Diabetes mellitus in stroke unit: prevalence and outcomes-the Verona acute coronary syndrome and stroke in diabetes outcome (VASD-OUTCOME) study.

BACKGROUND: Cerebrovascular accidents (CVA) represent a major complication in diabetes (DM). Real-life evidence as to whether modern management of CVA and DM have softened this relationship is limited. Therefore, we estimated prevalence and impact of DM on in-hospital survival and complications in a contemporary cohort of subjects with CVA. METHODS: We retrospectively evaluated the records of 937 patients admitted for CVA at the Stroke Unit of Verona University Hospital during a 3-year period. Pre-existing or de novo DM was ascertained by prior diagnosis, glucose-lowering therapy at admission/discharge or admittance plasma glucose ≥ 200 mg/dL. Multiple regressions were applied to test DM as predictor of in-hospital mortality, complications (composite of infections, cardio- and cerebrovascular complications, major bleeding and pulmonary complications), duration and costs of hospitalization. RESULTS: Diabetes prevalence was 21%, of which 22% de novo diagnoses. Compared to non-DM, diabetic individuals were older and carried an increased burden of cardiovascular risk factors. Compared to known DM, de novo DM individuals were younger, had higher admittance plasma glucose and poorer cardiovascular comorbidities. Overall, DM versus non-DM individuals did not show significantly increased risk of death (14.0 vs. 9.3%; crude-OR 1.59 95% CI 0.99-2.56). Controlling for confounders did not improve significance. DM resulted independent predictor for in-hospital complications (36.2% vs. 26.9%; adj-OR 1.49, 1.04-2.13), but not for duration and costs of hospitalization. CONCLUSION: DM frequently occurs in patients admitted for stroke and carries an excess burden of adverse in-hospital complications, urgently calling for strategies to anticipate DM diagnosis and tailored treatment in high-risk individuals.

Insulin resistance and beta-cell dysfunction in newly diagnosed type 2 diabetes: Expression, aggregation and predominance. Verona Newly Diagnosed Type 2 Diabetes Study 10.

AIMS: We investigated quantitative expression, mutual aggregation and relation with hyperglycemia of insulin resistance (IR) and beta-cell dysfunction (BCD) in newly diagnosed type 2 diabetes. METHODS: We assessed IR with euglycemic hyperinsulinemic clamp and BCD with modelled glucose/C-peptide response to oral glucose in 729 mostly drug-naïve patients. We measured glycated hemoglobin, pre-prandial, post-prandial and meal-related excursion of blood glucose. RESULTS: IR was found in 87.8% [95% confidence intervals 85.4-90.2] and BCD in 90.0% [87.8-92.2] of subjects, ranging from mild to moderate or severe. Approximately 20% of subjects had solely one defect: BCD 10.8% [8.6-13.1] or IR 8.6% [6.6-10.7]. Insulin resistance and BCD aggregated in most subjects (79.1% [76.2-82.1]). We arbitrarily set nine possible combinations of mild, moderate or severe IR and mild, moderate or severe BCD, finding that each had a similar frequency (∼10%). In multiple regression analyses parameters of glucose control were related more strongly with BCD than with IR. CONCLUSIONS: In newly-diagnosed type 2 diabetes, IR and BCD are very common with a wide range of expression but no specific pattern of aggregation. Beta-cell dysfunction is likely to play a greater quantitative role than IR in causing/sustaining hyperglycemia in newly-diagnosed type 2 diabetes.

Growing up with type 1 diabetes mellitus: Data from the Verona Diabetes Transition Project.

