Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly called non-alcoholic fatty liver disease (NAFLD), is today the leading cause of chronic liver conditions in the context of a global epidemic of obesity and metabolic disorders. Our study aims to determine the prevalence of MASLD and advanced liver fibrosis as well as the associated factors in patients with type 2 diabetes Mellitus (T2D). Cross-sectional study including 149 patients with T2D, conducted in the Endocrinology-Diabetology and Hepato-Gastroenterology departments over a period of 6 months. Screening for steatosis and liver fibrosis was carried out using FibroScan. The average age of the patients was 57.9 ± 11.8 years, with a female predominance (63.8%). Based on the EASL cutoffs, the MASLD ratio was 69.1% [95% CI (61.7-76.5], n = 103). Multivariable analysis identified high Body Mass Index [aOR = 1.25; 95% CI (1.13-1.38); p < 0.001] and total cholesterol [aOR = 1.69; 95% CI (1.15-2.48); p = 0.007] as independent predictors of MASLD. The median liver stiffness measurement was 5.0 kPa (IQR 4.0-6.5). Advanced fibrosis was confidently ruled out (< 8 kPa) in 82.6% (n = 123) of patients. Advanced fibrosis could not be ruled out (≥8 kPa) in 17.4% [95% CI (11.7-24.5), n = 26], which included 13.4% (n = 20) in the intermediate-risk zone (8-11.99 kPa) and 4% (n = 6) at high risk of advanced fibrosis (≥12 kPa). Higher platelet distribution width (PDW) was associated with nearly a threefold increase in the odds of advanced fibrosis (aOR = 2.78; 95% CI: 1.08-7.21; p = 0.035), while increasing GGT levels were also significantly associated with advanced fibrosis (aOR = 1.12; 95% CI: 1.03-1.21; p = 0.006). In our study, we found that 69.1% of participants met the criteria for MASLD, and advanced fibrosis could not be ruled out in 17.4% of patients, with 4% being at high risk (≥12 kPa). It is essential to identify these at-risk patients who require multidisciplinary management in order to prevent progression to cirrhosis and its complications.
Health literacy (HL) is a key determinant of diabetes self-management and clinical outcomes in type 2 diabetes mellitus (T2DM). The Diabetes Health Literacy Scale (DHLS) is a 14-item instrument assessing informational, numeracy, and communicative HL, with established validity in Korean, Persian, Malay, and Chinese populations. This study aimed to translate and culturally adapt the DHLS into Italian and evaluate its structural validity, internal consistency, construct validity, and measurement invariance across Italian-born and foreign-born adults with T2DM. A total of 300 adults with T2DM were recruited from two outpatient diabetology clinics in Florence, Italy. DHLS translation followed ISPOR guidelines with cognitive debriefing. Psychometric evaluation followed COSMIN recommendations and included confirmatory factor analysis, McDonald's omega, Pearson's correlations with comparator instruments, and multigroup confirmatory factor analysis (CFA). CFA supported the three-factor second-order structure (CFI = 0.921, RMSEA = 0.077). Internal consistency was satisfactory across domains (ω = 0.759-0.868) and excellent for the total scale (ω = 0.940; ωH = 0.770). All convergent validity hypotheses were supported. Multigroup CFA demonstrated configural but only partial metric invariance across birthplace groups. The DHLS-IT is a valid and reliable instrument for assessing diabetes HL in Italian adults with T2DM. Partial metric invariance cautions against direct latent score comparisons between Italian-born and foreign-born patients.
