Gastrin treatment stimulates beta cell regeneration and improves glucose tolerance in 95% pancreatectomized rats

β-Cell mass reduction is a central aspect in the development of type 1 and type 2 diabetes, and substitution or regeneration of the lost β-cells is a potentially curative treatment of diabetes. To study the effects of gastrin on β-cell mass in rats with 95% pancreatectomy (95%-Px), a model of pancreatic regeneration, rats underwent 95% Px or sham Px and were treated with [15 leu] gastrin-17 (Px+G and S+G) or vehicle (Px+V and S+V) for 15 d. In 95% Px rats, gastrin treatment reduced hyperglycemia (280 ± 52 mg vs. 436 ± 51 mg/dl, P < 0.05), and increased β-cell mass (1.15 ± 0.15 mg)) compared with vehicle-treated rats (0.67 ± 0.15 mg, P < 0.05). Gastrin treatment induced β-cell regeneration by enhancing β-cell neogenesis (increased number of extraislet β-cells in Px+G: 0.42 ± 0.05 cells/mm(2) vs. Px+V: 0.27 ± 0.07 cells/mm(2), P < 0.05, and pancreatic and duodenal homeobox 1 expression in ductal cells of Px+G: 1.21 ± 0.38% vs. Px+V: 0.23 ± 0.10%, P < 0.05) and replication (Px+G: 1.65 ± 0.26% vs. S+V: 0.64 ± 0.14%; P < 0.05). In addition, reduced β-cell apoptosis contributed to the increased β-cell mass in gastrin-treated rats (Px+G: 0.07 ± 0.02%, Px+V: 0.23 ± 0.05%; P < 0.05). Gastrin action on β-cell regeneration and survival increased β-cell mass and improved glucose tolerance in 95% Px rats, supporting a potential role of gastrin in the treatment of diabetes

Efectos de la administración de un análogo del GLP-1 sobre las células endocrinas del páncreas

[spa] Un aspecto central del desarrollo de la diabetes tanto de tipo 1 como de tipo 2 es la reducción en el número de células productoras de insulina. En la diabetes de tipo 1, la masa de células beta se pierde debido a la destrucción autoinmune de las células beta, mientras que en la diabetes de tipo 2 existe una alteración en la función beta que junto con la reducción parcial de la masa de células beta no permite hacer frente al aumento en la demanda metabólica generada por la resistencia a la insulina. Por tanto, los tratamientos que se proponen como potencialmente capaces de curar ambos tipos de diabetes son los que están destinados a restablecer o regenerar la masa beta. En esta óptica nos hemos interesado por los agonistas del receptor de GLP-1. El GLP-1 es una potente hormona glucoreguladora producida por las células L enteroendocrinas en respuesta a la ingesta oral. En el páncreas, el GLP-1 actúa como una incretina estimulando la secreción de insulina en respuesta a la ingesta de forma dependiente de glucosa. Por otra parte, se ha descrito que el GLP-1 es también capaz de aumentar la masa beta insular estimulando la proliferación y la neogénesis de las células beta e inhibiendo su apoptosis. Nuestro estudio describe los efectos in vivo de la administración de un análogo del GLP-1 sobre la regeneración de las células beta en la pancreactectomía subtotal y sobre la masa de células beta restablecida por transplante de islotes. La hipótesis básica del proyecto es que el análogo del GLP-1 es capaz de aumentar la masa beta insular tanto en una situación de regeneración como de sustitución de la masa beta. El objetivo es caracterizar la acción del tratamiento con el análogo del GLP-1 y comprobar si la acción del análogo puede verse modificada según la estrategia elegida para restablecer la glucemia normal del animal. Los efectos de la administración del análogo del GLP-1 podrían verse afectados por la situación de los islotes, el contexto glucémico del animal o la presencia de inflamación. En el presente estudio hemos demostrado que el tratamiento con el análogo del GLP-1 en dos modelos diferentes de deficiencia de masa beta tiene claros efectos sobre la regulación de la glucosa sanguínea y un efecto estimulador de la proliferación sobre las células beta. En las ratas pancreatectomizadas, el tratamiento con el análogo del GLP-1 evitó la aparición de hiperglucemia severa y aumentó la masa de células beta por aumento de neogénesis de células beta y proliferación de las mismas. En los animales transplantados los efectos fueron menos aparentes, aunque detectamos una tendencia a un mejor control metabólico y un discreto aumento de la replicación de las células beta en caso de los animales diabéticos. No se pudo demostrar protección frente a la apoptosis por el tratamiento con el GLP-1 en ninguno de nuestros grupos experimentales. En conjunto, los resultados muestran que los efectos de GLP-1 sobre la masa beta pueden ser diferentes dependiendo de las características y situación del receptor del tratamiento. En esta tesis se muestra que el mismo tratamiento puede incrementar de forma muy significativa la masa beta en modelos de regeneración en los que induce un aumento de la neogénesis y replicación beta, mientras que, en otros modelos como el trasplante de islotes, el efecto sobre la replicación fue muy escaso o inexistente, y no modificó la masa beta.[eng] Diabetes is a major public health problem characterized by an absolute (type 1) or relative (type 2) loss of the insulin producing beta cells of the pancreas Therapies aimed at maintaining or restoring the existing beta cells in diabetic patients remain highly needed. GLP-1 is a glucoregulator hormone, produced by the L cells of the gut in response to oral ingestion. In the pancreas, GLP-1 stimulates insulin secretion in response to ingestion in a glucose-dependent manner. Moreover, it has been shown that GLP-1 could also increase beta cell mass by stimulating proliferation and neogenesis as well as by inhibiting apoptosis. Our study describes the in vivo effects of the administration of a GLP-1 analogue on beta cell regeneration in the subtotal pancreatectomy and on beta cell mass in islet transplantation. The aim of the study is to characterise the effects of the GLP-1 analogue treatment and check if the analogue action could be modified according to the strategy that has been used to restore the normoglycemia of the animal. The present study demonstrates that GLP-1 analogue treatment in two different models of beta cell mass deficiency has clear effects on the blood glucose regulation and proliferation stimulating effects on the beta cells. In the pancreatectomized rats, GLP-1 analogue treatment prevented severe hiperglycemia and increased the beta cell mass by increasing beta cell replication and neogenesis. In transplanted animals, effects were less apparent but we detected a trend toward a better metabolic control and a discrete increase in beta cell replication in diabetic animals. We did not showed protection against apoptosis with GLP-1 analogue treatment in neither of the experimental groups. Taken together, these results show that the GLP-1 effects on beta cell mass can be modified by characteristics of the recipient of treatment. This thesis shows that the same treatment can increase in a very significant way beta cell mass in regeneration models, where it induces an increase in neogenesis and replication while, in other models as transplantation, the effect on replication was poor or inexistent and the beta cell mass was not modified

