Nicotinamide protects against diabetic kidney disease through regulation of Sirt1.

PURPOSE: To investigate the effect of nicotinamide (Nam) on diabetic kidney disease (DKD) in mice and explore its mechanism. METHODS: Thirty DBA/2 J mice were randomly assigned to three groups. After 8 weeks of hyperglycemia induced by streptozocin (STZ), Nam and saline were administrated to STZ + Nam and STZ + NS mice, respectively, for 8 weeks. Non-diabetic mice (NDM) were used as control group. Twenty In2-/- Akita mice were randomly divided into two groups. After 8 weeks of hyperglycemia, Nam and saline were administered to Akita + Nam and Akita + NS mice, respectively, for 6 weeks. Wild-type littermates were used as control group. Markers of renal injury were analyzed, and the molecular mechanisms were explored in human proximal tubular HK2 cells. RESULTS: Urinary albumin-to-creatinine ratio (UACR) and kidney injury molecule 1 (KIM-1) decreased in the STZ + Nam and Akita + Nam groups. Pathological analysis showed that Nam improved the structure of glomerular basement membrane, ameliorated glomerular sclerosis, and decreased the accumulation of extracellular matrix and collagen. Compared to the diabetic control group, renal fibrosis, inflammation, and oxidative stress were reduced in the Nam-treated mice. The expression of sirtuin 1 (Sirt1) in human proximal tubular HK2 cells was inhibited by high glucose and Nam treatment enhanced its expression. However, in HK2 cells with Sirt1 knockdown, the protective effect of Nam was abolished, indicating that the beneficial effect of Nam was partially dependent on Sirt1. CONCLUSIONS: Nam has a renoprotective effect against renal injury caused by hyperglycemia and may be a potential target for the treatment of DKD.

Does Aerobic plus Machine-Assisted Resistance Training Improve Vascular Function in Type 2 Diabetes? A Systematic Review and Meta-Analysis of Randomized Controlled Trials with Trial Sequential Analysis.

Type 2 diabetes mellitus (T2DM) is a chronic disease characterized by hyperglycemia, insulin resistance, and pancreatic B cell dysfunction. Hyperglycemia can cause several complications, including nephrological, neurological, ophthalmological, and vascular complications. Many modalities, such as medication, physical therapies, and exercise, are developed against vascular disorders. Among all exercise forms, aerobic plus machine-assisted resistance training is widely applied. However, whether this intervention can significantly improve vascular conditions remains controversial. In this study, an electronic search was processed for the Pubmed, Embase, and Cochrane libraries for randomized controlled trials (RCTs) comparing the efficacy of aerobic plus machine-assisted resistance training with no exercise (control) on patients with T2DM. Pulse wave velocity (PWV), the index of arterial stiffness, was chosen as primary outcome. The reliability of the pooled outcome was tested by trial sequential analysis (TSA). Secondary outcomes included systolic blood pressure (SBP) and hemoglobin A1c (HbA1c). Finally, five RCTs with a total of 328 patients were included. Compared with control, aerobic plus machine-assisted resistance training failed to provide significant improvement on PWV (MD -0.54 m/s, 95% CI [-1.69, 0.60], p = 0.35). On the other hand, TSA indicated that this results till needs more verifications. Additionally, this training protocol did not significantly decrease SBP (MD -1.05 mmHg, 95% CI [-3.71, 1.61], p = 0.44), but significantly reduced the level of HbA1c (MD -0.55%, 95% CI [-0.88, -0.22], p = 0.001). In conclusion, this meta-analysis failed to detect a direct benefit of aerobic plus machine-assisted resistance training on vascular condition in T2DM population. Yet the improvement in HbA1c implied a potential of this training method in mitigating vascular damage. More studies are needed to verify the benefit.

The association of erythrocyte sedimentation rate, high-sensitivity C-reactive protein and diabetic kidney disease in patients with type 2 diabetes.

BACKGROUND: To evaluate the association between high-sensitivity C-reactive protein (hsCRP) and erythrocyte sedimentation rate (ESR), and diabetic kidney disease (DKD) in patients with type 2 diabetes mellitus (T2DM). METHODS: A cross-sectional study was conducted in 1210 patients with T2DM, among whom 265 had DKD. The severity of DKD was assessed by estimated-glomerular filtration rate (eGFR) and urinary albumin creatinine ratio (ACR). The relationship between ESR, hsCRP and DKD was analyzed by multivariate logistic analysis. The relationship between ESR and eGFR, ESR or ACR was analyzed by multivariate linear regression. RESULTS: ESR (23.0 [12.0 ~ 41.5] mm/h versus 12.0 [7.0 ~ 22.0] mm/h, P <  0.001) and hsCRP (3.60 [2.20 ~ 7.65] versus 2.90 [1.80 ~ 5.60] mg/L mg/L, P <  0.01) values were significantly higher in patients with DKD than those without. Patients with higher ESR or hsCRP had lower eGFR and higher ACR. After adjusted for gender, age, hemoglobin, plasma proteins, HbA1c, lipid profiles, and the usage of renin-angiotensin system inhibitors, ESR but not hsCRP was independently associated with the rate and severity of DKD in patients with T2DM. CONCLUSION: ESR was independently associated with the rate and severity of DKD in patients with T2DM.

