RESUMO
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.
Assuntos
Resistência à Insulina , Neoplasias , Tiazolidinedionas , Ratos , Animais , Pioglitazona/farmacologia , Pioglitazona/uso terapêutico , Insulina , Caquexia/tratamento farmacológico , Caquexia/etiologia , Caquexia/prevenção & controle , Tiazolidinedionas/farmacologia , Tiazolidinedionas/uso terapêutico , Redução de Peso , Aumento de Peso , Neoplasias/tratamento farmacológico , Hipoglicemiantes/farmacologiaRESUMO
Meta-analyses from 2018-2022 have shown that obesity increases the risk of various cancers such as acute myeloid lymphoma, chronic myeloid lymphoma, diffuse beta cell lymphoma, Hodgkin's lymphoma, leukemia, multiple myeloma, non-Hodgkin's lymphoma, bladder, breast, cholangiocarcinoma, colorectal, ovarian, esophageal, kidney, liver, prostate, thyroid, and uterus. Contextually, obesity, and its comorbidities, is the largest, most lethal pandemics in the history of mankind; hence, identification of underlying mechanisms is needed to adequately address this global health threat. Herein, we present the metabolic and hormonal mechanisms linked to obesity that might etiologically contribute to neoplasia, including hyperinsulinemia and putative places in the insulin-signaling pathway. Excess insulin, acting as a growth factor, might contribute to tumorigenesis, while abundant ATP and GDP supply the additional energy needed for proliferation of rapidly dividing cells. Our observations in the Ecuadorian cohort of subjects with Laron syndrome (ELS) prove that obesity does not always associate with increased cancer risk. Indeed, despite excess body fat from birth to death, these individuals display a diminished incidence of cancer when compared to their age- and sex-matched relatives. Furthermore, in cell cultures exposed to potent oxidizing agents, addition of ELS serum induces less DNA damage as well as increased apoptosis. ELS individuals have absent growth hormone (GH) counter-regulatory effects in carbohydrate metabolism due to a defective GH receptor. The corresponding biochemical phenotype includes extremely low basal serum concentrations of insulin and insulin-like growth factor-I, lower basal glucose and triglyceride (TG) levels, and diminished glucose, TG, and insulin responses to orally administered glucose or to a mixed meal.
Assuntos
Síndrome de Laron , Neoplasias , Masculino , Feminino , Humanos , Síndrome de Laron/genética , Equador , Fator de Crescimento Insulin-Like I , Insulina , Neoplasias/epidemiologia , Neoplasias/complicações , Obesidade/epidemiologia , Obesidade/complicações , GlucoseRESUMO
Lixisenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, is used in the treatment of type 2 diabetes mellitus (T2DM). It increases insulin (INS) secretion and can decrease INS resistance, improving metabolic disorders in this disease. However, its effects on metabolic disturbances in cancer-bearing, which also exhibit decreased INS secretion and INS resistance, changes that may contribute to weight loss (cachexia), have not yet been evaluated. The purpose of this study was to investigate the lixisenatide treatment effects on mild cachexia and related metabolic abnormalities in Walker-256 tumour-bearing rats. Lixisenatide (50 µg kg-1 , SC) was administered once daily, for 6 days, after inoculation of Walker-256 tumour cells. Acute lixisenatide treatment did not improve hypoinsulinemia, INS secretion and INS resistance of tumour-bearing rats. It also did not prevent the reduced glucose and increased triacylglycerol and lactate in the blood and nor the loss of retroperitoneal and epididymal fat of these animals. However, acute lixisenatide treatment accentuated the body mass loss of tumour-bearing rats. Therefore, lixisenatide, unlike T2DM, does not improve hypoinsulinemia and INS resistance associated with cancer, evidencing that it does not have the same beneficial effects in these two diseases. In addition, lixisenatide aggravated weight loss of tumour-bearing rats, suggesting that its use for treatment of T2DM patients with cancer should be avoided. SIGNIFICANCE OF THE STUDY: Lixisenatide increases insulin secretion and appears to reduce insulin resistance in T2DM. However, lixisenatide treatment does not improve hypoinsulinemia and insulin resistance associated with cancer, as it does in T2DM, and aggravated weight loss, suggesting that its use for treatment of T2DM patients with cancer should be avoided.
