Association between equol producers and type 2 diabetes mellitus among Japanese older adults.

AIMS/INTRODUCTION: Equol, which is produced by enteric bacteria from soybean isoflavones, has a chemical structure similar to estrogen. Both in vivo and in vitro studies have shown the beneficial metabolic effects of equol. However, its effects on type 2 diabetes remain unclear. We investigated the association between the equol producers/non-producers and type 2 diabetes. MATERIALS AND METHODS: The participants included 147 patients with type diabetes mellitus aged 70-89 years, and 147 age- and sex-matched controls. To ascertain the equol producers or non-producers, we used the comparative logarithm between the urinary equol and daidzein concentrations (cut-off value -1.75). RESULTS: The urinary equol concentration was significantly lower in the diabetes group compared with the non-diabetes group (P = 0.01). A significant difference in the proportion of equol producers was observed among all participants (38.8% in the diabetes group and 53.1% in the non-diabetes group; P = 0.01). The proportion of equol producers among women was significantly lower in the diabetes group (31.4%) than in the non-diabetes group (52.8%; P < 0.01). Additionally, the frequency of dyslipidemia in female equol producers was significantly lower than that in female non-equol producers (P < 0.01). Among men, no such differences were observed. We found a significant positive correlation between the urinary equol and daidzein concentrations among equol producers (r = 0.55, P < 0.01). CONCLUSIONS: Our study findings showed that postmenopausal women had a low proportion of equol producers with diabetes and dyslipidemia.

Based on urine metabolomics to study the mechanism of Qi-deficiency affecting type 2 diabetes rats using ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry.

Qi-deficiency also called energy deficiency, which approximates to the term of sub-health in contemporary medical theory. Diabetes is similar to the symptoms of "xiaoke" in traditional Chinese medicine (TCM) which is linked with Qi-deficiency. However, the mechanism of Qi-deficiency on type 2 diabetes (T2D) has not been completely elucidated. In this study, a model on Qi-deficiency T2D rat was established by using diet with high fat and high sugar and small-dose STZ induction combined with exhaustive swimming, and the model was evaluated by pathological section, hematological index and serum biochemical parameters. Applying urine metabolomics based on ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry to explore the underlying molecular mechanism of Qi-deficiency on T2D and 32 urinary metabolites were identified as prospective biomarkers for Qi-deficiency T2D rats. Metabolic pathway analysis indicated that synthesis and degradation of ketone bodies, starch and sucrose metabolism, phenylalanine metabolism, arachidonic acid metabolism, butanoate metabolism and TCA cycle, etc., were closely related to potential mechanisms of Qi-deficiency on T2D. The metabolomics results can provide reliable data support for complex TCM syndrome diagnosis.

Effect of Oral carnosine supplementation on urinary TGF-ß in diabetic nephropathy: a randomized controlled trial.

BACKGROUND: Activation of the transforming growth factor beta (TGF-ß) pathway is a significant contributor to the pathogenesis of diabetic nephropathy. Carnosine is a dipeptide that can inhibit TGF-ß synthesis. We tested the hypothesis that carnosine supplement added to standard therapy will result in reduced urinary TGF-ß levels among patients with diabetic nephropathy. METHODS: We randomly assigned 40 patients with diabetic nephropathy and albuminuria 30-299 mg/day to treatment with carnosine (2 g/day) or placebo for 12 weeks. Urinary TGF-ß level was determined using ELISA, urine albumin was ascertained by immunonephelometric assay, and renal function and metabolic profiles were determined at baseline and during 12 weeks of active treatment. Primary outcome was decrease in urinary levels of TGF-ß. RESULTS: The 2 groups were comparable for baseline characteristics, blood pressure, urine albumin, urine TGF-ß and renal function measurements. Urinary TGF-ß significantly decreased with carnosine supplement (- 17.8% of the baseline values), whereas it tended to increase with placebo (+ 16.9% of the baseline values) (between-group difference P < 0.05). However, blood urea nitrogen, serum creatinine, glomerular filtration rate and other biochemical parameters remained unchanged during the study period including urinary albuminuria. Both groups were well tolerated with no serious side-effects. CONCLUSIONS: These data indicated an additional renoprotective effect of oral supplementation with carnosine to decrease urinary TGF-ß level that serves as a marker of renal injury in diabetic nephropathy. TRIAL REGISTRATION: Thai Clinical Trials, TCTR20200724002 . Retrospectively Registered 24 July 2020.

