Regression analysis confirmed that increased CK acted as an independent predictor for a “severe” outcome. HyperCKemia was generally transient, returning to normal during hospitalization in the majority of both “severe” and “mild” patients. Although the direct infection of voluntary muscle is unproven, transient muscular dysfunction is common during the course of COVID-19. The influence of this novel coronavirus on voluntary muscle really needs to be clarified.

Il piede diabetico rappresenta una delle complicanze più severe del Diabete Mellito (DM) oltre che la prima causa di amputazione non traumatica degli arti inferiori; si stima, infatti, che ogni anno più di un milione di persone con DM siano sottoposte a trattamento demolitivo come conseguenza di questa condizione. Nonostante l’esistenza di linee guida nazionali ed internazionali sul management del piede diabetico, per alcuni aspetti gestionali le raccomandazioni proposte non raggiungono un forte livello di evidenza. Ciò rappresenta una potenziale fonte di incertezza decisionale, ma anche uno spunto da cui partire per chiarire aspetti legati al management del piede diabetico nella realtà italiana. L’obiettivo del presente documento è, quindi, quello di riadattare le raccomandazioni internazionali sulla gestione del piede diabetico alla luce dell’opinione di esperti italiani.

Patients with Type I Diabetes may develop some complications during their lifetime as a result of impaired metabolic control; among others, some of these common complications concerns microvascular function. The possibility of evaluating the cutaneous microcirculation is considered an important translational model because it could offer a important opportunity to non-invasive evaluation of diabetes-related vascular disorders.

Background Transferring results obtained in cardiovascular outcome trials (CVOTs) to the real-world setting is challenging. We herein transposed CVOT results to the population of patients with type 2 diabetes (T2D) seen in routine clinical practice and who may receive the medications tested in CVOTs. Methods We implemented the post-stratification approach based on aggregate data of CVOTs and individual data of a target population of diabetic outpatients. We used stratum-specific estimates available from CVOTs to calculate expected effect size for the target population by weighting the average of the stratum-specific treatment effects according to proportions of a given characteristic in the target population. Data are presented as hazard ratio (HR) and 95% confidence intervals. Results Compared to the target population (n = 139,708), the CVOT population (n = 95,816) was younger and had a two to threefold greater prevalence of cardiovascular disease. EMPA-REG was the CVOT with the largest variety of details on stratum-specific effects, followed by TECOS, whereas DECLARE and PIONEER-6 had more limited stratum-specific information. The post-stratification HR estimate for 3 point major adverse cardiovascular event (MACE) based on EMPA-REG was 0.88 (0.74–1.03) in the target population, compared to 0.86 (0.74–0.99) in the trial. The HR estimate based on LEADER was 0.88 (0.77–0.99) in the target population compared to 0.87 (0.78–0.97) in the trial. Consistent results were obtained for SUSTAIN-6, EXSCEL, PIONEER-6 and DECLARE. The effect of DPP-4 inhibitors observed in CVOTs remained neutral in the target population. Conclusions Based on CVOT stratum-specific effects, cardiovascular protective actions of glucose lowering medications tested in CVOTs are transferrable to a much different real-world population of patients with T2D.

Type 2 diabetes (T2D) is a risk factor for metabolic dysfunction-associated fatty liver disease (MAFLD), which is becoming the commonest cause of chronic liver disease worldwide. We estimated MAFLD prevalence among patients with T2D using the hepatic steatosis index (HSI) and validated it against liver ultrasound. We also examined whether glucose-lowering medications (GLM) beneficially affected HSI.We collected data from 46 diabetes clinics (n = 281,381 T2D patients), extracted data to calculate HSI and validated it against ultrasound-detected hepatic steatosis. We then examined changes in HSI among patients with a follow-up visit within 1 year after initiating newer GLMs.MAFLD (defined by HSI 36, i.e., a high probability of steatosis) was present in 76.3% of the 78,895 included patients, while only 2.7% had HSI 30 (low probability of steatosis). After age- and sex-adjusting, higher HSI was associated with higher prevalence of chronic kidney disease (odds ratio 1.35; 95%CI 1.22-1.51) and macroangiopathy (odds ratio 1.18; 95%CI 1.07-1.30). Among 2,179 subjects in the validation cohort, the prevalence of MAFLD was 67.8% and was greater in those with high HSI. Performance of HSI for ultrasound-detected MAFLD was moderate (AUROC 0.70), yet steatosis prevalence was threefold higher among subjects with HSI 36 than among those with HSI 30. Notably, HSI declined significantly ~ 6 months after initiation of dapagliflozin or incretin-based therapies, but not gliclazide.About three quarters of patients with T2D have HSI values suggestive of MAFLD, a condition associated with macroangiopathy and nephropathy. Treatment with dapagliflozin or incretin therapies might improve MAFLD in T2D.

Diabetic foot ulcers (DFUs) are common, complex, costly complications, associated with frequent recurrences and increased morbidity and mortality. DFUs can be prevented and their healing can be mostly influenced by appropriately and aggressively managing any infection, but the role of antiseptic therapies in reducing healing time lacks sufficient evidence. Several therapeutic interventions have been developed based on the principles of photomedicine to overcome the issue of poor drug circulation in infected areas, with the aim of killing microbial agents while leaving the surrounding host cells unharmed. Such techniques use absorption of photons by specific chromophores. Among these, RLP068 is a tetracationic Zn(II) phthalocyanine derivative activated by exposure to red light, used as a topical treatment for superficial bacterial and fungal infections. The photoactivation of RLP068 results in the production of singlet oxygen and other reactive oxygen species, able to affect a range of cellular targets, including cell membrane and/or wall, cytoplasm, and cellular components, resulting in a rapid, broad range, bactericidal and fungicidal effect. The phase IIa study showed that photoactivated RPL068 is capable of inducing a dose-dependent reduction in total and pathogen microbial load in infected diabetic foot ulcers. In this article, a case series of 22 DFU treated with photoactivated RLP068 at 5 different centers in Italy is presented. Considering microbial agents reduction, ulcer healing facilitation, healing rate (9 DFUs out of 22), and amputation rate (only 1 case over 22), the decrease in the cost of DFU seems to be a point in favor of RLP068 and its cost-effectiveness.

