The retinal pigment epithelium (RPE) plays a pivotal role in retinal homeostasis and energy metabolism. A recent study demonstrates that RPE cells release insulin in response to photoreceptor outer segment (POS) phagocytosis and starvation conditions. However, the downstream signalling pathway of this local insulin production has not yet been identified. Therefore, using the ARPE-19 cell line as an in vitro model of human RPE, we have investigated insulin signalling in basal conditions and after rod OS phagocytosis. Our data show that ARPE-19 cells express key pancreatic β-cell markers, including the transcription factor Pancreatic and Duodenal Homeobox-1 (PDX-1), which translocates to the nucleus in response to phagocytosis, and prohormone convertase 1/3 (PC1/3). In addition, ARPE-19 cells synthesize and secrete insulin already in basal conditions, increasing their release after phagocytosis. The RPE-secreted insulin acts in an autocrine manner, activating the canonical insulin signalling pathway and leading to increased phosphorylation of insulin receptor (IR), insulin receptor substrate-1 (IRS-1), and AKT. An upregulation of the insulin-responsive glucose transporter GLUT4 and increased glucose uptake was also observed, fueling the ARPE-19 cells’ oxidative energy metabolism, incrementing the oxidative phosphorylation activity, probably to sustain the high energy demand associated with phagocytosis. At the same time, a decrease in lactate release has been observed. These features may have important implications for understanding retinal energy metabolism and developing novel therapeutic strategies for retinal neurodegenerative diseases.

To examine associations between physical activity (PA) characteristics and psychosocial outcomes – quality of life (QoL) and fear of hypoglycemia (FH) – in children, adolescents, and young adults with type 1 diabetes (T1D). In this cross-sectional study, 100 insulin pump-treated outpatients T1D completed 7-day PA logs capturing timing, type, intensity, and volume. QoL and FH were assessed using age-appropriate validated instruments. General linear models evaluated associations between PA characteristics and psychosocial outcomes, accounting for age group and, in sensitivity analyses, sex and HbA1c. In pooled analyses (N = 82 complete cases), age group was significantly associated with both QoL (p = 0.037) and FH (p < 0.001), with a large effect size observed for FH. In sensitivity analyses adjusting for sex and HbA1c, the age-group effect on FH remained robust, whereas associations with QoL were attenuated. Exercise timing was associated with FH (p = 0.047), with higher adjusted FH scores observed among individuals reporting evening exercise. However, pairwise comparisons were not significant after correction. No significant AgeGroup×Timing interactions were detected. Preferred exercise type and intensity were not independently associated with psychosocial outcomes. In sensitivity analyses adjusted for sex and HbA1c (N = 62), the age-group effect on FH remained robust, whereas timing showed borderline significance. Developmental stage appears to be a major determinant of fear of hypoglycemia in youths with T1D. Exercise timing may contribute modestly to perceived hypoglycemia risk, particularly for evening activity, although findings were attenuated after adjustment. These cross-sectional associations highlight the importance of developmentally tailored exercise counselling, while longitudinal studies are needed to clarify directionality.

Background: The most common form of monogenic diabetes is maturity onset diabetes of the young (MODY). This study investigates the molecular basis of MODY type 2 (GCK-MODY) in a group of Italian patients, focusing on the functional characterization of a synonymous variant, c.579G>T (p.Gly193Gly), in the glucokinase gene (GCK). Methods: Clinical evaluation and genetic analysis, including whole exome sequencing and Sanger sequencing, were used to identify the variant in GCK, then functional studies using a minigene approach allowed the functional characterization. Results: This study identified the synonymous variant, along with a nonsense mutation, c.859C>T (p.Gln287Ter), in GCK in two Italian patients. Minigene approach demonstrated that the synonymous variant disrupts splicing at the exon 5 boundary, leading to a frameshift and premature stop codon. Similarly, the nonsense mutation also altered splicing, exacerbating the molecular defect. Conclusions: These findings highlight the importance of functional assays, particularly minigene studies, in interpreting the pathogenicity of synonymous and nonsense variants, especially in genes like GCK where splicing alterations can significantly impact protein function. This study underscores the clinical utility of targeted genetic screening for personalized diabetes management.

