To assess the efficacy of a four-drug regimen (POLYCHEM) vs. standard diabetes care (SDC) in inducing remission in patients with newly diagnosed type 2 diabetes. A multicenter, open-label, pragmatic, phase III, randomized clinical trial (NCT04271189) was conducted in 6 Italian Diabetes Outpatient Clinics. Patients were randomized (visit 1) to receive POLYCHEM or SDC for 16 weeks, after which, if there was regression of diabetic hyperglycemia (visit 2), drug therapy was suspended. The primary endpoint was remission (HbA1c < 6.5

BACKGROUND:There is uncertainty regarding the association between continuous glucose monitoring (CGM), derived glycemic metrics, and metabolic dysfunction-associated steatotic liver disease (MASLD) in individuals with type 1 diabetes (T1D). METHODS:We consecutively enrolled 262 adult individuals with established T1D undergoing vibration-controlled transient elastography (VCTE) with liver stiffness measurement (LSM) and controlled attenuation parameter (CAP). All participants underwent CGM. MASLD was defined as CAP ≥248 dB/m and the presence of at least one cardiometabolic risk factor. Significant liver fibrosis was defined as LSM ≥8 kPa. RESULTS:Participants had a mean age of 54±13 years, a mean body mass index (BMI) of 25.8 ± 5.6 kg/m2 and a mean HbA1c of 7.7 ± 1.4 %. The prevalence of MASLD and significant liver fibrosis was 35.1 % (n = 92) and 4.6 % (n = 12), respectively. Using quantile regression analysis, time above range 180-250 mg/dl (TAR1) was significantly associated with increased CAP values (coefficient: 1.037; 95 % confidence interval [0.216;1.858]; P = 0.013). This association remained significant even after adjusting for age, sex, BMI, HbA1c, and total daily insulin dose. Other variables independently associated with CAP were older age, male sex, BMI, and total daily insulin dose. Using a random forest regression model, BMI was found to be the most important factor, followed by age, total daily insulin dose, and TAR1. CONCLUSIONS:TAR1 was independently associated with increased CAP values, even after adjustment for age, BMI, sex, HbA1c, and total daily insulin dose, suggesting a potential role for glycemic variability in hepatic fat accumulation in adults with T1D.

BACKGROUND AND AIMS:Total pancreatectomy with islet autotransplantation (TPIAT) is a surgical option to mitigate the risk of anastomotic complications and preserve endogenous insulin secretion in patients undergoing pancreaticoduodenectomy. However, the utility of continuous glucose monitoring (CGM) in assessing islet graft performance remains poorly characterized. Thereby, the aim of this study was to investigate the relationship between CGM-derived glycemic metrics and islet function following TPIAT. MATERIALS AND METHODS:Ten patients with pancreatic neoplasms (male/female 5/5, median age 60 [IQR 55-68] years) underwent TPIAT between September 2023 and March 2025 at the Verona University Hospital, receiving a median islet dose of 1912 IEQ/kg [IQR 1724-3074]. CGM data were collected at 3 (n = 10), 6 (n = 8), and 12 (n = 7) months post-transplantation. Islet metabolic function was assessed using Igls criteria and BETA-2 score. CGM metrics were compared across Igls-defined graft function categories and correlated with BETA-2 scores. RESULTS:Of 25 total assessments, islet function was classified as optimal (n = 10), good (n = 6), marginal (n = 8), or failure (n = 1). Median BETA-2 score decreased significantly across these groups (19.4, 13.6, 5.3, 1.4, respectively; P < 0.001). Optimal function was associated with superior glycemic control (time in range, TIR: 97.0%; time in tight range, TITR: 86.5%; time above range, TAR: 1.5%) and lower glycemic variability (coefficient of variation, CV: 20.5%; glycemia risk index, GRI: 44.0), compared with good and marginal groups (all P < 0.01). These same CGM metrics were significantly correlated with both Igls classification and BETA-2 score (all P < 0.015). CONCLUSIONS:CGM parameters reflect islet graft performance following TPIAT and are strongly correlated with established markers of β-cell function. Metrics such as TIR, TITR, TAR, CV, and GRI may serve as practical and sensitive tools for post-transplant metabolic surveillance in endocrine clinical practice.

