Sunjie Yan

Fetuin A promotes lipotoxicity in β cells through the TLR4 signaling pathway and the role of pioglitazone in anti-lipotoxicity

OBJECTIVE Fetuin A (FetA), a secreted glycoprotein, is known to affect inflammation and insulin resistance (IR) in obese humans and animals. Lipotoxicity from chronic hyperlipidemia damages pancreatic β cells, hastening the onset of diabetes. We sought to determine whether FetA promotes lipotoxicity through modulation of the toll-like receptor 4 (TLR4) inflammatory signaling pathway as well as the protective effect of pioglitazone(PIO) on lipotoxicity. METHODS βTC6, a glucose-sensitive mouse pancreatic β cell line, and Sprague-Dawley rats with diet-induced obesity, were used to investigate FetA-mediated lipotoxicity. Protein expression/activation were measured by Western blotting. Small interfering (si)RNAs for TLR4 were used. Cell apoptosis was quantified by TUNEL analysis or flow cytometry, respectively. Insulin release was assessed with an insulin ELISA. RESULTS FetA dose-dependently aggravated palmitic acid (PA)-induced βTC6 cell apoptosis, insulin secretion impairment, and inhibition of the expression of G-protein-coupled receptor 40 (GPR40) and pancreatic duodenal homeobox-1(PDX-1). Combined FetA + PA induced TLR4 expression, and subsequent inhibition of TLR4 signaling or expression was shown to prevent the strengthening effect of FetA on PA-induced lipotoxicity in βTC6 cells. FetA + PA induced p-JNK and nuclear factor-κB (NF-κB) subunit P65 expression, and inhibition of this activity reduced PA+ FetA lipotoxicity in βTC6 cells. PIO could ameliorate PA+ FetA-induced damage to βTC6 cells. Similarly, PIO improved insulin secretion disorder, reduced apoptosis, decreased FetA, TLR4, p-JNK, NF-κB subunit P65 and cleaved caspase 3 expression, and increased GPR40 and PDX-1 expression in islet β cells of diet-induced obese rats. The correlative bivariate analysis showed that increases in Fetuin A were directly proportional to the development of β cell injury. CONCLUSIONS FetA can promote lipotoxicity in β cells through the TLR4-JNK-NF-κB signaling pathway. The protective effects of PIO on lipotoxicity in β cells may involve the inhibition of the activation of the FetA and TLR4 signaling pathway.

The effect of FFAR1 on pioglitazone-mediated attenuation of palmitic acid-induced oxidative stress and apoptosis in βTC6 cells

OBJECTIVE We sought to determine whether free fatty acid receptor 1 (FFAR1), a receptor for free fatty acids on the β-cell membrane, can mediate the pioglitazone (PIO)-attenuating effect on lipoapoptosis in β cells and its relationship to oxidative stress. METHODS The glucose-sensitive mouse beta pancreatic cell line βTC6 was used to investigate the effect of FFAR1 on PIO-attenuating palmitic acid (PA)-induced oxidative stress and apoptosis. RESULTS (1) PIO reduced PA-induced lipoapoptosis in β cells and upregulated the expression of FFAR1 at the mRNA and protein levels in a dose- and time-dependent manner. Silencing of FFAR1 expression was shown to weaken the protective effect of PIO on PA-induced lipoapoptosis in βTC6 cells; while lentiviral-mediated overexpression of FFAR1 was shown to enhance the protective effect of PIO against lipoapoptosis in β cells. (2) Downregulation of FFAR1 expression reduced the attenuating effect of PIO on the expression of NAPDH oxidase subunit p47(phox), Bax, cleaved caspase 3, and the production of reactive oxygen specific (ROS) induced by lipotoxicity, thereby preventing the upregulation of the expression of bcl-2. Inducing the overexpression of FFAR1 enhanced the anti-oxidative stress effect of PIO. Similarly, these effects of FFAR1 on PIO were reproduced under conditions of oxidative stress and apoptosis in βTC6 cells that were induced by H2O2. (3) PIO was found to increase the expression of PLCγ, ERK1/2, and PPARγ in lipotoxic β cells. Silencing FFAR1 expression reduced the PIO-mediated increases in the expression of above proteins; while inducing FFAR1 overexpression showed the opposite effect. Use of an inhibitor of PLCγ, ERK1/2, PPARγ was shown to restrict the protective effect of PIO on oxidative stress and lipoapoptosis of β cells. CONCLUSIONS FFAR1 can mediate PIO suppression of β-cell lipoapoptosis through anti-oxidative stress, which may be related to the activation of the PLCγ-ERK1/2-PPARγ pathway.

The effectiveness of age on HbA1c as a criterion for the diagnosis of diabetes in Chinese different age subjects

To analyse the effectiveness of age on HbA1c as a criterion for the diagnosis of diabetes in Chinese different age subjects.

Sarcopenia associated with renal function in the patients with type 2 diabetes

AIMS Studies have suggested that low muscle mass is associated with declining renal function in healthy populations, whether the association is relevant to patients with type 2 diabetes is not well understood. This study investigates the association between sarcopenia and estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratios (UACR) in the patients with type 2 diabetes. METHODS Two recruited groups consisted of 793 persons without diabetes (males/females=550/243) and 762 persons with type 2 diabetes (males/females=501/261). RESULTS The non-sarcopenia population demonstrated higher ASM/HT(2), GFR (P<0.001) and lower UACR (P＜0.05) than the sarcopenia population. In studied men, the association between ASM/HT(2) and eGFR was statistically significant in the group without diabetes (OR=0.580, P=0.020), a trend which persisted in women (OR=0.491, P=0.014). The association between ASM/HT(2) and UACR persisted in studied women of two groups (OR=0.269, P=0.005; OR=0.405, P=0.008, respectively). The highest quartile of ASM/HT(2) in the non-sarcopenia population exhibited a 3.753-fold risk of abnormal eGFR within the diabetes group (OR=3.753, P=0.020). The cutoff point of ASM/HT(2) to indicate abnormal renal function for population with non-sarcopenia was 6.32kg/m(2) in the group without diabetes and 6.31kg/m(2) in diabetes group. CONCLUSIONS Sarcopenia is associated with declining renal function, which induces lower eGFR and higher UACR. In the non-sarcopenia population, ASM/HT(2) presents as renal function risk factor, which perhaps associated with higher muscle mass to induce a greater underestimation for creatinine and urinary albumin.

