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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.

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.

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.

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.

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.

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. 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.

Considering old GDM diagnostic criteria, alterations in insulin secretion and action are present in women with GDM as well as in women with one abnormal value (OAV) during OGTT. Our aim is to assess if changes in insulin action and secretion during pregnancy are related to 1-hour plasma glucose concentration during OGTT. We evaluated 3 h/100 g OGTT in 4,053 pregnant women, dividing our population on the basis of 20 mg/dL increment of plasma glucose concentration at 1 h OGTT generating 5 groups (n=661; 120–139 mg/dL,n=710; 140–159 mg/dL,n=912; 160–179 mg/dL,n=885; and ≥180 mg/dL,n=996). We calculated incremental area under glucose (AUCgluc) and insulin curves (AUCins), indexes of insulin secretion (HOMA-B), and insulin sensitivity (HOMA-R), AUCins/AUCgluc. AUCglucand AUCinsprogressively increased according to 1-hour plasma glucose concentrations (bothP<0.0001for trend). HOMA-B progressively declined (P<0.001), and HOMA-R progressively increased across the five groups. AUCins/AUCglucdecreased in a linear manner across the 5 groups (P<0.001). Analysing the groups with 1-hour value P<0.001). Progressive increase in 1-hour OGTT is associated with deterioration of glucose tolerance and alterations in indexes of insulin action and secretion.

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

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.

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.

OBJECTIVE: To analyze hospitalization for lower extremity amputations (LEAs) and amputee rates in persons with and without diabetes in Italy. RESEARCH DESIGN AND METHODS: All patients with LEAs in the period 2001-2010 were identified analyzing the National Hospital Discharge Record database. For each year, amputee and hospitalization rates for LEAs were calculated either for persons with diabetes or without. Time trend for major and minor amputations were analysed. RESULTS: From 2001 to 2010 a mean annual number of 11,639 individuals underwent a lower extremity amputation: 58.6% had diabetes accounting for 60.7% of total hospitalizations. In 2010, the crude amputee rate for LEAs was 20.4 per 100,000 inhabitants: 247.2 for 100.000 persons with diabetes, and 8.6 for those without diabetes. Having diabetes was associated to an increased risk of amputation (Poisson estimated RR 10.9, 95%CI 9.4-12.8). Over the whole period, a progressive reduction of amputee rates was observed for major amputations either among persons with diabetes (-30.7%) or without diabetes (-12.5%), while the rates of minor amputations increased progressively (+22.4%) among people without diabetes and were nearly stable in people with diabetes (-4.6%). A greater number of minor amputations were performed among persons with than without diabetes: in 2010, the minor-to-major ratio among persons with diabetes (2.5) was more than twice than in those without diabetes (1.0). CONCLUSIONS: The nationwide analyses confirm a progressive reduction of hospitalization and amputee rates for major LEAs, suggesting an earlier and more diffuse approach aimed at limb salvage.

