Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association最新文献

This study investigated the organ-specific effects of a high-methionine (HM) diet in streptozotocin (STZ)-induced diabetic rats, focusing on hepatic and renal metabolic adaptations. Male Wistar rats were divided into four groups (n=8/group): normal control, HM (2% methionine), STZ-diabetic, and HM+STZ. Over 12 weeks, HM supplementation in diabetic rats significantly reduced hepatic triglyceride accumulation (42.00±7.71 vs. 20.76±3.63 mg/g tissue, P<0.01), coinciding with AMP-activated protein kinase (AMPK) activation (1.96-fold, P<0.05) and downregulation of lipogenic genes (sterol regulatory element-binding protein 1c ↓63.2%, P<0.05). Conversely, HM exacerbated diabetic nephropathy, elevating urinary albumin-creatinine ratio (411.90±88.86 vs. 238.41±62.52 mg/g, P<0.05) and glomerulosclerosis index (2.5±0.5 vs. 1.8±0.4, P<0.001). Hyperhomocysteinemia (105.69±33.81 μmol/L) persisted across HM groups without altering folate/vitamin B12 levels (P>0.05). These findings demonstrate a striking dichotomy: HM diet ameliorates hepatic steatosis through AMPK-mediated lipid modulation while accelerating renal injury via homocysteine-dependent pathways. The results highlight the need for organ-specific nutritional strategies in diabetes management.

To assess the necessity of additional imaging by comparing the characteristics of adrenal lesions incidentally detected on abdominal, stone protocol, and chest computed tomography (CT) with those obtained from a second imaging modality specifically targeting the adrenal glands.A total of 162 adrenal lesions imaged in 112 patients with adrenal incidentalomas were retrospectively analyzed. Radiology reports were reviewed for adrenal lesion laterality, location, number of lesions, maximum diameter, the number of dimensions specified, lesion density on CT measured in Hounsfield Units (HU), lesion characterization, presence of heterogeneity, and functional status. Cohen's Kappa test assessed the agreement between the first and second imaging evaluations. Additionally, sensitivity, specificity, positive predictive value, and negative predictive value of the first imaging were calculated using adrenal-specific second imaging as the reference standard.No concordance was found between the initial and follow-up imaging in terms of HU measurements (κ=0.079; p=0.123). However, concordance ranging from weak to excellent was observed regarding bilaterality, localization, lesion count, diameter, and heterogeneity. Based on the second imaging reports as reference, the sensitivity of the initial imaging for diagnosing adenoma and myelolipoma was determined to be 26.49% and 42.85%, respectively. The success rate of adenoma diagnosis was associated with the number of lesions in the adrenal gland (≥2 lesions>single lesion), lesion size (>2 cm>≤ 2 cm), and location (left>right). Nine lesions initially reported as<4 cm on the first imaging were found to be≥4 cm on the second imaging, and seven lesions initially reported as unilateral were noted to be bilateral on the second imaging. In eight patients, adrenal lesions were detected on the first imaging, but the second imaging was reported as normal.A more detailed definition of adrenal incidentalomas, especially in terms of heterogeneity and HU values in the first images in radiology reports, and the use of a standard reporting system will guide clinical practice and provide a cost-effective approach while avoiding unnecessary imaging and radiation.