Introduction and Objective: Despite the well-documented benefits of physical activity (PA) for health and diabetes management, individuals with type 1 diabetes (T1D) face significant barriers to exercise. Methods: This cross-sectional study investigated PA determinants and psychometric outcomes in ninety well-controlled individuals with T1D from Northwest Italy (55% female; age: 16 ± 6 years; HbA1c: 6.8 ± 1%). PA timing, type, duration, intensity, and volume were recorded through a 7-day training log, and participants were grouped by exercise timing: morning (6 am-12 pm), afternoon (12 pm-6 pm), and evening (6 pm-12 am). Results: Higher PA volume was associated with improved quality of life (Pearson r = -0.25, P = 0.02) and reduced fear of hypoglycemia (Spearman Rho = -0.23, P = 0.03). Mixed-model analysis revealed that quality of life was significantly influenced by PA type (P = 0.03) and intensity (P = 0.04), with low-intensity aerobic activity yielding better scores than mixed activity (P = 0.009). Fear of hypoglycemia was significantly affected by PA type (P = 0.007) and timing (P = 0.03), with greater anxiety reported for evening (P = 0.01) and anaerobic activities (P = 0.018) compared to afternoon and mixed activities, respectively. Gender had no significant effect on these outcomes. Conclusion: These findings highlight the importance of tailoring exercise recommendations for youth with T1D, emphasizing consistent routines and careful selection of activity types and intensities to enhance quality of life while minimizing fear of hypoglycemia. Promoting adherence to such strategies could optimize both physical and psychological well-being in this population. R. Codella: None. A. Bisio: None. D. Gotti: None. M. Bassi: None. N. Minuto: Consultant; Novo Nordisk. P. Ruggeri: None. L. Luzi: Speaker's Bureau; A. Menarini Diagnostics, Amgen Inc. Research Support; Boehringer-Ingelheim. Advisory Panel; Eli Lilly and Company. Speaker's Bureau; Eli Lilly and Company. Research Support; Medtronic. Speaker's Bureau; Novartis AG, Novo Nordisk. D. Maggi: None. E. Faelli: None.

Insulin is a key anabolic hormone traditionally considered to be exclusively produced by pancreatic β-cells. Insulin exerts several systemic effects involved in glucose uptake and metabolism. In the retina, insulin signaling acts as a regulator of photoreceptor- retinal pigment epithelium (RPE) metabolic coupling as well as of neuronal survival via the PI3K/Akt and MAPK/ERK pathways. Impaired insulin signaling contributes to diabetic retinopathy, retinitis pigmentosa, and age-related degeneration by disrupting energy homeostasis and trophic support. However, growing evidence suggests that the retina, particularly RPE, locally synthesizes and secretes insulin. Although the role of local insulin production in the retina remains to be clarified, this discovery introduces a paradigm shift in retinal physiology, suggesting a self-sustaining insulin signaling system that supports glucose uptake, lipid metabolism, and neurovascular integrity. Emerging data indicate that RPE-derived insulin is stimulated by photoreceptor outer segment (POS) phagocytosis and may act through autocrine and paracrine mechanisms to maintain retinal function, even under conditions of systemic insulin deficiency. Understanding this extra-pancreatic insulin source opens new therapeutic perspectives aimed at enhancing local insulin signaling to preserve vision and prevent retinal degeneration. Thus, the objective of this review is to summarize current evidence on RPE-derived insulin and to discuss its potential implications for retinal homeostasis and disease.

To evaluate how the timing, type, and intensity of bout-related physical activity (PA) influence glycemic control across age groups in youths and young adults with type 1 diabetes (T1D). In this cross-sectional study, 100 insulin pump-treated individuals with T1D (55 females; mean age 16.6 ± 6.6 years; HbA1c 6.8 ± 1.0

The retinal pigment epithelium (RPE) contributes to retinal homeostasis, and its metabolic dysfunction is implied in the development of retinal degenerative disease. The isoform M2 of pyruvate kinase (PKM2) is a key factor in cell metabolism, and its function may be affected by insulin-like growth factor 1 (IGF-1). This study aims to investigate the effect of IGF-1 on PKM2 modulation of RPE cells and whether co-treatment with klotho may preserve it. ARPE-19 cells, an ex vivo model of human pigmented epithelium, were exposed to IGF-1. Then, we evaluated PKM2 expression, dimerization and subcellular localization, energy metabolism, and redox balance, and whether pre-treatment with Klotho may antagonize the effects of IGF-1. The results show that IGF-1 favors PKM2 dimerization, thus reducing the activity of PKM2 and leading to an altered cellular energy status coupled with reduced oxidative stress. In conclusion, PKM2 plays a pivotal role in the modulation of RPE metabolism and redox balance and could explain the mechanisms through which IGF-1 participates in the pathogenesis of some retinal diseases. Klotho may exert protective effects by mitigating the IGF-1 signal and its effect on mitochondrial function.