Reduced glutathione (GSH) and activity of GSH related enzymes play a key role in defence against oxygen free radicals, whose production is, as known, raised in patients affected by diabetes mellitus, and at the same time they may contribute to the process of platelet aggregation. The purpose of this study was to evaluate GSH levels and activity of glutathione peroxidase (GSH-Px), glutathione reductase (GSSG-Red), glutathione transferase (GSH-Tr), glucose-6-phosphate-dehydrogenase (G6PDH), and thioltransferase (TT) in platelets of insulin-dependent diabetic patients in fair metabolic control (mean glycated haemoglobin: 6.5%), as related to presence of retinopathy, neuropathy or nephropathy and to platelet aggregation by arachidonic acid (AA) in vitro. Mean effective dose (ED50) of AA was on average significantly lower in the group of insulin-dependent diabetic patients (0.41 +/- 0.02 mM (SEM), n = 46) as compared with that of control subjects strictly matched for age, sex and weight (0.77 +/- 0.02, n = 51; P = 0.0001). Mean platelet GSH as well as the activity of GSH related enzymes expressed as geometric mean (95% confidence intervals) were similar in diabetic patients and in controls, except for GSSG-Red whose activity was significantly higher in diabetic subjects (28.5 (14.4-57.5) mU 10(-9) platelets vs. 20.3 (8.7-56) mU 10(-9) platelets; P = 0.01). In the diabetic group TT was reduced when compared with healthy controls (3.8 (0.9-12.2) mU 10(-9) platelets vs. 6 (1.6-26.1) mU 10(-9) platelets; P = 0.04).(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities of pulmonary function tests have been described in type 1 (insulin-dependent) diabetes mellitus (IDDM). To better characterise such abnormalities and to verify whether these latter are associated with the presence of diabetic microvascular disease we compared 23 non-smoking patients who had IDDM with 24 non-smoking healthy control subjects strictly matched for sex, age, and body mass index. Compared with controls, diabetic patients had a reduced forced vital capacity (FVC) (87.5 +/- 13.1% vs. 96.4 +/- 13.6% of the predicted; P = 0.03) and forced expiratory volume in 1 s (FEV1) (90.5 +/- 17.7% vs. 101.2 +/- 13.2% of the predicted; P = 0.02). While within the group of patients the presence of retinopathy and autonomic neuropathy were not associated with modifications of pulmonary function tests, those with altered urinary albumin excretion rate (AER > or = 20 micrograms/min; range 21-589) (n = 7) had a significantly lower pulmonary diffusion capacity (DLCO) than the 16 normoalbuminuric subjects (62.6 +/- 7.2% vs. 88.7 +/- 20.1% of the predicted; P = 0.01). Moreover, in the group of patients, DLCO was inversely related with AER (r = -0.43; P = 0.04). In conclusion, IDDM is characterised by reduced FVC and FEV1, while a significant decrease in DLCO may be considered as selectively associated with renal disease.

Taurine acts as antioxidant, cell osmolyte, modulator of glucose metabolism, and plays a role in the retinal function. It is 103-fold more concentrated in the intracellular than in the extracellular milieu due to a specific taurine-Na-dependent transporter (TauT), which is upregulated by hypertonicity, low extracellular taurine, or oxidative stress and acutely downregulated ‘in vitro’ by high glucose concentrations. Aim of this study was to investigate whether TauT expression was modified in mononuclear peripheral blood cells (MPC) of type 2 diabetic patients with or without micro/macrovascular complications. Plasma taurine, as well as other sulphur-containing aminoacids (assayed by HPLC) and TauT gene expression (assayed by real-time PCR analysis) were measured in MPC of 45 controls and of 81 age-and-sex matched type 2 diabetic patients with or without micro/macrovascular complications. Median value (interquartile range) of plasma taurine was significantly lower in diabetic patients than in controls [28.7 (13.7) μmol/l vs. 46.5 (20.3) μmol/l; P

AIMS: The question asked by this study was whether β-cell function expressed by insulin secretion/sensitivity measured during pregnancy in women with gestational diabetes (GDM) predicts post-partum long-term derangement in glucose metabolism. METHODS: Seventy-four Caucasian women with previous GDM were retested through a 75 g-2-h-OGTT after 8 [6] years (median[interquartile range]) from index pregnancy, measuring at pregnancy and follow-up insulin sensitivity, insulin secretion (1-h-incremental-insulin-area/incremental-glucose-area: ΔAUC60 I /ΔAUC60 G ) as well as the product of Stumvoll-first-phase - secretion x insulin sensitivity (insulin-secretion-sensitivity index (ISSI). RESULTS: At follow-up 47 women were normotelerant to glucose and 27 had altered glucose metabolism (AGM:10 with type 2 diabetes and 17 with IGT). Women progressed to AGM had at their index pregnancy higher mean 2-h-OGTT-glucose area (1.15±0.09 VS. 1.09±0.09 mol l 2-h −1 ;p=0.014), and lower ΔAUC60 I /ΔAUC60 (median [interquantile range]) (54.4 [51.7] vs. 73.4 [60] pmol mmol −1 ) and ISSI (2 977 [766] vs. 3 708 [1 141]; p

