RESUMEN
BACKGROUND: Insulin (INS) resistance and hypoinsulinemia commonly observed in cancer-carrying, can contribute to cachexia. However, the effects of INS and INS sensitizers, such as pioglitazone (PIO), particularly when used in combination therapy, on cancer cachexia have not been evaluated sufficiently. We investigated the effects of INS and PIO, at various doses, either isolated or combined, on cachexia in Walker-256 tumor-bearing rats (TB rats). METHODS: INS or INS + PIO were administered in TB rats, for 6 or 12 days, starting from the day of tumor cells inoculation. RESULTS: INS at 18 or 27 U/kg (12-days treatment), but not 9 U/kg, reduced fat loss and slightly prevented weight loss. However, INS 18 U/kg + PIO 5, 10, 20, or 40 mg/kg (6 or 12-day treatment) reduced fat loss and markedly prevented weight loss but did not affect muscle wasting. While TB rats lost weight (37.9% in 12 days), TB rats treated with INS 18 U/kg + PIO 5 mg/kg showed pronounced weight gain (73.7%), which was greater than the sum (synergism) of the weight gains promoted by isolated treatments with INS 18 U/kg (14.7%) or PIO 5 mg/kg (13.1%). The beneficial effect of the INS 18 U/kg + PIO 5 mg/kg on weight loss was associated with improved INS sensitivity, as indicated by the higher blood glucose clearance constant (kITT), decreased levels of free fatty acids and triacylglycerols (INS resistance-inducing factors) in the blood, and increased expression of p-Akt (INS signaling pathway protein) in adipose tissue. CONCLUSIONS: The combined treatment with INS 18 U/kg + PIO 5 mg/kg was more effective in preventing advanced cachexia in TB rats than each treatment alone, emerging as the best approach, considering the lower dosage and higher efficacy. This combination completely preserved adipose mass and markedly reduced weight loss through a synergistic mechanism linked to improved insulin sensitivity. These findings provide new insights into the importance of drug combinations in effectively combating fat loss in advanced cachexia.
Asunto(s)
Resistencia a la Insulina , Neoplasias , Tiazolidinedionas , Ratas , Animales , Pioglitazona/farmacología , Pioglitazona/uso terapéutico , Insulina , Caquexia/tratamiento farmacológico , Caquexia/etiología , Caquexia/prevención & control , Tiazolidinedionas/farmacología , Tiazolidinedionas/uso terapéutico , Pérdida de Peso , Aumento de Peso , Neoplasias/tratamiento farmacológico , Hipoglucemiantes/farmacologíaRESUMEN
Insulin (INS) resistance is often found in cancer-bearing, but its correlation with cachexia development is not completely established. This study investigated the temporal sequence of the development of INS resistance and cachexia to establish the relationship between these factors in Walker-256 tumor-bearing rats (TB rats). INS hepatic sensitivity and INS resistance-inducing factors, such as free fatty acids (FFA) and tumor necrosis factor-α (TNF-α), were also evaluated. Studies were carried out on Days 2, 5, 8, and/or 12 after inoculation of tumor cells in rats. The peripheral INS sensitivity was assessed by the INS tolerance test and the INS hepatic sensitivity in in situ liver perfusion. TB rats with 5, 8, and 12 days of tumor, but not 2 days, showed decreased peripheral INS sensitivity (INS resistance), retroperitoneal fat, and body weight, compared to healthy rats, which were more pronounced on Day 12. Gastrocnemius muscle wasting was observed only on Day 12 of tumor. The peripheral INS resistance was significantly correlated (r = -.81) with weight loss. Liver INS sensitivity of TB rats with 2 and 5 days of tumor was unchanged, compared to healthy rats. TB rats with 12 days of tumor showed increased plasma FFA and increased TNF-α in retroperitoneal fat and liver, but not in the gastrocnemius, compared to healthy rats. In conclusion, peripheral INS resistance is early, starts along with fat and weight loss and before muscle wasting, progressive, and correlated with cachexia, suggesting that it may play an important role in the pathogenesis of the cachectic process in TB rats. Therefore, early correction of INS resistance may be a therapeutic approach to prevent and treat cancer cachexia.
Asunto(s)
Resistencia a la Insulina , Neoplasias , Ratas , Animales , Caquexia/etiología , Caquexia/patología , Insulina , Factor de Necrosis Tumoral alfa , Ratas Wistar , Pérdida de Peso , Neoplasias/complicacionesRESUMEN
Sepsis induces several metabolic abnormalities, including hypoglycaemia in the most advanced stage of the disease, a risk factor for complications and death. Although hypoglycaemia can be caused by inhibition of hepatic gluconeogenesis, decreased and increased gluconeogenesis were reported in sepsis. Furthermore, gluconeogenesis from glycerol was not yet evaluated in this disease. The main purpose of this study was to investigate the gluconeogenesis from alanine, lactate, pyruvate and glycerol in rats with early (8 hours) and late (18 hours) sepsis. Parameters related to the characterization of sepsis were also evaluated. Sepsis was induced by cecal ligation and puncture and gluconeogenesis was assessed in liver perfusion. Rats with early and late sepsis showed increased lactataemia, depletion of liver glycogen and peripheral insulin resistance, characterizing the establishment of sepsis. Rats with early and late sepsis showed decreased gluconeogenesis from alanine, lactate and pyruvate. Interestingly, gluconeogenesis from glycerol, a precursor that enters in the pathway at a later step, subsequent to the entry of alanine, lactate and pyruvate, was maintained in rats with early and late sepsis. In conclusion, gluconeogenesis is decreased from alanine, lactate and pyruvate, but maintained from glycerol, in liver perfusion of rats with early and late sepsis. SIGNIFICANCE OF THE STUDY: The maintenance of gluconeogenesis from glycerol, but not from alanine, lactate and pyruvate, together with the liver glycogen depletion, points the glycerol as an important precursor for the maintenance of glycaemic homeostasis in sepsis. The findings open the possibility of further investigation on the administration of glycerol in the treatment of hypoglycaemia associated with more advanced sepsis.