AIM: Transition from paediatric to adult care is a critical step in life of emerging adults with type 1 diabetes. We assessed, according to indicators established by panel of experts, clinical, socio-demographic and psychosocial factors in young adults with type 1 diabetes throughout structured transition to investigate the associations, if any, with HbA1c value at time of transition. METHODS: The "Verona Diabetes Transition Project" started in January 2009: a structured transition program, shared between paediatric and adult clinic, was organised with a multi-disciplinary team. All young adults underwent a semi-structured interview by a psychologist, before transition. Minimum age for transition was 18 years. RESULTS: 222 (M/F = 113/109) young adults moved to adult care from January 2009 to March 2020. The mean time between the last paediatric visit and the first adult visit ranged from 13.6 ± 6.1 months at the beginning of the project to 3.6 ± 11.5 months over the following years. At first adult clinic attendance, women showed higher HbA1c values (70 ± 11 mmol/mol vs. 65 ± 7 mmol/mol or 8.57% ± 1.51% vs. 8.14% ± 0.98%, p = 0.01), higher frequency of disorders of eating behaviours (15.6% vs. 0%, p < 0.001) and poor diabetes acceptance (23.9% vs. 9.7%, p < 0.001) than men. Mediation analyses showed a significant mediating role of glucose control 2 years before transition in the relationship between poor diabetes acceptance and glucose control at transition. CONCLUSIONS: This study demonstrated a delay reduction in establishing care with an adult provider and suggested the potential role of low diabetes acceptance on glycemic control at transition. Further studies are needed to confirm and expand these data.

Fertility and reproductive outcome after tubal ectopic pregnancy: comparison among methotrexate, surgery and expectant management.

PURPOSE: To compare fertility and reproductive outcome after surgical, medical, and expectant management for tubal ectopic pregnancy (EP). METHODS: 133 of 228 patients, who were managed between January 2012 and December 2017 for a tubal EP, tried to conceive immediately after treatment: 86 out of 173 (49.7%) underwent surgical treatment; 38 (21.9%) were treated with methotrexate (MTX), and 49 (28.3%) had expectant management. Clinical data were retrieved by medical records, fertility outcomes were obtained by phone follow-up. The cumulative incidence (CI) of intrauterine clinical pregnancy (CP), miscarriage, live birth (LB), and recurrent EP, and the time between treatment and first intrauterine CP were compared between women treated with MTX, surgery and expectant management. RESULTS: The CI of intrauterine CP starting from 12 months after the EP was 65.3% for the expectant management, 55.3% for the MTX group, and 39.5% for surgery (p = 0.012). Post-hoc analysis showed expectant management having higher intrauterine CP and LB, and shorter time between treatment and first intrauterine CP compared to surgery (p < 0.05). The CI of recurrent EP was comparable between the 3 groups. The analysis stratified per ßhCG cut-off of 1745 mUI/mL and EP mass cut-off of 25 mm reported consistent results. CONCLUSIONS: Women successfully managed by expectation appear to have better reproductive outcomes compared to women who underwent surgery, with the shortest time to achieve a subsequent intrauterine CP. Therefore, if safely applicable the expectant management should be considered in the case of tubal EP. The fact that the chosen treatment was primarily guided by the ßhCG value and EP mass diameter based on the protocol, which is intrinsically related to the characteristics of the EP, represents the main limitation of the present study. Indeed, we cannot completely exclude that the observed differences between treatments are related to the EP itself instead of the treatment.

Chronic complications in patients with newly diagnosed type 2 diabetes: prevalence and related metabolic and clinical features: the Verona Newly Diagnosed Type 2 Diabetes Study (VNDS) 9.

INTRODUCTION: We explored the presence of chronic complications in subjects with newly diagnosed type 2 diabetes referred to the Verona Diabetes Clinic. Metabolic (insulin secretion and sensitivity) and clinical features associated with complications were also investigated. RESEARCH DESIGN AND METHODS: The comprehensive assessment of microvascular and macrovascular complications included detailed medical history, resting ECG, ultrasonography of carotid and lower limb arteries, quantitative neurological evaluation, cardiovascular autonomic tests, ophthalmoscopy, kidney function tests. Insulin sensitivity and beta-cell function were assessed by state-of-the-art techniques (insulin clamp and mathematical modeling of glucose/C-peptide curves during oral glucose tolerance test). RESULTS: We examined 806 patients (median age years, two-thirds males), of whom prior clinical cardiovascular disease (CVD) was revealed in 11.2% and preclinical CVD in 7.7%. Somatic neuropathy was found in 21.2% and cardiovascular autonomic neuropathy in 18.6%. Retinopathy was observed in 4.9% (background 4.2%, proliferative 0.7%). Chronic kidney disease (estimated glomerular filtration rate <60 mL/min/1.73 m2) was found in 8.8% and excessive albuminuria in 13.2% (microalbuminuria 11.9%, macroalbuminuria 1.3%).Isolated microvascular disease occurred in 30.8%, isolated macrovascular disease in 9.3%, a combination of both in 9.1%, any complication in 49.2% and no complications in 50.8%.Gender, age, body mass index, smoking, hemoglobin A1c and/or hypertension were independently associated with one or more complications. Insulin resistance and beta-cell dysfunction were associated with macrovascular but not microvascular disease. CONCLUSIONS: Despite a generally earlier diagnosis for an increased awareness of the disease, as many as ~50% of patients with newly diagnosed type 2 diabetes had clinical or preclinical manifestations of microvascular and/or macrovascular disease. Insulin resistance might play an independent role in macrovascular disease. TRIAL REGISTRATION NUMBER: NCT01526720.