Effect of high-dose mineralocorticoid receptor antagonist eplerenone on urinary albumin excretion in patients with type 2 diabetes and high cardiovascular risk: Data from the MIRAD trial.

AIM: As mineralocorticoid receptor antagonists (MRAs) may possess renoprotective effects in type 2 diabetes (T2D), it was decided to investigate the impact of high-dose MRA on prespecified secondary endpoints-namely, change in urinary albumin-creatinine ratio (UACR) and 24-h ambulatory blood pressure-in the MIRAD trial. METHODS: This was a double-blind clinical trial in which T2D patients at high risk of or with established cardiovascular disease (CVD) were randomized to either high-dose (100-200 mg) eplerenone or a dose-matched placebo as an add-on to background antihypertensive treatment for 26 weeks. Safety was evaluated by the incidence of hyperkalaemia and kidney-related adverse events. RESULTS: A total of 140 patients were enrolled (70 in each group). Baseline UACR was 17 mg/g (geometric mean; 95% CI: 13-22); this decreased by 34% in the eplerenone group compared with the placebo group at week 26 (95% CI: -51% to -12%; P = 0.005). There was no significant decrease in 24-h systolic blood pressure (SBP) due to treatment (-3 mmHg; 95% CI: -6 to 1; P = 0.150). However, the observed change in 24-h SBP correlated with the relative change in UACR in the eplerenone group (r = 0.568, P < 0.001). Mean baseline (± SD) estimated glomerular filtration rate (eGFR) was 85 (± 18.6) mL/min/1.73 m2, and 12 (± 9%) had an eGFR of 41-59 mL/min/1.73 m2. No significant differences in the incidence of mild hyperkalaemia (≥ 5.5 mmol/L; eplerenone vs placebo: 6 vs 2, respectively; P = 0.276) and no severe hyperkalaemia (≥ 6.0 mmol/L) were observed. CONCLUSION: The addition of high-dose eplerenone to T2D patients at high risk of CVD can markedly reduce UACR with an acceptable safety profile.

Inspiratory Muscle Training on Glucose Control in Diabetes: A Randomized Clinical Trial.

This study evaluated the effects of inspiratory muscle training (IMT) in glucose control and respiratory muscle function in patients with diabetes. It was a randomized clinical trial conducted at the Physiopathology Laboratory of the Hospital de Clínicas de Porto Alegre. Patients with Type 2 diabetes were randomly assigned to IMT or placebo-IMT (P-IMT), performed at 30% and 2% of maximal inspiratory pressure, respectively, every day for 12 weeks. The main outcome measures were HbA1c, glycemia, and respiratory muscle function. Thirty patients were included: 73.3% women, 59.6 ± 10.7 years old, HbA1c 8.7 ± 0.9% (71.6 ± 9.8 mmol/mol), and glycemia 181.8 ± 57.8 mg/dl (10.5 ± 3.2 mmol/L). At the end of the training, HbA1c was 8.2 ±0.3% (66.1 ± 3.3 mmol/mol) and 8.7 ± 0.3% (71.6 ± 3.3 mmol/mol) for the IMT and P-IMT groups, respectively (p = .8). Fasting glycemia decreased in both groups with no difference after training although it was lower in IMT at 8 weeks: 170.0 ± 11.4 mg/dl(9.4 ± 0.6 mmol/L) and 184.4 ± 15.0 mg/dl (10.2 ± 0.8 mmol/L) for IMT and P-IMT, respectively (p < .05). Respiratory endurance time improved in the IMT group (baseline = 325.9 ± 51.1 s and 305.0 ± 37.8 s; after 12 weeks = 441.1 ± 61.7 s and 250.7 ± 39.0 s for the IMT and P-IMT groups, respectively; p < .05). Considering that glucose control did not improve, IMT should not be used as an alternative to other types of exercise in diabetes. Higher exercise intensities or longer training periods might produce better results. The clinical trials identifier is NCT03191435.

