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Erectile dysfunction (ED) is a long-term complication of type 2 diabetes (T2D) widely known to affect the quality of life. Several aspects of altered metabolism in individuals with T2D may help to compromise the penile vasculature structure and functions, thus exacerbating the imbalance between smooth muscle contractility and relaxation. Among these, advanced glycation end-products and reactive oxygen species derived from a hyperglycaemic state are known to accelerate endothelial dysfunction by lowering nitric oxide bioavailability, the essential stimulus of relaxation. Although several studies have explained the pathogenetic mechanisms involved in the generation of erectile failure, few studies to date have described the efficacy of glucose-lowering medications in the restoration of normal sexual activity. Herein, we will present current knowledge about the main starters of the pathophysiology of diabetic ED and explore the role of different anti-diabetes therapies in the potential remission of ED, highlighting specific pathways whose activation or inhibition could be fundamental for sexual care in a diabetes setting. [ABSTRACT FROM AUTHOR]

Bariatric surgery and consequent weight loss improve metabolic and anthropometric parameters in obese subjects. However, a detailed assessments about the impact of bariatric surgery on quality of life (QoL), body image perception, and sex life is lacking. The aim of this study was to assess the QoL, body image satisfaction and sexual function in 389 female patients with obesity (age 40±10 years, pre-surgery weight 120.4±17.7 kg) before and at least 6 months after bariatric surgery (60% sleeve gastrectomy, 40% gastric bypass). All participants were asked to complete the following online self-report questionnaires seven days before and six months after bariatric surgery: the Body Uneasiness Test (BUT) to assess self-perception of body image, the Short Form-12 (SF-12) to QoL as per the physical (PCS) and mental (MCS) domains, and the Female Sexual Function Index (FSFI) to screen for sexual dysfunctions in women. After bariatric surgery, patients lost 44.5±16.5 kg (p<0.001), with an increase of the PCS (53.3±7.2 vs. 31.9±21.4, p<0.001) and MCS (50.5±8.8 vs. 39.6±12.5, p<0.001) scores, that fell within the normal range of healthy individuals. All patients showed a significant improvement of the global score index domain of the BUT (1.9±1.1 vs. 3.7±0.9, p<0.001). The youngest patients (18-39 years old) who lost at least 40% of the baseline weight obtained a normalization of their body image concern domain results, reaching the reference range for healthy non-obese subjects. After bariatric surgery, patients also had a significant improvement of the FSFI (26.8±9.7 vs. 19.6±8.8, p<0.001), with an increase of non-dysfunctional, sexually active women from 26.2% to 78.2%. Significant correlations were found between the extent of weight loss and the improvement of all the psychometric parameters. Bariatric surgery is an efficient and safe treatment for obesity, and the physical gains related to weight loss are also mirrored by significant improvements in mental and physical health and sexual function. Disclosure: L. Di gioia: None. A. Natalicchio: Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Sanofi. L. Laviola: Advisory Panel; Self; A. Menarini Diagnostics, Abbott, AstraZeneca, Lilly Diabetes, Novo Nordisk Inc., Roche Diabetes Care, Sanofi-Aventis, Speaker's Bureau; Self; Boehringer Ingelheim International GmbH, Medtronic. A. Bertolino: None. F. Giorgino: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Novo Nordisk, Roche Diabetes Care, Sanofi, Research Support; Self; Lilly Diabetes, Roche Diabetes Care. S. Perrini: None. A. Braun: None. E. Rossi: None. F. Giordano: None. F. Guarini: None. E. Siciliano: None. A. Cignarelli: None. A. Leonardini: None. [ABSTRACT FROM AUTHOR]

Diabetic Nephropathy (DN) is a chronic complication of diabetes and the primary cause of end stage renal disease. Differential diagnosis for DN requires invasive histological investigation, thus there is need for non-invasive biomarkers to discriminate among different histological lesions in diabetic patients. With the aim to identify a pattern of differentially expressed miRNAs in kidney biopsies of DN patients, we assayed miRNA expression in kidney biopsies from DN patients, diabetic patients with membranous nephropathy and patients with normal histology. Nine miRNAs were differentially expressed among the three groups, and 2 miRNAs (miR-27b-3p and miR-1228-3p) showed interaction with an ubiquitin-conjugating E2 enzyme variant (UBE2v1). UBE2v1 mediates the formation of lysine 63-linked ubiquitin chains, a mechanism we previously showed as involved in DN kidney fibrosis. Both miRNAs were validated as down-regulated in biopsies and urines of DN patients, possibly affected by DNA methylation. Interestingly, the urinary levels of both miRNAs could also discriminate among different degrees of renal fibrosis. Finally, we showed that the combined urinary expression of both miRNAs was also able to discriminate DN patients from other glomerulonephritides in diabetic patients. In conclusion we identified two miRNAs potentially useful as candidate biomarkers of tubular-interstitial fibrosis in diabetic patients with DN. [ABSTRACT FROM AUTHOR]

Despite the growing evidence supporting the outpatient use of continuous glucose monitoring (CGM) for improving glycaemic control and reducing hypoglycaemia, there is a need for a detailed understanding of the specific features of CGM devices that best meet individual patient needs. This expert opinion, based on a comprehensive literature review and the personal perspectives of clinicians, aims to provide the healthcare professionals (HCPs) with a comprehensive framework for selecting CGM devices. It evaluates the current state of CGM technology, categorizing features into essential features, major drivers of choice, and additional/useful features. Moreover, the practical model presented outlines a patient's journey with CGM, emphasising the importance of aligning device features with patient needs. This includes understanding the patient's lifestyle, clinical conditions, and personal preferences to optimize CGM use and improve diabetes management outcomes., (© 2024. The Author(s).)