Effects of Aerobic and Resistance Training on Circulating Micro-RNA Expression Profile in Subjects With Type 2 Diabetes.

CONTEXT: Structured exercise programs are of great benefit for the treatment of type 2 diabetes (T2DM). However, whether aerobic (AER) or resistance (RES) exercise training exerts specific epigenetic changes through the expression profile of circulating miRNAs (c-miRNAs) is still largely unknown. OBJECTIVE: To assess whether the c-miRNAs profile changes after either AER or RES training in subjects with T2DM. DESIGN: Twenty-four patients with T2DM randomized to AER or RES training protocols were randomly selected from the Resistance vs. Aerobic Exercise in Type 2 Diabetes (RAED2) Trial (NAER = 12; NRES = 12). The baseline and post-training levels of 179 c-miRNAs were initially measured by RT-PCR in 6 individuals (NAER = 3; NRES = 3). C-miRNAs exhibiting ≥40% fold change variation and/or nominal significance from baseline were measured in the whole group. RESULTS: Nineteen c-miRNAs were eventually assessed in the whole group. Compared with baseline, the post-training levels of miR-423-3p, miR-451a, and miR-766-3p were significantly up-regulated, irrespective of exercise type (P < 0.0026; 0.05/19), and targeted upstream pathways relevant to fatty acids biosynthesis and metabolic regulation. MiR-451a and miR-423-3p were significantly correlated with fat loss (ρ = 0.45 and 0.43, respectively) and resulted, alone or in combination, in being predictors of fat loss in generalized linear regression models including exercise type as covariate. Only the association with miR-451a eventually retained significance after further correction for age, sex, body mass index, and HbA1c. CONCLUSIONS: Exercise training in T2DM is associated with substantial c-miRNAs profile changes, irrespective of exercise type and other relevant metabolic covariates. The mechanistic significance of the observed relationship between fat loss and the epigenetic modifications induced by exercise warrants further investigation in larger datasets.

Sex differences in the association of psychological status with measures of physical activity and sedentary behaviour in adults with type 2 diabetes.

AIM: To assess the association of psychological variables on leisure-time physical activity and sedentary time in men and women with type 2 diabetes mellitus (T2D). METHODS: In this cross-sectional study, we evaluated 163 patients with T2D, consecutively recruited at the Diabetes Centre of the Verona General Hospital. Scores on depression and anxiety symptoms, psychosocial factors (including self-efficacy, perceived interference, perceived severity, social support, misguided support behaviour, spouse's positive behaviour), physical activity and time spent sitting were ascertained using questionnaires responses to the Beck Depression Inventory-II, Beck Anxiety Inventory, Multidimensional Diabetes Questionnaire, International Physical Activity Questionnaire. RESULTS: Physical activity was significantly associated with higher social support in women and with increased self-efficacy in men. Sedentary time was significantly associated with higher perceived interference, anxiety and depressive symptoms, and with reduced diabetes self-efficacy in women, while it was associated solely with anxiety in men. Depressive symptoms and self-efficacy in women and anxiety symptoms in men were independent predictors of sedentary time when entered in a multivariable regression model also including age, BMI, haemoglobin A1c, diabetes duration, perceived interference and self-efficacy as covariates. CONCLUSIONS: Lower self-efficacy and higher symptoms of depression were closely associated with increased sedentary time in women, but not in men, with T2D. It is possible that individualized behavioural interventions designed to reduce depressive symptoms and to improve diabetes self-efficacy would ultimately reduce sedentary behaviours, particularly in women with T2D.

