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Background: The Italian population’s habits changed dramatically during the “COVID- 19 lockdown” due to physical distancing and self-isolation. Moreover, medical consultations of patients with chronic diseases, such as type 2 diabetes (T2D), were suspended or postponed, unless urgent or semi-urgent, for several consecutive months. Thus, it is expected that the lockdown could have affected glucometabolic control in T2D. Purpose: The aim of the study was to assess changes in glucometabolic control in a cohort of T2D patients before (T1) and after (T2) the COVID-19 lockdown (March-May 2020). Methods: The study was approved by the Ethics Committee of the University of Bari, and all patients provided informed written consent to participate. Medical history, complete physical examination, and laboratory assessment were conducted as real-life clinical practice. Changes in clinical and laboratory variables between T1 and T2 were calculated. Results: In detail, 13 patients were on metformin as monotherapy, 36 on GLP-1RA, 12 on sodiumglucose transporter 2 inhibitors (SGLT-2i), and 2 on dipeptidyl-peptidase 4 inhibitors (DPP4i). The mean age was 65.3 years (43-83). Study participants were mainly men (73%). The body weight (BW) ranged from 56 to 145 kg, and the waist circumference ranged from 88 to 146 cm. The mean HbA1c was 51.0 mmol/mol. At T2, no statistically significant changes were observed from baseline except for BW [-1.6 (-2.60 to -0.62)] and HbA1c [-2.90 (-4.69; -1.12)]. Conclusion: We evaluated the effects of the COVID-19 lockdown on glucometabolic control in patients with background well-controlled T2D. We found that the lockdown had no adverse effects on metabolic profile regardless of background clinical characteristics and antihyperglycemic management. Despite limitations due to the nature of this study (sample size, retrospective observation, lack of data on lifestyle changes in our patients' everyday lives), T2D patients managed in our Diabetes Centers faced the lockdown-related restrictions without any detrimental consequence.

Expression of LPAR1-5 mRNA levels in peritumoral and HCC cell lines (S1); Cell cycle analysis of LPAR6-knocked-down cells versus controls (S2); Absence of apoptosis in stably LPAR6-knocked-down cells (S3); LPAR6 knockdown impairs HCC migration and actin organization but not cells adhesion (S4); Ectopic expression of LPAR6 in human hepatocarcinoma cell line HLE (S5); LPAR6 knockdown affects the gene expression profile in HCC cells (S6); The PIM3 inhibitor, SGI-1776 decreases tumor growth in vivo and in vitro (S7).

List of genes up-regulated in LPAR6 knocked down cells.

Description of additional methods and procedures used in the study.

Legends for Supplementary Tables S1-S3 and Supplementary Figures S1-S7.

We evaluated the clinical impact, in daily clinical practice, of sodium-glucose co-transporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1RA) therapies in patients with type 2 diabetes. Data from 500 unselected consecutive patients were retrospectively analyzed. Only those with a full assessment at baseline (T0) and after 3 (T3), 6 (T6), and 12 (T12) months of treatment with SGLT2i or GLP1RA were included in the study (n = 167). At baseline, patients had a high mean body weight (BW), abdominal circumference (AC), body mass index (BMI), and HOMA index. Despite normal C-peptide values, 39 patients were being treated with insulin (up to 120 IU/day). During therapy, a progressive improvement in BW, BMI, and AC was observed with both the molecules. Fasting glucose and glycated Hb decrease was already significant at T3 in all patients, while the HOMA index selectively improved with SGLT2i therapy. Renal function parameters remained stable regardless of the drug used. Finally, SGLT2i reduced serum uric acid and improved the lipid profile, while GLP1RA reduced serum levels of liver enzymes. Both the therapeutic regimens allowed a significant reduction or complete suspension of unnecessary insulin therapies. Our real life data confirm the results obtained from randomized clinical trials and should be taken as a warning against inappropriate use of insulin in patients with preserved β-cell function.

