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The very low-calorie ketogenic diet (VLCKD) represents an opportunity to attain clinically relevant weight loss in obese patients. Functional hypogonadism represents a frequent hormonal disorder associated with obesity and visceral fat accumulation characterized by low testosterone levels and subnormal LH levels.To evaluate the early effects of VLCKD on serum total testosterone (TT) levels in non-diabetic obese patients.Twenty-two obese male patients (mean age 39.3 ± 11.7 years, mean BMI 38.2 ± 6.4 kg/mAfter 7 and 28 days on a VLCKD, a significant and persistent reduction in body weight, BMI, fat mass, blood glucose, insulin, and HOMA index was observed compared with baseline. TT significantly increased after 7 days (+35 ± 64 ng/dl) and 28 days (+74 ± 97 ng/dl) on a VLCKD. In addition to TT, a significant increase in serum sex hormone-binding globulin (SHBG) levels was observed after 7 (+2.1 ± 4.1) and 28 days (+7.7 ± 10.0). However, both calculated free testosterone and LH did not change after 7 or 28 days of VLCKD. Following cessation of VLCKD, hypogonadal subjects achieved a higher percentage of total weight loss (8.5 ± 1.5%), a greater reduction in weight (-9.94 ± 1.66 kg), fat mass (-7 ± 2.1 kg), and waist circumference (-6.31 ± 2.65 cm), and a greater improvement in glycaemia (-8.75 ± 10.92 mg/dl) as compared with eugonadal subjects. Furthermore, hypogonadal subjects exhibited a trend of higher TT increase (+98.12 ± 71.51 ng/dl) as compared with eugonadal subjects.VLCKD results in rapid improvements in TT levels associated with weight loss in male obese non-diabetic subjects, particularly in the presence of obesity-related hypogonadism. This article is protected by copyright. All rights reserved.

We evaluated the role of the p66Shc redox adaptor protein in pancreatic β-cell insulin resistance that develops under lipotoxic conditions and with excess body fat. Prolonged exposure to palmitate in vitro or the presence of overweight/obesity augmented p66Shc expression levels and caused an impaired ability of exogenous insulin to increase cellular insulin content and secreted C-peptide levels in INS-1E cells and human and murine islets. In INS-1E cells, p66Shc knockdown resulted in enhanced insulin-induced augmentation of insulin content and C-peptide secretion and prevented the ability of palmitate to impair these effects of insulin. Conversely, p66Shc overexpression impaired insulin-induced augmentation of insulin content and C-peptide secretion in both the absence and presence of palmitate. Under lipotoxic condition, the effects of p66Shc are mediated by a p53-induced increase in p66Shc protein levels and JNK-induced p66Shc phosphorylation at Ser36 and appear to involve the phosphorylation of the ribosomal protein S6 kinase at Thr389 and of insulin receptor substrate 1 at Ser307, resulting in the inhibition of insulin-stimulated protein kinase B phosphorylation at Ser473. Thus, the p66Shc protein mediates the impaired β-cell function and insulin resistance induced by saturated fatty acids and excess body fat.

Introduction Obstructive sleep apnoea (OSA) is an underdiagnosed condition frequently associated with glycaemic control impairment in patients with type 2 diabetes. Aim To assess the relationship between glycometabolic parameters and OSA in obese non-diabetic subjects. Methods Ninety consecutive subjects (mean age 44.9 ± 12 years, mean BMI 42.1 ± 9 kg/m2) underwent polysomnography and a 2-h oral glucose tolerance test (OGTT). Results OSA was identified in 75% of subjects, with a higher prevalence of males compared to the group of subjects without OSA (62% vs 32%, p = 0.02). Patients with OSA had comparable BMI (42.8 kg/m2 vs 39.4 kg/m2), a higher average HbA1c (5.8% vs 5.4%, p p = 0.009) and diastolic blood pressure (81.1 mmHg vs 76.2 mmHg, p = 0.046) than obese subjects without OSA. HbA1c and 2 h-PG were found to be correlated with the apnoea-hypopnoea index (AHI; r = 0.35 and r = 0.42, respectively) and with percent of sleep time with oxyhaemoglobin saturation r = 0.44 and r = 0.39, respectively). Further, in a linear regression model, ST90 and AHI were found to be the main determinants of 2 h-PG (β = 0.81, p β = 0.75, p = 0.02, respectively) after controlling for age, sex, waist circumference, physical activity, and C-reactive protein. Similarly, ST90 and AHI persisted as independent determinants of HbA1c (β = 0.01, p = 0.01 and β = 0.01, p = 0.01, respectively). Conclusion Beyond the traditional clinical parameters, the presence of a normal-high value of 2 h-PG and HbA1c should raise suspicion of the presence of OSA in obese subjects.

