Impact of diabetic kidney disease on post-operative complications after primary elective total hip arthroplasty: a nationwide database analysis.

BACKGROUND: The high prevalence of diabetic kidney disease (DKD) in the United States necessitates further investigation into its impact on complications associated with total hip arthroplasty (THA). This study utilizes a large nationwide database to explore risk factors in DKD cases undergoing THA. METHODS: This research utilized a case-control design, leveraging data from the national inpatient sample for the years 2016 to 2019. Employing propensity score matching (PSM), patients diagnosed with DKD were paired on a 1:1 basis with individuals free of DKD, ensuring equivalent age, sex, race, Elixhauser Comorbidity Index (ECI), and insurance coverage. Subsequently, comparisons were drawn between these PSM-matched cohorts, examining their characteristics and the incidence of post-THA complications. Multivariate logistic regression analysis was then employed to evaluate the risk of early complications after surgery. RESULTS: DKD's prevalence in the THA cohort was 2.38%. A 7-year age gap separated DKD and non-DKD patients (74 vs. 67 years, P < 0.0001). Additionally, individuals aged above 75 exhibited a substantial 22.58% increase in DKD risk (49.16% vs. 26.58%, P < 0.0001). Notably, linear regression analysis yielded a significant association between DKD and postoperative acute kidney injury (AKI), with DKD patients demonstrating 2.274-fold greater odds of AKI in contrast with non-DKD individuals (95% CI: 2.091-2.473). CONCLUSIONS: This study demonstrates that DKD is a significant risk factor for AKI in patients undergoing total hip arthroplasty. Optimizing preoperative kidney function through appropriate interventions might decrease the risk of poor prognosis in this population. More prospective research is warranted to investigate the potential of targeted kidney function improvement strategies in reducing AKI rates after THA. The findings of this study hold promise for enhancing preoperative counseling by surgeons, enabling them to provide DKD patients undergoing THA with more precise information regarding the risks associated with their condition.

SIRT1-dependent deacetylation of Txnip H3K9ac is critical for exenatide-improved diabetic kidney disease.

Glucagon-like peptide 1 receptor agonist exenatide (exendin-4) has potential protective capabilities against diabetic kidney disease (DKD). However, the underlying mechanism has not been fully elucidated. The expression of thioredoxin-interacting protein (Txnip) is upregulated during DKD progression by histone acetylation. Sirtuin 1 (SIRT1) is a deacetylase and is decreased in DKD, which indicates that it may regulate Txnip in this disease. Here, we used whole-body heterozygous Sirt1 knockout (Sirt1+/-) and kidney-specific Sirt1 knockout (KSK) mice to investigate whether SIRT1 regulates Txnip via histone deacetylation in DKD and exenatide-alleviated DKD. Exenatide substantially improved renal pathological damage, decreased the albumin-to-creatinine ratio (ACR), upregulated SIRT1 expression, and downregulated Txnip expression in kidneys of high-fat diet-treated C57BL/6J mice. However, these effects diminished in Sirt1+/- and KSK mice under exenatide treatment. The downregulation of Txnip expression by exendin-4 in high-glucose-treated SV40 MES13 cells was hampered during Sirt1 knockdown. These results demonstrate that kidney SIRT1 is indispensable in exenatide-improved DKD and downregulation of Txnip expression. Exendin-4 mechanistically downregulated Txnip histone 3 lysine 9 acetylation (H3K9ac) in a SIRT1-dependent manner and decreased spliced X-box binding protein 1 (XBP1s) recruitment to the Txnip promoter. These findings provide epigenetic evidence elucidating the specific mechanism for exenatide-mediated DKD alleviation and highlight the importance of Txnip as a promising therapeutic target for DKD.

Dysregulated hepatic lipid metabolism and gut microbiota associated with early-stage NAFLD in ASPP2-deficiency mice.