The Effect of Diacerein on Type 2 Diabetic Mellitus: A Systematic Review and Meta-Analysis of Randomized Controlled Trials with Trial Sequential Analysis.

AIMS: To figure out the effect of diacerein supplementation on type 2 diabetes mellitus (T2DM). METHODS: An electronic search was processed on Pubmed, Embase, and Cochrane library for randomized controlled trials (RCTs) comparing the efficacy of diacerein with placebo on T2DM. The primary outcome was fasting blood glucose (FBG). Trial sequential analysis (TSA) was used to test the reliability of this pooled outcome. Secondary outcomes were glycosylated hemoglobin A1c (HbA1c), body mass index (BMI), lipid profiles, hematological indexes including hematocrit and platelet count, and systematic inflammatory level expressed as a C-reactive protein (CRP) level. Safety outcome was the rate of complications. The difference in continuous data was measured by mean difference (MD) and 95% confidence interval (CI), while the difference of dichotomous data was calculated by relative risk (RR) and 95% CI. A two-tailed P < 0.05 was regarded as statistically significant. RESULTS: Five RCTs with 278 participants were included. Compared with control, diacerein provided significant improvement on FBG (MD -0.52; 95% CI (-0.89~-0.14); P < 0.05 was regarded as statistically significant. P < 0.05 was regarded as statistically significant. P < 0.05 was regarded as statistically significant. P < 0.05 was regarded as statistically significant. P < 0.05 was regarded as statistically significant. CONCLUSION: Based on the current analysis, diacerein as an add-on treatment provided better glycemic control for T2DM but this benefit requires more verification. Compared with control, additional diacerein also lowered body weight and CRP level in T2DM, but increased the rate of gastrointestinal syndromes.

High-Performance Liquid Chromatography-Mass Spectrometry-Based Lipid Metabolite Profiling of Acromegaly.

CONTEXT: Metabolic disorders, especially dysregulated lipid metabolism, increase the risk of cardiovascular mortality in acromegaly. Previous studies measuring plasma macromolecular lipids have yielded conflicting results. PURPOSE: To explore the plasma lipid metabolite profiles by metabolomics analysis and identify potential metabolites associated with cardiac function in acromegaly. METHODS: Plasma was obtained from 80 newly diagnosed, untreated patients with acromegaly and 80 healthy controls. Echocardiography was performed. Based on the results of an oral glucose tolerance test (OGTT), patients were categorized into 2 groups: normal glucose tolerance (NGT, n = 28) and impaired glucose tolerance or diabetes mellitus (IGT/DM, n = 52). High-performance liquid chromatography-mass spectrometry (HPLC-MS)-based metabolomics analysis was conducted. Data were processed by principal components analysis (PCA), orthogonal partial least square-discriminant analysis (OPLS-DA), and MetaboAnalyst 4.0. Associations between metabolic substances and cardiovascular parameters were also explored. RESULTS: Metabolomics uncovered a distinct metabolic pattern between acromegaly and healthy controls, and perturbed pathways mainly include glycerophospholipid metabolism, sphingolipid metabolism, as well as linoleic acid metabolism. Collective analysis showed that phosphatidylethanolamine (PE) (22:6/16:0) was positively correlated with LV mass, while lysophosphatidylcholine (LysoPC) (16:0) was positively correlated with fractional shortening (FS) and left ventricle ejection fraction (LVEF). CONCLUSION: Patients with acromegaly have distinct lipid metabolite profiling, while PE (22:6/16:0) and LysoPC (16:0) are correlated with cardiac structure and function, which may contribute to the risk of cardiovascular complications.

Nicotinamide protects against skeletal muscle atrophy in streptozotocin-induced diabetic mice.

Context: Skeletal muscle atrophy is a complication of diabetes, partially induced by nicotinamide adenine dinucleotide (NAD+) deficiency. Objective: This study investigates the potential of nicotinamide (NAM) supplementation, a precursor of NAD+, against muscle atrophy. Methods: Mice were separated into normal control group, normal control with NAM administration group, diabetic group, and diabetic mice with NAM administration group. Basic characteristics, muscle weight, maximal grip strength, and myofibers cross-sectional area were analysed. Markers reflecting muscle atrophy and hypertrophy, and transforming growth factor ß1/Smad2 (TGF-ß1/Smad2) pathway were examined. Results: NAM did not influence body weight and blood glucose. In diabetic mice, NAM increased NAD+ level, rescued muscle weight and strength loss, and increased myofibers cross-sectional area. NAM inhibited MuRF1 and Atrogin1, while elevated phosphorylation of Akt. Overactivation of TGF-ß1/Smad2 pathway was repressed by NAM. Conclusion: NAM ameliorated diabetic muscle atrophy by rebalancing protein anabolism and catabolism, probably through de-activation of TGF-ß1/Smad2 signaling.