Osilodrostat has demonstrated efficacy in clinical trials for Cushing's syndrome (CS). Real-world data remain limited. To assess real-world effectiveness and safety of osilodrostat in a large cohort of CS patients. Multicenter, retrospective, phase IV-study across 11 Italian endocrine referral centers. 100 CS patients [74% pituitary, 16% adrenal, 10% ectopic]. Primary endpoint was the percentage of patients with UFC≤ULN at their last observation. Secondary endpoints included biochemical and hormonal control, clinical outcomes, QoL, AEs. 81% of patients had normal UFC levels at last observation, 92% at least once within study period. Excluding 12 patients with normal baseline UFC levels, 78.4% of patients had normal UFC levels at their last observation, whereas 90.9% at least once within the study period.The mean±SD (median,range) time to the first normalization of UFC levels, in the 80 patients who achieved normalization, was 92.1±86.3 (67.5,8-455) days, at a mean± SD (median,range) osilodrostat dose of 7.2±6.8 (5,1-40) mg/day.Significant reductions in late-night salivary cortisol and morning serum cortisol levels were observed. Improvements were noted in anthropometric parameters, blood pressure, glucose metabolism, clinical signs, and QoL. AEs occurred in 29% of patients, mostly mild-to-moderate; adrenal insufficiency was the most common AE reported in 20% of patients. Hormonal control and safety profiles were consistent across CS etiologies. Osilodrostat is effective, generally well tolerated in routine clinical practice, representing a valuable therapy for CS management, able to achieve rapid and sustained hormonal control, significant metabolic, cardiovascular, clinical and QoL improvements with a well-tolerated safety profile.
Background/Objectives: Lower serum 25-hydroxyvitamin D [25(OH)D] is common in pediatric overweight and obesity, but it remains unclear whether direct adiposity assessment adds information beyond an age- and sex-adjusted model containing BMI z-score and season. We tested whether DXA-derived total body fat percentage is associated with 25(OH)D and whether it adds explanatory power to that model. Methods: We analyzed cross-sectional data from 768 children/adolescents (10-18 years) with overweight/obesity. Anthropometry was available for all; DXA data for 489. The primary analysis used complete-case DXA data (n = 485). Vitamin D supplementation status was not available. Results: Participants with and without DXA were similar in age, sex, BMI z-score, and serum 25(OH)D, but blood sampling season differed (p < 0.001). Adding DXA-derived body fat percentage to the age- and sex-adjusted base model increased R2 from 0.0498 to 0.0657 (ΔR2 = 0.0159). Within the complete-case DXA subgroup (n = 485), DXA-derived total body fat percentage was inversely associated with 25(OH)D after adjustment for BMI z-score, season, age, and sex (B = -0.265; 95% CI, -0.448 to -0.082; p = 0.005). BMI z-score was significant in the base model but not after adjustment for DXA fat percentage. Conclusions: DXA-derived total body fat percentage added explanatory value for serum 25(OH)D beyond BMI z-score and season, but the incremental gain was small (ΔR2 = 0.0159). The findings are consistent with BMI z-score acting as a less direct proxy for the adiposity compartment that DXA quantifies more specifically. Causal interpretation is precluded by the cross-sectional design, unknown supplementation status, and non-random DXA availability.
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To evaluate the pharmacokinetics, pharmacodynamics, and safety of a novel U500 insulin aspart formulation (AT278 [500 U/mL]; AT278-U500) compared with standard concentration insulin aspart (InsAsp [100 U/mL]; InsAsp-U100) and U500 human regular insulin (HumIns [500 IU/mL]; HumIns-U500). This single-centre, randomised, double-blind crossover 12-h euglycaemic clamp study was conducted in 41 overweight and obese people with type 2 diabetes (BMI 25.0-38.7 kg/m2) receiving a single subcutaneous dose (0.5 U/kg) of AT278-U500 and InsAsp-U100. HumIns-U500 was consecutively studied open label in a 24-h clamp. AT278-U500 exhibited a significantly faster insulin absorption than InsAsp-U100 and HumIns-U500 (tEarly50%Cmax: 9 min vs. 35 min vs. 55 min), leading to a significantly higher glucose-lowering effect within the first hour (AUCGIR,0-60min) compared with both InsAsp-U100 (treatment ratio 2.02 [95% CI 1.64; 2.50]) and HumIns-U500 (3.91 [2.89; 5.27]). When divided by median BMI (29.7 kg/m2), AUCGIR,0-60min was significantly higher with AT278-U500 in both the low-BMI and high-BMI subgroup compared to InsAsp-U100. Linear regression showed a significant inverse relationship between BMI and AUCGIR,0-60min for InsAsp-U100 (slope -0.142, p < 0.0001), whereas AT278-U500 showed no such relationship. Overall insulin exposure was similar for AT278-U500 and InsAsp-U100, while overall glucose-lowering effect was comparable across all three treatments. AT278-U500 maintains its ultra-rapid onset characteristics independent of BMI, representing the first ultra-rapid U500 option for prandial dosing in insulin-resistant people with type 2 diabetes requiring high-dose therapy. ClinicalTrials.gov identifier: NCT05754424.
