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Background Estimated pulse-wave velocity (ePWV), a surrogate measure of arterial stiffness, was shown to independently predict morbidity and mortality from cardiovascular disease and other causes in both the general population and high-risk individuals. However, in people with type 2 diabetes, it is unknown whether ePWV adds prognostic information beyond the parameters used for calculating it. Aims To assess the independent association of ePWV with all-cause mortality in individuals with type 2 diabetes. Design Prospective cohort study that enrolled 15 773 patients in 19 Italian centres in 2006–08. Methods ePWV was calculated from a regression equation using age and mean blood pressure (BP). All-cause mortality was retrieved for 15 656 patients in 2015. Results Percentage and rate of deaths, Kaplan–Meier estimates and unadjusted hazard ratios increased from Quartile I to Quartile IV of ePWV. After adjustment for age, sex, BP levels and anti-hypertensive treatment, the strength of association decreased but mortality risk remained significantly higher for Quartiles II (+34%), III (+82%) and IV (+181%) vs. Quartile I and was virtually unchanged when further adjusting for other cardiovascular risk factors and complications/comorbidities. Each m·s− 1 increase in ePWV was associated with an increased adjusted risk of death in the whole cohort (+53%) and in participants with (+52%) and without (+65%) cardiorenal complications. Moreover, ePWV significantly improved prediction of mortality risk over cardiovascular risk factors and complications/comorbidities, though the net increase was modest. Conclusions These findings suggest that ePWV may represent a simple and inexpensive tool for providing prognostic information beyond traditional cardiovascular risk factors. Trial registration ClinicalTrials.gov , NCT00715481, https://clinicaltrials.gov/ct2/show/NCT00715481. [ABSTRACT FROM AUTHOR]

Objective: Cystic fibrosis (CF)-related diabetes (CFRD) resulting from partial-tocomplete insulin deficiency occurs in 40-50% of adults with CF. In people with CFRD, poor glycemic control leads to a catabolic state that may aggravate CFinduced nutritional impairment and loss of muscle mass. Sensor augmented pump (SAP) therapy may improve glycemic control as compared to multiple daily injection (MDI) therapy. Research design and methods: This non-randomized clinical trial was aimed at evaluating the effects of insulin therapy optimization with SAP therapy, combined with a structured educational program, on glycemic control and body composition in individuals with insulin-requiring CFRD. Of 46 participants who were offered to switch from MDI to SAP therapy, 20 accepted and 26 continued the MDI therapy. Baseline demographic and clinical characteristics were balanced between groups using a propensity score-based overlap weighting procedure and weighted mixed-effects regression models were used to estimate changes in study outcomes. Results: After 24 months changes in HbA1c were: -1.1% (-12.1 mmol/mol) (95% CI: -1.5; -0.8) and -0.1% (-1 mmol/mol) (95% CI: -0.5; 0.3) in the SAP and MDI therapy group, respectively, with a between-group difference of -1.0 (-10 mmol/mol) (-1.5; -0.5). SAP therapy was also associated with a decrease in mean glucose (between group difference: -32 mg/dL; 95% CI: -44; -20) and an increase in TIR (between group difference: 19.3%; 95% CI 13.9; 24.7) and in fatfree mass (between group difference: +5.5 Kg, 95% CI: 3.2; 7.8). Conclusion: Therapy optimization with SAP led to a significant improvement in glycemic control, which was associated with an increase in fat-free mass. [ABSTRACT FROM AUTHOR]

Hydrocracking of α-cellulose has been conducted in a semi-batch reactor at 400, 450, and 500 °C with hydrogen flow (30 mL/min.) for 4 h. Mordenite (MOR) and Co, Ni and Pd metal supported on the MOR were used as solid catalysts. The catalysts were characterized using X-ray Diffractometer (XRD), Fourier Transform Infrared (FTIR) spectroscopy, and Scanning Electron Microscopy (SEM) to evaluate the physical-chemical properties. Energy Dispersive X-ray (EDX) and Inductively Coupled Plasma (ICP) were used to analyze the amount of metal impregnated on the catalysts. The liquid product was analyzed using Gas Chromatograph-Mass Spectroscopy (GC-MS). Thermal hydrocracking was also conducted at 450 °C with the amount of liquid product was 37.86 wt.%. The highest liquid conversion obtained by mordenite catalyst was 94.66 wt.% at 450 °C and the highest liquid conversion (98.08 wt.%) was reached by Pd/MOR catalyst at 400 °C.

Cystic fibrosis (CF)-related diabetes (CFRD), characterized by partial to complete impaired insulin secretion, is the most common extra-pulmonary complication of CF. Actually, insulin is the only approved therapy for its management. Advanced hybrid closed loop (AHCL) systems are the gold standard therapy for type 1 diabetes and have been proposed for other insulin-dependent forms of diabetes, including CFRD. With AHCL systems, people with CFRD can better manage several typical disease-related issues, such as minimal insulin requirements, its variability due to exacerbations or concomitant steroid therapies, nutritional behaviors, the co-existence of CF complications as intestinal malabsorption or liver disease. SmartGuard, the AHCL system for Medtronic Minimed 780G, requires a minimum of 8 units per day to operate. In this paper, we expose a case of two young women with CFRD with total daily insulin requirements < 8 UI, using off-label SmartGuard system over a 3 years of follow-up period, suggesting an evaluation of its use also in people with minimal insulin needs, considering its beneficial impact in glucose control and quality of life., (© 2024. Springer-Verlag Italia S.r.l., part of Springer Nature.)

