The polygenic New Zealand obese (NZO) mouse model displays the characteristics of early type 2 diabetes: fasting hyperglycemia, hyperinsulinemia, and insulin resistance. The expression of the ATP-sensitive potassium (KATP) channels in the β cells was reported to be reduced. To define at the cellular level the role of the KATP channel function for the altered insulin secretion of NZO mice. We measured the plasma membrane potential, KATP channel currents, cytosolic Ca2+ concentration ([Ca2+]i), and insulin secretion of NZO mouse islets and β cells in comparison with those of metabolically healthy NMRI mice. The potassium current of NZO β cells had half the extent of that of NMRI β cells and remained so in the presence of the KATP channel opener, diazoxide. The KATP channel blocker, tolbutamide, reduced the currents to the same low level. At low glucose and in the presence of diazoxide, the plasma membrane potential of NZO β cells was less polarized, and consequently, [Ca2+]i was higher in NZO β cells than in NMRI β cells. The depolarization and [Ca2+]i increase by tolbutamide were not different. Insulin secretion of the NZO islets was higher than that of NMRI islets at low glucose and in the presence of diazoxide, but was lower than that of NMRI islets in the presence of tolbutamide and of high glucose. The higher insulin secretion at basal glucose, but not the lower stimulated secretion of NZO islets, is at least partly due to the reduced expression of the KATP channels.
Propylthiouracil (PTU) use has decreased due to adverse events (AEs), but it is still needed for patients who cannot tolerate thiamazole. To compare the efficacy and safety of the PTU protocol between high-dose monotherapy and low-dose combination therapy with potassium iodide (KI). This is a retrospective observational study including patients who were newly diagnosed with Graves disease (GD) and received PTU as initial therapy between January 2005 and October 2024. Patients who received an initial dose of 300 mg (high-dose group) and those who received 150 mg of PTU combined with 50 mg of KI (low-dose group) were included. The propensity-score matching method was employed to adjust for confounders. A total of 1171 patients (high-dose: low-dose = 1133: 38, all female) with a median age of 32 (interquartile range [IQR]: 28-36) years were included. Median levels of free-thyroxine (FT4) and thyroid-stimulating hormone receptor antibody were 4.97 (IQR: 3.67-7.31) ng/dL, 12.4 (IQR: 6.4-26.8) IU/L. Adverse events occurred in 294 patients (high-dose: low-dose = 289:5). Free-thyroxine levels were significantly lower at Week 2 in the low-dose group than in the high-dose group (P = .014), but the difference disappeared afterwards. The prevalence of inadequate efficacy with the initial dose was significantly higher in the low-dose group (12.8% vs 35.5%, P = .002). Despite a lower rate of efficacy from the initial dose, the low-dose protocol was effective in controlling hyperthyroidism with up-titration in young women with GD, with the potential for fewer AEs.
Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant syndrome characterized by tumors in multiple endocrine tissues. Its management is challenging because of its unpredictable course, particularly regarding thymic tumors, whose prognosis remains poor. To identify the genetic factors associated with the development of thymic tumors in patients with MEN1. Nested case-control study in the Groupe d'étude des Tumeurs Endocrines and of the Association Francophone de Chirurgie Endocrinnienne cohort (>1600 patients included from the 1990s through 2024). Ambulatory and hospitalized care in referral centers. All men with a confirmed thymic tumor in the Groupe d'étude des Tumeurs Endocrines/Association Francophone de Chirurgie Endocrinnienne cohort were selected and matched to 2 nearest controls without thymic tumors, with a diagnosis of MEN1 identified at the same period (<1990; 1990-2000; ≥2000) and with an age at their last follow-up at least equal to the age of their paired case at the time of thymic tumor discovery. Development of thymic tumor. Fifty-two cases and 104 controls were included. Mean age at diagnosis of thymic tumor was 44 (SD = 11). Nonsense mutations were associated with a higher risk of thymic tumors (OR = 3.77; 95% CI, 1.36-10.50) than men with frameshift mutations. Among cases, the median age of onset of thymic tumor was almost identical between patients with a nonsense mutation and those without (43.8 vs 43.2 years, respectively). Men carrying nonsense MEN1 mutations may have an increased risk of thymic tumors and could benefit from enhanced thymic surveillance.
