The role of insulin at brain-liver axis in the control of glucose production.

Glucose is an essential metabolic substrate for all mammalian cells, and its availability in the circulation is carefully controlled to avoid wide variations. Different mechanisms are involved in the glucose disposal, such as an adequate pancreatic and hepatic function. Insulin is the main hormone in glycemic control, and its action occurs directly in the cells, as well as in the liver, in an indirect way, to ultimately control the glycemia. Insulin has also an important action within the central nervous system, more precisely in the hypothalamus that projects directly to preautonomic nuclei in the brain stem to control hepatic glucose production. The central action of insulin relies on autonomic outflow through the vagal innervation of the liver, where insulin is able to modulate the production of glucose at this organ level. In this way, responses generated in the CNS reach the effector organs by autonomic efferent pathways as part of an important brain-organ axis in the control of glycemia. The purpose of this minireview is to shed light on the brain-liver axis in the control of hepatic glucose by central action of insulin via the autonomic nervous system.

Protein disulfide isomerase-mediated transcriptional upregulation of Nox1 contributes to vascular dysfunction in hypertension.

Nox1 signaling is a causal key element in arterial hypertension. Recently, we identified protein disulfide isomerase A1 (PDI) as a novel regulatory protein that regulates Nox1 signaling in VSMCs. Spontaneously hypertensive rats (SHR) have increased levels of PDI in mesenteric resistance arteries compared with Wistar controls; however, its consequences remain unclear. Herein, we investigated the role of PDI in mediating Nox1 transcriptional upregulation and its effects on vascular dysfunction in hypertension. We demonstrate that PDI contributes to the development of hypertension via enhanced transcriptional upregulation of Nox1 in vascular smooth muscle cells (VSMCs). We show for the first time that PDI sulfenylation by hydrogen peroxide contributes to EGFR activation in hypertension via increased shedding of epidermal growth factor-like ligands. PDI also increases intracellular calcium levels, and contractile responses induced by ANG II. PDI silencing or pharmacological inhibition in VSMCs significantly decreases EGFR activation and Nox1 transcription. Overexpression of PDI in VSMCs enhances ANG II-induced EGFR activation and ATF1 translocation to the nucleus. Mechanistically, PDI increases ATF1-induced Nox1 transcription and enhances the contractile responses to ANG II. Herein we show that ATF1 binding to Nox1 transcription putative regulatory regions is augmented by PDI. Altogether, we provide evidence that HB-EGF in SHR resistance vessels promotes the nuclear translocation of ATF1, under the control of PDI, and thereby induces Nox1 gene expression and increases vascular reactivity. Thus, PDI acts as a thiol redox-dependent enhancer of vascular dysfunction in hypertension and could represent a novel therapeutic target for the treatment of this disease.