Aims: To compare the efficacy and safety of different hybrid closed loop (HCL) systems in people with diabetes through a network meta-analysis., Methods: We searched MEDLINE, EMBASE, CENTRAL and PubMed for randomised clinical trials (RCTs) enrolling children, adolescents and/or adults with type 1 or type 2 diabetes, evaluating Minimed 670G, Minimed 780G, Control-IQ, CamAPS Fx, DBLG-1, DBLHU, and Omnipod 5 HCL systems against other types of insulin therapy, and reporting time in target range (TIR) as outcome., Results: A total of 28 RCTs, all enrolling people with type 1 diabetes, were included. HCL systems significantly increased TIR compared with subcutaneous insulin therapy without continuous glucose monitoring (SIT). Minimed 780G achieved the highest TIR ahead of Control IQ (mean difference (MD) 5.1%, 95% confidence interval (95% CI) [0.68; 9.52], low certainty), Minimed 670G (MD 7.48%, 95% CI [4.27; 10.7], moderate certainty), CamAPS Fx (MD 8.94%, 95% CI [4.35; 13.54], low certainty), and DBLG1 (MD 10.69%, 95% CI [5.73; 15.65], low certainty). All HCL systems decreased time below target range, with DBLG1 (MD -3.69%, 95% CI [-5.2; -2.19], high certainty), Minimed 670G (MD -2.9%, 95% CI [-3.77; -2.04], moderate certainty) and Minimed 780G (MD -2.79%, 95% CI [-3.94; -1.64], high certainty) exhibiting the largest reductions compared to SIT. The risk of severe hypoglycaemia and diabetic ketoacidosis was similar to other types of insulin therapy., Conclusions: We show a hierarchy of efficacy among the different HCL systems in people with type 1 diabetes, thus providing support to clinical decision-making., Trial Registration: PROSPERO CRD42023453717., (© 2024 The Author(s). Diabetes/Metabolism Research and Reviews published by John Wiley & Sons Ltd.)

Purpose: Carney complex (CNC) is a rare, autosomal dominant syndrome, most commonly caused by PRKAR1A gene mutations and characterized by pigmented skin and mucosal changes with multiple endocrine and non-endocrine tumours. This case report highlights the diagnostic challenges associated with CNC in a patient with multiple neoplasms and a complex medical history, including cortisol-producing adrenal adenoma, breast cancer, melanoma, and atrial myxoma., Methods: We report the case of a 41-year-old woman with a medical history of left adrenalectomy for cortisol producing adenoma (2005) with no sign of adrenal insufficiency at follow-up, right mastectomy for BRCA1/2 negative carcinoma (2013) and left parotid BRAF-V600E wild-type melanoma (2019), treated with nivolumab adjuvant therapy. In August 2019, following the fifth nivolumab administration, the patient developed central hypocortisolism due to iatrogenic hypophysitis, confirmed by brain MRI and properly treated with oral hydrocortisone. Nivolumab was discontinued due to the patient's decision. In October 2020 and April 2021, the patient had ischaemic strokes, requiring systemic thrombolysis. Echocardiographic examination then revealed a left atrial mass, with histological finding of myxoma., Results: Given the rarity of this neoplasm and the suspicion of a syndromic disorder, a genetic evaluation was conducted, which confirmed a PRKAR1A gene mutation and the diagnosis of Carney complex., Conclusion: This case illustrates the diagnostic challenges in CNC, especially in patients with multiple tumourous manifestations and a wide spectrum of life-threatening clinical presentations. It underscores the importance of a multidisciplinary approach to diagnose and manage rare diseases, improving patient outcomes through timely genetic testing and coordinated care., (© 2024. The Author(s).)

Background: Extended glucose predictions are novel in diabetes management. Currently, there is no solution widely available. People with diabetes mellitus (DM) are offered features like trend arrows and limited predictions linked to predefined situations. Thus, the impact of extended glucose predictions on the burden of diabetes and person-reported outcomes (PROs) is unclear., Methods: In this online survey, 206 people with type 1 and type 2 diabetes (T1D and T2D), 70.9% and 29.1%, respectively, who participated in the dia·link online panel and were current continuous glucose monitoring (CGM) users, were presented with different scenarios of hypothetical extended glucose predictions. They were asked to imagine how low glucose predictions of 30 minutes and overnight as well as glucose predictions up to 2 hours would influence their diabetes management. Subsequently, they completed the Hypoglycemia Fear Survey II (HFS-II) and the T1 Diabetes Distress Scale (T1-DDS) by rating each item on a 5-point scale (-2: strong deterioration to +2: strong improvement) according to the potential change due to using glucose predictions., Results: For all glucose prediction periods, 30 minutes, up to 2 hours, and at nighttime, the surveyed participants expected moderate improvements in both fear of hypoglycemia (HFS-II: 0.57 ± 0.49) and overall diabetes distress (T1-DDS = 0.44 ± 0.49). The T1-DDS did not differ for type of therapy or diabetes., Conclusions: People with T1D and T2D would see glucose predictions as a potential improvement regarding reduced fear of hypoglycemia and diabetes distress. Therefore, glucose predictions represent a value for them in lowering the burden of diabetes and its management., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: D.E. reports lecture fees from Roche Diabetes Care, Sanofi-Aventis, and Dexcom Germany and is an Advisory Board member of Roche Diabetes Care and Dexcom Germany. L.L. reports lecture fees from Abbott, AstraZeneca, Boehringer-Ingelheim, Eli Lilly, Merck Sharp & Dohme, Medtronic, Menarini, MOVI SpA, Mundipharma, Novo Nordisk, Roche Diabetes Care, Sanofi-Aventis, and Terumo. He is an Advisory Board member of Abbott, AstraZeneca, Boehringer-Ingelheim, Eli Lilly Italia, Medtronic, MOVI SpA, Novo Nordisk, Roche Diabetes Care, Sanofi-Aventis, and Terumo. L-S.P. reports lecture fees from Ypsomed. N.H. reports Advisory Board member fees from Abbott Diabetes Care and Insulet as well as honoraria for lectures from Berlin Chemie AG, Becton Dickenson, Sanofi Germany, Roche Diabetes Care, and Dexcom Germany. N.B. and T.G. are employees and stockholders of Roche Diabetes Care GmbH.

Diabetes mellitus is a chronic metabolic disease, the prevalence of which is constantly increasing worldwide. It is often burdened by disabling comorbidities that reduce the quality and expectancy of life of the affected individuals. The traditional complications of diabetes are generally described as macrovascular complications (e.g., coronary heart disease, peripheral arterial disease, and stroke), and microvascular complications (e.g., diabetic kidney disease, retinopathy, and neuropathy). Recently, due to advances in diabetes management and the increased life expectancy of diabetic patients, a strong correlation between diabetes and other pathological conditions (such as liver diseases, cancer, neurodegenerative diseases, cognitive impairments, and sleep disorders) has emerged. Therefore, these comorbidities have been proposed as emerging complications of diabetes. P66 Shc is a redox protein that plays a role in oxidative stress, apoptosis, glucose metabolism, and cellular aging. It can be regulated by various stressful stimuli typical of the diabetic milieu and is involved in various types of organ and tissue damage under diabetic conditions. Although its role in the pathogenesis of diabetes remains controversial, there is strong evidence regarding the involvement of p66 Shc in the traditional complications of diabetes. In this review, we will summarize the evidence supporting the role of p66 Shc in the pathogenesis of diabetes and its complications, focusing for the first time on the emerging complications of diabetes.