Aims: According to the 2023 International Consensus, glucose metrics derived from two-week-long continuous glucose monitoring (CGM) can be extrapolated up to 90 days before. However, no studies have focused on adults with type 1 diabetes (T1D) on multiple daily injections (MDIs) and with second-generation intermittently scanned CGM (isCGM) sensors in a real-world setting. Methods: This real-world, retrospective study included 539 90-day isCGM data from 367 adults with T1D on MDI therapy. For each sensor metric, the coefficients of determination ( R2) were computed for sampling periods from 2 to 12 weeks versus the whole 90-day interval. Correlations were considered strong for R2 ≥0.88. Results: The two-week sampling period displayed strong correlations for time in range (TIR, 70-180 mg/dl; R2 = 0.89) and above range (TAR, >180 mg/dl; R2 = 0.88). The four-week sampling period showed additional strong correlations for time in tight range (TITR, 70-140 mg/dl; R2 = 0.92), for the coefficient of variation (CV; R2 = 0.88), and for the glycemia risk index (GRI; R2 = 0.92). The six-week sampling period displayed an additional strong correlation for time below range (TBR, <70 mg/dl; R2 = 0.90). After stratification by clinical variables, lower R2 values were found for older age quartiles (>40 years), higher CV (>36%), lower sensor use (≤94%), and higher HbA1c (>7.5%). Conclusion: In patients with T1D on MDI, two- to six-week intervals of isCGM use can provide clinically useful estimates of TIR, TAR, TITR, TBR, CV, and GRI, which can be extrapolated to longer (up to 90 days) time intervals. Longer intervals might be needed in case of older age, higher glucose variability, lower sensor use, and higher HbA1c.

BACKGROUND AND AIM:We assessed the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) and significant liver fibrosis in adults with type 1 diabetes mellitus (T1DM) and the association of MASLD with insulin sensitivity and continuous glucose monitoring metrics. METHODS:We consecutively enrolled 198 adults with T1DM undergoing vibration-controlled transient elastography with liver stiffness measurement (LSM) and controlled attenuation parameter (CAP). All participants had a continuous glucose monitoring (CGM) device. Insulin sensitivity was evaluated by estimated glucose disposal rate (eGDR). MASLD was defined as CAP ≥ 248 db/m and the presence of at least one cardiometabolic risk factor. Significant liver fibrosis was defined as LSM ≥ 7 kPa. RESULTS:Patients had a mean age of 56 years, mean BMI of 26.0 ± 5.9 kg/m2, and mean eGDR of 7.1 ± 2.3 mg/kg/min. 73 (37%) patients had MASLD (using a CAP threshold of 274 dB/m), 16 (8.1%) of whom had significant liver fibrosis. MASLD was associated with a significantly lower eGDR (beta coefficient = -0.367, 95% confidence interval -0.472 to -0.261; p < 0.001). This association remained significant, even after adjustment for age, sex, body mass index, plasma triglycerides, diabetes duration, daily insulin dose, time above the range of glucose levels, LSM and chronic kidney disease. No association was observed between MASLD and CGM-derived metrics. These results were not different when we used a CAP threshold of 274 dB/m for diagnosing MASLD. CONCLUSION:In T1DM, MASLD was inversely associated with eGDR and biomarkers of insulin resistance but not with CGM-derived metrics.

