Deficiency of ADAR2 ameliorates metabolic-associated fatty liver disease via AMPK signaling pathways in obese mice.

Non-alcoholic fatty liver disease (NAFLD) is a chronic disease caused by hepatic steatosis. Adenosine deaminases acting on RNA (ADARs) catalyze adenosine to inosine RNA editing. However, the functional role of ADAR2 in NAFLD is unclear. ADAR2+/+/GluR-BR/R mice (wild type, WT) and ADAR2-/-/GluR-BR/R mice (ADAR2 KO) mice are fed with standard chow or high-fat diet (HFD) for 12 weeks. ADAR2 KO mice exhibit protection against HFD-induced glucose intolerance, insulin resistance, and dyslipidemia. Moreover, ADAR2 KO mice display reduced liver lipid droplets in concert with decreased hepatic TG content, improved hepatic insulin signaling, better pyruvate tolerance, and increased glycogen synthesis. Mechanistically, ADAR2 KO effectively mitigates excessive lipid production via AMPK/Sirt1 pathway. ADAR2 KO inhibits hepatic gluconeogenesis via the AMPK/CREB pathway and promotes glycogen synthesis by activating the AMPK/GSK3ß pathway. These results provide evidence that ADAR2 KO protects against NAFLD progression through the activation of AMPK signaling pathways.

Calsarcin-2 May Play a Compensatory Role in the Development of Obese Sarcopenia.

Although obese sarcopenia is a major public health problem with increasing prevalence worldwide, the factors that contribute to the development of obese sarcopenia are still obscure. In order to clarify this issue, a high-fat-diet-induced obese sarcopenia mouse model was utilized. After being fed with a high-fat diet for 24 weeks, decreased motor functions and muscle mass ratios were found in the C57BL/6 mice. In addition, the expression of calsarcin-2 was significantly increased in their skeletal muscle, which was determined by a microarray analysis. In order to clarify the role of calsarcin-2 in muscle, lentiviral vectors containing the calsarcin-2 gene or short hairpin RNA targeted to calsarcin-2 were used to manipulate calsarcin-2 expressions in L6 myoblasts. We found that an overexpression of calsarcin-2 facilitated L6 myoblast differentiation, whereas a calsarcin-2 knockdown delayed myoblast differentiation, as determined by the expression of myogenin. However, the calsarcin-2 knockdown showed no significant effects on myoblast proliferation. In addition, to clarify the relationship between serum calsarcin-2 and sarcopenia, the bilateral gastrocnemius muscle mass per body weight in mice and appendicular skeletal muscle mass index in humans were measured. Although calsarcin-2 facilitated myoblast differentiation, the serum calsarcin-2 concentration was negatively related to skeletal muscle mass index in mice and human subjects. Taken together, calsarcin-2 might facilitate myoblast differentiation and appear to play a compensatory role in sarcopenia.

Growth differentiation factor-15 is independently associated with metabolic syndrome and hyperglycemia in non-elderly subjects.

Metabolic syndrome (MetS) is a major health issue worldwide accompanied by cardiovascular comorbidities. Growth differentiation factor-15 (GDF-15) is a stress-responsive cytokine expressed in cardiomyocytes, adipocytes, macrophages, and endothelial cells. Previous research in elderly subjects revealed that GDF-15 levels were associated with the MetS. However, the association between GDF-15 levels and MetS or its components in the non-elderly subjects remains unclear. In this study, a total of 279 subjects younger than 65-year-old with (n = 84) or without (n = 195) MetS were recruited. MetS was defined according to modified NCEP/ATP III criteria. The GDF-15 levels were measured by an enzyme-linked immunosorbent assay. A multiple linear regression analysis was conducted to identify factors independently associated with GDF-15 levels. Subjects with MetS had higher GDF-15 levels than those without MetS (median (interquartile range), 1.72 ng/mL (1.38, 2.26) vs. 1.63 ng/mL (1.27, 2.07), P = 0.037). With the number of MetS components increased, the GDF-15 levels increased significantly (P for trend = 0.005). Multiple linear regression analysis revealed that the presence of MetS was positively associated with the GDF-15 levels (ß = 0.132, P = 0.037). When substituting MetS with its components, only the presence of hyperglycemia was positively associated with the GDF-15 levels after adjustment for covariates (ß = 0.193, P = 0.003). Taken together, the presence of the MetS in non-elderly was associated with higher GDF-15 levels. Among the MetS components, only hyperglycemia was significantly associated with the GDF-15 levels. Future longitudinal studies will be needed to explore whether GDF-15 has the potential to be a biomarker of gluco-metabolic dysfunction in non-elderly subjects.

