AIMS: To investigate the independent association between long-term glycemic variability, measured as the coefficient of variation (CV) of HbA1c, and the presence of diabetic retinopathy (DR) in a cohort of adults with di...AIMS: To investigate the independent association between long-term glycemic variability, measured as the coefficient of variation (CV) of HbA1c, and the presence of diabetic retinopathy (DR) in a cohort of adults with diabetes within a systematic eye screening program. METHODS: This study screened 379 adults with type 1 and type 2 diabetes. Long-term glycemic variability was calculated as the CV of serial HbA measurements. DR was assessed via dilated fundus photography. The association between HbA CV and DR was analyzed using multivariable logistic regression adjusting for confounders. RESULTS: DR incidence of 12.4%, mostly mild non-proliferative. The median HbA CV was 7.0% (53 mmol/mol). In unadjusted bivariate analysis, the incidence of mild DR was higher in the low- glycemic variability group (CV < 5%) compared to the high- glycemic variability group. However, the multivariable logistic regression analysis revealed that higher HbA CV was independently associated with the presence of DR (β = 0.643, P = 0.042), alongside diabetes duration (P < 0.001) and age (P < 0.001). CONCLUSIONS: In conclusion, in a cohort of individuals with both type 1 and type 2 diabetes and a low incidence of DR, long-term glycemic variability, estimated as HbA CV, was independently associated with an increased risk of this complication.
Type 2 diabetes mellitus develops when insulin resistance raises insulin demand and pancreatic beta cells fail to sustain insulin supply. Genome-wide association studies support a polygenic architecture and enrich for lo...Type 2 diabetes mellitus develops when insulin resistance raises insulin demand and pancreatic beta cells fail to sustain insulin supply. Genome-wide association studies support a polygenic architecture and enrich for loci that affect beta cell stimulus secretion coupling and secretory stress responses. Polygenic risk scores summarize liability across many variants and guide genetic stratification in cohort studies. This review uses TCF7L2 and CDKAL1 as two mechanistically interpretable loci to connect inherited variation to measurable physiology. TCF7L2 risk alleles reduce incretin potentiation of insulin secretion after oral nutrient exposure, which blunts early postprandial insulin release. CDKAL1 risk alleles impair the ms2 modification of t6A37 at position 37 of tRNALys(UUU), which increases proinsulin mistranslation and raises endoplasmic reticulum stress in beta cells. These defects converge during repeated postprandial cycles that require rapid insulin synthesis and secretion. Reduced incretin signaling prolongs glycemic excursions and increases secretory workload, which intensifies folding stress when translation quality control is limited. The model predicts earlier postprandial dysglycemia under obesity or aging related insulin resistance and faster loss of beta cell reserve when both pathways constrain supply. The framework supports mechanistic phenotyping and pharmacogenetic testing within a broader polygenic risk setting.
Giaccari A, Gliozzo G, Ciccarelli G
… +12 more, Di Giuseppe G, Castellano C, Cum S, Delle Monache L, Gallo M, Lastretti M, Medea G, Monesi M, Napoli R, Pintaudi B, Succurro E, Turchetti G
BACKGROUND AND AIMS: Although continuous glucose monitoring (CGM) devices are now standard of care among Type 1 diabetes patients, they are still relatively underutilized in Type 2 diabetes (T2D), particularly in those p...BACKGROUND AND AIMS: Although continuous glucose monitoring (CGM) devices are now standard of care among Type 1 diabetes patients, they are still relatively underutilized in Type 2 diabetes (T2D), particularly in those patients not treated with insulin. Widespread adoption continues to be hindered by a combination of factors. Chief among these is the scarcity of long-term, large-scale clinical trials demonstrating the benefits of the use of CGM in T2D. This meta-analysis aimed to address this gap by comparing CGM with self-blood glucose monitoring (SBMG), with primary outcomes of HbA1c and time in range (TIR) in insulin-treated and non-insulin-treated TD2 patients. METHODS AND RESULTS: Following the stringent rules mandated by our National Health Service (which requires a panel composed of all stakeholders involved in diabetes treatment, and includes PICO, GRADE, AGREE, and meta-analyses), we performed a systematic review of RCTs that enrolled two groups of individuals with T2D, those treated with insulin (including basal and basal-bolus regimens), and those receiving treatments other than insulin. All included trials compared CGM with structured blood glucose monitoring (SBGM) with glycated hemoglobin (HbA1c) as the main endpoint. Based on the strength and consistency of the evidence, the panel issued a strong recommendation in favor of CGM for individuals with T2D treated with insulin (including those on basal insulin alone) and for individuals with T2D not treated with insulin, particularly for those with glycated hemoglobin levels ≥ 7%. From a pharmacoeconomic perspective, outcomes were positive in both patient groups. CONCLUSION: CGM represents a clinically effective and cost-efficient approach to optimizing glycemic control in T2D, becoming mandatory among individuals on insulin therapy. Our findings support a shift in clinical practice toward the more widespread use of CGM in T2D, with regulatory frameworks and reimbursement policies needing to adapt accordingly.
