ORIGINAL ARTICLE Variations in adrenal gland medulla and dopamine effects induced by the lack of Irs2 Leonardo Catalano-Iniesta 1,2,3 & María Carmen Iglesias-Osma 1,2,3 & Virginia Sánchez-Robledo 1,2,3 & Marta Carretero-Hernández 2,3,4 & Enrique J. Blanco 2,3,4 & José Carretero 2,3,4 & María José García-Barrado 1,2,3 Received: 20 December 2017 /Accepted: 18 October 2018 /Published online: 26 October 2018 # University of Navarra 2018 Abstract The adrenomedullary chromaffin cells’ hormonal pathway has been related to the pathophysiology of diabetes mellitus. In mice, the deletion of insulin receptor substrate type 2 (Irs2) causes peripheral insulin resistance and reduction in β-cell mass, leading to overt diabetes, with gender differences on adrenergic signaling. To further unravel the relevance of Irs2 on glycemic control, we analyzed in adult Irs2 deficient (Irs2 -/- ) mice, of both sexes but still normoglycemic, dopamine effects on insulin secretion and glycerol release, as well as their adrenal medulla by an immunohistochemical and morphologic approach. In isolated islets, 10 μM dopamine significantly inhibited insulin release in wild-type (WT) and female Irs2 -/- mice; however, male Irs2 -/- islets were insensitive to that catecholamine. Similarly, on isolated adipocytes, gender differences were observed between WT and Irs2 -/- mice in basal and evoked glycerol release with crescent concentrations of dopamine. By immunohistochemistry, reactivity to tyrosine hydroxylase (TH) in female mice was significantly higher in the adrenal medulla of Irs2 -/- compared to WT; although no differences for TH-immunopositivity were observed between the male groups of mice. However, compared to their corre- sponding WT animals, adrenomedullary chromaffin cells of Irs2 -/- mice showed a significant decrease in the cellular and nuclear areas, and even in their percentage of apoptosis. Therefore, our observations suggest that, together with gender differences on dopamine responses in Irs2 -/- mice, disturbances in adrenomedullary chromaffin cells could be related to deficiency of Irs2. Accordingly, Irs2 could be necessary for adequate glucose homeostasis and maintenance of the population of the adrenomedullary chromaffin cells. Keywords Adrenal chromaffin cells . Adipocytes . Apoptosis . Beta-cells . Dopamine . Glycerol release . Insulin secretion Proliferation . Tyrosine hydroxylase Introduction Insulin and insulin growth factor of type 1 (IGF-1) have neu- rotrophic activity at the central and peripheral nervous system, including the autonomic sympathetic system [10]. The bind- ing of these hormones to their tyrosine kinase receptors acti- vates the phosphorylation of specific insulin receptor substrate (Irs) proteins, mainly Irs1 and Irs2. These proteins are expressed ubiquitously in mammalian cells and trigger intra- cellular signaling pathways that mediate trophic effects and regulate glucose homeostasis [6, 36, 39]. Interestingly, mice lacking the insulin receptor substrate type 2 (Irs2 -/- ) display a combination of peripheral insulin resistance and pancreatic β-cell dysfunction that culminates in diabetes [5]. Moreover, the diabetic phenotype that appears after Irs2 deletion shows sexual dimorphism. Indeed, the Irs2 -/- male mice often die of diabetic complications by Leonardo Catalano-Iniesta, María Carmen Iglesias-Osma, José Carretero and María José García-Barrado contributed equally to this work. * María José García-Barrado barrado@usal.es 1 Department of Physiology and Pharmacology, INCyL and IBSAL, Faculty of Medicine, University of Salamanca, Avda. Alfonso X el Sabio, s/n, E-37007 Salamanca, Spain 2 Laboratory of Neuroendocrinology, Institute of Neurosciences of Castilla y León (INCyL), University of Salamanca, Salamanca, Spain 3 Laboratory of Neuroendocrinology and Obesity, Institute of Biomedical Research of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain 4 Department of Human Anatomy and Histology, Faculty of Medicine, University of Salamanca, Salamanca, Spain Journal of Physiology and Biochemistry (2018) 74:667–677 https://doi.org/10.1007/s13105-018-0655-8