Real-World Comparative Evaluation of Add-On Glucagon-like Peptide 1 Receptor Agonist in Type 2 Diabetes Treated with or without Insulin.

Glucagon-like peptide 1 receptor agonist (GLP-1 RA) is a potent antidiabetic agent with cardiorenal and weight-losing benefits in patients with type 2 diabetes (T2D). The combination of GLP-1 RA with basal insulin has been suggested in several clinical studies as a useful treatment for intensifying insulin therapy in T2D. However, there has been no real-world evidence study comparing the glycemic effects of GLP-1 RAs add-on to background treatment with and without insulin. A retrospective study was performed in 358 patients with T2D who initiated liraglutide or dulaglutide. Among them, 147 patients were prior and concurrent insulin users, and 211 patients were non-insulin users. After 12 months of GLP-1 RA treatment, the changes in hemoglobin A1c (HbA1C) and body weight were evaluated. The effectiveness of GLP-1 RAs on HbA1C reduction was greater in insulin users than non-insulin users at 12 months (−1.17% vs. −0.76%; p = 0.018). There was no significant difference in body weight change between insulin users and non-insulin users at 12 months (−1.42 kg vs. −1.87 kg; p = 0.287). The proportion of responders (decrease of HbA1C > 1%) in insulin users was much higher than that in non-insulin users (48% vs. 37 %; p = 0.04). In insulin users, those who had increased insulin dosage at 12 months had significantly less HbA1C reduction than that of non-increased patients (−0.62% vs. −1.57%; p = 0.001). GLP-1 RAs provide superior glucose-lowering effects in insulin-treated patients compared with non-insulin-treated patients with T2D without significant differences in body weight decrease.

Sucralose, a Non-nutritive Artificial Sweetener Exacerbates High Fat Diet-Induced Hepatic Steatosis Through Taste Receptor Type 1 Member 3.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease globally, and it is strongly associated with obesity. To combat obesity, artificial sweeteners are often used to replace natural sugars, and sucralose is one of the most extensively used sweeteners. It was known that sucralose exerted effects on lipid metabolism dysregulation, and hepatic inflammation; however, the effects of sucralose on hepatic steatosis were still obscure. In this study, we found that supplements of sucralose enhanced high-fat-diet (HFD)-induced hepatic steatosis. In addition, treatment of sucralose increased reactive oxygen species (ROS) generation and induced endoplasmic reticulum (ER) stress in HepG2 cells. Pretreatment of ROS or ER stress inhibitors reversed the effects of sucralose on lipogenesis. Furthermore, pretreatment of taste receptor type 1 membrane 3 (T1R3) inhibitor or T1R3 knockdown reversed sucralose-induced lipogenesis in HepG2 cells. Taken together, sucralose might activate T1R3 to generate ROS and promote ER stress and lipogenesis, and further accelerate to the development of hepatic steatosis.

Beyond Sarcopenia: older adults with type II diabetes mellitus tend to experience an elevated risk of poor dynamic balance-a case-control study.