Asunto(s)
Alanina/metabolismo , Ácido Láctico/metabolismo , Hígado/metabolismo , Ácido Pirúvico/metabolismo , Sepsis/metabolismo , Animales , Gluconeogénesis , Glicerol/metabolismo , Masculino , Perfusión , Ratas , Ratas WistarRESUMEN
Lixisenatide, a glucagon-like peptide-1 receptor agonist, is used to stimulate insulin secretion in patients with type 2 diabetes mellitus. However, its effect on insulin secretion in cancer patients, particularly during the cachexia course, has not yet been evaluated. The purpose of this study was to investigate the lixisenatide effect on INS secretion decline during the cachexia course (2, 6, and 12 days of tumor) in pancreatic islets isolated from Walker-256 tumor-bearing rats. Pancreatic islets of healthy and tumor-bearing rats were incubated in the presence or absence of lixisenatide (10 nM). Tumor-bearing rats showed reduction of body weight and fat and muscle mass, characterizing the development of cachexia, as well as reduction of insulinemia and INS secretion stimulated by glucose (5.6, 8.3, 11.1, 16.7, and 20 mM) on days 2, 6, and/or 12 of tumor. Lixisenatide increased the 16.7 mM glucose-stimulated insulin secretion, but not by 5.6 mM glucose, in the islets of healthy rats, without changing the insulin intracellular content. However, lixisenatide did not prevent the decreased 16.7 mM glucose-stimulated insulin secretion in the pancreatic islets of rats with 2, 6, and 12 days of tumor and neither the decreased insulin intracellular content of rats with 12 days of tumor. In consistency, in vivo treatment with lixisenatide (50 µg kg-1, SC, once daily, for 6 days) visually increased insulinemia of healthy fasted rats, but did not prevent hypoinsulinemia of tumor-bearing rats. In conclusion, Walker-256 tumor-bearing rats showed early decline (2 days of tumor) of insulin secretion, which followed the cachexia course (6 and 12 days of tumor) and was not improved by lixisenatide, evidencing that this insulin secretagogue, used to treat type 2 diabetes, does not have beneficial effect in cancer bearing-rats.
Asunto(s)
Caquexia/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Secreción de Insulina/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Péptidos/uso terapéutico , Animales , Caquexia/metabolismo , Insulina/sangre , Insulina/metabolismo , Masculino , Neoplasias/metabolismo , Ratas WistarRESUMEN
Gluconeogenesis (GN) is increased in patients with cancer cachexia, but is reduced in liver perfusion of Walker-256 tumor-bearing cachectic rats (TB rats). The causes of these differences are unknown. We investigated the influence of circulating concentrations of lactate (NADH generator) and NADH on GN in perfused livers of TB rats. Lactate, at concentrations similar to those found on days 5 (3.0 mM), 8 (5.5 mM), and 12 (8.0 mM) of the tumor, prevented the reduction of GN from 2.0 mM lactate (lactatemia of healthy rat) in TB rats. NADH, 50 or 75 µM, but not 25 µM, increased GN from 2.0 mM lactate in TB rats to higher values than healthy rats. High concentrations of pyruvate (no NADH generator, 5.0 and 8.0 mM) did not prevent the reduction of GN from 2.0 mM pyruvate in TB rats. However, 50 or 75 µM NADH, but not 25 µM, increased GN from 2.0 mM pyruvate in TB rats to similar or higher values than healthy rats. High concentration of glutamine (NADH generator, 2.5 mM) or 50 µM NADH prevented the reduction of GN from 1 mM glutamine in TB rats. Intraperitoneal administration of pyruvate (1.0 mg/kg) or glutamine (0.5 mg/kg) similarly increased the glycemia of healthy and TB rats. In conclusion, high lactate concentration, similar to hyperlactatemia, prevented the reduction of GN in perfused livers of TB rats, an effect probably caused by the increased redox potential (NADH/NAD+ ). Thus, the decreased GN in livers from TB rats is due, at least in part, to the absence of simulation of in vivo hyperlactatemia in liver perfusion studies.
RESUMEN
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.
Asunto(s)
AMP Cíclico/metabolismo , Glucosa/metabolismo , Glucogenólisis/fisiología , Insulina/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Hígado/metabolismo , Glucógeno Hepático/metabolismo , Masculino , Perfusión/métodos , Ratas , Ratas WistarRESUMEN
Tumor necrosis factor α (TNFα) is a cytokine involved in many metabolic responses in both normal and pathological states. Considering that the effects of TNFα on hepatic gluconeogenesis are inconclusive, we investigated the influence of this cytokine in gluconeogenesis from various glucose precursors. TNFα (10 µg/kg) was intravenously injected in rats; 6 h later, gluconeogenesis from alanine, lactate, glutamine, glycerol, and several related metabolic parameters were evaluated in situ perfused liver. TNFα reduced the hepatic glucose production (p < 0.001), increased the pyruvate production (p < 0.01), and had no effect on the lactate and urea production from alanine. TNFα also reduced the glucose production (p < 0.01), but had no effect on the pyruvate production from lactate. In addition, TNFα did not alter the hepatic glucose production from glutamine nor from glycerol. It can be concluded that the TNFα inhibited hepatic gluconeogenesis from alanine and lactate, which enter in gluconeogenic pathway before the pyruvate carboxylase step, but not from glutamine and glycerol, which enter in this pathway after the pyruvate carboxylase step, suggesting an important role of this metabolic step in the changes mediated by TNFα.