The application of metabolomics in investigating anti-diabetic activity of medicinal plants.

Diabetes mellitus is the most prevalent endocrine disease in the world and is likely to be the major epidemic in human history. In current years, many modern anti-diabetic medicines have been produced and introduced into the markets, however, long-term treatment of diabetes using synthetic drugs is limited. Medicinal plants play a great role in the treatment of diabetes. Many medicinal plants and their related traditional treatments for diabetes are used throughout the world and represent promising alternatives for the management of diabetes treatment. Metabolomics researches on diabetes have contributed to many aspects of exploring biomarkers and understanding the progression of the disease at metabolic levels. In addition, in the last decade, a number of metabolomics studies have focused on investigating the action mechanism of various herbal medicines. This paper aims to highlight and review a series of metabolomics studies that carried out on the role of herbal medicines on obesity and diabetes, finding potential biomarkers and also characterizing the metabolic disturbances associated with diabetes development. The findings showed that the metabolism of glycolysis/gluconeogenesis (glucose, pyruvate, lactate), TCA cycle (succinate, citrate, ß-hydroxybutyrate, 2-oxoglutarate), lipid metabolism (acetoacetate, acetate) and amino acid metabolic pathways (valine, leucine, and isoleucine, hippurate, creatine) were more significantly disturbed metabolic pathways and biomarkers in diabetic models and herbal medicines affect these metabolic pathways by different mechanisms.

Changes of urine metabolites in response to n-3 fatty acid supplements and their correlation with metabolic risk factors in patients with type 2 diabetes.

The present study aimed to investigate the effects of n-3 fatty acid supplements on urine metabolite profiling and their correlation with metabolic risk factors in Chinese T2D patients. A double-blind randomized controlled trial was conducted in 59 Chinese patients with T2D, who were randomized to receive fish oil (FO), flaxseed oil (FSO) or corn oil (CO, serving as a control group) capsules for 180 days. Morning urine samples were collected before and after the intervention and were analyzed for metabolomics by UHPLC-Q-Exactive Orbitrap/MS in positive and negative ionization modes. In the FO group, levels of 2-hexenoylcarnitine (C6:1) (p < 0.001) and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) (p = 0.004) were significantly increased while hydroxyisovaleroyl carnitine (C5:OH) (p < 0.001) was significantly decreased compared with the CO group. In addition, geranylacetone (p = 0.023) and citronellyl propionate (p = 0.038) levels were significantly elevated, while dihydrojasmonic acid (p = 0.003) was significantly reduced in the FSO group compared with that in the CO group. Moreover, increased C6:1 was correlated with decreased serum triglycerides (r = -0.340, p = 0.020). The change of urine CMPF showed inverse correlation with blood urea nitrogen (BUN) (r = -0.338, p = 0.020), while C5:OH was positively correlated with apolipoprotein B (APOB) and BUN (r = 0.386, p = 0.015; r = 0.327, p = 0.025). Besides, the change of urine CMPF was positively correlated with serum CMPF (r = 0.646, p < 0.001). In conclusion, the present study confirmed that CMPF is a strong biomarker of fish oil, and indicated that marine n-3 PUFA intake might have a beneficial effect on lipid metabolism and renal function in patients with T2D.

Serum and Urinary Selenium Status in Patients with the Pre-diabetes and Diabetes in Northeast China.

Homeostasis imbalance of selenium (Se) in diabetes has received great attention. This study investigated serum and urinary Se levels in patients with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), type 1 diabetes (T1D), and type 2 diabetes (T2D) in Northeast Chinese populations. From January 2010 to October 2011, patients with IFG (n = 12), IGT (n = 15), T1D (n = 25), T2D (n = 137), and healthy controls (n = 50) were enrolled in the First Hospital of Jilin University. Se was detected using inductively coupled plasma spectrometer. The serum Se level was dramatically lower in patients with T1D and was significantly higher in IFG subjects, and the urinary Se concentration was markedly lower in IGT and T2D groups. The serum Se levels were positively correlated with serum zinc (Zn) in both IFG and IGT groups, while urinary Se were positively associated with urinary Zn and copper (Cu) in IGT group. The serum Se levels were positively correlated with serum Cu in both T1D and T2D groups, and urinary levels of Se were positively associated with serum zinc and urinary Cu, Zn, calcium (Ca), and magnesium (Mg) and negatively correlated with serum Ca and Mg in T2D group, while the urinary levels of Se were positively correlated with urinary Zn and Mg both in peripheral neuropathy (DPN) and retinopathy (DR) groups. One month of simvastatin therapy reduced serum Se levels. These results suggest the potential role of Se in diabetes should receive attention.