Elevated saturated fatty acid deposition in the heart results in insulin resistance, stress kinase activation, and increased cardiovascular risk in humans. The viability of human cardiac progenitor cells (hCPC) is essential for myocardium homeostasis. This study investigates the ability of palmitate, a saturated fatty acid, to impair insulin signaling in hCPC isolated from right auricle biopsies, and the potential protective effects of oleate, a mono-unsaturated fatty acid. hCPC were found to express both insulin receptor (IR) isoforms, IR-A and IR-B, with higher IR-A:IR-B ratio. Exposure of hCPC to 100 nM insulin for 15 min induced Akt (S473) phosphorylation (p In conclusion, oleate prevents the palmitate-induced abnormalities in insulin signaling in hCPC, largely by counteracting p38 MAPK and JNK activation. Hence, oleate supplementation might limit lipotoxicity, thus contributing to cardiac protection. Disclosure R.Doria: None. F.Giorgino: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk, Consultant; Lilly Diabetes, Sanofi, Research Support; Lilly Diabetes, Roche Diabetes Care, Takeda Pharmaceutical Company Limited. L.Laviola: Advisory Panel; Lilly Diabetes, Novo Nordisk, Roche Diabetes Care, Sanofi, Speaker's Bureau; A. Menarini Diagnostics, Abbott Diabetes, Medtronic, Terumo Corporation. I.Calderoni: None. C.Caccioppoli: None. V.Genchi: None. G.Santarpino: None. A.Leonardini: None. A.Natalicchio: Consultant; Novo Nordisk, Other Relationship; AstraZeneca, Lilly Diabetes, Sanofi. S.Perrini: None. A.Cignarelli: None.

Dysfunction of visceral and epicardial adipose tissue may alter heart performance and promote adverse cardiovascular outcomes in obesity and diabetes. We assessed whether the secretome from abdominal visceral (AV) and epicardial (E) adipose stem cells (ASC) and from AV mature adipocytes might affect the viability of human cardiac progenitor cells (hCPC) in human obesity, and the effects of dapagliflozin (DAPA) , a selective SGLT-2 inhibitor. ASC and mature adipocytes were isolated from AV and E adipose tissue biopsies of obese (Ob) and non-obese subjects, respectively. hCPC were isolated from right auricle biopsies of non-Ob, non-diabetic donors. hCPC were pretreated with uM DAPA for 24 h or left untreated, and then exposed to the conditioned media (CM) of AV-ASC, E-ASC, and AV mature adipocytes. The CM of AV-ASC, E-ASC, and AV mature adipocytes induced apoptosis, assessed by ELISA for cytoplasmic oligonucleosomes, in hCPC after 24 h (p In conclusion, in human obesity, the secretome of both AV and E ASC and mature adipocytes induces stress kinase activation in hCPC and impairs their viability and functionality, and these effects can be counteracted by SGLT-2 inhibitors directly acting on the hCPC. Disclosure G.Palma: None. F.Giorgino: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk, Consultant; Lilly Diabetes, Sanofi, Research Support; Lilly Diabetes, Roche Diabetes Care, Takeda Pharmaceutical Company Limited. S.Perrini: None. C.Caccioppoli: None. R.Doria: None. V.Genchi: None. G.Santarpino: None. A.Cignarelli: None. A.Natalicchio: Consultant; Novo Nordisk, Other Relationship; AstraZeneca, Lilly Diabetes, Sanofi. L.Laviola: Advisory Panel; Lilly Diabetes, Novo Nordisk, Roche Diabetes Care, Sanofi, Speaker's Bureau; A. Menarini Diagnostics, Abbott Diabetes, Medtronic, Terumo Corporation. A.Pezzolla: None.

