Serotonin- and Dopamine-Related Gene Expression in db/db Mice Islets and in MIN6 β-Cells Treated with Palmitate and Oleate.

L R Cataldo,D Mezzano,M L Mizgier,D Busso,E Aranda,V A Cortés,P Olmos,J E Galgani,J L Santos,R Valenzuela

doi:10.1155/2016/3793781

Abstract

High circulating nonesterified fatty acids (NEFAs) concentration, often reported in diabetes, leads to impaired glucose-stimulated insulin secretion (GSIS) through not yet well-defined mechanisms. Serotonin and dopamine might contribute to NEFA-dependent β-cell dysfunction, since extracellular signal of these monoamines decreases GSIS. Moreover, palmitate-treated β-cells may enhance the expression of the serotonin receptor Htr2c, affecting insulin secretion. Additionally, the expression of monoamine-oxidase type B (Maob) seems to be lower in islets from humans and mice with diabetes compared to nondiabetic islets, which may lead to increased monoamine concentrations. We assessed the expression of serotonin- and dopamine-related genes in islets from db/db and wild-type (WT) mice. In addition, the effect of palmitate and oleate on the expression of such genes, 5HT content, and GSIS in MIN6 β-cell was determined. Lower Maob expression was found in islets from db/db versus WT mice and in MIN6 β-cells in response to palmitate and oleate treatment compared to vehicle. Reduced 5HT content and impaired GSIS in response to palmitate (−25%; p < 0.0001) and oleate (−43%; p < 0.0001) were detected in MIN6 β-cells. In conclusion, known defects of GSIS in islets from db/db mice and MIN6 β-cells treated with NEFAs are accompanied by reduced Maob expression and reduced 5HT content.

Highlights

Both insulin resistance and β-cell failure are involved in the etiology of type-2 diabetes (DM2) phenotype [1]
It is known that db/db mice islets have functional defects and increased compensatory β-cell mass [40,41,42]; in agreement we observed a higher size in islets from db/db compared to WT mice
We have shown that islets from WT and db/db mice expressed mRNAs of most genes related to the serotonin and dopamine metabolism, including enzymes involved in the synthesis (Tph1/2, Tyrosine hydroxylase (TH), and Ddc), vesicular transport (Slc18a1/2-VMAT1/2), and degradation (Maoa, monoamine-oxidase type B (Maob), and Comt) of these monoamines

Summary

Introduction

Both insulin resistance and β-cell failure are involved in the etiology of type-2 diabetes (DM2) phenotype [1]. Lipid infusion in nondiabetic subjects leading to circulating NEFAs levels similar to those found in diabetic people (500–800 μM) decreased glucose-stimulated insulin secretion (GSIS) [7]. Several in vitro studies have demonstrated that long-term exposure of β-cells lines and murine islets to palmitic (C16:0) and oleic (C18:1) acids leads to impaired GSIS [5, 8,9,10]. Other studies have explained impaired GSIS as a consequence of excessive production of radical oxygen species (ROS), which is dependent on mitochondrial fatty acid metabolism [9]. These mechanisms do not fully explain such decreased GSIS, and alternative mechanisms may be taking place

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