Effects of Different Doses of Irbesartan Combined With Spironolactone on Urinary Albumin Excretion Rate in Elderly Patients With Early Type 2 Diabetic Nephropathy.

BACKGROUND: There is a lack of research on the effect of low dose of angiotensin receptor blockers combined with spironolactone, and the effect of high dose of angiotensin receptor blockers alone on the urinary albumin excretion rate (UAER) in elderly patients with early type 2 diabetic nephropathy (DN). METHODS: We conducted a prospective, randomized, open-label, parallel-controlled study that included 244 elderly patients with early DN and mild-to-moderate essential hypertension. Patients were randomly divided into 4 groups: low-dose irbesartan (group A), high-dose irbesartan (group B), low-dose irbesartan combined with spironolactone (group C) and high-dose irbesartan combined with spironolactone (group D). Changes in UAER, serum potassium and blood pressure were compared. RESULTS: There were no statistical differences in the baseline characteristics among groups. Furthermore, no significant difference in blood pressure before and after treatment was found among different groups. After 72-week treatment, UAER in group D was lower compared to group A and B (P < 0.05). Meanwhile, compared with group B, UAER in group C decreased significantly (P < 0.05). Additionally, significantly higher serum potassium was found in group D compared to other groups (P < 0.05). Also, group D had the highest count of patients who withdrew from the study due to hyperkalemia compared to other groups (P < 0.05). CONCLUSIONS: Our results indicate high-dose irbesartan combined with spironolactone may be more efficient in reducing UAER in elderly patients with early DN, but this treatment could cause hyperkalemia. Low-dose irbesartan combined with spironolactone was shown to be safer and more effective in decreasing UAER compared to high-dose irbesartan.

Metabolomic analysis and biochemical changes in the urine and serum of streptozotocin-induced normal- and obese-diabetic rats.

Diabetes mellitus (DM) is a chronic disease that can affect metabolism of glucose and other metabolites. In this study, the normal- and obese-diabetic rats were compared to understand the diabetes disorders of type 1 and 2 diabetes mellitus. This was done by evaluating their urine metabolites using proton nuclear magnetic resonance (1H NMR)-based metabolomics and comparing with controls at different time points, considering the induction periods of obesity and diabetes. The biochemical parameters of the serum were also investigated. The obese-diabetic model was developed by feeding the rats a high-fat diet and inducing diabetic conditions with a low dose of streptozotocin (STZ) (25 mg/kg bw). However, the normal rats were induced by a high dose of STZ (55 mg/kg bw). A partial least squares discriminant analysis (PLS-DA) model showed the biomarkers of both DM types compared to control. The synthesis and degradation of ketone bodies, tricarboxylic (TCA) cycles, and amino acid pathways were the ones most involved in the variation with the highest impact. The diabetic groups also exhibited a noticeable increase in the plasma glucose level and lipid profile disorders compared to the control. There was also an increase in the plasma cholesterol and low-density lipoprotein (LDL) levels and a decline in the high-density lipoprotein (HDL) of diabetic rats. The normal-diabetic rats exhibited the highest effect of all parameters compared to the obese-diabetic rats in the advancement of the DM period. This finding can build a platform to understand the metabolic and biochemical complications of both types of DM and can generate ideas for finding targeted drugs.

Comparison of Acarbose and Metformin on Albumin Excretion in Patients With Newly Diagnosed Type 2 Diabetes: A Randomized Controlled Trial.