Aims: To assess whether and to what extent excess risk of all-cause death is reduced in individuals with type 2 diabetes by achieving optimal control of traditional cardiovascular risk factors., Methods: This observational, prospective, cohort study enrolled 15,773 Caucasian patients in 19 Italian centres in 2006-2008. Participants were stratified according to the number of the following risk factors outside target: haemoglobin A 1c , blood pressure, micro/macroalbuminuria, current smoking, LDL cholesterol, and triglycerides. All-cause mortality was retrieved for 15,656 patients (99.3 %) on 31 October 2015., Results: Age-adjusted mortality rates and hazard ratios were significantly higher in the whole RIACE cohort (by ∼20 %) and in patients with (by ∼100 %) but not in those without prior cardiovascular disease (CVD), as compared with the coeval Italian general population. In all patients and in those without prior CVD, the relationship with mortality according to the number of risk factors outside target was J-shaped, an effect that was attenuated after either excluding "overtreated " patients, i.e., those with haemoglobin A 1c ≤6.0 % on anti-hyperglycaemic agents causing hypoglycaemia and/or systolic blood pressure ≤120 mmHg on anti-hypertensive agents, or adjusting for "overtreatment". Conversely, in patients with prior CVD, mortality remained higher than in the general population in all categories and increased progressively from +70 % to +314 %, without J-effect., Conclusions: In patients with type 2 diabetes, optimal treatment of traditional cardiovascular risk factors completely eliminated the excess mortality risk versus the general population, provided that they were not "overtreated". However, this effect was observed only in participants without history of CVD., Trial Registration: ClinicalTrials.gov, NCT00715481, retrospectively registered 15 July 2008., Competing Interests: Declaration of Competing Interest Monia Garofolo: consultant fees from Eli Lilly, and lecture fees from Eli Lilly, Merck Sharp & Dohme, and Novo Nordisk. Giuseppe Penno: consultant fees from Bayer and Eli Lilly, and lecture fees from AstraZeneca, Boerhinger Ingelheim, Eli-Lilly, Merck Sharp & Dohme, Mundipharma, Novo Nordisk, and Takeda. Anna Solini: consultant fees from Axxam, Bayer, and Novo Nordisk, and lecture fees from Eli Lilly, Novo Nordisk, and Sanofi-Aventis. Emanuela Orsi: consultant fees from Eli Lilly and Novo Nordisk, and lecture fees from Astellas. Martina Vitale: lecture fees from MundiPharma and Novo Nordisk. Veronica Resi: lecture fees from Astra-Zeneca, Eli Lilly, and Sanofi-Aventis. Enzo Bonora: consultant fees from Abbott, Bayer, Becton Dickinson, Boehringer Ingelheim, Daiichi-Sankyo, Eli Lilly, and Novo Nordisk. Cecilia Fondelli: lecture fees from Abbot, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Merck Sharp & Dohme, Mundipharma, and Theras Lifetech. Roberto Trevisan: consultant fees from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Novo Nordisk, and Sanofi-Aventis, and lecture fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, and Novo Nordisk. Monica Vedovato: lecture fees from Lifescan and Novo Nordisk. Antonio Nicolucci: consultant fees from AstraZeneca, lecture fees from Eli Lilly, Medtronic, and Novo Nordisk, and grant support from AlfaSigma, Novo Nordisk, Pikdare, Sanofi, Shionogi, SOBI, and Theras. Giuseppe Pugliese: consultant fees from Abbot, Bayer, and Novo Nordisk, and lecture fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Mundipharma, and Novo Nordisk., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Estimated pulse-wave velocity (ePWV), a surrogate measure of arterial stiffness, was shown to independently predict morbidity and mortality from cardiovascular disease and other causes in both the general population and high-risk individuals. However, in people with type 2 diabetes, it is unknown whether ePWV adds prognostic information beyond the parameters used for calculating it., Aims: To assess the independent association of ePWV with all-cause mortality in individuals with type 2 diabetes., Design: Prospective cohort study that enrolled 15 773 patients in 19 Italian centres in 2006-08., Methods: ePWV was calculated from a regression equation using age and mean blood pressure (BP). All-cause mortality was retrieved for 15 656 patients in 2015., Results: Percentage and rate of deaths, Kaplan-Meier estimates and unadjusted hazard ratios increased from Quartile I to Quartile IV of ePWV. After adjustment for age, sex, BP levels and anti-hypertensive treatment, the strength of association decreased but mortality risk remained significantly higher for Quartiles II (+34%), III (+82%) and IV (+181%) vs. Quartile I and was virtually unchanged when further adjusting for other cardiovascular risk factors and complications/comorbidities. Each m·s- 1 increase in ePWV was associated with an increased adjusted risk of death in the whole cohort (+53%) and in participants with (+52%) and without (+65%) cardiorenal complications. Moreover, ePWV significantly improved prediction of mortality risk over cardiovascular risk factors and complications/comorbidities, though the net increase was modest., Conclusions: These findings suggest that ePWV may represent a simple and inexpensive tool for providing prognostic information beyond traditional cardiovascular risk factors., Trial Registration: ClinicalTrials.gov, NCT00715481, https://clinicaltrials.gov/ct2/show/NCT00715481., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The incidence of acute pancreatitis (AP) in liver transplanted people is reported to be 1.5-8%. On the other hand, the evidence for a causal relationship between glucagon-like peptide 1 receptor agonists (GLP1RAs) and pancreatitis in people with type 2 diabetes is still weak. In addition, there are currently no data on a possible increased risk of AP in liver-transplanted individuals with diabetes treated with GLP1RAs. In a population of liver-transplanted individuals with diabetes receiving GLP1RA-based therapy, we reported an incidence of AP of 3.0% (two subjects). No cases were reported in liver-transplanted individuals with diabetes receiving SGLT2 inhibitors, insulin or metformin, neither in kidney or lung-transplanted patients treated with GLP1RAs. In both patients with AP, the only additional risk factor for its development was a history of re-transplantation (liver or combined kidney/liver). For this reason, we suggest particular caution when considering GLP1RAs-based therapies in liver transplanted patients with multiple risk factors for AP, such as a history of repeated and complex abdominal surgery., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Grancini, Cogliati, Gaglio, Resi and Orsi.)