Maturity-onset diabetes of the young (MODY) represents the most frequent form of monogenic diabetes mellitus (DM), currently classified in 14 distinct subtypes according to single gene mutations involved in the differentiation and function of pancreatic β-cells. A significant proportion of MODY has unknown etiology, suggesting that the genetic landscape is still to be explored. Recently, novel potentially MODY-causal genes, involved in the differentiation and function of β-cells, have been identified, such as RFX6, NKX2.2, NKX6.1, WFS1, PCBD1, MTOR, TBC1D4, CACNA1E, MNX1, AKT2, NEUROG3, EIF2AK3, GLIS3, HADH, and PTF1A. Genetic and clinical features of MODY variants remain highly heterogeneous, with no direct genotype–phenotype correlation, especially in the low-penetrant subtypes. This is a narrative review of the literature aimed at describing the current state-of-the-art of the novel likely MODY-associated variants. For a deeper understanding of MODY complexity, we also report some related controversies concerning the etiological role of some of the well-known pathological genes and MODY inheritance pattern, as well as the rare association of MODY with autoimmune diabetes. Due to the limited data available, the assessment of MODY-related genes pathogenicity remains challenging, especially in the setting of rare and low-penetrant subtypes. In consideration of the crucial importance of an accurate diagnosis, prognosis and management of MODY, more studies are warranted to further investigate its genetic landscape and the genotype–phenotype correlation, as well as the pathogenetic contribution of the nongenetic modifiers in this cohort of patients.

Purpose: To assess the role of artificial intelligence (AI) based automated software for detection of Diabetic Retinopathy (DR) compared with the evaluation of digital retinography by two double masked retina specialists. Methods: Two-hundred one patients (mean age 65 ± 13 years) with type 1 diabetes mellitus or type 2 diabetes mellitus were included. All patients were undergoing a retinography and spectral domain optical coherence tomography (SD-OCT, DRI 3D OCT-2000, Topcon) of the macula. The retinal photographs were graded using two validated AI DR screening software (Eye Art TM and IDx-DR) designed to identify more than mild DR. Results: Retinal images of 201 patients were graded. DR (more than mild DR) was detected by the ophthalmologists in 38 (18.9%) patients and by the AI-algorithms in 36 patients (with 30 eyes diagnosed by both algorithms). Ungradable patients by the AI software were 13 (6.5%) and 16 (8%) for the Eye Art and IDx-DR, respectively. Both AI software strategies showed a high sensitivity and specificity for detecting any more than mild DR without showing any statistically significant difference between them. Conclusions: The comparison between the diagnosis provided by artificial intelligence based automated software and the reference clinical diagnosis showed that they can work at a level of sensitivity that is similar to that achieved by experts.

Identifying the best exercise timing to mitigate hypoglycemia is critical for patients with type 1 diabetes (T1D). Despite the established health benefits, concerns persist regarding post-exercise glucose stabilization in this population. In a cross-sectional design of one hundred well-compensated individuals from Northwest Italy (55% female, 45% male; age: 16 ± 6 years; HbA1c: 6.8 ± 1%), physical activity (PA), glycemic profiles, and psychometric traits were monitored. The timing, duration, intensity, and volume of PA were derived from a 7-day training log. Glycemic control was assessed through continuous glucose monitoring, including time in range (TIR; 70-180 mg/dL), time below range (TBR; <70 mg/dL), time below the extreme hypoglycemia range (TBER; <54 mg/dL), time above range (TAR; 180-250 mg/dL), time >250 mg/dL, mean glycemia (MGLU), and total daily insulin dose. Subjects were categorized based on the prevalent timing of exercise into three groups: morning (6am - 12pm), afternoon (12pm - 6pm), and night (6pm - 12 am). Non-exercising days (NO-activity) for each subject were also considered. The mixed model analysis for fixed effects revealed that TIR, TAR, TBER, and MGLU were significantly influenced by the timing of exercise. However, post-hoc analysis indicated that this difference was observed only when comparing NO-activity vs afternoon exercise. Pairwise comparisons showed no significant differences in TIR, TAR, TBER, and MGLU when comparing exercise timing (morning vs afternoon vs night). Additionally, active participants exhibited better quality of life, reduced fear of hypoglycemia, and improved diabetes management self-efficacy compared to their less active counterparts. The findings suggest that exercise timing may be secondary to the overarching goal of helping individuals with T1D develop a consistent and adherent exercise routine. This insight is valuable in guiding recommendations for managing glycemic control in T1D. Disclosure R. Codella: None. L. Della Guardia: None. M. Bassi: Speaker's Bureau; Movi spa. N. Minuto: Consultant; Novo Nordisk A/S. A. Bisio: None. P. Ruggeri: None. E. Faelli: None. D. Maggi: Consultant; Bayer Inc.

From the failure of gut extracts in diabetic patients’ therapy to the effective action in cardiovascular outcomes [...]