Some studies have shown that fetal outcome observed in patients using insulin lispro is much the same as in pregnant women using regular insulin. This study aims to analyze the Italian data emerging from a multinational, multicenter, retrospective study on mothers with type 1 diabetes mellitus before pregnancy, comparing those treated with insulin lispro for at least 3 months before and 3 months after conception with those treated with regular insulin. The data collected on pregnant women with diabetes attending 15 Italian centers from 1998 to 2001 included: HbA1c at conception and during the first and third trimesters, frequency of severe hypoglycemic episodes, spontaneous abortions, mode and time of delivery, fetal malformations and mortality. Seventy-two diabetic pregnancies treated with lispro and 298 treated with regular insulin were analyzed, revealing a trend towards fewer hypoglycemic episodes in the former, who also had a significantly greater reduction in HbA1c during the first trimester. The rate of congenital malformations was similar in the offspring of the two groups of women treated with insulin lispro or regular insulin. These findings suggest that insulin lispro could be useful for the treatment of hyperglycemia in type 1 diabetic pregnant women.

Gestational diabetes (GDM) carries a high risk of subsequent diabetes. We asked what impact prior GDM has on beta cell function and insulin action in women who maintain normal glucose tolerance (NGT) for a long time.Ninety-one women with NGT (aged 41 +/- 8 years, mean+/-SD) were studied (by mathematical modelling of the C-peptide response to an OGTT) 7 [6] years (median [interquartile range]) after the index pregnancy, during which 52 had GDM (pGDM) and 39 had NGT (pNGT). In all women an OGTT had also been performed at 29 +/- 3 weeks of the index pregnancy.Women with pGDM were matched with women with pNGT for age, familial diabetes, time and weight gain since index pregnancy, parity, BMI (25.4 +/- 3.9 vs 26.8 +/- 6.4 kg/m(2)), and fasting (4.64 +/- 0.56 vs 4.97 +/- 0.46 mmol/l) and 2 h plasma glucose levels (5.91 +/- 1.14 vs 5.91 +/- 1.21 mmol/l). Nonetheless, fasting (49 [29] vs 70 [45] pmol min(-1) m(-2), p0.001) and total insulin secretion (32 [17] vs 48 [21] nmol m(-2), p0.0001) and beta cell glucose sensitivity (slope of the insulin secretion/plasma glucose concentration-response function) (95 [71] vs 115 [79] pmol min(-1) m(-2) (mmol/l)(-1), p = 0.025) were reduced in the pGDM group compared with the pNGT group, while insulin sensitivity was preserved (424 [98] vs 398 [77] ml min(-1) m(-2)). At index pregnancy, women with pGDM and those with pNGT had similar age and BMI. However, both insulin sensitivity (359 [93] vs 417 [92] ml min(-1) m(-2), p = 0.0012) and the insulin/glucose incremental area ratio (an empirical index of beta cell function; 98 [74] vs 138 [122] pmol/mmol, p = 0.028) were reduced in women with pGDM.Even in women who maintain normal insulin sensitivity, impaired beta cell function is carried over into the NGT status several years after a GDM pregnancy.

The aim of this prospective study was to evaluate the efficacy of the implementation of the International Consensus on the Diabetic Foot (ICDF) in the area of Pistoia (Tuscany, Italy), in terms of percentage of population screened, reduction of hospitalization, and reduction of lower extremity amputations. The study was carried out over a 5-year period (1999-2003) in a district general hospital covering a clearly defined and relatively static population. The implementation of ICDF was performed at district health care level, in collaboration with general practitioners, and at the hospital with the establishment of a multidisciplinary care team. The database for this study was extracted from the DRG Tuscany database, and the diabetes foot lesion data source was taken from the Data Elaboration Centre of the Health Care District of Pistoia, cross-checked with the clinical records of the Diabetes Unit. In the period of the study, there was an increase in both the total number of diabetic foot lesions observed and the number of patients with diabetes referred for evaluation to the Diabetes Unit of Pistoia. Following implementation, the total number of hospitalizations for diabetic foot lesions and the duration of clinical stay were reduced. The total incidence of amputations per 100,000 inhabitants decreased from 10.7 in 1999, to 10.1 in 2000, 2.7 in 2001, 6.3 in 2002 and 6.24 in 2003. In particular, while the incidence of major amputations decreased over time, the relative number of minor amputations increased in the first years, stabilizing at a higher rate in later years. Finally, while before 1999 most people from the Pistoia area were referred to various hospitals in Tuscany for diabetic foot problems, during the implementation period almost all were referred to the Diabetic Unit of Pistoia. This study shows the advantages of prospective data collection, demonstrating that the implementation of the International Consensus on the Diabetic Foot can improve foot care in diabetes.

