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Intermittent fasting has become of interest for its possible metabolic benefits and reduction of inflammation and oxidative damage, all of which play a role in the pathophysiology of diabetic nephropathy. We tested in a streptozotocin (60 mg/kg)-induced diabetic apolipoprotein E knockout mouse model whether repeated fasting mimicking diet (FMD) prevents glomerular damage. Diabetic mice received 5 FMD cycles in 10 wk, and during cycles 1 and 5 caloric measurements were performed. After 10 wk, glomerular endothelial morphology was determined together with albuminuria, urinary heparanase-1 activity, and spatial mass spectrometry imaging to identify specific glomerular metabolic dysregulation. During FMD cycles, blood glucose levels dropped while a temporal metabolic switch was observed to increase fatty acid oxidation. Overall body weight at the end of the study was reduced together with albuminuria, although urine production was dramatically increased without affecting urinary heparanase-1 activity. Weight loss was found to be due to lean mass and water, not fat mass. Although capillary loop morphology and endothelial glycocalyx heparan sulfate contents were preserved, hyaluronan surface expression was reduced together with the presence of UDP-glucuronic acid. Mass spectrometry imaging further revealed reduced protein catabolic breakdown products and increased oxidative stress, not different from diabetic mice. In conclusion, although FMD preserves partially glomerular endothelial glycocalyx, loss of lean mass and increased glomerular oxidative stress argue whether such diet regimes are safe in patients with diabetes. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide-1-based (GLP-1-based) therapies improve glycemic control in patients with type 2 diabetes. While these agents augment insulin secretion, they do not mimic the physiological meal-related rise and fall of GLP-1 concentrations. Here, we tested the hypothesis that increasing the number of intestinal L cells, which produce GLP-1, is an alternative strategy to augment insulin responses and improve glucose tolerance. Blocking the NOTCH signaling pathway with the γ- secretase inhibitor dibenzazepine increased the number of L cells in intestinal organoid-based mouse and human culture systems and augmented glucose-stimulated GLP-1 secretion. In a high-fat diet-fed mouse model of impaired glucose tolerance and type 2 diabetes, dibenzazepine administration increased L cell numbers in the intestine, improved the early insulin response to glucose, and restored glucose tolerance. Dibenzazepine also increased K cell numbers, resulting in increased gastric inhibitory polypeptide (GIP) secretion. Using a GLP-1 receptor antagonist, we determined that the insulinotropic effect of dibenzazepine was mediated through an increase in GLP-1 signaling. Together, our data indicate that modulation of the development of incretin- producing cells in the intestine has potential as a therapeutic strategy to improve glycemic control., Introduction Glucagon-like peptide-1 (GLP-1) is a gut hormone with a powerful insulinotropic effect (1, 2). GLP-1 based therapies are widely used for the treatment of patients with type 2 diabetes [...]

