Alcohol consumption exacerbates liver abnormalities in animal models, but whether it increases the severity of liver disease in early diabetic or prediabetic rats is unclear. To investigate the ...molecular mechanisms underlying alcohol‐induced liver steatosis or hepatitis, we used a prediabetic animal model. Otsuka Long‐Evans Tokushima Fatty (OLETF) and Long‐Evans Tokushima Fatty (LETO) rats were pair‐fed with an ethanol‐containing liquid diet for 6 weeks. Compared with controls, OLETF and LETO rats displayed more pronounced liver steatosis and higher plasma levels of serum glutamic oxaloacetic transaminase (SGOT) and serum glutamate pyruvate transaminase (SPGT), indicating liver injury. Ethanol‐fed LETO (Pd‐L‐E) rats showed mild liver steatosis and no inflammation compared with ethanol‐fed OLETF (Pd‐O‐E) rats. Although precursor and active SREBP‐1 levels in the liver of ethanol‐fed OLETF rats significantly increased compared with control diet‐fed OLETF rats (Pd‐O‐C), those of Pd‐L‐E rats did not. Bone morphogenetic protein (BMP) and TGF‐β1 balance in Pd‐O‐E rats was significantly altered because BMP signaling was upregulated by inducing BMP2, BMP4, BMP7, BMP9, Smad1, and Smad4, whereas TGF‐β1, Smad3, and Erk were downregulated. Activation of TGF‐β/Smad signaling inhibited BMP2 and BMP9 expression and increased epithelial‐mesenchymal transition (EMT) marker levels (Hepcidin, Snail, and Twist) in the liver of LETO rats. Livers of ethanol‐fed OLETF rats showed increased levels of vimentin, FSP‐1, α‐SMA, MMP1, MMP13, and collagen III compared with rats of other groups, whereas EMT marker levels did not change. Thus, BMP exerted anti‐ and/or pro‐fibrotic effects in ethanol‐fed rats. Therefore, BMP and TGF‐β, two key members of the TGF‐β superfamily, play important but diverse roles in liver steatosis in young LETO and OLETF rats.
This article proposes practical design techniques to enhance performance and reliability of 1024 GB/s high-bandwidth memory-3 (HBM3). Effective data-bus design methods are applied to transfer data ...from multi-bank to a data-bus with a sufficient data fetch margin. A symbol-based on-die error-correcting code (OD-ECC) to correct a 16-bit error, bounded by a sub-wordline (WL), and parallelized data-bus inversion (DBI) are implemented. Error check and scrub (ECS) mode and repair capability check (RCC) mode with an internal serial interface are designed to support system reliability, availability, and serviceability (RAS). A memory built-in self-test (MBIST) provides a unified at-speed test with programmability based on test-set units (TUs). A 16 GB HBM3 fabricated in the third generation of the 10 nm class DRAM process achieves a bandwidth up to 1024 GB/s (8 Gb/s/pin) and provides stable operation at a high temperature (e.g., 105 °C) while improving an error detection rate by 92.2%.
Aim
To assess the efficacy and safety of add‐on therapy with the dipeptidyl peptidase‐4 inhibitor teneligliptin compared with sitagliptin in patients with type 2 diabetes (T2DM) inadequately ...controlled with metformin and glimepiride.
Materials and Methods
This was a phase 3, randomized, double‐blind, non‐inferiority study of adult Korean subjects with T2DM (n = 201), with HbA1c ranging from 7.0% to 11.0%, on stable doses of metformin plus glimepiride. Subjects were randomized in a 1:1 fashion to receive either oral teneligliptin 20 mg or sitagliptin 100 mg for 24 weeks. The primary endpoint was change from baseline in HbA1c.
Results
At baseline, mean age was 60.56 ± 9.41 years, body mass index was 25.23 ± 2.85 kg/m2 and HbA1c was 8.11% ± 0.79%. At 24 weeks, both groups achieved significant reductions from baseline in HbA1c (teneligliptin, −1.03% ± 0.10% P < 0.0001; sitagliptin, −1.02% ± 0.10% P < 0.0001). The inter‐group difference was −0.01% (95% confidence interval CI: −0.28, 0.26; P = 0.9497); the upper limit of the 95% CI was within the preset limit for non‐inferiority (0.4%). There were no significant differences between groups in the proportion of patients achieving HbA1c targets, or changes from baseline in fasting plasma glucose, body weight or lipid levels at 24 weeks. Rates of adverse events (teneligliptin, n = 63 61.76%; sitagliptin, n = 61 62.24%; P = 0.9442) and hypoglycaemia (teneligliptin, n = 32 31.37%; sitagliptin, n = 28 28.57%; P = 0.6656) were similar.
Conclusion
Teneligliptin was non‐inferior to sitagliptin in the context of triple therapy for T2DM and is an important option in this setting.