Purpose: Continuous Glucose Monitoring (CGM) is a key tool for insulin-treated people with diabetes (PwD). CGM devices include both real-time CGM (rtCGM) and intermittently scanned CGM (isCGM), which are associated with an improvement of glucose control and less hypoglycemia in clinical trials of people with type 1 and type 2 diabetes., Methods: This is an expert position to update a previous algorithm on the most suitable choice of CGM for insulin-treated PwD in light of the recent evidence and clinical practice., Results: We identified six different clinical scenarios, including type 1 diabetes, type 2 diabetes, pregnancy on intensive insulin therapy, regular physical exercise, new onset of diabetes, and frailty. The use of rtCGM or isCGM is suggested, on the basis of the predominant clinical issue, as suboptimal glucose control or disabling hypoglycemia, regardless of baseline HbA 1c or individualized HbA 1c target., Conclusion: The present algorithm may help to select the best CGM device based on patients' clinical characteristics, needs and clinical context, offering a further opportunity of a "tailored" therapy for people with insulin-treated diabetes., (© 2023. The Author(s).)

Background: Innovative GLP-1 receptor agonist (GLP-1RA)-based treatment strategies-such as tirzepatide, GLP-1RA plus basal insulin fixed-ratio combinations [FRC], GLP-1RA plus sodium glucose cotransporter-2 inhibitors [SGLT-2i] combinations, and high-dose GLP-1RA-have been listed among the most efficacious options for type 2 diabetes management. However, differences in their glucometabolic effects have not been assessed in dedicated head-to-head trials. In the absence of such trials, we aimed to provide a useful comparison among these treatment strategies to guide clinical practice., Methods: In this network meta-analysis, we searched PubMed, MEDLINE, and Web of Science (from database inception to June 24, 2023) for randomised controlled studies, published in English, that enrolled individuals with type 2 diabetes treated with tirzepatide, iGlarLixi, iDegLira, GLP-1RA plus SGLT-2i combination, or high-dose GLP-1RA (dulaglutide 3 mg and 4.5 mg, semaglutide 2 mg) compared with placebo or active comparators. Eligible studies reported change from baseline in HbA1c as an outcome, which was the primary outcome of this analysis. Secondary outcomes were changes in fasting and post-prandial glucose, bodyweight, LDL-cholesterol, blood pressure and risk of hypoglycaemia. We assessed risk of bias through the Cochrane Collaboration's tool (RoB2 tool), publication bias through visual inspection of funnel plots and Egger's test, and heterogeneity by comparing the magnitude of the common between-study variance (τ 2 ) for each outcome with empirical distributions of heterogeneity variances. This network meta-analysis was registered in PROSPERO (CRD42022329878)., Findings: 40 trials were included. Tirzepatide 15 mg ranked first in terms of HbA1c reduction compared to other GLP-1RA-based strategies, even those including insulin (vs. iDegLira MD -0.40%, 95% CI [-0.66; -0.14], low certainty; vs. iGlarLixi MD -0.48%, 95% CI [-0.75; -0.21], low certainty), without increasing the risk of hypoglycaemia (vs. iDegLira OR 0.35, 95% CI [0.16; 0.79], high certainty; vs. iGlarLixi OR 0.31, 95% CI [0.20; 0.48], high certainty). Tirzepatide 15 mg was also the most efficacious on weight lowering, even compared to high-dose GLP-1RA (eg, semaglutide 2 mg MD -6.56 kg, 95% CI [-7.38; -5.73], low certainty) and GLP-1RA plus SGLT-2i combination (MD -4.61 kg, 95% CI [-5.29; -3.93], low certainty). Risk of bias and publication bias were generally low throughout studies, while high levels of heterogeneity were detected for most outcomes., Interpretation: Aiming to support clinicians in tailoring treatment to patients' needs, we suggest that a hierarchy among treatment strategies be devised considering the best options for type 2 diabetes. Tirzepatide, followed by GLP-1RA plus basal insulin FRC and GLP-1RA plus SGLT-2i combination, was associated with greater benefit on HbA1c than high-dose GLP-1RA., Funding: Fondazione per la Ricerca Biomedica "Saverio e Isabella Cianciola" and Next Generation EU, in the context of the National Recovery and Resilience Plan, Investment PE8-Project Age-It: Ageing Well in an Ageing Society., Competing Interests: AC reports the following: AstraZeneca, Eli Lilly, Novo Nordisk, Roche Diagnostics, Sanofi Aventis (honoraria). AN reports the following: AstraZeneca, Novo Nordisk, and Sanofi Aventis (honoraria). FG reports the following: Eli Lilly, Roche Diabetes Care (grants); Eli Lilly, Novo Nordisk (consulting fees); AstraZeneca, Boehringer-Ingelheim, Eli Lilly, Lifescan, Merck Sharp & Dohme, Medtronic, Novo Nordisk, Roche Diabetes Care, Sanofi Aventis; Eli Lilly, Sanofi Aventis (support for attending meetings/travel); AstraZeneca, Boehringer-Ingelheim, Eli Lilly, Lifescan, Merck Sharp & Dohme, Medimmune, Medtronic, Novo Nordisk, Roche Diabetes Care, Sanofi Aventis (participation on Advisory Boards); EASD/EFSD, Società Italiana di Endocrinologia (SIE), Fo.Ri.SIE (unpaid leadership); AstraZeneca, Eli Lilly, Novo Nordisk, Sanofi Aventis (support for medical writing and statistical analysis). GFMS: no competing interests. IC reports the following: Eli Lilly, Novo Nordisk (honoraria); Eli Lilly, Novo Nordisk (support for attending meeting or travels); LDG reports the following: Eli Lilly, MOVI SpA, Roche Diabetes Care (honoraria). LL reports the following: Abbott, AstraZeneca, Boehringer-Ingelheim, Eli Lilly, Merck Sharp & Dohme, Medtronic, Menarini, MOVI SpA, Mundipharma, Novo Nordisk, Roche Diabetes Care, Sanofi Aventis, Terumo (honoraria); Abbott, AstraZeneca, Boeringher-Ingelheim, Eli Lilly Italia, Medtronic, MOVI SpA, Novo Nordisk, Roche Diabetes Care, Sanofi Aventis, Terumo (participation on Advisory Boards). PN: no competing interests. SDM reports the following: Ascensia, MOVI SpA, Roche Diabetes Care (honoraria); Ascensia, MOVI SpA, Roche Diabetes Care (participation on Advisory Boards). SCP: no competing interests. SP reports the following: AstraZeneca, Eli Lilly, Novo Nordisk, Sanofi Aventis (honoraria)., (© 2023 The Author(s).)