To assess the effect of all the approved classes of medications for type 2 diabetes on Major Adverse Cardiovascular events (MACE) and all-cause mortality. We performed a pairwise and network meta-analysis, including randomised controlled trials with a duration of at least 40 weeks, comparing medications versus placebo or an active comparator, in which MACE and deaths were adjudicated. We included 93 studies. In pairwise meta-analyses, versus all comparators, GLP-1 receptor agonists (GLP1RA), SGLT-2 inhibitors (SGLT2i), metformin and pioglitazone were associated with a significant reduction of MACE and sulfonylureas with increased MACE. Furthermore, tirzepatide, SGLT2i and GLP1RA were associated with a significantly reduced all-cause mortality. In the principal (frequentist) network meta-analysis, metformin (OR 0.69, 95% CI 0.53-0.89), SGLT2i (0.82, 0.75-0.90), GLP1RA (0.87, 0.83-0.92) and tirzepatide (0.82, 0.72-0.93) were associated with a significant reduction of MACE versus placebo; no effect was observed for insulin, DPP4 inhibitors (DPP4i) or sulfonylureas. Tirzepatide (0.72, 0.64-0.82), SGLT2i (0.85, 0.80-0.91) and GLP1RA (0.85, 0.80-0.91) were associated with a significantly reduced mortality versus placebo; no effect was detected for other drugs. The sensitivity (Bayesian) analysis did not confirm the significance of results for pioglitazone on MACE. The certainty of evidence was moderate-to-high for GLP1RA, SGLT2i, Tirzepatide, DPP4i; low for metformin; low-to-moderate for other drugs. SGLT2i, GLP1RA, tirzepatide and (with lower quality of evidence) pioglitazone and metformin are associated with a reduced incidence of cardiovascular events; tirzepatide, SGLT2i and GLP1RA are also associated with a reduced all-cause mortality.
DiabEthic trial examined the effectiveness of a culturally sensitive intervention on diabetes care delivered by dieticians and cultural mediators, targeting knowledge, attitudes, and self-management behaviours in a multi-ethnic cohort of immigrants in Italy. A total of 202 adult first-generation immigrants with type 2 diabetes newly diagnosed or with HbA1c > 8% were randomized 1:1 to intervention (cultural-sensitive help, with multidisciplinary and co-creative approaches) or standard care approach (guidelines based) in a multicentric, randomized, parallel-controlled, clinical trial. The primary outcome was HbA1c change at 12-month follow-up. Secondary outcomes included blood pressure, lipids, anthropometric measures, diet, physical activity, and adherence to therapy. Mixed-effects models and an intention-to-treat approach were applied. Structural equation modelling investigated mediating pathways. The intervention group showed a greater improvement in HbA1c [-0.70%, 95% confidence interval(CI): -1.31 to -0.09;P = 0.026] at 12-month follow-up, compared with the control group. A significant intervention effect was evident for waist circumference, triglycerides, total cholesterol, non-refined cereals servings/week, and adherence to therapy but not for blood pressure, body mass index, LDL, and physical activity. At mediation analysis, changes in non-refined cereals consumption and waist circumference indirectly mediated 40% of intervention effect on HbA1c changes. A culturally-tailored self-management intervention led to a greater HbA1c reduction in immigrants and ethnic minorities (https://clinicaltrials.gov/study/NCT06131411).