Aims: Several drug classes are now available to achieve a satisfactory metabolic control in patients with type 2 diabetes (T2DM), but patients’ preferences may differ. Methods: In a discrete-choice experiment, we tested T2DM patients’ preferences for recent antidiabetic drugs, in the event that their treatment might require intensification. The following attributes were considered: (a) route of administration; (b) type of delivery; (c) timing; (d) risk of adverse events; (e) effects on body weight. Twenty-two possible scenarios were built, transferred into 192 paired choices and proposed to 491 cases naïve to injectable treatments and 171 treated by GLP-1 receptor agonists (GLP-1RAs). Analyses were performed by descriptive statistics and random effects logit regression model. Results: Preferences according to dosing frequency, risk of nausea and urinary tract infections (UTls) were similar across groups, age, sex and BMI. Administration route and delivery type accounted for 1/3 of relative importance; the risk of UTIs, nausea and dosing frequency for ≈ 20% each, and weight loss for only 6%. Two significant interactions emerged (p < 0.01): type of delivery × group, and weight change × BMI class. Irrespective of previous treatment, the three preferred choices were injectable, coupled with weekly dosing and a ready-to-use device (first two choices). In a regression model, being naïve or non-naïve changed the ranking of preferences (p < 0.001), and the order was systematically shifted towards injectable medications in non-naïve subjects. Conclusion: Easy-to-deliver, injectable treatment is preferred in T2DM, independently of treatment history, and previous experience with GLP-1RAs strengthens patients’ willingness to accept injectable drugs.

Background Limited Joint Mobility (LJM) is a dreaded complication of Diabetes Mellitus (DM). During the last half century, LJM has been studied in patients of different age because it has been considered useful for the monitoring of a patient's condition and for the prevention of vascular disease and diabetic foot. Objectives The main aims of this review are to describe the relationship between DM and joint mobility as well as its prevalence and assessment. We have also investigated the role of LJM in the development of diabetic foot ulcers. Methodology An in-depth literature search was conducted to identify studies that examined the prevalence and characteristics of LJM in patients with DM of different types, age, durations and chronic complications. Results Many factors (therapy improvements, population characteristics and different evaluation methods) concur to hinder an exact assessment of the prevalence of LJM. However, it has been confirmed that LJM is widespread among patients with DM and may affect more than two-thirds of them in addition to being a major risk factor for foot ulcer. Its role in the monitoring of a patient's condition is also important for the definition of risk thresholds such as in patients with diabetic foot. The efficacy of exercise therapy for the treatment of LJM, also in patients at risk of foot ulcer, has not been discussed. Conclusion Difficulties encountered in the definition of the prevalence of LJM may hinder its study and the establishment of preventive interventions. However, LJM plays a key role in the monitoring of patients, especially those at risk for ulcer.

Diabetic foot is a major public health issue, driven by diabetes complications (neuropathy, peripheral vascular disease, foot deformity, and abnormal leucocyte function), which may lead to leg amputation, thus resulting in severe disability, reduced quality of life, and high health costs. The prevention of diabetes complications and the early detection and proper management of diabetic foot wounds are the milestones to avoid major amputations. Unfortunately, in many areas, the prevention of diabetic foot lesions is inadequate and wounds may proceed toward infection and chronicity, with limb- and life-threatening results. Using the Delphi method, we conducted a survey on diabetic foot among Italian experts, selected across different Italian clinical centers. This method was used to achieve a consensus on current opinion and clinical leanings on the diagnosis and management of diabetic foot ulcers. Specifically, the aim of the survey was to evaluate the current management of the diabetic foot syndrome; highlight the differences in the approach among a group of experts; evaluate the role of wound bed preparation and antisepsis; and discuss any areas of disagreement in which evidences are sparse and the clinical judgment plays a crucial role in the decision-making process.

To provide data on hospitalization and incidence rates of Charcot neuroarthropathy (CN) and its relation to lower limbs' amputations/revascularizations in population with diabetes of Italy as well as of one of its regions (Tuscany).Hospitalizations with CN diagnosis (codes ICD-9-CM: 7130, 7135, 7138) have been recorded in people with diabetes over years 2003-2013 in Italy and 2008-2015 in Tuscany. Amputations, peripheral vascular disease, revascularizations and infections were likewise evaluated.Between 2003 and 2013 CN hospitalizations were very infrequent in Italy ranging between 14×100,000 and 11×100,000 patients with diabetes. In Tuscany they declined to a minimum of 7×100,000 patients in 2015, after a previous increase to a maximum of 22×100,000 (p=NS for both). Yearly CN incidence remained constant in Italy, declining in Tuscany to a minimum of 3.4×100,000 diabetic patients in 2015 (p=0.047). CN patients were younger and with longer length of hospital stay than those with non-Charcot diabetic foot (p0.05 for both). Amputation and infection rates were manifold higher in CN patients than in those with non-Charcot diabetic foot, while the revascularization rate was similar in both.Over last decade, in Italy and Tuscany yearly CN incidence and hospitalization rates concerned only a small percentage of patients, remaining constant over years and declining in Tuscany in the last couple of years. CN was significantly associated to younger age, longer hospital stay and greater risk of amputations and infections while the need of revascularization was similar to that of non-Charcot diabetic foot.

