(DM) suggest that increased nitric oxide (NO) bioactivity contributes to renal hyperfiltration. However, the role of NO in mediating hyperfiltration has not been fully elucidated in humans. Our aim was to examine the effect of NO synthase inhibition on renal and peripheral vascular function in normotensive subjects with uncomplicated type 1 DM. Renal function and brachial artery flow-mediated vasodilatation (FMD) were measured before and after an intravenous infusion of the NO synthase inhibitor N G -nitro-Larginine methyl ester (L-NMMA) in 21 healthy control and 37 type 1 DM patients. Measurements in DM participants were made under clamped euglycemic conditions. The effect of L-NMMA on circulating and urinary NO metabolites (NOx) and cGMP and on urinary prostanoids was also determined. Baseline characteristics were similar in the two groups. For analysis, the DM patients were divided into those with hyperfiltration (DM-H, n ϭ 18) and normal glomerular filtration rate (GFR) levels (DM-N, n ϭ 19). Baseline urine NOx and cGMP were highest in DM-H. L-NMMA led to a decline in GFR in DM-H (152 Ϯ 16 to 140 Ϯ 11 ml·min Ϫ1 ·1.73 m Ϫ2 ) but not DM-N or healthy control participants. The decline in effective renal plasma flow in response to L-NMMA (806 Ϯ 112 to 539 Ϯ 80 ml·min Ϫ1 ·1.73 m Ϫ2 ) in DM-H was also exaggerated compared with the other groups (repeated measures ANOVA, P Ͻ 0.05), along with declines in urinary NOx metabolites and cGMP. Baseline FMD was lowest in DM-H compared with the other groups and did not change in response to L-NMMA. L-NMMA reduced FMD and plasma markers of NO bioactivity in the healthy control and DM-N groups. In patients with uncomplicated type 1 DM, renal hyperfiltration is associated with increased NO bioactivity in the kidney and reduced NO bioactivity in the systemic circulation, suggesting a paradoxical state of high renal and low systemic vascular NO bioactivity. endothelial function; hyperfiltration; nitric oxide; type 1 diabetes GLOMERULAR HYPERFILTRATION is an early renal hemodynamic change in animal and human studies of diabetes mellitus (DM) and may help to predict the risk for the subsequent development of diabetic nephropathy (38). The pathogenesis of hyperfiltration is complex and involves both tubuloglomerular feedback and hemodynamic abnormalities. Renal hemodynamic changes associated with hyperfiltration include afferent vasodilatation and efferent constriction. Hyperfiltration is, however, only partially corrected after selective cyclooxygenase-2 inhibition (predominant afferent constriction) or renin angiotensin system (RAS) blockade (predominant efferent vasodilatation) in humans with uncomplicated type 1 DM (8, 54). These findings suggest the presence of nonprostaglandin, non-RAS-dependent hemodynamic mechanisms that perpetuate the hyperfiltration state (60).Functional expression studies in DM models have determined that endothelial nitric oxide (NO) synthase (eNOS) expression is consistently upregulated and localized to the afferent arteriole, renal cortex, and medull...

OBJECTIVEDiabetes is associated with renin-angiotensin system (RAS) activation, leading to renal and systemic vascular dysfunction that contribute to end-organ injury and significant morbidity. RAS blockade with ACE inhibitors reduces, but does not abolish, RAS effects. Accordingly, our aim was to determine if direct renin inhibition alone, and in combination with an ACE inhibitor, corrects early hemodynamic abnormalities associated with type 1 diabetes.RESEARCH DESIGN AND METHODSArterial stiffness (augmentation index), flow-mediated vasodilatation (FMD), and renal hemodynamic function (inulin and paraaminohippurate clearance) were measured at baseline under clamped euglycemic and hyperglycemic conditions (n = 21). Measures were repeated after 4 weeks of aliskiren therapy and again after aliskiren plus ramipril.RESULTSBlood pressure–lowering effects of aliskiren were similar during clamped euglycemia and hyperglycemia. Combination therapy augmented this effect under both glycemic conditions (P = 0.0005). Aliskiren reduced arterial stiffness under clamped euglycemic and hyperglycemic conditions, and the effects were augmented by dual RAS blockade (−3.4 ± 11.2 to −8.0 ± 11.5 to −14.3 ± 8.4%, respectively, during euglycemia, P = 0.0001). During clamped euglycemia, aliskiren increased FMD; dual therapy exaggerated this effect (5.1 ± 3.3 to 7.5 ± 3.0 to 10.8 ± 3.5%, repeated-measures ANOVA, P = 0.0001). Aliskiren monotherapy caused renal vasodilatation during clamped hyperglycemia only. In contrast, dual therapy augmented renal vasodilatory effects during clamped euglycemia and hyperglycemia.CONCLUSIONSIn patients with uncomplicated type 1 diabetes, aliskiren-based dual RAS blockade is associated with greater arterial compliance, FMD, and renal vasodilatation.

