Effect of Prosopis ruscifolia on incretin and insulin secretion in alloxan-induced hyperglycemic rats / Efecto de Prosopis ruscifolia sobre la secreción de incretina e insulina de ratas hiperglicémicas por aloxano

Background: Diabetes mellitus treatment is based on oral hypoglycemic agents or insulin. Medicinal plants constitute an option, and the leaves of Prosopis ruscifolia (Pr) were shown to be effective in reducing glycemia in hyperglycemic animals. Objective: In this paper, we report the effect of P. rusciofolia (Pr) on insulin and incretin secretion in alloxan-induced hyperglycemic rats. Methodology: The effective dose was selected, and four groups (n=10) of Wistar rats were used. Two groups with normal glycemia received water or Pr (75 mg/Kg, per os, p.o.), and two groups with hyperglycemia induced by alloxan (intraperitoneal, ip), received water or Pr (75 mg/Kg, p.o.) for 2 weeks. Oral glucose tolerance test, and incretin and insulin levels were measured at the end of the experimental period. Results: The results showed that extract promotes better tolerance to oral glucose overload, in addition to a statistically significant (p<0.001) increase in blood levels of incretin and insulin, compared to the hyperglycemic rats. Conclusion: It is concluded that the ethanolic extract of P. ruscifolialeaves has a hypoglycemic effect in hyperglycemic animals by a mechanism that involves the incretin-insulin system

Antecedentes: la diabetes mellitus es una enfermedad metabólica cuyo tratamiento se basa en el uso de agentes hipoglicemiantes orales o insulina. Una opción al tratamiento son las plantas medicinales y en ese sentido, estudios previos en animales con hojas de Prosopis ruscifolia (Pr) han demostrado efecto hipoglicemiante. Objetivo: en este trabajo se reporta el efecto de P. rusciofolia (Pr) en la secreción de insulina e incretina, en ratas hiperglicémicas por aloxano. Metodología: se emplearon cuatro grupos de ratas Wistar (n=10). Dos grupos con glicemia normal que fueron tratadas con agua Pr (75 mg/Kg, per os, p.o.) y dos grupos con hiperglicemia inducida por la inyección intraperitoneal de aloxano recibieron agua Pr (75 mg/Kg, per os, p.o.) durante dos semanas. Se midieron la tolerancia oral a la glucosa, y los niveles de incretina e insulina al final del periodo de experimentación. Resultados: se encontró que el extracto promueve una mayor tolerancia a la sobrecarga de glucosa, y además un incremento significativo (p<0.001) de los niveles de incretina e insulina en sangre, comparados al grupo de ratas hiperglicémicas. Conclusión: se concluye que e l estracto etanólico de las hojas de P. ruscifolia tienen efecto hipoglicemiante en animales hiperglicémicos por un mecanismo que incluye al sistema incretina-insulina

Rol de las incretinas / Role of the incretins

Incretins are gut hormones that are released from gut endocrine cells following oral ingestion of nutrients. The incretin hormones include glucagon-like peptide-1 (GLP-1) and lucosedependentinsulinotropic polypeptide (GIP). GIP and GLP-1 are jointly responsible for the socalled “incretin effect”. That is, oral administration of an amount of glucose causes a greater stimulus of insulin secretion than the same amount of glucose administered by the intravenous route. Both incretins potentiate glucose-dependent insulin secretion and enhance beta-cell massthrough regulation of beta-cell proliferation, neogenesis and apoptosis. In contrast, GLP-1, but not GIP, inhibits gastric emptying, glucagon secretion, and food intake. The incretins share similar effects on the pancreatic beta cell; however, there are a number of differences in extrapancreatic actions. Both incretins are rapidly deactivated by an enzyme called dipeptidyl peptidase 4(DPP4). Type 2 diabetes mellitus (T2DM) is associated with abnormal incretin physiology, the incretin effect is severely reduced or absent. In patients with T2DM the secretion of GIP is nearnormal, but its effect on insulin secretion is severely impaired. GLP-1 secretion, on the other hand, is also impaired, but its insulinotropic action is preserved, although the potency of GLP-1 in this respect is decreased compared to healthy subjets.