Irisin is a hormone secreted by skeletal muscle following exercise or excess of saturated fatty acids (SFAs) , able to improve metabolic homeostasis and promote energy expenditure. Serum irisin levels are reduced in type 2 diabetes (T2D) , while exogenous irisin administration improves glycemic control in diabetic mice. We have previously demonstrated that irisin protects human and rodent β-cells and pancreatic islets from SFAs-induced apoptosis, increases insulin biosynthesis and glucose-stimulated insulin secretion (GSIS) , and promotes β-cell proliferation, both in vitro and in vivo in healthy wild-type mice. Irisin may also restore the defective GSIS and reduce the high rate of apoptosis that are characteristic of islets from T2D patients. However, the β-cellular effects of irisin administration to diabetic mice are still unknown. 6 weeks-old C57Bl/6 mice (n = 8) were fed a high-fat diet (HFD, 60% of energy deriving from fat) for weeks and then intraperitoneally injected with streptozotocin (STZ, 100 mg/Kg) to induce diabetes. 4 standard diet (SD) -fed mice were used as control. HFD/STZ mice were then treated with 0.5 μg/g irisin (n = 4) or vehicle (n = 4) for 14 days. Glucose tolerance, glycemia, insulinemia, body weight, pancreatic islet architecture and function were assessed throughout the study. As expected, compared to SD mice, HFD/STZ mice showed higher glycemia and body weight, glucose intolerance, and reduced GSIS; in addition, HFD/STZ mice showed reduced islet volume (-78%) , β-cell area (-35%) , and insulin content (-60%) , while increased α-cell area (+54%) . Irisin administration significantly restored glycemia (-31%) , body weight (-13%) , glucose tolerance (-27%, AUC) , GSIS (+23%, AUC) , islet volume (+61%) , β-cell (+34%) and α-cell (-49%) areas, and insulin content (+36%) . Of note, irisin treatment induced a 9-fold increase in β-cell proliferation rate. These results show for the first time that irisin can restore β-cell functional mass when administered in vivo to diabetic mice. Disclosure N.Marrano: None. G.Biondi: None. A.Borrelli: None. L.Roberto: None. A.Cignarelli: None. S.Perrini: None. L.Laviola: Advisory Panel; Lilly Diabetes, Novo Nordisk, Roche Diabetes Care, Sanofi, Speaker's Bureau; A. Menarini Diagnostics, Abbott Diabetes, Medtronic, Terumo Corporation. F.Giorgino: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk, Consultant; Lilly Diabetes, Sanofi, Research Support; Lilly Diabetes, Roche Diabetes Care, Takeda Pharmaceutical Company Limited. A.Natalicchio: Consultant; Novo Nordisk, Other Relationship; AstraZeneca, Lilly Diabetes, Sanofi. Funding EU – ESF PON R&I 2014-20, AIM

We evaluated the role of the p66Shc redox adaptor protein in pancreatic beta-cell insulin resistance that develops under lipotoxic conditions and with excess body fat. Prolonged exposure to palmitate in vitro or the presence of overweight/obesity augmented p66Shc expression levels and caused an impaired ability of exogenous insulin to increase cellular insulin content and secreted C-peptide levels in INS-1E cells and human and murine islets. In INS-1E cells, p66Shc knockdown resulted in enhanced insulin-induced augmentation of insulin content and C-peptide secretion and prevented the ability of palmitate to impair these effects of insulin. Conversely, p66Shc overexpression impaired insulin-induced augmentation of insulin content and C-peptide secretion both in the absence and presence of palmitate. Under lipotoxic condition, the effects of p66Shc are mediated by p53-induced increase in p66Shc protein levels and JNK-induced p66Shc phosphorylation at Ser36 and appear to involve the phosphorylation of the ribosomal protein S6 kinase at Thr389 and of insulin receptor substrate-1 at Ser307, resulting in the inhibition of insulin-stimulated protein kinase b phosphorylation at Ser473. Thus, the p66Shc protein mediates the impaired beta-cell function and insulin resistance induced by saturated fatty acids and excess body fat.

Obesity is a chronic disease caused by an excess of adipose tissue that may impair health by altering the functionality of various organs, including the lungs. Excessive deposition of fat in the abdominal area can lead to abnormal positioning of the diaphragm and consequent reduction in lung volume, leading to a heightened demand for ventilation and increased exposure to respiratory diseases, such as chronic obstructive pulmonary disease, asthma, and obstructive sleep apnoea. In addition to mechanical ventilatory constraints, excess fat and ectopic deposition in visceral depots can lead to adipose tissue dysfunction, which promotes metabolic disorders. An altered adipokine-secretion profile from dysfunctional adipose tissue in morbid obesity fosters systemic, low-grade inflammation, impairing pulmonary immune response and promoting airway hyperresponsiveness. A potential target of these adipokines could be the NLRP3 inflammasome, a critical component of the innate immune system, the harmful pro-inflammatory effect of which affects both adipose and lung tissue in obesity. In this review, we will investigate the crosstalk between adipose tissue and the lung in obesity, highlighting the main inflammatory mediators and novel therapeutic targets in preventing pulmonary dysfunction.

Endothelial progenitor cells (EPCs) are key for angiogenic responses in multiple tissues and mediate a coordinate augmentation of the capillary network as adipose tissue (AT) expands in response to positive energy balance. However, isolation and culture of EPCs from human AT has been difficult. Here we describe a new method for obtaining well-characterized EPCs from human AT. Subcutaneous and visceral AT specimens (approximately 1-2 g) were obtained from 10-20 obese subjects by needle biopsy of abdominal subcutaneous AT and removal of omental AT fragments during abdominal surgery, respectively. Human EPCs were isolated from both the digested (SVCI) and undigested (SVCII) stromal vascular fractions of AT by anti-CD31 beads. After 5 days of in vitro culture, EPCs from SVCII exhibited an endothelial-like cobblestone morphology as compared to EPCs from SVCI. Flow cytometry analysis showed that the percentage of CD31+ and CD144+ cells was much higher in the SVCII compared to SVCI fraction (SVCII: CD31 97.9±2.9%, CD144 93.3±4.7%; SVCI: CD31 4.0±1.2%, CD144 3.8±0.7%). Immunofluorescence staining demonstrated that CD31+ EPCs from SVCII expressed Von Willebrand Factor (vWF) and VE-cadherin. Additionally, significantly higher mRNA and protein levels of CD31, E-selectin, e-NOS, VEGFR, and CD34 were found in CD31+ EPCs from SVCII than in control cells (CD31- cells from SVCI). EPCs from SVCII maintained the expression of endothelial markers (CD144 mRNA and protein levels) up to the fourth cell passage. Lastly, CD31+ EPCs from SVCII, but not control cells, were able to form tubes in 3D scaffolds (Matrigel) resembling capillary structures, as well as to incorporate acetylated LDL in vitro. Thus, we have successfully isolated EPCs with high proliferative potential and specific functional properties from the human AT. This will potentially increase our understanding of AT biology particularly in relation to altered expansion of distinct AT depots in human obesity. Disclosure C. Caccioppoli: None. S. Perrini: None. V. Genchi: None. R. Doria: None. G. Palma: None. A. Cignarelli: 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. 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.

