Essential Amino Acid-Enriched Diet Alleviates Dexamethasone-Induced Loss of Muscle Mass and Function through Stimulation of Myofibrillar Protein Synthesis and Improves Glucose Metabolism in Mice

Dexamethasone (DEX) induces dysregulation of protein turnover, leading to muscle atrophy and impairment of glucose metabolism. Positive protein balance, i.e., rate of protein synthesis exceeding rate of protein degradation, can be induced by dietary essential amino acids (EAAs). In this study, we investigated the roles of an EAA-enriched diet in the regulation of muscle proteostasis and its impact on glucose metabolism in the DEX-induced muscle atrophy model. Mice were fed normal chow or EAA-enriched chow and were given daily injections of DEX over 10 days. We determined muscle mass and functions using treadmill running and ladder climbing exercises, protein kinetics using the D2O labeling method, molecular signaling using immunoblot analysis, and glucose metabolism using a U-13C6 glucose tracer during oral glucose tolerance test (OGTT). The EAA-enriched diet increased muscle mass, strength, and myofibrillar protein synthesis rate, concurrent with improved glucose metabolism (i.e., reduced plasma insulin concentrations and increased insulin sensitivity) during the OGTT. The U-13C6 glucose tracing revealed that the EAA-enriched diet increased glucose uptake and subsequent glycolytic flux. In sum, our results demonstrate a vital role for the EAA-enriched diet in alleviating the DEX-induced muscle atrophy through stimulation of myofibrillar proteins synthesis, which was associated with improved glucose metabolism.

The Efficacy of Tofogliflozin on Metabolic Dysfunction-Associated Fatty Liver Disease

The increasing number of patients with fatty liver disease is a major health problem. Fatty liver disease with metabolic dysfunction has been recognized as nonalcoholic fatty liver disease (NAFLD). Although there is no standard therapy for NAFLD, previous reports support the effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors on NAFLD. Recently, fatty liver disease with metabolic dysfunction was proposed to be defined as a novel concept, “metabolic associated fatty liver disease (MAFLD)”, and it was proposed that new criteria for MAFLD diagnosis be established. To clarify the effect of SGLT2 inhibitors on MAFLD, we analyzed the efficacy of tofogliflozin in patients with MAFLD. We conducted a single-center, retrospective study to evaluate the efficacy of tofogliflozin in patients with MAFLD treated at Kyushu University Hospital between 2017 and 2019. Tofogliflozin was used to treat 18 patients with MAFLD. To determine the efficacy of tofogliflozin, we evaluated glucose metabolism, insulin resistance, liver injury, hepatic steatosis, and body composition three and six months after drug initiation. Although our study was a preliminary study because of some limitations (e.g., retrospective, observational, single-arm study, small sample size), we show that tofogliflozin could improve liver injury in patients with MAFLD by improving glucose metabolism and insulin resistance without causing muscle loss.

PFKP Activation Ameliorates Foot Process Fusion in Podocytes in Diabetic Kidney Disease

BackgroundGlycolysis dysfunction is an important pathogenesis of podocyte injury in diabetic kidney disease (DKD). Foot process fusion of podocytes and increased albuminuria are markers of early DKD. Moreover, cytoskeletal remodeling has been found to be involved in the foot process fusion of podocytes. However, the connections between cytoskeletal remodeling and alterations of glycolysis in podocytes in DKD have not been clarified.MethodsmRNA sequencing of glomeruli obtained from db/db and db/m mice with albuminuria was performed to analyze the expression profiling of genes in glucose metabolism. Expressions of phosphofructokinase platelet type (PFKP) in the glomeruli of DKD patients were detected. Clotrimazole (CTZ) was used to explore the renal effects of PFKP inhibition in diabetic mice. Using Pfkp siRNA or recombinant plasmid to manipulate PFKP expression, the effects of PFKP on high glucose (HG) induced podocyte damage were assessed in vitro. The levels of fructose-1,6-bisphosphate (FBP) were measured. Targeted metabolomics was performed to observe the alterations of the metabolites in glucose metabolism after HG stimulation. Furthermore, aldolase type b (Aldob) siRNA or recombinant plasmid were applied to evaluate the influence of FBP level alteration on podocytes. FBP was directly added to podocyte culture media. Db/db mice were treated with FBP to investigate its effects on their kidney.ResultsmRNA sequencing showed that glycolysis enzyme genes were altered, characterized by upregulation of upstream genes (Hk1, and Pfkp) and down-regulation of downstream genes of glycolysis (Pkm, and Ldha). Moreover, the expression of PFKP was increased in glomeruli of DKD patients. The CTZ group presented more severe renal damage. In vitro, the Pfkp siRNA group and ALDOB overexpression group showed much more induced cytoskeletal remodeling in podocytes, while overexpression of PFKP and suppression of ALDOB in vitro rescued podocytes from cytoskeletal remodeling through regulation of FBP levels and inhibition of the RhoA/ROCK1 pathway. Furthermore, targeted metabolomics showed FBP level was significantly increased in HG group compared with the control group. Exogenous FBP addition reduced podocyte cytoskeletal remodeling and renal damage of db/db mice.ConclusionsThese findings provide evidence that PFKP may be a potential target for podocyte injury in DN and provide a rationale for applying podocyte glycolysis enhancing agents in patients with DKD.