Introduction: One of the most common complications of cirrhosis is diabetes, which prevalence is strictly related to severity of hepatopathy. Actually, there are no data on the persistence of post-transplant glucose abnormalities and on a potential impact of diabetes on development of fibrosis in the transplanted liver. To this aim, we evaluated liver fibrosis in cirrhotic subjects before and after being transplanted., Methods: The study included 111 individuals who had liver transplantation. The assessment was performed before and two years after surgery to investigate a potential impact of the persistence of diabetes on developing de novo fibrosis in the transplanted liver. The degree of fibrosis was assessed using the Fibrosis Index Based on 4 Factors (FIB-4) and the Aspartate to Platelet Ratio Index (APRI)., Results: At pre-transplant evaluation, 63 out of 111 (56.8%) subjects were diabetic. Diabetic subjects had higher FIB-4 (Geometric mean, 95% confidence interval: 9.74, 8.32-11.41 vs 5.93, 4.71-7.46, P <0.001) and APRI (2.04, 1.69-2.47 vs 1.18, 0.90-1.55, P <0.001) compared to non-diabetic subjects. Two years after transplantation, 39 out of 111 (35.1%) subjects remained with diabetes and continued to show significantly higher FIB-4 (3.14, 2.57-3.82 vs 1.87, 1.55-2.27, P <0.001) and APRI (0.52, 0.39-0.69 vs 0.26, 0.21-0.32, P <0.001) compared to subjects without diabetes., Discussion: Thus, persistence of diabetes after surgery is a possible risk factor for an evolution to fibrosis in the transplanted liver, potentially leading to worsened long-term outcomes in this population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Grancini, Cogliati, Alicandro, Gaglio, Gatti, Donato, Orsi and Resi.)

Background: Foot ulcers and/or infections are common long-term complications of diabetes and are associated with increased mortality, especially from cardiovascular disease, though only a few studies have investigated the independent contribution of these events to risk of death. This study aimed at assessing the association of history of diabetic foot with all-cause mortality in individuals with type 2 diabetes, independent of cardiovascular risk factors, other complications, and comorbidities., Methods: This prospective cohort study enrolled 15,773 Caucasian patients in 19 Italian centers in the years 2006-2008. Prior lower extremity, coronary, and cerebrovascular events and major comorbidities were ascertained by medical records, diabetic retinopathy by fundoscopy, diabetic kidney disease by albuminuria and estimated glomerular filtration rate, cardiovascular risk factors by standard methods. All-cause mortality was retrieved for 15,656 patients on 31 October 2015., Results: At baseline, 892 patients (5.7%) had a history of diabetic foot, including ulcer/gangrene and/or amputation (n = 565; 3.58%), with (n = 126; 0.80%) or without (n = 439; 2.78%) lower limb revascularization, and revascularization alone (n = 330; 2.09%). History of diabetic foot was associated with all-cause death over a 7.42-year follow-up (adjusted hazard ratio, 1.502 [95% confidence interval, 1.346-1.676], p < 0.0001), independent of confounders, among which age, male sex, smoking, hemoglobin A 1c , current treatments, other complications, comorbidities and, inversely, physical activity level and total and HDL cholesterol were correlated independently with mortality. Both ulcer/gangrene and amputation alone were independently associated with death, with a higher strength of association for amputation than for ulcer/gangrene (1.874 [1.144-3.070], p = 0.013 vs. 1.567 [1.353-1.814], p < 0.0001). Both ulcer/gangrene/amputation and lower limb revascularization alone were independently associated with death; mortality risk was much higher for ulcer/gangrene/amputation than for revascularization (1.641 [1.420-1.895], p < 0.0001 vs. 1.229 [1.024-1.475], p = 0.018) and further increased only slightly for combined ulcer/gangrene/amputation and revascularization (1.733 [1.368-2.196], p < 0.0001)., Conclusions: In patients with type 2 diabetes, an history of diabetic foot event, including ulcer/gangrene, amputation, and lower limb revascularization, was associated with a ~ 50% increased risk of subsequent death, independent of cardiovascular risk factors, other complications and severe comorbidities, which were also significantly associated with mortality. The association with mortality was greatest for amputation, whereas that for revascularization alone was relatively modest., Trial Registration: ClinicalTrials.gov, NCT00715481, retrospectively registered 15 July, 2008., (© 2024. The Author(s).)

The current board of the interassociative Italian association of medical diabetologists (AMD)/Italian society of diabetology (SID) Diabetes and Pregnancy Italian Study Group commented about two recent papers published in the New England Journal of Medicine that investigated the screening and diagnostic methods for gestational diabetes mellitus (GDM). It is well recognized that effective screening and accurate, early diagnosis of GDM contributes to better management of these women in order to reduce adverse maternal and fetal/neonatal outcomes. However, there is worldwide controversy concerning which screening (selective or universal; one step or two steps) and which diagnostic criteria (glucose thresholds) are appropriate. The main findings of these papers are discussed along with their implications for the management of pregnant women., Competing Interests: Conflict of interest All authors declare no conflict of interest., (Copyright © 2023 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Objective: This document purpose is to create an evidence-based position statement on the role of metformin therapy in pregnancy complicated by obesity, gestational diabetes (GDM), type 2 diabetes mellitus (T2DM), polycystic ovary syndrome (PCOS) and in women undergoing assisted reproductive technology (ART)., Methods: A comprehensive review of international diabetes guidelines and a search of medical literature was performed to identify studies presenting data on the use of metformin in pregnancy. The document was approved by the councils of the two scientific societies., Results: In condition affecting the fertility, as PCOS, metformin use in pre-conception or early in pregnancy may be beneficial for clinical pregnancy, even in ART treatment, and in obese-PCOS women may reduce preterm delivery. In obese women, even in the presence of GDM or T2DM, metformin use in pregnancy is associated with a lower gestational weight gain. In pregnancy complicated by diabetes (GDM or T2DM), metformin improves maternal glycemic control and may reduce insulin dose. Neonatal and infant outcomes related to metformin exposure in utero are lacking. Metformin use in women with GDM or T2DM is associated with lower birth weight. However, an increased tendency to overweight-obesity has been observed in children, later in life., Conclusions: Metformin may represent a therapeutic option in selected women with obesity, PCOS, GDM, T2DM, and in women undergoing ART. However, more research is required specifically on the long-term effects of in utero exposition to metformin., (© 2023. The Author(s).)