Objective: to assess the incremental efficacy of a four-drug (POLYCHEM: metformin/pioglitazone/sitagliptin/empagliflozin) regimen vs standard diabetes care (SDC) in inducing remission in patients with newly diagnosed type 2 diabetes. Research Design and Methods: A multicenter, open-label, pragmatic, phase III, randomized clinical trial was conducted in 6 Italian Diabetes Outpatient Clinics. Major inclusion criteria were age 35-75 years, HbA1c <10% (97 mmol/mol), fasting C-peptide >0.3 nmol/l, GAD-antibody negative. Patients were randomized (visit 1) to receive POLYCHEM or SDC for 16 weeks, after which, if there was regression of diabetic hyperglycemia (visit 2), drug therapy was suspended. The primary endpoint was remission (HbA1c < 6.5 %; 48 mmol/mol) assessed at least 12 weeks (visit 3) after ceasing any glucose-lowering pharmacotherapy. Results: 108 patients (80% males, age: 58±9 yrs), were enrolled in the study, of whom 60 were randomized to POLYCHEM and 48 to SDC treatment. After 16 weeks, 54 (90.0%) and 37 (77.1%) patients achieved regression of diabetic hyperglycemia in the POLYCHEM and SDC arm, respectively (p=0.002). At visit 3, 23 (38.3%) and 21 (43.8%) patients achieved diabetes remission in the POLYCHEM and SDC arm, respectively (p=0.59). The difference between the upper 95% CI in POLYCHEM (50.9%) and the lower 95% CI in SDC (30.4%) of diabetes remission was 20.5%. Conclusion: A four-drug regimen with minimal to null weight-lowering effect is not superior to current SDC in achieving remission in patients with newly diagnosed type 2 diabetes. If a superiority of POLYCHEM over SDC exists, it is expected to be less than 21%. ### Competing Interest Statement The authors declare the following financial interests/personal relationships, which may be considered as potential competing interests: A.D.C. has participated on speaker's bureaus for Novo Nordisk, Lilly Italia, Boehringer Ingelheim, AstraZeneca spa. P.D.B has participated on speaker's bureaus for Novo Nordisk, Lilly Italia, Boehringer Ingelheim, AstraZeneca spa. Sanofi Italia, Theras Italia, Bayer Italia, Glaxo Italia, Amgen, and advisory board for Novo Nordisk, Eli Lilly, Boehringeh-Ingelheim, Astra Zeneca, Sanofi Italia, Amgen Italia, Bayer Italia. R.C.B received speaker fees from Novo Nordisk, Eli Lilly, Boehringer-Ingelheim, Astra-Zeneca and advisory board fees from Novo Nordisk, Eli Lilly, Boehringer-Ingelheim, and Vertex. M.T. received speaker fees from Abbott and Theros. R.A., G.M., G.D., E.B., M.G., G.P., A.C., S.F., M.A., A.V., V.M, V.S., G.C., F.F, M.M., U.P., C.C. have nothing to declare. ### Clinical Trial NCT04271189 ### Funding Statement This study was funded by the Italian Ministry of Health in the framework of the call 'Bando Ricerca Finalizzata 2016, Project Code: RF-2016-02363327' ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the local Ethics Committee Comitato Etico dell'Area Vasta Emilia Nord with EUDRACT registration no. 2018-000833-12 I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present studyare not publicly available but are available from the corresponding author on reasonable request

BACKGROUND AND AIM:Bone as an endocrine organ regulates metabolic processes independently of mineral metabolism through the production/release of proteins collectively named 'osteokines'. Relevant connections were reported between the insulin/glucose system, calcification of the atherosclerotic plaque, and several osteokines. We aimed to test the hypothesis that the osteokine network could be involved in beta-cell function, insulin sensitivity, and vascular damage in a cohort of people with newly diagnosed type 2 diabetes (T2D). SUBJECTS AND METHODS:In 794 drug-naive, GADA-negative, newly-diagnosed T2D patients (mean ± SD age: 59 ± 9.8 years; BMI: 29.3 ± 5.3 kg/m2; HbA1c: 6.6 ± 1.3%) we assessed: plasma concentration of osteocalcin (OCN), osteopontin (OPN), RANKL, and its putative decoy receptor osteoprotegerin (OPG); insulin sensitivity (SI) by hyperinsulinemic euglycemic clamp; beta cell function (BCF), estimated by OGTT minimal modelling and expressed as derivative (DC) and proportional (PC) control. Echo-doppler of carotid and lower limb arteries were also performed in 708 and 701 subjects, respectively. RESULTS:OCN, RANKL and OPG were significantly associated with PC (p < 0.02); OCN was positively related to DC (p = 0.018). OPG was associated with lower IS (p < 0.001). Finally, the higher RANKL levels, the greater was the severity of atherosclerosis in common carotid artery (p < 0.001). Increased OPG and OPN concentrations were related to subclinical atherosclerosis in peripheral arteries of lower limbs (p = 0.023 and p = 0.047, respectively). CONCLUSION:These data suggest that, in patients with newly diagnosed T2D, the osteokine network crosstalks with the glucose/insulin system and may play a role in modulating the atherosclerotic process.