Klotho (Kl) is considered an antiaging gene, mainly for the inhibition of the insulin-like growth factor-1 signaling. Kl exists as full-length transmembrane, which acts as co-receptor for fibroblast growth factor receptor, and in soluble forms (sKl). The sKl may exert pleiotropic effects on organs and tissues by regulating several pathways involved in the pathogenesis of diseases associated with oxidative and inflammatory state. In diabetic Patients, serum levels of Kl are significantly decreased compared to healthy subjects, and are related to duration of diabetes. In diabetic retinopathy (DR), one of the most common microvascular complications of type 2 diabetes, serum Kl levels are negatively correlated with progression of the disease. A lot of evidences showed that Kl regulates several mechanisms involved in maintaining homeostasis and functions of retinal cells, including phagocytosis, calcium signaling, secretion of vascular endothelial growth factor A (VEGF-A), maintenance of redox status, and melanin biosynthesis. Experimental data have been shown that Kl exerts positive effects on several mechanisms involved in onset and progression of DR. In particular, treatment with Kl: (1) Prevents apoptosis induced by oxidative stress in human retinal endothelial cells and in retinal pigment epithelium (RPE) cells; (2) reduces secretion of VEGF-A by RPE cells; and (3) decreases subretinal fibrosis and preserves autophagic activity. Therefore, Kl may become a novel biomarker and a good candidate for the treatment of DR.

Caveolae are 50–100 nm cell surface plasma membrane invaginations observed in terminally differentiated cells. They are characterized by the presence of the protein marker caveolin-1. Caveolae and caveolin-1 are involved in regulating several signal transduction pathways and processes. It is well recognized that they have a central role as regulators of atherosclerosis. Caveolin-1 and caveolae are present in most of the cells involved in the development of atherosclerosis, including endothelial cells, macrophages, and smooth muscle cells, with evidence of either pro- or anti-atherogenic functions depending on the cell type examined. Here, we focused on the role of caveolin-1 in the regulation of the LDLs’ fate in endothelial cells.

OBJECTIVE COVID-19 clinical presentation ranges from asymptomatic infection to an inflammatory cytokine storm with multi-organ failure and fatal outcomes. The identification of high-risk patients for severe disease is crucial to plan an early treatment and intensive follow-up. We aimed to investigate negative prognostic factors in a group of patients hospitalized for COVID-19. PATIENTS AND METHODS 181 patients (90 men and 91 women, mean age 66.56 ± 13.53 years) were enrolled. Each patient received a work-up including medical history, clinical examination, arterial blood gas analysis, laboratory blood tests, feasible ventilatory support required during hospital stay, intensive care setting required, duration of illness and length of hospital stay (>or<25 days). For the assessment of the severity of COVID-19, three main indicators were considered: 1) the intensive care unit (ICU) admission 2) the hospitalization length >25 days; 3) the need of non-invasive ventilation (NIV). RESULTS The independent risk factor associated with the ICU admission were lactic dehydrogenase elevation (p=0.046), C reactive protein elevation (p=0.014) at hospital admission and direct oral anticoagulant home therapy (p=0.048); for hospital length >25 days: early corticosteroid therapy (p=0.035); for NIV treatment: ferritin elevation at hospital admission (p=0.006). CONCLUSIONS The presence of the above factors may be useful to identify patients at high risk of developing a severe COVID-19 that need an early treatment and intensive follow-up.

Background and aimsTandem Control-IQ and MiniMed 780G are the main Advanced Hybrid Closed Loop (AHCL) systems currently available in pediatric and adult patients with Type 1 Diabetes (T1D). The aim of our study was to evaluate glycemic control after 1-year of follow-up extending our previous study of 1-month comparison between the two systems.MethodsWe retrospectively compared clinical and continuous glucose monitoring (CGM) data from the patients included in the previous study which have completed 1-year observation period. The study population consisted of 74 patients, 42 Minimed 780G users and 32 Tandem Control-IQ users. Linear mixed models with random intercept were performed to study the variations over time and the interaction between time and system; Mann-Whitney or T-test were used to compare systems at 1-year.ResultsBoth systems have been shown to be effective in maintaining the glycemic improvement achieved one month after starting AHCL. Significant changes over time were observed for TIR, TAR, TAR>250mg/dl, average glucose levels and SD (p<0.001). At 1-year follow-up Minimed 780G obtained better improvement in TIR (p<0.001), TAR (p=0.002), TAR>250mg/dl (p=0.001), average glucose levels (p<0.001). The comparison of the glycemic parameters at 1-year showed a significant superiority of Minimed 780G in terms of TIR (71% vs 68%; p=0.001), TAR (p=0.001), TAR>250 (p=0.009), average glucose levels(p=0.001) and SD (p=0.031).ConclusionsThe use of AHCL systems led to a significant improvement of glycemic control at 1-month, which is maintained at 1-year follow-up. MiniMed is more effective than Tandem in reaching the International recommended glycemic targets. Continuous training and education in the use of technology is essential to get the best out of the most advanced technological tools.