BACKGROUND: People with type 2 diabetes mellitus (T2DM) tend to be vulnerable to geriatric syndromes such as sarcopenia and frailty. Reduced physical activity also accompanies sarcopenia and frailty, which is generally typical of patients with T2DM. However, a comprehensive assessment of physical fitness in patients with T2DM has seldom been carried out and verified. This study is thus an attempt to determine the associations among sarcopenia, frailty, and the SFT in diabetic patients and non-diabetic controls to provide a more comprehensive understanding of such associations in future evaluations of T2DM in older individuals. METHODS: Sarcopenia, frailty, and the senior fitness test (SFT) were compared between 78 older men with T2DM (66.5 ± 9.0 years) and 48 age-matched normoglycemic controls (65.8 ± 5.3 years) in this case-control study. The skeletal muscle index (SMI), grip strength, and 4-m walk test were employed to assess for sarcopenia. Frailty was evaluated using the Study of Osteoporotic Fractures index (SOF). The SFT comprises five components, including body composition, muscle strength, flexibility, balance, and aerobic endurance. RESULTS: The risk level of sarcopenia was significantly higher (p < 0.05) in the T2DM group as compared to the control group. No significant difference between-group differences were found in SMI and grip strength in the T2DM and control groups. However, the T2DM group showed a significant decrease in gait speed (p < 0.01) in comparison with the control group, as well as significant increases in frailty (p < 0.01) and depression (p < 0.05). With respect to the SFT, obvious elevation in BMI, significant declines in extremity muscle strength (elbow extensor, knee flexor, hip abductor, hip flexor, sit to stand), static/dynamic balance (single leg stand: p < 0.05; up-and-go: p < 0.01) and aerobic endurance (2-min step: p < 0.01; 6-min walk: p < 0.01) were found in the T2DM group. Furthermore, the SOF (OR = 2.638, 95% CI = 1.333-5.221), BMI (OR = 1.193, 95% CI = 1.041-1.368) and up-and-go (OR = 2.089, 95% CI = 1.400-3.117) were found to be positively and significantly associated with T2DM. CONCLUSIONS: The findings of this study indicated the importance of countering frailty and maintaining physical fitness, especially dynamic balance, during the early physical deterioration taking place in diabetic patients.

The Serum Concentrations of Hedgehog-Interacting Protein, a Novel Biomarker, Were Decreased in Overweight or Obese Subjects.

Although it was known that obesity is an independent risk factor for metabolic disorders including diabetes, the factors that link these diseases were obscure. The Hedgehog-interacting protein (Hhip) is a negative regulator in tissue remodeling, and inhibits the proliferation of adipocytes, and promotes their differentiation. In addition, Hhip was positively associated with diabetes. However, the relationship between Hhip and obesity in the human body remains unclear. An analysis of the relationship between Hhip and normal weight, overweight, and obesity levels. Participants receiving a physical checkup were recruited. Anthropometric and biochemical data were collected. Serum Hhip levels were determined by enzyme-linked immunosorbent assay (ELISA). Subjects were classified into normal-weight, overweight, and obese groups based on their body mass index (BMI). The association between Hhip and obesity was examined by multivariate linear regression analysis. In total, 294 subjects who were either of a normal weight (n = 166), overweight (n = 90), or obese (n = 38) were enrolled. Hhip concentrations were 6.51 ± 4.86 ng/mL, 5.79 ± 4.33 ng/mL, and 3.97 ± 3.4 ng/mL in normal-weight, overweight, and obese groups, respectively (p for trend = 0.032). Moreover, the regression analysis showed that BMI (ß = -0.144, 95% confidence interval (CI) = -0.397-0.046, p = 0.013) was negatively associated with Hhip concentrations after adjusting for sex and age. Being overweight (ß = -0.181, 95% CI = -3.311-0.400, p = 0.013) and obese (ß = -0.311, 95% CI = -6.393-2.384, p < 0.001) were independently associated with Hhip concentrations after adjusting for sex, age, fasting plasma glucose, the insulin level, and other cardiometabolic risk factors. Our results showed that overweight and obese subjects had lower Hhip concentrations than those of normal weight. Being overweight and obese were negatively associated with Hhip concentrations. Hhip might be a link between obesity and diabetes.

Discovery of a role of the novel hepatokine, hepassocin, in obesity.