Increased urinary albumin excretion in diabetes not only signals nephropathy but also serves as a risk marker for cardiovascular disease. The data of MARCH (Metformin and AcaRbose in Chinese as the initial Hypoglycaemic treatment) trial demonstrated that acarbose and metformin were similarly efficacious at lowering blood glucose and blood pressure, as well as improving insulin sensitivity in Chinese patients newly diagnosed with type 2 diabetes mellitus. The purpose of this study was to identify the effects of acarbose and metformin therapy on albumin excretion in MARCH study.Baseline urine albumin/creatinine ratio (ACR) of 762 newly diagnosed, drug-naïve patients with type 2 diabetes mellitus was measured. Included patients were randomized to receive either acarbose or metformin and followed for 48 weeks. In addition to change in ACR, the estimated glomerular filtration rates (eGFR) and frequency of metabolic syndrome (MetS) were also assessed.Elevated ACR levels (≥30 mg/g) were present at baseline in 21.9% of all participants. A significant decline in urine ACR was observed in both the acarbose and metformin groups at week 24 and 48 (all P < 0.001). The proportion of patients with elevated ACRs was also reduced in both treatment groups at week 24 and 48 compared with baseline values (all P < 0.05). The change in urine ACR at week 48 was significantly greater in patients prescribed acarbose than in those prescribed metformin (P = 0.01). Both acarbose and metformin significantly decreased the frequency of MetS at week 24 and 48 (both P < 0.05). Neither treatment affected eGFR.In sum, both acarbose and metformin decreased urine ACR levels and reduced the frequency of elevated ACR and MetS in Chinese patients with newly diagnosed type 2 diabetes mellitus without affecting eGFR. After 48 weeks' intervention, acarbose therapy resulted in a greater reduction in urine ACR compared with metformin.

Urine phyto-oestrogen metabolites are not significantly associated with risk of type 2 diabetes: the Singapore Chinese health study.

We evaluated the relationship between urine concentrations of phyto-oestrogens (isoflavones and lignans) and risk of incident type 2 diabetes in middle-aged and elderly Chinese residing in Singapore. Urine metabolites of isoflavones and lignans were assayed by HPLC among 564 diabetes cases and 564 matched controls in a case-control study nested within the Singapore Chinese Health Study cohort. Participants were free of diagnosed diabetes, CVD and cancer at morning urine collections during 1999-2004. Cases were participants who reported to have physician-diagnosed diabetes at follow-up visits during 2006-2010, whereas controls were randomly selected among those who remained free of diabetes and were matched to the index cases by age, sex, dialect group and date of urine collection. Conditional logistic regression models were used to calculate OR and 95 % CI with adjustment for potential confounders. The mean age of the participants at the time of urine collection was 59·8 years, and the average interval between urine collection and diabetes diagnosis was 4·0 years. The multivariate-adjusted OR for diabetes were 1·00 (reference), 0·76 (95 % CI 0·52, 1·11), 0·78 (95 % CI 0·53, 1·14) and 0·79 (95 % CI 0·54, 1·15) across quartiles of urine isoflavones (P for trend=0·54), and were 1·00 (reference), 0·87 (95 % CI 0·60, 1·27), 1·10 (95 % CI 0·77, 1·56) and 0·93 (95 % CI 0·63, 1·37) for lignans (P for trend=0·93). The results were similar in men and women, as well as for individual metabolites of isoflavones (genistein, daidzein, glycitin and equol) or lignans (enterodiol and enterolactone). The present study did not find a significant association between urine phyto-oestrogen metabolites and risk of type 2 diabetes in Chinese adults.

Protective Effects of Curcumin on Renal Oxidative Stress and Lipid Metabolism in a Rat Model of Type 2 Diabetic Nephropathy.