To investigate whether statins reduce the risk to first hospitalization of bacterial infections, in patients with or without diabetes taking into account prior or incident comorbidities. By using administrative databases, the effect of current statin use was measured on the risk of first hospitalizations due to bacterial infections in people living in Tuscany, Italy, in the period January 1, 2011–December 31, 2015, after excluding those with previous statins use. Population was stratified as with (n = 128,207) or without diabetes (n = 3,304,906), and the hospitalization risk was analyzed by a Cox proportional hazards regression analysis after adjusting for age, gender, previous comorbidities, chronic renal failure, and prior or incident cardiovascular diseases. During the 5-year follow-up, 31,543 hospitalizations for bacterial infections were observed: 2.08(2.06–2.10) per 1000 person-year in non-diabetic and 5679: 9.13(8.94–9.32) per 1000 person-year in diabetic population. Diabetes conferred a greater risk of hospitalizations, independently from confounders [adjusted HR (95% CI) 2.04 (1.97–2.10); P

While in non-diabetic people the risk for cardiovascular disease is higher in men, diabetes completely reverts this sex-gender difference conferring to women a greater burden of cardiovascular complications. Additionally, all risk factors associated with cardiovascular disease appear to be more active in diabetic females than in their male counterparts. The reasons of this different impact of diabetes between genders are not completely clear. The aim of this review is trying to clarify these issues in a sex and gender perspective. Both genetic and hormonal factors are at the basis of sex-gender differences in diabetes, even do not explain the totality of data. Possibly women arrive later and in worse conditions to the diagnosis of diabetes, receive both diagnostic and therapeutic supports in a lesser measure and, finally, reach therapeutic goals as recommended by guidelines in a lesser extent. Further aspects of sex-gender differences in diabetic complications are represented by a more frequent prevalence of drug side effects in women, as well as by increased resistance to the action of drugs used in prevention or in the therapy of cardiovascular diseases. As to microvascular complications, the issue of sex-gender differences is even more complex, with some important differences emerging in experimental models 'in vitro', as well as in human pathology 'in vivo'. The main problem, however, also in this case, is that it is difficult to differentiate how common pathogenetic mechanisms acting in diabetes may differently impact between genders. In conclusion what is evident is that diabetes represents a 'risk magnifier' for the damage of both micro and macrovessels differently in men and in women. This issue deserves, therefore, a more careful approach from people involved in both clinical aspects and research regarding diabetes and its complications, in a sex-gender oriented perspective.

Objective Women with diabetes have a greater excess risk for cardiovascular diseases (CVD) than men. This study was aimed at clarifying whether this effect is lifelong or more evident in some life-periods. Methods The effect of diabetes and gender on the risk of first ever hospitalization for acute myocardial infarction (AMI), ischemic stroke (IS), congestive heart failure (CHF), lower extremity amputations (LEA) or any of these major cardiovascular events (MACE) have been evaluated by a Cox-hazard model, over years 2008–2012 querying administrative databases of a cohort living in Tuscany, Italy. Results Comparing subjects with diabetes to those without it the overall age-adjusted excess risk was higher in women than in men for AMI and MACE and higher in men for LEA, with no difference for IS or CHF. In women the excess risk for AMI and MACE started earlier (46 yr) and lasted until age of more than 85 yr, while ‘risk-windows’ opened later and had a shorter duration for CHF (56–65 yr) and IS (66–75 yr). Conclusion Diabetic women have a significant diabetes-associated excess of CVD risk, except for LEA, with a ‘risk window’ opening earlier and lasting longer for AMI and MACE, later and with a shorter duration for IS and CHF.

An increasing amount of evidence confirms that abnormalities in glucose metabolism are associated with cardiovascular morbidity and mortality in acute coronary syndromes (ACS). The in-hospital management of hyperglycemic diabetic patients with ACS is complex, and the traditional clinical-organizational approaches show a high degree of heterogeneity nationwide in Italy.The current survey (March 2016-January 2017), carried out through the Delphi method, was focused on some management issues to verify the modalities/possibilities of resolution in daily clinical practice. In addition to the 12 members of the Board, who defined the web-based questionnaire and coordinated the various stages of the process, 66 specialists, cardiologists or diabetologists, were involved in 6 Italian Regions (Lombardy, Tuscany, Lazio, Friuli-Venezia Giulia, Puglia and Sicily). Three iterative rounds of evaluation of the 24 statements included in the questionnaire were scheduled. For each statement, the median evaluation value and the degree of convergence of the Panel of specialists were determined.The final analysis reveals two key aspects with a broad convergence of opinions: (i) the need, since admission to hospital, of a close collaboration between cardiologists and diabetologists in the assistance of high-risk patients; and (ii) the opportunity of a specific diagnostic therapeutic care pathway extended to post-discharge management, where the role of the general practitioner should be adequately emphasized.

Background The burden of type 1 diabetes (T1D) is growing worldwide, stressing the requirement to limit the threat of its long-term complications. In this regard, the development of methods for the early diagnosis and non-invasive monitoring of vascular abnormalities is widely recognized as one of the greatest priorities of the clinical research in this field. Objective To assess the deterioration of physiological properties extracted from laser Doppler flowmetry (LDF) signals of microvascular perfusion and, secondly, to investigate their association with the quality of long-term metabolic control. Methods Microvascular perfusion was recorded at the hallux of 63 control subjects and 47 T1D patients, whose glycaemic control was characterized in terms of the annual average levels of glycosylated haemoglobin (HbA1c). Pulse Decomposition Analysis was applied to the LDF data, in order to derive non-invasive markers of vascular stiffness based on a multi-Gaussian representation of the peripheral pulse waveforms; furthermore, wavelet transform analysis was used to evaluate the microvascular myogenic vasomotion and, finally, a physiological model of the reactive hyperaemia to a local thermal stimulus at 43 was used to test the integrity of the neurovascular pathways. Results Compared to the control group, T1D patients showed a lower microvascular perfusion at baseline, and a larger vasodilatory reserve upon local heating, but no significant difference in myogenic activity. Moreover, the results of the PDA carried out on the LDF pulse waves, indicate the presence of a significant strong relation between large artery stiffness and the overall loss of glycaemic control over the past year.