Leptin is a principal adipose-derived hormone mostly implicated in the regulation of energy balance through the activation of anorexigenic neuronal pathways. Comprehensive studies have established that the maintenance of certain concentrations of circulating leptin is essential to avoid an imbalance in nutrient intake. Indeed, genetic modifications of the leptin/leptin receptor axis and the obesogenic environment may induce changes in leptin levels or action in a manner that accelerates metabolic dysfunctions, resulting in a hyperphagic status and adipose tissue expansion. As a result, a vicious cycle begins wherein hyperleptinaemia and leptin resistance occur, in turn leading to increased food intake and fat enlargement, which is followed by leptin overproduction. In addition, in the context of obesity, a defective thermoregulatory response is associated with impaired leptin signalling overall within the ventromedial nucleus of the hypothalamus. These recent findings highlight the role of leptin in the regulation of adaptive thermogenesis, thus suggesting leptin to be potentially considered as a new thermolipokine. This review provides new insight into the link between obesity, hyperleptinaemia, leptin resistance and leptin deficiency, focusing on the ability to restore leptin sensitiveness by way of enhanced thermogenic responses and highlighting novel anti-obesity therapeutic strategies.

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 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.

Myocardial ectopic lipid deposition has been associated with insulin resistance and cardiovascular risk. Palmitate, one of the most abundant saturated fatty acids, has been shown to impair insulin signaling in multiple cell types. Human cardiac progenitor cells (CPC) represent a compartment of multipotent stem cells essential for constant tissue repair and renewal in the adult heart. In this study, the ability of palmitate to impair insulin signaling, and the modulatory effects of oleate, a mono-unsaturated fatty acid, on palmitate-induced abnormalities were investigated in human CPC isolated from control subjects undergoing cardiac surgery. Human CPC express insulin receptor (IR), as assessed by quantitative RT-PCR and immunoblotting. Specifically, in human CPC both IR isoforms, A (IR-A) and B (IR-B), were identified, and IR-A was more expressed than IR-B. Exposure of human CPC to 100 nM insulin for 15 minutes resulted in increased Akt and p44/p42 MAPK phosphorylation (p In conclusion, oleate prevents some of the palmitate-induced impairments in insulin signaling in human CPC, thus contributing to cardiac protection from lipotoxicity-induced metabolic alterations. Disclosure R. Doria: 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. C. Caccioppoli: None. R. Schipani: None. V. Genchi: None. A. Leonardini: None. A. Natalicchio: Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Sanofi. S. Perrini: None. A. Cignarelli: None. 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.

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.

Irisin is a hormone secreted by skeletal muscle following physical activity or excess of saturated fatty acids, able to promote energy expenditure and improve metabolic homeostasis. Serum irisin levels are reduced in type 2 diabetes (T2D), while exogenous irisin administration improves glycemic control in diabetic mice. We have previously demonstrated that irisin promotes beta-cell viability and insulin secretory function. This study investigated serum irisin levels in T2D patients according to their antidiabetes treatment. 127 T2D patients were enrolled and stratified by antidiabetes therapy: diet only (17); metformin only (met, 37); met plus sulfonylureas (5); met plus pioglitazone (7); met plus GLP-1 receptor agonists (GLP-1RAs, 31); met plus DPP-4 inhibitors (DPP-4i, 15); and met plus SGLT2 inhibitors (SGLT2i, 15). The control group included 36 sex-, and BMI-matched subjects without diabetes. T2D patients showed lower irisin levels than controls (21.5 [10.1-50.8] vs. 29.1 [14.1-43.5] ng/mL, P In conclusion, in T2D GLP-1-based therapies significantly increase serum irisin to levels comparable to those of nondiabetic subjects, possibly through GLP-1 receptor-mediated stimulation of irisin release by skeletal muscle cells. Irisin may thus represent a new factor in the mechanism of action of GLP-1-based therapies. Disclosure A. Natalicchio: Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Sanofi. S. Perrini: None. 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. 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. N. Marrano: None. G. Biondi: None. A. Montedoro: None. G. Le grazie: None. L. Di gioia: None. F. Guarini: None. A. Borrelli: None. A. Cignarelli: None. Funding European Union–European Social Fund; PON R&I (2014-2020); AIM (1810057)