[This corrects the article DOI: 10.1016/j.lanepe.2026.101715.].
Sarcopenia is a major contributor to frailty and mortality in ageing and obesity and is tightly linked to metabolic dysfunction. Imeglimin is a first-in-class oral hypoglycaemic agent targeting mitochondrial function; however, despite the central role of mitochondria in skeletal muscle homeostasis, its effects on skeletal muscle under sarcopenia-relevant conditions remain unclear. Imeglimin was administered to male C57BL/6 mice with high-fat diet (HFD)-induced obesity for 6 weeks and to naturally aged (18 months old) male mice for 12 weeks. Skeletal muscle fibre morphology and transcriptomic profiles were analysed in fast- and slow-twitch muscles. In parallel, C2C12 myotubes were exposed to palmitate with or without imeglimin, and inflammatory gene expression and reactive oxygen species (ROS) generation were assessed. Imeglimin significantly increased the cross-sectional area (CSA) of Type II fibres in the extensor digitorum longus (EDL) muscle of HFD-fed mice (+66%, p < 0.01 vs. controls). Transcriptomic analyses revealed suppression of conserved molecular signatures of muscle atrophy, including activation of immediate-early genes and inflammatory pathways (-62% to -79%, p < 0.05 vs. HFD-fed mice). In palmitate-treated C2C12 myotubes, imeglimin attenuated lipotoxicity-induced inflammatory gene expression (-28% to -72%, p < 0.05 vs. controls) with reduced ROS generation, consistent with its cell-autonomous effect on myocytes. Notably, in naturally aged mice, 12-week imeglimin treatment preserved EDL muscle fibre size (+14%, p < 0.05 vs. controls) without altering systemic glucose tolerance, accompanied by transcriptomic changes overlapping with those observed in the HFD model (-27% to -82%, p < 0.05 vs. aged controls). Imeglimin attenuates skeletal muscle atrophy in obesity and ageing, accompanied by coordinated suppression of stress- and inflammation-associated transcriptional programmes. These findings indicate that pharmacological regulation of mitochondrial stress responses influences skeletal muscle vulnerability under chronic metabolic stress and identify skeletal muscle as a previously underappreciated target of imeglimin action.
Insulin secretion measured in vivo reflects the integrated output of pancreatic islets within a multi-organ regulatory network, whereas ex vivo stimulation of isolated human islets captures intrinsic, islet-autonomous secretory competence. Whether these two levels of β cell function mirror each other in humans remains unclear. We studied 63 individuals undergoing partial pancreatectomy who underwent preoperative OGTT with model-based assessment of β cell function and provided pancreatic tissue for ex vivo islet isolation and glucose stimulation. Ex vivo function was quantified as the stimulation index at 16.7 mmol/l glucose (SI16.7) and related to in vivo indices of insulin secretion. SI16.7 was reduced in islets from people with T2D but showed marked inter-individual variability with overlapping distributions between individuals with and without T2D. In non-diabetic individuals, no significant associations were detected between SI16.7 and OGTT-derived indices. In contrast, in people with T2D, SI16.7 was positively associated with multiple measures of glucose-driven insulin secretion and inversely with potentiation. In multivariable analysis, a composite index of intrinsic glucose-dependent β cell competence remained independently related to SI16.7. These findings indicate that a direct correspondence between systemic β cell function and intrinsic islet secretory capacity emerges only in T2D. This state-dependent alignment suggests that loss of network-mediated regulation may unmask islet-intrinsic defects, allowing ex vivo islet performance to better reflect in vivo insulin secretion and supporting integrated in vivo-ex vivo phenotyping as a tool for functional stratification of T2D.