Aims: To investigate the benefits of using the Personalized Treatment Tool (PTT), a web-based clinical decision support tool assisting the diabetologist in the evaluation of patient's clinical characteristics and SMBG data, in the management of patients with non-insulin treated type 2 diabetes and inadequate glucose control., Methods: We conducted a single-center, 16-week, cluster-randomized controlled trial., Results: Eighty-two patients with 64.3 ± 9.4 years of age, disease duration 13.2 ± 9.1 years and HbA1c 7.8 ± 0.6%, 41 in the PTT group and 41 in the control group, completed the study. At follow-up, changes in indicators of glucose control and variability were not statistically different between the two groups. However, when considering the subgroup of patients on a single anti-diabetes drug at baseline (9 in the PTT group, 14 in the control group), changes in HbA1c and CGM-derived TIR 70-140 mg/dl, 24-hour MSG, GRADE, and HBGI were significantly improved in the PTT group compared to the control group., Conclusion: When performed in a structured manner and used to modify the diabetes therapy through an algorithm-driven digital tool, SMBG can lead to significant improvements of glycemic control and variability in patients with type 2 diabetes not treated with insulin., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Hyperglucagonemia is one of the 'ominous' eight factors underlying the pathogenesis of type 2 diabetes (T2D). Glucagon is a peptide hormone involved in maintaining glucose homoeostasis by increasing hepatic glucose output to counterbalance insulin action. Long neglected, the introduction of dual and triple agonists exploiting glucagon signalling pathways has rekindled the interest in this hormone beyond its classic effect on glycaemia. Glucagon can promote weight loss by regulating food intake, energy expenditure, and brown and white adipose tissue functions through mechanisms still to be fully elucidated, thus its role in T2D pathogenesis should be further investigated. Moreover, the role of glucagon in the development of T2D micro- and macro-vascular complications is elusive. Mounting evidence suggests its beneficial effect in non-alcoholic fatty liver disease, while few studies postulated its favourable role in peripheral neuropathy and retinopathy. Contrarily, glucagon receptor agonism might induce renal changes resembling diabetic nephropathy, and data concerning glucagon actions on the cardiovascular system are conflicting. This review aims to summarise the available findings on the role of glucagon in the pathogenesis of T2D and its complications. Further experimental and clinical data are warranted to better understand the implications of glucagon signalling modulation with new antidiabetic drugs., (© 2023 John Wiley & Sons Ltd.)

Accumulating evidence supports the early use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium glucose transporter-2 inhibitors (SGLT-2is) for the treatment of type 2 diabetes. Indeed, these compounds exert numerous pleiotropic actions that favorably affect metabolism and diabetes comorbidities, showing an additional effect beyond glucose control. Although a substantial amount of knowledge has been generated regarding the mechanism of action of both drug classes, much remains to be understood. Growth hormone (GH) is an important driver for multiple endocrine responses involving changes in glucose and lipid metabolism, and affects several tissues and organs (e.g., bone, heart). It acts directly on several target tissues, including skeletal muscle and bone, but several effects are mediated indirectly by circulating (liver-derived) or locally produced IGF-1. In consideration of the multiple metabolic and cardiovascular effects seen in subjects treated with GLP-1RAs and SGLT-2is (e.g., reduction of hyperglycemia, weight loss, free/fat mass and bone remodeling, anti-atherosclerosis, natriuresis), it is reasonable to speculate that GH and IGF-1 may play a about a relevant role in this context. This narrative mini-review aims to describe the involvement of the GH/IGF-1/IGF-1R axis in either mediating or responding to the effects of each of the two drug classes., Competing Interests: FG received research support from Eli Lilly, LifeScan, and Takeda and served as a consultant and author for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp and Dohme, Novo Nordisk, Roche Diabetes Care, and Sanofi. The remaining 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 © 2022 Cignarelli, Genchi, Le Grazie, Caruso, Marrano, Biondi, D’Oria, Sorice, Natalicchio, Perrini, Laviola and Giorgino.)

Cardiovascular outcome trials (CVOT) showed that treatment with glucagon-like peptide-1 receptor agonists (GLP-1RA) is associated with significant cardiovascular benefits. However, CVOT are scarcely representative of everyday clinical practice, and real-world studies could provide clinicians with more relatable evidence. Here, literature was thoroughly searched to retrieve real-world studies investigating the cardiovascular and renal outcomes of GLP-1RA vs. other glucose-lowering drugs and carry out relevant meta-analyses thereof. Most real-world studies were conducted in populations at low cardiovascular and renal risk. Of note, real-world studies investigating cardio-renal outcomes of GLP-1RA suggested that initiation of GLP-1RA was associated with a greater benefit on composite cardiovascular outcomes, MACE (major adverse cardiovascular events), all-cause mortality, myocardial infarction, stroke, cardiovascular death, peripheral artery disease, and heart failure compared to other glucose-lowering drugs with the exception of sodium-glucose transporter-2 inhibitors (SGLT-2i). Initiation of SGLT-2i and GLP-1RA yielded similar effects on composite cardiovascular outcomes, MACE, stroke, and myocardial infarction. Conversely, GLP-1RA were less effective on heart failure prevention compared to SGLT-2i. Finally, the few real-world studies addressing renal outcomes suggested a significant benefit of GLP-1RA on estimated glomerular filtration rate (eGFR) reduction and hard renal outcomes vs. active comparators except SGLT-2i. Further real-world evidence is needed to clarify the role of GLP-1RA in cardio-renal protection among available glucose-lowering drugs.

