Empagliflozin rescues lifespan and liver senescence in naturally aged mice.

Empagliflozin is currently known to decrease blood glucose levels, delay renal failure, and reduce the risk of cardiovascular death and all-cause mortality in patients with type 2 diabetes with cardiovascular disease. However, the effects of empagliflozin on the lifespan and health of naturally aged organisms are unclear. This study was designed to investigate the impacts and potential mechanisms of empagliflozin on lifespan and liver senescence in naturally aged mice. Our study revealed that empagliflozin improved survival and health in naturally aged mice. Empagliflozin extended the median survival of male mice by 5.9%. Meanwhile, empagliflozin improved learning memory and motor balance, decreased body weight, and downregulated the hepatic protein expression of P21, P16, α-SMA, and COL1A1. Empagliflozin modulates the structure of the intestinal flora, increasing the relative abundance of Lachnospiraceae, Ruminococcaceae, Lactobacillus, Blautia, and Muribaculaceae and decreasing the relative abundance of Erysipelotrichaceae, Turicibacter, and Dubosiella in naturally aged mice. Further exploration discovered that empagliflozin increased the concentration of SCFAs, decreased the levels of the inflammatory factors TNF-α, IL-6, and CXCL9, and regulated the PI3K/AKT/P21 and AMPK/SIRT1/NF-κB pathways, which may represent the underlying mechanisms involved in these beneficial hepatic effects. Taken together, the above results indicated that empagliflozin intervention could be considered a potential strategy for extending lifespan and slowing liver senescence in naturally aged mice.

Causal Relationship Between Sleep Traits and Hypothalamic-Pituitary-Target Gland Axis Function: A Mendelian Randomization Study.

Background: In recent years, multiple observational studies have confirmed the association between sleep traits and various human physiopathological states. However, the causal relationship between sleep traits and hypothalamic-pituitary-target gland axis (HPTGA) function remains unknown. Methods: We obtained summary statistics on sleep traits (insomnia, chronotype, and sleep duration (long and short)) from the UK Biobank database. Data related to the HPTGA functions were obtained from the publicly available database. Subsequently, a two-sample Mendelian randomization (MR) analysis was performed to investigate the causal relationship between different sleep traits and the HPTGA function. Reverse MR analysis was conducted to examine the direction of causality. Results: The MR analysis results suggested that chronotype is associated with decreased levels of six hormones in HPTGA. Sleep duration was causally associated with decreased levels of free thyroxine and progesterone. Both long and short sleep durations are detrimental to the secretion of prolactin-releasing peptide, somatostatin, and plasma cortisol, while short sleep duration can promote progesterone secretion. After gender stratification, we found that female reproductive function is more susceptible to the influence of unfavorable sleep traits. Conclusion: Our MR analysis indicated a significant causal association between chronotype and suppressed gonadal function in healthy adult humans, with no apparent gender-specific effect. Extreme sleep durations were also found to be detrimental to the maintenance of normal HPTGA secretion function. Compared to males, gonadal function in the female cohort is more susceptible to extreme sleep habits. Subsequent observational studies are urgently needed to confirm the underlying mechanisms.

The SGLT2 inhibitor empagliflozin inhibits skeletal muscle fibrosis in naturally aging male mice through the AMPKα/MMP9/TGF-ß1/Smad pathway.

ABSTACT: With advancing age, the incidence of sarcopenia increases, eventually leading to a cascade of adverse events. However, there is currently a lack of effective pharmacological treatment for sarcopenia. Sodium-glucose co-transporter 2 inhibitor (SGLT2i) empagliflozin demonstrates anti-fibrotic capabilities in various organs. This study aims to determine whether empagliflozin can improve skeletal muscle fibrosis induced by sarcopenia in naturally aging mice. A natural aging model was established by feeding male mice from 13 months of age to 19 months of age. A fibrosis model was created by stimulating skeletal muscle fibroblasts with TGF-ß1. The Forelimb grip strength test assessed skeletal muscle function, and expression levels of COL1A1, COL3A1, and α-SMA were analyzed by western blot, qPCR, and immunohistochemistry. Additionally, levels of AMPKα/MMP9/TGFß1/Smad signaling pathways were examined. In naturally aging mice, skeletal muscle function declines, expression of muscle fibrosis markers increases, AMPKα expression is downregulated, and MMP9/TGFß1/Smad signaling pathways are upregulated. However, treatment with empagliflozin reverses this phenomenon. At the cellular level, empagliflozin exhibits similar anti-fibrotic effects, and these effects are attenuated by Compound C and siAMPKα. Empagliflozin exhibits anti-fibrotic effects, possibly associated with the AMPK/MMP9/TGFß1/Smad signaling pathways.