Aims To study the effect of parity on impairment of insulin sensitivity during pregnancy and on the risk of gestational diabetes (GDM). Methods We studied the relationship between parity and peripheral insulin sensitivity index (ISIOGTT) or GDM in 1880 caucasian women, who underwent a 100-g, 3-h oral glucose tolerance test (OGTT) between the 24th and 28th gestational week and in 75 women who underwent an OGTT in two consecutive pregnancies. A proxy for β-cell function (basal plasma C peptide/fasting plasma glucose; CP/FPG) was also measured. Results By univariate analysis parity was related to decreased ISIOGTT and to increased CP/FPG in those with parity > 3 and likewise GDM, diagnosed in 124 women (6.58%), was linearly related to parity (P = 0.0034) and strongly age dependent. The relationships between parity and ISIOGTT, CP/FPG and GDM were no longer significant after adjustment for age, pregestational body mass index (BMI), and weight gain. GDM was significantly related to age and pregestational weight, while ISIOGTT and CP/FPG were inversely related to prepregnancy BMI or weight gain. In comparison with the index pregnancy, the subsequent pregnancy was characterized by an increase in actual and prepregnancy BMI, in 2 h area under curve (AUC) glucose and by a decrease in ISIOGTT (P = 0.0001). The longer the time interval between pregnancies and the higher the increment in pregestational BMI or in weight gain during the pregnancy, the greater were the ISIOGTT decrease and 2-h AUC glucose increase. Conclusions Parity is not directly linked to insulin sensitivity deterioration, to CP/FPG increase during pregnancy, or to GDM appearance, although it is linked through the mediation of progressive ageing and weight gain either before or during pregnancy, when there is a sufficiently long time interval between pregnancies.

Serum homocysteine (sHcy) has been found to be elevated in patients with type 2 diabetes mellitus, as well as in other clinical conditions associated with insulin resistance and/or vascular diseases. The aims of this study were to measure the relationship between sHcy with biohumoral markers of insulin resistance in pregnant women affected with gestational diabetes mellitus (GDM). We studied 2 groups of pregnant women categorized, after a 100-g, 3-hour oral glucose tolerance test (OGTT) as nondiabetic (n = 78) or affected with GDM (n = 15), by measuring sHcy, serum folate, albumin, vitamin B(12), uric acid, and lipids. In both groups, peripheral insulin sensitivity was measured by using the OGTT-derived index of Matsuda and DeFronzo (ISI(OGTT)). Serum homocysteine was significantly higher in the group with GDM compared with nondiabetic women (5.88 +/- 2.26 micromol/L v 4.45 +/- 1.52 micromol/L; P =.003); was inversely related to serum folate (r = -.48; P =.0001), and was significantly related to serum albumin (r =.27; P =.009), 2-hour plasma glucose (r =.25; P =.01), as well as to serum uric acid (r =.23; P =.03). No relationship was observed between sHcy and serum vitamin B(12), serum triglycerides, total, or high-density lipoprotein (HDL) cholesterol, mean blood pressure and ISI(OGTT). Vitamin B(12) was correlated with ISI(OGTT) (r =.36; P =.0005) and inversely with mean blood pressure (r = -.24; P =.02). GDM remained significantly associated with higher sHcy concentrations also after adjusting for age, serum folate, albumin, uric acid, ISI(OGTT), and vitamin B(12) (P =.006). In conclusion, we found that sHcy is significantly increased in women with GDM, independently of other confounding variables, is significantly related to 2-hour OGTT plasma glucose, and seems unrelated to insulin resistance in these subjects.