PURPOSE: Diabetic nephropathy is a serious complication of type 2 diabetes mellitus, and delaying the development of diabetic nephropathy in patients with diabetes mellitus is very important. In this study, we investigated inflammation, oxidative stress, and lipid metabolism to assess whether curcumin ameliorates diabetic nephropathy. MATERIALS AND METHODS: Animals were divided into three groups: Long-Evans-Tokushima-Otsuka rats for normal controls, Otsuka-Long-Evans-Tokushima Fatty (OLETF) rats for the diabetic group, and curcumin-treated (100 mg/kg/day) OLETF rats. We measured body and epididymal fat weights, and examined plasma glucose, adiponectin, and lipid profiles at 45 weeks. To confirm renal damage, we measured albumin-creatinine ratio, superoxide dismutase (SOD), and malondialdehyde (MDA) in urine samples. Glomerular basement membrane thickness and slit pore density were evaluated in the renal cortex tissue of rats. Furthermore, we conducted adenosine monophosphate-activated protein kinase (AMPK) signaling and oxidative stress-related nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling to investigate mechanisms of lipotoxicity in kidneys. RESULTS: Curcumin ameliorated albuminuria, pathophysiologic changes on the glomerulus, urinary MDA, and urinary SOD related with elevated Nrf2 signaling, as well as serum lipid-related index and ectopic lipid accumulation through activation of AMPK signaling. CONCLUSION: Collectively, these findings indicate that curcumin exerts renoprotective effects by inhibiting renal lipid accumulation and oxidative stress through AMPK and Nrf2 signaling pathway.

The Expression of Tristetraprolin and Its Relationship with Urinary Proteins in Patients with Diabetic Nephropathy.

OBJECTIVE: Tristetraprolin (TTP), also known as zinc finger protein 36, is an RNA binding protein that has a significant role in regulating the expression of mRNAs containing AU-rich elements. We postulated that TTP might regulate interleukin (IL)-6 and IL-18 expression in diabetes. This study aimed to test the hypothesis that the levels of TTP are correlated with nephropathy in patients with type 2 diabetes. METHODS: Eighty-seven patients (61.3±9.6 years old) who had been diagnosed with type 2 diabetes mellitus and 41 age and sex matched healthy control subjects were enrolled. The diabetes patients were classified into those without proteinuria, with microalbuminuria, and with clinical proteinuria groups according to the ratio of urinary excretion of albumin/creatinine (ACR). RESULTS: Serum and urinary levels of IL-6 and IL-18 were significantly elevated, but those of TTP were significantly decreased in patients with diabetes as compared with control subjects. In addition, serum and urinary levels of IL-6 and IL-18 were significantly higher, but those of TTP were significantly lower in patients with proteinuria than in patients without proteinuria or with microalbuminuria. There was a significant correlation between serum TTP and IL-6/IL-18 (correlation coefficients of -0.572 and -0.685, P < 0.05). CONCLUSION: These results show that diabetes with clinical proteinuria is accompanied by decreased urinary and serum level of TTP and increased levels of IL-6 and IL-18. Decreased TTP expression might occur prior to the increase in IL-6 and IL-18, and decrease of TTP might provide an earlier marker for glomerular dysfunction than IL-6 and IL-18.

Moderate oral supplementation with docosahexaenoic acid improves platelet function and oxidative stress in type 2 diabetic patients.

Platelets from patients with type 2 diabetes are characterised by hyperactivation and high level of oxidative stress. Docosahexaenoic acid (DHA) may have beneficial effects on platelet reactivity and redox status. We investigated whether moderate DHA supplementation, given as a triglyceride form, may correct platelet dysfunction and redox imbalance in patients with type 2 diabetes. We conducted a randomised, double-blind, placebo-controlled, two-period crossover trial (n=11 post-menopausal women with type 2 diabetes) to test the effects of 400 mg/day of DHA intake for two weeks on platelet aggregation, markers of arachidonic acid metabolism, lipid peroxidation status, and lipid composition. Each two week-period was separated from the other by a six-week washout. Daily moderate dose DHA supplementation resulted in reduced platelet aggregation induced by collagen (-46.5 %, p< 0.001), and decreased platelet thromboxane B2 (-35 %, p< 0.001), urinary 11-dehydro-thromboxane B2 (-13.2 %, p< 0.001) and F2-isoprostane levels (-19.6 %, p< 0.001) associated with a significant increase of plasma and platelet vitamin E concentrations (+20 % and +11.8 %, respectively, p< 0.001). The proportions of DHA increased both in plasma lipids and in platelet phospholipids. After placebo treatment, there was no effect on any parameters tested. Our findings support a significant beneficial effect of low intake of DHA on platelet function and a favourable role in reducing oxidative stress associated with diabetes.

Hyperbaric oxygen therapy (HBOT) suppresses biomarkers of cell stress and kidney injury in diabetic mice.