Empagliflozin improves kidney senescence induced by D-galactose by reducing sirt1-mediated oxidative stress.

Sodium-glucose cotransporter-2 (SGLT-2) inhibitors have received widespread attention because of their significant protective effects on the kidney. Previous studies have shown that Sirt1, as which is an antiaging protein, is closely related to the maintenance of redox homeostasis. The goal of this study was to determine whether empagliflozin could ameliorate D-galactose-induced renal senescence in mice, and examine the possible mechanisms of Sirt1. We constructed a rapid ageing model in mice by administering D-galactose. An ageing model was constructed by treating cells with high glucose. Treadmill and Y-maze tests were used to assess exercise tolerance and learning memory ability. Pathologically stained sections were used to assess kidney injury. Tissue and cell senescence were evaluated by senescence-associated ß-galactosidase staining. The expression levels of P16, SOD1, SOD2 and Sirt1 were detected by immunoblotting. D-gal-treated mice exhibited significant age-related changes, as measured by behavioural tests and ageing marker protein levels. empagliflozin alleviated these ageing manifestations. In addition, Sirt1, SOD1 and SOD2 levels were downregulated in model mice and upregulated by empagliflozin treatment. Empagliflozin had similar protective effects at the cellular level, and these effects were reduced by the Sirt1 inhibitor. Empagliflozin has an antiaging effect, which may be related to reducing Sirt1-mediated oxidative stress.

Effect of Umbilical Cord Mesenchymal Stem Cell Transplantation Under LIFPUS Pretreatment on Thyroid Function in EAT Rats.

BACKGROUND: A growing number of studies have demonstrated that mesenchymal stem cells (MSCs) can effectively regulate the progression of multiple autoimmune diseases and can respond positively to mechanical stimulation by ultrasound in an in vitro setting to improve transplantation efficacy. OBJECTIVE: The aim of this study was to activate hUC-MSCs by pretreatment with low-intensity focused pulsed ultrasound (LIFPUS) in an in vitro environment and transplant them into a rat model of EAT via tail vein. To investigate the efficacy and potential mechanism of action of hUC-MSCs in the treatment of EAT. METHODS: In this study, 40 female lewis rats were divided into control, EAT, hUC-MSCs treatment and LIFPUS pretreatment transplantation group. EAT models were established by subcutaneous multi-point injection of PTG+Freund's adjuvant, and the primary hUC-MSCs were treated with different gradients of LIFPUS irradiation or sham irradiation in an in vitro environment and screened by Western Blot (WB), flow cytology cycle analysis, and cellular immunofluorescence to find the optimal treatment parameters for LIFPUS to promote cell proliferation. After tail vein injection of different pretreatment groups of hUC-MSCs, Homing sites of hUC-MSCs in vivo, circulating autoantibody expression levels and local thyroid histopathological changes were assessed by enzyme-linked immunosorbent assay (ELISA), spleen index, tissue hematoxylin-eosin (HE) staining and immunohistochemistry. The expression levels of apoptotic proteins Bcl-2, Bax and endoplasmic reticulum stress-related proteins Chop and EIF2α in thyroid tissue were also examined by WB. RESULTS: LIFPUS can effectively stimulate hUC-MSCs in vitro to achieve the most optimal proliferative and secretory activity. In the EAT model, hUC-MSCs can effectively reduce thyroid cell apoptosis, improve thyroid function and reduce excessive accumulation of autoimmune antibodies in the body. in comparison, the LIFPUS pretreatment group showed a more favorable treatment outcome. Further experiments demonstrated that hUC-MSCs transplantation may effectively inhibit the apoptotic state of thyroid follicles and follicular epithelial cells by down-regulating the unfolded protein reaction (UPR) of the PERK pathway, thus providing a therapeutic effect for AIT. CONCLUSION: hUC-MSCs can effectively reverse the physiological function of EAT thyroid tissue and reduce the accumulation of circulating antibodies in the body. in comparison, hUC-MSCs under LIFPUS pretreatment showed more desirable therapeutic potential. hUC-MSCs transplanted under LIFPUS pretreatment may be a new class of safe therapeutic modality for the treatment of AIT.