In recent years, GLP-1 receptor agonists (GLP-1RA), and SGLT-2 inhibitors (SGLT-2i) have become available, which have become valuable additions to therapy for type 2 diabetes as they are associated with low risk for hypoglycemia and cardiovascular benefits. Indeed, SGLT-2i have emerged as a promising class of agents to treat heart failure (HF). By inhibiting SGLT-2, these agents lead to excretion of glucose in urine with subsequent lowering of plasma glucose, although it is becoming clear that the observed benefits in HF cannot be explained by glucose-lowering alone. In fact, multiple mechanisms have been proposed to explain the cardiovascular and renal benefits of SGLT-2i, including hemodynamic, anti-inflammatory, anti-fibrotic, antioxidant, and metabolic effects. Herein, we review the available evidence on the pathophysiology of the cardiological benefits of SGLT-2i. In diabetic heart disease, in both clinical and animal models, the effect of SGLT-2i have been shown to improve diastolic function, which is even more evident in HF with preserved ejection fraction. The probable pathogenic mechanisms likely involve damage from free radicals, apoptosis, and inflammation, and therefore fibrosis, many of which have been shown to be improved by SGLT-2i. While the effects on systolic function in models of diabetic heart disease and HF with preserved ejection fraction is limited and contrasting, it is a key element in patients with HF and reduced ejection fraction both with and without diabetes. The significant improvement in systolic function appears to lead to subsequent structural remodeling of the heart with a reduction in left ventricle volume and a consequent reduction in pulmonary pressure. While the effects on cardiac metabolism and inflammation appear to be consolidated, greater efforts are still warranted to further define the entity to which these mechanisms contribute to the cardiovascular benefits of SGLT-2i., (© 2023. The Author(s).)

Aims: As recommended by the Institute of Medicine (IOM), health practitioners should encourage a healthy nutrition and adequate weight gain during pregnancy in order to ensure favorable pregnancy and fetal outcomes, and to prevent diseases later in life for both mother and child. The purpose of this online survey was to determine the knowledge, attitude, and practice of the 2009 IOM recommendations among healthcare professionals managing nutritional therapy in pregnancies complicated by diabetes in Italy., Methods: A cross-sectional survey was conducted by using an online self-administered questionnaire undertaken between October and December 2021., Results: Of the 220 participants 89% were diabetologists/endocrinologists/internal medicine specialists and 11% dietitians/nutritionists. The survey found that the 53% of respondents provide a personalized diet to pregnant women with diabetes, while 32% a standard diet plan and only 15% healthy dietary advice. The 69% of the participants investigated for appropriate gestational weight gain, mainly based on pre-pregnancy BMI (96%), gestational weight gain (GWG) at first prenatal visit (80%) and presence of twin pregnancy (58%). Maternal weight gain was evaluated at each regularly scheduled prenatal visit and compared with IOM recommendations for the 87% of healthcare professionals. Diet plan was periodically re-evaluated and/or modified (90% of participants), based on inadequate maternal weight gain and/or fetal growth abnormalities (78%), trimester transition (53%), changes in physical activity and/or a "feel hungry" (50%)., Conclusions: This survey reported the knowledge and attitude of IOM guidelines and the nutritional knowledge and practice of Italian professionals on the nutritional management of diabetes in pregnancy. The application of these recommendations seemed more feasible in clinics/team dedicated to "Diabetes in Pregnancy"., (© 2022. The Author(s).)

