RESUMEN
AIMS: To characterize the pharmacology of MEDI0382, a peptide dual agonist of glucagon-like peptide-1 (GLP-1) and glucagon receptors. MATERIALS AND METHODS: MEDI0382 was evaluated in vitro for its ability to stimulate cAMP accumulation in cell lines expressing transfected recombinant or endogenous GLP-1 or glucagon receptors, to potentiate glucose-stimulated insulin secretion (GSIS) in pancreatic ß-cell lines and stimulate hepatic glucose output (HGO) by primary hepatocytes. The ability of MEDI0382 to reduce body weight and improve energy balance (i.e. food intake and energy expenditure), as well as control blood glucose, was evaluated in mouse models of obesity and healthy cynomolgus monkeys following single and repeated daily subcutaneous administration for up to 2 months. RESULTS: MEDI0382 potently activated rodent, cynomolgus and human GLP-1 and glucagon receptors and exhibited a fivefold bias for activation of GLP-1 receptor versus the glucagon receptor. MEDI0382 produced superior weight loss and comparable glucose lowering to the GLP-1 peptide analogue liraglutide when administered daily at comparable doses in DIO mice. The additional fat mass reduction elicited by MEDI0382 probably results from a glucagon receptor-mediated increase in energy expenditure, whereas food intake suppression results from activation of the GLP-1 receptor. Notably, the significant weight loss elicited by MEDI0382 in DIO mice was recapitulated in cynomolgus monkeys. CONCLUSIONS: Repeated administration of MEDI0382 elicits profound weight loss in DIO mice and non-human primates, produces robust glucose control and reduces hepatic fat content and fasting insulin and glucose levels. The balance of activities at the GLP-1 and glucagon receptors is considered to be optimal for achieving weight and glucose control in overweight or obese Type 2 diabetic patients.
Asunto(s)
Glucemia/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Receptor del Péptido 1 Similar al Glucagón/agonistas , Hepatocitos/efectos de los fármacos , Células Secretoras de Insulina/efectos de los fármacos , Péptidos/farmacología , Receptores de Glucagón/agonistas , Pérdida de Peso/efectos de los fármacos , Animales , Peso Corporal/efectos de los fármacos , Células CHO , Línea Celular , Cricetulus , Modelos Animales de Enfermedad , Hepatocitos/metabolismo , Humanos , Técnicas In Vitro , Células Secretoras de Insulina/metabolismo , Macaca fascicularis , Ratones , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , RatasRESUMEN
BACKGROUND AND PURPOSE: Oral salmon calcitonin (sCT), a dual-action amylin and calcitonin receptor agonist, improved glucose homeostasis in diet-induced obese rats. Here, we have evaluated the anti-diabetic efficacy of oral sCT using parameters of glycaemic control and beta-cell morphology in male Zucker diabetic fatty (ZDF) rats, a model of type 2 diabetes. EXPERIMENTAL APPROACH: Male ZDF rats were treated with oral sCT (0.5, 1.0 or 2 mg·kg(-1) ) or oral vehicle twice daily from age 8 to 18 weeks. Zucker lean rats served as control group. Fasting and non-fasted blood glucose, glycosylated haemoglobin (HbA1c) and levels of pancreas and incretin hormones were determined. Oral glucose tolerance test and i.p. glucose tolerance test were compared, and beta-cell area and function were evaluated. KEY RESULTS: Oral sCT treatment dose-dependently attenuated fasting and non-fasted hyperglycaemia during the intervention period. At the end of the study period, oral sCT treatment by dose decreased diabetic hyperglycaemia by â¼9 mM and reduced HbA1c levels by 1.7%. Furthermore, a pronounced reduction in glucose excursions was dose-dependently observed for oral sCT treatment during oral glucose tolerance test. In addition, oral sCT treatment sustained hyperinsulinaemia and attenuated hyperglucagonaemia and hypersecretion of total glucagon-like peptide-1 predominantly in the basal state. Lastly, oral sCT treatment dose-dependently improved pancreatic beta-cell function and beta-cell area at study end. CONCLUSIONS AND IMPLICATIONS: Oral sCT attenuated diabetic hyperglycaemia in male ZDF rats by improving postprandial glycaemic control, exerting an insulinotropic and glucagonostatic action in the basal state and by preserving pancreatic beta-cell function and beta-cell area.
