Beta-Hydroxybutyric Acid Inhibits Renal Tubular Reabsorption via the AKT/DAB2/Megalin Signalling Pathway.

Aim: Patients with diabetic ketosis often exhibit albuminuria. We previously found that acute hyperglycaemia can cause nephrotoxic injury. Here, we explored whether an excessive ketone body level causes kidney injury and the potential underlying mechanism. Methods: Fifty-six type 2 diabetes without ketosis (NDK group), 81 type 2 diabetes with ketosis (DK group), and 38 healthy controls (NC group) were enrolled. Clinical data were collected before and after controlling diabetic ketosis. Beta-hydroxybutyric acid (BOHB), an AKT activator, an AKT inhibitor, or plasmids encoding DAB2 were transformed into human renal proximal tubule epithelial cells (HK-2 cells). Results: The urinary albumin-to-creatinine ratio (ACR), transferrin (TF), immunoglobulin G (IgG), Beta2-microglobulin (ß2-MG), retinol-binding protein (RBP), N-acetyl-beta-glucosaminidase (NAG), and Beta-galactosidase (GAL) were higher in the DK than NC and NDK groups. The proportion of patients with an increased urinary level of TF, IgG, ß2-MG, RBP, NAG, or GAL was higher in the DK group too. After controlling ketosis, urinary microalbumin, TF, IgG, ß2-MG, and RBP decreased significantly. In HK-2 cells, albumin endocytosis and megalin expression decreased with increasing BOHB concentration. Compared with BOHB treatment, BOHB with AKT activator significantly increased the DAB2, megalin levels and albumin endocytosis; the AKT inhibitor treatment exhibited the opposite effects. Compared with BOHB treatment, megalin expression and albumin endocytosis were significantly increased after BOHB with DAB2 overexpression treatment. Conclusions: Patients with diabetic ketosis may suffer from glomerular and tubular injuries that recover after ketosis control. High concentrations of BOHB downregulate megalin expression by inhibiting the AKT/DAB2/megalin signalling pathway and albumin endocytosis in proximal renal tubules.

Vildagliptin Attenuates Myocardial Dysfunction and Restores Autophagy via miR-21/SPRY1/ERK in Diabetic Mice Heart.

Aim: Vildagliptin (vild) improves diastolic dysfunction and is associated with a lower relative risk of major adverse cardiovascular events in younger patients. The present study aimed to evaluate whether vild prevents the development of diabetic cardiomyopathy in type 2 diabetic mice and identify its underlying mechanisms. Methods: Type 2 diabetic mouse model was generated using wild-type (WT) (C57BL/6J) and miR-21 knockout mice by treatment with HFD/STZ. Cardiomyocyte-specific miR-21 overexpression was achieved using adeno-associated virus 9. Echocardiography was used to evaluate cardiac function in mice. Morphology, autophagy, and proteins levels in related pathway were analyzed. qRT-PCR was used to detect miR-21. Rat cardiac myoblast cell line (H9c2) cells were transfected with miR-21 mimics and inhibitor to explore the related mechanisms of miR-21 in diabetic cardiomyopathy. Results: Vild restored autophagy and alleviated fibrosis, thereby enhancing cardiac function in DM mice. In addition, miR-21 levels were increased under high glucose conditions. miR-21 knockout DM mice with miR-21 knockout had reduced cardiac hypertrophy and cardiac dysfunction compared to WT DM mice. Overexpression of miR-21 aggravated fibrosis, reduced autophagy, and attenuated the protective effect of vild on cardiac function. In high-glucose-treated H9c2 cells, the downstream effectors of sprouty homolog 1 (SPRY1) including extracellular signal-regulated kinases (ERK) and mammalian target of rapamycin showed significant changes following transfection with miR-21 mimics or inhibitor. Conclusion: The results of our study indicate that vild prevents DCM by restoring autophagy through the miR-21/SPRY1/ERK/mTOR pathway. Therefore, miR-21 is a target in the development of DCM, and vild demonstrates significant potential for clinical application in prevention of DCM.

Hyperinsulinemia contributes to impaired-glucose-tolerance-induced renal injury via mir-7977/SIRT3 signaling.

BACKGROUND: Increasing evidence indicates that impaired glucose tolerance (IGT) is independently associated with chronic kidney disease, but the characteristics and underlying mechanisms remain largely unknown. METHODS: Here, the cross-sectional study was performed to study the characteristics of IGT-induced renal injury (IGT-RI). Furthermore, urine microRNA profile was evaluated and microRNAs involved in tubular injury were determined by in-vitro experiments. RESULTS: It was found that 12.1% of IGT patients had microalbuminuria, which we termed "IGT-RI." Overall, 100% of patients with IGT-RI exhibited reabsorption dysfunction and 58.3% had structural damage in the renal tubules. Two-hour postprandial insulin, retinol-binding protein, and N-acetyl-ß-glucosaminidase were significantly associated with microalbuminuria and they were independent risk factors for IGT-RI. The expression of mir-7977 was altered in IGT-RI patients and may be involved in cellular response to oxidative stress. In proximal tubule epithelial cells in vitro, a high level of insulin increased the expression of mir-7977 and decreased that of sirtuin 3 (SIRT3), leading to oxidative stress. Overexpression of mir-7977 further decreased SIRT3 expression, whereas inhibition of mir-7977 had the opposite effect. Furthermore, mir-7977 can bind to the 3'-untranslated region of SIRT3 mRNA and inhibit its expression. Moreover, inhibition of SIRT3 reduced the expression of cubilin and the endocytosis of albumin. CONCLUSIONS: In conclusion, IGT-RI mainly manifests as tubular injury, especially reabsorption dysfunction. Compensatory hyperinsulinemia may be involved. A high level of insulin can activate mir-7977/SIRT3 signaling, resulting in tubular injury by inducing oxidative stress as well as reabsorption dysfunction by inhibiting the expression of cubilin, ultimately contributing to IGT-RI.

