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Background: The goal was to study lipid profiles (TG, TC, LDL, HDL), effects on serum leptin, and fat tissue adiponectin, and resistin as well as body weight effects of Shan He Jian Fei Granules (SHJFG) in rats on a high fat diet.
Methods: Rats were randomly divided into five groups: normal control group fed with normal fat diet, rats on high fat diet receiving low dosage, middle dosage, high dosage of Shan He Jian Fei Granules (SHJFG) as well as a high fat diet group receiving placebo. Rats were treated for 8 weeks. Body weight and naso-anal length of each rat were recorded and Lee's index was calculated. Serum TG, TC, LDL, HDL and leptin concentrations were analyzed. The gene expressions of adiponectin and resistin in adipose tissues were tested by RT-PCR.
Results: Compared to the high-fat diet group, body weights, Lee's indexes, weight of fat tissues and serum TG, TC, LDL and leptin of SHJFG groups significantly decreased (p<0.05), whereas mRNA expressions of adiponectin and resistin of SHJFG groups significantly increased (p<0.05).
Conclusions: SHJFG could significantly lower body weight and serum TG, TC, and LDL of obese rats. The effects of SHJFG in lowering leptin synthesis and raising mRNA expression of adiponectin and resistin in fat tissues may act as part of the mechanisms in lowering body weight of obese rats. Further studies are needed to demonstrate whether SHJFG may also reduce overall cardiovascular morbidity and mortality like other lipid lowering drugs.
To analyze the association between fetal brain growth and late gestational blood serum cortisol in normal pregnancy.Blood total cortisol was quantified at delivery in 432 Chinese mother/child pairs. Key inclusion criteria of the cohort were: no structural anomalies of the newborn, singleton pregnancy, no alcohol abuse, no drug abuse or history of smoking no hypertensive disorders and no impairment of glucose tolerance and no use of steroid medication during pregnancy. Differential ultrasound examination of the fetal body was done in early (gestational day 89.95 +/- 7.31), middle (gestational day 160.17 16.12) and late pregnancy (gestational day 268.89 +/- 12.42). Newborn's cortisol was not correlated with any of the ultrasound measurements during pregnancy nor with birth weight. Multivariable regression analysis, considering timing of the ultrasound examination, the child's sex, maternal BMI, maternal age, maternal body weight at delivery, the timing of cortisol measurement and maternal uterine contraction states, revealed that maternal serum total cortisol was significantly negative correlated with ultrasound parameters describing the fetal brain: late biparietal diameter (R-2 =0.512, p =0.009), late head circumference (R-2 = 0.498, p= 0.001), middle biparietal diameter (R-2= 0.819, p = 0.013), middle cerebellum transverse diameter R-2 = 0.76, p= 0.014) and early biparietal diameter(R-2 = 0.819, p = 0.013). The same analysis revealed that birth weight as well as ultrasound parameters such as abdominal circumference and femur length were not correlated to maternal cortisol levels.
In conclusion, our study demonstrates that maternal cortisol secretion within physiological ranges may be inversely correlated to fetal brain growth but not to birth weight. It remains to be demonstrated whether maternal cortisol secretion negatively influencing fetal brain growth translates to adverse neurological outcomes in later life.
Hypomagnesemia affects insulin resistance and is a risk factor for diabetes mellitus type 2 (DM2) and gestational diabetes mellitus (GDM). Two single nucleotide polymorphisms (SNPs) in the epithelial magnesium channel TRPM6 ((VI)-I-1393, (KE)-E-1584) were predicted to confer susceptibility for DM2. Here, we show using patch clamp analysis and total internal reflection fluorescence microscopy, that insulin stimulates TRPM6 activity via a phosphoinositide 3-kinase and Rac1-mediated elevation of cell surface expression of TRPM6. Interestingly, insulin failed to activate the genetic variants TRPM6 ((VI)-I-1393) and TRPM6((KE)-E-1584), which is likely due to the inability of the insulin signaling pathway to phosphorylate TRPM6(T-1391) and TRPM6(S-1583). Moreover, by measuring total glycosylated hemoglobin (TGH) in 997 pregnant women as a measure of glucose control, we demonstrate that TRPM6((VI)-I-1393) and TRPM6((KE)-E-1584) are associated with higher TGH and confer a higher likelihood of developing GDM. The impaired response of TRPM6((VI)-I-1393) and TRPM6((KE)-E-1584) to insulin represents a unique molecular pathway leading to GDM where the defect is located in TRPM6.