Palopegteriparatide is a prodrug of parathyroid hormone (PTH) (1-34), administered once daily. It is designed to provide active PTH within the physiologic range for 24 hours/day. The effects of palopegteriparatide on serum and urine markers were explored to determine if the pharmacodynamic profile of palopegteriparatide reflects continuous disease control in adults with hypoparathyroidism. A 24-hour sub-study was conducted during the PaTH Forward trial. Eligible participants were those who completed the Week 58 visit and received stable doses of palopegteriparatide for the prior week. Upon admission to the clinical research unit, participants received their usual dose of palopegteriparatide. Plasma PTH, serum calcium (albumin-adjusted), and serum phosphate concentrations were evaluated at 4-hour intervals. Urinary calcium, phosphate, and citrate concentrations were determined from each of six 4-hour collection periods. Descriptive statistics were performed. Palopegteriparatide doses ranged from 12 to 33 µg/day and resulted in continuous exposure to active PTH within the estimated normal range over 24 hours. Mean serum calcium and serum phosphate were maintained near or within the normal ranges. Median urine calcium concentration was stable in the normal range for all 4-hour collection periods. Urine phosphate concentrations showed minor variability across collection intervals, and urine citrate was maintained above the lower limit of normal. Palopegteriparatide provided continuous exposure to active PTH within the physiological range. The expected pharmacodynamic effects of continuous PTH exposure on serum and urine chemistries were consistent with the efficacy and safety of palopegteriparatide demonstrated in the published PaTH Forward and PaTHway clinical trials.
No prior meta-analysis has systematically assessed efficacy and safety of C-type natriuretic peptide (CNP) analogs within the context of evolving understanding of FGFR3 biology and achondroplasia natural history. To evaluate the safety and efficacy of CNP analogs in children with achondroplasia and contextualize clinical outcomes and natural history. Systematic review of randomized control trials and real-world studies evaluating the safety and efficacy of CNP analogs (vosoritide and navepegritide) in children aged <18 years with genetically confirmed achondroplasia was performed. Coprimary outcomes of interest were adverse events (AEs) and changes from baseline in annualized growth velocity (AGV) at the end of the trials. Secondary outcomes included changes from baseline in height Z-score, standing height, and upper-to-lower body segment (ULS) ratio. Eleven studies (N = 542) were included, of which 4 RCTs (n = 326) with low overall risk of bias were meta-analyzed. Overall and serious AE rates were comparable between CNP analogs and placebo, except for higher relative risks of injection site reactions (1.65), urticaria (4.04), and swelling (3.57). C-type natriuretic peptide analogs significantly increased mean differences in AGV (1.36 cm/year; 95% CI: 1.05-1.68; P < .00001) and standing height (1.24 cm; 95% CI: 0.47-2.01; P = .002), without short-term effect on ULS ratio. Real-world studies demonstrated sustained growth benefits with infrequent serious AEs or treatment discontinuations. C-type natriuretic peptide analogs provide slight but statistically meaningful improvements in linear growth in children with achondroplasia with acceptable short-term safety profile. Long-term studies are needed to define optimal timing of therapy on adult height, functional outcomes, and achondroplasia-related complications.
Lenvatinib (LEN) is effective in the treatment of radioactive iodine refractory differentiated thyroid cancer (DTC), though it is associated with frequent and potentially severe adverse events (AEs). The dose dependency of LEN-related toxicity remains unclear, since no data are available on this topic. This study aimed to investigate the relationship between LEN dose and plasma concentrations in real-life patients by a novel and validated method for quantifying LEN in plasma samples. A sensitive high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS) assay for LEN quantification in plasma was set up, with a wide analytical range (0.7-500 ng/mL). Consecutive plasma samples from 19 patients with radioactive iodine-refractory, metastatic DTC were analyzed. A positive correlation between the administered LEN dose and plasma concentrations was found, particularly in patients on low doses (<18 mg daily). Linear mixed-effects models (LMMs) demonstrated significant interindividual variability in plasma LEN concentrations, contributing to 17% to 28% of the total variance. This variability was more pronounced at higher doses (≥18 mg), being more likely the consequence of LEN-related AEs than of a dose-dependent effect. This is the first real-life evaluation of interindividual LEN pharmacokinetics variability in advanced DTC patients, obtained by means of the newly developed HPLC-MS/MS method. Our results suggest that the dose-response relationship of LEN in radioactive iodine-refractory DTC may be more complex than previously understood, with substantial interpatient variability and dose-dependent effects. Further studies are needed to determine the implications of our findings in the clinical management of these patients.