Incretinas, incretinomiméticos, inhibidores de DPP IV: (2ª parte) / Incretins, Incretinmimetics, Inhibitors (2nd part)

En los últimos años se reconoce un nuevo mecanismo involucrado en la fisiopatología de la Diabetes Mellitus tipo 2: el déficit de producción y/o acción de las incretinas. Las incretinas son enterohormonas que estimulan la secreción de insulina en respuesta a la ingesta de nutrientes. Glucagon like peptide-1 (GLP1) y Polipéptido insulinotrópico glucosa dependiente (GIP) son las principales incretinas descubiertas hasta hoy. Ambas presentan también efecto trófico sobre las células beta de los islotes pancreáticos. GLP-1 presenta otras acciones como son la inhibición de la secreción de glucagón, enlentecimiento del vaciamiento gástrico e inhibición del apetito. Ambas incretinas son rápidamente clivadas por la enzima dipeptidil peptidasa 4 (DPP-4). Nuevas drogas como los incretinomiméticos, análogos y los inhibidores de DPP-4 se presentan como una terapéutica prometedora para los pacientes con diabetes tipo 2. Conflicto de intereses: Dr. León Litwak - Miembro del Board Latinoamericano de Eli Lilly y Sanofi Aventis - Miembro del Board Nacional de los laboratorios Novo Nordisk, Novartis, GlaxoSmithKline, Sanofi Aventis, Boheringer Ingelheim, Bristol Myers, Astra Zeneca - Investigador principal de protocolos pertenecientes a Eli Lilly, Novo Nordisk, Novartis, GlaxoSmithKline, Takeda, PPDF, Pfizer, Merck Sharp and Dôhme, Amger, Roche, Minimed, Quintiles - Conferencista de los laboratorios mencionados.

Two main pathophysiological mechanisms are currently involved in Type 2 Diabetes (T2DM), insulin resistance and impairment of beta cell function. However, in recent years a new mechanism was reported: a significant decrease in incretins production and/or action. Incretins are gastrointestinal hormones whose main action is stimulating insulin secretion in response to nutrients. The best known incretins are glucagon like peptide-1 (GLP-1) and Gastric insulinotropic peptide (GIP). GLP-1 and GIP not only increase insulin secretion, but also decrease glucagon secretion, slow gastric emptying and reduce apetite, generating weight loss. Both incretins are rapidly clived by the enzyme dipeptidil peptidase 4 (DPP4). In order to emulate incretins action, several drugs were developed: GLP-1 receptor agonists, GLP-1 mimetics, and DPP4 inhibitors. All of them seem to became a very promising tool for the treatment of T2DM. Financial Interests: Dr. León Litwak - Member of the Latin American Board of Eli Lilly and Sanofi Aventis - Member of the National Board of the following laboratories: Novo Nordisk, Novartis, GlaxoSmithKlein Sanofi, Aventis, Boheringer Ingelheim, Bristol Myers, Astra Zeneca - Principal Investigator of Protocols from: Eli Lilly, Novo Nordisk, Novartis, GlaxoSmithKlein, Takeda, PPDF, Pfizer, Merck Sharp and Dôhme, Amgen, Roche, Minimed, Quintiles - Lecturer for the former laboratories.

Incretinas, Incretinomiméticos, Inhibidores de DPP IV: 1er parte / Incretins, Incretinmimetics, Inhibitors

En los últimos años se reconoce un nuevo mecanismo involucrado en la fisiopatología de la Diabetes Mellitus tipo 2: el déficit de producción y/o acción de las incretinas. Las incretinas son enterohormonas que estimulan la secreción de insulina en respuesta a la ingesta de nutrientes. Glucagon like péptido-1 (GLP1) y Polipéptido insulinotrópico glucosa dependiente (GIP) son las principales incretinas descubiertas hasta hoy. Ambas presentan también efecto trófico sobre las células beta de los islotes pancreáticos. GLP-1 presenta otras acciones como son la inhibición de la secreción de glucagón, enlentecimiento del vaciamiento gástrico e inhibición del apetito. Ambas incretinas son rápidamente clivadas por la enzima dipeptidil peptidasa 4 (DPP-4). Nuevas drogas como los incretinomiméticos, análogos y los inhibidores de DPP-4 se presentan como una terapéutica prometedora para los pacientes con diabetes tipo 2.

Two main patophysiological mechanisms are currently involved in Type 2 Diabetes (T2DM), insulin resistance and impairment of beta cell function. However in the last years a new mechanism was reported: a significant decrease in incretins production and or action. Incretins are gut hormones whose main action is stimulating insulin secretion in response to nutrients. The more known incretins are glucagon like peptide-1 (GLP-1) and Gastric insulinothropic peptide (GIP). GLP-1 and GIP not only increase insulin secretion, nor decrease glucagon secretion, slow gastric emptying and reduce apetite generating weight lose. Both incretins are rapidly clived by the enzyme dipeptidil peptidase 4 (DPP4). In order to emulate incretins action, several drugs where developed: agonists of GLP-1 receptors, GLP-1 mimetics, and inhibitors of the DPP4. All of them seems to became a very promise tool for the treatment of T2DM.