Oxidation of PTH at methionine residues results in loss of biological activity. PTH may be oxidized in patients with renal disease. The aim of this study was to develop an assay considering oxidation of PTH. Oxidized hPTH was analyzed by high resolution nano-liquid chromatography coupled to ESI-FTT tandem mass spectrometry (nanoLC-ESI-FT-MS/MS) directly and after proteolytic cleavage. The oxidized hPTH(1-84) sample shows TIC-peaks at 18-20 min and several mass peaks due to mass shifts caused by oxidations. No significant signal for oxidized hPTH(1-84) species after removal of oxidized PTH molecules by a specific column with monoclonal antibodies (MAB) raised against the oxidized hPTH was detectable. By using this column in samples from 18 patients on dialysis we could demonstrate that measured PTH concentrations were substantially lower when considering oxidized forms of PTH. The relationship between PTH concentrations determined directly and those concentrations measured after removal of the oxidized PTH forms varies substantially. In some patients only 7% of traditionally measured PTH was free of oxidation, whereas in other patients 34% of the traditionally measured PTH was real intact PTH. In conclusion, a huge but not constant proportion of PTH molecules are oxidized in patients requiring dialysis. Since oxidized PTH is biologically inactive, the currently used methods to detect PTH in daily clinical practice may not adequately reflect PTH-related bone and cardiovascular abnormalities in patients on dialysis.
Background: Environmental alternations leading to fetal programming of cardiovascular diseases in later life have been attributed to maternal factors. However, animal studies showed that paternal obesity may program cardio-metabolic diseases in the offspring. In the current study we tested the hypothesis that paternal BMI may be associated with fetal growth.
Methods and Results: We analyzed the relationship between paternal body mass index (BMI) and birth weight, ultrasound parameters describing the newborn's body shape as well as parameters describing the newborns endocrine system such as cortisol, aldosterone, renin activity and fetal glycated serum protein in a birth cohort of 899 father/mother/child triplets. Since fetal programming is an offspring sex specific process, male and female offspring were analyzed separately. Multivariable regression analyses considering maternal BMI, paternal and maternal age, hypertension during pregnancy, maternal total glycated serum protein, parity and either gestational age (for birth weight) or time of ultrasound investigation (for ultrasound parameters) as confounding showed that paternal BMI is associated with growth of the male but not female offspring. Paternal BMI correlated with birth parameters of male offspring only: birth weight; biparietal diameter, head circumference; abdominal diameter, abdominal circumference; and pectoral diameter. Cortisol was likewise significantly correlated with paternal BMI in male newborns only.
Conclusions: Paternal BMI affects growth of the male but not female offspring. Paternal BMI may thus represent a risk factor for cardiovascular diseases of male offspring in later life. It remains to be demonstrated whether this is linked to an offspring sex specific paternal programming of cortisol secretion.
Renal and cardiac effects of DPP-4 inhibitors - from preclinical development to clinical research
(2012)
Inhibitors of type 4 dipeptidyl peptidase (DDP-4) were developed and approved for the oral treatment of type 2 diabetes. Its mode of action is to inhibit the degradation of incretins, such as type 1 glucagon like peptide (GLP-1), and GIP. GLP-1 stimulates glucose-dependent insulin secretion from pancreatic beta-cells and suppresses glucagon release from alpha-cells, thereby improving glucose control. Besides its action on the pancreas type 1 glucagon like peptide has direct effects on the heart, vessels and kidney mainly via the type 1 glucagon like peptide receptor (GLP-1R). Moreover, there are substrates of DPP-4 beyond incretins that have proven renal and cardiovascular effects such as BNP/ANP, NPY, PYY or SDF-1 alpha. Preclinical evidence suggests that DPP-4 inhibitors may be effective in acute and chronic renal failure as well as in cardiac diseases like myocardial infarction and heart failure. Interestingly, large cardiovascular meta-analyses of combined Phase II/III clinical trials with DPP-4 inhibitors point all in the same direction: a potential reduction of cardiovascular events in patients treated with these agents. A pooled analysis of pivotal Phase III, placebo-controlled, registration studies of linagliptin further showed a significant reduction of urinary albumin excretion after 24 weeks of treatment. The observation suggests direct renoprotective effects of DPP-4 inhibition that may go beyond its glucose-lowering potential. Type 4 dipeptidyl peptidase inhibitors have been shown to be very well tolerated in general, but for those excreted via the kidney dose adjustments according to renal function are needed to avoid side effects. In conclusion, the direct cardiac and renal effects seen in preclinical studies as well as meta-analysis of clinical trials may offer additional potentials - beyond improvement of glycemic control - for this newer class of drugs, such as acute kidney failure, chronic kidney failure as well as acute myocardial infarction and heart failure.
Background: The ONTARGET trial revealed an association of ACEI/ARB combination treatment (telmisartan and ramipril) with adverse renal outcome versus respective monotherapy; preclinical evidence regarding renal outcome in ACEI/ARB combination treatment is scarce.
