Hydrogen sulfide (H 2 S) has recently been identified as an endogenous gaseous signaling molecule. The aim of the present study was to investigate the effect of H 2 S on high glucose-(HG-) induced ADAM17 expression and sFlt-1 production in 3T3-L1 adipocytes. Firstly, we found that HG DMEM upregulated the expression of ADAM17 and production of sFlt-1 in 3T3-L1 adipocytes. Knocking down ADAM17 attenuated the effect of high glucose on sFlt-1 production in adipocytes. HG decreased the expression of CSE and 3-MST, as well as the endogenous H 2 S production. Furthermore, knocking down CSE and 3-MST significantly increased ADAM17 expression and sFlt-1 production. The addition of exogenous H 2 S through the administration of sodium hydrosulfide (NaHS) inhibited HG-induced upregulation of ADAM17 expression and sFlt-1 production. In conclusion, decreased expression of CSE and 3-MST and the subsequent decrease in H 2 S production contribute to high glucose-induced sFlt-1 production via activating ADAM17 in adipocytes. Exogenous H 2 S donor NaHS has a potential therapeutic value for diabetic vascular complications.
Background. Irisin, an exercise-induced myokine and adipocytokine, has been reported to decrease in type 2 diabetic patients. Recently, several research studies indicated that circulating levels were correlated with bone mineral density (BMD). To evaluate bone metabolism, bone turnover markers (BTMs) should be included. However, with respect to newly diagnosed T2DM patients, the relevance of their irisin levels to their BTMs and BMD remains unclear. The investigation of serum irisin levels in patients who have been newly diagnosed with type 2 diabetes and illumination of the relationship between serum irisin levels and those two indices of BMD and BTMs mentioned above are the intention of this cross-sectional study. Methods. 66 new-onset type 2 diabetic patients (T2DM group), together with 82 control subjects (NGT group), were recruited in this study. Serum irisin concentrations and BTMs (including osteocalcin (OC), procollagen type 1 N-terminal propeptide (P1NP), and β-C-terminal telopeptides of type I collagen (β-CTX)) were determined by the enzyme-linked immunosorbent assay (ELISA). Glucose, lipid profile, and insulin were considered as measuring indicators as well. Dual-energy X-ray absorptiometry (DXA) was utilized to evaluate the indicator of BMD. Serum irisin, BTMs, and BMD were compared between diabetic patients and healthy individuals. Pearson and Spearman correlation analyses were applied as well to assess correlations between irisin and BTMs and BMD. Multiple stepwise regression analysis was conducted to identify the independent factors of irisin. ROC curve analyses were carried out for serum irisin prediction for osteoporosis/osteopenia (OP). Results. The serum levels of irisin, procollagen type 1, intact N-terminal propeptide (P1NP), and osteocalcin (OC) were evidently lower in T2DM subjects than in NGT subjects (10.90 ± 1.88 vs .11.69 ± 2.06 ng/mL, P < 0.05; 36.42(25.68,51.70) vs. 44.52(35.73,58.05)ng/ml, P < 0.05; 16.15(12.40,21.66) vs. 18.70(15.56, 23.22)ng/ml, P < 0.05). Among patients with T2DM, the circulating irisin level of those with OP was lower than that of normal BMD (9.98 ± 2.09 vs. 11.39 ± 1.57 ng/ml, P < 0.01); irisin had a negative correlation with β-C-terminal telopeptides of type I collagen (β-CTX) (r = −0.496, P < 0.001) and came back unrelated to Lumbar BMD; Lumbar BMD was negatively relevant to OC (r = −0.274, P < 0.05) and β-CTX (r = −0.410, P < 0.01). Multiple linear regression analyses of stepwise models implied that TG, LDL-C, and β-CTX were independently associated with serum irisin concentrations ( P < 0.01 or P < 0.05). Conclusion. Serum irisin level was declined in patients with type 2 diabetes diagnosed in the near term and had a certain association with bone turnover markers. It is suggested to consider irisin as a potential biomarker of bone metabolic disorder in T2DM patients with the initial diagnosis.
Activation of the NACHT leucine rich repeat and pyd domains-containing 3 (NLRP3) inflammasome plays an important role in the initiation of inflammation in adipose tissue in diabetic patients. However, the mechanisms underlying this are not fully understood. Hydrogen sulfide (H 2 S) has been shown to have anti-inflammatory properties in various cell types. The present study aimed to investigate the effect of H 2 S on high glucose (HG)-induced NLRP3 inflammasome activation in adipocytes. Adipocytes were differentiated from 3T3-L1 cells and treated with low glucose (LG), HG, H 2 S donor sodium hydrosulfide (NaHS) or N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone, an inhibitor of the cysteine protease caspase-1. The expression levels of NLRP3, apoptosis-associated speck-like protein containing A CARD (ASC) and caspase-1, and the release of interleukin (IL)-1β and IL-18 were measured. The results of the present study indicated that HG increased the expression levels of NLRP3, ASC and cleaved caspase-1, and the release of IL-1β and IL-18 in adipocytes. Caspase-1 inhibition abolished HG-induced production of IL-1β and IL-18 in adipocytes. Furthermore, NaHS inhibited the expression of NLRP3, ASC and cleaved caspase-1, and the production of IL-1β and IL-18 in adipocytes treated with HG. In conclusion, HG may increase and exogenous H 2 S may inhibit HG-induced NLRP3 inflammasome activation in adipocytes.
The placenta may play a key role in the activation of inflammation and initiation of insulin resistance (IR) during gestational diabetes mellitus (GDM) pathogenesis. Interleukin (IL)-1β and IL-18, regulated by NLR family pyrin domain containing-3 (NLRP3) inflammasome, are important inflammatory cytokines in the initiation of maternal IR during GDM. However, the mechanism responsible for the regulatory of NLRP3 inflammasome in placenta remains unknown. Hydrogen sulfide (H 2 S) exerts anti-inflammatory function partially via suppressing the activation of the NLPR3 inflammasome. The present study aimed to investigate the role of NLRP3 inflammasome, H 2 S synthetase cystathionine-γ-lyase (CSE) and cystathionine-β-synthetase (CBS) in placenta in the pathogenesis of GDM. Clinical placenta samples were collected from pregnant women with GDM (n=16) and healthy pregnant women at term (n=16). Western blot analysis was performed to detect the protein expression levels of NLRP3, cleaved caspase-1, CBS and CSE in the placenta samples. Pearson's correlation analysis was performed to assess the correlation between NLRP3 inflammasome and H 2 S synthetase. Human placental cells were cultured and treated with different concentrations of NaHS (0, 10, 25 and 50 nmol/l) or L-cysteine (0, 0.25, 0.50 and 1.00 mmol/l). In addition, western blot analysis was performed to detect the protein expression levels of NLRP3 and cleaved caspase-1, while ELISA was performed to measure the production of IL-1β and IL-18 in the culture media. The results demonstrated that the expression levels of NLRP3 and cleaved caspase-1 increased, while the expression levels of CBS and CSE decreased in the placenta samples. In addition, the expression levels of NLRP3 and cleaved caspase-1 were inversely correlated with the expression levels of CBS and CSE. Notably, NaHS and L-cysteine significantly suppressed the expression levels of NLRP3 and cleaved caspase-1, and the production of IL-1 and IL-18 in human placental cells. Taken together, the results of the present study suggest that H 2 S synthetase deficiency in placenta may contribute to excessive activation of NLRP3 inflammasome in GDM.
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