The loss of beta-cell functional mass is a necessary and early condition in the development of type 2 diabetes (T2D). In T2D patients, beta-cell function is already reduced by about 50% at diagnosis and further declines thereafter. Beta-cell mass is also reduced in subjects with T2D, and islets from diabetic donors are smaller compared to non-diabetic donors. Thus, beta-cell regeneration and/or preservation of the functional islet integrity should be highly considered for T2D treatment and possibly cure. To date, the available anti-diabetes drugs have been developed as "symptomatic" medications since they act to primarily reduce elevated blood glucose levels. However, a truly efficient anti-diabetes medication, capable to prevent the onset and progression of T2D, should stop beta-cell loss and/or promote the restoration of fully functional beta-cell mass, independently of reducing hyperglycemia and ameliorating glucotoxicity on the pancreatic islets. This review provides a view of the experimental and clinical evidence on the ability of available anti-diabetes drugs to exert protective effects on beta-cells, with a specific focus on human pancreatic islets and clinical trials. Potential explanations for the lack of concordance between evidence of beta-cell protection in vitro and of persistent amelioration of beta-cell function in vivo are also discussed., Competing Interests: Declaration of competing interest A.N., N.M., G.B., A.C., and S.P. declare no competing interests. For L.L.: Advisory Boards: AstraZeneca, Eli Lilly, Novo Nordisk, Roche Diabetes Care, Sanofi. For F.G.: Advisory Boards: AstraZeneca, Eli Lilly, Novo Nordisk, Roche Diabetes Care; Consultant: Boehringer Ingelheim, Lifescan, Merck Sharp & Dohme, Sanofi, AstraZeneca, Medimmune, Roche Diabetes Care; Research Support: Eli Lilly; Lifescan, Takeda., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of competing interest I.C., A.C., S.P.: No conflict of interests. A.N.: Consultant for AstraZeneca, NovoNordisk, Sanofi. L.L.: Consultant: Abbott, AstraZeneca, Boehringer-Ingelheim, Eli Lilly, NovoNordisk, Roche Diabetes Care, Sanofi. F.G.: Research support: Eli Lilly, Lifescan, Takeda. Consultant and author for AstraZeneca, Boehringer-Ingelheim, Eli Lilly, Merck Sharp and Dohme, NovoNordisk, Roche Diabetes Care, Sanofi.

Background/objectives: The histone deacetylases SIRT1 and SIRT2 have been shown to be involved in the differentiation of rodent adipocyte precursors. In light of the differences in gene expression and metabolic function of visceral (V) and subcutaneous (S) adipose tissue (AT) and their resident cells, the aim of this study was to investigate the role of SIRT1 and SIRT2 in the differentiation of adipose stem cells (ASCs) isolated from SAT and VAT biopsies of nondiabetic obese and nonobese individuals., Methods: Human ASCs were isolated from paired SAT and VAT biopsies obtained from 83 nonobese and 92 obese subjects and were differentiated in vitro. Adipogenesis was evaluated by analyzing the lipid deposition using an image processing software, and gene expression by RT-qPCR. SIRT1 and SIRT2 protein expression was modified by using recombinant adenoviral vectors., Results: Visceral but not subcutaneous ASCs from obese subjects showed an intrinsic increase in both adipogenesis and lipid accumulation when compared with ASCs from nonobese subjects, and this was associated with reduced SIRT1 and SIRT2 mRNA and protein levels. Moreover, adipose tissue mRNA levels of SIRT1 and SIRT2 showed an inverse correlation with BMI in the visceral but not subcutaneous depot. Overexpression of SIRT1 or SIRT2 in visceral ASCs from obese subjects resulted in inhibition of adipocyte differentiation, whereas knockdown of SIRT1 or SIRT2 in visceral ASCs from nonobese subjects enhanced this process. Changes in SIRT1 or SIRT2 expression and adipocyte differentiation were paralleled by corresponding changes in PPARG, CEBPA, and other genes marking terminal adipocyte differentiation., Conclusions: SIRT1 and SIRT2 modulate the differentiation of human ASC. Reduced expression of SIRT1 and SIRT2 may enhance the differentiation capacity of visceral ASC in human obesity, fostering visceral adipose tissue expansion.

Background: 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., Methods: 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., Results and Conclusions: 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.

Reactive oxygen species (ROS) are reactive intermediates of molecular oxygen that act as important second messengers within the cells; however, an imbalance between generation of reactive ROS and antioxidant defense systems represents the primary cause of endothelial dysfunction, leading to vascular damage in both metabolic and atherosclerotic diseases. Endothelial activation is the first alteration observed, and is characterized by an abnormal pro-inflammatory and pro-thrombotic phenotype of the endothelial cells lining the lumen of blood vessels. This ultimately leads to reduced nitric oxide (NO) bioavailability, impairment of the vascular tone and other endothelial phenotypic changes collectively termed endothelial dysfunction(s). This review will focus on the main mechanisms involved in the onset of endothelial dysfunction, with particular focus on inflammation and aberrant ROS production and on their relationship with classical and non-classical cardiovascular risk factors, such as hypertension, metabolic disorders, and aging. Furthermore, new mediators of vascular damage, such as microRNAs, will be discussed. Understanding mechanisms underlying the development of endothelial dysfunction is an important base of knowledge to prevent vascular damage in metabolic and cardiovascular diseases., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Diabetes mellitus (DM)-associated hyperglycemia contributes to the initiation and progression of chronic microvascular (MIC) and macrovascular (MAC) complications. To carry out early identification of MIC, standardized and inexpensive tests are needed. Computerized nailfold video-capillaroscopy (CNVC) is a noninvasive tool to easily evaluate MIC at the level of the fingers and could be useful to detect the so-called 'diabetic capillaropathy'., Aim: This was a prospective study using CNVC to examine the prevalence of capillaroscopic patterns in a cohort of type 1 (T1D) and type 2 (T2D) diabetic individuals, and to assess their relationship with the level of glycemic control (HbA1c) and DM-related complications., Results: Nailfold alterations were found to be more prevalent in diabetics, including tortuosity (p < 0.01), avascular zones (p < 0.01), ectasiae (p < 0.01) and capillary with bizarre shape (p < 0.01). At least two of these patterns were found with a higher prevalence in T1D and T2D individuals vs. controls (p < 0.01). Finally, a higher frequency of 'capillary score' equal to or higher than 2 points was found to be associated with worse glycemic control, and with the presence of diabetic retinopathy., Conclusions: These results confirm the presence of a 'diabetic capillaropathy', and nailfold capillary alterations appear to be related to the level of glycemic control and the existence of MIC, particularly when retinal damage is involved.