Methods: Spontaneously hypertensive stroke prone rats (SHR-SP) rats on a salt-rich diet were randomly allocated to 4 groups: SHR (untreated, n = 24), SHR + telmisartan (SHR-T, 2.39 +/- 0.69 mg/kg bw; n = 27), SHR + ramipril (SHR-R, 6.28 +/- 3.48 mg/kg bw; n = 27) and combination treatment (SHR-TR, 0.51 +/- 0.14 mg/kg bw; same dose for telmisartan and ramipril; n = 26). Study duration was 12 weeks, blood pressure was assessed weekly and doses were adjusted to maintain equal blood pressure. Finally, blood and urine samples were obtained and kidneys were harvested for histological studies.
Results: Blood pressure in untreated rats rose to a maximum of 239 mmHg, whereas in all treatment groups it remained stable betvveen 140 and 150 mmHg. Mortality was 50% in the untreated group, whereas all treatment groups survived completely. Renal function - as indicated by plasma urea and cystatin c - was significantly worse in SHR-TR animals compared to all other groups. With plasma creatinine a similar trend was observed. All treatment options significantly decreased albuminuria. Renal glomerulosclerosis was decreased by monotherapy, whereas combination therapy failed to have a significant effect. Interstitial fibrosis was decreased to a similar extent by all treatment options.
Conclusions: ACEI/ARB combination treatment failed to render significant additional benefits on renal outcome in hypertensive rats when compared to monotherapy. Instead our data indicate that dual RAAS blockade might have an adverse effect on kidney function and histology when compared to monotherapy in salt-loaded SHR-SP.
Background: The renin-angiotensin-aldosterone system (RAAS) is involved in the pathogenesis of insulin resistance and type 2 diabetes in the general population. The RAAS is activated during pregnancy. However, it is unknown whether the RAAS contributes to glycemia in pregnant women.
Methods: Plasma renin activity (PRA) and plasma aldosterone levels were quantified at delivery in 689 Chinese mothers. An oral glucose tolerance test in fasted women was performed in the second trimester of pregnancy. The diagnosis of gestational diabetes mellitus (GDM) and impaired glucose tolerance during pregnancy were made according to the guidelines of the Chinese Society of Obstetrics.
Results: Plasma aldosterone was significantly higher in pregnant women with GDM as compared to those without impairment of glycemic control (normal pregnancies: 0.27 +/- 0.21 ng/mL, GDM: 0.36 +/- 0.30 ng/mL; p<0.05). Regression analyses revealed that PRA was negatively correlated with fasting blood glucose (FBG) (R-2 = 0.03, p = 0.007), whereas plasma aldosterone and aldosterone/PRA ratio were positively correlated with FBG (R-2 = 0.05, p<0.001 and R-2 = 0.03, p = 0.007, respectively). Multivariable regression analysis models considering relevant confounding factors confirmed these findings.
Conclusions: This study demonstrated that fasting blood glucose in pregnant women is inversely correlated with the PRA, whereas plasma aldosterone showed a highly significant positive correlation with fasting blood glucose during pregnancy. Moreover, plasma aldosterone is significantly higher in pregnant women with GDM as compared to those women with normal glucose tolerance during pregnancy. Although causality cannot be proven in association studies, these data may indicate that the RAAS during pregnancy contributes to the pathogenesis of insulin resistance/new onset of diabetes during pregnancy.
OBJECTIVE-BMI and albumin are commonly accepted parameters to recognize wasting in dialysis patients and are powerful predictors of morbidity and mortality. However, both parameters reveal limitations and may not cover the entire range of patients with wasting. The visceral protein transthyretin (TTR) may be helpful in overcoming the diagnostic and prognostic gap. Therefore, the aim of this study was to assess the association of TTR with morbidity and mortality in hemodialysis patients.
RESEARCH DESIGN AND METHODS-The TTR concentration was determined in plasma samples of 1,177 hemodialysis patients with type 2 diabetes. Cox regression analyses were used to determine hazard ratios (HRs) for the risk of cardiovascular end points (CVEs) and mortality according to quartiles of TTR concentration for the total study cohort and the subgroups BMI >= 23 kg/m(2), albumin concentration >= 3.8 g/dL, and a combination of both.
RESULTS-A low TTR concentration was associated with an increased risk for CVE for the total study cohort (HR 1.65 [95% CI 1.27-2.14]), patients with BMI >= 23 kg/m(2) (1.70 [1.22-2.37]), albumin >= 3.8 g/dL (1.68 [1.17-2.42]), and the combination of both (1.69 [1.13-2.53]). Additionally, a low TTR concentration predicted mortality for the total study cohort (1.79 [1.43-2.24]) and patients with BMI >= 23 kg/m(2) (1.46 [1.09-1.95]).
CONCLUSIONS-The current study demonstrated that TTR is a useful predictor for cardiovascular outcome and mortality in diabetic hemodialysis patients. TTR was particularly useful in patients who were not identified to be at risk by BMI or albumin status.