BACKGROUND AND PURPOSE Quercetin lowers plasma glucose, normalizes glucose tolerance tests and preserves pancreatic β‐cell integrity in diabetic rats. However, its mechanism of action has never been explored in insulin‐secreting β‐cells. Using the INS‐1 β‐cell line, the effects of quercetin were determined on glucose‐ or glibenclamide‐induced insulin secretion and on β‐cell dysfunctions induced by hydrogen peroxide (H₂O₂). These effects were analysed along with the activation of the extracellular signal‐regulated kinase (ERK)1/2 pathway. N‐acetyl‐L‐cysteine (NAC) and resveratrol, two antioxidants also known to exhibit some anti‐diabetic properties, were used for comparison.EXPERIMENTAL APPROACH Insulin release was quantified by the homogeneous time resolved fluorescence method and ERK1/2 activation tested by Western blot experiments. Cell viability was estimated by the [3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide] (MTT) colorimetric assay.KEY RESULTS Quercetin (20 µmol·L⁻¹) potentiated both glucose (8.3 mmol·L⁻¹)‐ and glibenclamide (0.01 µmol·L⁻¹)‐induced insulin secretion and ERK1/2 phosphorylation. The ERK1/2 (but not the protein kinase A) signalling pathway played a crucial role in the potentiation of glucose‐induced insulin secretion by quercetin. In addition, quercetin (20 µmol·L⁻¹), protected β‐cell function and viability against oxidative damage induced by 50 µmol·L⁻¹ H₂O₂ and induced a major phosphorylation of ERK1/2. In the same conditions, resveratrol or NAC were ineffective.CONCLUSION AND IMPLICATIONS Quercetin potentiated glucose and glibenclamide‐induced insulin secretion and protected β‐cells against oxidative damage. Our study suggested that ERK1/2 played a major role in those effects. The potential of quercetin in preventing β‐cell dysfunction associated with diabetes deserves further investigation.

The endothelin system has emerged as a novel target for the treatment of diabetic nephropathy. Endothelin-1 promotes mesangial cell proliferation and sclerosis. However, no direct pathogenic effect of endothelin-1 on podocytes has been shown in vivo and endothelin-1 signaling in podocytes has not been investigated. This study investigated endothelin effects in podocytes during experimental diabetic nephropathy. Stimulation of primary mouse podocytes with endothelin-1 elicited rapid calcium transients mediated by endothelin type A receptors (ETARs) and endothelin type B receptors (ETBRs). We then generated mice with a podocyte-specific double deletion of ETAR and ETBR (NPHS2-Cre×Ednra(lox/lox)×Ednrb(lox/lox) [Pod-ETRKO]). In vitro, treatment with endothelin-1 increased total β-catenin and phospho-NF-κB expression in wild-type glomeruli, but this effect was attenuated in Pod-ETRKO glomeruli. After streptozotocin injection to induce diabetes, wild-type mice developed mild diabetic nephropathy with microalbuminuria, mesangial matrix expansion, glomerular basement membrane thickening, and podocyte loss, whereas Pod-ETRKO mice presented less albuminuria and were completely protected from glomerulosclerosis and podocyte loss, even when uninephrectomized. Moreover, glomeruli from normal and diabetic Pod-ETRKO mice expressed substantially less total β-catenin and phospho-NF-κB compared with glomeruli from counterpart wild-type mice. This evidence suggests that endothelin-1 drives development of glomerulosclerosis and podocyte loss through direct activation of endothelin receptors and NF-κB and β-catenin pathways in podocytes. Notably, both the expression and function of the ETBR subtype were found to be important. Furthermore, these results indicate that activation of the endothelin-1 pathways selectively in podocytes mediates pathophysiologic crosstalk that influences mesangial architecture and sclerosis.

Sulfonylureas are a class of drugs commonly used in the management of non-insulin-dependent diabetes mellitus. Their therapeutic action results primarily from their ability to inhibit ATP-sensitive potassium (KATP) channels in the plasma membrane of pancreatic beta cells and thereby stimulate insulin release. A key question is whether an endogenous ligand for the KATP channel exists that is able to mimic the inhibitory effects of sulfonylureas. We describe here the cloning of the cDNA encoding human alpha-endosulfine, a 13-kDa peptide that is a putative candidate for such a role. alpha-Endosulfine is expressed in a wide range of tissues including muscle, brain, and endocrine tissues. The recombinant protein displaces binding of the sulfonylurea [3H]glibenclamide to beta cell membranes, inhibits cloned KATP channel currents, and stimulates insulin secretion. We propose that endosulfine is an endogenous regulator of the KATP channel, which has a key role in the control of insulin release and, more generally, couples cell metabolism to electrical activity.

Terlipressin has been proposed as an alternative treatment to catecholamines to restore blood pressure in septic shock. Terlipressin is considered as a vasopressin prodrug capable of releasing small but sustained amounts of [Lysine] vasopressin (LVP) and to provide prolonged biological effect. However, terlipressin may act as a direct vasopressor beyond its conversion into LVP. We investigated terlipressin direct vasoconstrictive properties and consequences on myocardial perfusion and performance. Experimental studies. National Research Institute Laboratories. Rat aorta and heart, human uterine artery. Studies of vasoconstriction on isolated vascular rings obtained either from rat aorta or human uterine artery, and of coronary flow, ventricular performance, and heart rhythm on rat hearts using a modified Langendorff heart apparatus. Terlipressin induced a rapid, saturable, and dose-dependent contraction of rat aortas and human uterine arteries. Although the maximal terlipressin-induced vasoconstriction observed on rat arteries was weaker than LVP, or arginine-vasopressin, pharmacologic properties on human arteries, such as full agonism and strong maximal effect (900% of the maximal response obtained with phenylephrine), suggest a high potential of terlipressin to directly vasoconstrict human vessels. Similarly, terlipressin induced a saturable and dose-dependent vasoconstriction of coronary arteries that was reversible and antagonized by selective V1a antagonists. Maximum rates of left ventricle pressure rise (dP/dtmax) and fall (dP/dtmin) decreased both only in proportion to the decrease in coronary flow. Besides long lasting effect through slow conversion into LVP, terlipressin is a fast acting vasopressor peptide per se that has an impact on coronary circulation and myocardial function.