The microvascular perfusion is modulated by physiological functions, which have been associated with specific frequency ranges. Although cardio-respiratory interactions have been widely analyzed at a macrocirculation level, only few studies have been conducted with the aim to understand the effect of breathing on the peripheral circulation. Diabetic microangiopathy is characterized by structural and functional alterations of the blood microvessels, which reflect in a modification of the physical properties of peripheral microvascular beds, such as vascular stiffness. A wavelet phase coherence (WPC) analysis was performed to elucidate the time-phase relationship between the respiratory activity and vascular-dependent features of the peripheral pulse, reconstructed by means of a novel multi-Gaussian modeling algorithm. The present WPC analysis was conducted on a group of 24 healthy volunteers, mean age 30±15 years, in comparison with 21 type-1 diabetic (T1D) subjects, mean age 26±3 years, in order to detect the effects of T1D on the physiological coupling between breathing and microcirculation. The peripheral cutaneous perfusion was assessed on the pulp of the index finger with the laser Doppler flowmetry (LDF) technique, while the respiratory signal was simultaneously recorded with a wearable chest band. In 17 out of the 24 control subjects involved (i.e., 71%), significant WPC values were identified in the respiratory frequency range (0.145-0.6 Hz), with respect to the area beneath the diastolic portion of the peripheral pulse (median WPC: 77.9%). This outcome indicates that the diastolic phase of the pulse exhibits a marked periodicity linked to the breathing activity. The analysis conducted on the T1D group highlighted a loss of synchronization, with significant WPC levels found in only 33% of the investigated subjects. These results suggest that the proposed method is able to detect the detrimental effects of T1D on the blood microcirculation. Disclosure A. Perrella: None. M. Sorelli: None. P. Francia: None. L. Capirchio: None. R. Anichini: Advisory Panel; Self; Abbott. Speaker's Bureau; Self; Novartis Pharmaceuticals Corporation, Boehringer Ingelheim GmbH. Advisory Panel; Self; Eli Lilly and Company, AstraZeneca. Speaker's Bureau; Self; Merck & Co., Inc., Takeda Development Centre Europe Ltd.. Advisory Panel; Self; Sanofi, Janssen Pharmaceuticals, Inc.. Research Support; Self; Grünenthal Group. A. de Bellis: Speaker's Bureau; Self; Eli Lilly and Company, AstraZeneca, Novo Nordisk A/S. Research Support; Self; Grünenthal Group. M. Gulisano: None. L. Bocchi: None.

In patients with diabetic foot (DF) the risk of developing cardiovascular events or renal failure is strongly increased. While DF is more frequent in males, it is yet unknown if there is a gender difference about cardiovascular events or renal failure incidence in patients with diabetic foot. The aim of this study was to evaluate the risk of hospitalization for cardiovascular events (ASCVD: heart attack, ischemic stroke or heart failure) or chronic renal failure (CKD), stratified by gender, in a population of diabetic patients living in Tuscany from 2012 to 2016. On the basis of administrative data bases, patients living in Tuscany at the 1st of January 2012 were divided into 2 subgroups: patients previously hospitalized for diabetic foot (ulcers, infections, major or minor amputations, gangrene or Charcot foot) and patients without history of hospitalization for diabetic foot. Data were collected from the regional hospitalization registry, and in the two groups the risk of developing ASCVD or CKD by the Cox regression corrected by age and comorbidities (Charlson Index of previous hospitalizations) separately in males and females was evaluated. 240238 patients with diabetes (121442 males, 118796 females) were identified. After the corrections made by age, sex and Charlson index, males showed a major risk of developing diabetic foot (DF): Odds Ratio (OR):2.018 (95% CI:1.901-2.141); p Disclosure R. Anichini: Advisory Panel; Self; Abbott. Speaker's Bureau; Self; Novartis Pharmaceuticals Corporation, Boehringer Ingelheim GmbH. Advisory Panel; Self; Eli Lilly and Company, AstraZeneca. Speaker's Bureau; Self; Merck & Co., Inc., Takeda Development Centre Europe Ltd.. Advisory Panel; Self; Sanofi, Janssen Pharmaceuticals, Inc.. Research Support; Self; Grünenthal Group. L. Policardo: None. P. Francesconi: None. P. Francia: None. A. de Bellis: Speaker's Bureau; Self; Eli Lilly and Company, AstraZeneca, Novo Nordisk A/S. Research Support; Self; Grünenthal Group. M. Gulisano: None. G. Seghieri: None.