Background: Growing evidence indicates that lipid metabolism disorders and gut microbiota dysbiosis were related to the progression of non-alcoholic fatty liver disease (NAFLD). Apoptosis-stimulating p53 protein 2 (ASPP2) has been reported to protect against hepatocyte injury by regulating the lipid metabolism, but the mechanisms remain largely unknown. In this study, we investigate the effect of ASPP2 deficiency on NAFLD, lipid metabolism and gut microbiota using ASPP2 globally heterozygous knockout (ASPP2+/-) mice. Methods: ASPP2+/- Balb/c mice were fed with methionine and choline deficient diet for 3, 10 and 40 day to induce an early and later-stage of NAFLD, respectively. Fresh fecal samples were collected and followed by 16S rRNA sequencing. HPLC-MRM relative quantification analysis was used to identify changes in hepatic lipid profiles. The expression level of innate immunity-, lipid metabolism- and intestinal permeability-related genes were determined. A spearman's rank correlation analysis was performed to identify possible correlation between hepatic medium and long-chain fatty acid and gut microbiota in ASPP2-deficiency mice. Results: Compared with the WT control, ASPP2-deficiency mice developed moderate steatosis at day 10 and severe steatosis at day 40. The levels of hepatic long chain omega-3 fatty acid, eicosapentaenoic (EPA, 20:5 n-3) and docosahexaenoic (DHA, 22:6 n-3), were decreased at day 10 and increased at day 40 in ASPP+/- mice. Fecal microbiota analysis showed significantly increased alpha and beta diversity, as well as the composition of gut microbiota at the phylum, class, order, family, genus, species levels in ASPP2+/- mice. Moreover, ASPP-deficiency mice exhibited impaired intestinal barrier function, reduced expression of genes associated with chemical barrier (REG3B, REG3G, Lysozyme and IAP), and increased expression of innate immune components (TLR4 and TLR2). Furthermore, correlation analysis between gut microbiota and fatty acids revealed that EPA was significantly negatively correlated with Bifidobacterium family. Conclusion: Our findings suggested that ASPP2-deficiency promotes the progression of NAFLD, alterations in fatty acid metabolism and gut microbiota dysbiosis. The long chain fatty acid EPA was significantly negatively correlated with Bifidobacterial abundance, which is a specific feature of NAFLD in ASPP2-deficiency mice. Totally, the results provide evidence for a mechanism of ASPP2 on dysregulation of fatty acid metabolism and gut microbiota dysbiosis.

Effect of basal insulin supplement therapy on diabetic retinopathy in short-duration type 2 diabetes: A one-year randomized parallel-group trial.

BACKGROUND: In this study, we compared the effect on diabetic retinopathy (DR) between oral antidiabetic drugs (OADs) alone and in combination with basal insulin-supported OADs therapy (BOT). [Correction added on 11 November 2019, after first online publication: In Abstract under Background section, "DR" has been corrected into "diabetic retinopathy (DR)".] METHODS: Between January 2015 and January 2018, this study enrolled 290 patients (age 18-65 years) with diabetes duration between 0 and 5 years. Patients were randomly assigned to receive OADs or BOT after 14 days intensive insulin treatment. Examinations were performed at the beginning and end of the study. RESULTS: Fewer patients developed DR in the BOT than OADs group (8 [6.06%] vs 12 [8.3%], respectively), and all cases of DR were non-proliferative. Blood glucose concentrations were higher in the BOT than OADs group at the 3rd month, but lower in the former at the 6th and 12th month. The rate of reaching target HbA1c ≤7% was lower in the BOT than OADs group at the 3rd month (63.6% vs 72.2%, respectively), similar between the two groups at the 6th month (60.6% vs 66.6%, respectively) and higher in the BOT group at the 12th month (75.0% vs 61.1%, respectively). The SD of fasting blood glucose (FBG), coefficient of variation of FBG, SD of blood glucose (SDBG), and mean amplitude of glycemic excursions were lower in the BOT than OADs group. Changes in the levels of three cytokines (interleukin [IL]-1ß, IL-6, and IL-17α) were significantly less in the BOT than OADs group. CONCLUSIONS: Twelve months of BOT decreased the incidence of DR in short-duration type 2 diabetes by reducing glycemia more effectively, stably, and completely than OADs alone.

[The effects of insulin and gliclazide therapy on endoplasmic reticulum stress and insulin sensitivity in liver of type 2 diabetic rats].