The effect of plasma hepcidin concentrations on the long-term risk of developing adverse cardiovascular outcomes in people with type 2 diabetes mellitus (T2DM) is unclear. We followed for a median of 55.6 months 213 outpatients with established T2DM (45.5

Cerebrovascular accidents (CVA) represent a major complication in diabetes (DM). Real-life evidence as to whether modern management of CVA and DM have softened this relationship is limited. Therefore, we estimated prevalence and impact of DM on in-hospital survival and complications in a contemporary cohort of subjects with CVA. We retrospectively evaluated the records of 937 patients admitted for CVA at the Stroke Unit of Verona University Hospital during a 3-year period. Pre-existing or de novo DM was ascertained by prior diagnosis, glucose-lowering therapy at admission/discharge or admittance plasma glucose ≥ 200 mg/dL. Multiple regressions were applied to test DM as predictor of in-hospital mortality, complications (composite of infections, cardio- and cerebrovascular complications, major bleeding and pulmonary complications), duration and costs of hospitalization. Diabetes prevalence was 21

Background: Currently, it remains uncertain whether metabolic dysfunction-associated fatty liver disease (MAFLD) is associated with increased risk of supraventricular and ventricular tachyarrhythmias in people with type 2 diabetes mellitus (T2DM).Methods: We retrospectively examined the data of 367 ambulatory patients with T2DM who underwent 24 -hour Holter monitoring between 2015 and 2022 for clinical indications, and who did not have pre-existing permanent atrial fibrillation (AF), kidney failure or known liver diseases. Paroxysmal supraventricular tachy-cardia (PSVT), paroxysmal AF and episodes of ventricular tachyarrhythmias (i.e., presence of ventricular tachycardia, >30 premature ventricular complexes per hour, or both) were recorded. The presence and severity of MAFLD was diagnosed by ultrasonography and fibrosis-4 (FIB-4) index.Results: Patients with T2DM who had MAFLD (n = 238) had a significantly greater prevalence of PSVT (51.7% vs. 38.8%), paroxysmal AF (6.3% vs. 1.3%) and combined ventricular tachyarrhythmias (31.9% vs. 20.2%) com-pared to their counterparts without MAFLD (n = 129). MAFLD was significantly associated with a greater than two-fold risk of having PSVT (adjusted-odds ratio [OR] 2.04, 95% confidence interval 1.04-4.00) or ven-tricular tachyarrhythmias (adjusted-OR 2.44, 95%CI 1.16-5.11), after adjusting for age, sex, smoking, alcohol intake, diabetes-related factors, comorbidities, medication use and left ventricular ejection fraction on echo-cardiography. The risk of supraventricular and ventricular tachyarrhythmias was even greater amongst patients with MAFLD and FIB-4 >= 1.3.Conclusions: In ambulatory patients with T2DM, the presence and severity of MAFLD was strongly associated with an increased risk of supraventricular and ventricular arrhythmias on 24-hour Holter monitoring.(c) 2022 Elsevier Masson SAS. All rights reserved.