Considering that the knowledge and control of the daily physical activity performed (PAP) is an important element in the management of patients with history of foot ulcers, peripheral neuropathy and/or peripheral vascular disease (at risk), the analysis of the social network map (SNM) perceived by themselves directly could also provide useful information to manage their diabetes. This study aimed to verify the possibility to evaluate the presence of a relationship between the characteristic of the SNM perceived and the PAP in addition to the metabolic control maintained in patients with longstanding diabetes mellitus at risk of foot ulcer. Interviews were conducted in 27 people: 10 patients: (males/females:6/4), mean age 56,2±16,7 years, duration of diabetes 18,3±10,3 years, mean HbA1c 8,0±1,1%, body mass index (BMI) 27,0±4,1 kg/m2, and in 17 age, sex and BMI matched nondiabetic controls. Participants were asked to fill in an egocentric SNM, which was divided into 5 areas: leisure and PAP, family, job, health care, and other. It was assigned a value ranging from 0 (none) to 5 (maximum) to define the importance and frequency of the relationships reported. The PAP was evaluated by the International Physical Activity Questionnaire-Short Form (IPAQ). In the patient group the duration of the disease was directly correlated with the health area (r = 0.83, p Disclosure P. Francia: None. A. Tedeschi: None. M. Gulisano: None. G. Iannone: None. A. Vittori: None. U. Santosuosso: None. F. Paternostro: None. R. Anichini: Advisory Panel; Self; Abbott. Speaker's Bureau; Self; Novartis Pharmaceuticals Corporation, Boehringer Ingelheim GmbH. Advisory Panel; Self; Eli Lilly and Company, AstraZeneca. Speaker's Bureau; Self; Merck & Co., Inc., Takeda Development Centre Europe Ltd.. Advisory Panel; Self; Sanofi, Janssen Pharmaceuticals, Inc.. Research Support; Self; Grünenthal Group.

Among diabetic patients, microangiopathy represents a relevant cause of morbidity and mortality. Diabetes induces detrimental changes in the biomechanical characteristics of blood microvessels, and fuels the development of a dysfunctional vascularization. Since the structural properties of the circulatory system affect the microvascular pulse, the aim of this study was to detect these vascular alterations through a model-based quantitative analysis of its waveform. Baseline microvascular perfusion was recorded on the hallux with a laser Doppler flowmeter. 54 healthy subjects (age: 34 ± 26 years) and 22 type 1 diabetic (T1D) patients without known cardiovascular complications and smoking history (age: 34 ± 17 years) were compared. A novel multi-Gaussian decomposition algorithm was applied to reconstruct the heartbeat-related oscillations, which were evaluated according to normalized and physiologically-motivated shape descriptors. Eight out of the nine properties assessed significantly differed between the groups (p < 0.001), indicating that the proposed pulse modeling method is sensitive to the effects of T1D on the peripheral perfusion.

This study has been performed in diabetic type 2 patients with pain due to peripheral artery disease (PAD) in order to evaluate the efficacy and tolerability of tapentadol prolonged release (PR). Methods. 25 patients with type 2 diabetes (13 F and 12 M) were admitted in the study. The evaluation of the analgesic efficacy of tapentadol PR was based on both the assessment of the intensity of the pain (NRS scale from 0 to 10) and the nature of the pain (DN4 questionnaire) and on assessment of the patient’s quality of life and state of health (SF-12 Health Survey). Study duration was 3 months: a baseline visit and follow-up included visits after 1 week, 1 month, 2 months, and 3 months. Results. At the beginning of the study, the mean intensity of the pain was 7.88 ± 1.17 on the NRS scale and at visit 2 it reduced in a statistically significant way; at the end of the treatment with tapentadol PR, the mean intensity was 2.84 points on the NRS scale. Conclusion. In type 2 diabetic patients with chronic severe pain due to PAD, tapentadol PR reduced pain intensity, improving the quality of life.

Objective To retrospectively evaluate the impact of pedal arch quality on tissue loss and time to healing in diabetic patients with foot wounds undergoing infrainguinal endovascular revascularization. Materials and Methods Between January 2014 and June 2015, 137 consecutive diabetic patients with foot wounds underwent infrainguinal endovascular revascularization (femoro-popliteal or below-the-knee, arteries). Postprocedural angiography of the foot was used to divide the patients into the following three groups according to the pedal arch status: complete pedal arch (CPA), incomplete pedal arch (IPA), and absent pedal arch (APA). Time to healing and estimated 1-year outcomes in terms of freedom from minor amputation, limb salvage, and survival were evaluated and compared among the three groups. Results Postprocedural angiography showed the presence of a CPA in 42 patients (30.7%), IPA in 60 patients (43.8%), and APA in 35 patients (25.5%). Healing within 3 months from the procedure was achieved in 21 patients with CPA (50%), 17 patients with IPA (28.3%), and in 7 patients with APA (20%) (p = 0.01). There was a significant difference in terms of 1-year freedom from minor amputation among the three groups (CPA 84.1% vs. IPA 82.4% vs. APA 48.9%, p = 0.001). Estimated 1-year limb salvage was significantly better in patients with CPA (CPA 100% vs. IPA 93.8% vs. APA 70.1%, p < 0.001). Estimated 1-year survival was significantly better in patients with CPA (CPA 90% vs. IPA 80.8% vs. APA 62.7%, p = 0.004). Conclusion Pedal arch status has a positive impact on time to healing, limb salvage, and survival in diabetic patients with foot wounds undergoing infrainguinal endovascular revascularization.

To evaluate the effect of diabetes by gender on the peak-risk of first-ever-ischemic stroke and its recurrence.Administrative datasets including all hospital discharges for ischemic stroke (N = 43,332) in the diabetic (N = 207,568) and non-diabetic (N = 2,808,554) population of the Tuscany region, Italy were used to calculate Hazard ratios (HR) after Cox-regression, of first-ever and recurrent ischemic strokes, between 2005 and 2011.Overall, diabetes increased the HR of first-ever ischemic stroke by about 50% in both genders. However, this risk significantly declined with age and was higher in women aged 55-74 yr than in men of the same age (HR; 95% CI: 1.392; 1.228-1.579 in age-class 55-64 yr and 1.203; 1.110-1.304 in age class 65-74 yr; p0.001). Diabetes also increased the adjusted risk of three-year-stroke recurrence (N = 5,998) in women, independently of age, whereas this was the case in men70 yr.Diabetes is associated with increased risk of ischemic stroke although it declines with age though at lower rate among women than men. Moreover, diabetic women have greater risk of recurrence than in men70 yrs old, supporting a high-risk "time-window" in postmenopausal-elderly diabetic women.