We summarize and discuss evidence on management of chronic hypoparathyroidism (HypoPT) and primary hyperparathyroidism (PHPT) in pregnancy and lactation to provide guidance for clinical care. Women with HypoPT are at increased risk of certain pregnancy complications, though most pregnancies are uncomplicated. Conventional therapy with activated vitamin D and calcium is continued throughout pregnancy, but there are unpredictable changes in the required dosages warranting regular surveillance during pregnancy (e.g., all 3 to 4 weeks). Data on parathyroid hormone (PTH) replacement therapy in pregnancy are limited, but a few case reports suggest favourable outcomes with this treatment. During lactation, dosage requirements for conventional therapy of HypoPT are often reduced and usually normalize again after weaning. In women with PHPT, surgical treatment should be pursued before conception. PHPT is not associated with adverse pregnancy outcomes in women with mild hypercalcemia but maternal and fetal complications significantly increase with higher calcium concentrations. There is no clear threshold for this risk increase, but several studies and expert groups support a cut-off concentration of about 2.85 mmol/L in albumin-adjusted calcium and 1.45 mmol/L in ionized calcium. For pregnant women with PHPT and calcium above these cut-off concentrations, parathyroidectomy, preferentially in the second trimester, is recommended. Medical treatment for hypercalcaemic PHPT is limited and requires individual decision making. Immediately after delivery, hypercalcemia may worsen in women with PHPT. Clinical care of women with HypoPT and PHPT in pregnancy and lactation requires intensive surveillance and consideration of the specific changes in bone and mineral metabolism during these times.
Chronic urticaria (CU) is a condition characterized by recurrent wheals/angioedema lasting longer than 6 weeks. It is treated in a stepwise manner, starting with antihistamines and escalating to more advanced therapies, if needed. It is frequently associated with autoimmune thyroiditis (AT), and thyroid autoantibodies and thyroid-stimulating hormone (TSH) may contribute to the severity of symptoms, though the exact pathogenesis remains unclear. We performed a systematic search on Scopus and Pubmed databases, finding nine studies published between 1989 and 2018. Five studies were therefore included in our meta-analysis, and we found that the treatment with L-thyroxine (LT4) is associated with a significant improvement in CU symptoms (sMD -2.31, 95% CI -2.98 to -1.64; p < 0.00001). However, when compared with placebo or standard care, LT4 did not demonstrate superiority in terms of symptom scores. It is unclear whether it provides greater benefit in individuals with normal thyroid function or hypothyroidism, or whether it is more effective when used as suppressive or replacement therapy. Therefore, evidence for LT4 treatment improving urticaria is conflicting, with uncertain benefit prompting further evaluation and in-depth study of the molecular mechanisms and markers linking CU and AT.
Type 2 diabetes mellitus and chronic kidney disease are associated with increasing risk of constipation. We previously reported that Bifidobacterium bifidum G9-1 improved stool consistency, bowel movement, and quality of life of patients with type 2 diabetes mellitus, chronic kidney disease, and constipation. However, the effect of patients' background characteristics on the efficacy of B. bifidum G9-1 has not yet been investigated. This prespecified subgroup analysis of the BIRDIE study investigated the effect of age, sex, and baseline renal function on the efficacy of B. bifidum G9-1. The primary endpoint, the percentage of participants with normal stool consistency at week 12, significantly increased in participants aged ≥65 years, male, and those with estimated glomerular filtration rate of ≥60 mL/min/1.73 m2. Regarding the secondary endpoints, although the improved variables differed according to subgroup, the constipation score on the Gastrointestinal Symptom Rating Scale and abdominal bloating among the abdominal symptoms significantly improved in most of the subgroups, except for the subgroup including only a few participants. Metformin users were more likely to experience relief from constipation, whereas insulin users were less likely to experience improvement. Patients aged ≥65 years, male, and those with estimated glomerular filtration of ≥60 mL/min/1.73 m2 are more likely to benefit from treatment with B. bifidum G9-1. These results may provide useful guidance for considering treatment options based on patients' background characteristics upon treatment of constipation in patients with type 2 diabetes mellitus and chronic kidney disease.