AIMS: Evidence suggests that resistin, through its pro-inflammatory and pro-oxidative actions, may contribute to the development of cardiovascular and kidney diseases. Although resistin has been investigated in insulin-r...AIMS: Evidence suggests that resistin, through its pro-inflammatory and pro-oxidative actions, may contribute to the development of cardiovascular and kidney diseases. Although resistin has been investigated in insulin-resistant states, data on this cytokine in pediatric patients with type 1 diabetes mellitus (T1DM) remain scarce. This study aimed to examine the relationship between circulating resistin and oxidative stress biomarkers, as well as with urinary albumin excretion in children and adolescents with T1DM. METHODS: Serum resistin levels, metabolic control, lipid and redox biomarkers, including prooxidant-antioxidant balance (PAB), advanced oxidation protein products (AOPP), total sulfhydryl (SH) groups, superoxide dismutase (SOD) activity and total antioxidant status (TAS) were determined in 159 pediatric T1DM patients. RESULTS: The highest resistin tertile was characterized by the largest proportion of poorly controlled patients (P < 0.05). These patients also showed significantly elevated AOPP and SH-groups, while the patients in the lowest tertile exhibited significantly higher PAB. Resistin correlated positively with urinary albumin excretion, AOPP and hsCRP, and negatively with PAB (P < 0.05). Patients in the highest resistin tertile had a greater likelihood of early elevation of albumin excretion (OR = 2.27; 97% CI: 1.00-5.15; P = 0.05). This relationship remained significant after adjustment for demographic, lipid and redox parameters, but attenuated after adjustment for diabetes-related parameters. CONCLUSIONS: Elevated serum resistin concentrations in pediatric patients with T1DM were associated with suboptimal metabolic control, enhanced oxidative stress and an early increase in urinary albumin excretion rate. Further studies are needed to clarify the mechanisms through which resistin contributes to early kidney dysfunction in T1DM.
BACKGROUND: Immune checkpoint inhibitor (ICI)-induced diabetes is a rare endocrine immune-related adverse event, and long-term pancreatic magnetic resonance imaging (MRI) findings after disease onset have not been well c...BACKGROUND: Immune checkpoint inhibitor (ICI)-induced diabetes is a rare endocrine immune-related adverse event, and long-term pancreatic magnetic resonance imaging (MRI) findings after disease onset have not been well characterized. CASE PRESENTATION: An individual developed abrupt hyperglycemia during pembrolizumab therapy for recurrent renal cell carcinoma and subsequently required insulin therapy. Serum C-peptide rapidly declined to below the detection threshold, whereas pancreatic enzyme levels remained within normal limits throughout follow-up. MRI performed 1 day after diagnosis demonstrated diffuse high signal intensity on diffusion-weighted imaging (DWI) and reduced apparent diffusion coefficient (ADC) values throughout the pancreas. Serial imaging over 25 months showed progressive pancreatic atrophy, whereas the DWI/ADC features persisted. CONCLUSION: This case provides a new descriptive longitudinal radiological observation of persistent diffusion-related pancreatic MRI findings and progressive pancreatic atrophy after the onset of ICI-induced diabetes.