Ensayos clínicos de exenatida y su rol en el tratamiento de la diabetes tipo 2 / Exenatide trials for the treatment of type 2 diabetes

La diabetes mellitus tipo 2 es una enfermedad metabólica crónica, frecuente y progresiva, responsable del 90% de los casos de diabetes a nivel mundial. Aproximadamente el 60% de los individuos que padecen este desorden no alcanzan niveles óptimos de hemoglobina glicosilada, a pesar de la disponibilidad de numerosas alternativas terapéuticas. Los dos objetivos más importantes a cumplir en el manejo actual de la diabetes tipo 2 son la capacidad de los agentes antidiabéticos de exhibir eficacia prolongada y la capacidad de preservar la función de las células beta pancreáticas. El efecto incretina se encuentra reducido en pacientes con diabetes tipo 2. Exenatida pertenece a un nuevo grupo de drogas antidiabéticas que mejoran el control de la glucemia en estos pacientes a través de mecanismos fisiológicos glucorregulatorios que mejoran el efecto incretina. Los ensayos clínicos fase III con exenatida demostraron una reducción media de aproximadamente el 1% en los valores de hemoglobina glicosilada. Los datos a largo plazo de estudios de extensión no controlados indican una mejoría sostenida en los niveles de hemoglobina glicosilada y una reducción progresiva del peso luego de 3 años de tratamiento con esta droga. La droga es generalmente bien tolerada y los efectos adversos más frecuentes son los gastrointestinales, con una intensidad leve a moderada. El objetivo de esta revisión es analizar la evidencia publicada hasta la fecha sobre la eficacia y tolerabilidad del tratamiento con exenatida y su rol en el tratamiento de la diabetes tipo 2.

Type 2 diabetes mellitus is a common, chronic and progressive metabolic disorder, which accounts for 90% of diabetes cases worldwide. Approximately 60% of individuals with the disease do not achieve target glycosylated hemoglobin levels, despite the availability of many antidiabetic agents. The two most important needs in the present management of diabetes are the ability of antidiabetic agents to exhibit prolonged efficacy in reducing hyperglycemia and to preserve beta-cell function. The incretin effect appears to be reduced in patients with type 2 diabetes. Exenatide is the first in a novel class of antidiabetic drugs that improves glycemic control in patients with type 2 diabetes through several physiological glucoregulatory mechanisms which improve the incretin effect. Overall, mean glycosylated hemoglobin (HbA1c) reductions achieved in the exenatide phase III clinical trials were in the order of 1%. Long-term data from the uncontrolled open-label extension studies indicate that adjunctive exenatide therapy leads to sustained improvements in HbA1c and progressive weight loss for at least 3 years. The drug is generally well tolerated. The most common adverse events were gastrointestinal in nature and mild to moderate in severity. The objective of this review is to discuss the available published evidence on exenatide therapeutic efficacy and tolerability, and the role of this new drug in the treatment of type 2 diabetes.

Adjuvantes no tratamento da hiperglicemia do diabetes melito tipo 1: [revisão] / Adjunctive therapies to glycaemic control of type 1 diabetes mellitus: [review]

Desde o Diabetes Control and Complications Trial (DCCT), a terapia insulínica intensiva tem sido direcionada para alcançar valores de glicemia e hemoglobina glicada (HbA1c) tão próximos do normal quanto a segurança permita. Entretanto, a hiperglicemia (especialmente a hiperglicemia pós-prandial) e a hipoglicemia continuam a ser um problema no manejo do diabetes tipo 1. O objetivo de associar outras drogas à terapia insulínica é diminuir a glicemia pós-prandial. A terapia adjunta pode ser dividida em três grupos, conforme seu mecanismo de ação: 1. Aumento da ação da insulina (metformina e tiazolidinedionas); 2. Alteração da liberação de nutrientes no trato gastrintestinal (acarbose e amilina); 3. Outros modos de ação [pirenzepina, fator de crescimento insulina-símile (IGF-1) e peptídeo semelhante ao glucagon 1 (GLP-1). Muitos desses agentes mostraram, em estudos de curto prazo, diminuição de 0,5 por cento a 1 por cento na HbA1c, diminuir a hiperglicemia pós-prandial e as doses diárias de insulina.

Since Diabetes Control and Complications Trial (DCCT), intensive therapy has been directed at achieving glucose and glycosylated hemoglobin (HbA1c) values as close to normal as possible regarding safety issues. However, hyperglycemia (especially postprandial hyperglycemia) and hypoglicemia continue to be problematic in the management of type 1 diabetes. The objective of associating other drugs to insulin therapy is to achieve better metabolic control lowering postprandial blood glucose levels. Adjunctive therapies can be divided in four categories based on their mechanism of action: enhancement of insulin action (e.g. the biguanides and thiazolidinediones), alteration of gastrointestinal nutrient delivery (e.g. acarbose and amylin) and other targets of action (e.g. pirenzepine, insulin-like growth factor I and glucagon-like peptide-1). Many of these agents have been found to be effective in short-term studies with decreases in HbA1c of 0.5-1 percent, lowering postprandial blood glucose levels and decreasing daily insulin doses.