The disease burden from diabetic kidney disease is large and growing. Effective therapies are lacking, despite an urgent need. Hyperbaric oxygen therapy (HBOT) activates Nrf2 and cellular antioxidant defenses; therefore, it may be generally useful for treating conditions that feature chronic oxidative tissue damage. Herein, we determined how periodic exposure to oxygen at elevated pressure affected type 2 diabetes mellitus-related changes in the kidneys of db/db mice. Two groups of db/db mice, designated 2.4 ATA and 1.5 ATA, were treated four times per week with 100 % oxygen at either 1.5 or 2.4 ATA (atmospheres absolute) followed by tests to assess kidney damage and function. The sham group of db/db mice and the Hets group of db/+ mice were handled but did not receive HBOT. Several markers of kidney damage were reduced significantly in the HBOT groups including urinary biomarkers neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C (CyC) along with significantly lower levels of caspase-3 activity in kidney tissue extracts. Other stress biomarkers also showed trends to improvement in the HBOT groups, including urinary albumin levels. Expressions of the stress response genes NRF2, HMOX1, MT1, and HSPA1A were reduced in the HBOT groups at the end of the experiment, consistent with reduced kidney damage in treated mice. Urinary albumin/creatinine ratio (ACR), a measure of albuminuria, was significantly reduced in the db/db mice receiving HBOT. All of the db/db mouse groups had qualitatively similar changes in renal histopathology. Glycogenated nuclei, not previously reported in db/db mice, were observed in these three experimental groups but not in the control group of nondiabetic mice. Overall, our findings are consistent with therapeutic HBOT alleviating stress and damage in the diabetic kidney through cytoprotective responses. These findings support an emerging paradigm in which tissue oxygenation and cellular defenses effectively limit damage from chronic oxidative stress more effectively than chemical antioxidants.

Impact of a 6-wk olive oil supplementation in healthy adults on urinary proteomic biomarkers of coronary artery disease, chronic kidney disease, and diabetes (types 1 and 2): a randomized, parallel, controlled, double-blind study.

BACKGROUND: Olive oil (OO) consumption is associated with cardiovascular disease prevention because of both its oleic acid and phenolic contents. The capacity of OO phenolics to protect against low-density lipoprotein (LDL) oxidation is the basis for a health claim by the European Food Safety Authority. Proteomic biomarkers enable an early, presymptomatic diagnosis of disease, which makes them important and effective, but understudied, tools for primary prevention. OBJECTIVE: We evaluated the impact of supplementation with OO, either low or high in phenolics, on urinary proteomic biomarkers of coronary artery disease (CAD), chronic kidney disease (CKD), and diabetes. DESIGN: Self-reported healthy participants (n = 69) were randomly allocated (stratified block random assignment) according to age and body mass index to supplementation with a daily 20-mL dose of OO either low or high in phenolics (18 compared with 286 mg caffeic acid equivalents per kg, respectively) for 6 wk. Urinary proteomic biomarkers were measured at baseline and 3 and 6 wk alongside blood lipids, the antioxidant capacity, and glycation markers. RESULTS: The consumption of both OOs improved the proteomic CAD score at endpoint compared with baseline (mean improvement: -0.3 for low-phenolic OO and -0.2 for high-phenolic OO; P < 0.01) but not CKD or diabetes proteomic biomarkers. However, there was no difference between groups for changes in proteomic biomarkers or any secondary outcomes including plasma triacylglycerols, oxidized LDL, and LDL cholesterol. CONCLUSION: In comparison with low-phenolic OO, supplementation for 6 wk with high-phenolic OO does not lead to an improvement in cardiovascular health markers in a healthy cohort.

Evaluation of urinary N-acetyl-beta-D-glucosaminidase as a marker of early renal damage in patients with type 2 diabetes mellitus.