Low-grade albuminuria associated with brachial-ankle pulse wave velocity in young adults with type 2 diabetes mellitus in China

Cardiovascular disease is prevalent in type 2 diabetics, and microalbuminuria is associated with cardiovascular disease morbidity. We aimed to investigate the potential association between low‐grade albuminuria and arterial stiffness in patients with type 2 diabetes.

Low-grade Albuminuria Associated with Subclinical Left Ventricular Diastolic Dysfunction and Left Ventricular Remodeling.

AIMS Low-grade albuminuria (LGA) has been shown to be associated with increased risk for cardiovascular disease. Our study investigated the relationship between normal urinary albumin-to-creatinine ratios (UACRs) and subclinical left ventricular (LV) diastolic dysfunction and remodeling in diabetics and non-diabetics. METHODS A total of 888 diabetic and 208 non-diabetic patients with normal UACRs (< 30 mg/g) from Fuzhou, Fujian Province, China were examined. The subjects were stratified into quartiles based on their respective UACR levels. LV diastolic function was defined by early diastolic transmitral velocities (E)/average early diastolic annular velocities (average e), accompanied by average e. LV remodeling was defined by LV mass indexed to body surface area and relative wall thickness based on 2-dimensional and Doppler echocardiography. RESULTS UACR was independently associated with cardiac diastolic function as defined by E/e and average e (OR=1.042, P=0.001) and LV remodeling (OR=1.037, P=0.001) in all participants. Diabetic patients in the highest quartile of UACR demonstrated a greater risk of developing LV diastolic dysfunction by a magnitude of 1.625 (OR=1.625, P=0.037) than patients in the lowest quartile; those in the third and highest quartiles demonstrated a greater risk of LV remodeling by a magnitude of 1.729-1.994 compared to the lowest quartile (OR=1.729, P=0.027 and OR=1.994, P=0.005, respectively). The association between UACR and subclinical diastolic dysfunction was most prevalent in younger, non-obese, non-hypertensive females or patients who had experienced diabetes for fewer than 10 years. The association between UACR and LV remodeling was most prevalent in non-obese, older males, in patients with normal low-density lipoprotein levels, in patients who had experienced diabetes for fewer than 10 years, and in patients without hypertension. CONCLUSION UACR was associated with subclinical LV diastolic dysfunction and remodeling in both patients with and without Type 2 diabetes. We conclude that LGA may also be a marker for subclinical cardiovascular damage in Type 2 diabetics.

Osteocalcin Improves Metabolic Profiles, Body Composition and Arterial Stiffening in an Induced Diabetic Rat Model

Recent studies have demonstrated the benefits of osteocalcin (OCN) on glucose homeostasis and metabolic dysregulation. However, its role in body composition and vascular function remains unknown. This study was designed to examine changes in metabolic parameters and body composition as well as arterial stiffness after OCN treatment in type 2 diabetic rats. Adult male Sprague Dawley (SD) rats were fed chow or high fat diet (HFD) for 8 weeks, and then diabetes was induced with an injection of low-dose streptozotocin (STZ) and treated daily with intraperitoneal injections of OCN for 12 weeks. Our data showed that OCN treatment improved glucose homeostasis and lipid metabolism. Further analysis revealed that OCN treatment resulted in increased insulin sensitivity. In addition, untreated diabetic rats experienced significant weight loss, whereas OCN-treated rats better maintained body weight (300.75±38.14 g vs. 335.50±23.70, p=0.005). OCN also changed body composition, as evidenced by reduced body fat mass, specifically abdominal fat mass. OCN-treated diabetic rats also demonstrated decreased pulse-wave velocity, indicating of improved arterial stiffness. Taken together, our findings in the current study revealed that OCN therapy prevents arteriosclerosis in an induced diabetic rat model by exerting beneficial effects on glucose levels, insulin sensitivity, lipid metabolites, and body composition changes.

Abnormal Regional Body Fat Distribution Also Exists in Non-Obese Subjects with High Blood Pressure

A cross-sectional analysis was performed to explore the relationship between regional body fat distribution and blood pressure in non-obese subjects with different status of blood pressure. Dual-energy X-ray absorptiometry was performed to measure fat mass. Obesity was defined as present body fat ≥25% in males and ≥35% in females. The ratio of leg fat mass to total fat mass (L/T) decreased gradually while the ratio of trunk fat mass to total fat mass (Tr/T) increased gradually with the increasing blood pressure for both genders in non-obese subjects (P < .01), which was consistent with the change in obese ones; and the blood pressure status in the low Tr/T + high L/T group was better than that in the high Tr/T + low L/T group, obviously. After adjustment for confounding factors, blood pressure was still positively related with Tr/T but negatively associated with L/T in non-obese groups. A multiple linear regression analysis showed that L/T was the major negative factors of blood pressure in the non-obese population. Abnormal fat distribution also exists in non-obese subjects with high blood pressure; compared to trunk fat, leg fat may be a more important factor against blood pressure.