Background: The role of polyphenol intake on cardiovascular risk factors is little explored, particularly in people with diabetes., Aim: To evaluate the association between the intake of total polyphenols and polyphenol classes with the major cardiovascular risk factors in a population with type 2 diabetes., Methods: Dietary habits were investigated in 2573 males and females participants of the TOSCA.IT study. The European Prospective Investigation on Cancer and Nutrition (EPIC) questionnaire was used to assess dietary habits. In all participants, among others, we assessed anthropometry, plasma lipids, blood pressure, C-reactive protein and HbA1c following a standard protocol. The USDA and Phenol-Explorer databases were used to estimate the polyphenol content of the habitual diet., Results: Average intake of polyphenols was 683.3 ± 5.8 mg/day. Flavonoids and phenolic acids were the predominant classes (47.5% and 47.4%, respectively). After adjusting for potential confounders, people with the highest intake of energy-adjusted polyphenols (upper tertile) had a more favorable cardiovascular risk factors profile as compared to people with the lowest intake (lower tertile) (BMI was 30.7 vs 29.9 kg/m 2 , HDL-cholesterol was 45.1 vs 46.9 mg/dl, LDL-cholesterol was 103.2 vs 102.1 mg/dl, triglycerides were 153.4 vs 148.0 mg/dl, systolic and diastolic blood pressure were respectively 135.3 vs 134.3 and 80.5 vs 79.6 mm/Hg, HbA1c was 7.70 vs 7.67%, and C-reactive Protein was 1.29 vs 1.25 mg/dl, p < .001 for all). The findings were very similar when the analysis was conducted separately for flavonoids or phenolic acids, the two main classes of polyphenols consumed in this population., Conclusions: Polyphenol intake is associated with a more favorable cardiovascular risk factors profile, independent of major confounders. These findings support the consumption of foods and beverages rich in different classes of polyphenols particularly in people with diabetes., Clinical Trial: http://www.clinicaltrials.gov; Study ID number: NCT00700856., (Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Context: Increased apoptosis of cardiomyocytes and cardiac progenitor cells (CPCs) in response to saturated fatty acids (SFAs) can lead to myocardial damage and dysfunction. Ceramides mediate lipotoxicity-induced apoptosis. Glucagonlike peptide-1 receptor (GLP1R) agonists exert beneficial effects on cardiac cells in experimental models., Objective: To investigate the protective effects of GLP1R activation on SFA-mediated apoptotic death of human CPCs., Design: Human CPCs were isolated from cardiac appendages of nondiabetic donors and then exposed to palmitate with or without pretreatment with the GLP1R agonist exendin-4. Ceramide accumulation was evaluated by immunofluorescence. Expression of key enzymes in de novo ceramide biosynthesis was studied by quantitative reverse-transcription polymerase chain reaction and immunoblotting. Apoptosis was evaluated by measuring release of oligonucleosomes, caspase-3 cleavage, caspase activity, and terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling., Results: Exposure of the CPCs to palmitate resulted in 2.3- and 1.9-fold higher expression of ceramide synthase 5 (CERS5) and ceramide desaturase-1, respectively (P < 0.05). This was associated with intracellular accumulation of ceramide and activation of c-Jun NH2-terminal protein kinase (JNK) signaling and apoptosis (P < 0.05). Both coincubation with fumonisin B1, a specific ceramide synthase inhibitor, and CERS5 knockdown prevented ceramide accumulation, JNK activation, and apoptosis in response to palmitate (P < 0.05). Exendin-4 also prevented the activation of the ceramide biosynthesis and JNK in response to palmitate, inhibiting apoptosis (P < 0.05)., Conclusions: Excess palmitate results in activation of ceramide biosynthesis, JNK signaling, and apoptosis in human CPCs. GLP1R activation counteracts this lipotoxic damage via inhibition of ceramide generation, and this may represent a cardioprotective mechanism., (Copyright © 2017 Endocrine Society)

PKB/Akt and MAP/ERK are intracellular kinases regulating cell survival, proliferation and metabolism and as such hold a strategical role in preeclampsia. In fact intracellular pathways related to immunological alterations, endothelial dysfunction and insulin resistance in preeclampsia converge on these molecules. Inositol second messengers are involved in metabolic and cell signaling pathways and are highly expressed during preeclampsia. To evaluate the pathophysiological significance of this response, the effect of myo-inositol and d-chiro inositol on the activation of PKB/Akt and MAPK/ERK was assessed in human endothelial cells in vitro. Time-course and dose-response analyses of phosphorylation following incubation with inositols showed an approximately 6-fold and 15-fold increase for myo-inositol and d-chiro inositol (p<0.05), respectively. Both inositols promoted a significantly higher PKB/Akt and MAPK/ERK phosphorylation than insulin. Thus, exogenously administered inositols can activate PKB/Akt and MAPK/ERK in human endothelial cells in vitro. The increased production of d-chiro inositol phosphoglycans (IPG-P) during preeclampsia may thus represent a compensatory response, potentially promoting cell survival and metabolism., (Copyright © 2017 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

The effects of prolonged exposure of pancreatic β-cells to high saturated fatty acids on glucagon-like peptide-1 (GLP-1) action were investigated. Murine islets, human pancreatic 1.1B4 cells, and rat INS-1E cells were exposed to palmitate for 24 hours. mRNA and protein expression/phosphorylation were measured by real-time RT-PCR and immunoblotting, respectively. Specific short interfering RNAs were used to knockdown expression of the GLP-1 receptor (Glp1r) and Srebf1. Insulin release was assessed with a specific ELISA. Exposure of murine islets, as well as of human and INS-1E β-cells, to palmitate reduced the ability of exendin-4 to augment insulin mRNA levels, protein content, and release. In addition, palmitate blocked exendin-4-stimulated cAMP-response element-binding protein and v-akt murine thymoma viral oncogene homolog phosphorylation, whereas phosphorylation of MAPK-ERK kinase-1/2 and ERK-1/2 was not altered. Similarly, RNA interference-mediated suppression of Glp1r expression prevented exendin-4-induced cAMP-response element-binding protein and v-akt murine thymoma viral oncogene homolog phosphorylation, but did not impair exendin-4 stimulation of MAPK-ERK kinase-1/2 and ERK-1/2. Both islets from mice fed a high fat diet and human and INS-1E β-cells exposed to palmitate showed reduced GLP-1 receptor and pancreatic duodenal homeobox-1 (PDX-1) and increased sterol regulatory element-binding protein (SREBP-1C) mRNA and protein levels. Furthermore, suppression of SREBP-1C protein expression prevented the reduction of PDX-1 and GLP-1 receptor levels and restored exendin-4 signaling and action. Finally, treatment of INS-1E cells with metformin for 24 h resulted in inhibition of SREBP-1C expression, increased PDX-1 and GLP-1 receptor levels, consequently, enhancement of exendin-4-induced insulin release. Palmitate impairs exendin-4 effects on β-cells by reducing PDX-1 and GLP-1 receptor expression and signaling in a SREBP-1C-dependent manner. Metformin counteracts the impairment of GLP-1 receptor signaling induced by palmitate.