OBJECTIVE: To evaluate the clinical usefulness of urinary N-acetyl-beta-D-glucosaminidase (NAG) excretion for the detection of early tubular damage in type 2 diabetes mellitus (T2DM). SUBJECTS AND METHODS: Thirty six patients with T2DM were divided into two groups based on urinary albumin to creatinine ratio (ACR): normoalbuminuria (ACR <30 mg/g; n=19) and microalbuminuria (ACR =30-300 mg/g; n=17). The following parameters were determined in both groups: urinary NAG and albumin, serum and urine creatinine, fasting plasma glucose and glycated hemoglobin (HbA1c). RESULTS: Urinary NAG levels [Units/g creatinine; median (range)] were significantly increased in microalbuminuria group [17.0 (5.9 - 23.3)] compared to normoalbuminuria group [4.4 (1.5 - 9.2)] (P<0.001). No differences between groups were observed in fasting glucose, HbA1c, serum creatinine levels and estimated glomerular filtration rates (eGFR). Urinary NAG positively correlated with ACR (r=0.628; p<0.0001), while no significant association was observed between NAG and glycemia, HbA1c, serum creatinine and eGFR. CONCLUSIONS: The increase of urinary NAG at the microalbuminuria stage of diabetic nephropathy (DN) suggests that tubular dysfunction is already present in this period. The significant positive association between urinary NAG excretion and ACR indicates the possible clinical application of urinary NAG as a complementary marker for early detection of DN in T2DM.

Extreme urinary betaine losses in type 2 diabetes combined with bezafibrate treatment are associated with losses of dimethylglycine and choline but not with increased losses of other osmolytes.

PURPOSE: Betaine deficiency is a probable cardiovascular risk factor and a cause of elevated homocysteine. Urinary betaine excretion is increased by fibrate treatment, and is also often elevated in diabetes. Does fibrate further increase betaine excretion in diabetes, and does it affect the plasma concentrations and excretions of related metabolites and of other osmolytes? METHODS: Samples from a previous study of type 2 diabetes were selected if participants were taking bezafibrate (n = 32). These samples were compared with participants matched for age and gender and not on a fibrate (comparator group, n = 64). Betaine, related metabolites, and osmolytes were measured in plasma and urine samples from these 96 participants. RESULTS: Median urinary betaine excretion in those on bezafibrate was 5-fold higher than in the comparator group (p < 0.001), itself 3.5-fold higher than the median reported for healthy populations. In the bezafibrate group, median dimethylglycine excretion was higher (9-fold, p < 0.001). Excretions of choline, and of the osmolytes myo-inositol, taurine and glycerophosphorylcholine, were not significantly different between groups. Some participants excreted more betaine than usual dietary intakes. Several betaine fractional clearances were >100 %. Betaine excretion correlated with excretions of the osmolytes myo-inositol and glycerophosphorylcholine, and also with the excretion of choline and N,N-dimethylglycine, but it was inconclusive whether these relationships were affected by bezafibrate therapy. CONCLUSIONS: Increased urinary betaine excretions in type 2 diabetes are further increased by fibrate treatment, sometimes to more than their dietary intake. Concurrent betaine supplementation may be beneficial.

[Study on mechanism of combined administration of Coptidis Rhizoma and Rehmanniae Radix in treating type II diabetes mellitus].

To make a preliminary study on the mechanism of Coptidis Rhizoma(CR) and Rehmanniae Radix(RR) before and after the combined administration in treating type II diabetes mellitus. The type I diabetes animal model in rats was established by fat emulsion and intraperitoneal injection with streptozotocin, in order to compare the hpyerglycemic and hypolipidemic effects of CR, RR and their combined administration of different ratio. The urinary metabolic profiling in rats of Coptidis Rhizoma and Rehmanniae Radix before and after the combined administration was analyzed by using the gas chromatography-mass spectrometry. The differences among groups in metabolome were analyzed by the principal component analysis (PCA). The biochemical index results indicated that both CR and RR before and after the combined administration could lower high blood glucose, hypertriglyceride and high cholesterol. According to the analytical results of PCA of the rats' urine samples, the CR group was the most close to the normal group, with no significant difference in CR and RR group of different combination ratios. Twelve differentiated metabolites were identified to be related to type II diabetes. Compared with the normal group, the CR-treated group showed significant increase in seven differentiated metabolites. Among CR and RR drugs with different combination ratios, CR played a major role and thus acted as the monarch drug. Whereas RR served as the ministerial drug and assisted CR to show the efficacy. This study laid a foundation for the explanation of the combination mechanism of traditional Chinese medicines.