Type 2 Diabetes (T2D) is the most prevalent metabolic disorder globally, characterized by chronic hyperglycemia resulting from impaired insulin secretion, insulin resistance, or both. It primarily arises from disruptions...Type 2 Diabetes (T2D) is the most prevalent metabolic disorder globally, characterized by chronic hyperglycemia resulting from impaired insulin secretion, insulin resistance, or both. It primarily arises from disruptions in insulin action and secretion, often accompanied by impaired pancreatic function. T2D is closely associated with serious microvascular complications such as nephropathy, neuropathy, and retinopathy, as well as macrovascular conditions including hypertension, atherosclerosis, and stroke. Both genetic predisposition and environmental influences contribute to its onset and progression. Although genome-wide association studies have identified numerous loci associated with type 2 diabetes, these common genetic variants collectively explain only ~ 10-15% of the estimated heritability of the disease, indicating that the majority of genetic risk remains unexplained by known variants. Altered DNA methylation patterns have been identified in key tissues involved in T2D, including adipose tissue, liver, skeletal muscle, and pancreatic islets. These epigenetic alterations modulate the expression of genes governing insulin signaling and glucose metabolism. Notably, appropriate DNA methylation is essential for the development and functional integrity of pancreatic β-cells, and disruptions in these patterns can lead to impaired insulin synthesis and secretion. These modifications are dynamic and can be influenced by age, lifestyle, family history, and disease state, thereby linking environmental factors to long-term metabolic outcomes. Emerging evidence highlights that epigenetic modifications particularly changes in DNA methylation patterns in genes such as TXNIP, PPARGC1A, and ABCG1 may serve as early biomarkers of metabolic dysfunction, detectable even before clinical symptoms arise. These epigenetic signatures hold potential for early disease prediction, risk assessment, and monitoring of therapeutic response. Furthermore, since epigenetic changes are dynamic and reversible, they represent attractive therapeutic targets. Agents such as DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors may help restore normal gene expression and improve insulin sensitivity. Additionally, lifestyle interventions including diet, exercise, and weight management can beneficially modulate epigenetic marks, offering a complementary approach to pharmacological therapies.
AIM: This study investigated the effects of angiotensin (1-7) on diabetes-induced renal injury and renal miRNA levels in obese type 2 diabetic db/db mice. METHODS: Treatment with angiotensin (1-7) (500 μg/kg; i.p.) was s...AIM: This study investigated the effects of angiotensin (1-7) on diabetes-induced renal injury and renal miRNA levels in obese type 2 diabetic db/db mice. METHODS: Treatment with angiotensin (1-7) (500 μg/kg; i.p.) was started when the mice were 12 weeks old and given daily for four weeks. Renal function was assessed by measuring creatinine clearance and albumin excretion rate. The effect of diabetes and/or angiotensin (1-7) treatment on renal miR-29a-3p, miR-29a-5p, miR-155-5p, and miR-30 mRNA expression was studied using real-time PCR. Nephrin and podocin mRNA and protein expressions were studied using real-time PCR and Western blotting. RESULTS: At 16 weeks, diabetes caused a significant increase in albumin excretion rate, which was further increased with angiotensin (1-7) treatment. Diabetes and/or angiotensin (1-7) did not affect creatinine clearance. Real-time PCR showed no significant changes in expressions of miR-29a-3p, miR-29a-5p, miR-155-5p, or miR-30 in untreated or angiotensin (1-7)-treated control or db/db mice. There was no change in podocin mRNA or protein expression; however, nephrin mRNA expression was increased in angiotensin (1-7)-treated db/db mice. Nephrin protein expression was increased in kidney homogenates of db/db mice but was unaltered in renal membrane fractions. Treatment with angiotensin (1-7) did not affect nephrin or podocin protein expressions in homogenates or membrane fractions. CONCLUSIONS: The marked albuminuria observed at 16 weeks in db/db mice was independent of the expression of the studied miRNAs or nephrin and podocin expression. Angiotensin (1-7) was not protective as it further exacerbated albuminuria despite having no impact on nephrin and podocin renal protein expression.