OBJECTIVE—To study the relationship between low birth weight and the presence of gestational diabetes mellitus (GDM) or peripheral insulin resistance during pregnancy. RESEARCH DESIGN AND METHODS—We studied the relationship between peripheral insulin sensitivity (calculated by Matsuda and DeFronzo’s oral glucose tolerance test (OGTT)-derived insulin sensitivity index [ISIOGTT]) or GDM prevalence and birth weight in 604 pregnant women, classified as normally glucose tolerant (n = 462) or affected with GDM (n = 142) after a 100-g 3-h oral glucose tolerance test. We then categorized these subjects into two groups: individuals with birth weight in the 10th percentile (n = 536). RESULTS—GDM prevalence was higher in the group in the lowest birth weight decile ( CONCLUSIONS—Low maternal birth weight was associated with a twofold higher risk for GDM, independent of major confounders. Such a risk was highest in women with low birth weight who delivered macrosomic babies, and in the group with low birth weight, the relationship between maternal glucose tolerance or insulin resistance and offspring’s neonatal weight was much more evident.

Background: The measurement of the peroxidase scavenging system represented by the activities of superoxide dismutase (SOD), catalase and glutathione peroxidase (GSH-Px) in blood cells of diabetic patients has, in the past, given equivocal results. Likewise, the role of these intracellular enzymatic scavengers against the oxidative stress of diabetes-associated microangiopathic complications is unknown. Methods: Choosing platelets as cell model (as commonly done in previous studies), the aim of this study was to relate the platelet content of SOD, catalase and GSH-Px to the presence of diabetes, as well as to the presence of nephropathy and retinopathy in 35 insulin-dependent diabetic patients, as compared to 10 age-matched control subjects. Results: The enzymatic activities were not changed in diabetic patients in comparison with healthy controls. After stratifying patients according to presence of nephropathy (24-h urinary albumin excretion rate persistently ≥20 μg min−1) or retinopathy, the group of albuminuric patients was characterized by a significant decrease in SOD activity as compared to those in the normoalbuminuric range (4.36±1.06 vs. 6.81±2.26 mU 10−9 platelets; p=0.01). Catalase and GSH-Px did not change. No modification in platelet enzyme activities has been found in diabetic subjects with retinopathy. Conclusions: These results suggest that diabetic nephropathy, at least in its early stage, may be related to an altered redox state of platelets, as tested by the reduction in SOD activity, thus, indicating that the renal damage in these patients may be associated to a selective increase in platelet susceptibility to variation in the redox state.

The relationship between glycaemic metabolic control and intracellular concentration of reduced glutathione (GSH) and related enzymes GSH-peroxidase (GSH-Px), GSH-reductase (GSH-Red), GSH-transferase (GSH-Tr), glucose-6-P-dehydrogenase (G6PDH), and thioltransferase (TT) in patients with insulin-dependent diabetes mellitus (IDDM) is controversial. Choosing platelets as cell model (as commonly done in previous studies), the aim of this study was to relate the platelet content of GSH and related enzymes to glycaemic metabolic control, expressed as glycated haemoglobin (HbA1c), as well as to presence of retinopathy and nephropathy in 114 IDDM patients. As compared to controls, both GSH and GSH-Red (geometric means (95% CI)) were significantly increased in platelets of diabetic patients: 3.3 (0.7-9.6) vs. 2.4 (0.8-7.6) mmol 10(-9) platelets; P=0.01 for GSH, and 30.6 (14.7-61.6) vs. 22.2 (8.7-52.2) mU 10(-9) platelets, P=0.0002 for GSH-Red, and TT activity was marginally decreased in the IDDM group (P=0.06). While no clear relationship was present between GSH-related enzymes and HbA1c, a trend was present toward a non-linear relation between HbA1c and GSH, being significantly related by a parabolic curve (P=0.002). As compared to patients with normoalbuminuria (n=88), diabetic patients with increased urinary albumin excretion rate (n=26) had a significant decrease in platelet TT concentration (3.2 (0.9-6.7) vs. 5.1 (1.9-18.7) mU 10(-9) platelets; P=0.0002), whereas retinopathy was not associated to modifications in GSH or in the enzymatic pattern. In summary: (a) platelet GSH and GSH-Red are increased in IDDM, while other enzymes are unmodified; (b) GSH seems to be related to metabolic control according to non-linear parabolic curve; (c) presence of increased albuminuria is associated to a selective decrease in platelet TT content.