Vascular endothelium is covered with an extensive mesh of glycocalyx constituents, which acts like an effective barrier up to several micrometers thick that shields the luminal surface of the vasculature from direct exposure to flowing blood. Many studies report that various enzymatic and pharmaceutical challenges are able to increase glycocalyx porosity, resulting in farther permeation of plasma macromolecules and greater access of red blood cells into glycocalyx domain. Attenuation of glycocalyx barrier properties therefore potentially increases the amount of blood that effectively occupies available microvascular volume. We tested in the present study whether attenuation of coronary glycocalyx barrier properties actually increases coronary blood volume and whether such changes would be noticeable during measurements of coronary flow reserve using adenosine. In anesthetized goats (n = 6) with cannulated left main coronary artery that were perfused under controlled pressure, coronary blood volume was measured via the indicator-dilution technique using high-molecular-weight (2,000 kDa) dextrans as plasma tracer and labeled red blood cells as red blood cell tracer. Coronary blood volume was determined at baseline and during intracoronary infusion of adenosine causing maximal vasodilation (0.2-0.6 mg'*[kg.sup.-]*[h.sup.-1]) before and after intracoronary hyaluronidase treatment (170,000 units) of the glycocalyx. With an intact glycocalyx, coronary blood volume was 18.9 [+ or -] 1.1 ml/100 g heart tissue at baseline, which increased to 26.3 [+ or -] 2.7 ml/100 g after hyaluronidase treatment of the coronary glycocalyx. Maximal vasodilation by administration of adenosine further increased coronary blood volume to 33.9 [+ or -] 6.8 ml/100 g, a value not different from the maximal coronary blood volume of 33.2 [+ or -] 5.3 ml/100 g obtained by administration of adenosine in the absence of hyaluronidase treatment. Adenosine-induced increases in coronary conductance were not affected by hyaluronidase treatment. We conclude that acute attenuation of glycocalyx barrier properties increases coronary blood volume by ~40%, which is of similar magnitude as additional changes in coronary blood volume during subsequent maximal vasodilation with adenosine. Furthermore, maximal coronary blood volume following administration of adenosine was similar with and without prior hyaluronidase degradation of the glycocalyx, suggesting that adenosine and hyaluronidase potentially increase glycocalyx porosity to a similar extent. Hyaluronidase-mediated changes in coronary blood volume did not affect baseline and adenosine-induced increases in coronary conductance, demonstrating that measurements of coronary flow reserve are insufficient to detect impairment of coronary blood volume recruitment in conditions of damaged glycocalyx. adenosine; blood flow; coronary circulation; indicator-dilution doi: 10.1152/ajpheart.01306.2008.

It was hypothesized that endothelial glycocalyx perturbation contributes to increased vulnerability of the arterial wall exposed to atherogenic risk factors. Glycocalyx and intima-to-media ratios (IMR) were studied at a low- and a high-risk region within the murine carotid artery (common region) and internal carotid branch (sinus region) in control C57BL/6J (C57BL6) and age-matched C57BL/6J/apoE*3-Leiden (apoE*3; on an atherogenic diet) mice. Electron micrographs revealed significantly thinner glycocalyces [73 (SD 36) vs. 399 (SD 174) nm, P < 0.05] and greater IMR [0.096 (SD 0.045) vs. 0.044 (SD 0.023), P < 0.05] at the sinus region of C57BL6 mice than in the common region. Thinner glycocalyces [100 (SD 27) vs. 399 (SD 174) nm, P < 0.05] and greater IMR [0.071 (SD 0.024) vs. 0.044 (SD 0.023), P < 0.05] were also observed in the common region of age-matched apoE*3 mice on an atherogenic diet for 6 wk vs. C57BL6 mice on a normal diet. Greater IMR were due to greater intima layers, without significant changes in media layer dimension. In addition, atherogenic diet resulted in increased endothelial cell thickness at the sinus region [0.85 (SD 0.49) vs. 0.53 (SD 0.28) [micro]m, P < 0.05] but not at the common region [0.66 (SD 0.37) vs. 0.62 (SD 0.32) [micro]m]. It is concluded that both regional and diet-induced increases in atherogenic risk are associated with smaller glycocalyx dimensions and greater IMR and that vascular sites with diminished glycocalyx are more vulnerable to proinflammatory and atherosclerotic sequelae. flow; permeability

Syndecan-4, a model proteoglycan to study endothelial glycocalyx mechanosensing and signal transduction In the present issue of I Acta Physiologica i , Jiang, et al[1] tested how the endothelial glycocalyx transmits the blood flow shear stress to the cytoskeleton. In a series of large-scale molecular dynamics computational experiments the dynamics of the proteoglycan syndecan-4 force transmission is examined under varying conditions, that is, blood flow velocity changes and proteoglycan sugar chain shedding. Within the current article focusing on syndecan-4, the authors build further on the published all-atom glycocalyx model[15] to scrutinize the dynamics of this particular proteoglycan within the endothelial glycocalyx using direct simulation and molecular dynamics modelling. [Extracted from the article]