Incretins are gut hormones that potentiate glucose-stimulated insulin secretion (GSIS) after meals. Glucagon-like peptide-1 (GLP-1) is the most investigated incretin hormone, synthesized mainly by L cells in the lower gut tract. GLP-1 promotes β-cell function and survival and exerts beneficial effects in different organs and tissues. Irisin, a myokine released in response to a high-fat diet and exercise, enhances GSIS. Similar to GLP-1, irisin augments insulin biosynthesis and promotes accrual of β-cell functional mass. In addition, irisin and GLP-1 share comparable pleiotropic effects and activate similar intracellular pathways. The insulinotropic and extra-pancreatic effects of GLP-1 are reduced in type 2 diabetes (T2D) patients but preserved at pharmacological doses. GLP-1 receptor agonists (GLP-1RAs) are therefore among the most widely used antidiabetes drugs, also considered for their cardiovascular benefits and ability to promote weight loss. Irisin levels are lower in T2D patients, and in diabetic and/or obese animal models irisin administration improves glycemic control and promotes weight loss. Interestingly, recent evidence suggests that both GLP-1 and irisin are also synthesized within the pancreatic islets, in α- and β-cells, respectively. This review aims to describe the similarities between GLP-1 and irisin and to propose a new potential axis–involving the gut, muscle, and endocrine pancreas that controls energy homeostasis.

AIMS: To assess changes in glucose metrics and their association with psychological distress and lifestyle changes in patients with type 1 diabetes (T1D) using flash glucose monitoring (FGM) during lockdown following severe acute respiratory syndrome coronavirus 2 outbreak. MATERIALS AND METHODS: Single-centre, observational, retrospective study enrolling T1D patients who attended a remote visit on April 2020 at the Endocrinology division of the University Hospital Policlinico Consorziale, Bari, Italy. Lockdown-related changes in physical activity level and dietary habits were assessed on a semi-quantitative basis. Changes in general well-being were assessed by the General Health Questionnaire-12 items with a binary scoring system. Glucose metrics were obtained from the Libreview platform for the first 2 weeks of February 2020 (T0) and the last 2 weeks before the phone visit (T1). RESULTS: Out of 84 patients assessed for eligibility, 48 had sufficient FGM data to be included in the analysis. FGM data analysis revealed significant reductions in coefficient of variation, number of hypoglycaemic events, and time below range, while no changes were found in time in range, time above range, mean sensor glucose, and glucose management indicator. Moreover, the frequency of sweets consumption was inversely related to the occurrence of hypoglycaemic events during lockdown. CONCLUSIONS: Lockdown-related lifestyle changes, albeit unhealthy, may lead to reduction in FGM-derived measures of hypoglycaemia and glycaemic variability in patients with T1D.

The way by which subcutaneous adipose tissue (SAT) expands and undergoes remodeling by storing excess lipids through expansion of adipocytes (hypertrophy) or recruitment of new precursor cells (hyperplasia) impacts the risk of developing cardiometabolic and respiratory diseases. In unhealthy obese subjects, insulin resistance, type 2 diabetes, hypertension, and obstructive sleep apnoea are typically associated with pathologic SAT remodeling characterized by adipocyte hypertrophy, as well as chronic inflammation, hypoxia, increased visceral adipose tissue (VAT), and fatty liver. In contrast, metabolically healthy obese individuals are generally associated with SAT development characterized by the presence of smaller and numerous mature adipocytes, and a lower degree of VAT inflammation and ectopic fat accumulation. The remodeling of SAT and VAT is under genetic regulation and influenced by inherent depot-specific differences of adipose tissue-derived stem cells (ASCs). ASCs have multiple functions such as cell renewal, adipogenic capacity, and angiogenic properties, and secrete a variety of bioactive molecules involved in vascular and extracellular matrix remodeling. Understanding the mechanisms regulating the proliferative and adipogenic capacity of ASCs from SAT and VAT in response to excess calorie intake has become a focus of interest over recent decades. Here, we summarize current knowledge about the biological mechanisms able to foster or impair the recruitment and adipogenic differentiation of ASCs during SAT and VAT development, which regulate body fat distribution and favorable or unfavorable metabolic responses.