Objective To assess the effects of pravastatin on lipoprotein levels and composition in patients with type 2 diabetes mellitus and hypercholesterolemia. The role of pravastatin in glucose control also was assessed. Background Several factors, including abnormalities of lipoprotein composition, may contribute to the increased risk of coronary heart disease in diabetes mellitus. Methods Patients with type 2 diabetes mellitus of at least 3 years' duration entered the study at the 4-week run-in period, during which they received a standard diet. For the remaining 18 weeks of the study, they received pravastatin 20 mg/d. Results In 51 patients, pravastatin decreased total cholesterol concentrations (289 ± 40 to 227 ± 37) ( P P P P Conclusions In patients with type 2 diabetes mellitus and hypercholesterolemia, pravastatin improved the lipid profile and the atherogenic potential associated with abnormal lipoprotein composition.

Objective Insulin resistance is a potential target for pharmacologic intervention in non-insulin-dependent diabetes. Troglitazone is being evaluated as an insulin enhancer in insulin resistant states. Research design and methods We randomized 40 patients with non-insulin-dependent diabetes to diet plus placebo (n = 15) or diet plus troglitazone (n = 25; 200 mg/day) treatment for 8 weeks. Fasting endogenous glucose production (EGP, by the stable isotope technique) and whole-body insulin sensitivity (by the insulin suppression test) were measured at baseline and on days 3, 7, 14, 28, and 56 of treatment. Results By day 56, fasting plasma glucose had risen from 12.0 ± 0.9 to 12.8 ± 1.2 mmol/L in the placebo group and had fallen from 12.4 ± 0.6 to 11.3 ± 0.6 mmol/L in the troglitazone group (p = 0.03). This was the result of small improvements in whole-body insulin sensitivity (steady-state plasma glucose during the insulin suppression test: from 11.09 ± 1.1 to 10.3 ± 0.8 mmol/L versus 13.8 ± 1.0 to 10.0 ± 0.9 mmol/L, placebo versus troglitazone; p = 0.01) and EGP (from 103% ± 3% versus 96% ± 2% of baseline, placebo versus troglitazone; p = 0.09). The time course of insulin action showed an early (first week of treatment) decrease in EGP in the troglitazone group that was maintained throughout, whereas steady-state plasma glucose levels began to diverge toward the end of treatment. The effects of insulin on plasma free fatty acid and potassium concentrations were not different between placebo and troglitazone. The cardiovascular risk profile (heart rate; serum triglycerides; total, low-density lipoprotein, and high-density lipoprotein cholesterol; proinsulin; uric acid; plasminogen activator inhibitor-1 antigen and activity; 24-hour blood pressure monitoring; and urinary albumin excretion) was unaltered by troglitazone treatment. Conclusions Troglitazone as monotherapy for typical non-insulin-dependent diabetes had a modest anti-hyperglycemic effect and, at the dose used in this study, had no effect on cardiovascular risk factors. Clinical Pharmacology & Therapeutics (1997) 62, 194–202; doi

Erythrocyte content of polyamines has been previously found increased in insulin-dependent diabetes mellitus with microalbuminuria. Since increased urinary albumin excretion (AER) is associated with the presence of vascular diseases in non-insulin-dependent diabetes mellitus (NIDDM) the aim of this study was to verify the hypothesis that the presence of increased urinary albumin excretion (AER), and of macroangiopathy in NIDDM would be related to a significant modification in polyamine erythrocyte levels. The erythrocyte content of spermine and spermidine was measured by a HPLC method in 39 patients affected with NIDDM and in 24 age- and sex-matched healthy control subjects, evaluating the relationship between erythrocyte polyamines of NIDDM patients with the presence of macroangiopathy as well as with retinopathy or increased AER (> or = 20 micrograms/ml). Both spermidine and spermine were not modified in the group of NIDDM patients while the presence of raised urinary AER was characterised by an increase in erythrocyte spermine (11 +/- 1.7 vs. 7.7 +/- 1.7 nmol/ml packed erythrocytes; P = 0.04) and spermidine (18.9 +/- 1.7 vs. 12.6 +/- 1.5 nmol/ml packed erythrocytes; P = 0.02), being both polyamines significantly related to AER and to metabolic control. Erythrocyte spermidine and spermine were moreover significantly higher in the group of patients with macroangiopathy (22.8 +/- 1.5 vs. 12.3 +/- 1.5 nmol/ml; P = 0.0001 and 11.5 +/- 1.7 vs. 7.8 +/- 1.7 nmol/l packed erythrocytes; P = 0.04) and being, moreover, erythrocyte spermidine augmented in patients with retinopathy (24.2 +/- 1.5 vs. 12.2 +/- 1.5 nmol/ml packed erythrocytes; P = 0.009). In conclusion the levels of erythrocyte spermine and spermidine are both associated with the presence of albuminuria and macroangiopathy in NIDDM, while spermidine is on the average increased in the group of diabetic patients with retinopathy.