Evaluation of how ankle joint mobility (AJM) can be useful in the identification of patients with diabetes at risk of foot ulcer (FU).Plantar and dorsal flexion of foot were evaluated using an inclinometer in 87 patients (54 type 2 and 33 type 1), and 35 healthy sex- and age-matched control subjects. Patients with diabetes were followed up for diagnosis of FU over the next 8 years and subsequently, patients were subdivided into: those without a history of FU (18 type 1 and 33 type 2), those who had a history of FU detected before baseline evaluation (14 type 2) and those who had history of first ulceration detected by the 8th year of the evaluation period (7 type 2).Aging and diabetes caused a significant reduction in mobility of each of the movements investigated (p0.001), whereas after adjusting for the confounding effect of age, diabetes specifically reduced plantar flexion (p0.0001). AJM was significantly lower in those with history of previous FU compared to all the other groups (p0.001). The first ulceration was detected in the same foot presenting lower AJM in 17 of the 22 subjects with diabetes with history of ulcer (77.27%).Diabetes and aging reduce AJM although diabetes seems to reduce plantar flexion to a more specific extent. Reduced AJM is mostly associated with a previous history of FU. The evaluation of AJM is a valid and reliable ulcer risk scale that indicates which foot is at higher ulcer risk.

Background The aim of this study was to evaluate the impact of pedal arch status and direct-angiosome revascularization (DAR) on clinical outcomes in diabetic patients with foot wounds undergoing endovascular revascularization. Methods Between January 2014 and June 2015, 93 diabetic patients with foot wounds underwent endovascular revascularization of at least one below-the-knee vessel. Patients were divided into three groups according to the pedal arch status: complete pedal arch (CPA), incomplete pedal arch (IPA) and absent pedal arch (APA). Healing within 3 months and 1-year outcomes in terms of freedom from minor amputation, limb salvage, and survival were evaluated on the basis of DAR and pedal arch status. Results DAR did not affect healing within 3 months from the procedure (DAR, 13/55 cases, 23.6% vs. n-DAR, 9/38 cases, 23.7%; P=1), estimated 1-year freedom from minor amputation (DAR 74.4% vs. n-DAR 76.8%, P=0.80), limb salvage (DAR 88.2% vs. n-DAR 89.5%, P=0.44), and survival (DAR 83.3% vs. n-DAR 66.6%, P=0.15). Pedal arch had positive impact on wound healing within 3 months from the procedure (CPA 45.8% vs. IPA 12.5% vs. APA 20.7%, P=0.009), estimated 1-year limb salvage (CPA 100% vs. IPA 90.9% vs. APA 76.1%, P=0.02), and 1-year survival (CPA 100% vs. IPA 87.2% vs. APA 60.3%, P=0.02). Conclusions DAR is not a predictor of good outcomes in diabetic patients undergoing endovascular procedure. Pedal arch patency seems to be a key factor to obtain good outcomes in terms of wound healing, and limb salvage.

Background. Taurine transporter gene expression (RNA-TauT) has a role in retinal cell function and is modulatedin vitroandin vivoby hyperglycemia and/or oxidative stress. This study was aimed at testing whether RNA-TauT gene expression is modified in blood mononuclear peripheral cells (MPCs) of type 1 diabetic patients, is related to plasma markers of oxidative stress or endothelial dysfunction, or, finally, is related to presence of retinopathy.Methods. RNA-TauT was measured in MPCs by real-time PCR-analysis in 35 type 1 diabetic patients and in 33 age- and sex-matched controls, additionally measuring plasma and cell taurine and markers of oxidative stress and endothelial dysfunction.Results. RNA-TauT, expressed as2-ΔΔCt, was significantly higher in MPCs of type 1 diabetic patients than in controls [median (interquartile range): 1.32(0.31) versus 1.00(0.15);P=0.01]. In diabetic patients RNA-TauT was related to HbA1c (r=0.42;P=0.01) and inversely to plasma homocysteine (r=-0.39;P=0.02) being additionally significantly higher in MPCs of patients without retinopathy [(n=22); 1.36(0.34)] compared to those with retinopathy [(n=13); 1.16(0.20)], independently from HbA1c or diabetes duration.Conclusions. RNA-TauT gene expression is significantly upregulated in MPCs of type 1 diabetes patients and is related to HbA1c levels and inversely to plasma homocysteine. Finally, in diabetes patients, RNA-TauT upregulation seems to be blunted in patients with retinopathy independently of their metabolic control or longer diabetes duration.