Introduction New antidiabetic drugs have simplified treatment regimens in patients with type-2 diabetes (T2D). More importantly, they have proven to reduce cardiovascular risk by lowering insulin-resistance, blood pressure and body weight, in addition to avoiding inappropriate insulin therapy, responsible for hypoglycemic episodes and weight gain. In this context, accurate assessment of the metabolic status of T2D patients becomes essential. The C-peptide assay is a simple but often overlooked test that can provide a fundamental contribution to the correct disease classification and optimal therapeutic management of diabetic patients. Clinical case We report the case of a 72-year-old patient, treated with insulin for 26 years after a diagnosis of type-1 diabetes (T1D), resulting in inadequate glycemia control and a severe evolution of cardiovascular complications. After an accurate evaluation of the clinical history, phenotype and laboratory data, including the determination of C-peptide serum levels, a diagnosis was made of T2D not T1D. Considering the patient's very high cardiovascular risk and dysmetabolic profile, insulin therapy was discontinued and more appropriate therapy with dulaglutide and metformin was instituted. These overall therapeutic modifications yielded remarkable clinical advantages in terms of the glycometabolic profile, weight reduction, abdominal circumference and body mass index decrease, as well as a better quality of life, with complete resolution of the dangerous hypoglycemic episodes. Conclusion In the era of new cardioprotective antidiabetic drugs, we believe the importance of the C-peptide assay should be re-evaluated in order to avoid misdiagnosis and to improve the therapeutic approach to T2D.

Despite the increasing incidence of hepatocellular carcinoma (HCC) worldwide, current pharmacological treatments are still unsatisfactory. We have previously shown that lysophosphatidic acid receptor 6 (LPAR6) supports HCC growth and that 9-xanthenylacetic acid (XAA) acts as an LPAR6 antagonist inhibiting HCC growth without toxicity. Here, we synthesized four novel XAA derivatives, (±)-2-(9H-xanthen-9-yl)propanoic acid (compound 4 - MC9), (±)-2-(9H-xanthen-9-yl)butanoic acid (compound 5 - MC6), (±)-2-(9H-xanthen-9-yl)hexanoic acid (compound 7 - MC11), and (±)-2-(9H-xanthen-9-yl)octanoic acid (compound 8 - MC12, sodium salt) by introducing alkyl groups of increasing length at the acetic α-carbon atom. Two of these compounds were characterized by X-ray powder diffraction and quantum mechanical calculations, while molecular docking simulations suggested their enantioselectivity for LPAR6. Biological data showed anti-HCC activity for all XAA derivatives, with the maximum effect observed for MC11. Our findings support the view that increasing the length of the alkyl group improves the inhibitory action of XAA and that enantioselectivity can be exploited for designing novel and more effective XAA-based LPAR6 antagonists.

Background Metabolic syndrome (MetS) is a clinical condition potentially promoting the development of atherosclerotic disease. To date, the clinical impact of elevated serum homocysteine (Hcy) levels in MetS is still under discussion. The aim of this cross sectional study was to evaluate the relationship between MetS and hyperhomocysteinemia and the potential role of Hcy in the pathogenesis of atherosclerotic complications of MetS. Methods We recruited 300 outpatients with MetS. All patients underwent a medical history collection, physical examination, blood sampling and carotid ultrasound echo-color Doppler. According to Hcy levels, MetS patients were divided into two groups: “normal” ( Results Patients with high Hcy were predominantly male and slightly older than group 1 patients. Smokers and non-smokers exhibited similar Hcy levels, nor was a statistical relationship between pack-years and Hcy observed. Group 2 showed lower levels of folic acid, vitamin D, high density lipoprotein (HDL)-cholesterol and glomerular filtration rate (e-GFR) than group 1, but higher levels of C-peptide, uric acid and triglycerides. In all patients, Hcy was positively correlated with C-peptide and uric acid and negatively with folic acid and e-GFR. Intima-media thickness (IMT) and carotid stenosis degree were significantly higher in patients with high Hcy and a positive relationship between Hcy and both IMT and carotid stenosis was detected in all patients. Finally, Hcy atherogenic effects were independent of other well-known atherosclerosis risk factors. Conclusions Our results highlight a link between MetS and hyperhomocysteinemia and a direct effect of Hcy on atherogenic process during MetS. Early correction of folic acid levels may contribute to prevent cardiovascular complications in MetS patients.