AIMS: Rural, agro-pastoralist Maasai in East Africa exhibit low prevalence of diabetes, yet little is known about their physiological response to glucose loads and whether sex has an impact on glucose metabolism, includi...AIMS: Rural, agro-pastoralist Maasai in East Africa exhibit low prevalence of diabetes, yet little is known about their physiological response to glucose loads and whether sex has an impact on glucose metabolism, including incretin hormones. METHODS: We included 58 (29 men, 29 women) adult Maasai without diabetes living in rural Tanzania. Clinical background characteristics were measured, and they were exposed to an oral glucose tolerance test (OGTT) after an overnight fast. Plasma glucose, insulin/C-peptide, glucagon, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-1 (GLP-1) were analysed. RESULTS: Mean age was 34.8 (range 17-65) years, and mean body mass index (BMI) was 20.3 (range 14.0-30.9) kg/m with two individuals being overweight and 14 being underweight. Men had a higher mean fasting glucose concentration (5.2 vs. 4.9 mmol/L, p = 0.031), while women exhibited a higher OGTT-derived mean GLP-1 concentration at 2-h (8.5 vs. 5.1 pmol/L, p = 0.005). Total area-under-the-curve (tAUC) for GLP-1 was higher in women compared to men (1336 vs. 870 pmol x min, p = 0.011). Sex- and BMI-adjusted regression analyses for tAUC showed higher values of insulin, C-peptide and GLP-1 in women (p < 0.10). CONCLUSIONS: Sex differences were found in fasting glucose and OGTT-derived insulin/C-peptide and GLP-1 concentrations. Research using more sophisticated methodology is needed to further explain the glucose metabolism phenotype in Maasai people.
INTRODUCTION: Sodium-glucose co-transporter 2 (SGLT-2) inhibitors are oral antidiabetic agents that have been increasingly used in recent years. One of their lesser-known adverse effects is polycythemia (erythrocytosis),...INTRODUCTION: Sodium-glucose co-transporter 2 (SGLT-2) inhibitors are oral antidiabetic agents that have been increasingly used in recent years. One of their lesser-known adverse effects is polycythemia (erythrocytosis), for which data remain limited. In this study, we aimed to investigate the incidence of erythrocytosis associated with SGLT-2 inhibitor use and the risk factors influencing these changes. METHODS: All patients who initiated SGLT-2 inhibitor therapy in our clinic between January 2020 and January 2021 were retrospectively evaluated. Hb and Hct levels were monitored for a median of 16 months following treatment initiation. RESULTS: Polycythemia developed in 15.1% (n = 58) of the 385 patients included in the study. Male sex and smoking were identified as significant risk factors for erythrocytosis, whereas insulin use and iron deficiency were found to be protective factors. The mean increase in hemoglobin levels among all patients was 0.97 ± 0.94 g/dL. A negative correlation was observed between baseline Hb levels and the degree of Hb increase associated with SGLT-2 inhibitor use. Patients who were excluded from the study due to baseline polycythemia (n = 18) were evaluated separately, and no significant change in their Hb levels was detected during follow-up. CONCLUSIONS: SGLT-2 inhibitors significantly increase Hb and Hct levels in all patients without polycythemia. In anemic individuals, SGLT-2 inhibitors appear to induce greater increases in Hb and Hct, suggesting a potential additional hematologic benefit in this subgroup. Moreover, SGLT-2 inhibitors have been shown to be safe in patients with pre-existing polycythemia.
BACKGROUND: Diabetic cardiomyopathy (DCM) frequently begins with diastolic dysfunction (DD), which leads to increased left ventricular filling pressures and subsequent left atrial enlargement, quantified by the left atri...BACKGROUND: Diabetic cardiomyopathy (DCM) frequently begins with diastolic dysfunction (DD), which leads to increased left ventricular filling pressures and subsequent left atrial enlargement, quantified by the left atrial volume index (LAVI). SGLT-2 inhibitors have demonstrated cardioprotective benefits extending beyond glycemic control; however, their specific impact on early cardiac structural remodeling in DCM remains incompletely understood. METHODS: This single-center, prospective observational study enrolled 36 patients with type 2 diabetes mellitus (T2DM) who were initiated on dapagliflozin (10 mg once daily). Thirty-five patients completed 6-month follow-up. Transthoracic echocardiography, exercise ECG testing, and comprehensive laboratory analyses were performed at baseline and at 6 months. RESULTS: LAVI decreased significantly over 6 months during dapagliflozin treatment (31.7 ± 10.6 vs. 27.9 ± 10.6 ml/m², p < 0.01). Interventricular septum and posterior wall thicknesses were significantly reduced (p < 0.01). Descriptive subgroup patterns were observed: LAVI decrease was statistically significant in asymptomatic patients without clinical heart failure (baseline LAVI < 34 ml/m²), whereas a numerical decrease in the heart failure subgroup did not reach statistical significance; no formal interaction testing was performed. HDL cholesterol increased significantly (46.0 ± 7.4 vs. 48.2 ± 8.1 mg/dL, p = 0.03), while AST and ALT levels declined significantly. Exercise duration and maximum METs improved significantly (p < 0.01). Resting heart rate decreased from 78.0 ± 15.4 to 71.2 ± 13.3 bpm (p < 0.01). CONCLUSION: LAVI was significantly lower at 6 months compared to baseline in T2DM patients during dapagliflozin treatment, consistent with a possible association with early structural changes in diabetic cardiomyopathy. Given the uncontrolled, single-arm design, causality cannot be inferred; these findings are hypothesis-generating and require confirmation in randomized controlled studies. Secondary exploratory findings, including improved exercise capacity, reduced resting heart rate, raised HDL cholesterol, and improved hepatic enzyme profiles, should likewise be interpreted with caution.