Maternal Pre-Pregnancy Obesity Combined With Abnormal Glucose Metabolism Further Increases Adverse Pregnancy Outcomes in Chinese Pregnant Women

AimsOur aim was to evaluate the separate and combined effects of maternal pre-pregnancy obesity and gestational abnormal glucose metabolism (GAGM) on adverse perinatal outcomes.MethodsA total of 2,796 Chinese pregnant women with singleton delivery were studied, including 257 women with pre-pregnancy obesity alone, 604 with GAGM alone, 190 with both two conditions, and 1,745 with neither pre-pregnancy obesity nor GAGM as control group. The prevalence and risks of adverse pregnancy outcomes were compared among the four groups.ResultsCompared with the normal group, pregnant women with maternal pre-pregnancy obesity alone, GAGM alone, and both two conditions faced significantly increased risks of pregnancy-induced hypertension (PIH) (odds ratio (OR) 4.045, [95% confidence interval (CI) 2.286–7.156]; 1.993 [1.171–3.393]; 8.495 [4.982–14.485]), preeclampsia (2.649 [1.224–5.735]; 2.129 [1.128–4.017]; 4.643 [2.217–9.727]), cesarean delivery (1.589 [1.212–2.083]; 1.328 [1.095–1.611]; 2.627 [1.908–3.617]), preterm delivery (1.899 [1.205–2.993]; 1.358 [0.937–1.968]; 2.301 [1.423–3.720]), macrosomia (2.449 [1.517–3.954]; 1.966 [1.356–2.851]; 4.576 [2.895–7.233]), and total adverse maternal outcomes (1.762 [1.331–2.332]; 1.365 [1.122–1.659]; 3.228 [2.272–4.587]) and neonatal outcomes (1.951 [1.361–2.798]; 1.547 [1.170–2.046]; 3.557 [2.471–5.122]). Most importantly, there were no obvious risk differences in adverse pregnancy outcomes between maternal pre-pregnancy obesity and GAGM group except PIH, but pregnant women with both obesity and GAGM exhibited dramatically higher risks of adverse pregnancy outcomes than those with each condition alone.ConclusionsMaternal pre-pregnancy obesity and GAGM were independently associated with increased risks of adverse pregnancy outcomes. The combination of pre-pregnancy obesity and GAGM further worsens adverse pregnancy outcomes compared with each condition alone.

Association Between Triglyceride Glucose Index and Carotid Artery Plaque in Different Glucose Metabolic States in Patients with Coronary Heart Disease — A RCSCD-TCM Study in China

BackgroundThe triglyceride glucose (TyG) index serves as a surrogate indicator of insulin resistance. However, there are limited data on the association between TyG index and carotid artery plaque (CAP) in patients with coronary heart disease (CHD).MethodsA total of 10,535 CHD patients were included in this study. TyG index was divided into quartiles, Q1: TyG index ＜ 8.52, Q2: 8.52 ≤ TyG index ＜ 8.93, Q3: 8.93 ≤ TyG index ≤ 9.40, Q4: TyG index ＞9.40. Logistic regression was used to analyze the relationship between TyG index and CAP in CHD patients, and further analyzed the relationship between TyG index and CAP in different genders, different age groups and different glucose metabolism states. ResultsA baseline analysis of CHD patients divided into four groups according to the quartile of the TyG index showed that there were significant differences in related parameters between the groups. As the TyG index increases, the incidence of CAP increases significantly. After adjustment for multivariate, TyG index levels for Q3 and Q4 correlated with increased OR in CAP, which Q4 has the highest correlation (OR: 1.42; 95% CI: 1.33 -1.53). The correlation between the Tyg index of female (OR:1.38; 95% CI: 1.31-1.45) and CAP was higher than that of male (OR:1.23; 95% CI: 1.16, 1.30). The OR value of middle-aged (≤ 60 years old) patients (OR:1.14; 95% CI: 1.07-1.22) is higher than that of elderly (＞dayu 60 years old) patients (OR:1.07; 95% CI: 1.02-1.13). Under different glucose metabolism states, the TyG index of CHD patients was significantly related to the risk of CAP, and the OR value of diabetes (DM) was the highest (OR: 1.35; 95% CI: 1.26-1.45).ConclusionsThere is a significant correlation between the TyG index and CAP in CHD patients. In addition, the correlation between TyG index and CAP in CHD patients is higher in female than in male, and the correlation in middle-aged and elderly patients is higher than that in elderly patients. Under the condition of DM, the correlation between TyG index and carotid artery plaque in CHD patients is higher.

