Journal of Endocrinological Investigation最新文献

Background and aims: Patients with childhood-onset type 1 diabetes (T1D) are at increased risk of developing microvascular complications, including neuropathy and nephropathy. Hormonal dysregulation and markers of atherosclerotic plaque instability and platelet activation may play key roles in the pathogenesis of these complications. The aim of this study was to investigate the impact of hormonal levels on atherosclerotic risk markers and platelet function, as well as to explore the association between diabetic neuropathy and nephropathy in individuals with childhood-onset type 1 diabetes.

Methods: In this cross-sectional analysis of a longitudinal cohort, 34 individuals with childhood-onset type 1 diabetes (mean age 27.6 ± 4.2 years; diabetes duration 8.2 ± 5.6 years) were examined. S-IGF-I, long-term HbA1c, micro/macroalbuminuria, triiodothyronine and thyroxine, S-Cortisol, P-ACTH, P-Renin, sP-Selectin, P-MMP-9, P-TIMP-1, P-Adiponectin, and platelet adhesion to albumin, collagen, and fibrinogen were assessed. An abnormality in nerve conduction tests was defined as diabetic neuropathy.

Results: S-IGF-I was negatively correlated with age (r = -0.36, p = 0.007), and with long-term HbA1c (r = -0.426, p = 0.019, corrected for age). IGF-I levels in patients diagnosed with clinical neuropathy (n = 6) were lower (123 ± 38 µg/L) than in patients without neuropathy (n = 26, 178 ± 56 µg/L, p = 0.029). S-IGF-I levels were also lower in patients with nephropathy (n = 7, 122 ± 28 µg/L) compared with patients without nephropathy (n = 27, 180 ± 60 µg/L, p = 0.02). S-IGF-I was negatively correlated with P-TIMP-1 (r = -0.44, p = 0.009), sP-Selectin (r = -0.53, p = 0.001), and positively correlated with platelet adhesion to fibrinogen (r = 0.38, p = 0.035). S-free-Triiodothyronine correlated negatively with P-MMP-9, (r = -0.46, p = 0.005), and P-MMP-/P-TIMP-1 ratio (r = -0.40, p = 0.018), and P-Adiponectin (r = -0.49, p = 0.018). P-Renin correlated negatively with P-Adiponectin (r = -0.34, p = 0.045).

Conclusions: Low serum IGF-I levels were associated with the presence of diabetic neuropathy and nephropathy in young adults with type 1 diabetes. Additionally, both IGF-I and S-free-Triiodothyronine levels were linked to changes in platelet activation and atherosclerotic markers, suggesting that hormonal dysregulation may contribute to early vascular complications in this population.

Aims: This study aimed to investigate the association between early-onset type 2 diabetes (EOT2D) and the risk of falls, focusing on the role of sarcopenic obesity.

Methods: A total of 580 patients (290 with EOT2D and 290 with late-onset type 2 diabetes [LOT2D]) were selected through propensity score matching. Participants were categorized into four groups: non-sarcopenia/non-obesity, obesity-only, sarcopenia-only, and sarcopenic obesity. Binary logistic regression models were employed to examine the relationships between age at diabetes onset, sarcopenic obesity, and fall risk. Additionally, 472 patients were followed longitudinally to assess the associations between EOT2D, LOT2D, sarcopenic obesity, and fall risk.

Results: Patients with EOT2D exhibited a higher prevalence of sarcopenic obesity compared to those with LOT2D. EOT2D was significantly associated with an increased risk of falls, both directly and indirectly via sarcopenic obesity (β = 0.81, OR_SO-VFA = 2.25, 95% CI: 1.79-2.82). EOT2D patients with sarcopenic obesity, particularly characterized by visceral fat area (VFA), demonstrated a substantially higher fall risk (HR_EOT2D+SO-VFA = 3.98; 95% CI: 2.57-6.16) compared to those with sarcopenia or obesity alone.

Conclusions: Patients with EOT2D are more prone to developing sarcopenic obesity, and visceral obesity contributes to the elevated risk of falls in this population. Therefore, interventions to preserve muscle mass and strength while reducing visceral fat accumulation are critical in mitigating fall risk among patients with EOT2D.

Adipose tissue exhibits remarkable plasticity, defined as its capability of adapting to various environments and energy demands by undergoing shifts in phenotypic, metabolic characteristics, and structure. However, obesity often results in diminished adipose tissue plasticity. Long non-coding RNA (lncRNA) is a class of RNA defined as being more than 200 nucleotides long and lacking protein-coding capability. With advancements in ribosome profiling, mass spectrometry, and other research technologies, an increasing number of studies have confirmed that short open reading frames (less than 300 nucleotides) within lncRNAs have the capacity to encode functional micropeptides. In our study, we initially identified a biologically active micropeptide, lncRNA Esrp2-as-ORF1(LEAO), encoded by lncRNA Esrp2-as in mice. In diet-induced obesity (DIO)mice, this micropeptide demonstrates the ability to induce fat browning, enhance adipose tissue plasticity, and subsequently improve metabolic homeostasis. Additionally, we observed that the micropeptide LEAO exerts its effects on adipocytes by stimulating IL6 secretion in adipose tissue macrophages. In summary, LEAO may have therapeutic potential for obesity-related metabolic diseases.

Background: The rising prevalence of childhood obesity is a serious global public health issue and poses a significant threat to male reproductive health. Aromatase (CYP19A1) expression is often elevated in obese men, associated with diminished testosterone levels, but the underlying mechanisms linking childhood obesity to long-term male infertility remain poorly understood.

Methods: We conducted a multi-faceted study combining a cross-sectional clinical investigation, a Mendelian randomization (MR) analysis, bioinformatic analysis of public datasets, and a mechanistic animal study. The clinical study included 30 obese and 30 normal-weight prepubertal boys. Two-sample MR was used to infer the causal relationship between different classes of obesity and male infertility. Gene Expression Omnibus (GEO) datasets were analyzed to identify differentially expressed genes (DEGs) and pathways. A high-fat diet (HFD)-induced obese mouse model was established to validate the bioinformatic hypotheses by investigating the STAT3/CYP19A1 pathway.

Results: Clinically, obese boys exhibited significantly smaller testicular volume, shorter penis length, and lower levels of testosterone, LH, Inhibin B, and FSH (P < 0.05). MR analysis revealed a significant causal relationship between childhood obesity (P = 0.038), class 1 obesity (P = 0.0423), and class 2 obesity (P = 0.0041) with male infertility. Bioinformatic analysis of fertility-related datasets implicated CYP19A1 as a key gene, while analysis of adipose tissue datasets highlighted inflammatory pathways. STAT3 was predicted and subsequently confirmed as a key transcription factor linking inflammation to CYP19A1 expression. The HFD-induced obese mouse model recapitulated the human phenotype, showing testicular damage, ectopic lipid deposition, increased apoptosis, and reduced testosterone. Molecularly, we confirmed a significant upregulation of STAT3 and CYP19A1 specifically in the epididymal adipose tissue of obese mice (P < 0.05).

Conclusion: Our integrated findings suggest that childhood obesity is a causal risk factor for impaired male reproductive function. The mechanism involves a local, paracrine effect of inflamed epididymal adipose tissue, which promotes STAT3-mediated upregulation of CYP19A1, leading to increased local aromatization of androgens and subsequent testicular damage. This STAT3-CYP19A1-testosterone signaling pathway represents a potential therapeutic target for mitigating obesity-related male reproductive disorders.