Glucagon-like peptide-1 receptor agonists are widely used for the management of obesity and dysglycaemia, and current evidence does not support a causal association with pancreatic cancer. We report a 55-year old woman w...Glucagon-like peptide-1 receptor agonists are widely used for the management of obesity and dysglycaemia, and current evidence does not support a causal association with pancreatic cancer. We report a 55-year old woman with obesity and prediabetes who started once-weekly semaglutide 0.25 mg for weight management and glycaemic control. Baseline fasting plasma glucose was 107 mg/dL and glycated haemoglobin was 6.0%. After one month, despite a 4 kg weight loss and no significant gastrointestinal symptoms, fasting plasma glucose increased to 169 mg/dL and glycated haemoglobin to 6.6%. Latent autoimmune diabetes in adults was excluded by negative autoantibodies and preserved C-peptide. Further evaluation revealed markedly elevated carbohydrate antigen 19-9 and pancreatic magnetic resonance imaging demonstrated a 4 × 3 cm irregular mass in the pancreatic head. Surgical exploration identified liver metastases, and biopsy confirmed metastatic pancreatobiliary adenocarcinoma. This case highlights that atypical glycaemic changes during early semaglutide treatment should be interpreted cautiously, particularly during subtherapeutic dose escalation. Such observations do not imply causality, but may warrant individualized assessment when accompanied by additional clinical suspicion.
Diabetic cardiomyopathy (DCM) is a major contributor to the cardiovascular complications associated with diabetes. This condition is characterized by structural and functional abnormalities of the myocardium that occur i...Diabetic cardiomyopathy (DCM) is a major contributor to the cardiovascular complications associated with diabetes. This condition is characterized by structural and functional abnormalities of the myocardium that occur independently of factors such as hypertension or other established cardiac diseases. In this review, we focus on the mitochondrial quality control (MQC) system, a critical determinant in the pathogenesis of DCM. In the diabetic milieu, chronic hyperglycemia and lipid overload disrupt mitochondrial homeostasis, leading to oxidative stress, impaired energy metabolism, and dysregulated mitochondrial dynamics. These disturbances serve as precursors to severe pathological outcomes, including cardiomyocyte death, myocardial fibrosis, and the progression of heart failure. This paper systematically examines the four pillars of MQC regulation-mitochondrial dynamics, selective autophagy (mitophagy), mitochondrial biogenesis, and the mitochondrial unfolded protein response (UPRmt)-and discusses how dysregulation of these regulatory networks contributes to the development of DCM. We further explore the molecular mechanisms involving key regulators such as Drp1 and Parkin, emphasizing their potential as therapeutic targets. Although current research has identified promising strategies, including hypoglycemic agents, melatonin, and various natural compounds that modulate MQC in preclinical models, translating these findings into clinical practice remains challenging due to species differences and the inherent complexity of MQC regulation. Future research should prioritize multi-target combination therapies and personalized treatment strategies aimed at preserving mitochondrial homeostasis and delaying the progression of DCM.
