Acute hyperbilirubinemia determines an early subclinical renal damage: Evaluation of tubular biomarkers in cholemic nephropathy.

BACKGROUND AND AIMS: Cholemic nephropathy is a cause of acute kidney injury occurring in patients with jaundice. The aim of this study was to evaluate early renal function impairment in patients with mild acute hyperbilirubinemia in the absence of alterations of the common parameters used in clinical practice (serum creatinine or urea) and with normal renal morphology. We studied urinary biomarkers of tubular damage urinary neutrophil gelatinase-associated lipocalin (u-NGAL), urinary beta-2-microglobulin (u-B2M), urinary osteopontin (u-OPN), urinary trefoil factor 3 (u-TFF3) and urinary Cystatin C (u-Cys). METHODS: This is a case-control study investigating the following urinary biomarkers of tubular damage: u-NGAL, u-B2M, u-OPN, u-TFF3 and u-Cys, in patients with mild acute hyperbilirubinemia. Seventy-four patients were included in this study: 36 patients with jaundice and 38 patients without jaundice. RESULTS: Subjects with jaundice (total bilirubin 12.4 ± 7.3 mg/dL) showed higher u-NGAL, u-B2M, u-OPN, u-TFF3 and u-Cys compared with controls. After logistic regression analyses, including the following independent variables: age, estimated Glomerular Filtration Rate (eGFR), haemoglobin, diabetes, hypertension and jaundice, we observed a higher risk of elevated u-NGAL values (OR = 3.8, 95% CI 1.07-13.5, p = .03) and u-B2M (OR = 9.4, 95% CI 2.3-38.9, p = .0018) in jaundiced subjects. Moreover, urinary biomarkers had a direct correlation with serum cholestasis indexes. CONCLUSIONS: This study demonstrated increased urinary biomarkers of tubular damage (u-NGAL, u-B2M, u-OPN, u-TFF3, and u-Cys) in patients with mild hyperbilirubinemia in comparison with a control group. These findings suggest early renal tubular damage in the absence of alterations of the normal parameters used in clinical practice (eGFR, serum urea and renal morphology).

Cardiovascular risk and renal injury profile in subjects with type 2 diabetes and non-albuminuric diabetic kidney disease.

BACKGROUND: In the last years, the classical pattern of diabetic kidney disease (DKD) has been partially overcome, because of the uncovering of a new DKD phenotype with significant renal dysfunction without presence of albuminuria: the non-albuminuric DKD (NA-DKD). To date, the cardiovascular risk associated with this phenotype is still debated. We investigated the cardiovascular risk and renal injury profile of NA-DKD subjects in comparison with other DKD phenotypes. METHODS: Pulse wave velocity (PWV), intima-media thickness, presence of carotid atherosclerotic plaque, renal resistive index (RRI), and a panel of urinary biomarkers of kidney injury were evaluated in 160 subjects with type 2 diabetes, stratified according to estimated glomerular filtration rate (eGFR) and urinary albumin to creatinine ratio (UACR) into four groups: controls (UACR < 30 mg/g and eGFR ≥ 60 mL/min/1.73 m2), A-DKD (Albuminuric-DKD, UACR ≥ 30 mg/g and eGFR ≥ 60 mL/min/1.73 m2), NA-DKD (UACR < 30 mg/g and eGFR < 60 mL/min/1.73 m2), AL-DKD (Albuminuric and Low eGFR-DKD; UACR ≥ 30 mg/g and eGFR < 60 mL/min/1.73 m2). RESULTS: Subjects with NA-DKD showed a higher PWV (11.83 ± 3.74 m/s vs. 10.24 ± 2.67 m/s, P = 0.045), RRI (0.76 ± 0.11 vs. 0.71 ± 0.09, P = 0.04), and prevalence of carotid atherosclerotic plaque (59% vs. 31%, P = 0.009) compared with controls. These characteristics were similar to those of subjects with AL-DKD, whereas the profile of A-DKD subjects was closer to controls. After multiple regression analyses, we found that RRI, that is in turn influenced by eGFR (ß = - 0.01, P = 0.01), was one of the major determinants of PWV (ß = 9.4, P = 0.02). Urinary TreFoil Factor 3, a marker of tubular damage, was higher in NA-DKD subjects vs. controls (1533.14 ± 878.31 ng/mL vs. 1253.84 ± 682.17 ng/mL, P = 0.047). Furthermore, after multiple regression analyses, we found that urinary osteopontin was independently associated with PWV (ß = 2.6, P = 0.049) and RRI (ß = 0.09, P = 0.006). CONCLUSIONS: Our data showed a worse cardiovascular and renal injury profile in NA-DKD subjects. This finding emphasizes the central role of eGFR in the definition of cardiovascular risk profile of diabetic subjects together with albuminuria.

