Although diabetic glomerulopathy is a characteristic of diabetic kidney disease (DKD), manifesting as a thickened glomerular basement membrane, mesangial expansion with increased matrix, capillary microaneurysms, hypocellular nodules, and even glomerulosclerosis, accumulating data has shown that diabetic tubulopathy (DT) exists from the beginning of hyperglycemia and throughout the duration of diabetic mellitus (DM), playing a pivotal role in the pathogenesis of DKD. Under hyperglycemic conditions, proximal tubular epithelium cells (PTECs) disturbs the tubule-globular glucose, lipid, and protein feedback metabolism, then initiates a series of pathophysiological events, such as volume overload, glomerular hyperfiltration, reactive oxidative stress, and hyperoxide overproduction, which result in hypertrophy, senility, autophagy dysfunction, and PTEC apoptosis in the early stage of DM, as well as tubule atrophy, atherosclerosis tubulointerstitial inflammation, and fibrosis in the development of DKD. Clinically, DT contributes to hyperglycemia, hypertension, proteinuria, dyslipidemia, and hyperuricemia, which accelerate DKD. The biomarkers released from injured tubules are better able than albuminuria to predict early-stage DKD. Therapeutic approaches targeting tubulointerstitial disorders (e.g. acute interstitial nephritis, chronic interstitial nephritis, acute tubular necrosis and tubulointerstitial fibrosis) in DKD have highlighted the comprehensive pathogenesis of DT and the need for early diagnosis of and intervention in DKD.

Objective: Triglyceride glucose index (TyG index) has been recommended as an alternative indicator of insulin resistance. However, the association between TyG and regression from prediabetes to normoglycemia remains to be elucidated. Methods: This retrospective cohort study involved 25,248 subjects with prediabetes at baseline conducted from 2010 to 2016. A Cox proportional hazard regression model was designed to evaluate the role of TyG in identifying people at converting from prediabetes to normoglycemia. Cox proportional hazards regression with cubic spline functions and smooth curve fitting was used to dig out the nonlinear relationship between them. Detailed evaluations for TyG were also performed using sensitivity and subgroup analyse. Results: Among the included prediabetes subjects (n = 25,248), the mean age was 49.27 ± 13.84 years old, and 16,701 (66.15%) were male. The mean TyG was 8.83 ± 0.60. The median follow-up time was 2.96 ± 0.90 years. 11,499 (45.54%) individuals had a final diagnosis of normoglycemia. After adjusting for covariates, TyG was negatively affecting the results of glucose status conversion in prediabetes people (HR 0.895, 95% CI 0.863, 0.928). There was a nonlinear connection between TyG and normoglycemia in prediabetes people, and the inflection point was 8.88. The effect sizes (HR) on the left and right sides of the inflection point were 0.99 (0.93, 1.05) and 0.79 (0.74, 0.85), respectively. Sensitivity analysis confirmed the robustness of these results. Subgroup analysis showed that TyG was more strongly associated with incident glucose status conversion in male, BMI ≥ 25. In contrast, there was a weaker relationship in those with female, BMI < 25. Conclusion: Based on sample of subjects evaluated between 2010 and 2016, TyG index appears to be a promising marker for predicting normoglycemic conversion among prediabetes people in China. This study demonstrates a negative and non-linear association between TyG and glucose status conversion from prediabetes to normoglycemia. TyG is strongly related to glucose status conversion when TyG is above 8.88. From a therapeutic point of view, it is meaningful to maintain TyG levels within the inflection point to 8.88.