The objective of this study was to investigate molecular and physiological changes in response to long‐term insulin glargine treatment in the skeletal muscle of OLETF rats. Male Otsuka Long‐Evans ...Tokushima Fatty (OLETF) and Long‐Evans Tokushima Otsuka (LETO) rats aged 24 weeks were randomly allocated to either treatment with insulin for 24 weeks or no treatment, resulting in three groups. Insulin glargine treatment in OLETF rats (OLETF‐G) for 24 weeks resulted in changes in blood glucose levels in intraperitoneal glucose tolerance tests compared with age‐matched, untreated OLETF rats (OLETF‐C), and the area under the curve was significantly decreased for OLETF‐G rats compared with OLETF‐C rats (P < 0.05). The protein levels of MHC isoforms were altered in gastrocnemius muscle of OLETF rats, and the proportions of myosin heavy chain type I and II fibers were lower and higher, respectively, in OLETF‐G compared with OLETF‐C rats. Activation of myokines (IL‐6, IL‐15, FNDC5, and myostatin) in gastrocnemius muscle was significantly inhibited in OLETF‐G compared with OLETF‐C rats (
P < 0.05). MyoD and myogenin levels were decreased, while IGF‐I and GLUT4 levels were increased, in the skeletal muscle of OLETF‐G rats (
P < 0.05). Insulin glargine treatment significantly increased the phosphorylation levels of AMPK, SIRT1, and PGC‐1α. Together, our results suggested that changes in the distribution of fiber types by insulin glargine could result in downregulation of myokines and muscle regulatory proteins. The effects were likely associated with activation of the AMPK/SIRT1/PGC‐1α signaling pathway. Changes in these proteins may at least partly explain the effect of insulin in skeletal muscle of diabetes mellitus.
Inconsistent results have been observed regarding the independent effect of diabetes on the severity of coronavirus disease 2019 (COVID-19). We conducted a nationwide population-based cohort study to ...evaluate the relationship between diabetes and COVID-19 severity in South Korea.
Patients with laboratory-confirmed COVID-19 aged ≥30 years were enrolled and medical claims data were obtained from the Korean Health Insurance Review and Assessment Service. Hospitalization, oxygen treatment, ventilator application, and mortality were assessed as severity outcomes. Multivariate logistic regression analyses were performed after adjusting for age, sex, and comorbidities.
Of 5,307 COVID-19 patients, the mean age was 56.0±14.4 years, 2,043 (38.5%) were male, and 770 (14.5%) had diabetes. The number of patients who were hospitalized, who received oxygen, who required ventilator support, and who died was 4,986 (94.0%), 884 (16.7%), 121 (2.3%), and 211 (4.0%), respectively. The proportion of patients with diabetes in the abovementioned outcome groups was 14.7%, 28.1%, 41.3%, 44.6%, showing an increasing trend according to outcome severity. In multivariate analyses, diabetes was associated with worse outcomes, with an adjusted odds ratio (aOR) of 1.349 (95% confidence interval CI, 1.099 to 1.656; P=0.004) for oxygen treatment, an aOR of 1.930 (95% CI, 1.276 to 2.915; P<0.001) for ventilator use, and an aOR of 2.659 (95% CI, 1.896 to 3.729; P<0.001) for mortality.
Diabetes was associated with worse clinical outcomes in Korean patients with COVID-19, independent of other comorbidities. Therefore, patients with diabetes and COVID-19 should be treated with caution.
While randomized controlled trials provide useful information about drug safety and efficacy, they do not always reflect the observed results in the real world. The prospective, observational, ...non-comparative trial in South Korea was designed to evaluate the efficacy and safety of pitavastatin in clinical practice in 28,343 patients.
This study was conducted in 893 facilities in Korea from April 2, 2012 to April 1, 2017. This study was designed to administer 1, 2, or 4 mg pitavastatin to patients with hyperlipidemia at the age of 20 or older for at least 8 weeks.
For 126 days of mean duration of administration of pitavastatin, the % change of low density lipoprotein cholesterol indicated a dose dependent reduction: -23.4%, -29.1%, and -35.2% in the 1, 2, and 4 mg groups, respectively in patients who have not been treated with lipid lowering medications prior to study. Only 1.74% (492/28,343) of pitavastatin-treated patients experienced adverse events, of which 0.43% (123/28,343) were adverse drug reactions. Less than 1% of patients experienced the grade 2 or more toxicity (Common Terminology Criteria for Adverse Events v4.03) in alanine aminotransferase, aspartate aminotransferase, serum creatinine, and serum creatine phosphokinase. Although there were no rhabdomyolysis in 28,343 patients, 0.04% of patients had been reported pitavastatin-related musculoskeletal disorders.
Overall, this observational study showed that pitavastatin was well tolerated and effectively modified the lipid profile, reducing cardiovascular and cerebrovascular risk in Korean patients with hypercholesterolemia in the real world.