Preventive Role of Salsalate in Diabetes Is Associated With Reducing Intestinal Inflammation Through Improvement of Gut Dysbiosis in ZDF Rats.

A safe and effective approach is needed to prevent and reduce the incidence of diabetes worldwide. The hypoglycemic efficacy of salicylic acid (salsalate, SAL), which has anti-inflammatory properties, has been empirically demonstrated in studies conducted at the Joslin Diabetes Center and elsewhere. Here, we investigated the potential role of SAL in preventing the onset of diabetes in Zucker diabetic fatty (ZDF) rats and attempted to elucidate its underlying mechanisms. ZDF and Zucker lean (ZL) rats were administered a high-fat diet with or without SAL intervention, and their relative rates of diabetes were compared. Our results showed that all rats in the placebo group developed diabetes, whereas only 10% of the SAL-treated rats presented with impaired glucose tolerance (IGT). None of the latter progressed to diabetes. Relative to the untreated rats, SAL lowered plasma glucagon and insulin while improving insulin sensitivity and ß-cell function. SAL may protect against hyperglycemia by increasing the microbial diversity, ameliorating gut dysbiosis, restoring intestinal epithelial cell connections, inhibiting endotoxin influx into the blood, and attenuating inflammation. Together, these findings suggest that SAL may be a candidate prophylactic therapy against diabetes. The protective role of SAL may be attributed to its ability to reduce intestinal inflammation and improve gut dysbiosis.

Evaluation of urinary biomarkers for prediction of diabetic kidney disease: a propensity score matching analysis.

BACKGROUND: The aim of this study was to evaluate the diagnostic value of six urinary biomarkers for prediction of diabetic kidney disease (DKD). METHODS: The cross-sectional study recruited 1053 hospitalized patients with type 2 diabetes mellitus (T2DM), who were categorized into the diabetes mellitus (DM) with normoalbuminuria (NA) group (n = 753) and DKD group (n = 300) according to 24-h urinary albumin excretion rate (24-h UAE). Data on the levels of six studied urinary biomarkers [transferrin (TF), immunoglobulin G (IgG), retinol-binding protein (RBP), ß-galactosidase (GAL), N-acetyl-beta-glucosaminidase (NAG), and ß2-microglobulin (ß2MG)] were obtained. The propensity score matching (PSM) method was applied to eliminate the influences of confounding variables. RESULTS: Patients with DKD had higher levels of all six urinary biomarkers. All indicators demonstrated significantly increased risk of DKD, except for GAL and ß2MG. Single RBP yielded the greatest area under the curve (AUC) value of 0.920 compared with the other five markers, followed by TF (0.867) and IgG (0.867). However, GAL, NAG, and ß2MG were shown to have a weak prognostic ability. The diagnostic values of the different combinations were not superior to the single RBP. CONCLUSIONS: RBP, TF, and IgG could be used as reliable or good predictors of DKD. The combined use of these biomarkers did not improve DKD detection.

Renal impairment markers in type 2 diabetes patients with different types of hyperuricemia.

AIMS/INTRODUCTION: Hyperuricemia (HUA) occurs because of decreased excretion of uric acid, increased synthesis of uric acid or a combination of both mechanisms. The proportions of these three types of HUA in type 2 diabetes patients are not known. In the mean time, we assume that different types of HUA might manifest with different renal damage, even in patients with normal renal filtration function. MATERIALS AND METHODS: We included 435 inpatients with type 2 diabetes at the Metabolic Disease Hospital of Tianjin Medical University from 2015 to 2016. Based on the clearance of uric acid, 90 patients with HUA were divided into three types: synthesis-increased HUA, excretion-decreased HUA and mixed type of HUA. RESULTS: Patients with the mixed type of HUA had the severest kidney injury manifested by a high level of 24 h urinary microalbumin, urinary immunoglobulin G, transferrin, α-galactosidase and ß2-microglobulin compared with the normal uric acid group. Urinary immunoglobulin G, transferrin and α-galactosidase were also increased in patients with synthesis-increased HUA compared with the normal uric acid group. Patients with excretion-decreased HUA did not have an increased level of renal impairment markers; however, these patients had an increased body mass index, which might cause dysfunction of kidney excretion. CONCLUSIONS: Excretion-decreased HUA is a more common type of HUA in type 2 diabetes patients that might be caused by dysfunction of tubular excretion instead of structural damage. The mixed type of HUA patients had the severest kidney glomerular and tubular damage compared with the normal uric acid group. Clinically, different types of hyperuricemia should be given individualized treatment according to their own characteristics.