Lipodystrophy syndromes represent a diverse group of rare disorders characterized by deficiency and abnormal distribution of adipose tissue that may be generalized (GL) or partial (PL), leading to significant metabolic abnormalities. To elucidate the natural history of critical comorbidities of lipodystrophy. Ongoing, prospective, multicenter, registry study (LD Lync; NCT03087253). This analysis reports 266 patients with lipodystrophy enrolled until October 11, 2023. The median age was 39 years ([28-54], range: 6-76 years; male/female: 50/216). Hypertriglyceridemia (n = 202, 75.9%) was the most common comorbidity, followed by diabetes (n = 190, 72.0%), hepatic steatosis (n = 182, 68.4%), and hypertension (n = 130, 48.8%). Pancreatitis was detected in 21.8% of patients (n = 58), and cirrhosis in 7.1% of patients (n = 19). The median age at diagnosis was significantly earlier in patients with GL compared to those with PL for both diabetes (16 [14-32] years in GL vs 35 [25-50] years in PL) and hypertriglyceridemia (20 [15-26] years in GL vs 30 [22-49] years in PL) (P < .0001). Seven (2.6%) patients died during follow-up. Multiple medications were used to treat metabolic disease. Eighty-one (30.4%) patients received at least one dose of metreleptin during clinical studies or commercially during follow-up. Our findings confirm that patients with lipodystrophy face a significant risk of comorbidities, with an earlier onset of diabetes, hypertriglyceridemia, and hepatic steatosis in those with GL compared to PL. This registry will serve as a crucial resource for gaining insights into the burden of disease in lipodystrophy.
Classic congenital adrenal hyperplasia (CAH) is a rare genetic condition characterized by impaired cortisol and aldosterone synthesis. Historical management required glucocorticoid (GC) therapy to replace cortisol and, often, to suppress excess ACTH and adrenal androgens. However, supraphysiologic GC doses can lead to substantial complications. This study aimed to characterize the clinical burden associated with CAH and quantify the degree to which CAH- and/or GC-related complications manifest. Retrospective cohort analyses were conducted using administrative claims data from MarketScan® Research Databases (1/1/2020-12/31/2022) to quantify the burden of CAH- and/or GC-related complications among insured patients with CAH in the United States compared with a matched cohort. A total of 719 patients with CAH receiving GC therapy were matched 1:5 with 3595 individuals based on age, sex, payer, region, and enrollment duration. Patients with CAH had significantly higher rates of predominantly GC-related complications, including cardiovascular/circulatory diseases, type 2 diabetes, hypertension, hyperglycemia, metabolic complications, obesity, and osteoporosis (all P < .05). Patients with CAH demonstrated significantly higher rates and risks of nearly all CAH-related complications compared with matched controls (P < .05). Rates and risks of nearly all complications categorized as both CAH- and GC-related were significantly higher among patients with CAH (P < .05). Rates were consistently higher in adults than pediatric patients, underscoring the progressive and cumulative nature of CAH- and GC-related morbidity. Individuals with CAH experience higher rates and risks of CAH- and/or GC-related complications, highlighting the considerable burden associated with CAH and supraphysiologic GC treatment. Higher complication rates in adults emphasize the need for early and effective management of CAH. Novel non-GC therapies may enable GC dose reduction while maintaining androgen control, potentially mitigating these complications.
The insulin/insulin-like growth factor (IGF) system is a key regulator of fetal growth and placental nutrient regulation. The objective of this study was to investigate associated gene and protein expressions of the insulin/IGF, adiponectin, and peroxisome proliferator-activated receptor (PPAR) pathways in placenta and cord blood from small-, appropriate-, or large-for-gestational-age (SGA, AGA, LGA) infants and corresponding first-trimester maternal blood. A total of 60 SGA, 109 AGA, and 55 LGA term infants (birth weight z scores <-2, -2 to +2, and >2, respectively) were included. Placental mRNA expression of 22 genes was analyzed using RT-qPCR. Immunohistochemistry (IHC) was used to determine the protein localization and abundance of 5 differentially expressed genes in 78 representative placental samples. Cord blood and maternal blood concentrations of related proteins were analyzed by ELISA. Placental gene expression of IGF1, IGF2, IGBP2, IGF2R, and PPARA was significantly lower in the SGA group. A moderate correlation in expression levels was observed among differentially expressed genes, except for IGF2R. In the SGA group, IHC staining for IGF1, IGF2, IGF2R, and PPARα was weaker, while IGFBP2 staining was stronger. In the cord blood, the IGF1 and IGF2 concentrations increased successively from the SGA group to the LGA group, whereas the IGFBP2 concentration decreased successively. No differences in maternal blood were observed between the groups. Placental IGF1, IGF2, and PPARα signaling are positively associated with birth weight, whereas that of IGFBP2 is negatively associated, possibly reflecting a shared upstream regulation by nutrition. Conversely, placental IGF2R signaling may aid in normalizing abnormal fetal growth.