Background: Biomarkers are used for diagnosis, risk stratification and medical decisions. Copeptin and mid-regional proadrenomedullin (MR-proADM) are markers of stress and endothelial function, respectively, which have been studied in pneumonia, sepsis and septic shock. This study aimed to assess whether copeptin and MR-proADM could predict coronavirus disease 2019 (COVID-19) in-hospital outcomes, that is multi-system complications, length of stay and mortality., Methods: Copeptin and MR-proADM were assessed at admission in 116 patients hospitalized with COVID-19. Data were retrospectively extracted from an online database. The primary endpoint was in-hospital mortality. The secondary endpoints were in-hospital complications, the composite outcome 'death, or admission to intensive care unit, or in-hospital complications', and length of stay. The predictive power was expressed as area under the receiver operator characteristic curve (AUROC)., Results: Copeptin was increased in non-survivors (median 29.7 [interquartile range 13.0-106.2] pmol/L) compared to survivors (10.9 [5.9-25.3] pmol/L, p < 0.01). The AUROC for mortality was 0.71, with a hazard ratio of 3.67 (p < 0.01) for copeptin values > 25.3 pmol/L. MR-proADM differentiated survivors (0.8 [0.6-1.1] nmol/L) from non-survivors (1.5 [1.1-2.8] nmol/L, p < 0.001) and yielded a AUROC of 0.79 and a hazard ratio of 7.02 (p < 0.001) for MR-proADM values > 1.0 nmol/L. Copeptin and MR-proADM predicted sepsis (AUROC 0.95 and 0.96 respectively), acute kidney injury (0.87 and 0.90), the composite outcome (0.69 and 0.75) and length of stay (r = 0.42, p < 0.001, and r = 0.46, p < 0.001)., Conclusions: Admission MR-proADM and copeptin may be implemented for early risk stratification in COVID-19-hospitalized patients to help identify those eligible for closer monitoring and care intensification., (© 2022 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Context: Coronavirus disease 2019 (COVID-19) represents a global health emergency, and infected patients with chronic diseases often present with a severe impairment. Adrenal insufficiency (AI) is supposed to be associated with an increased infection risk, which could trigger an adrenal crisis., Objective: Our primary aim was to evaluate the incidence of COVID-19 symptoms and complications in AI patients., Design and Setting: We conducted a retrospective case-control study. All patients were on active follow-up and lived in Lombardy, Italy, one of the most affected areas., Patients: We enrolled 279 patients with primary and secondary AI and 112 controls (patients with benign pituitary lesions without hormonal alterations). All AI patients had been previously trained to modify their replacement therapy on stress doses., Intervention: By administering a standardized questionnaire by phone, we collected data on COVID-19 suggestive symptoms and consequences., Results: In February through April 2020, the prevalence of symptomatic patients (complaining at least 1 symptom of viral infection) was similar between the 2 groups (24% in AI and 22.3% in controls, P = 0.79). Highly suggestive COVID-19 symptoms (at least 2 including fever and/or cough) also occurred equally in AI and controls (12.5% in both groups). No patient required hospitalization and no adrenal crisis was reported. Few nasopharyngeal swabs were performed (n = 12), as indicated by sanitary regulations, limiting conclusions on the exact infection rate (2 positive results in AI and none in controls, P = 0.52)., Conclusions: AI patients who are adequately treated and trained seem to display the same incidence of COVID-19-suggestive symptoms and disease severity as controls., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society.)

The COronaVirus DISease 19 (COVID-19) is a pandemic infectious disease caused by the novel coronavirus Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2). Older age and presence of comorbidities, including diabetes, were shown to be associated with a more severe course and a higher fatality rate. Studies from the most affected countries, including China, United States and Italy, seem to indicate that prevalence of diabetes among patients affected by COVID-19 is not higher than that observed in the general population, thus suggesting that diabetes is not a risk factor for SARS-CoV-2 infection. However, a large body of evidence demonstrate that diabetes is a risk factor for disease progression towards critical illness, development of acute respiratory distress syndrome, need for mechanical ventilation or admission to intensive care unit, and ultimately death. The mechanisms underlying the relationship between COVID-19 and diabetes remain to be elucidated. In particular, it is still unresolved whether is diabetes per se, especially if poorly controlled, or rather the various comorbidities/complications associated with it that predispose patients with COVID-19 to a worse prognosis. In fact, conditions that cluster with diabetes in the context of the metabolic syndrome, such as obesity and hypertension, or complicate chronic hyperglycemia, such as cardiovascular disease and chronic kidney disease, have also been associated with poor prognosis in these individuals and the available studies have not consistently shown that diabetes predict disease severity independently of them.

Achieving and maintaining recommended glycemic targets without causing adverse e ffects, including hypoglycemia, is challenging, especially in older patients with type 2 diabetes mellitus (T2DM). The introduction of dipeptidyl peptidase-4 (DPP-4) inhibitors, more than 10 years ago, has provided an alternative to conventional medications for the intensification of glucose-lowering treatment after failure of metformin monotherapy, and therefore, marked an important advance in the management of T2DM. By prolonging the activity of incretin hormones, DPP-4 inhibitors induce insulin release and decrease glucagon secretion in a glucose-dependent manner. This results in a more physiologic glycemic control as compared to that ensured by insulin secretagogues (sulfonylureas and glinides). Overall, DPP-4 inhibitors have a favorable safety profile and can be used without dose adjustments in older adults and in patients with mild renal impairment; they have a neutral effect on body weight and do not cause hypoglycemia by themselves. Safety issues, reported mainly in post-marketing surveillance programs and including cardiovascular outcomes and the risk of acute pancreatitis, are being extensively investigated. The aim of this review is to discuss the impact of DPP-4 inhibitors on the treatment of T2DM, after 10 years of experience, with an emphasis on diabetes care in Italy. We will first describe T2DM treatment in Italy and then provide an overview of the main findings from randomized controlled trials, real-world studies and post-marketing surveillance programs with DPP-4 inhibitors.

