Recent animal studies have indicated that overexpression of the elongation of long-chain fatty acids family member 6 (Elovl6) gene can cause insulin resistance and β-cell dysfunction. These are the major factors involved in the development of type 2 diabetes mellitus (T2DM). To identify the relationship between single nucleotide polymorphisms (SNP) of ELOVL6 and T2DM pathogenesis, we conducted a case-control study of 610 Han Chinese individuals (328 newly diagnosed T2DM and 282 healthy subjects). Insulin resistance and islet first-phase secretion function were evaluated by assessment of insulin resistance in a homeostasis model (HOMA-IR) and an arginine stimulation test. Three SNPs of the ELOVL6 gene were genotyped with polymerase chain reaction-restriction fragment length polymorphism, with DNA sequencing used to confirm the results. Only genotypes TT and CT of the ELOVL6 SNP rs12504538 were detected in the samples. Genotype CC was not observed. The T2DM group had a higher frequency of the C allele and the CT genotype than the control group. Subjects with the CT genotype had higher HOMA-IR values than those with the TT genotype. In addition, no statistical significance was observed between the genotype and allele frequencies of the control and T2DM groups for SNPs rs17041272 and rs6824447. The study indicated that the ELOVL6 gene polymorphism rs12504538 is associated with an increased risk of T2DM, because it causes an increase in insulin resistance.

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BackgroundThe T2T guideline in RA recommended the normal csDMARDs irresponsive patients (pts) switching to other treatment target. Tacrolimus (TAC), the inhibitor of T cell activation, is candidate for these pts, especially with extrarticular complications (EC).ObjectivesTo observe the efficacy and safety of TAC-based csDMARDS regimen refractory RA (RRA) pts and the characteristics of TAC combined treatment.MethodsThis prospective cohort study (ClinicalTrials.gov Identifier NCT02837978) was conducted in China. According to baseline DAS28-ESR, RRA pts (ACR 1987 criteria [1]) were classified to severe (>5.1, S) or moderate (> 3.2,≦5.1, M) groups. The efficacy indicators and AE were recorded untill 144w.The combined medicine with TAC was based on the past history of csDMARD prescription and EC, including TAC with/wo MTX (T+M or T group), Pred, HCQ.Results150 pts (52±14y) were involved, 15 finished 144w observation, 50 still following up and 85 lost.As shown with GEE analysis, DAS28-ESR, CRP, HAQ were decreased significantly in all pts within 24ws, and maintained stable in later period (Figure 1). The REM or LDA, achieved ACR20, good or moderate EULAR response (G+M) proportion of 103 pts completed the 24w were 41.75%, 56.31%, 76.70%.Figure 1.Disease activity index of 150 RRA pts decreased in 144weeksSimilar to the Japanese study [2], DAS28-ESR, CRP and HAQ typically declined rapidly in S group, but still higher than M (Figure 2A-C). According to GBTM analysis, S group, longer disease course or higher HAQ had a higher ACR20 remission rate (Figure 2D).Figure 2.Disease activity index of 103 pts declined rapidly in 24weeks.(A). DAS28-ESR; (B) CRP; (C). HAQ declined significantly in S (n=53) than M (n=50) during 24ws. (D).higher increased ACR20 remission group (90.6%), compared with low-stable (0%) in 24ws. *p< 0.05, compared to M; #p< 0.05, compared to baseline.A total of 69 RA pts (46.0%) had 177 times (23.07%) AE, including 2 SAEs. Infection was the dominating AE (30%) due to asymptomatic positive urinary leucocyte and cold were classified, higher than (3.4%) Japanese study [3]. AEs were mainly happened in pts with higher TAC blood concentration 4.55(3-14.5) ng/ml, compared to No AE group 3.8(2.4-7.8) ng/ml, p=0.048, extremely in those abnormal glucose tolerance and hypertensive pts, p=0.002, 0.022.The most common reasons of lost were drug ineffective (32.94%), economic reasons (29.1%). There was no difference in efficacy of TAC combined treatment. Combination MTX reduce AE, decrease the usage rate and dosage of Pred. Combination Pred increased AE.Pts that achieved REM+LDA, G+M, had better TAC survival rate (Figure 3A-B). The combination of MTX, HCQ reduce lost rate (Figure 3C-D).Figure 3.TAC survival ratio were compared in different response and csDMARDs combination groups.(A).The pts acquired remission (n= 31) or LDA (n= 18) had higher TAC survival rate than high (n=28) & moderate (n=73) group, * p < 0.05, compared to group High; # p < 0.05, compared to Moderate; & p < 0.05, compared to Low; (B). The pts G+M (n=95) had better TAC survival rate, compared with no response (N, n=55), ** p < 0.01; (C). Combine MTX reduced lost rate, ** p < 0.01, compared to T; (D). Combine MTX and HCQ reduced lost rate, * p < 0.05 compared to MTX-HCQ-; # p < 0.05 compared to MTX+HCQ-.The Logistic regression showed baseline DAS28-ESR was an independent protective factor for poor response. Baseline DAS28-ESR and previous Perd use were independent protective factors for ACR20 remission.　ConclusionTAC-based combined therapies are effective and tolerable for RRA, especially to the higher disease activity pts. TAC blood concentration related to AE. The lower disease activity index and better respond, the higher TAC survival ratio. MTX is recommended as TAC combined treatment.References[1]Levin RW, et al. Scand J Rheumatol 1996, 25(5):277-281.[2]Kanzaki T,et al., Rheumatology International,2013. 33(4):871-877.[3]Takeuchi T, et al. Mod Rheumatology 2018,28(1): 48-57.AcknowledgementsAcknowledgements: Funded by ECCM Program of Clinical Research Center of Shandong University (No. 2021SDUCRCB010)Disclosure of InterestsNone declared

Abstract. The aim of the present study was to examine the post-infarct acute effect of adenosine-5'-triphosphate (ATP) on myocardial infarction (MI) size as well as its precise molecular mechanism. Sixty New Zealand white male rabbits were exposed to 40 min of ischemia followed by 180 min of reperfusion. The rabbits were intravenously administered 3 mg/kg of ATP (ATP group) or saline (control group) immediately after reperfusion and maintained throughout the first 30 min. The wortmannin+ATP, PD-98059+ATP, and 5-hydroxydecanoic acid (5-HD) sodium salt+ATP groups were separately injected with wortmannin (0.6 mg/kg), PD-98059 (0.3 mg/kg), and 5-HD (5 mg/kg) 5 min prior to ATP administration. MI size was calculated as the percentage of the risk area in the left ventricle. Myocardial apoptosis was determined using a TUNEL assay. Western blot analysis was performed to examine the levels of protein kinase B (Akt)/ p-Akt and extracellular signal-regulated kinase (ERK)/p-ERK in the ischemic myocardium, 180 min after reperfusion. The infarct size was significantly smaller in the ATP group than in the control group (p<0.05). The infarct size-reducing effect of ATP was completely blocked by wortmannin, PD-98059 and 5-HD. Compared with the control group, cardiomyocyte apoptosis was significantly reduced in the ATP group, while this did not occur in the wortmannin+ATP, PD-98059+ATP and 5-HD+ATP groups. Western blot analysis revealed a higher myocardial expression of p-Akt and p-ERK 180 min following reperfusion in the ATP versus the control group. In conclusion, cardioprotection by postischemic ATP administration is mediated through activation of the reperfusion injury salvage kinase (RISK) pathway and opening of the mitochondrial ATP-dependent potassium channels.