Variants of the HNF4A and HNF1A genes in patients with impaired glucose metabolism and dyslipidemia

Maturity onset diabetes of the young is a dominantly inherited form of monogenic diabetes, diagnosed mainly before the age of 35 years. Mutations in the HNF1A and HNF4A genes are associated with diabetes mellitus of the HNF1A-MODY and HNF4A-MODY subtypes, respectively. These two forms of MODY are characterized by dyslipidemia in addition to impaired glucose metabolism due to the altered function HNF1A and HNF4A proteins. The aim of this study was a genetic analysis of young patients with the MODY phenotype and dyslipidemia with a burdened family history. Material and methods. The probands underwent targeted DNA sequencing using the Illumina MiSeq NGS System. The target panel included the coding regions and splicing sites of MODY-associated genes: HNF4A, GCK, HNF1A, PDX1, HNF1B, NEUROD1, KLF11, CEL, PAX4, INS, BLK, KCNJ11, ABCC8, and APPL1. Results. A heterozygous single nucleotide deletion NM_000457.4: c.153del (3’rule) was found in proband P1 in the HNF4A gene. In proband P2, single nucleotide deletion NM_000545.8: c.335del (3 ‘rule) in the HNF1A gene was detected in a heterozygous state. Both variants are located in the coding parts of the genes, led to a shift in the reading frame and have not been described in the literature and databases earlier. Conclusions. Taking into account the phenotypic features of probands, we assume that the variants NM_000545.8: c.335del (rule 3) in the HNF1A gene and NM_000457.4: c.153del (rule 3) of the HNF4A gene are associated with different MODY subtypes in these individuals. After verification of MODY-HNF1A and MODY-HNF4A diagnosis, it is necessary to monitor the lipid profile parameters (total cholesterol, low and high density lipoprotein cholesterol, triglycerides) and prescribe appropriate drug therapy.

Validation of the revised Diabetes Self-Management Questionnaire (DSMQ-R) in the primary care setting

Background Available tools measuring self-management in diabetes are often improperly validated or do not correlate with glucose metabolism. The Diabetes Self-Management Questionnaire (DSMQ-R) is a valid tool, that showed strong relationship with glucose metabolism in tertiary care among people with mostly type 1 diabetes. Aim of the study To validate the translated DSMQ-R questionnaire in a Hungarian sample of people with predominantly type 2 diabetes in primary care. Methods We enrolled 492 adults from 38 practices in this cross-sectional cohort study, who filled out the self-administered questionnaire, consisting of DSMQ-R and the Summary of Diabetes Self-Care Activities (SDSCA) questionnaires. Family doctors provided clinical data. The translation process was performed in six steps, reaching the expert committee appraisal. The validity of the questionnaire was evaluated by assessing reliability and construct validity. Results Cronbach’s alpha showed the questionnaire to reach good reliability (α = 0.845), although subscales had lower alphas. Contrary to the SDSCA questionnaire, the DSMQ-R sum scale differed significantly between persons on target vs not on target (median (interquartile range): 7.23 (6.17–8.44) vs 6.91 (5.91–8.02), and the DSMQ-R sum scale correlated significantly with BMI, HbA1c and SDSCA sum scale. In multivariate analysis higher DSMQ-R scores were significant predictor of achieving glycemic target goal. Conclusion The Hungarian translation of the DSMQ-R is a comprehensible tool to assess self-management of persons with diabetes. The questionnaire is valid and reliable in family practice, although its association with achievement of diabetes HbA1c target is weaker in primary than in tertiary care.