RESUMO
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 ß-cell dysfunction, since extracellular signal of these monoamines decreases GSIS. Moreover, palmitate-treated ß-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 ß-cell was determined. Lower Maob expression was found in islets from db/db versus WT mice and in MIN6 ß-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 ß-cells. In conclusion, known defects of GSIS in islets from db/db mice and MIN6 ß-cells treated with NEFAs are accompanied by reduced Maob expression and reduced 5HT content.
Assuntos
Células Secretoras de Insulina/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Transcriptoma/genética , Acetilserotonina O-Metiltransferasa/efeitos dos fármacos , Acetilserotonina O-Metiltransferasa/genética , Animais , Arilalquilamina N-Acetiltransferase/efeitos dos fármacos , Arilalquilamina N-Acetiltransferase/genética , Catecol O-Metiltransferase/efeitos dos fármacos , Catecol O-Metiltransferase/genética , Linhagem Celular , Dopa Descarboxilase/efeitos dos fármacos , Dopa Descarboxilase/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Dopamina beta-Hidroxilase/efeitos dos fármacos , Dopamina beta-Hidroxilase/genética , Insulina/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Camundongos , Monoaminoxidase/efeitos dos fármacos , Monoaminoxidase/genética , Ácido Oleico/farmacologia , Ácido Palmítico/farmacologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Transcriptoma/efeitos dos fármacos , Triptofano Hidroxilase/efeitos dos fármacos , Triptofano Hidroxilase/genética , Tirosina 3-Mono-Oxigenase/efeitos dos fármacos , Tirosina 3-Mono-Oxigenase/genéticaRESUMO
Pancreatic beta cells sense glucose flux and release as much insulin as required in order to maintain glycaemia within a narrow range. Insulin secretion is regulated by many factors including glucose, incretins, and sympathetic and parasympathetic tones among other physiological factors. To identify the mechanisms linking obesity-related insulin resistance with impaired insulin secretion represents a central challenge. Recently, it has been argued that a crosstalk between skeletal muscle and the pancreas may regulate insulin secretion. Considering that skeletal muscle is the largest organ in non-obese subjects and a major site of insulin- and exercise-stimulated glucose disposal, it appears plausible that muscle might interact with the pancreas and modulate insulin secretion for appropriate peripheral intracellular glucose utilization. There is growing evidence that muscle can secrete so-called myokines that can have auto/para/endocrine actions. Although it is unclear in which direction they act, interleukin-6 seems to be a possible muscle-derived candidate protein mediating such inter-organ communication. We herein review some of the putative skeletal muscle-derived factors mediating this interaction. In addition, the evidence coming from in vitro, animal and human studies that support such inter-organ crosstalk is thoroughly discussed.