Histone deacetylase 6 (HDAC6) is the specific subtype of HDACs which preferentially located in the cytoplasm, and is crucial in insulin signalling. However, the role of HDAC6 in type 2 diabetic nephropathy (DN) remains undefined. In current study, we observed that HDAC6 was markedly activated in the kidneys of type 2 diabetic patients and db/db mice with albuminuria, along with the advanced glycation end products (AGE)‐treated podocytes. Selective inhibition of HDAC6 activity protected kidneys from hyperglycaemia in db/db mice. Notably, overexpressing HDAC6 inhibited autophagy and promoted motility aside from the apoptosis of podocytes exposed to AGE. We further determined that HDAC6 regulated the autophagy partially by decreasing the acetylation of α‐tubulin at the residue of lysine 40. In contrast, we confirmed that there was no interaction of HDAC6 with α‐tubulin at the sites of lysine 112 and lysine 352. Consistently, inhibiting HDAC6 by siRNA or the selective inhibitor, tubacin, restored the autophagy level and motility of podocytes and rescued podocytes from AGE stimulation. We provide strong evidence of an unexpected role of HDAC6 in the cascade that modulates podocytes autophagy and motility, enlightening that HDAC6 may be a promising therapeutic target for DN treatment.

A dietary protein intake (DPI) of between 0.6 and 0.8 g protein per kilogram body weight per day (g/kg/day) is frequently recommended for adults with moderate-to-advanced chronic kidney disease (CKD). However, evidence on whether patients with diabetic kidney disease (DKD) actually benefit from a DPI of ≤ 0.8 g/kg/day and from a low-protein diet (LPD) at CKD stages 1–3 has not been consistent. We systematically searched MEDLINE, EMBASE, Cochrane Library, Web of Knowledge, as well as the bibliographies of articles identified in the search, for eligible randomized controlled trials that had investigated the effects of LPD (prescribed DPI < 0.8 g/kg/day) versus control diet on the progression of DKD. Nine trials that included 506 participants and follow-up periods varying from 4.5 to 60 months were included in the subsequent systematic review and meta-analysis. The data showed that patients with DKD who consumed < 0.8 g protein/kg/day had a significantly reduced decline in glomerular filtration rate (GFR) (mean difference [MD] 22.31 mL/min/1.73 m², 95% confidence interval [CI] 17.19, 27.42; P  < 0.01) and a significant decrease in proteinuria (standard mean difference [SMD] − 2.26 units, 95% CI − 2.99, − 1.52; P  < 0.001) versus those on the control diet. The benefits of LPD to patients with DKD at CKD stages 1–3 were a markedly decreased proteinuria (SMD − 0.96 units, 95% CI − 1.81, − 0.11; P  = 0.03) and slight but significant decreases in glycated hemoglobin (− 0.42%) and cholesterol levels (− 0.22 mmol/L). Our meta-analysis indicated that a DPI of < 0.8 g/kg/day was strongly associated with a slow decline in GFR and decreased proteinuria in the patients with DKD. Patients with CKD stages CKD 1–3 benefited from LPD in terms of a marked decrease of proteinuria and slight but significant improvements in lipid and glucose control.

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) has proven to be downregulated in podocytes challenged with high glucose (HG), and knockout of PTEN in podocytes aggravated the progression of diabetic kidney disease (DKD). However, whether podocyte-specific knockin of PTEN protects the kidney against hyperglycemia in vivo remains unknown. The inducible podocyte-specific PTEN knockin (PPKI) mice were generated by crossing newly created transgenic loxP-stop- loxP-PTEN mice with podocin-iCreER^T2 mice. Diabetes mellitus was induced in mice by intraperitoneal injection of streptozotocin at a dose of 150 mg/kg. In vitro, small interfering RNA and adenovirus interference were used to observe the role of PTEN in HG-treated podocytes. Our data demonstrated that PTEN was markedly reduced in the podocytes of patients with DKD and focal segmental glomerulosclerosis, as well as in those of db/db mice. Interestingly, podocyte-specific knockin of PTEN significantly alleviated albuminuria, mesangial matrix expansion, effacement of podocyte foot processes, and incrassation of glomerular basement membrane in diabetic PPKI mice compared with wild-type diabetic mice, whereas no alteration was observed in the level of blood glucose. The potential renal protection of overexpressed PTEN in podocytes was partly attributed with an improvement in autophagy and motility and the inhibition of apoptosis. Our results showed that podocyte-specific knockin of PTEN protected the kidney against hyperglycemia in vivo , suggesting that targeting PTEN might be a novel and promising therapeutic strategy against DKD.