Pasireotide is a new-generation somatostatin analog used for the treatment of acromegaly, Cushing’s disease and neuroendocrine tumors. However, due to its high affinity for somatostatin receptors (SSTR) 2 and 5, highly expressed in enteroendocrine- and pancreatic β-cells, it can reduce insulin, GLP-1 and GIP release and increase glucagonemia, causing marked hyperglycemia in some patients. The diabetogenic effects of pasireotide are significantly reduced in vivo by the co-administration of liraglutide or vildagliptin. The aim of this study was to evaluate the effects of pasireotide on β-cell survival and function, and the ability of molecules with known beneficial action on β-cells (incretin-based drugs and irisin, a myokine with β-cellular trophic properties) to prevent these effects. In INS-1E cells, both acute and chronic administration of pasireotide 10-50 nM reduced glucose-induced insulin secretion by 30% and 50% respectively and proinsulin mRNA levels by 20%, without altering cellular insulin content. Furthermore, pasireotide induced apoptosis in INS-1E cells and human pancreatic islets. Pretreatment with both incretin-based drugs (exendin-4, lixisenatide, liraglutide, saxagliptin) and irisin prevented pasireotide-induced apoptosis in INS-1E cells. In addition, pasireotide increased the protein levels of SSTR2 (2-fold) but not of SSTR5. Among the protective molecules examined, only irisin was able to prevent this increase. In conclusion, pasireotide can induce hyperglycemia and diabetes via direct effects on β-cells, resulting in reduced insulin secretory capacity and survival. Both GLP-1 receptor agonists and DPP-4 inhibitors and irisin can reduce the proapoptotic effects of pasireotide, acting through partially different molecular mechanisms. These results demonstrate for the first time a functional antagonism between SSTR2/5 activation and incretin-based drugs or irisin in pancreatic β-cells. Disclosure A. Natalicchio: Consultant; Self; AstraZeneca, Novo Nordisk Inc., Sanofi-Aventis. G. Biondi: None. N. Marrano: None. L. Vincenti: None. A. Cignarelli: None. S. Perrini: None. L. Laviola: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk Inc., Roche Diabetes Care, Sanofi-Aventis. Speaker’s Bureau; Self; Abbott, Medtronic. F. Giorgino: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc., Roche Diabetes Care, Sanofi. Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., LifeScan, Inc., MedImmune, Merck Sharp & Dohme Corp., Roche Diabetes Care, Sanofi. Research Support; Self; Eli Lilly and Company, LifeScan, Inc., Takeda Development Centre Europe Ltd. Funding Novartis

This study aimed to assess whether the secretome from abdominal visceral (AV) and epicardial (E) adipose stem cells (ASC), ASC-derived mature adipocytes, and isolated AV mature adipocytes may affect the viability of cardiac progenitor cells (CPC) in human obesity, and whether dapagliflozin (DAPA) may reduce the proapoptotic effects in injured CPC. ASC were isolated from AV and E adipose tissue biopsies of nondiabetic subjects with varying levels of BMI and used before and after differentiation into adipocytes in vitro. CPC were isolated from right auricle biopsies of non-obese (Ob) subjects, preincubated in the presence or absence of 10 uM DAPA, and exposed or not to conditioned media (CM) of AV-ASC, E-ASC, AV-ASC-derived adipocytes and isolated AV mature adipocytes. The CM of AV-ASC and differentiated adipocytes from Ob subjects induced CPC apoptosis after 4-8-24 h (p In conclusion, the secretome of adipose cells from Ob subjects impairs insulin action and viability of the CPC, and these effects can be counteracted by DAPA. Disclosure S. Porro: None. S. Perrini: None. C. Caccioppoli: None. R. Doria: None. V. Genchi: None. R. Schipani: None. A. Cignarelli: None. A. Natalicchio: Consultant; Self; AstraZeneca, Novo Nordisk Inc., Sanofi-Aventis. L. Laviola: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk Inc., Roche Diabetes Care, Sanofi-Aventis. Speaker’s Bureau; Self; Abbott, Medtronic. F. Giorgino: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc., Roche Diabetes Care, Sanofi. Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., LifeScan, Inc., MedImmune, Merck Sharp & Dohme Corp., Roche Diabetes Care, Sanofi. Research Support; Self; Eli Lilly and Company, LifeScan, Inc., Takeda Development Centre Europe Ltd.