Glucagon in type 2 diabetes: Friend or foe?

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.

Professional continuous glucose monitoring in patients with diabetes mellitus: A systematic review and meta-analysis.

AIM: To evaluate the effect on glucose control of professional continuous glucose monitoring (p-CGM)-based care as compared with standard care in the management of patients with type 1 and type 2 diabetes. MATERIALS AND METHODS: The PubMed database was searched comprehensively to identify prospective or retrospective studies evaluating p-CGM as a diagnostic tool for subsequent implementation of lifestyle and/or medication changes and reporting glycated haemoglobin (HbA1c) as an outcome measure. RESULTS: We found 872 articles, 22 of which were included in the meta-analysis. Overall, the use of p-CGM was associated with greater HbA1c reduction from baseline (-0.28%, 95% confidence interval [CI] -0.36% to -0.21%, I2  = 0%, P < 0.00001) than usual care, irrespective of type of diabetes, length of follow-up, frequency of continuous glucose monitoring (CGM) use and duration of CGM recording. In the few studies describing CGM-derived glucose metrics, p-CGM showed a beneficial effect on change in time in range from baseline (5.59%, 95% CI 0.12 to 11.06, I2  = 0%, P = 0.05) and a neutral effect on change in time below the target range from baseline (-0.11%, 95% CI -1.76% to 1.55%, I2  = 33%, P = 0.90). CONCLUSIONS: In patients with type 1 and type 2 diabetes, p-CGM-driven care is superior to usual care in improving glucose control without increasing hypoglycaemia.

The p66Shc Redox Protein and the Emerging Complications of Diabetes.

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. P66Shc 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 p66Shc in the traditional complications of diabetes. In this review, we will summarize the evidence supporting the role of p66Shc in the pathogenesis of diabetes and its complications, focusing for the first time on the emerging complications of diabetes.

Adipose Tissue Secretion Pattern Influences ß-Cell Wellness in the Transition from Obesity to Type 2 Diabetes.

The dysregulation of the ß-cell functional mass, which is a reduction in the number of ß-cells and their ability to secure adequate insulin secretion, represents a key mechanistic factor leading to the onset of type 2 diabetes (T2D). Obesity is recognised as a leading cause of ß-cell loss and dysfunction and a risk factor for T2D. The natural history of ß-cell failure in obesity-induced T2D can be divided into three steps: (1) ß-cell compensatory hyperplasia and insulin hypersecretion, (2) insulin secretory dysfunction, and (3) loss of ß-cell mass. Adipose tissue (AT) secretes many hormones/cytokines (adipokines) and fatty acids that can directly influence ß-cell function and viability. As this secretory pattern is altered in obese and diabetic patients, it is expected that the cross-talk between AT and pancreatic ß-cells could drive the maintenance of the ß-cell integrity under physiological conditions and contribute to the reduction in the ß-cell functional mass in a dysmetabolic state. In the current review, we summarise the evidence of the ability of the AT secretome to influence each step of ß-cell failure, and attempt to draw a timeline of the alterations in the adipokine secretion pattern in the transition from obesity to T2D that reflects the progressive deterioration of the ß-cell functional mass.

Reduction of hypoglycaemia, lifestyle modifications and psychological distress during lockdown following SARS-CoV-2 outbreak in type 1 diabetes.

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.

Impaired Leptin Signalling in Obesity: Is Leptin a New Thermolipokine?

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.

Reduced SIRT1 and SIRT2 expression promotes adipogenesis of human visceral adipose stem cells and associates with accumulation of visceral fat in human obesity.

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.

Irisin increases the expression of anorexigenic and neurotrophic genes in mouse brain.

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.

Insulin and Insulin Receptors in Adipose Tissue Development.

Insulin is a major endocrine hormone also involved in the regulation of energy and lipid metabolism via the activation of an intracellular signaling cascade involving the insulin receptor (INSR), insulin receptor substrate (IRS) proteins, phosphoinositol 3-kinase (PI3K) and protein kinase B (AKT). Specifically, insulin regulates several aspects of the development and function of adipose tissue and stimulates the differentiation program of adipose cells. Insulin can activate its responses in adipose tissue through two INSR splicing variants: INSR-A, which is predominantly expressed in mesenchymal and less-differentiated cells and mainly linked to cell proliferation, and INSR-B, which is more expressed in terminally differentiated cells and coupled to metabolic effects. Recent findings have revealed that different distributions of INSR and an altered INSR-A:INSR-B ratio may contribute to metabolic abnormalities during the onset of insulin resistance and the progression to type 2 diabetes. In this review, we discuss the role of insulin and the INSR in the development and endocrine activity of adipose tissue and the pharmacological implications for the management of obesity and type 2 diabetes.