OBJECTIVE: To investigate the effect of insulin and gliclazide therapy on endoplasmic reticulum (ER) stress and insulin sensitivity in the liver of type 2 diabetic rats. METHODS: A high fat diet plus a low-dose of streptozotocin was implemented to create a type 2 diabetic rats which were randomly divided into diabetes mellitus (DM) group, insulin treatment (INS) group and gliclazide treatment (GT) group; and healthy rats were as normal control group. Diabetic rats in INS and GT groups were given neutral protamine hagedorn (NPH) insulin and gliclazide respectively for 3 weeks. Protein expression levels of immunoglobulin binding protein (Bip), spliced X-box binding protein 1 (XBP-1s), phosphorylated c-Jun on serine 73 (p-c-Jun), phosphorylated insulin receptor substrate 1 on serine 307 (p-IRS-1), and glucose-6-phosphatase (G6Pase) in liver homogenate were detected by Western blotting. RESULTS: Compared with the normal rats, Bip and XBP-1s in the DM group were up-regulated (0.28 ± 0.07 vs 0.90 ± 0.10 for Bip; 0.41 ± 0.07 vs 0.95 ± 0.07 for XBP-1s; both P < 0.01); p-c-Jun (0.59 ± 0.18 vs 1.94 ± 0.03), p-IRS-1 (1.73 ± 0.18 vs 5.32 ± 0.22) and G6Pase(0.11 ± 0.01 vs 0.45 ± 0.01) were increased (all P values < 0.01). In the INS group, all of aforementioned changes were reversed (0.90 ± 0.10 vs 0.25 ± 0.04 for Bip; 0.95 ± 0.07 vs 0.47 ± 0.01 for XBP-1s; 1.94 ± 0.03 vs 0.50 ± 0.10 for p-c-Jun; 5.32 ± 0.22 vs 1.59 ± 0.32 for p-IRS-1; 0.45 ± 0.01 vs 0.15 ± 0.02 for G6Pase, all P values < 0.01). In the GT group, all of aforementioned changes were also attenuated (0.90 ± 0.10 vs 0.53 ± 0.02 for Bip; 0.95 ± 0.07 vs 0.78 ± 0.02 for XBP-1s; 1.94 ± 0.03 vs 1.33 ± 0.11 for p-c-Jun; 5.32 ± 0.22 vs 3.13 ± 0.02 for p-IRS-1; 0.45 ± 0.01 vs 0.25 ± 0.01 for G6Pase, all P values < 0.05). Furthermore, all of aforementioned protein levels were down-regulated more obviously in the INS group comparing to the GT group (all P values < 0.01). CONCLUSIONS: Both insulin and gliclazide therapy could relieve ER stress and c-Jun N-terminal kinase activity and improved insulin sensitivity. The effect of insulin on Bip, XBP-1s, p-c-Jun, p-IRS-1 and G6Pase protein expressions is more obvious than that of gliclazide, which indicates besides lowering glucose, insulin might have protective effects of anti-inflammation, anti-oxidative stress or stimulation of lipid redistribution.

[Effects of early insulin therapy on sterol regulatory element binding protein 1 pathway and lipid accumulation in liver of type 2 diabetic rats].

OBJECTIVE: To explore the effect of early insulin therapy on sterol regulatory element binding protein 1 (SREBP1) pathway and lipid accumulation in liver of type 2 diabetic rats (DM). METHODS: A high-fat diet plus a low-dose of streptozotocin (STZ) was administered to the Sprague-Dawley (SD) rats to create a type 2 diabetic animal model. Then the rats were divided into 3 groups: normal control (NC), DM (untreated diabetic rats) and INS (a 3-week treatment of NPH insulin initiated from day 3 of STZ injection). Insulin was delivered daily by a 3-week subcutaneous injection (6 - 8 U/day). Liver homogenate was prepared. The protein levels of ER stress marker immunoglobulin binding protein (Bip), oxygen-regulated protein 150 (ORP150), insulin-induced gene 1 (Insig1), SREBP1 and nuclear SREBP1 (nSREBP1) were assayed by Western blot. Adipose tissue mass was measured. RESULTS: In the DM group, ER (endoplasmic reticulum) stress marker Bip and ORP150 were up-regulated (0.67 ± 0.02 vs 0.43 ± 0.01 for Bip; 1.11 ± 0.04 vs 1.83 ± 0.03 for ORP150, P < 0.05 for both) and Insig1 decreased (0.25 ± 0.02 vs 0.80 ± 0.07, P < 0.05). And the expressions of SREBP1 and nSREBP1 were elevated (1.03 ± 0.14 vs 0.41 ± 0.01 for SREBP1; 3.63 ± 0.77 vs 0.96 ± 0.20 for nSREBP1, P < 0.05 for both) in comparison with the normal control rats. In the INS group, all aforementioned changes became attenuated or reversed (0.41 ± 0.04 vs 0.67 ± 0.02 for Bip; 1.83 ± 0.03 vs 1.11 ± 0.04 for ORP150; 0.43 ± 0.02 vs 0.25 ± 0.02 for Insig1; 0.46 ± 0.01 vs 1.03 ± 0.14 for SREBP1; 1.65 ± 0.18 vs 3.63 ± 0.77 for nSREBP1, P < 0.05 for all). Furthermore, adipose tissue mass increased (22.4 g ± 3.6 g vs 12.0 g ± 2.6 g, P < 0.05). CONCLUSION: The early insulin therapy induces a fat redistribution from liver to adipose tissue. The mechanism is probably through a reduction of ER stress and a down-regulated pathway of SREBP1 in liver of diabetic rats.