Spironolactone Protects against Diabetic Cardiomyopathy in Streptozotocin-Induced Diabetic Rats.

Spironolactone (SPR) has been shown to protect diabetic cardiomyopathy (DCM), but the specific mechanisms are not fully understood. Here, we determined the cardioprotective role of SPR in diabetic mice and further explored the potential mechanisms in both in vivo and in vitro models. Streptozotocin- (STZ-) induced diabetic rats were used as the in vivo model. After the onset of diabetes, rats were treated with either SPR (STZ + SPR) or saline (STZ + NS) for 12 weeks; nondiabetic rats were used as controls (NDCs). In vitro, H9C2 cells were exposed to aldosterone, with or without SPR. Cardiac structure was investigated with transmission electron microscopy and pathological examination; immunohistochemistry was performed to detect nitrotyrosine, collagen-1, TGF-ß1, TNF-α, and F4/80 expression; and gene expression of markers for oxidative stress, inflammation, fibrosis, and energy metabolism was detected. Our results suggested that SPR attenuated mitochondrial morphological abnormalities and sarcoplasmic reticulum enlargement in diabetic rats. Compared to the STZ + NS group, cardiac oxidative stress, fibrosis, inflammation, and mitochondrial dysfunction were improved by SPR treatment. Our study showed that SPR had cardioprotective effects in diabetic rats by ameliorating mitochondrial dysfunction and reducing fibrosis, oxidative stress, and inflammation. This study, for the first time, indicates that SPR might be a potential treatment for DCM.

Exogenous Pancreatic Kallikrein Improves Diabetic Cardiomyopathy in Streptozotocin-Induced Diabetes.

Aims: To evaluate the protective effects of exogenous pancreatic kallikrein (PKK) treatment on diabetic cardiomyopathy (DCM) and explore the underlying mechanisms. Methods and Results: Streptozotocin (STZ)-induced diabetic rats, a type 1 diabetic model, were treated with either PKK or saline for 12 weeks. Non-diabetic rats were used as controls. PKK administration attenuated the mitochondria swelling, Z line misalignments, myofibrosis and interstitial collagen accumulation in diabetic myocardial tissue. The oxidative stress imbalance including increased nitrotyrosine, decreased anti-oxidative components such as nuclear receptor nuclear factor like 2 (Nrf2), glutathione peroxidase 1(GPx-1), catalase (CAT) and superoxide dismutase (SOD), were recovered in the heart of PKK-treated diabetic rats. In diabetic rats, protein expression of TGF-ß1 and accumulation of collagen I in the heart tissues was decreased after PKK administration. Markers for inflammation were decreased in diabetic rats by PKK treatment. Compared to diabetic rats, PKK reversed the degradation of IκB-α, an inhibitive element of heterotrimer nuclear factor kappa B (NF-κB). The endothelial nitric oxide synthase (eNOS) protein and myocardial nitrate/nitrite were impaired in the heart of diabetic rats, which, however, were restored after PKK treatment. The sarcoplasmic reticulum Ca2+-ATPase 2 (SERCA2) and phospholamban (PLN) were mishandled in diabetic rats, while were rectified in PKK-treated diabetic rats. The plasma NT-proBNP level was increased in diabetic rats while was reduced with PKK treatment. Conclusion: PKK protects against DCM via reducing fibrosis, inflammation, and oxidative stress, promoting nitric oxide production, as well as restoring the function of the calcium channel.

Myo-inositol lowers the risk of developing gestational diabetic mellitus in pregnancies: A systematic review and meta-analysis of randomized controlled trials with trial sequential analysis.