Effect of GLP-1R rs2254336 and rs3765467 polymorphisms on gastrointestinal adverse reactions in type 2 diabetes patients treated with liraglutide.

PURPOSE: Gastrointestinal adverse reactions (GIARs) to liraglutide exhibit significant individual differences in type 2 diabetes. This study investigated the association between glucagon-like peptide-1 receptor (GLP-1R) single-nucleotide polymorphisms (SNPs) and GIARs. METHODS: Adverse events of liraglutide were observed in 376 T2DM patients. Seven tag SNPs at GLP-1R were sequenced in 152 participants. The influencing factors of GIARs and the genetic model of tag SNPs were examined by logistic regression analysis. The relationship between the tag SNPs and GIARs was determined by the chi-square test and cochran-armitage trend test. Multifactor dimensionality reduction (MDR) analysis was used to explore interactive analysis in GIARs risk. RESULTS: Twenty-nine percent of subjects had side effects, mainly GIARs. Nausea was the most common GIARs. Compared with males, females were more likely to develop GIARs (P = 0.043, OR = 1.895, 95% CI: 1.021-3.517). The T allele at GLP-1R rs2254336 (P = 0.028) and the A allele at GLP-1R rs3765467 (P = 0.007) were associated with GIARs of liraglutide. As the number of rs2254336 T alleles (P = 0.014) or rs3765467 A alleles (P = 0.008) increased, the subjects tended to develop GIARs. MDR analysis identified that there were no significant interactions among rs2254336, rs3765467 and sex. CONCLUSION: Our results suggest that female sex, the T allele at GLP-1R rs2254336 and the A allele at GLP-1R rs3765467 could be predictors of GIARs with liraglutide in T2DM patients.

Correlation of Significantly Decreased Serum Circulating Mesencephalic Astrocyte-Derived Neurotrophic Factor Level With an Increased Risk of Future Cardiovascular Disease in Adult Patients With Growth Hormone Deficiency.

Objective: Adult growth hormone deficiency (AGHD) is a rare chronic inflammatory disease caused by damage to the pituitary gland and is accompanied by disorders of multiple metabolic pathways. By examining the correlation between the serum mesencephalic astrocyte-derived neurotrophic factor (MANF) levels of AGHD patients and those of normal controls, we hope to elucidate the close relationship among MANF, lipid metabolism and insulin resistance in AGHD and discuss the potential therapeutic value of MANF. Methods: This study included 101 AGHD patients and 100 healthy subjects matched for sex, age, height, and weight. Anthropometric parameters and biochemical indicators such as body mass index, waist circumference, hip circumference, serum MANF level, blood lipids and insulin level were measured. The above patients were also divided into several subgroups for correlation analysis based on indicators such as insulin resistance and BMI. Results: The serum circulating MANF content of AGHD patients was significantly lower than that of the normal control group (5.235 (0.507-17.62) ng/ml (n=101) vs. 10.30 (1.84-16.65) ng/ml (n=100); p<0.0001), and circulating MANF levels were linearly correlated with HOMA-IR in the AGHD population (R=0.481, P=0.0041). When MANF was at pathological concentrations (lower than the mean circulating MANF of normal controls), the lowest concentration tertile (OR=21.429 p<0.0001) had a significantly higher disease odds ratio, Framingham risk score and 10-year risk of atherosclerotic cardiovascular disease than the highest concentration tertile. Conclusions: MANF has a significant correlation with insulin resistance in the AGHD state. There is a strong correlation with abnormal glucose and lipid metabolism in the obese AGHD population. MANF is also a good assessment factor for the risk of cardiovascular disease in AGHD patients and has excellent therapeutic potential.