Influence of Ulipristal Acetate Therapy on Uterine Fibroid-Related Symptoms and on Uterine and Fibroid Volumes and Vascularity Indices Assessed by Ultrasound.

OBJECTIVES: To investigate the modifications of uterine and fibroid volume, to study Doppler changes in uterine arteries and fibroid-supplying vessels, and to assess possible symptomatic relief after 3 months of treatment with ulipristal acetate. METHODS: Forty-two premenopausal women with symptomatic fibroids were included in the study. They were evaluated clinically for the symptoms reported and underwent ultrasound examinations before starting treatment and after 3 months of therapy with ulipristal acetate. Transvaginal scanning was performed by the same sonographer, who measured the uterine volume and uterine artery pulsatility index and resistive index. Considering that some patients had more than 1 fibroid, the vascularization (supplying vessel pulsatility and resistive indices), locations, and sizes of a total of 73 fibroids were also recorded. RESULTS: After 3 months of ulipristal acetate, patients had a significant improvement of all symptoms (P < .05). The percentage of uterine volume reduction was 14% (P = .03), with fibroid volume reduction of 32.8% (P = .01). Uterine artery vascular indices decreased after treatment, but their reduction did not reach significant results, whereas all fibroid vascular indices decreased significantly after 3 months of ulipristal acetate (P < .05). When the fibroids were divided according to their localization, all had significant volume reduction after therapy, but type 5 had the highest decrease (42%) compared to other fibroid types (P = .03). CONCLUSIONS: Fibroid treatment with ulipristal acetate resulted in a significant improvement of fibroid-related symptoms; moreover, it proved to be effective in decreasing both uterine and fibroid volumes and fibroid vascularization. Type 5 fibroids seem to have the most major response to treatment.

Long-Acting GLP-1 Receptor Agonist Exenatide Influence on the Autonomic Cardiac Sympatho-Vagal Balance.

Long-acting glucagon-like peptide 1 receptor agonists are increasingly used to treat type 2 diabetes. An increase of heart rate (HR) has been observed with their use. To elucidate the role of the cardiac sympatho-vagal balance as a possible mediator of the reported increase in HR, we performed power spectral analysis of HR variability (HRV) in patients receiving exenatide extended-release (ER). Twenty-eight ambulatory patients with type 2 diabetes underwent evaluation at initiation of exenatide-ER and thereafter at 3 and at 6 months. To obtain spectral analyses of HRV, a computerized acquisition of 10 minutes of RR electrocardiogram intervals (mean values of ~700 RR intervals) were recorded both in lying and in standing positions. All patients showed a substantial increase of HR both in lying and in standing positions. Systolic blood pressure, body weight, and glycated hemoglobin A1c significantly decreased both at 3 and 6 months compared with basal levels. The low-frequency/high-frequency ratio varied from 3.05 ± 0.4 to 1.64 ± 0.2 (P < 0.001) after 3 months and to 1.57 ± 0.3 (P < 0.001) after 6 months in a lying position and from 4.56 ± 0.8 to 2.24 ± 0.3 (P < 0.001) after 3 months and to 2.38 ± 0.4 (P < 0.001) after 6 months in a standing position compared with basal values, respectively. HR variations, induced by exenatide-ER treatment, do not appear to be related to sympathetic autonomic tone. Of note, we observed a relative increase of vagal influence on the heart.

Interleukin-6 as a potential positive modulator of human beta-cell function: an exploratory analysis-the Verona Newly Diagnosed Type 2 Diabetes Study (VNDS) 6.