Childhood, adolescent, and young adult cancer survivors (CAYA) are at an increased risk for metabolic disorders such as diabetes mellitus. Although this risk has been well-documented for leukemia survivors and those exposed to abdominal radiotherapy, the metabolic risk profile for brain tumor survivors remains largely unexplored. This study assessed the prevalence of diabetes and dysglycemia in 2 CAYA survivor cohorts. The first included medulloblastoma and ependymoma survivors (HIT-MED), with data collected via self-reported online questionnaires. The second (CLI) was a retrospective analysis of an unselected cohort from our late effects clinic. In this cohort, dysglycemia was defined using hemoglobin A1c measurements alone, without additional glucose-based diagnostic criteria. In the HIT-MED group, 37% (197/527) participated in an online-based questionnaire, revealing a diabetes mellitus prevalence of 3.05%. A total of 122 were male and 75 female, mean age was 27.1 ± 4.5 years (range 19-41). In comparison to an age-matched general population, there was no significant difference (P = .468). Among survivors in the CLI group who received craniospinal irradiation (mean age 38 years at assessment), 34.6% (9/26) exhibited dysglycemia, including 7.7% (2/26) with diabetes mellitus and 26.9% (7/26) with prediabetic glucose levels. This represented the second highest prevalence of impaired glucose regulation among all irradiation subgroups. CAYA brain tumor survivors exposed to craniospinal radiotherapy have an elevated risk of dysglycemia compared to other survivor cohorts. These findings support the need for structured, risk-adapted long-term metabolic monitoring to enable early intervention and reduce long-term morbidity.
Early prediction of ovarian reserve is essential to improve fertility counseling in girls with Turner syndrome (TS). This work aimed to examine the occurrence of puberty and longitudinal hormone patterns in girls with TS, and to take an initial step toward developing a prediction model for ovarian function. Main outcome measures included thelarche, menarche, and age of premature ovarian insufficiency (POI). A retrospective cohort study was conducted of girls with TS. Levels of serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), antimüllerian hormone (AMH), inhibin B, and information on karyotype and puberty were extracted from the medical records. A joint model combining a Cox survival model and 2 linear mixed-effects models for FSH and AMH was used to model the association between POI and longitudinal hormone values. A total of 365 girls were included, of whom 287 had available data on pubertal development. In this patient cohort, 43% had monosomy 45,X, 17% had mosaic 45,X/46,XX, 18% had an isochromosome X, and 22% had an "other" karyotype in lymphocytes. Girls with spontaneous puberty had lower FSH and higher AMH before age 8 years compared to girls without spontaneous puberty. The joint model showed that lower AMH is significantly related to POI, while FSH was not significantly related to POI. The individual predicted risks on POI come with large uncertainty. AMH and FSH patterns contribute to understanding ovarian reserve at an early age in girls with TS. Creating a prediction model remained challenging and more data are needed.
Medical treatment of Cushing syndrome (CS) with steroidogenesis inhibitors or ACTH-directed agents is typically given using a titration strategy to achieve "normal" exposure to cortisol, as determined by a 24-hour urine free cortisol (UFC) measurement. This approach generally achieves similar serum cortisol levels across the day and fails to provide a normal diurnal pattern of cortisol. Chronotherapy addresses this problem through weighted afternoon/evening dosing of cortisol-lowering drugs. Additionally, because of day-to-day variability of cortisol production, patients may be undertreated on days of higher cortisol production and overtreated on days of lower cortisol production. A "block and replace" strategy is an alternative approach in which consistent biochemical glucocorticoid deficiency is the goal, with added glucocorticoid replacement to provide physiologic diurnal exposure to cortisol. Recently, the term mild autonomous cortisol secretion (MACS) has been used to describe patients without clinical features of CS who fail to suppress cortisol after 1 mg dexamethasone. MACS includes individuals with an adrenal mass(es) who may have hypertension, type 2 diabetes mellitus, and/or osteoporosis. The role of medical vs surgical treatment of MACS is currently debated. We here review the advantages and disadvantages of each approach to medical treatment of CS and MACS, concluding that "block and replace" deserves wider consideration, especially in patients who have severe disease, and to avoid adrenal insufficiency in those with highly variable UFC, or are taking agents that may cause adrenal insufficiency. Conversely, in those with mild disease, chronotherapy normalizes nighttime cortisol exposure while reducing drug burden.