Background and aims: Diabetic women have a more adverse plasma lipid profile than men. Sex differences in dietary habits may play a role, but are little investigated. The study evaluates the quality of diet, adherence to the nutritional recommendations of the Diabetes and Nutrition Study Group and their relation with plasma lipid in men and women with diabetes. Methods and results: We studied 2573 people, aged 50e75, enrolled in the TOSCA.IT study (clinicaltrials.gov; NCT00700856). Plasma lipids were measured centrally. Diet was assessed with a semi-quantitative food frequency questionnaire.Women had a more adverse plasma lipid profile than men.Women consumed significantly more legumes, vegetables, fruits, eggs, milk, vegetable oils, and added sugar, whereas men consumed more starchy foods, soft drinks and alcoholic beverages. This stands for a higher proportion (%) of energy intake from saturated fat and added sugar (12.0 2.4 vs 11.5 2.5 and 3.4 3.2 vs 2.3 3.2, P < 0.04), and a higher intake of fiber (11.2 2.8 vs 10.4 2.6 g/1000 Kcal/day) in women. Adherence to the recommendations for saturated fat and fiber consumption was associated with significantly lower LDL-cholesterol regardless of sex. Adherence to the recommendations for added sugars was associated with significantly lower triglycerides and higher HDL-cholesterol in men and women. Conclusions: Men and women with diabetes show significant differences in adherence to nutritional recommendations, but sex differences in plasma lipid profile are unlikely to be explained by nutritional factors. Adherence to the nutritional recommendations is associated with a better plasma lipid profile regardless of sex, thus reinforcing the importance of substituting saturated for unsaturated fat sources, increasing fiber and reducing added sugar intake.

Aims To identify incidental previously unrecognized diabetes (IPUD) among hospitalized patients and corresponding mortality risk in comparison with individuals with known diabetes (KDM). Methods Out of 214,991 individuals discharged in year 2011 from all hospitals of Tuscany, Italy we retrospectively identified IPUD as individuals with no known diabetes and/or previous antidiabetic medication, receiving at least two prescriptions of glucose-lowering-drugs over the next 6months after discharge. Two-year (2012–2013) adjusted mortality risk was tested by a Cox-regression-analysis, comparing IPUD and KDM patients with at least one hospital admission in 2011. Results 974 patients with IPUD (375.6×100,000 hospitalized people) have been identified. IPUD risk was associated with aging, male gender and greater burden of co-morbidities, was higher in migrants of non-Italian ancestry and was reduced among patients of family physicians adhering to guidelines resulting in a proactive model of care delivery. In IPUD patients alive at 1st January 2012, (n=865) the adjusted risk of two-year mortality was similar to that of KDM subjects (HR=1.08; 95% CI: 0.92–1.26; p=NS). Conclusions IPUD occurs more commonly in older male subjects, migrants of non-Italian ancestry, and among patients of physicians non-adhering to a shared diabetes care model. People with IPUD have similar two-year-mortality risk compared with KDM individuals.

Cardiovascular risk among diabetic patients is at least twice as much the one for non-diabetic individuals and even greater when diabetic women are considered. Heart failure (HF) is a common unfavorable outcome of cardiovascular disease in diabetes. However, since the comparison among sexes of heart failure prevalence in diabetic patients remains limited, this study is aimed at expanding the information about this point.We have evaluated the association between diabetes and HF by reviewing the medical records of all subjects discharged from the Internal Medicine and Cardiology Units of all hospitals in the Tuscany region, Italy, during the period January 2002 through December 2008. In particular we sought concomitance of ICD-9-CM codes for diabetes and HF.Patients discharged by Internal Medicine were on average older, more represented by women, and had a lesser number of individuals coded as diabetic (pAlthough there is not a difference in the overall HF risk between hospitalized male and female diabetic patients, women have an excess risk at perimenopausal age.

Obesity and weight increase during adult life are strong predictors of type 2 diabetes. Whether fasting plasma glucose (FPG) is likewise related to body weight as well as with its increase during the adult life in obese-overweight people and whether this relationship is different between the genders is the question asked by the present study. We measured FPG in 1063 overweight-obese subjects (395M/668F) with BMIor =25 kgm(-2) and classified with no history of diabetes and with a FPG7 mmol/l, who consequently came to the Outpatient Clinic of our Diabetes Unit to obtain dietetic advice. Weight increase was determined as the difference between actual weight and weight at 18 years (weight-diff), including only patients with weight-diff0. By univariate analysis age, BMI, waist circumference and weight change were loosely related to FPG in both sexes, even if the relation between plasma glucose and anthropometric variables was more consistent in females. By multivariate regression analysis, after adjusting for age, waist circumference, menopausal status and smoking habit, FPG was significantly related to both waist circumference and weight-diff only in women. Odds Ratio for fasting hyperglycaemia (FPG6.11 mmol/l), for each S.D. unit increase in weight-diff, after adjusting for age, waist circumference, smoking habit and menopausal status was 1.272; 95% CI: 0.863-1.901 (p=ns) for males and 1.800; 95% CI: 1.239-2.652 (p=0.002) for women. In conclusion our findings suggest that in non-diabetic overweight-obese people, after controlling for main cofounders, anthropometric variables and in particular waist circumference and weight change after 18 years are linearly related to FPG in women, independently predicting the risk of fasting hyperglycaemia only in these latter.