In human volunteers it has been shown that taurine supplementation decreases collagen-induced thromboxane release and platelet aggregation (6). In addition, we found that, while in vitro taurine did not modify platelet aggregation per se, it potentiated the effect of anti-aggregating agents such as aspirin, papaverine, or sodium nitroprusside (13). These observations seem to indicate a possible role for taurine in the modulation of platelet function.

The question, of whether long-term treatment of essential hypertension with angiotensin-converting enzyme (ACE) inhibitors is capable of modifying glucose tolerance or insulin sensitivity in Type 2 (non-insulin dependent) diabetes, is still unsolved. We studied 14 moderately overweight Type 2 diabetic patients with essential hypertension in stable metabolic control after a run-in period and again after 3 months of antihypertensive treatment with the ACE inhibitor, Captopril. Glucose tolerance was tested with a 75-g oral glucose load and insulin sensitivity was measured by the insulin suppression test, while dietary and drug treatment of the diabetes remained constant. In the whole group, mean blood pressure (MBP) fell progressively over 3 months from a baseline value of 123 ± 3 mmHg to a final value of 115 ± 2 mmHg (p < 0.005); in six patients, the change in MBP was < 5 mmHg (non-responders), thus giving a clinical response rate of ˜60%. After treatment, fasting plasma glucose, insulin, free fatty acid (FFA), potassium, and glycated haemoglobin concentrations were unchanged from baseline. During the oral glucose tolerance test, the incremental glucose area-under-curve was 0.75 ± 0.05 mol 120 min I−1 before and 0.76 ± 0.06 mol 120 min I−1 after treatment (p = ns). Endogenous insulin response and suppression of plasma FFA levels were superimposable on the two occasions. During the insulin suppression test, steady-state plasma glucose levels were 14.4 ± 1.3 vs 14.2 ±1.1 mmol I−1 before and after chronic ACE inhibition, respectively, at comparable hyperinsulinaemic plateaux (291 ± 21 vs 287 ± 14 pmol I−1). Neither endogenous (oral glucose) nor exogenous (insulin suppression test) insulin caused any change in plasma potassium concentrations. This resistance to the hypokalemic action of insulin was not affected by Captopril. The eight blood pressure responders, or the seven patients with less fasting hyperglycaemia, had similar baseline characteristics as the whole group, and likewise showed no significant treatment-related change in glucose tolerance or insulin sensitivity. We conclude that chronic ACE inhibition does not change glucose tolerance, endogenous insulin response, and sensitivity of glucose disposal, lipolysis, and potassium metabolism to insulin in stable Type 2 diabetic patients whose glycaemic control by other means (diet and/or drugs) is held constant.

We investigated the frequency of microalbuminuria (albumin excretion rate, AER greater than 15 micrograms/min) ('overnight' urine collection and radioimmunological evaluation) and its relation to retinopathy (assessed by fluorangiography) in 113 type I (insulin-dependent) diabetic subjects (aged 31 +/- 13 years; diabetes duration 11 +/- 7 years), all Albustix-negative. Sixty eight patients (60.2%) were free of retinal lesions, 31 (27.4%) had background retinopathy and 14 (12.4%) had proliferative retinopathy. Microalbuminuria was found in 25 patients (22%). Fifteen patients (13%) showed both retinopathy and microalbuminuria. Fifteen % (10/68) of the patients with no retinopathy and sixteen % (5/31) of those with background retinal lesions had microalbuminuria, while 29% (4/14) of the patients with proliferative retinopathy were normoalbuminuric. Among the 29 patients with diabetes for less than five years, 1 had retinopathy and 4 had microalbuminuria. Out of 15 patients with both retinopathy and microalbuminuria, 13 (87%) had had diabetes for more than 10 years. Diabetic retinopathy is more frequent than microalbuminuria (40 vs 22%). Although the linkage between retinopathy and microalbuminuria is weak, after ten years of diabetes the two complications may frequently coincide.