The relationship between body composition, especially fat mass (FM), and bone mineral density (BMD) is still a matter of debate. The aim of this study was to test whether FM and lean mass (LM) are predictors of osteoporosis and if the association between body composition and BMD varies by sex, age, and body mass index (BMI) status. We analyzed 1316 participants from the ELSA-Brasil Cohort who underwent dual-energy X-ray absorptiometry. Osteoporosis prevalence was stratified by BMI category and sex. Multivariable regression analyses were performed with lean and FM indexes as predictors of osteoporosis and BMD at different sites according to sex, age, and BMI category. Osteoporosis was prevalent in 18.6% of postmenopausal females and 8% of males aged ≥50 years. In the fully adjusted model, LM was inversely associated with osteoporosis in the overall male population and in females with BMI ≥30 kg/m2 and positively associated with BMD in males and in postmenopausal females with BMI ≥25 kg/m2. FM was positively associated with BMD in postmenopausal females with BMI < 25 kg/m2. In postmenopausal women with a BMI < 25 kg/m2, BMD is positively associated with FM, whereas in postmenopausal females with a BMI ≥25 kg/m2, BMD is positively associated with LM. These findings support the theory that FM is an important predictor of BMD-possibly due to its effect on estradiol levels through aromatization-up until a certain "fat threshold", after which other factors, including LM and its effect on mechanical loading, likely become more dominant factors affecting BMD.
Thyroid cancer incidence is rising worldwide, yet comprehensive longitudinal data linking contemporary demographic, pathological, and surgical trends to recurrence risk remain scarce. A retrospective analysis was performed on 9504 thyroid cancer patients from 2008 to 2023. Based on the year of treatment, patients were categorized into 3 groups for comparative assessment. Demographic features, clinical pathological characteristics, surgical approaches, and prognostic outcomes were evaluated. Over the 16-year period, the annual number of new thyroid cancer cases demonstrated a consistent upward trend, with a growing proportion detected through routine health screenings. The male-to-female ratio was 1:2.76, with a gradual increase in male patients. The peak age at diagnosis remained between 30 and 60 years, while the proportion of juvenile patients declined steadily. Papillary thyroid carcinoma constituted the predominant histologic type. Surgical management shifted toward more conservative approaches. Although tumor size decreased over time, the incidence of multifocal lesions and the BRAF V600E mutation rate rose. Lymph node metastasis rates also increased, particularly in patients with central region metastases and metastases in ≤5 lymph nodes. Multivariate analysis identified age, tumor size, and number of metastatic lymph nodes as independent risk factors for recurrence in papillary thyroid carcinoma. Patients older than 55 years, those with larger lesions, or those with more lymph node metastases exhibited a significantly elevated recurrence risk. Although thyroid cancers are being detected at earlier stages and smaller sizes, the burdens of molecular, multifocal, and lymph node disease are increasing. Age, tumor size, and nodal metastatic load constitute robust independent predictors of recurrence in papillary thyroid carcinoma, informing risk-adapted surveillance and surgical strategies.