BACKGROUND:Currently, there is no information about the association between circulating levels of ferritin and hepcidin and liver fibrosis in patients with type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD).METHODS:We enrolled 153 patients with T2DM with no known liver diseases, who consecutively attended our diabetes outpatient service and who underwent liver ultrasonography and liver stiffness measurement (LSM) by vibration-controlled transient elastography (Fibroscan® for the non-invasive assessment of liver fibrosis). Plasma ferritin and hepcidin concentrations were measured with an electrochemiluminescence immunoassay and mass spectrometry-based assay, respectively.RESULTS:After stratification of patients by LSM tertiles [1st tertile median LSM: 3.6 (interquartile range: 3.3-4.0) kPa, 2nd tertile: 5.3 (4.9-5.9) kPa and 3rd tertile: 7.9 (6.7-9.4) kPa], we found that plasma ferritin and hepcidin concentrations increased across LSM tertiles [median ferritin: 68.7 (interquartile range: 25.1-147) vs. 85.8 (48.3-139) vs. 111 (59.3-203) μg/L, p = 0.021; median hepcidin: 2.5 (1.1-5.2) vs. 4.4 (2.5-7.3) vs. 4.1 (1.9-6.8) nmol/L, p = 0.032]. After adjustment for age, sex, diabetes duration, waist circumference, haemoglobin A1c, HOMA-insulin resistance score, triglycerides, haemoglobin, presence of hepatic steatosis on ultrasonography and patatin-like phospholipase domain-containing-3 (PNPLA3) rs738409 genetic variant, higher plasma ferritin levels were associated with greater LSM values (adjusted-odds ratio 2.10, 95% confidence interval 1.23-3.57, p = 0.005). Higher plasma hepcidin levels were also associated with greater LSM values (adjusted-odds ratio 1.90, 95% confidence interval 1.15-3.13, p = 0.013).CONCLUSIONS:Higher levels of plasma ferritin and hepcidin were associated with greater NAFLD-related liver fibrosis (assessed by LSM) in patients with T2DM, even after adjustment for established cardiometabolic risk factors, diabetes-related variables and other potential confounders.

Aim: To evaluate the relationship of genetic variability of adiponectin (ADIPOQ), leptin (LEP) and leptin receptor (LEPR) genes with glucose-insulin system and markers of subclinical atherosclerosis (ATS) in patients with newly diagnosed type 2 diabetes. Materials and methods: In 794 subjects we performed: 1) euglycemic hyperinsulinemic clamp to assess insulin sensitivity; 2) mathematical modelling of a 5h-OGTT to estimate ss-cell function; 3) resting ECG; 4) carotid artery and lower limb artery ecodoppler sonography to identify ATS; 5) genotyping of tag-SNPs within ADIPOQ, LEP and LEPR gene. Results: Regression analyses showed: 1) adiponectin levels were negatively associated with BMI, waist-to-hip ratio and triglycerides and positively with HDL and insulin sensitivity (p-all<0.03); 2) leptin levels were positively associated with BMI, HDL-cholesterol and plasma triglycerides and negatively with insulin sensitivity (p- all<0.001). Two SNPs (rs1501299 and rs2241767) within ADIPOQ gene were associated with circulating levels of adiponectin. The ADIPOQ-GAACA haplotype was associated with plasma adiponectin (p=0.034; ss=-0.24), ECG abnormalities ( p=0.012; OR=2.76), carotid ATS (p= 0.025; OR=2.00) and peripheral limb artery ATS ( p=0.032; OR=1.90). The LEP-CTA haplotype showed an association with ischemic ECG abnormalities (p=0.017; OR= 2.24). Finally, LEPR-GAACGG was associated with circulating leptin (p=0.005; ss=-0.31) and worst ss-cell function ( p=0.023; ss=-15.10). Omnibus haplotype analysis showed that ADIPOQ haplotypes were associated with levels of adiponectin and common carotid artery ATS, LEP with peripheral limb artery ATS, whereas LEPR haplotypes influenced circulating levels of leptin. Conclusions: Results of this study reinforce knowledge on adipokines' role in regulating glucose metabolism; in particular highlighted the potential atherogenic role of leptin and the anti atherogenic role of adiponectin.

Currently, there is little and inconsistent evidence regarding the possible adverse effects of circulating levels of non-esterified fatty acids (NEFA) on kidney function decline in patients with type 2 diabetes mellitus (T2DM). We followed for a median of 4.6 years 85 post-menopausal women with non-insulin-treated T2DM and preserved kidney function at baseline. Serum NEFA concentrations were measured using an enzymatic colorimetric method. Glomerular filtration rate (eGFR) was estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Enrolled patients had a baseline mean eGFRCKD-EPI of 83 ± 12 mL/min/1.73 m2 and a median serum NEFA concentration of 662 uEq/L (interquartile range 524–842 uEq/L). During the follow-up period, 13 patients developed kidney function decline at follow-up (defined as an eGFRCKD-EPI decline ≥ 30