Assuntos
Hipoglicemiantes/farmacologia , Secreção de Insulina/efeitos dos fármacos , Peptídeos/farmacologia , Animais , Glicemia/análise , Caquexia/prevenção & controle , Linhagem Celular Tumoral , Glucose/farmacologia , Humanos , Hipoglicemiantes/uso terapêutico , Insulina/sangue , Resistência à Insulina , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/metabolismo , Masculino , Peptídeos/uso terapêutico , Ratos , Ratos Wistar , Transplante Heterólogo , Triglicerídeos/sangue , Redução de Peso/efeitos dos fármacosRESUMO
BACKGROUND: McArdle disease is a myopathy caused by mutations in PYGM gene that is characterized by reduced or absent activity of myophosphorylase. Reports of patients with concomitant McArdle disease and diabetes are scarce. We report a case of a patient with a late diagnosis of McArdle disease and we postulate that symptoms may be related to hypoinsulinemia. CASE PRESENTATION: This report describes the evolution of an elderly diabetic patient with confirmed diagnosis of McArdle's disease based on the absence of myophosphorylase activity in the analysis of muscle biopsy, and a homozygous mutation in the PYGM gene. The variant - Chr11: 64.525 (p. Asn168*fs) has not been previously described. The diagnosis of McArdle disease was confirmed after two episodes of rhabdomyolysis, at 77 and 81 years of age, as the symptoms were, until then, discrete. The "second-wind phenomenon" was not spontaneously reported, but it was confirmed when directly questioned. We postulate that the later episodes of rhabdomyolysis occurred because of a progressive decrease in insulin production with a consequent reduction in the uptake of blood glucose by muscle cells, thus compromising the cellular energy balance. To our knowledge, this is the first report of recurrent rhabdomyolysis in an elderly diabetic patient with genetically proven McArdle disease. Our initial attempt to reduce insulin resistance with metformin and pioglitazone was not effective, possibly because of inadequate insulinemia. However, an improvement was evident after the administration of low doses of intermediate-acting insulin. CONCLUSIONS: In view of the patient's clinical evolution, we suggest the use of medication that reduces insulin resistance for patients with McArdle disease and type 2 diabetes, pre-diabetes or even normoglycemic metabolic syndrome.
Assuntos
Diabetes Mellitus Tipo 2 , Glicogênio Fosforilase Muscular , Doença de Depósito de Glicogênio Tipo V , Rabdomiólise , Idoso , Glicogênio Fosforilase Muscular/genética , Doença de Depósito de Glicogênio Tipo V/complicações , Doença de Depósito de Glicogênio Tipo V/diagnóstico , Doença de Depósito de Glicogênio Tipo V/genética , Humanos , Mutação , Rabdomiólise/complicações , Rabdomiólise/diagnóstico , Rabdomiólise/genéticaRESUMO
Metformin (MET) is widely used in the correction of insulin (INS) resistance and metabolic abnormalities in type 2 diabetes. However, its effect on INS resistance and metabolic disorders associated with cancer cachexia is not established. We investigated the MET effects, isolated or associated with INS, on INS resistance and metabolic changes induced by Walker-256 tumor in rats with advanced cachexia. MET (500 mg·kg-1, oral) and MET + INS (1.0 IU·kg-1, s.c.) were administered for 12 days, starting on the day of tumor cell inoculation. Tumor-bearing rats showed adipose and muscle mass wasting, body mass loss, anorexia, decreased Akt phosphorylation in retroperitoneal and mesenteric adipose tissue, peripheral INS resistance, hypoinsulinemia, reduced INS content and secretion from pancreatic islets, and also inhibition of glycolysis, gluconeogenesis, and glycogenolysis in liver. MET and MET + INS treatments did not prevent these changes. It can be concluded that treatments with MET and MET + INS did not prevent the adipose and muscle mass wasting and body mass loss of tumor-bearing rats possibly by not improving INS resistance. Therefore, MET, used for the treatment of INS resistance in type 2 diabetes, is not effective in improving INS resistance in the advanced stage of cancer cachexia, evidencing that the drug does not have the same beneficial effect in these 2 diseases.
Assuntos
Caquexia/complicações , Caquexia/metabolismo , Resistência à Insulina , Metformina/farmacologia , Neoplasias/complicações , Animais , Caquexia/tratamento farmacológico , Caquexia/patologia , Insulina/metabolismo , Masculino , Metformina/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacosRESUMO
Dermatophytosis is one of the most common human infections affecting both immunocompetent individuals and immunocompromised patients, in whom the disease is more aggressive and can reach deep tissues. Over the last decades, cases of deep dermatophytosis have increased and the dermatophyte-host interplay remains poorly investigated. Pattern recognition molecules, such as Toll-like receptors (TLR), play a crucial role against infectious diseases. However, there has been very little research reported on dermatophytosis. In the present study, we investigated the role of TLR2 during the development of experimental deep dermatophytosis in normal mice and mice with alloxan-induced diabetes mellitus, an experimental model of diabetes that exhibits a delay in the clearance of the dermatophyte, Trichophyton mentagrophytes (Tm). Our results demonstrated that inoculation of Tm into the footpads of normal mice increases the expression of TLR2 in CD115+Ly6Chigh blood monocytes and, in hypoinsulinemic-hyperglycemic (HH) mice infected with Tm, the increased expression of TLR2 was exacerbated. To understand the role of TLR2 during the development of murine experimental deep dermatophytosis, we employed TLR2 knockout mice. Tm-infected TLR2-/- and TLR2+/+ wild-type mice exhibited similar control of deep dermatophytic infection and macrophage activity; however, TLR2-/- mice showed a noteworthy increase in production of IFN-γ, IL-10, and IL-17, and an increased percentage of splenic CD25+Foxp3+ Treg cells. Interestingly, TLR2-/- HH-Tm mice exhibited a lower fungal load and superior organization of tissue inflammatory responses, with high levels of production of hydrogen peroxide by macrophages, alongside low TNF-α and IL-10; high production of IL-10 by spleen cells; and increased expansion of Tregs. In conclusion, we demonstrate that TLR2 diminishes the development of adaptive immune responses during experimental deep dermatophytosis and, in a diabetic scenario, acts to intensify a non-protective inflammatory response.