Asunto(s)
Calcitonina/administración & dosificación , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hiperglucemia/tratamiento farmacológico , Hipoglucemiantes/administración & dosificación , Células Secretoras de Insulina/efectos de los fármacos , Administración Oral , Animales , Glucemia/análisis , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Polipéptido Inhibidor Gástrico/sangre , Péptido 1 Similar al Glucagón/sangre , Prueba de Tolerancia a la Glucosa , Hemoglobina Glucada/análisis , Hiperglucemia/metabolismo , Hiperglucemia/patología , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patología , Masculino , Ratas , Ratas ZuckerRESUMEN
A novel oral form of salmon calcitonin (sCT) was recently demonstrated to improve both fasting and postprandial glycemic control and induce weight loss in diet-induced obese and insulin-resistant rats. To further explore the glucoregulatory efficacy of oral sCT, irrespective of obesity and metabolic dysfunction, the present study investigated the effect of chronic oral sCT treatment on fasting and postprandial glycemic control in male lean healthy rats. 20 male rats were divided equally into a control group receiving oral vehicle or an oral sCT (2 mg/kg) group. All rats were treated twice daily for 5 weeks. Body weight and food intake were monitored during the study period and fasting blood glucose, plasma insulin and insulin sensitivity were determined and an oral glucose tolerance test (OGTT) performed at study end. Compared with the vehicle group, rats receiving oral sCT had improved fasting glucose homeostasis and insulin resistance, as measured by homeostatic model assessment of insulin resistance index (HOMA-IR), with no change in body weight or fasting plasma insulin. In addition, the rats receiving oral sCT had markedly reduced glycemia and insulinemia during OGTT. This is the first report showing that chronic oral sCT treatment exerts a glucoregulatory action in lean healthy rats, irrespective of influencing body weight. Importantly, oral sCT seems to exert a dual treatment effect by improving fasting and postprandial glycemic control and insulin sensitivity. This and previous studies suggest oral sCT is a promising agent for the treatment of obesity-related insulin resistance and type 2 diabetes.
Asunto(s)
Glucemia/metabolismo , Calcitonina/farmacología , Ingestión de Alimentos/efectos de los fármacos , Periodo Posprandial/efectos de los fármacos , Animales , Peso Corporal/efectos de los fármacos , Peso Corporal/fisiología , Ingestión de Alimentos/fisiología , Prueba de Tolerancia a la Glucosa , Insulina/sangre , Resistencia a la Insulina/fisiología , Masculino , Distribución Aleatoria , Ratas , Ratas Sprague-DawleyRESUMEN
AIM: To investigate the effects of acute and chronic administration of a novel oral formulation of salmon calcitonin (sCT) on glycaemic control, glucose homeostasis and body weight regulation in diet-induced obese (DIO) rats-an animal model of obesity-related insulin resistance and type 2 diabetes. METHODS: DIO rats were acutely given a single dose of oral sCT (0.5 and 2 mg/kg), its oral vehicle N-(5-chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC) or injectable sCT (5 and 10 µg/kg) (n = 8), followed by oral glucose tolerance test (OGTT). Other DIO rats were chronic treated twice daily with oral vehicle 5-CNAC (n = 6), oral sCT (0.5 and 2 mg/kg) or injectable sCT (10 µg/kg) (n = 8). Fasting and postprandial glucose and pancreatic hormones, body weight and insulin sensitivity were assessed. RESULTS: A single dose of oral sCT acutely reduced glucose and insulin area under the curve during OGTT by approximately 65 and 85%, respectively, compared with vehicle (p < 0.001). Chronic treatment with oral sCT significantly reduced both fasting and postprandial glucose and insulin levels by approximately 1.5 mM and 65%, respectively, compared with vehicle. Oral sCT concomitantly improved insulin sensitivity (homeostatic model assessment, HOMA). In contrast, injectable sCT resembling higher systemic exposure did not improve glycaemic control, either acutely or during chronic treatment. Furthermore, both oral and injectable sCT reduced body weight by 15% compared with vehicle (p < 0.05). CONCLUSION: A novel oral form of sCT showed antidiabetic effects in DIO rats by improving glycaemic control, glucose homeostasis, insulin sensitivity and body weight.