AIMS: Recent studies in mouse models of T2D showed that interleukin-6 (IL-6), released from skeletal muscle, is associated with increased glucose-dependent insulin secretion. Few data currently exist exploring the relationship between IL-6 and beta-cell function in humans. We investigated whether IL-6 is positively associated with beta-cell function in newly diagnosed T2D. We extended the same analyses to IL-10, because it regulated similarly to IL-6 in skeletal muscle, and TNF-α and C-reactive protein (CRP), as general biomarkers of inflammation. METHODS: In 330 VNDS participants, we assessed (1) basal plasma concentrations of IL-6, IL-10, TNF-α, and CRP; (2) beta-cell function, estimated by OGTT minimal modeling and expressed as derivative (DC) and proportional control (PC); (3) insulin sensitivity, by euglycemic insulin clamp. RESULTS: IL-6 was positively associated with PC in both univariate analysis (p = 0.04) and after adjustment for age, sex, BMI, HbA1c, and M-clamp (p = 0.01). HbA1c was the major independent contributor to the overall variance of PC (16 %), followed by BMI and IL-6 (~2 % each). Similar results were obtained for IL-10 (p = 0.048, univariate; p = 0.04, fully adjusted). TNF-α and CRP were not significantly associated with any component of beta-cell function. CONCLUSIONS: Our data are the first evidence in human subjects that an endocrine loop involving IL-6 may act as positive modulator of glucose-dependent insulin secretion. Further functional studies are needed to corroborate IL-6 system as a potential druggable target in diabetes. CLINICAL TRIAL REGISTRATION NUMBER: NCT01526720 ( http://www.clinicaltrial.gov ).

Prevalence of Cardiovascular Autonomic Neuropathy in a Cohort of Patients With Newly Diagnosed Type 2 Diabetes: The Verona Newly Diagnosed Type 2 Diabetes Study (VNDS).

OBJECTIVE: Cardiovascular autonomic diabetic neuropathy (CAN) is a serious complication of diabetes. No reliable data on the prevalence of CAN among patients with newly diagnosed type 2 diabetes are available. Therefore, the aim of this study was to estimate the prevalence of CAN among patients with newly diagnosed type 2 diabetes. RESEARCH DESIGN AND METHODS: A cohort of 557 patients with newly diagnosed type 2 diabetes with cardiovascular autonomic test results available was selected. Early and confirmed neuropathy were assessed using a standardized methodology and their prevalences determined. A multivariate logistic regression analysis was modeled to study the factors associated with CAN. RESULTS: In the entire cohort, the prevalence of confirmed CAN was 1.8%, whereas that of early CAN was 15.3%. Prevalence did not differ between men and women. In the multivariate analyses BMI results were independently and significantly associated with CAN after adjusting for age, sex, hemoglobin A1c, pulse pressure, triglyceride-to-HDL cholesterol ratio, kidney function parameters, and antihypertensive treatment. CONCLUSIONS: CAN could be detected very early in type 2 diabetes. This study may suggest the importance of performing standardized cardiovascular autonomic tests after diagnosis of type 2 diabetes.

HOMA-estimated insulin resistance is an independent predictor of cardiovascular disease in type 2 diabetic subjects: prospective data from the Verona Diabetes Complications Study.

OBJECTIVE: To evaluate whether homeostasis model assessment-estimated insulin resistance (HOMA-IR) is an independent predictor of cardiovascular disease (CVD) in type 2 diabetes. RESEARCH DESIGN AND METHODS: Conventional CVD risk factors (sex, age, smoking, plasma lipids, blood pressure, and metabolic control) and insulin resistance (estimated by HOMA) were evaluated at baseline in 1,326 patients with type 2 diabetes examined within the Verona Diabetes Complications Study. At baseline and after a mean follow-up of 4.5 years, CVD was assessed by medical history, physical examination, electrocardiography, and echo-Doppler of carotid and lower limb arteries. Death certificates and medical records of subjects who died during the follow-up were carefully scrutinized to identify cardiovascular deaths. In statistical analyses, CVD was an aggregate end point including both fatal and nonfatal coronary, cerebrovascular, and peripheral vascular disease as well as ischemic electrocardiographic abnormalities and vascular lesions identified by echo-Doppler. RESULTS: At baseline, 441 subjects were coded positive for CVD (prevalent cases). Incident cases numbered 126. Multiple logistic regression analyses showed that, along with sex, age, smoking, HDL/total cholesterol ratio, and hypertension, HOMA-IR was an independent predictor of both prevalent and incident CVD. A 1-unit increase in (log)HOMA-IR value was associated with an odds ratio for prevalent CVD at baseline of 1.31 (95% CI 1.10-1.56, P = 0.002) and for incident CVD during follow-up of 1.56 (95% CI 1.14-2.12, P < 0.001). CONCLUSIONS: HOMA-IR is an independent predictor of CVD in type 2 diabetes. The improvement of insulin resistance might have beneficial effects not only on glucose control but also on CVD in patients with type 2 diabetes.