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

Regulators of G protein signaling (RGSs) are key modulators of β-cell function and stress adaptation. Similarly, circadian clock components are intricately implicated in the regulation of insulin secretion and β-cell physiology. However, their responses to sustained cellular stimulation under depolarizing conditions remain incompletely understood. MIN6 cells were subjected to prolonged potassium chloride (KCl) exposure to induce sustained membrane depolarization, mimicking conditions of chronic β-cell stimulation. The expression levels of RGSs and core clock genes were analyzed, and associated changes in cellular stress and differentiation markers were assessed.KCl treatment led to the upregulation of endoplasmic reticulum (ER) stress markers, including C/-EBP homologous protein (CHOP) and activating transcription factor 4 (ATF4), with no induction of oxidative stress. Expression of RGS2, RGS4, and RGS16 was elevated. RGS2 partially co-localized with eukaryotic initiation factor-2α (eIF2α), suggesting a role in translational control during stress. Furthermore, KCl-induced depolarization was associated with characteristic changes in β-cell differentiation markers and disallowed genes, indicative of a dedifferentiation-like state. Transcript levels of several circadian genes were altered, including significant downregulation of D-site binding protein (DBP) and upregulation of its repressor E4-binding Protein 4 (E4BP4). Notably, differentiated embryo-chondrocyte expressed gene-1 (DEC1), a clock gene known to be inducible by various external stimuli, was also upregulated, suggesting broader circadian disruption under depolarizing conditions.Sustained membrane depolarization induces ER stress and transcriptional remodeling in MIN6 β-cells, including the modulation of RGS proteins and key circadian regulators such as DBP, E4BP4, and DEC1. These alterations may contribute to functional impairment and a dedifferentiation-like state of β-cells under chronic stimulatory conditions.

Sodium-glucose co-transporter inhibitors significantly reduce cardiovascular mortality, hospitalization for heart failure, and improve renal outcomes regardless of diabetes status. This study investigated the effect of empagliflozin on plasma biomarkers to explore underlying mechanisms.Adult patients with type 2 diabetes and heart failure with either left ventricular ejection fraction≤45% (EFFORT-1) or>45% (EFFORT-2) were recruited. Patients received 25 mg empagliflozin or placebo for 48 weeks. Plasma levels of endothelin-1, galectin-3, insulin-like growth factor binding protein-7, and kidney injury molecule-1 (KIM-1) were measured at baseline and at weeks 2, 12, 24, and 48. A total of 63 patients were recruited, 24 in EFFORT-1 and 39 in EFFORT-2. Empagliflozin significantly reduced KIM-1 levels by 38% at week 48 in EFFORT-2 compared with placebo (95% confidence interval: -57%, -13%). No significant impact on other biomarkers was observed.Empagliflozin demonstrated, as shown by the decrease in KIM-1 levels, a renal tubular protective effect in heart failure patients with type 2 diabetes.

This study retrospectively evaluates the risk of chronic kidney disease (CKD) progression in patients with type 2 diabetes and mild-to-moderate reduction in the estimated glomerular filtration rate (eGFR).Sixty-six patients with type 2 diabetes and an eGFR between 45 and 60 mL/min/1.73 m² were included, from April 1, 2014, to March 31, 2015, with an 8-year follow-up ending on March 31, 2023. Baseline clinical parameters, including the body mass index, blood pressure, and biochemical markers, were recorded. The HbA1c and eGFR levels were measured annually. The eGFR slope (mL/min/1.73 m²/year) was used to evaluate the CKD progression.Patients with a negative eGFR slope (n=40) exhibited significantly greater HbA1c fluctuations and a higher coefficient of variation (CV) compared with those with an eGFR decline (P=0.011 for both) and were also markedly older (P=0.049). Logistic regression analysis showed a significant association between each one standard deviation increase in the CV and eGFR decline (odds ratio, 1.99; P=0.041), whereas the HbA1c fluctuation showed a trend toward association.Greater variability in glycemic control is linked to an increased risk for CKD progression in type 2 diabetes with mild-to-moderate kidney dysfunction.

Sitagliptin, an inhibitor of dipeptidyl peptidase-4 widely used in type 2 diabetes therapy, impairs the barrier formed by retinal endothelial cells (REC) during prolonged exposure. Because diabetic macular edema is treated with inhibitors of vascular endothelial growth factor (VEGF)-A signaling, we now studied (1) if sitagliptin interfered with this therapeutic approach and (2) if VEGF-A is involved in sitagliptin-induced barrier dysfunction.Confluent immortalized bovine REC (iBREC) were exposed for two days to sitagliptin and/or tivozanib, an inhibitor of the VEGF receptor 2, with or without VEGF-A. The cell index as an indicator of permeability was continuously measured, and cells and supernatants were harvested. Expressions of regulators of para- and transcellular flow, i.e., claudin-1, claudin-5, and plasmalemma vesicle-associated protein (PLVAP), were determined by subsequent Western blot analyses, and potential secretion of VEGF-A was measured by ELISA.Sitagliptin-exposed iBREC did not secrete VEGF-A, and, accordingly, tivozanib did not prevent the sitagliptin-induced decline of the cell index and the increased expression of tight junction (TJ) protein claudin 1. More TJ-protein claudin-5 was isolated together with proteins from membranes or organelles from sitagliptin-treated iBREC, which did not express PLVAP. The VEGF-A₁₆₅-induced declines of the cell index and TJ-protein claudin-1 were prevented by tivozanib, and this process was not modulated by sitagliptin.The underlying mechanisms of barrier dysfunctions caused by sitagliptin or VEGF-A are different and independent. Most importantly, the DPP-4 inhibitor does not interfere with blocking VEGF signaling to correct VEGF-A-dependent barrier dysfunction.

Diabetic peripheral neuropathy (DPN) is one of the most frequent complications of diabetes mellitus (DM). This brief narrative review discusses the relationship between DPN and balance impairment. DPN may alter movement perception as a result of diminished proprioceptive and cutaneous input from skin, muscles and joints, leading to balance impairment. In everyday practice, diagnosis of impaired balance relies on a combination of clinical history, physical examination and functional tests, such as the Timed Up and Go test or the Berg Balance Scale, as well as instrumental assessments where available. Therapeutic principles include optimised glycaemic control and management of vascular risk factors for the prevention and management of DPN. While these measures do not directly improve balance, they may contribute to better postural stability by preserving peripheral nerve function, reducing the progression of neuropathic deficits, and maintaining muscle strength. In addition, general exercises for balance improvement, physiotherapy, and focused and specialised strengthening, stretching and functional training programmes may improve static and dynamic balance. Finally, electric stimulation has demonstrated positive results in improving postural stability in DPN.

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.