Premature pubarche (PP) is a frequent reason for endocrine evaluation. Between 5% and 20% of children presenting with PP may have 21OHD nonclassic congenital adrenal hyperplasia (21OHD-NCAH). To define optimal basal and ACTH-stimulated 17OHP cutoffs for diagnosing 21OHD-NCAH in children with PP, using CYP21A2 genotyping as the gold standard. A diagnostic accuracy study including 203 children with PP (median age: 7.5 years [6.4-8.3]; 85% female) who underwent ACTH stimulation testing. Biallelic pathogenic variants upon CYP21A2 genotyping defined 21OHD-NCAH. Diagnostic performance of basal and post-ACTH 17OHP levels assessed by ROC curve analysis and thresholds defined according to the Youden index. 21OHD-NCAH was confirmed in 32 children (15.7%; 7.1 years [6.1-8.6]; 78% female). Basal 17OHP demonstrated excellent diagnostic accuracy (AUC = 0.98). A cutoff of 170 ng/dL (5.1 nmol/L) provided the best diagnostic balance, with 97% sensitivity and 91% specificity. A higher threshold of 410 ng/dL (12.4 nmol/L) achieved 100% specificity but reduced sensitivity (75%), whereas a lower cutoff of 118 ng/dL (3.5 nmol/L) yielded 100% sensitivity at the expense of specificity (84%). A post-ACTH 17OHP > 1104 ng/dL (33.4 nmol/L) yielded 100% sensitivity and specificity. Androgen levels overlapped substantially, and no clinical feature reliably distinguished 21OHD-NCAH from PP. Basal 17OHP provides excellent diagnostic accuracy for 21OHD-CAH in children with PP. A dual-threshold strategy is supported: 170 ng/dL (5.1 nmol/L) as optimal screening cutoff and 410 ng/d (12.4 nmol/L) as highly specific diagnostic threshold, obviating ACTH testing. These genotype-anchored, RIA-derived cutoffs are readily applicable in clinical settings using comparable assays.
Thyrotropin receptor blocking antibodies (TBAbs) are uncommon but not a rare cause of hypothyroidism. However, clinical outcomes of thyroid function in patients with TBAb-positive hypothyroidism remain unclear. The aim of this study was to explore the clinical outcomes of thyroid function in patients with TBAb-positive hypothyroidism and investigate factors associated with hypothyroidism outcomes. A single-center retrospective observational study was conducted from 2024 to 2025. Overall, 137 patients with TBAb-positive hypothyroidism without Graves' disease (Non-GD group) and 181 with TBAb-positive hypothyroidism during or after antithyroid drug therapy for Graves' disease (Prior GD group), almost all Japanese, were included. Thyroid functional outcomes were assessed in all patients; serial TBAb measurements were available for 31% and 36% of the patients, respectively. The main outcome was thyroid function at the final visit after a median follow-up period of 6.8 years. Clinical factors associated with hypothyroidism outcomes were analyzed using logistic regression analysis. Hypothyroidism persisted in 84% and 43% of the patients in the Non-GD and Prior GD groups, respectively. In both groups, persistent TBAb positivity was associated with hypothyroid outcomes (Non-GD: univariate analysis, odds ratio [OR], 3.51; 95% CI, 1.14-40.6; P = .013; Prior GD: univariate analysis, OR, 6.75; 95% CI, 1.87-24.4; P = .0016; multivariate analysis, OR, 6.88; 95% CI, 1.89-25.1; P = .0015). Most patients with TBAb-positive hypothyroidism remain hypothyroid over the long term, whereas outcomes are more heterogeneous in patients with prior Graves' disease who develop TBAb-positive hypothyroidism. Persistent TBAb positivity is associated with the hypothyroidism outcomes.
The coexistence of diabetes and hyperinsulinemic hypoglycemia (HI) within a family is rare. Activating MAFA variants have been described in 3 families with this dual phenotype and are associated with sex-dependent clinical patterns. We studied a family where members were affected by HI (n = 5), diabetes (n = 5), or both conditions (n = 1). Clinical, biochemical, and imaging data were collected. Genetic testing for variants in known monogenic diabetes and HI genes was performed in the proband, followed by cascade testing in available relatives. Pancreatic tissue was examined by immunohistochemistry and immunofluorescence. A heterozygous, p.(Ser64Phe) MAFA variant was identified in the male proband, who had presented with diabetes at 28 years and developed HI due to insulinomatosis 6 years later. The variant was confirmed in 5 relatives, 4 with HI and 1 with diabetes (including obligate heterozygotes). Among the 5 presenting with HI, 3 were female, whereas 4 of 6 presenting with diabetes were male, consistent with reported sex-dependent patterns.Increased nuclear expression of the transcription factor MafA (MAFA) was detected by immunofluorescence in insulin-positive tumor regions compared to the adjacent islets, supporting a pathogenic role for the variant in beta-cell regulation. We describe the fourth family with a pathogenic MAFA variant and the second individual with the dual phenotype of diabetes and HI. Our findings highlight challenges in clinical management of this condition and underscore the need to consider MAFA in cases of adult-onset HI or those with an atypical course of diabetes especially when there is family history.