Background & Aims: Diabetes occurring as a direct consequence of loss of liver function is usually characterized by non-diabetic fasting plasma glucose (FPG) and haemoglobin A 1c (HbA 1c ) levels and should regress after orthotopic liver transplantation (OLT). This observational, longitudinal study investigated the relationship between the time-courses of changes in all 3 direct determinants of glucose regulation, i.e., β-cell function, insulin clearance and insulin sensitivity, and diabetes regression after OLT., Methods: Eighty cirrhotic patients with non-diabetic FPG and HbA 1c levels underwent an extended oral glucose tolerance test (OGTT) before and 3, 6, 12 and 24 months after OLT. The OGTT data were analysed with a mathematical model to estimate derivative control (DC) and proportional control (PC) of β-cell function and insulin clearance (which determine insulin bioavailability), and with the Oral Glucose Insulin Sensitivity (OGIS)-2 h index to estimate insulin sensitivity., Results: At baseline, 36 patients were diabetic (45%) and 44 were non-diabetic (55%). Over the 2-year follow-up, 23 diabetic patients (63.9%) regressed to non-diabetic glucose regulation, whereas 13 did not (36.1%); moreover, 4 non-diabetic individuals progressed to diabetes (9.1%), whereas 40 did not (90.9%). Both DC and PC increased in regressors (from month 3 and 24, respectively) and decreased in progressors, whereas they remained stable in non-regressors and only PC decreased in non-progressors. Insulin clearance increased in all groups, apart from progressors. Likewise, OGIS-2 h improved at month 3 in all groups, but thereafter it continued to improve only in regressors, whereas it returned to baseline values in the other groups., Conclusions: Increased insulin bioavailability driven by improved β-cell function plays a central role in favouring diabetes regression after OLT, in the presence of a sustained improvement of insulin sensitivity., Lay Summary: Diabetes occurring in cirrhosis as a direct consequence of loss of liver function should regress after transplantation of a new functioning liver, though the pathophysiological mechanisms are unclear. This is the first study evaluating the contribution of all 3 direct determinants of insulin-dependent glucose regulation using a sophisticated mathematical model. Results show that β-cell function is the key process governing favourable or detrimental changes in glucose regulation in cirrhotic patients undergoing transplantation, pointing to the need to develop therapies to sustain β-cell function in these individuals., Trial Registration: ClinicalTrials.gov, NCT02038517., (Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Diabetes is a common feature in cirrhotic individuals both before and after liver transplantation and negatively affects prognosis. Certain aetiological agents of chronic liver disease and loss of liver function per se favour the occurrence of pre-transplant diabetes in susceptible individuals, whereas immunosuppressant treatment, changes in lifestyle habits, and donor- and procedure-related factors contribute to diabetes development/persistence after transplantation. Challenges in the management of pre-transplant diabetes include the profound nutritional alterations characterizing cirrhotic individuals and the limitations to the use of drugs with liver metabolism. Special issues in the management of post-transplant diabetes include the diabetogenic potential of immunosuppressant drugs and the increased cardiovascular risk characterizing solid organ transplant survivors. Overall, the pharmacological management of cirrhotic patients undergoing liver transplantation is complicated by the lack of specific guidelines reflecting the paucity of data on the impact of glycaemic control and the safety and efficacy of anti-hyperglycaemic agents in these individuals., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

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.

Gestational Diabetes Mellitus is a condition strongly related to the development of type 2 diabetes later in life, although the risk and the onset have not been fully identified yet. Although glucose tolerance returns to normal levels after delivery in the majority of women with GDM, this condition represents an early stage in the natural history of T2DM. In addition, women with previous GDM exhibit an increased cardiovascular risk profile and a raised incidence of cardiovascular diseases. Lifestyle changes and pharmacological interventions might be able to reduce the incidence of type 2 diabetes in pGDM women, although results are still not conclusive. Long term continuous programs specifically addressed to women with pGDM should be implemented, with the ambitious target to encourage them to regularly check glucose tolerance, lipid profile and other parameters related to cardiovascular diseases, aimed at improving women's health. In this paper, we review the relationship between type 2 diabetes, cardiovascular diseases and a history of GDM., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: The Williams-Beuren syndrome (WS) is associated with impaired glucose metabolism (IGM) early in adulthood. However, the pathophysiology of IGM remains poorly defined, due to the lack of longitudinal studies investigating the contribution of β-cell dysfunction and impaired insulin sensitivity. This study aimed at assessing incidence of IGM and the underlying mechanisms in WS adults., Methods: This observational, longitudinal (5-year), cohort study enrolled thirty-one consecutive WS subjects attending a tertiary referral center. An oral glucose tolerance test (OGTT) was performed yearly and used to classify patients as normal or IGM, including impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) and diabetes mellitus (DM), and to calculate surrogate measures of insulin secretion and/or sensitivity., Results: IGM patients were 18 (58.1%, three DM) at baseline and 19 (61.3%, five DM) at end-of-follow-up. However, 13 individuals changed category of glucose homeostasis in both directions during follow-up (8 progressors, 5 regressors) and 18 did not (8 non-progressors, 10 non-regressors). New cases of IGM and DM were 11.1 and 2.53 per 100 persons-year, respectively, and were treated non-pharmacologically. In the whole cohort and, to a higher extent, in progressors, indices of early-phase insulin secretion and insulin sensitivity decreased significantly from baseline to end-of-follow-up, with concurrent reduction of the oral disposition index and insulin secretion-sensitivity index-2 (ISSI-2), compensating insulin secretion for the level of insulin resistance. No baseline measure independently predicted progression, which correlated with change from baseline in ISSI-2. Compared with patients with normal glucose homeostasis, IGT subjects had impaired insulin sensitivity, whereas insulin secretion was reduced only in those with IFG+IGT or DM., Conclusions: IGM incidence is high in young adults with WS, suggesting the need of early screening and timed intervention. As in classical type 2 diabetes, impaired insulin sensitivity and β-cell dysfunction contribute, in this sequence, to progression to IGM and DM.