Irisin is a hormone secreted by skeletal muscle following physical activity and excess of saturated fatty acids, able to improve metabolic homeostasis and promote energy expenditure. In a previous study, we have demonstrated that, in beta-cells, irisin promotes proliferation and glucose-stimulated insulin secretion (GSIS), increases insulin content levels, and reduces lipotoxicity-induced apoptosis. The aim of this study was to evaluate the effects of irisin on the function and survival of pancreatic islets isolated from patients with type 2 diabetes mellitus (T2DM), characterized by reduced ability to secrete insulin and high levels of apoptosis, and to investigate the molecular mechanisms underlying this action. Pancreatic islets isolated from T2DM patients (n=7) and nondiabetic subjects (ND) (n=3), as well as INS-1E cells, were exposed to 100 nM irisin for different times. GSIS, insulin content, apoptosis and cytoplasmic calcium levels were measured by ELISA assays; the activation of the main mediators of beta-cell intracellular signalling (AKT, CREB and PKA) was evaluated by immunoblotting. Irisin increased GSIS approximately 2-fold (p In conclusion, the myokine irisin is able to increase the secretory function and survival of human pancreatic islets and to improve the functional defects typical of the T2DM islets. The mechanisms underlying the secretagogue effects of irisin in the T2DM islets do not apparently involve the known signaling machinery of this novel hormone. Disclosure N. Marrano: None. A. Natalicchio: Consultant; Self; AstraZeneca, Novo Nordisk Inc., Sanofi-Aventis. G. Biondi: None. A. Cignarelli: None. L. Vincenti: None. L.G. Lupo: None. S. Perrini: None. L. Laviola: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk Inc., Roche Diabetes Care, Sanofi-Aventis. Speaker’s Bureau; Self; Abbott, Medtronic. F. Giorgino: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc., Roche Diabetes Care, Sanofi. Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., LifeScan, Inc., MedImmune, Merck Sharp & Dohme Corp., Roche Diabetes Care, Sanofi. Research Support; Self; Eli Lilly and Company, LifeScan, Inc., Takeda Development Centre Europe Ltd. Funding European Union (AIM1810057)

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.

Reactive oxygen species (ROS) are highly reactive chemical species containing oxygen, controlled by both enzymatic and nonenzymatic antioxidant defense systems. In the heart, ROS play an important role in cell homeostasis, by modulating cell proliferation, differentiation, and excitation-contraction coupling. Oxidative stress occurs when ROS production exceeds the buffering capacity of the antioxidant defense systems, leading to cellular and molecular abnormalities, ultimately resulting in cardiac dysfunction. In this review, we will discuss the physiological sources of ROS in the heart, the mechanisms of oxidative stress-related myocardial injury, and the implications of experimental studies and clinical trials with antioxidant therapies in cardiovascular diseases.

Subjects with Klinefelter syndrome (KS) develop several metabolic abnormalities more frequently than normal males, with a higher prevalence of obesity, type 2 diabetes (T2D), dyslipidemia, and metabolic syndrome. The etiology factors causing the increased prevalence of metabolic disorders have not been completely clarified and may involve several mechanisms, rather than simply the direct consequence of hypogonadism alone. While reduced levels of testosterone cause an unfavorable change in body composition, with higher fraction of body fat in KS compared to 46-XY peers, testosterone replacement therapy in hypogonadal KS subjects, even if associated with an improvement of body composition, is not totally effective in ameliorating lipid and glycemic abnormalities. Moreover, changes in body composition develop before puberty in KS subjects, suggesting a role of non-hormonal factors. Most genes on the redundant X chromosome(s) are subject to X inactivation, but there is a pseudo-autosomal region containing multiple genes that escape inactivation. The association of more severe karyotypes with higher prevalence of T2D suggests a role of the supernumerary X chromosomes in the onset of T2D in KS. Nevertheless, KS is associated with DNA methylation changes across the entire genome, which might be important in this context since the genetic basis of complex traits such as T2D is thought to be much related with subtle changes in the epigenome and transcriptome. Further research is needed to address this.

GLP-1 receptor agonists (GLP-1RA) and SGLT2 inhibitors (SGLT2i) have been associated with improved glycemic control, body weight loss and favorable changes in cardiovascular risk factors and outcomes. We conducted a systematic review and meta-analysis to evaluate the effects of the addition of GLP-1RA to SGLT2i in patients with type 2 diabetes mellitus and inadequate glycemic control. Six databases were searched until March 2019. Randomized controlled trials (RCT) with a follow-up of at least 24 weeks reporting on HbA1c, body weight, systolic blood pressure, lipids, achievement of HbA1c

Very low calorie ketogenic diet (VLCKD) has been proposed as a promising option to achieve a significant weight loss in a short time period. We conducted a systematic review and meta-analysis to evaluate its efficacy and safety in patients with overweight and obesity. Four databases were searched on May 2019. Studies reporting data on body weight, body mass index (BMI), waist circumference, body composition, blood pressure, HbA1c, lipids, and markers of liver and kidney function were selected. Discontinuation was also assessed. Twelve studies were included. VLCKD was associated with weight losses of −10.0 kg (I2 = 6%) and − 15.6 kg (I2 = 37%) in studies with a ketogenic phase up to and of at least four weeks, respectively. The weight lost during the ketogenic phase was stable in the subsequent follow-up up to two years (p = 0.12). Also, VLCKD was associated with reductions of BMI (−5.3 kg/m2), waist circumference (−12.6 cm), HbA1c (−0.7%), total cholesterol (−28 mg/dl), triglycerides (−30 mg/dl), AST (−7 U/l), ALT (−8 U/l), GGT (−8 U/l), systolic and diastolic blood pressure (−8 and − 7 mmHg, respectively). No changes in LDL cholesterol, HDL cholesterol, serum creatinine, serum uric acid and serum potassium were found. Serum sodium increased during VLCKD (+1.6 mEq/l). The overall prevalence of patients discontinuing VLCKD was 7.5% and this was similar to patients undergoing a low calorie diet (p = 0.83). The present review supports the use of VLCKD as an effective strategy for the management of overweight and obesity. Future guidelines should include a specific recommendation for this intervention.