We have developed a radioimmunoassay method (RIA) to measure urinary albumin excretion. We determined the albumin excretion rate (AER) (micrograms/min) of 122 healthy subjects and 145 diabetic patients (115 type I, 30 type II). The results indicate that the RIA is sensitive (0.39 +/- 0.08 mg/L), precise (CV 5-8%), and gives reliable results on previously frozen urine samples. The distribution of the AER values in healthy subjects and diabetic patients was not normal. It was normalized by log or square-root transformation of the data. Seventy-three percent of diabetic patients lay within the normal range (0.6-10.6 micrograms/min). Twenty percent could be considered "at risk" to develop overt diabetic nephropathy because their albuminuria exceeded a threshold level of 15 micrograms/min chosen previously as the cutoff value for microalbuminuria. We found no correlation between AER and glycated hemoglobin, and only a weak correlation between AER and diabetes duration in type I diabetic patients.

This study was designed to assess the antimicrobial effect and tolerability of a single dose of a photo-activated gel containing RLP068 in the treatment for infected foot ulcers in subjects with diabetes. A randomized, double-blind, parallel series, placebo-controlled phase IIa trial was performed with three concentrations of RLP068 (0.10, 0.30, and 0.50 %), measuring total and pathogen microbial load on Day 1 (before and 1 h after topical gel application and photoactivation with 689 nm red light), on Days 3, 8, and 15, as add-on to systemic treatment with amoxicillin and clavulanic acid. Blood samples were also drawn 1, 2, and 48 h after administration for the assessment of systemic drug absorption. The trial was performed on 62 patients aged ≥18 years, with type 1 or type 2 diabetes and infected foot ulcer, with an area of 2-15 cm(2) and a maximum diameter ≤4.6 cm. A dose-dependent reduction in total microbial load was observed (-1.92 ± 1.21, -2.94 ± 1.60, and -3.00 ± 1.82 LogCFU/ml for 0.10, 0.30, and 0.50 % RPL068 vs. -1.00 ± 1.02 LogCFU/ml with placebo) immediately after illumination, with a progressive fading of the effect during follow-up. No safety issues emerged from the analysis of adverse events. Systemic absorption of RLP068 was negligible. Photodynamic antimicrobial treatment with RLP068 of infected diabetic foot ulcers is well tolerated and produces a significant reduction in germ load. Further clinical trials are needed to verify the efficacy of this approach as add-on to systemic antibiotic treatment.

Lower extremity ulcers represent a serious and costly complication of diabetes mellitus. Many factors contribute to the development of diabetic foot. Peripheral neuropathy and peripheral vascular disease are the main causes of foot ulceration and contribute in turn to the growth of additional risk factors such as limited joint mobility, muscular alterations and foot deformities. Moreover, a deficit of balance, posture and biomechanics can be present, in particular in patients at high risk for ulceration. The result of this process may be the development of a vicious cycle which leads to abnormal distribution of the foot's plantar pressures in static and dynamic postural conditions. This review shows that some of these risk factors significantly improve after a few weeks of exercise therapy (ET) intervention. Accordingly it has been suggested that ET can be an important weapon in the prevention of foot ulcer. The aim of ET can relate to one or more alterations typically found in diabetic patients, although greater attention should be paid to the evaluation and possible correction of body balance, rigid posture and biomechanics. Some of the most important limitations of ET are difficult access to therapy, patient compliance and the transitoriness of the results if the training stops. Many proposals have been made to overcome such limitations. In particular, it is important that specialized centers offer the opportunity to participate in ET and during the treatment the team should work to change the patient’s lifestyle by improving the execution of appropriate daily physical activity.