Background and Aims: The administration of Liraglutide, a long-acting GLP-1 receptor (GLP-1R) agonist, is associated with C-cell adenomas and carcinomas in rats. In humans, GLP-1R is highly expressed in C-cells hyperplasia (CCH) and in medullary thyroid cancer (MTC), though no changes in basal serum calcitonin (bCT) levels were recorded in type 2 diabetic (T2DM) patients treated with Liraglutide. To diagnose the possible development of CCH during Liraglutide treatment, we evaluated CT levels stimulated by calcium test (sCT)., Materials and Methods: bCT and sCT and metabolic and anthropometric parameters were evaluated in 26 T2DM patients at baseline and at 1, 3, 6 and 12 months of treatment., Results: In all patients, bCT remained within the normal range during the entire study period. In females and males, the higher sCT values were reached after 3 months and 1 month, respectively, with a progressive reduction at 6-12 months. The greater decrease of HbA1c values was reached at 3 months, while body weight and waist circumference decreased over the first 4 weeks of therapy. Lipase levels significantly increased, with a peak value at 1 month., Conclusion: The chronic administration of Liraglutide did not lead to statistically significant variations in both bCT and sCT. Stimulated CT levels increased, though always below the normal range, during the first 1-3 months of treatment, and progressively decreased to baseline levels. This finding is consistent with the effects recorded at the glycometabolic level, and suggests the possible induction of a drug tolerance involving also the C cells and thus preventing CCH., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background & Aims: This study evaluated the contribution of β-cell dysfunction and insulin resistance to cirrhosis-associated diabetes., Methods: One-hundred and sixty cirrhotic patients with normal fasting plasma glucose (FPG), three with impaired fasting glucose and seven with untreated diabetes mellitus (DM) underwent an extended oral glucose tolerance test (OGTT). The OGTT data were analyzed with a Minimal Model to estimate dynamic (derivative) control (DC) and static (proportional) control (PC) of β-cell function, and with the Oral Glucose Insulin Sensitivity (OGIS)-2h index to estimate insulin sensitivity., Results: Twenty-six patients (15.6%) had normal glucose tolerance (NGT), 60 (35.8%) had impaired glucose tolerance (IGT), and 84 (48.6%) had DM. DC was significantly reduced in DM vs. NGT and IGT patients. PC was significantly impaired in DM and IGT vs. NGT patients and in DM vs. IGT subjects. The OGIS-2h index was significantly reduced to a similar extent in DM and IGT vs. NGT patients. Patients with Child-Pugh class B and C cirrhosis had reduced DC and PC, but not OGIS-2h values, as compared with subjects in class A. Moreover, Child-Pugh class/score was an independent predictor of β-cell function even after adjustment for glucose tolerance., Conclusions: Abnormalities of glucose tolerance occur frequently in cirrhosis even in patients with normal FPG, thereby supporting the importance of performing an OGTT. Transition from IGT to DM is driven primarily by β-cell dysfunction. Insulin secretion worsens in parallel with the severity of liver disease, thus suggesting a detrimental effect of liver failure on pancreatic islets on its own., (Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Tyrosine kinase inhibitors (TKIs) have dramatically changed the prognosis of patients with chronic myeloid leukemia (CML). They have a distinct toxicity profile that includes glycometabolic alterations: i.e. diabetes mellitus (DM), impaired fasting glucose (IFG), and the metabolic syndrome (MS). The aim of this study was to evaluate the prevalence of these alterations in a cohort of CML-chronic phase patients treated with imatinib, dasatinib or nilotinib., Methods: The study involved 168 consecutive CML-chronic phase patients with no history of DM/IFG or MS. Anthropometric and metabolic parameters were assessed, and DM/IFG and MS were diagnosed based on the criteria of the American Diabetes Association and the National Cholesterol Education Program-Adult Treatment Panel III, respectively., Results: The nilotinib group had significantly higher levels of fasting plasma glucose, insulin, C-peptide, insulin resistance, and total and LDL cholesterol than the imatinib and dasatinib groups. DM/IFG were identified in 25% of the imatinib- and dasatinib-treated patients, and 33% of those in the nilotinib cohort (p = 0.39 vs imatinib and p = 0.69 vs dasatinib). A diagnosis of MS was made in 42.4% of the imatinib-treated patients, 37.5% of the dasatinib-treated patients, and 36.1% of the nilotinib-treated patients (p = 0.46 vs imatinib and p = 0.34 vs dasatinib)., Conclusions: Treatment with nilotinib does not seem to induce DM/IFG or the MS to a significantly higher extent than imatinib or dasatinib, though it causes a worse glycometabolic profile. These findings suggest the need for a close monitoring of glucose and lipid metabolism and a multidisciplinary approach in patients treated with nilotinib.

Changes in adipose tissue metabolism are central to adaptation of whole body energy homeostasis to pregnancy. To gain insight into the molecular mechanisms supporting tissue remodeling, we have characterized the longitudinal changes of the adipose transcriptome in human pregnancy. Healthy nonobese women recruited pregravid were followed in early (8-12 wk) and in late (36-38 wk) pregnancy. Adipose tissue biopsies were obtained in the fasting state from the gluteal depot. The adipose transcriptome was examined via whole genome DNA microarray. Expression of immune-related genes and extracellular matrix components was measured using real-time RT-PCR. Adipose mass, adipocyte size, and cell number increased in late pregnancy compared with pregravid measurements (P < 0.001) but remained unchanged in early pregnancy. The adipose transcriptome evolved during pregnancy with 10-15% of genes being differently expressed compared with pregravid. Functional gene cluster analysis revealed that the early molecular changes affected immune responses, angiogenesis, matrix remodeling, and lipid biosynthesis. Increased expression of macrophage markers (CD68, CD14, and the mannose-6 phosphate receptor) emphasized the recruitment of the immune network in both early and late pregnancy. The TLR4/NF-κB signaling pathway was enhanced specifically in relation to inflammatory adipokines and chemokines genes. We conclude that early recruitment of metabolic and immune molecular networks precedes the appearance of pregnancy-related physiological changes in adipose tissue. This biphasic pattern suggests that physiological inflammation is an early step preceding the development of insulin resistance, which peaks in late pregnancy.

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 (<120 mg/dL, 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 (AUC(gluc)) and insulin curves (AUC(ins)), indexes of insulin secretion (HOMA-B), and insulin sensitivity (HOMA-R), AUC(ins)/AUC(gluc). AUC(gluc) and AUC(ins) progressively increased according to 1-hour plasma glucose concentrations (both P < 0.0001 for trend). HOMA-B progressively declined (P < 0.001), and HOMA-R progressively increased across the five groups. AUC(ins)/AUC(gluc) decreased in a linear manner across the 5 groups (P < 0.001). Analysing the groups with 1-hour value <180 mg/dL, defects in insulin secretion (HOMA-B: -29.7%) and sensitivity (HOMA-R: +15%) indexes were still apparent (all 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.