Obesity is a public health problem that has raised concerns worldwide and is often associated with hepatic steatosis. Hepassocin is a novel hepatokine that causes hepatic steatosis and induces insulin resistance (IR). However, the role of hepassocin in obesity remains obscure. Thus, the aim of this study was to investigate the relationship between hepassocin levels and obesity. In total, 371 subjects who had a normal weight (NW), were overweight, or were obese were enrolled. We found that hepassocin levels in subjects who were overweight (6,705 ± 1,707 pg/ml) or obese (7,335 ± 2,077 pg/ml) were significantly higher than those of subjects with a NW (5,767 ± 1,500 pg/ml) (p < .001, test for trend). A multiple linear regression analysis showed that the body-mass index, waist circumference, nonalcoholic fatty liver disease, and homeostatic model assessment of IR were independently associated with hepassocin after adjusting for age, sex, high-sensitivity C-reactive protein, systolic blood pressure, high-density lipoprotein-cholesterol, log triglycerides, alanine transaminase, and the estimated glomerular filtration rate. This study provides evidence that subjects who were overweight or obese had significantly higher hepassocin levels than those with a NW. Hepassocin may be a useful biomarker in managing obesity and its related metabolic dysregulation.

Elevated Hedgehog-Interacting Protein Levels in Subjects with Prediabetes and Type 2 Diabetes.

BACKGROUND: The prevalence of diabetes is rapidly increasing worldwide and is highly associated with the incidence of cancers. In order to prevent diabetes, early diagnosis of prediabetes is important. However, biomarkers for prediabetes diagnosis are still scarce. The hedgehog-interacting protein (Hhip) is important in embryogenesis and is known to be a biomarker of several cancers. However, Hhip levels in subjects with diabetes are still unknown. METHODS: In total, 314 participants were enrolled and divided into normal glucose tolerance (NGT; n = 75), impaired fasting glucose (IFG; n = 66), impaired glucose tolerance (IGT; n = 86), and newly diagnosed diabetes (NDD; n = 87) groups. Plasma Hhip levels were determined by an ELISA. The association between the Hhip and the presence of diabetes was examined by a multivariate linear regression analysis. RESULTS: There were significant differences in the body mass index, systolic and diastolic blood pressure, fasting plasma glucose (FPG), post-load 2-h glucose, hemoglobin A1c (A1C), C-reactive protein, total cholesterol, triglyceride, and high- and low-density lipoprotein cholesterol levels among the groups. Concentrations of the Hhip were 2.45 ± 2.12, 4.40 ± 3.22, 4.44 ± 3.64, and 6.31 ± 5.35 ng/mL in subjects in the NGT, IFG, IGT, and NDD groups, respectively. In addition, we found that A1C and FPG were independently associated with Hhip concentrations. Using NGT as a reference group, IFG, IGT, and NDD were all independently associated with Hhip concentrations. CONCLUSIONS: Hhip was positively associated with prediabetes and type 2 diabetes mellitus.

Serum Secretogranin III Concentrations Were Increased in Subjects with Metabolic Syndrome and Independently Associated with Fasting Plasma Glucose Levels.

Secretogranin III (SCG3) plays a crucial role in the biogenesis of secretory granules in endocrine cells, and thus affects glucose homeostasis by regulating insulin secretion by pancreatic beta cells. Insulin resistance and compensatory hyperinsulinemia are hallmarks of metabolic syndrome (MetS). However, the role of SCG3 in MetS remains unclear. Therefore, we investigated the relationship between serum SCG3 levels and metabolic parameters in subjects with and without MetS. This was a case control study, and 295 subjects were recruited. Serum SCG3 concentrations were compared between groups. Associations between SCG3 levels and clinico-metabolic parameters were also examined. We found serum SCG3 levels were higher in the MetS group than non-MetS group (122.6 ± 79.2 vs. 90.6 ± 58.5 nmol/L, p = 0.009). Specifically, elevated SCG3 levels were found in subjects with high fasting plasma glucose (FPG) levels, central obesity, or hypertriglyceridemia. Additionally, MetS was an independent factor of serum SCG3 levels in multivariate linear regression analyses. Moreover, FPG, free fatty acids, and waist circumference were positively associated with serum SCG3 concentrations after adjusting for insulin levels, high-sensitivity C-reactive protein, and cardiovascular risk factors. In conclusion, serum SCG3 concentrations were higher in subjects with MetS and were independently associated with FPG levels.