[The functional analysis of glucokinase gene E339K mutation].

OBJECTIVE: To explore the molecular mechanisms of glucokinase (GCK) E339K mutation resulting in maturity-onset diabetes of the young-2 (MODY2). METHODS: Fasting plasma glucose (FPG), oral glucose tolerance test (OGTT) overload 2 h glucose (2hPG), glycosylated hemoglobin A1c (HbA1c) and fasting insulin (FIns) level were measured, respectively. Mutant glutathione S-transferase (GST)-GCK-cDNA was constructed with site-directed mutagenesis. Wild type and mutant GCK protein expressed in E. Coli were purified with affinity chromatography. Enzymatic kinetics and thermal stability were tested with enzyme-coupled analysis. RESULTS: Compared with non-mutants, mutants had higher FPG [(6.92±0.95) mmol/L vs (4.70±0.35) mmol/L, P<0.001] 2hPG [(9.00±1.49) mmol/L vs (5.51±0.86) mmol/L, P<0.001], HbA1c [(6.46±0.69)% vs (4.83±0.30)%, P<0.01], and lower FIns level [(6.15±1.97) mIU/L vs (10.79±4.93) mIU/L, P<0.01], HOMA-ß (34.16±3.62 vs 172.53±76.58, P<0.001). This mutation induced lower protein yield [(12.7±1.72) mg/L vs (16.2±2.65) mg/L, P<0.01], lower appetency for glucose [S0.5: (13.96±1.89) mmol/L vs (5.92±0.99) mmol/L, P<0.001] and ATP [Km:(3.27±1.14) mmol/L vs (0.30±0.09) mmol/L, P<0.001], lower catalytic ability [Kcat: (1.62±0.35)/s vs (25.18±2.10)/s, P<0.001]. It also showed protein thermal instability. CONCLUSION: Glucokinase gene E339K mutation promotes the development of MODY2 by affecting protein yield and protein stability as well as the enzymatic kinetics of GCK.

Lamin C protein deficiency in the primary fibroblasts from a new laminopathy case with ovarian cystadenoma.

BACKGROUND: Laminopathies are a group of rare genetic disorders characterized by multiple-tissue degeneration. We describe a new laminopathy with ovarian cystadenoma and explore its molecular etiology. METHODS: The case is a 15-year-old girl who presents the prominent progeroid disorders, multiple system degeneration and early-onset cystadenoma of the ovary. Candidate genes including LMNA, ZMPSTE24, PPAR G, INSR and WRN were sequenced to screen for DNA variants. The mRNA and protein expression levels of LMNA were examined in primary fibroblasts. The pathophysiological events such as morphologic alterations, cell senescence, cell proliferation, apoptosis and pRb as well as p53 protein expressions were also investigated in primary fibroblasts. RESULTS: No mutation was identified in the candidate genes screened. Nuclear abnormalities including nuclear blebs, mislocalization of lamin A/C were evident in the patient fibroblasts. Ultrastructurally, nucleus exhibited nuclear herniation and almost complete loss of peripheral heterochromatin. In addition, lamin C protein expression was markedly reduced whereas lamin A protein level was normal and no prelamin A was detected in the primary fibroblasts. Although the senescence-associated beta-galactosidase staining of patient' cells was negative, cells in S phase increased in accompany with a decrease in pRb protein expression. Furthermore, increases in apoptotic cell death and p53 expression were observed. CONCLUSIONS: Our data suggest that selective deficiency of lamin C protein is associated with a case of laminopathy with ovarian cystadenoma. The abnormalities in nuclear structure and alterations in gene expression such as the decrease in pRb and increase in p53 may be responsible for the multiple tissue degeneration.

[Identification of a novel glucokinase-E339K mutation in a Chinese maturity onset diabetes of the young 2 pedigree].