Six new 16-membered macrolides with a rare branched octose unit, aldgamycins J-O (1-6), along with two known compounds, swalpamycin B (7) and chalcomycin (8), were isolated from Streptomyces sp. HK-2006-1. Their structures were determined by detailed spectroscopic and X-ray crystallographic analysis. Natural products containing branched sugar units are rare. Aldgaropyranose and decarboxylated aldgaropyranose are branched octoses, specifically aldgarose-type branched octose. Until now, only 11 compounds have been reported to contain an aldgarose-type branched octose. The discovery of aldgamycins J-O (1-6) adds new members of this type of natural product. All the compounds (1-8) herein were tested for antimicrobial activities against Gram-positive Staphylococcus aureus 209P, Gram-negative Escherichia coli ATCC0111, and two fungi, Candida albicans FIM709 and Aspergillus niger R330. Most of these compounds showed antibacterial activity against S. aureus. Their preliminary structure-activity relationships are proposed.

Two new phenolic glucosides, hostaflavanone A (1) and anti-1-phenylpropane-1,2-diol-2-O-β-d-glucopyranoside (2), together with six known compounds, anti-1-phenylpropane-1,2-diol (3), phenethyl-O-β-d-glucopyranoside (4), phenethanol-β-d-gentiobioside (5), phenethyl-O-rutinoside (6), (1S, 3S)-1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (7), and (1R, 3S)-1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (8), were isolated from the flower of Hosta plantaginea, and their structures were elucidated by nuclear magnetic resonance (NMR), high resolution electrospray ionization mass spectroscopy (HRESIMS), and circular dichroism (CD) analyses. The cyclooxygenases (COX-1 and COX-2) inhibition and antioxidant activities of compounds 1 and 4–6 were investigated, and they showed moderate cyclooxygenases inhibition activities. Moreover, only compound 1 exhibited moderate antioxidant activity, with an IC50 value of 83.2 μM, while 4–6 showed insignificant activity with IC50 values of 282, 257, and 275 μM, respectively. This is the first report of compounds 3 and 5–8 from the Liliaceae family. The chemotaxonomic significance of the isolated compounds was also summarized.

Background: Knowledge about expected insulin requirements during pregnancy, in women with pre-existing diabetes may assist clinicians to effectively respond to gestation-specific changes in glycemic pattern. Few studies have examined differences between type 1 (T1DM) and type 2 diabetes (T2DM). Aims: To compare patterns of insulin requirements in pregnancy for women with pre-existing T1DM and T2DM. Women with T1DM had a net fall in insulin requirements (3.7% in the first trimester and 4.1% in the late third trimester) while those with T2DM did not. Conclusions: This is the largest comparison study of insulin requirements in women with pre-existing diabetes, highlighting important trimester-specific differences between T1DM and T2DM to guide insulin titration during pregnancy. Our findings suggest a differential effect of pregnancy-mediated insulin resistance by type of diabetes.

Endoplasmic reticulum (ER) stress is highly associated with liver steatosis. B-cell receptor-associated protein 31 (BAP31) has been reported to be involved in ER homeostasis, and plays key roles in hepatic lipid metabolism in high-fat diet-induced obese mice. However, whether BAP31 modulates hepatic lipid metabolism via regulating ER stress is still uncertain. In this study, wild-type and liver-specific BAP31-depleted mice were administrated with ER stress activator of Tunicamycin, the markers of ER stress, liver steatosis, and the underlying molecular mechanisms were determined. BAP31 deficiency increased Tunicamycin-induced hepatic lipid accumulation, aggravated liver dysfunction, and increased the mRNA levels of ER stress markers, including glucose-regulated protein 78 (GRP78), X-box binding protein 1 (XBP1), inositol-requiring protein-1α (IRE1α) and C/EBP homologous protein (CHOP), thus promoting ER stress in vivo and in vitro. Hepatic lipid export via very low-density lipoprotein (VLDL) secretion was impaired in BAP31-depleted mice, accompanied by reduced Apolipoprotein B (APOB) and microsomal triglyceride transfer protein (MTTP) expression. Exogenous lipid clearance was also inhibited, along with impaired gene expression related to fatty acid transportation and fatty acid β-oxidation. Finally, BAP31 deficiency increased Tunicamycin-induced hepatic inflammatory response. These results demonstrate that BAP31 deficiency increased Tunicamycin-induced ER stress, impaired VLDL secretion and exogenous lipid clearance, and reduced fatty acid β-oxidation, which eventually resulted in liver steatosis.

Islet transplantation is one of the most promising therapeutic options that could restore euglycaemia in type 1 diabetic individuals.

Within our population, of women who are not currently treated for GDM, obesity is associated with greater pregnancy risk than GDM diagnosed by IADPSG criteria.