To provide a descriptive summary and to quantitatively examine racial and ethnic disparities in the use of continuous glucose monitoring (CGM) and continuous subcutaneous insulin infusion (CSII) among people living with diabetes in the United States. We followed the Cochrane and PRISMA guidelines (PROSPERO: CRD420251124678). Search was conducted on PubMed, Embase, and Cochrane up to August 2025. Observational studies were included if they (1) were conducted in the United States, (2) evaluated the use of CGM/CSII across different races/ethnic groups, and (3) reported odds ratios (ORs) for between-group comparisons. Three-level random-effect meta-analyses examined OR in the use of CGM/CSII across different groups: Non-Hispanic White (NHW; reference group) vs Black/African American, Hispanic, Asian, and Other. Subgroup analyses were conducted for children vs adults, and type 1 vs type 2 diabetes. Totally, 1737 studies were screened, and 18 studies were included (N = 955 556 individuals). Most participants were NHW (70.9%). Approximately 40% of individuals had type 2 diabetes, and 98.9% were adults. Black/African Americans (OR = 0.47, 95% CI = 0.38-0.60), Hispanics (OR = 0.59, 95% CI = 0.50-0.69), and "Other" (OR = 0.69, 95% CI = 0.58-0.83) were less likely to use CGM, relative to NHW individuals, while Asians were equally likely. Black/African Americans (OR = 0.31, 95% CI = 0.23-0.42) and Hispanics (OR = 0.48, 95% CI = 0.42-0.55) were less likely to use a CSII when compared to NHW. No analysis was conducted for "Asian" or "Other." Limitations include moderate/substantial heterogeneity and reliance on electronic medical record data. Racial and ethnic disparities exist in the use of diabetes technologies. Its recognition is essential to advance solutions that promote equitable care in diabetes.
Incretin-based therapies-glucagon-like peptide-1 receptor agonists (GLP-1RAs) such as semaglutide and the dual GLP-1/GIP receptor agonist tirzepatide-have transformed the management of type 2 diabetes (T2D) and obesity. However, substantial interindividual variability in therapeutic response remains incompletely explained by clinical factors alone. A systematic search of PubMed, SciSpace, and Google Scholar was conducted (through May 2026) using terms including GLP1R, GIPR, polymorphisms, pharmacogenomics, semaglutide, tirzepatide, and Italian population. Relevant original studies, genome-wide association studies, and reviews were included. Common GLP1R variants-notably rs6923761 (Gly168Ser) and rs10305492 (Ala316Thr)-modulate receptor expression, G-protein coupling efficiency, and downstream cAMP signaling, translating to differential HbA1c reduction and weight loss with GLP-1RAs. GIPR rs1800437 (Glu354Gln), present at ∼20% frequency in Europeans, is associated with altered incretin effect and increased nausea/vomiting risk with tirzepatide (OR 1.83). Geographic analyses reveal significant allele frequency variation between European, East Asian, and African populations; Italian-specific data remain limited but suggest frequencies consistent with broader Southern European patterns. Pharmacogenomic profiling of GLP1R and GIPR variants holds promise for personalizing incretin therapy. Prospective studies in Italian and broader Mediterranean cohorts are needed to define clinically actionable genotype-phenotype relationships and inform precision endocrinology practice.
Children with cerebral palsy (CP) and spinal muscular atrophy (SMA) are at high risk of low bone mineral density, fractures, and low muscle mass. The gut-derived hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-2 (GLP-2) reduce bone resorption in adults, but their effects in pediatric populations with CP and SMA are unknown. In this preliminary study, 3 children (1 CP and 2 SMA) underwent 3 interventions: (1) oral liquid mixed-meal ingestion, (2) subcutaneous GIP+GLP-2 administration, and (3) placebo. Plasma levels of GIP, GLP-2, CTX (bone resorption), P1NP (bone formation), and parathyroid hormone (PTH) were measured over 240 minutes. The liquid mixed-meal significantly reduced CTX levels, indicating suppressed bone resorption, while exogenous GIP+GLP-2 administration had no significant effect on CTX or P1NP. PTH levels decreased after GIP+GLP-2 administration but were unaffected by the liquid mixed-meal. In these studies, exogenous GIP and GLP-2 unexpectedly did not modulate bone turnover in our children with CP or SMA. The study highlights the need for age- and disease-specific investigations into the gut-bone axis in pediatric populations.