The p66(Shc) redox adaptor protein is induced by saturated fatty acids and mediates lipotoxicity-induced apoptosis in pancreatic beta cells.

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.

The p66Shc protein controls redox signaling and oxidation-dependent DNA damage in human liver cells.

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.

Endocrine-metabolic assessment checklist for cancer patients treated with immunotherapy: A proposal by the Italian Association of Medical Oncology (AIOM), Italian Association of Medical Diabetologists (AMD), Italian Society of Diabetology (SID), Italian Society of Endocrinology (SIE) and Italian Society of Pharmacology (SIF) multidisciplinary group.

Immunotherapy with immune checkpoint inhibitors (ICI) is increasingly employed in oncology. National and international endocrine and oncologic scientific societies have provided guidelines for the management of endocrine immune-related adverse events. However, guidelines recommendations differ according to the specific filed, particularly pertaining to recommendations for the timing of endocrine testing. In this position paper, a panel of experts of the Italian Association of Medical Oncology (AIOM), Italian Association of Medical Diabetologists (AMD), Italian Society of Diabetology (SID), Italian Society of Endocrinology (SIE), and Italian Society of Pharmacology (SIF) offers a critical multidisciplinary consensus for a clear, simple, useful, and easily applicable endocrine-metabolic assessment checklist for cancer patients on immunotherapy.

Exendin-4 protects pancreatic beta cells from palmitate-induced apoptosis by interfering with GPR40 and the MKK4/7 stress kinase signalling pathway.

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.

Type 2 Diabetes and Alzheimer's Disease: The Emerging Role of Cellular Lipotoxicity.

Type 2 diabetes (T2D) and Alzheimer's diseases (AD) represent major health issues that have reached alarming levels in the last decades. Although growing evidence demonstrates that AD is a significant comorbidity of T2D, and there is a ~1.4-2-fold increase in the risk of developing AD among T2D patients, the involvement of possible common triggers in the pathogenesis of these two diseases remains largely unknown. Of note, recent mechanistic insights suggest that lipotoxicity could represent the missing ring in the pathogenetic mechanisms linking T2D to AD. Indeed, obesity, which represents the main cause of lipotoxicity, has been recognized as a major risk factor for both pathological conditions. Lipotoxicity can lead to inflammation, insulin resistance, oxidative stress, ceramide and amyloid accumulation, endoplasmic reticulum stress, ferroptosis, and autophagy, which are shared biological events in the pathogenesis of T2D and AD. In the current review, we try to provide a critical and comprehensive view of the common molecular pathways activated by lipotoxicity in T2D and AD, attempting to summarize how these mechanisms can drive future research and open the way to new therapeutic perspectives.

Evaluation of a digital tool supporting therapeutic decision making for the personalized management of patients with type 2 diabetes not treated with insulin: A pilot study.

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.

Very low-calorie ketogenic diet rapidly augments testosterone levels in non-diabetic obese subjects.

BACKGROUND: 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 characterised by low testosterone levels and subnormal luteinising hormone (LH) levels. AIM: To evaluate the early effects of VLCKD on serum total testosterone (TT) levels in non-diabetic obese patients. METHODS: Twenty-two obese male patients (mean age 39.3 ± 11.7 years, mean body mass index (BMI) 38.2 ± 6.4 kg/m2 ) were enrolled and treated for 28 days with VLCKD. Anthropometric and hormonal variables were assessed before, during and after diet intervention. RESULTS: After 7 and 28 days on a VLCKD, a significant and persistent reduction in body weight, BMI, fat mass, blood glucose, insulin and homeostasis model assessment 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 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. CONCLUSIONS: 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.

Glucometabolic outcomes of GLP-1 receptor agonist-based therapies in patients with type 2 diabetes: a systematic review and network meta-analysis.

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 (τ2) 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.

Polybrominated Diphenyl Ethers (PBDEs) and Human Health: Effects on Metabolism, Diabetes and Cancer.

There is increasing evidence of the role of endocrine disruptors (EDs) derived from commonly employed compounds for manufacturing and processing in altering hormonal signaling and function. Due to their prolonged half-life and persistence, EDs can usually be found not only in industrial products but also in households and in the environment, creating the premises for long-lasting exposure. Polybrominated diphenyl ethers (PBDEs) are common EDs used in industrial products such as flame retardants, and recent studies are increasingly showing that they may interfere with both metabolic and oncogenic pathways. In this article, a multidisciplinary panel of experts of the Italian Association of Medical Diabetologists (AMD), the Italian Society of Diabetology (SID), the Italian Association of Medical Oncology (AIOM), the Italian Society of Endocrinology (SIE) and the Italian Society of Pharmacology (SIF) provides a review on the potential role of PBDEs in human health and disease, exploring both molecular and clinical aspects and focusing on metabolic and oncogenic pathways.