AIMS: to explore the potential benefit of myo-inositol on pregnant women with high risk of developing gestational diabetes mellitus (GDM). METHODS: Pubmed, Embase, and Cochrane library were systematically searched for randomized controlled trials (RCTs) comparing myo-inositol with placebo for pregnant women with risk factors of GDM. Primary outcome were the incidence of GDM and birth weight. Secondary outcomes included fasting, 1h, and 2h oral glucose tolerance test (OGTT), and complications. Trial sequential analysis (TSA) was performed on primary outcomes to confirm the pooled results. Number needed to treat (NNT) was calculated to show the efficacy of myo-inositol supplement. RESULTS: Four RCTs with 586 patients were included. Compared with placebo, patients with myo-inositol supplement had significantly lower the risk of developing GDM (RR=0.44, 95% CI [0.32, 0.62], P<0.0001) without heterogeneity (I2=0%, P=0.99), which was confirmed by TSA. NNT was 6.2 and rounded to 7. Myo-inositol did not significantly decrease birth weight (60.60g, 95% CI [-177.21, 56.02], P=0.31) with significant heterogeneity (I2=52%, P=0.12), but was not confirmed by TSA. Myo-inositol supplement was related to significantly lower fasting, 1h, and 2h OGTT value and the incidence of pre-term delivery. Difference was not significant between myo-inositol and placebo regarding incidence of other complications. CONCLUSION: Myo-inositol is related to lower incidence of GDM, as well as fasting, 1h, and 2h OGTT value, in pregnant women with high risk of this condition. Myo-inositol might not be related to a lower birth weight, which needs further confirmation.

Exogenous kallikrein protects against diabetic nephropathy.

The kallikrein-kinin system has been shown to be involved in the development of diabetic nephropathy, but specific mechanisms are not fully understood. Here, we determined the renal-protective role of exogenous pancreatic kallikrein in diabetic mice and studied potential mechanisms in db/db type 2 diabetic and streptozotocin-induced type 1 diabetic mice. After the onset of diabetes, mice were treated with either pancreatic kallikrein (db/db+kallikrein, streptozotocin+kallikrein) or saline (db/db+saline, streptozotocin+saline) for 16 weeks, while another group of streptozotocin-induced diabetic mice received the same treatment after onset of albuminuria (streptozotocin'+kallikrein, streptozotocin'+saline). Db/m littermates or wild type mice were used as non-diabetic controls. Pancreatic kallikrein had no effects on body weight, blood glucose and blood pressure, but significantly reduced albuminuria among all three groups. Pathological analysis showed that exogenous kallikrein decreased the thickness of the glomerular basement membrane, protected against the effacement of foot process, the loss of endothelial fenestrae, and prevented the loss of podocytes in diabetic mice. Renal fibrosis, inflammation and oxidative stress were reduced in kallikrein-treated mice compared to diabetic controls. The expression of kininogen1, tissue kallikrein, kinin B1 and B2 receptors were all increased in the kallikrein-treated compared to saline-treated mice. Thus, exogenous pancreatic kallikrein both prevented and ameliorated diabetic nephropathy, which may be mediated by activating the kallikrein-kinin system.

The Associations Between the Polymorphisms of Vitamin D Receptor and Coronary Artery Disease: A Systematic Review and Meta-Analysis.

Vitamin D receptor (VDR) polymorphisms were indicated to be associated with coronary artery disease (CAD); however, published studies reported inconsistent results.The aim of this meta-analysis is to reach a more accurate estimation of the relationship between VDR genetic polymorphisms and CAD risk.Eligible studies were retrieved by searching PubMed, Embase, VIP, Wanfang and China National Knowledge Infrastructure databases. Included and excluded criteria were formulated. The case group was patients with CAD, and the control group was healthy subjects. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate VDR polymorphisms associations with CAD risk. Heterogeneity was evaluated by Q statistic and I statistic.Seven studies of a total of 2306 CAD patients and 4151 control subjects met the inclusion criteria. The pooled results from Taq1 showed increased risk in allelic model (OR = 1.14, 95% CI = 1.02-1.28), dominant model (OR = 1.21, 95% CI = 1.02-1.43), heterozygote model (OR = 1.19, 95% CI = 1.00-1.1.42), and homozygote model (OR = 1.27, 95% CI = 1.01-1.61). Besides, Fok1 T > C showed decreased risk in allelic model (OR = 0.81, 95% CI = 0.65-1.00) and Fok1 A > G also showed decreased risk in allelic model (OR = 0.67, 95% CI = 0.45-1.00) and recessive model (OR = 0.55, 95% CI = 0.31-0.97). In Caucasian subgroup, Bsm1showed increased risk in allelic model (OR = 1.23, 95% CI = 1.02-1.47), heterozygote model (OR = 1.20, 95% CI = 1.00-1.44), and homozygote model (OR = 1.22, 95% CI = 1.02-1.45). In CAD patients with type 2 diabetes mellitus (T2DM), Apa1showed a decreased risk in heterozygote model (OR = 0.80, 95% CI = 0.66-0.98); however, increased risk in recessive model (OR = 5.00, 95% CI = 2.74-9.13) was discovered in CAD patients without T2DM.The Fok1 polymorphism may play a protective role in CAD, and the possible protective role in Apa1 CA genotype in CAD patients with T2DM needs further studies. The Taq1 polymorphism is found to be associated with a significant increase in CAD risk based on our analysis; moreover, increased risk in Apa1 polymorphism in CAD patients without T2DM and Bsm1 polymorphism in Caucasian group is also detected.