Background Irisin, a newly discovered muscle-derived hormone, acts in different organs and tissues, improving energy homeostasis. In this study, we assessed, for the first time, the effects of intraperitoneal irisin injections on circulating levels of leptin and ghrelin, mRNA expression of the major hypothalamic appetite regulators and brain neurotrophic factors, as well as feeding behaviour in healthy mice. Methods Twelve male 6-week-old C57BL/6 mice were randomized into two groups and intraperitoneally injected daily with irisin (0.5 μg/g body weight) or vehicle (phosphate-buffered saline [PBS]) for 14 days. On the last day of observation, leptin and ghrelin levels were measured with an enzyme-linked immunosorbent assay (ELISA). mRNA levels of genes of interest were analysed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) in brain extracts. Results Irisin administration did not change leptin or ghrelin serum concentrations. However, irisin injection increased CART, POMC, NPY, and BDNF mRNA levels, without affecting the mRNA expression of AgRP, orexin, PMCH, and UCP2. Finally, over the time frame of irisin treatment, body weight and feeding behaviour were unaltered. Conclusions These results suggest that intraperitoneal injection of irisin, although without effects on feeding behaviour and body weight, can increase the expression of anorexigenic and neurotrophic genes in mouse brain.

Physical exercise may profoundly affect glucose variability (GV) in insulinopenic diabetes leading to both hypo- and hyperglycemia and feeling of discomfort reported by the patients after work out. Even if combined training reportedly reduces GV, an ideal training protocol is still not established in these patients. The aim of this study was to evaluate the effects of different combinations of continuous aerobic exercise (CON) and high intensity interval training (HIIT) on GV during a 24-h period after work out. A cross-over study was conducted on 14 outpatients [male 50%, mean age 31.9 (8.1) y, BMI 22.1 (2.5) Kg/m2] with either T1D (n=10) or LADA (n=4) on continuous subcutaneous insulin infusion (CSII) therapy [4 (3.9) y]. Data from flash glucose monitoring were collected for 72 h before work out. After different sequences of HIIT and CON work out (HIIT followed by CON, HIIT-CON; and CON followed by HIIT, CON-HIIT), 24-h glucose profiles were acquired. Several indices of GV and predictors of hypo-/hyperglycemia were analyzed. Indices of GV revealed no statistically significant difference when compared to baseline GV [mean -0.38 (1.85) vs. -0.43 (1.66); SD 0.02 (1.06) vs. -0.04 (0.94); CONGA: -0.18 (1.63) vs. -0.36 (1.69); MAG -0.12 (0.44) vs. -0.21 (0.47); MAGE 0.73 (1.65) vs. 1.11 (0.84); LBGI: 1.28 (6.83) vs. 1.71 (5.43); HBGI -0.18 (5.34) vs. -1.03 (4.89); HIIT-CON delta vs. baseline and CON-HIIT delta vs. baseline, respectively]. Moreover, time spent in 180 mg/dl 24 h after either HIIT-CON or CON-HIIT training was comparable to baseline [for 180 mg/dl: baseline 27.2% (22.7), HIIT-CON 22.6% (21.1), CON-HIIT 22.2% (16.8)]. The comparison between HIIT-CON and CON-HIIT also showed no differences in GV. Thus, a standardized combined work out (either HIIT-CON or CON-HIIT) avoids late glycemic fluctuations and dangerous hypo-/hyperglycemia in T1D and LADA patients on CSII therapy. Disclosure A. Cignarelli: Consultant; Self; Eli Lilly and Company. Speaker's Bureau; Self; Merck Sharp & Dohme Corp., Novo Nordisk A/S. G. Lisco: None. L. Di Gioia: None. A. Natalicchio: Other Relationship; Self; Novo Nordisk Inc., Sanofi-Aventis. S. Perrini: None. L. Laviola: Advisory Panel; Self; Abbott, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk Inc. Board Member; Self; AstraZeneca, Roche Diabetes Care, Sanofi-Aventis. Speaker's Bureau; Self; Medtronic, Mundipharma, Takeda Pharmaceutical Company Limited. F. Giorgino: Advisory Panel; Self; Aegerion Pharmaceuticals, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, MedImmune, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Roche Diabetes Care, Sanofi. Consultant; Self; Roche Diabetes Care, Sanofi. Research Support; Self; Eli Lilly and Company, LifeScan, Inc., Takeda Pharmaceutical Company Limited. Other Relationship; Self; AstraZeneca, Eli Lilly and Company, Sanofi.