The p66Shc protein mediates oxidative stress-related injury in multiple tissues. Steatohepatitis is characterized by enhanced oxidative stress-mediated cell damage. The role of p66Shc in redox signaling was investigated in human liver cells and alcoholic steatohepatitis. HepG2 cells with overexpression of wild-type or mutant p66Shc, with Ser36 replacement by Ala, were obtained through infection with recombinant adenoviruses. Reactive oxygen species and oxidation-dependent DNA damage were assessed by measuring dihydroethidium oxidation and 8-hydroxy-2'-deoxyguanosine accumulation into DNA, respectively. mRNA and protein levels of signaling intermediates were evaluated in HepG2 cells and liver biopsies from control and alcoholic steatohepatitis subjects. Exposure to H2O2 increased reactive oxygen species and phosphorylation of p66Shc on Ser36 in HepG2 cells. Overexpression of p66Shc promoted reactive oxygen species synthesis and oxidation-dependent DNA damage, which were further enhanced by H2O2. p66Shc activation also resulted in increased Erk-1/2, Akt, and FoxO3a phosphorylation. Blocking of Erk-1/2 activation inhibited p66Shc phosphorylation on Ser36. Increased p66Shc expression was associated with reduced mRNA levels of antioxidant molecules, such as NF-E2-related factor 2 and its target genes. In contrast, overexpression of the phosphorylation defective p66Shc Ala36 mutant inhibited p66Shc signaling, enhanced antioxidant genes, and suppressed reactive oxygen species and oxidation-dependent DNA damage. Increased p66Shc protein levels and Akt phosphorylation were observed in liver biopsies from alcoholic steatohepatitis compared with control subjects. In human alcoholic steatohepatitis, increased hepatocyte p66Shc protein levels may enhance susceptibility to DNA damage by oxidative stress by promoting reactive oxygen species synthesis and repressing antioxidant pathways., (Copyright © 2015 the American Physiological Society.)

Aims/hypothesis: The role of the redox adaptor protein p66(Shc) as a potential mediator of saturated fatty acid (FA)-induced beta cell death was investigated., Methods: The effects of the FA palmitate on p66(Shc) expression were evaluated in human and murine islets and in rat insulin-secreting INS-1E cells. p66(Shc) expression was also measured in islets from mice fed a high-fat diet (HFD) and from human donors with different BMIs. Cell apoptosis was quantified by two independent assays. The role of p66(Shc) was investigated using pancreatic islets from p66 (Shc-/-) mice and in INS-1E cells with knockdown of p66(Shc) or overexpression of wild-type and phosphorylation-defective p66(Shc). Production of reactive oxygen species (ROS) was evaluated by the dihydroethidium oxidation method., Results: Palmitate induced a selective increase in p66(Shc) protein expression and phosphorylation on Ser(36) and augmented apoptosis in human and mouse islets and in INS-1E cells. Inhibiting the tumour suppressor protein p53 prevented both the palmitate-induced increase in p66(Shc) expression and beta cell apoptosis. Palmitate-induced apoptosis was abrogated in islets from p66 (Shc-/-) mice and following p66 (Shc) knockdown in INS-1E cells; by contrast, overexpression of p66(Shc), but not that of the phosphorylation-defective p66(Shc) mutant, enhanced palmitate-induced apoptosis. The pro-apoptotic effects of p66(Shc) were dependent upon its c-Jun N-terminal kinase-mediated phosphorylation on Ser(36) and associated with generation of ROS. p66(Shc) protein expression and function were also elevated in islets from HFD-fed mice and from obese/overweight cadaveric human donors., Conclusions/interpretation: p53-dependent augmentation of p66(Shc) expression and function represents a key signalling response contributing to beta cell apoptosis under conditions of lipotoxicity.

Lipodystrophies are a genetically heterogeneous group of disorders characterized by loss of subcutaneous adipose tissue and metabolic dysfunction, including insulin resistance, increased levels of free fatty acids, abnormal adipocytokine secretion, and ectopic fat deposition, which are also observed in patients with visceral obesity and/or type 2 diabetes mellitus. Pathophysiological, biochemical, and genetic studies suggest that impairment in multiple adipose tissue functions, including adipocyte maturation, lipid storage, formation and/or maintenance of the lipid droplet, membrane composition, DNA repair efficiency, and insulin signaling, results in severe metabolic and endocrine consequences, ultimately leading to specific lipodystrophic phenotypes. In this review, recent evidences on the causes and metabolic processes of lipodystrophies will be presented, proposing a disease model that could be potentially informative for better understanding of common metabolic diseases in humans, including obesity, metabolic syndrome, and type 2 diabetes.

Aims/hypothesis: The mechanisms of the protective effects of exendin-4 on NEFA-induced beta cell apoptosis were investigated., Methods: The effects of exendin-4 and palmitate were evaluated in human and murine islets, rat insulin-secreting INS-1E cells and murine glucagon-secreting alpha-TC1-6 cells. mRNA and protein expression/phosphorylation were measured by real-time RT-PCR and immunoblotting or immunofluorescence, respectively. Small interfering (si)RNAs for Ib1 and Gpr40 were used. Cell apoptosis was quantified by two independent assays. Insulin release was assessed with an insulin ELISA., Results: Exposure of human and murine primary islets and INS-1E cells, but not alpha-TC1-6 cells, to exendin-4 inhibited phosphorylation of the stress kinases, c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK), and prevented apoptosis in response to palmitate. Exendin-4 increased the protein content of islet-brain 1 (IB1), an endogenous JNK blocker; however, siRNA-mediated reduction of IB1 did not impair the ability of exendin-4 to inhibit JNK and prevent apoptosis. Exendin-4 reduced G-protein-coupled receptor 40 (GPR40) expression and inhibited palmitate-induced phosphorylation of mitogen-activated kinase kinase (MKK)4 and MKK7. The effects of exendin-4 were abrogated in the presence of the protein kinase A (PKA) inhibitors, H89 and KT5720. Knockdown of GPR40, as well as use of a specific GPR40 antagonist, resulted in diminished palmitate-induced JNK and p38 MAPK phosphorylation and apoptosis. Furthermore, inhibition of JNK and p38 MAPK activity prevented palmitate-induced apoptosis., Conclusions/interpretation: Exendin-4 counteracts the proapoptotic effects of palmitate in beta cells by reducing GPR40 expression and inhibiting MKK7- and MKK4-dependent phosphorylation of the stress kinases, JNK and p38 MAPK, in a PKA-dependent manner.