Daily GH injections promote growth in girls with Turner syndrome (TS), but treatment burden is considerable. This study aims to evaluate 52-week efficacy and safety of once-weekly somapacitan, a long-acting GH, in girls with TS. REAL8 (NCT05330325) is a randomized, open-labelled, active-comparator, phase 3 basket study with a 52-week main phase and a 104-week extension. The study was conducted at 49 clinics in 18 countries worldwide. In total, 105 treatment-naïve, prepubertal girls with TS (aged 2.5-10 years), were randomized and exposed. No participants discontinued trial product due to adverse events. Participants were assigned 2:1 to somapacitan, 0.24 mg/kg/week, or daily GH 0.050 mg/kg/day, administered subcutaneously. The primary endpoint was height velocity (HV; cm/year) at week 52. Non-inferiority for once-weekly somapacitan vs. daily GH for the primary endpoint, HV at week 52, was confirmed. At week 52, mean observed HV was 9.0 (1.6) vs. 9.5 (2.2) cm/year for somapacitan and daily GH, respectively (ETD = -0.8 [-1.57; -0.11]95%CI). IGF-I SD score (SDS) increased in both groups. At week 52, mean (SD) IGF-I SDS was +1.71 (1.38) vs. + 1.95 (1.11) for somapacitan and daily GH, respectively. Safety profiles were similar between groups. Once-weekly somapacitan showed non-inferiority and is comparable to daily GH after 52 weeks of treatment in enhancing linear growth while maintaining IGF-I concentrations within a similar range in treatment-naïve girls with TS. Similar safety profiles and tolerability were observed for both groups.
To evaluate and compare the risk of diabetic retinopathy and kidney disease between once-daily liraglutide and once-weekly dulaglutide in Japanese participants with type 2 diabetes (T2D). A total of 331 participants newly initiated on once-daily liraglutide 0.9 mg or once-weekly dulaglutide 0.75 mg between 2015 and 2020 were included in this study. We used propensity score-based inverse probability of treatment weighting to adjust for baseline characteristics between the two groups. The participants were divided into three cohorts according to retinopathy, albuminuria, and glomerular filtration rate (GFR). The primary outcomes were the incidence or progression of diabetic retinopathy or kidney disease (albuminuria or reduced estimated GFR (eGFR) <60 mL/min/1.73 m2). The incidence rate and risk of outcomes were compared between the two groups using Poisson regression and Cox proportional hazard models. Over a mean follow-up of 4.4 and 3.6 years in the liraglutide and dulaglutide groups, respectively, there were no differences between the two groups in terms of the risk of incidence of retinopathy and reduced GFR (hazard ratio (HR): 0.98 [0.60-1.60] and 0.82 [0.36-1.84]). Dulaglutide showed a lower incidence or progression rate but similar risk of albuminuria compared to liraglutide (54.7 vs 25.8 per 1,000 person-years (P = 0.04), HR: 0.51 [0.25-1.05]). Our study showed that once-daily liraglutide and once-weekly dulaglutide have similar risks for retinopathy, albuminuria, and reduced GFR.
Environmental exposures have been adversely associated with the risk of diabetes but their role in the remission and progression of prediabetes (impaired glucose tolerance [IGT] and/or impaired fasting glucose [IFG]), especially different phenotypes, is poorly understood. This study aimed to investigate the relationship between environmental exposures and remission or progression of prediabetes phenotypes. Data were derived from the KORA (Cooperative Health Research in the Region of Augsburg) cohort in Southern Germany (2006-2022). Glucose tolerance status was defined according to the 1999/2006 WHO criteria. We included annual values of particulate matter (PM), light at night (LAN), normalised difference vegetation index (NDVI), imperviousness (IMP) and air temperature variation (Tsd). We fitted complementary log-log regression models for associations between IQR changes in exposures and the incidence of prediabetes phenotypes (isolated impaired fasting glucose [iIFG], isolated impaired glucose tolerance [iIGT], or their combination [IFG+IGT]), remission to normal glucose tolerance (NGT) or progression to type 2 diabetes. We also applied Quantile g-computation regression models for joint association analysis. During the follow-up, 370/1618 participants developed prediabetes (124 iIFG, 199 iIGT and 47 IFG+IGT). Among participants with prediabetes, 136/367 (without medication) regressed to NGT and 133/420 progressed to type 2 diabetes. We observed consistent associations of air pollutants and the built environment with iIGT or IFG+IGT. For example, an IQR increase in PM2.5 (aerodynamic diameter ≤2.5 μm) showed an HR of 1.89 (95% CI 1.07, 3.31) for the risk of IFG+IGT and 1.59 (95% CI 1.03, 2.46) with a decrease in NDVI. Co-exposure to environmental mixtures (higher air pollution, Tsd, IMP and LAN, and lower NDVI) was associated with increased risks of iIFG, iIGT and IFG+IGT. Additionally, lower NDVI (HR 0.52 [95% CI 0.28, 0.96]), higher LAN (HR 0.22 [95% CI 0.08, 0.62]) and higher IMP were associated with reduced remission of iIFG but we found no statistically significant associations with the progression to type 2 diabetes. The findings indicate potential heterogeneity in environmental exposures and prediabetes phenotypes. Specifically, they are associated with increased incidence of IGT and decreased remission of iIFG.