In the presence of intercarrier interference (ICI), conventional orthogonal frequency-division multiplexing (OFDM) radar exhibits serious performance degradation when estimating the Doppler frequency ...of a target. In this letter, a two-step Doppler estimation scheme is proposed for OFDM radar. In order to mitigate ICI, a sequence with a good correlation property is assigned to the subcarriers to generate an OFDM signal, and oversampling is applied to the received OFDM signal in the frequency domain. Then, Doppler estimation with coarse and fine estimating steps is performed to achieve accurate Doppler estimation. Also, it is shown that the proposed scheme enables parallel calculation of correlation values to reduce the latency and enlarges the Doppler estimation range by eliminating Doppler ambiguity. Finally, simulation results are provided to show that the proposed scheme outperforms the conventional scheme with slightly increased computational complexity.
Increased oxidative stress and impaired antioxidant defense are important mechanisms in the pathogenesis of diabetic myopathy. Alpha-lipoic acid (ALA) has been indicated as a weight-loss treatment in ...rodents and humans, but studies are limited. In the present study, we aimed to determine the influence of ALA, a potent biological antioxidant, on metabolic and growth processes in diabetic rat skeletal muscle.
Male 25-week-old type 2 diabetic rats (OLETF) were randomly divided into two groups, a control group (OLETF-C) and an ALA-treated group (OLETF-ALA) supplemented with 100 mg/kg ALA for 8 weeks. Age-matched, healthy, nondiabetic LETO (LETO-C) rats were used as controls.
At 32 weeks of age, body weight was decreased by 6.8%, and the areas under the curve of IP-GTT, fasting glucose, and insulin were less in OLETF-ALA rats compared with OLETF-C rats. ALA significantly preserved muscle mass and enhanced muscle fiber cross-sectional area and fiber frequency percentage in the skeletal muscle of OLETF rats. Although the activation of myoD, myogenin, and myostatin in gastrocnemius muscle was significantly inhibited in OLETF-ALA rats relative to OLETF-C rats, there were no differences in the expression levels of muscle atrogin-1 and MuRF1 between the two groups. ALA treatment significantly increased the levels of phosphorylated 5'-AMPK, SIRT1, and PGC-1α, as well as the levels of phosphorylated AKT, mTOR, and p70S6 kinase in OLETF-ALA rats compared with OLETF-C rats. In contrast, the levels of phosphorylated p38 MAPK, IRS-1, and FOXO1 were decreased in OLETF-ALA rats compared with OLETF-C rats.
ALA treatment preserved mass in the gastrocnemius muscles of OLETF rats. ALA significantly upregulated the AMPK/SIRT1/PGC-1α and AKT/mTOR/p70S6K signaling pathways in OLETF rat skeletal muscle. Therefore, ALA may be a potential therapeutic intervention for skeletal muscle loss in animal models of insulin resistance.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
To develop an external vehicle for skin hydration and enhanced dermal drug delivery, a hydrogel-based ultra-moisturizing cream (HUMC) was successfully formulated with carbopol 934P, urea, Tinocare ...GL, grape seed oil, and other excipients. The HUMC showed plastic flow behavior due to a gel structure with a cream base. Different types of drug-free vehicles such as a hydrogel, conventional cream (CC), and three HUMCs were prepared and subjected to an in vivo skin hydration test on a hairless mouse using a corneometer. Hydration effect (∆AU) was in the order of HUMC2>HUMC1 ≥ CC>HUMC3>hydrogel. Using nile red (NR) and 5-carboxyfluorescein (5-CF) as lipophilic and hydrophilic fluorescent probes, respectively, in vitro skin permeation and accumulation studies were conducted using Franz diffusion cells. The values of steady-state flux (Jss, ng/h/cm2) were obtained: 74.8 (CC), 145.6 (HUMC1), and 161.9 (HUMC2) for NR delivery; 6.8 (CC), 8.3 (HUMC1), and 10.9 (HUMC2) for 5-CF delivery. The amounts retained in the skin at 12 h (Qr, ng/cm2) were determined: 86.4 (CC) and 102.0 (HUMC2) for NR; and 70.1 (CC) and 195.6 (HUMC2) for 5-CF. Confocal microscopy was used to visualize the distribution of the fluorescent probes. NR tended to be localized into the deeper part of the skin with adipose tissue whereas 5-CF localized in the upper layer of the skin. Thus we propose that HUMC2 is an efficacious vehicle for skin hydration and enhances dermal delivery of lipophilic and hydrophilic drugs.
In this paper, data shortening methods for lowering error floors of systematic LDPC codes are proposed. Rather than attempting to analyze trapping (or stopping) sets of a given LDPC code rigorously, ...we search information bits associated with dominant trapping (or stopping) sets of systematic LDPC codes through simulation under various channels. Then, proper information bits forming dominant trapping (or stopping) sets are selected and known values are assigned to them before encoding to weaken the effect of dominant trapping (or stopping) sets. To decode codewords, fixed known values are assigned to the selected information bits, which gives rise to the disconnection of some edges in dominant trapping (or stopping) sets. Through simulation, it is shown that the proposed schemes result in remarkably better performance, especially at the error floor region, than the base LDPC codes under various channels with negligible loss of code rate.
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