Diabetic foot is a common complication in diabetes mellitus course, able to increase the overall morbidity/mortality risk of such a disease. The aim was to investigate the outcomes, the incidence of clinical events, the number of recurrent ulcers in patients with diabetic foot during 1 year follow-up after angioplasty (PTA) revascularization. From January 2007 to August 2009, 103 diabetic patients with diabetic foot undergoing revascularization of a lower limb by PTA were recruited. At 1 year follow-up we assessed: "major" (death, stroke, Myocardial Infaction (MI) and "minor" (Deep Vein Thrombosis (DVT), renal failure, restenosis) events incidence; recurrent ulcers incidence; the predictive elements of all these events. At 1 year follow-up, "major"/"minor" events incidence was 15% (deaths: 5, stroke: 1, MI: 9%) and 34% (renal failure: 11, DVT: 9, restenosis: 14%), respectively. Obesity, high low density level-cholesterol levels and distal arterial lesions (at posterior tibial artery in particular) were statistically significantly associated with major events (p < 0.05); only obesity resulted statistically associated with minors (p = 0.043). High levels of C-reactive protein had a statistically significant relationship with the recurrence of ulcers (p = 0.006) while distal arterial obstructions showed a trend toward significance. To improve diabetic foot mortality and morbidity rate, our study underlines the importance of a prompt diagnosis and appropriate revascularization treatment. Other studies are needed to ascertain these.

Glucagon-like peptide-1 and its analogs may preserve pancreatic beta-cell mass by promoting resistance to cytokine-mediated apoptosis. The mechanisms of TNFalpha-induced apoptosis and of its inhibition by exendin-4 were investigated in insulin-secreting cells. INS-1 and MIN6 insulinoma cells were exposed to 20 ng/ml TNFalpha, with or without pretreatment with 10 nm exendin-4. Treatment with TNFalpha increased c-Jun N-terminal protein kinase (JNK) phosphorylation 2-fold, reduced inhibitor-kappaBalpha (IkappaBalpha) protein content by 50%, induced opposite changes in caspase-3 and Bcl-2 protein content, and increased cellular apoptosis. Moreover, exposure to TNFalpha resulted in increased serine phosphorylation of both insulin receptor substrate (IRS)-1 and IRS-2 and reduced basal and insulin-induced Akt phosphorylation. However, in the presence of a JNK inhibitor, TNFalpha-induced apoptosis was diminished and serine phosphorylation of IRS proteins was prevented. When cells were pretreated with exendin-4, TNFalpha-induced JNK and IRS-1/2 serine phosphorylation was markedly reduced, Akt phosphorylation was increased, caspase-3 and Bcl-2 protein levels were restored to normal, and TNFalpha-induced apoptosis was inhibited by 50%. This was associated with a 2-fold increase in IRS-2 expression levels. A similar ability of exendin-4 to prevent TNFalpha-induced JNK phosphorylation was found in isolated pancreatic human islets. The inhibitory effect of exendin-4 on TNFalpha-induced JNK phosphorylation was abrogated in the presence of the protein kinase A inhibitor H89. In conclusion, JNK activation mediates TNFalpha-induced apoptosis and impairment of the IRS/Akt signaling pathway in insulin-secreting cells. By inhibiting JNK phosphorylation in a PKA-dependent manner, exendin-4 counteracts TNFalpha-mediated apoptosis and reverses the inhibitory events in the IRS/Akt pathway, resulting in promotion of cell survival.

The The aim of our study is to investigate the molecular mechanisms of diabetic cardiomyopathy through the identification of remarkable genes for the myocardial function that are expressed differently between diabetic and normal subjects. Moreover, we intend to characterize both in human myocardial tissue and in the related cardiac progenitor cells the pattern of gene expression and the levels of expression and protein activation of molecular effectors involved in the regulation of the myocardial function and differentiation to clarify whether in specific human pathological conditions (type 2 diabetes mellitus, cardiac failure, coronary artery disease) specific alterations of the aforementioned factors could take place. Thirty-five patients scheduled for coronary artery bypass grafting (CABG) or for aortic or mitral valve replacement were recruited into the study. There were 13 men and 22 women with a mean age of 64.8 +/- 13.4 years. A list of anamnestic, anthropometric, clinical, and instrumental data required for an optimal phenotypical characterization of the patients is reported. The small cardiac biopsy specimens were placed in the nourishing buffer, in a sterile tube provided the day of the procedure, to maintain the stability of the sample for several hours at room temperature. The cells were isolated by a dedicated protocol and then cultured in vitro. The sample was processed for total RNA extraction and levels of gene expression and protein activation of molecular effectors involved in the regulation of function and differentiation of human myocardium was analyzed. In particular, cardiac genes that modulate the oxidative stress response or the stress induced by pro-inflammatory cytokines (p66Shc, SOCS-1, SOCS-3) were analyzed. From a small sample of myocardium cardiac stem cells and cardiomyoblasts were also isolated and characterized. These cells showed a considerable proliferative capacity due to the fact that they demonstrate stability up to the eleventh passage. Analysis of gene expression in a subgroup of subjects showed the trend of a decrease in levels of expression of cardiac-specific transcription genes and oxidative stress-related proteins in tissues of diabetic patients compared with controls subjects. This trend is not confirmed in isolated cells. As for the coronary artery disease, diabetic cardiomyopathy could be associated with a reduction of the cardiac stem and progenitor cells pool. The expansion of the cardiac resident cells pool could be associated with a preservation of cardiac performance, suggesting that a preserved stamina compartment can counteract the impact of diabetes on the myocardium.