The histone acetyltransferase KAT8 has been implicated in stem cell biology, but its specific role in human umbilical cord mesenchymal stem cells (hucMSCs) senescence and therapeutic efficacy for diabetic wounds is unclear. This study aimed to investigate the role of KAT8 in hucMSC senescence and to determine if KAT8 knockdown could reverse senescence and enhance the efficacy of hucMSCs in promoting diabetic wound healing. hucMSCs were extracted from the umbilical cord, and senescence was induced. KAT8 expression was assessed in senescent and non-senescent hucMSCs. Senescence markers (senescence-associated β-galactosidase [SA-β-gal] staining, P16, P21 expression), proliferation (Cell Counting Kit-8 [CCK-8], colony formation), cell migration (cell scratch), and differentiation potential (alizarin red and oil red O staining) were evaluated in vitro. Western blotting and quantitative polymerase chain reaction were performed to detect protein expression and mRNA expression levels, respectively. For in vivo studies, a type 1 diabetes mellitus mouse wound healing model was established. Mice received local injections of phosphate-buffered saline (PBS), hucMSCs transduced with a negative control vector (NC hucMSCs), or KAT8-knockdown hucMSCs. Wound closure rates were monitored, and histological analyses (Hematoxylin and eosin [H&E], Masson staining). KAT8 expression decreased during hucMSCs senescence. Knockdown of KAT8 downregulated senescence-associated genes (e.g., P21 and P16) while enhancing hucMSCs proliferation, migration, and survival without altering surface stem cell marker expression. In vivo experiments further confirm that KAT8-knockdown hucMSCs significantly promoted wound healing in a type 1 diabetic mouse model, exhibiting superior therapeutic efficacy.Knockdown of KAT8 effectively reverses senescence in hucMSCs and enhances their therapeutic potential for diabetic wound healing.

Diabetic neuropathy, a debilitating complication of diabetes, arises from chronic hyperglycemia-induced inflammation and oxidative stress, leading to progressive nerve damage. Current therapeutic strategies often focus on symptomatic relief rather than addressing the underlying pathophysiology. Emerging evidence highlights the therapeutic potential of phytobioactives with robust anti-inflammatory and antioxidant properties as promising alternatives for diabetic neuropathy management. Phytobioactives such as flavonoids, polyphenols, alkaloids, and terpenoids demonstrate significant potential by mitigating oxidative stress, inhibiting pro-inflammatory cytokines, and promoting neuroprotection. Furthermore, combination approaches utilizing the synergistic effects of these phytobioactives have shown enhanced efficacy in preclinical models, targeting multiple pathways involved in the progression of diabetic neuropathy. However, clinical translation is hindered by challenges including low bioavailability, chemical instability, and suboptimal dosage. This review explores the mechanistic roles, preclinical evidence, and clinical challenges of phytobioactives in diabetic neuropathy therapy, emphasizing the need for advanced formulation strategies and well-designed clinical trials to optimize their therapeutic potential. Leveraging these phytobioactives could pave the way for more effective and holistic diabetic neuropathy treatments.

Diabetic neuropathy is a serious complication of diabetes mellitus (DM). Its commonest manifestation is diabetic peripheral neuropathy (DPN). Diabetic neuropathy may also affect the autonomic nervous system, cardiac autonomic neuropathy (CAN) being its most widely studied manifestation. Treatment of DPN and CAN relies on glycaemic control and symptom alleviation, emphasizing the need for improvement. To this purpose, the novel antidiabetic oral agents sodium-glucose cotransporter-2 inhibitors (SGLT-2is) have been studied. Beyond their favourable effects on metabolic control and cardiovascular and renal outcomes, these agents appear to harbour some beneficial actions in DPN and CAN as well. The underlying mechanisms are not entirely clear, but appear to involve the 5' adenosine monophosphate-activated protein kinase (AMPK)-pathway. So far, clinical experience has been limited. Significant improvement in electrophysiological parameters and thermal perception has been observed among subjects with type 2 diabetes mellitus (T2DM) in small studies. However, contradictory findings have also been reported. The same ambiguous effect of SGLT-2is has been observed in CAN. Thus, future large studies are required to delineate the utility of SGLT-2is in DPN and/or CAN.