Bombaci B, Bassi M, Castorani V
… +222 more, Di Candia F, Ferrari M, Martino M, Zagaroli L, Marigliano M, Bonfanti R, Diabetes Study Group of the Italian Society of Pediatric Endocrinology and Diabetology, Albino CA, Aloe M, Anzelotti MT, Arnaldi C, Barbetti F, Bassi M, Berioli MG, Bernardini L, Bertelli E, Biagioni M, Bobbio A, Bombaci B, Bonfanti R, Bonura C, Bracciolini GP, Bruzzese M, Bruzzi P, Buono P, Buscarino P, Cadario F, Calcaterra V, Calzi E, Cappa M, Cardani R, Cardella F, Cardinale GM, Casertano A, Castorani V, Cauvin V, Cenciarelli V, Ceruti F, Cherubini V, Chiarelli F, Chiari G, Cianfarani S, Cicchetti M, Cipriano P, Cirillo D, Citriniti F, Coccioli MS, Confetto S, Contreas G, Coro A, Correddu A, Corsini E, Crino A, D Annunzio G, De Berardinis F, De Donno V, De Filippo G, De Marco R, De Sanctis L, Del Duca E, Delvecchio M, Deodati A, Di Bonito P, Di Candia F, Faleschini E, Fattorusso V, Favia A, Federico G, Felappi B, Ferrari M, Ferrito L, Fichera G, Fontana F, Fornari E, Franceschi R, Franco F, Franzese A, Frongia AP, Frontino G, Gaiero A, Galassi SM, Gallo F, Gargantini L, Giani E, Gortan AJ, Graziani V, Grosso C, Gualtieri A, Guasti M, Guerraggio LP, Guzzetti C, Iafusco D, Iannicelli G, Iezzi ML, Ignaccolo MG, Innaurato S, Inzaghi E, Iovane B, Iughetti L, Kaufmann P, La Loggia A, Lambertini AG, Lapolla R, Lasagni A, Lazzaro N, Lazzeroni P, Lenzi L, Lera R, Levantini G, Lezzi M, Lia R, Liguori A, Lo Presti D, Lombardo F, Lonero A, Longhi S, Lorubbio A, Lucchesi S, Maccioni R, Macedoni M, Macellaro PC, Madeo SF, Maffeis C, Mainetti B, Maltoni G, Mameli C, Mammì F, Manca Bitti ML, Mancioppi V, Manco M, Marigliano M, Marino M, Marsciani A, Matteoli MC, Mazzali E, Minute M, Minuto N, Monti S, Morandi A, Morganti G, Morotti E, Mozzillo E, Musolino G, Olivieri F, Ortolani F, Pampanini V, Pardi D, Pascarella F, Pasquino B, Passanisi S, Patera IP, Pedini A, Pennati MC, Peruzzi S, Peverelli P, Pezzino G, Piccini B, Piccinno EER, Piona C, Piredda G, Piscopo A, Pistone C, Pozzi E, Prandi E, Predieri B, Prudente S, Pulcina A, Rabbone I, Randazzo E, Rapini N, Reinstadler P, Riboni S, Ricciardi MR, Rigamonti A, Ripoli C, Rossi V, Rossi P, Rutigliano I, Sabbion A, Salvatoni A, Salvo C, Salzano G, Sanseviero M, Savastio S, Savini R, Scanu M, Scaramuzza AE, Schiaffini R, Schiavone M, Schieven E, Scipione M, Secco A, Silvestri F, Siri G, Sogno Valin P, Sordelli S, Spiri D, Stagi S, Stamati FA, Suprani T, Talarico V, Tiberi V, Timpanaro TAL, Tinti D, Tirendi A, Tomaselli LG, Toni S, Torelli C, Tornese G, Trada M, Trettene AA, Tumini S, Tumminelli M, Valerio G, Vandelli S, Ventrici C, Zampolli M, Zanatta M, Zanfardino A, Zecchino C, Zonca S, Zucchini S
AIMS: Diabetic peripheral neuropathy (DN) is a major complication of type 1 diabetes (T1D), frequently subclinical in youth. Although international pediatric guidelines recommend annual screening, adherence in pediatric...AIMS: Diabetic peripheral neuropathy (DN) is a major complication of type 1 diabetes (T1D), frequently subclinical in youth. Although international pediatric guidelines recommend annual screening, adherence in pediatric care is uncertain. This study aimed to assess DN screening practices in Italian pediatric diabetes centers and identify barriers to implementation. METHODS: Between December 2024 and May 2025, we conducted a nationwide, cross-sectional survey among Italian centers affiliated with the ISPED Diabetes Study Group. One respondent per center completed a 27-item questionnaire exploring organizational features, DN screening practices, and professional training. RESULTS: Forty-eight centers responded to the survey. Written internal protocols for DN screening were available in 22.9% of centers. Only 18.6% reported annual screening, while more than 40% initiated screening only in the presence of symptoms. Recommended criteria (age ≥ 11 years and 2-5 years diabetes duration) were applied by 31.3% of centers. Clinical neurological examination was widely adopted (95.8%), whereas nerve conduction studies (29.2%) and the Michigan Neuropathy Screening Instrument (14.6%) were rarely used. Notably, 89.6% of respondents had never received formal training in DN screening. Centers where pediatric diabetologists personally conducted the assessment were more likely to adhere to annual screening (p = 0.010). CONCLUSIONS: Screening for DN in Italian pediatric diabetology is inconsistent and frequently delayed, contributing to probable underrecognition of early neuropathic changes. Strengthening professional awareness, promoting structured training, and implementing harmonized national protocols are essential steps to ensure timely identification and equitable care for children and adolescents with T1D.