OBJECTIVE— The aim of this article was to define the metabolic phenotype of pregnant women with one abnormal value (OAV) during an oral glucose tolerance test (OGTT) and to test whether OAV could be considered metabolically comparable to gestational diabetes mellitus (GDM) or a specific entity between GDM and normal pregnancy. RESEARCH DESIGN AND METHODS— After 100-g 3-h OGTTs, 4,053 pregnant women were classified as having GDM, OAV, or normal glucose tolerance (NGT). Those with OAV were subdivided into three subgroups: fasting hyperglycemia (one abnormal value at fasting during an OGTT), 1-h hyperglycemia (one abnormal value at 1 h during an OGTT [1h-OAV]), or 2- or 3-h hyperglycemia (one abnormal value at 2 or 3 h during an OGTT). As derived from the OGTT, we measured insulin sensitivity (insulin sensitivity index [ISI] Matsuda) and insulin secretion (homeostasis model assessment for the estimation of β-cell secretion [HOMA-B], first- and second-phase insulin secretion). The product of the first-phase index and the ISI was calculated to obtain the insulin secretion–sensitivity index (ISSI). RESULTS— GDM was diagnosed in 17.9% and OAV in 18.7% of pregnant women; women with GDM and OAV were older and had higher BMI and serum triglyceride levels than those with NGT (all P < 0.05). Women with NGT had the highest ISI followed by those with OAV (−21.7%) and GDM (−32.1%). HOMA-B results were comparable with those for OAV and GDM but significantly (P < 0.01) lower than those for NGT; first- and second-phase insulin secretion appeared progressively reduced from that in women with NGT to that in women with OAV and GDM (P < 0.01). ISSI was higher in women with NGT than in women with either OAV (−34%) or GDM (−51.7%) (P < 0.001). Among OAV subgroups, the 1h-OAV subgroup showed the lowest ISSI (P < 0.05). CONCLUSIONS— OAV and GDM are clinically indistinguishable, and both groups are different from women with NGT. Women with GDM and OAV showed impaired insulin secretion and insulin sensitivity, although these defects are more pronounced in women with GDM. Compared with other OAV subgroups, 1h-OAV could be considered a more severe condition.

Taurine is the most abundant amino acid in the human body and seems to play an important role in increasing glucose-mediated insulin secretion, as well as in programming beta-cell maturation during the prenatal life in utero. To test the hypothesis that plasma taurine is related to glucose tolerance, insulin sensitivity and insulin secretion in subjects with history of beta-cell dysfunction such as women with history of gestational diabetes (GDM), we studied 72 non-diabetic women with history of GDM (n=43), impaired glucose tolerance (IGT; n=7), and normal glucose tolerance (NGT; n=22) as previously classified by a 100g-3h-OGTT performed between the 24th and the 28th gestational week. Insulin sensitivity (ISIogtt, calculated through Matsuda-DeFronzo index) and a proxy for insulin secretion (basal plasma C-peptide/fasting plasma glucose; CP/glucose) were measured during and after pregnancy. Plasma taurine was measured after a median period of 6 years (2-11 years) from index pregnancy, when glucose tolerance was retested by a 75 g-2h-OGTT. Plasma taurine was significantly lower in women who had experienced GDM and was unrelated to ISIogtt. Moreover, plasma taurine was inversely related to previous gestational area-under-curve of glucose and directly related to post-gestational CP/glucose, as well to CP/glucose measured during pregnancy (p

Background Incidence of ischemic stroke and associated in-hospital mortality is decreasing in Western populations, while the prevalence of diabetes, a well-known risk factor for ischemic stroke, is progressively rising. This study was aimed at evaluating the effect of diabetes on ischemic stroke hospitalization and in-hospital mortality after ischemic stroke. Methods Discharges with diagnosis of ischemic stroke were identified in a database containing all hospitalizations of resident population of Tuscany, Italy, over years 2004–2011. Cases with diabetes were identified through specific drug prescriptions, official certifications or previous hospital diagnosis. Rates of annual ischemic stroke incidence and related in-hospital mortality were separately calculated for gender and age class, in subjects with and without diabetes. Results Sixty-five thousand one hundred sixty-five hospital discharges with ischemic stroke diagnosis were identified. Diabetes was associated with increased risk of stroke odds ratio(95% confidence interval):1.31(1.28–1.34) in men and 1.24(1.21–1.37) in women. Diabetic women, compared with men, had a higher in-hospital mortality risk after ischemic stroke (odds ratio:1.32; 1.06–1.64), whereas in non-diabetic subjects, there was no difference between genders. Incidence of ischemic stroke has declined in non-diabetic subjects, except for women aged ≤70 years; a similar reduction was observed for in-hospital mortality. Among diabetic patients, conversely, annual incidence of ischemic stroke rose by 3% in the elderly people (>70 years), and annual mortality trend remained unchanged. Conclusions In the last decade, the incidence of ischemic stroke and of related in-hospital mortality declined in persons without diabetes, while increasing among diabetic patients of advanced age. Women with diabetes, compared with men, had a higher in-hospital mortality risk. Copyright © 2014 John Wiley & Sons, Ltd.

Telemedicine systems based on mobile phones represent new promising educational tools. The "Diabetes Interactive Diary" (DID) is a carbohydrate/bolus calculator promoting the patient-physician communication via short message service. This study aimed to compare the efficacy of the DID versus usual care on metabolic control, hypoglycemia, and quality of life.Patients with type 1 diabetes on a basal:bolus regimen with insulin glargine and insulin glulisine, not previously educated on carbohydrate (CHO) counting, were randomized to DID (Group A; n=63) or traditional education (Group B; n=64). Generalized hierarchical linear regression models for repeated measures were applied to compare changes between groups. Incidence of hypoglycemia was compared using Poisson regression models.Of 127 patients (age, 36.9±10.5 years; diabetes duration, 16.3±9.3 years), 15 (11.8%) dropped out. After 6 months, hemoglobin A1c (HbA1c) levels decreased by -0.49±0.11 in Group A and -0.48±0.11 in Group B (P=0.73). Group A showed a 86% lower risk of grade 2 hypoglycemia than Group B. Compared with usual care, DID improved the "perceived frequency of hyperglycemic episodes" scale of the Diabetes Treatment Satisfaction Questionnaire and the "social relations" and the "fear of hypoglycemia" dimensions of the Diabetes Specific Quality of Life Scale. Results obtained with DID markedly differ among patients and centers.DID is no more effective than traditional CHO counting education in reducing HbA1c levels. DID reduces the risk of moderate/severe hypoglycemia and improves quality of life. A better understanding of patients' and healthcare professionals' attitudes associated with an effective care supported by technology is essential to avoid waste of resources.