OBJECTIVE: To identify the related gene for a typical maturity onset diabetes of the young 2 (MODY2) pedigree. METHODS: The genomic DNA of all the members of the pedigree was extracted and then PCR amplification on 5', 3' untranslated region and exon 1 - 10 of glucokinase (GCK) gene was carried out. Sequencing in both directions was performed to identify mutation on GCK gene. RESULTS: A novel GCK-E339K mutation which was cosegregated with diabetes/impaired glucose tolerance was identified. CONCLUSION: The novel GCK-E339K mutation might be linked to this MODY2 pedigree.

[Agonist-induced down-regulation of hepatic glucocorticoid receptor via peroxisome proliferator-activated receptor in SD rats].

OBJECTIVE: It was reported that a negative feedback loop might exist between peroxisome proliferator-activated receptor alpha (PPARalpha) and glucocorticoid receptor (GR). However, it is unclear whether GR expression is regulated by PPARalpha activation. To further demonstrate this possibility, we conducted the present study to investigate the regulatory effects of the PPARalpha agonist fenofibrate on GR expression in Sprague-Dawley rats. METHODS: GR gene and protein expression levels were determined in liver, visceral and muscle tissues. Adrenal 11beta-hydroxylase (CYP11B1) expression was examined by RT-PCR and circulating corticosterone level was measured by RIA method. RESULTS: GR expression was reduced by fenofibrate in a time- and does-dependent manner. The GR mRNA in the three fenofibrate groups of rats were 55% (FE1), 54% (FE2) and 68% (FE3) lower than that of the control rats. The GR protein were 28%, 77% and 99% lower than the control. The inhibition was observed in liver, but not in fat and muscle. The corticosterone level in the blood was increased significantly by fenofibrate(the levels of corticosterone in control, FE1, FE2, FE3, MK886 groups were (393 +/- 23), (495 +/- 44), (516 +/- 18), (622 +/- 93), (382 +/- 37) ng/ml respectively. These effects of fenofibrate were abolished by PPARalpha inhibitor MK886, suggesting that fenofibrate activated through PPARalpha. CONCLUSION: A new molecular mechanism has been found for a negative feedback regulation of GR activity by PPARalpha in SD rats.

[Effects of early insulin therapy on nuclear factor kappaB pathway in skeletal muscle of diabetes: experiment with rats].

OBJECTIVE: To investigate the effect of early insulin therapy on the nuclear factor kappaB (NF-kappaB) pathway and inflammatory cytokine responses in skeletal muscle in type 2 diabetes mellitus (DM). METHODS: SD rats underwent intraperitoneal injection of streptozotocin to establish DM models and then divided into 5 groups: early un-treated group, early gliclazide treated group (receiving gliclazide since the third day after blood glucose increase for 3 weeks for 3 weeks), early insulin treated group (receiving insulin since the third day after blood glucose increase for 3 weeks for 3 weeks), late un-treated group, and late insulin treated group (receiving insulin since the fourth week after blood glucose increase for 3 weeks). By the end of treatment the rats were killed. Homogenate of skeletal muscle was made. The NF-kappaB P65 DNA binding was assayed by ELISA-based assay kit. Real time PCR was used to detect the mRNA expression levels of the gene of the cytokines: glucose transporter 4 (Glut4), inhibitor kappaB (IkappaBalpha), IL-1beta, IL-6, and tumor necrosis factor (TNF)-alpha. And Glut4 and IkappaBalpha protein expression levels were assayed by Western blotting. RESULTS: The Glut4 mRNA level in the skeletal muscle of the untreated DM rats decreased by 59% and the Glut4 protein level in the muscle cell membrane decreased by 69%. Insulin treatment and gliclazide treatment increased the Glut4 mRNA expression by 17% and 13% respectively, increased the Glut4 protein expression in cell membrane by 23% and 10% respectively, and decreased the Glut4 protein expression in the cytoplasm. In the DM rats the IkappaBalpha protein expression in the skeletal muscle was significantly lower (P < 0.05) and the NF-kappaB P65 DNA binding activity increased, and TNF-alpha, IL-1B, and IL-6 expression levels were up-regulated in comparison with the normal control group. Early treatment of insulin and gliclazide increased the IkappaBalpha protein expression, decreased the NF-kappaB P65 DNA binding activity and the TNF-alpha expression in the skeletal muscle. CONCLUSION: Early insulin treatment inhibits the NFkappaB activity and inflammatory cytokine responses in skeletal muscle that are involved in the amelioration of insulin resistance in type 2 DM. Such results may be due to indirect antiinflammatory effects of insulin relieving glucotoxicity and lipotoxicity in peripheral tissues.