Helicobacter pylori eradication improves glycemic control in type 2 diabetes patients with asymptomatic active Helicobacter pylori infection.

AIMS/INTRODUCTION: Helicobacter pylori infection is associated with insulin resistance and glycemia in non-diabetes. However, the relationship between H. pylori infection and glycemia in diabetes remains inconclusive. Therefore, we explored the effect of H. pylori infection status and its eradication on glycemic control and antidiabetic therapy in type 2 diabetes patients. MATERIALS AND METHODS: A total of 549 diabetes patients were recruited for sequential two-step approach (immunoglobulin G [IgG] serology followed by 13 C-urea breath test [UBT]) to discriminate "active" (IgG+ and UBT+) from "non-active" (UBT- or IgG-) H. pylori infection, and "past" (IgG+ but UBT-) from "never/remote" (IgG-) infection. The differences in hemoglobin A1c (A1C) and antidiabetic regimens between groups were compared. In the "active" infection group, the differences in A1C changes between participants with and without 10-day eradication therapy were compared after 3 months. RESULTS: Despite no between-group difference in A1C, the "active" infection group (n = 208) had significantly more prescriptions of oral antidiabetic drug classes (2.1 ± 1.1 vs 1.8 ± 1.1, P = 0.004) and higher percentages of sulfonylurea use (67.3% vs 50.4%, P < 0.001) than the "non-active" infection group (n = 341). There were no differences in A1C and oral antidiabetic drug classes between "past" (n = 111) and "never/remote" infection groups (n = 230). Compared with the non-eradication group (n = 99), the eradication group (n = 98) had significant within-group (-0.17 ± 0.80%, P = 0.036) and between-group (-0.23 ± 0.10%, P = 0.024) improvements in A1C. CONCLUSIONS: Diabetes patients with active H. pylori infection need higher glycemic treatment intensity to achieve comparable glycemia. Furthermore, H. pylori eradication decreases A1C, and thus improves glycemic control.

Unsaturated Fatty Acids Increase the Expression of Hepassocin through a Signal Transducer and Activator of Transcription 3-Dependent Pathway in HepG2 Cells.

Hepassocin (HPS) is a hepatokine that regulates hepatocyte proliferation. It is known that HPS plays an important role in the development of nonalcoholic fatty liver diseases (NAFLD). Fatty acids, such as oleic acid (OLA), exhibit the ability to activate the signal transducer and activator of transcription-3 (STAT3), and the binding site of STAT3 is found in the promoter region of HPS. However, the regulation of HPS by fatty acids is still obscure. To clarify the regulation of HPS, we detected the expression of HPS by western blots. In addition, a hepatic steatosis cell culture model was established by treatment of different fatty acids, including linoleic acid (LNA), oleic acid, palmitic acid, and stearic acid. The intracellular lipid accumulation was confirmed by oil red O staining. Blocking of STAT3 activity was achieved by the pretreatment of the STAT3 inhibitor, stattic. We found that activation of STAT3 by interleukin-6 (IL-6) was mediated in the regulation of HPS expression. Treatment of unsaturated fatty acids significantly induced intracellular lipid accumulation in HepG2 cells. Moreover, the expressions of HPS were increased in unsaturated fatty acid-treated HepG2 cells, as compared with saturated fatty acid-treated groups. Also, the expression of HPS induced by OLA was blocked by the inhibition of STAT3 activity. Furthermore, we found that deletion of HPS by small interfering ribonucleic acid transfection decreased the protective effect of OLA on cell viability. Taken together, we provided evidence that STAT3 plays an important role in the regulation of OLA-induced HPS expression and the increased HPS may further participate in the development of NAFLD. In addition, the increase of HPS might be involved in the protective effect of OLA on cell viability.