Tumor necrosis factor alpha abolished the suppressive effect of insulin on hepatic glucose production and glycogenolysis stimulated by cAMP.

BACKGROUND: Tumor necrosis factor alpha (TNFα) is implicated in the development of insulin resistance in obesity, type 2 diabetes and cancer. However, its ability to modulate the action of insulin on glycogen catabolism in the liver is controversial. The aim of the present study was to investigate whether TNFα acutely affects the suppression by insulin of hepatic glucose production (HGP) and glycogenolysis stimulated by cyclic adenosine monophosphate (cAMP). METHODS: TNFα (10 µg/kg) was injected intravenously to rats and, 1 or 6h later, their livers were subjected to in situ perfusion with cAMP (3 µM), in the presence or absence of physiological (20 µU/mL) or supraphysiological (500 µU/mL) concentrations of insulin. RESULTS: The injection of TNFα, 1 or 6h before liver perfusion, had no direct effect on the action of cAMP in stimulating HGP and glycogenolysis. However, when TNFα was injected 1h, but not 6h, before liver perfusion it completely abolished (p<0.05) the suppressive effect of 20 µU/mL insulin on HGP and glycogenolysis stimulated by cAMP. Furthermore, the injection of TNFα 1h or 6h before liver perfusion did not influence the suppression of cAMP-stimulated HGP and glycogenolysis by 500 µU/mL insulin. CONCLUSION: TNFα acutely abolished the suppressive effect of physiological, but not supraphysiological, levels of insulin on HGP and glycogenolysis stimulated by cAMP, suggesting an important role of this mechanism to the increased HGP in several pathological states.

Changes in calcium fluxes in mitochondria, microsomes, and plasma membrane vesicles of livers from monosodium L-glutamate-obese rats.

The purpose of this work was to evaluate if the fat liver accumulation interferes with intracellular calcium fluxes and the liver glycogenolytic response to a calcium-mobilizing α(1)-adrenergic agonist, phenylephrine. The animal model of monosodium L-glutamate (MSG)-induced obesity was used. The adult rats develop obesity and steatosis. Calcium fluxes were evaluated through measuring the (45)Ca(2+) uptake by liver microsomes, inside-out plasma membrane, and mitochondria. In the liver, assessments were performed on the calcium-dependent glycogenolytic response to phenylephrine and the glycogen contents. The Ca(2+) uptake by microsomes and plasma membrane vesicles was reduced in livers from obese rats as a result of reduction in the Ca(2+)-ATPase activities. In addition, the plasma membrane Na(+)/K(+)-ATPase was reduced. All these matched effects could contribute to elevated resting intracellular calcium levels in the hepatocytes. Livers from obese rats, albeit smaller and with similar glycogen contents to those of control rats, released higher amounts of glucose in response to phenylephrine infusion, which corroborates these observations. Mitochondria from obese rats exhibited a higher capacity of retaining calcium, a phenomenon that could be attributed to a minor susceptibility of the mitochondrial permeability transition pore opening.

Respostas neuroendócrinas à inanição em equinos / Equine neuroendocrine responses to starvation

O equino saudável pode tolerar a inanição simples por 24 a 72 horas sem alterações sistêmicas. Com a redução da concentração sanguínea de glicose, a concentração de insulina diminui e a demanda energética é fornecida inicialmente pela glicogenólise, resultante do aumento da quebra dos estoques de glicogênio hepático. Com a progressão da inanição, o glicogênio é mobilizado a partir de outros tecidos, incluindo o muscular. A mobilização de lipídeos é disparada por alterações na concentração plasmática de insulina e glucagon, além da atividade da lípase sensível a hormônio. O perfil clássico da resposta hormonal à inanição inclui elevação da concentração plasmática de glicocorticóides, catecolaminas, grelina, glucagon e hormônio do crescimento, além da redução da concentração de insulina, gonadotrofinas, leptina e hormônios da tireóide. Esta resposta hormonal atua como um estímulo aferente para o início de uma resposta hipotalâmica à inanição resultando em redução do gasto energético e metabolismo.

The healthy adult horse can tolerate simple starvation for 24 to 72 hours with little systemic effect. A decline in blood glucose concentration occurs with starvation, insulin level fall, and energy demand are supplied initially by glycogenolysis, resulting in an increase the breakdown of liver glycogen stores. As starvation progresses, glycogen is mobilized from other tissues, including the muscle. Lipid mobilization is triggered by alterations in insulin and glucagon concentrations and the activity of hormone-sensitive lipase. The classic profile of hormonal response to starvation includes increased plasma levels of glucocorticoids, catecholamines, ghrelin, growth hormone and glucagon, and decreased levels of circulating insulin, gonadotropins, leptin and thyroid hormones. These hormone responses are an afferent stimulus for the hypothalamic response to starvation resulting in a decrease in energy expenditure and metabolism.

Hepatobiliary diseases and insulin resistance.

In recent years, there has been an increasing prevalence of obesity and related diseases. This epidemiological change has increased the interest of researchers in the molecular and biochemical pathways involved in the pathogenesis of hepatic and biliary diseases. Insulin resistance is considered the major mechanism involved in the hepatic and biliary manifestations of obesity. Epidemiological, clinical, and basic research demonstrates that insulin resistance is associated with gallstone disease, nonalcoholic fatty liver disease, and poor outcomes in viral hepatitis C treatments. Fascinating experimental evidence demonstrates that fat-induced hepatic insulin resistance may result from the activation of kinases leading to impaired insulin signaling. The insulin-resistant state is characterized by a failure to suppress hepatic glucose production and glycogenolysis, with enhanced fat accumulation in hepatocytes because of increased lipolysis, increased free fatty acid uptake by hepatocytes, and increased hepatic synthesis of triglycerides. This molecular signaling induces a low-grade chronic inflammatory state, characterized by increased levels of proinflammatory molecules and acute-phase proteins. This review summarizes the most important molecular and biochemical issues in the hepatic and biliary diseases associated with insulin resistance.

Modelling the role of excitatory and inhibitory neuronal activity in the generation of the BOLD signal.

A biophysical model of the coupling between neuronal activity and the BOLD signal that allows for explicitly evaluating the role of both excitatory and inhibitory activity is formulated in this paper. The model is based on several physiological assumptions. Firstly, in addition to glycolysis, the "glycogen shunt" is assumed for excitatory synapses as a mechanism for energy production in the astrocytes. As a result, oxygen-to-glucose index (OGI) is not constant but varies with excitatory neuronal activity. In contrast, a constant OGI=6 (glycolysis) is assumed for inhibitory synapses. Finally we assume that cerebral blood flow is not directly controlled by energy usage, but it is only related to excitatory activity. Simulations' results show that increases in excitatory activity amplify the oscillations associated with the transient BOLD response, by increasing the initial dip, the maximum, and the post-stimulus undershoot of the signal. In contrast, increasing the inhibitory activity evoked an overall decrease of the BOLD signal along the whole time interval of the response. Simultaneous increase of both types of activity is then expected to reinforce the initial dip and the post-stimulus undershoot, while respective effects on the maximum tend to counteract each other. Two mechanisms for negative BOLD response (NBS) generation were predicted by the model: (i) when inhibition was present alone or together with low activation levels and (ii) when deactivation occurred independently of the accompanying inhibition level. Interestingly, NBS was associated with negative oxygen consumption changes only for the case of mechanism (ii).