Background A close relationship between Metabolic Syndrome (MetS) and Chronic Obstructive Pulmonary Disease (COPD) has been described, but the exact nature of this link remains unclear. Current epidemiological data refer exclusively to the MetS prevalence among patients with COPD and data about the prevalence of COPD in MetS patients are still unavailable. Aim of the study To analyse and compare risk factors, clinical and metabolic characteristics, as well as the main respiratory function parameters, among patients affected by MetS, COPD or both diseases. Patients We recruited 59 outpatients with MetS and 76 outpatients with COPD. After medical history collection, physical examination, blood sampling for routine analysis, spirometric evaluation, they were subdivided into MetS (n = 46), MetS+COPD (n = 60), COPD (n = 29). Results A MetS diagnosis was assigned to 62% of COPD patients recruited in the COPD Outpatients Clinic of the Pneumology Department, while the COPD prevalence in MetS patients enrolled in the Internal Medicine Metabolic Disorders Outpatients Clinic was 22%. More than 60% of subjects enrolled in each Department were unaware that they suffered from an additional disease. MetS+COPD patients exhibited significantly higher C-peptide levels. We also found a positive relation between C-peptide and pack-years in all subjects and a negative correlation between C-peptide and vitamin D only in current smokers. Finally, a negative association emerged between smoking and vitamin D. Conclusions We have estimated, for the first time, the COPD prevalence in MetS and suggest a potential role of smoking in inducing insulin resistance. Moreover, a direct effect of smoking on vitamin D levels is proposed as a novel mechanism, which may account for both insulin resistance and COPD development.

Background: MLN2480 is an orally administered, investigational small molecule pan-RAF kinase inhibitor currently in Phase 1 clinical development. Here, we built integrated PK/PD/efficacy models to understand the relationship between MAPK pathway inhibition and efficacy as well as the effect of dose schedule in two melanoma xenograft models, A375 and SKMEL-2. Materials and Methods: We fit a one-compartment PK model to MLN2480 plasma concentration time profiles following a single dose in mice. Tumor pERK levels in xenograft-bearing mice, measured by Western blotting following single (A375) or multiple (SKMEL-2) doses of MLN2480 were fit to a direct or indirect inhibitory Emax model, respectively, to describe the PK/PD relationship between the plasma concentration and %pERK inhibition. Activity in each xenograft was evaluated as the percent growth rate inhibition (%GRI), the percent change between treated and control exponential tumor volume growth rates over the treatment cycle. To connect PK, PD, and efficacy for each xenograft, we simulated the PK and PD profiles over the treatment cycle for each dose group, and estimated the averages of plasma concentration (Cavg) and %pERK inhibition, respectively, using non-compartmental analysis. Results: From a multiple linear regression, schedule-related parameters are not predictive for drug effect demonstrating schedule-independent activity. For a variety of dose schedules, the relationship between total dose and SKMEL-2 xenograft growth rate is approximately linear (R = 0.90, p < 0.0001). A sigmoidal PK/efficacy model captures the relationship between Cavg and %GRI for both xenografts. A375 exhibits greater sensitivity than SKMEL-2 to the same Cavg of MLN2480, with the models predicting tumor regression (Emax = 172% GRI) and stasis (Emax = 102% GRI) as the maximal effects, respectively. Both xenografts have steep, sigmoidal PD/efficacy relationships, which show the same pERK inhibition is associated with greater %GRI in A375, and %GRI saturates with residual pERK (EC90 = 38% in A375, 22% in SKMEL-2). Conclusions: Integrated PK/PD and PK/efficacy modeling for MLN2480 response in A375 and SKMEL-2 xenografts shows a strong relationship between pERK inhibition and preclinical activity, and that maximal effect is achieved without complete inhibition of the MAPK pathway. The findings of pERK inhibition-dependent but not schedule-dependent activity provide translational guidance to clinical dose and schedule selection.