Painful diabetic neuropathy (PDN), a severe microvascular complication of diabetes, is closely associated with neuroinflammation. This study aimed to investigate the mechanism of circ_0002590 in neuroinflammation associated with PDN.The Schwann cells (HEI193) were treated with high glucose (HG, 150 mM) to simulate the diabetic microenvironment. Circ_0002590 expression was silenced using siRNA interference technology and was determined by quantitative real-time reverse transcription polymerase chain reaction. Inflammatory cytokines levels were measured by enzyme-linked immunosorbent assay. The cell counting kit-8 assay was utilized to determine cellular viability. Bioinformatic predictions (TargetScan 8.0 and circRNA Interactome databases) combined with dual-luciferase reporter gene assays and RNA pull-down assays were employed to validate the correlation linking circ_0002590 and miR-1184, as well as between miR-1184 and Nod-like receptor pyrin domain-containing 1 (NLRP1). Rescue assays were performed to confirm the function of the circ_0002590/miR-1184/NLRP1 competing endogenous RNA (ceRNA) network in PDN-associated neuroinflammation.HG treatment significantly upregulated circ_0002590 expression in HEI193 cells, promoted inflammatory cytokine release, and reduced cell viability. These effects were reversed after circ_0002590 silencing. Circ_0002590 directly interacted with miR-1184 and suppressed miR-1184 expression. miR-1184 targeted and inhibited NLRP1 expression. miR-1184 inhibition or NLRP1 overexpression reversed the anti-inflammatory effects mediated by circ_0002590 silencing.HG activates the inflammatory response in Schwann cells by inducing circ_0002590 expression, which competitively binds with miR-1184 and thereby alleviates its inhibitory effect on NLRP1.

To explore how methyltransferase like 14 (METTL14) regulates diabetic nephropathy (DN)-induced cell damage and analyze its underlying mechanisms. The gene expression data were obtained from the Gene Expression Omnibus (GEO) database and analyzed for differential expression using the DESeq2 package. The gene expression levels were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. Cell proliferation and apoptosis were examined through cell counting kit-8 (CCK8) and flow cytometry, respectively. The levels of inflammatory cytokines (interleukin-6 [IL-6], IL-8, and tumor necrosis factor-alpha (TNF-α)) were determined through enzyme-linked immunosorbent assay (ELISA). Levels of ferroptosis indicators, including reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), and ferrous iron (Fe²⁺), were measured using dedicated kits. The m6A modification of mRNA was predicted by the Sequence-based RNA Adenosine Methylation Site Predictor (SRAMP) database and was validated using RNA immunoprecipitation (RIP) assay. The m6A RIP-qPCR was performed to verify the interaction of thrombospondin-2 (THBS2) with METTL14 or YTHN6-methyladenosine RNA binding protein 2 (YTHDF2).THBS2 was highly expressed in both DN patients and high glucose (HG)-induced HK-2 cells. THBS2 silencing promoted HG-induced HK-2 cell proliferation and decreased apoptosis, fibrosis, inflammation, and ferroptosis. METTL14 stabilized THBS2 in an m6A-YTHDF2-mediated manner. Suppression of METTL14 expression could alleviate the HG-induced damage to HK-2 cells. THBS2 overexpression negated the protective effects of METTL14 knockdown in HK-2 cells.Conclusions: METTL14 exacerbates HG-induced damage in HK-2 cells by modulating THBS2 expression in an m6A-YTHDF2-dependent manner.

Aberrant expression of glucose-dependent insulinotropic peptide receptors (GIPR) might regulate increased steroidogenesis in patients with ACTH-independent cortisol hypersecretion. This study investigated the presence of aberrant GIPR expression in patients with ACTH-independent cortisol hypersecretion and bilateral adrenal adenomas.Patients with bilateral adrenal adenomas, ACTH-independent CS and aberrant GIPR screened via mixed meal test were included. Patients' demographic features and laboratory and imaging findings were obtained retrospectively.Twenty-one patients were included. Overt CS findings were present in 14.3% of the patients. One patient (4.7%) had a complete positive response (537% increase) and one patient (4.7%) had a partial response (41% increase) to the mixed meal test. In the remaining 19 patients, a mean change of -10.1% (range: -56.5% to+24.7%) in cortisol levels was observed at 120 min compared to baseline. The patient with a complete positive response was confirmed using 100 µg of IV octreotide. The patient underwent unilateral adrenalectomy after an inadequate long-term response to octreotide LAR therapy. The histopathology revealed bilateral macronodular adrenal cortical disease. We identified a germline heterozygous frameshift variant in the KDM1A gene in the patient's blood sample and a recurrent deletion of the p arm of chromosome 1 harboring the KDM1A locus in the adrenal sample.These results may provide useful insights into the screening of aberrant GIPR expression in patients with ACTH-independent hypercortisolism. It is essential to further investigate which patients require screening. Moreover, a significant cortisol peak observed during the mixed meal test in the presence of these receptors has drawn attention.