Hypophosphatasia (HPP) is the rare inborn-error-of-metabolism that features impaired mineralization of the skeleton and teeth due to a deactivating mutation or mutations of the gene ALPL which encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). We report 17-year follow-up of twin sisters and a brother referred in middle-age for painful proximal femoral "stress fractures" and then diagnosed with HPP. They reported generalized muscle and bone pain, metatarsal fractures, arthropathy and, since childhood, tooth loss. Their concordant findings were explained by compound heterozygosity in ALPL for a rare maternal missense mutation (c.1403C > T, p.Ala468Val) in exon 12, together with a novel presumably paternal change (c.863-14G > A) predicting a cryptic mRNA splice site in intron 8. Fractures continued during follow-up until one sister received a three-and-one-half-year course of hydroxyapatite-targeted TNSALP supplementation therapy (asfotase alfa) during which substantial improvement occurred in her clinical, biochemical, and functional parameters as well as quality of life. Following subsequent unplanned treatment cessation she suffered significant clinical deterioration, including new fractures and loss of mobility. Her bone histopathology documented osteomalacia. Treatment resumption restored its benefits. Among ten asymptomatic family members evaluated in this four-generation kindred, eight were carriers heterozygous for either ALPL mutation. Those harboring the maternal missense defect manifested mild hypophosphatasemia, suggesting a dominant-negative mutation effect. This experience underscores the importance of in-depth phenotyping and then clinical follow-up to characterize ALPL variant combinations, and for maintaining effective asfotase alfa treatment.
Sodium-glucose cotransporter 2 (SGLT2) selective inhibitors (flozins) are a class of antidiabetic drugs that improve glycaemic control and are associated with cardiovascular benefits, although the underlying mechanisms remain incompletely understood. This study aimed to explore potential mechanistic effects of dapagliflozin on erythrocyte nanomechanical properties in patients with type 1 diabetes. The subject of this exploratory study is the nanomechanical properties of red blood cells (RBCs) in a pilot group of type 1 diabetes patients undergoing a thirty-day dapagliflozin treatment. Measurements were conducted on RBCs obtained from a homogeneous group of 31 adult patients with type 1 diabetes and 34 healthy control volunteers. The elastic modulus of erythrocytes was measured immediately after sample collection using the nanoindentation method with an atomic force microscopy probe. Data obtained before therapy (BT) and after therapy (AT) were compared with those from a control group of healthy volunteers. A reduction in RBC stiffness after treatment was observed, which could be related to diabetes duration. Notably, the most significant improvement occurred in patients with diabetes duration exceeding 10 years, a group at elevated cardiovascular risk. Subgroup analyses were descriptive and not powered for inferential comparisons. The observed improvement in the elastic modulus of erythrocytes following dapagliflozin therapy in patients with type 1 diabetes suggests that SGLT2 inhibitors could provide additional benefits for this patient group The results provide preliminary mechanistic insights that are consistent with the reported vascular effects of SGLT2 inhibitors.
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