AIMS: To characterize switching among GLP-1 receptor agonists (GLP-1 RAs) in a large private-sector cohort in Poland and to quantify therapy- and patient-level associations with switching while accounting for switching o...AIMS: To characterize switching among GLP-1 receptor agonists (GLP-1 RAs) in a large private-sector cohort in Poland and to quantify therapy- and patient-level associations with switching while accounting for switching opportunity and calendar-time dynamics. METHODS: We conducted a retrospective analysis of GLP-1 RA prescription records from the LUX MED network (2018-2025). Switching was defined as any change in agent between consecutive prescriptions. Patients with more than one prescription were included (n = 42,423). The primary analysis used a transition-level discrete-time hazard model in which each prescription-to-prescription interval contributed one observation, and the outcome was switching at that interval. Current-therapy contrasts were reported relative to subcutaneous semaglutide. Sensitivity analyses examined alternative temporal parameterizations and additional adjustment for elapsed time. RESULTS: Overall, 29.7% of patients switched at least once and 14.3% switched two or more times. In the transition-level analysis, 12,620 patients contributed 27,095 transitions. After adjustment for opportunity and calendar time, liraglutide was associated with substantially lower odds of switching compared with subcutaneous semaglutide (OR, 0.02; 95% CI, 0.01-0.03), whereas oral semaglutide (OR, 1.30; 95% CI, 0.78-2.17) and dulaglutide (OR, 1.70; 95% CI, 0.95-3.04) did not differ significantly. Temporal analyses revealed peaks consistent with episodic substitution and accelerated tirzepatide uptake after market entry. The principal associations remained directionally consistent in sensitivity analyses. CONCLUSIONS: Switching among GLP-1 RAs is common and time-dependent. Time-aware modelling identified therapy-specific switching patterns and pronounced temporal variation; reasons for switching remain unmeasured, and the observed associations should be interpreted as hypothesis-generating.
OBJECTIVE: Current research has not yet drawn a definitive conclusion on the impact of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on the risk of osteoarthritis (OA) in patients with type 2 diabetes mellitus (T2...OBJECTIVE: Current research has not yet drawn a definitive conclusion on the impact of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on the risk of osteoarthritis (OA) in patients with type 2 diabetes mellitus (T2DM). To supplement the evidence base in this field, the present study sought to systematically investigate the association between GLP-1RA administration and the risk of OA in adult T2DM patients through a meta-analysis of relevant randomized controlled trials (RCTs). METHODS: An exhaustive literature search was conducted across five major databases-PubMed, Embase, Web of Science, ClinicalTrials.gov, and the Cochrane Library-covering the period from each database's inception up to May 6, 2025. The main objective of this literature search was to identify RCTs that enrolled adult patients with T2DM receiving GLP-1RAs and reported OA incidence. The Cochrane Risk of Bias 2.0 tool was employed to evaluate the risk of bias for all included studies, while the GRADE system was applied to assess the overall certainty of the evidence. Additionally, the node-splitting method was utilized to perform inconsistency testing between direct and indirect evidence. The occurrence of OA events was defined as the primary outcome of the study. A series of analyses were performed to evaluate the impact of each intervention on OA risk, including traditional meta-analysis, frequentist network meta-analysis (NMA), and sensitivity analysis. Summary estimates of effect size were presented as relative risk (RR) along with 95% confidence intervals (CI). RESULTS: The present study ultimately included 74 RCTs with a combined sample size of 105,415 individuals. Conventional pairwise meta-analysis revealed no statistically significant difference in OA risk between GLP-1RAs and placebo, insulin, or other oral antidiabetic drugs (OADs). Stratified subgroup analyses based on GLP-1RA formulation, treatment duration, and control group type also found no statistically significant differences in OA risk across all subgroups. Furthermore, NMA results indicated no notable variations in OA risk between GLP-1RAs and control interventions, and no such differences were observed among the different GLP-1RA formulations either. Sensitivity analyses verified the stability and reliability of the study outcomes. CONCLUSIONS: Among adult patients with T2DM, there was no significant difference in OA risk between GLP-1RA treatment and placebo, insulin, or OADs; this absence of statistical significance was also observed across different GLP-1RA formulations, varying treatment durations, and distinct control groups. PROSPERO REGISTRATION NUMBER: CRD420251034203.