Cushing's disease is a rare endocrine disorder characterized by excessive endogenous glucocorticoid production, primarily resulting from adrenocorticotropic hormone-secreting pituitary neuroendocrine tumors (ACTH-PitNETs). This study investigated the expression of several genes implicated in the development of ACTH-PitNETs, including EGFR, USP8, CABLES1, USP2, STAM2, VPS28, HDAC2, IL-6, SMARCA4, WEE1, CDKN2A, CCND1, NR4A1, NEUROD1, and RIPK1. The methylation levels of the USP8 and CDKN2A genes were also assessed for insights into their regulatory mechanisms.Formalin-fixed paraffin-embedded pituitary tumor tissue samples from 32 patients diagnosed with ACTH-PitNET and 15 anterior pituitary tissue samples were analyzed. Gene expression was analyzed through quantitative reverse transcription polymerase chain reaction, while methylation was examined through methylation-specific polymerase chain reaction. All data were analyzed with IBM SPSS Statistics 21. The relationships among gene expressions were assessed using principal component analysis.The expression of CABLES1, NR4A1, CCND1, NEUROD1, USP2, and WEE1 differed significantly between the patient and control groups. Additionally, significant correlations were observed between the levels of RIPK1, SMARCA4, and USP2 and pre-operative cortisol levels; WEE1 expression and pre-operative ACTH levels; CDKN2A expression and urinary cortisol levels; CABLES1, NEUROD1, SMARCA4, and STAM2 expression and post-operative cortisol levels at 48 h. CCND1 expression was correlated with adenoma size, while WEE1 expression was linked to remission status. Notably, the CDKN2A gene displayed partial methylation, whereas the USP8 gene was fully unmethylated.The altered expression levels of the USP2, CABLES1, CDKN2A, and WEE1 may be closely associated with the development of ACTH-PitNETs. Notably, WEE1 emerged as a target gene for predicting clinical remission in patients with Cushing's disease.

The impact of Type 1 diabetes mellitus (T1DM) on growth remains uncertain, with previous studies reporting mixed findings. This study aimed to evaluate whether T1DM affects final adult height (FAH) by comparing it to genetically predicted mid-parental height (MPH).This retrospective cohort study analyzed medical records of 91 individuals diagnosed with T1DM at Ajou University Hospital, Korea, between 2000 and 2024. All individuals were diagnosed at least one year before completing linear growth and continued receiving care until reaching FAH. FAH was compared with MPH, and multiple regression analysis was performed to identify factors influencing growth outcomes.FAH was 1.17 cm lower than MPH in males and 0.05 cm higher than MPH in females; however, neither difference reached statistically significance. Glycemic control (mean HbA1c) and pubertal status at diagnosis were not significantly associated with FAH standard deviation score (SDS) and FAH-MPH SDS. Multiple regression analysis identified height at diagnosis and parental height as significant predictors of FAH SDS, whereas a longer diabetes duration was significantly associated with a lower FAH SDS (B=- 0.058, 95% CI: - 0.111 to - 0.005, p=0.032).T1DM does not significantly impact FAH, but longer diabetes duration was negatively associated with final adult height. These findings emphasize the need for early growth monitoring and optimized diabetes management, particularly in individuals diagnosed at a younger age, to improve long-term outcomes.