Endothelial progenitor cells (EPCs) play a role in angiogenesis during pregnancy. The aim of this study was to evaluate circulating EPCs in pregnant women with gestational alterations of glucose tolerance. Glucose tolerance, insulin sensitivity and β-cell function were derived from oral glucose tolerance tests in 23 women with normal glucose tolerance (NGT), 18 with gestational impaired glucose tolerance (GIGT) and 24 with gestational diabetes mellitus (GDM). Circulating cells expressing CD34 in combination with CD133, kinase insert domain receptor (KDR) or both were quantified by flow cytometry. Women with GIGT and GDM had lower CD34(+)KDR(+) and CD34(+)CD133( +)KDR(+) cells at 27±3.2 weeks' gestation compared with NGT (ANOVA p<0.02 for both). CD34(+)KDR(+) and CD34(+)CD133(+)KDR(+) cells were inversely correlated with the area-under-the-glucose-curve (p<0.005, for both) and positively to insulin secretion-sensitivity index (p<0.05, for both). Alterations of glucose tolerance during pregnancy are associated with a decrease in EPCs. Hyperglycaemia might exert a direct effect on depletion of EPCs.

During pregnancy, complex changes occur in lipid profiles. From the 12th week of gestation, phospholipids, cholesterol (total, LDL, HDL), and triglycerides (TG) increase in response to estrogen stimulation and insulin resistance. Transition to a catabolic state favors maternal tissue lipid use as energy sources, thus sparing glucose and amino acids for the fetus. In addition, maternal lipids, that is, cholesterol, are available for fetal use in building cell membranes and as precursor of bile acids and steroid hormones. It is also required for cell proliferation and development of the growing body. Free-fatty acids (FFA), oxidized in the maternal liver as ketone-bodies, represent an alternative fuel for the fetus. Maternal hypertriglyceridemia (vs. other lipids) has many positive effects such as contributing to fetal growth and development and serving as an energy depot for maternal dietary fatty acids. However, increased TG during pregnancy appears to increase risk of preeclampsia and preterm birth. Some have suggested that maternal hypertriglyceridemia has a role in increasing cardiovascular risk later in life. This chapter reviews lipid metabolism during pregnancy to elucidate its effect on fetal growth and its potential role in pregnancy-associated complications and future cardiovascular risk.

Objectives: We designed this study to assess the potential effects of physical activity and dietary habits on glucose tolerance during pregnancy., Methods: This is an observational study involving 268 women who underwent a 50-g oral glucose challenge test (GCT) at 27±6.9 week of gestation. Plasma glucose level at 1-h GCT ≥ 140 mg/dl was used to define abnormal glucose tolerance (AGT). Physical activity was evaluated using the short form of the International Physical Activity Questionnaire (IPAQ), while for dietary habits we used a food frequency questionnaire linked to a computerised program., Results: One hundred five women had AGT (AGT+) and 163 had normal glucose tolerance (AGT−). There was no difference between the two groups in demographic and clinical data, with the exception of pre-pregnancy BMI and weight gain both higher in AGT+ women. Also, all parameters referring to physical activity energy and diet (Kcal and diet components) were not statistically different between the two groups. After a multivariate analysis, only pre-pregnancy BMI (F-value 9.264, p=0.002) remained an independent predictor of 1-h plasma glucose., Conclusions: Our study suggests that high pre-pregnancy BMI confers a substantially high risk of AGT, independently of lifestyle during pregnancy.

The aim of this study was to evaluate the effects of continuous subcutaneous insulin infusion (CSII) on glycemic control and pregnancy outcomes in Type 1 diabetic pregnant women. We retrospectively evaluated 42 subjects, 20 treated with CSII and 22 with multiple dose insulin injections (MDI). The two groups were comparable for age, pre-pregnancy BMI, and primiparous rate, whereas women in the CSII group showed a tendency toward a longer diabetes duration (p = 0.06). Pre-pregnancy diabetic retinopathy and/or nephropathy were present in nine women of CSII and three of MDI. In all women metabolic control improved during pregnancy, without differences between the two groups and at the end of gestation HbA1c was 6.3 +/- 0.6 in CSII and 6.1 +/- 1.1% in MDI. Moreover, there were no differences in weight gain, whereas insulin requirement resulted significantly (p = 0.009) lower in CSII than in MDI. We recorded only one severe hypoglycaemic episode in both groups. No cases of deteriorations of the chronic diabetic complications were observed. The delivery occurred at 36.4 +/- 2.2 weeks; birth weight, the rate of large for gestational age, and the parameters of foetal morbidity were similar in both groups. In conclusions, CSII and MDI are both effective in improving maternal glucose control and have both similar pregnancy outcomes.

In women with previous gestational diabetes (pGDM), the risk of developing Type 2 diabetes is greatly increased, to the point that GDM represents an early stage in the natural history of Type 2 diabetes. In addition, in the years following the index pregnancy, women with pGDM exhibit an increased cardiovascular risk profile and an increased incidence of cardiovascular disease. This paper will review current knowledge on the metabolic modifications that occur in normal pregnancy, underlining the mechanism responsible for GDM, the link between these alterations and the associated long-term maternal complications. In women with pGDM, accurate follow-up and prevention strategies (e.g., weight control and regular physical exercise) are needed to reduce the subsequent development of overt diabetes and other metabolic abnormalities related to cardiovascular disease. Therefore, our paper will provide arguments in favor of performing follow-up programs aimed at modifying risk factors involved in the pathogenesis of Type 2 diabetes and cardiovascular disease.