BACKGROUND: Common regulatory and coding variants may influence type 2 diabetes (T2D) risk by altering gene regulation or protein function. Identifying these variants and their associations with disease risk may inform d...BACKGROUND: Common regulatory and coding variants may influence type 2 diabetes (T2D) risk by altering gene regulation or protein function. Identifying these variants and their associations with disease risk may inform disease control strategies. This study prioritized candidate variants by integrating two-group comparative genotyping with in-silico structural and dynamic analyses. METHODS: Three prioritized variants (two missense, one TF-binding-site) were genotyped in 101 T2D cases and 100 controls from the Azeri population of Iran. Variant calls were validated by Sanger sequencing. Structural modelling, ligand docking, and 100-nanosecond molecular dynamics simulations were performed to assess molecular consequences. RESULTS: The TF-binding-site variant in PPP2R3A (rs184442184) was significantly associated with T2D (allelic OR ≈ 1.71, p = 0.014; TT OR ≈ 2.92, p = 0.020) and is located at a RegulomeDB 2a site overlapping EGR1/SP motifs. SLC39A11 (ZIP11) rs61736066 (A allele) was enriched in cases (allelic OR ≈ 1.87, p = 0.002; AA OR ≈ 3.49, p = 0.005), and the variant model demonstrated increased RMSD/RMSF, helix displacement, and modest destabilization. The TPCN2 missense variant exhibited only subtle in-silico effects and no genetic association. CONCLUSION: These findings highlight PPP2R3A rs184442184 and SLC39A11 rs61736066 as promising T2D candidate variants, supported by concordant genetic signals and mechanistic in-silico effects. The TPCN2 substitution demonstrated only mild structural changes and no association in this study. Overall, these results provide testable biological hypotheses that require validation through larger replication studies and targeted functional assays.
BACKGROUND: Orthostatic hypotension (OH) is associated with adverse cardiovascular outcomes and may reflect underlying autonomic and vascular dysfunction. Arterial stiffness is a key determinant of cardiovascular risk; h...BACKGROUND: Orthostatic hypotension (OH) is associated with adverse cardiovascular outcomes and may reflect underlying autonomic and vascular dysfunction. Arterial stiffness is a key determinant of cardiovascular risk; however, its relationship with OH in patients with diabetes mellitus (DM) remains unclear. OBJECTIVE: To evaluate factors associated with OH and investigate the relationship between arterial stiffness parameters and OH in patients with DM. METHODS: This single-center cross-sectional study included 193 patients with DM. Orthostatic blood pressure was measured in the supine position and 3 min after standing. Arterial stiffness was assessed using oscillometric pulse wave velocity (PWV) and related parameters with the Mobil-O-Graph device. Clinical, laboratory, and medication data were analyzed. Logistic regression analyses were performed to identify factors associated with OH. RESULTS: OH was present in 56 patients (29%). Patients with OH had significantly higher central blood pressure and arterial stiffness parameters, including PWV, augmentation pressure, and augmentation index. In multivariate analysis, female sex, older age, diabetic neuropathy, and PWV were independently associated with OH. PWV remained significantly associated with OH after adjustment for confounders. No significant differences were observed between groups regarding antihypertensive medication classes. CONCLUSION: In patients with DM, OH is independently associated with increased arterial stiffness and diabetic neuropathy. These findings suggest a link between orthostatic blood pressure dysregulation and adverse vascular characteristics. Prospective studies are needed to clarify causal relationships and clinical implications.