Screening for a Simple and Effective Indicator of Insulin Resistance in Chinese Reproductive-Aged Women, with the Insulin Clamp Technique as a Reference.

Background: Applying the hyperinsulinemic-euglycemic clamp to estimate insulin resistance (IR) is accurate but time-consuming, so identifying a simple and effective index for IR is vitally important. The present study aimed to compare the lipid accumulation product (LAP), visceral adiposity index (VAI), body mass index (BMI), waist circumference (WC), homeostasis model assessment of insulin resistance (HOMA-IR), and Chinese visceral adiposity index (CVAI) using the hyperinsulinemic-euglycemic clamp as a reference and to screen a simple and effective indicator for IR in Chinese women of childbearing age. Methods: The present study included a cross-sectional study of 537 reproductive-aged women and an interventional study of 90 randomly chosen polycystic ovarian syndrome (PCOS) women. Physical, laboratory, and hyperinsulinemic-euglycemic clamp were completed, and the BMI, WC, LAP, VAI, CVAI, and HOMA-IR were calculated. A linear correlation and a receiver operating characteristic curve were performed. After intervention with metformin, the effects were estimated in the third month. Results: PCOS women had worse glycometabolism, serum lipid metabolism and IR, and higher prevalence rates of metabolic disorders than those without PCOS. The CVAI was strongly associated with the M value (r = -0.6953, P < 0.0001) and outperformed other parameters with the largest area under the curve (0.903) and Youden index (71.07%) for IR diagnosis in Chinese reproductive-aged women, and the diagnostic point was >28.5. After 3 months of metformin therapy, IR improved with remarkable increases in M value and reductions in the CVAI. Conclusion: The CVAI can be used as an appropriate surrogate indicator for the hyperinsulinemic-euglycemic clamp to identify IR in Chinese women of childbearing age. The interventional trial part of this study has been registered as a clinical trial (no. ChiCTR-IIR-16007901).

The characteristics of 24-hour ambulatory blood pressure monitoring and its relationship with cardiovascular target organ damage in Chinese Han patients with concomitant type 2 diabetes and hypertension.

OBJECTIVE: The objective of this study was to investigate the characteristics of 24-hour ambulatory blood pressure monitoring and its relationship with cardiovascular target organ damage (left ventricular hypertrophy and carotid atherosclerosis) in Chinese Han patients with concomitant type 2 diabetes mellitus and hypertension. METHODS: A total of 830 hypertensive patients with or without type 2 diabetes mellitus were divided into four groups according to blood pressure patterns. Clinical characteristics and 24-hour ambulatory blood pressure monitoring indexes were compared among the four groups. Multivariable logistic regression was used to identify the associations among clinical characteristics, blood pressure variability and cardiovascular target organ damage. RESULTS: The prevalence of the non-dipper blood pressure profile (51.32% vs. 24.33%) was higher in patients with type 2 diabetes mellitus and hypertension than in those without type 2 diabetes mellitus. Logistic regression analysis showed that glycosylated haemoglobin A1c, 24hSBP, 24hSSD, dSBP, nSBP and nSSD were independently associated with the non-dipper blood pressure pattern. Type 2 diabetes mellitus patients with the non-dipper blood pressure pattern showed a higher occurrence of target organ damage compared to patients in the other three groups. Multivariate regression analyses revealed that duration of hypertension, fasting blood glucose, dDBP and nDSD were associated with left ventricular hypertrophy. Age, haemoglobin A1c, LDL-C, nSBP and HDL-C were independently related to carotid atherosclerosis. CONCLUSION: In the Chinese Han population, patients with concomitant type 2 diabetes mellitus and hypertension showed a remarkably high prevalence of non-dipper blood pressure patterns. Abnormal systolic blood pressure level and hyperglycemia were significantly associated with a non-dipper blood pressure pattern. Non-dipper blood pressure pattern, hyperglycemia and dyslipidemia were closely related to left ventricular hypertrophy and carotid atherosclerosis.