Gastrin treatment stimulates beta cell regeneration and improves glucose tolerance in 95% pancreatectomized rats

β-Cell mass reduction is a central aspect in the development of type 1 and type 2 diabetes, and substitution or regeneration of the lost β-cells is a potentially curative treatment of diabetes. To study the effects of gastrin on β-cell mass in rats with 95% pancreatectomy (95%-Px), a model of pancreatic regeneration, rats underwent 95% Px or sham Px and were treated with [15 leu] gastrin-17 (Px+G and S+G) or vehicle (Px+V and S+V) for 15 d. In 95% Px rats, gastrin treatment reduced hyperglycemia (280 ± 52 mg vs. 436 ± 51 mg/dl, P < 0.05), and increased β-cell mass (1.15 ± 0.15 mg)) compared with vehicle-treated rats (0.67 ± 0.15 mg, P < 0.05). Gastrin treatment induced β-cell regeneration by enhancing β-cell neogenesis (increased number of extraislet β-cells in Px+G: 0.42 ± 0.05 cells/mm(2) vs. Px+V: 0.27 ± 0.07 cells/mm(2), P < 0.05, and pancreatic and duodenal homeobox 1 expression in ductal cells of Px+G: 1.21 ± 0.38% vs. Px+V: 0.23 ± 0.10%, P < 0.05) and replication (Px+G: 1.65 ± 0.26% vs. S+V: 0.64 ± 0.14%; P < 0.05). In addition, reduced β-cell apoptosis contributed to the increased β-cell mass in gastrin-treated rats (Px+G: 0.07 ± 0.02%, Px+V: 0.23 ± 0.05%; P < 0.05). Gastrin action on β-cell regeneration and survival increased β-cell mass and improved glucose tolerance in 95% Px rats, supporting a potential role of gastrin in the treatment of diabetes

Gastrin treatment stimulates beta cell regeneration and improves glucose tolerance in 95% pancreatectomized rats

β-Cell mass reduction is a central aspect in the development of type 1 and type 2 diabetes, and substitution or regeneration of the lost β-cells is a potentially curative treatment of diabetes. To study the effects of gastrin on β-cell mass in rats with 95% pancreatectomy (95%-Px), a model of pancreatic regeneration, rats underwent 95% Px or sham Px and were treated with [15 leu] gastrin-17 (Px+G and S+G) or vehicle (Px+V and S+V) for 15 d. In 95% Px rats, gastrin treatment reduced hyperglycemia (280 ± 52 mg vs. 436 ± 51 mg/dl, P < 0.05), and increased β-cell mass (1.15 ± 0.15 mg)) compared with vehicle-treated rats (0.67 ± 0.15 mg, P < 0.05). Gastrin treatment induced β-cell regeneration by enhancing β-cell neogenesis (increased number of extraislet β-cells in Px+G: 0.42 ± 0.05 cells/mm(2) vs. Px+V: 0.27 ± 0.07 cells/mm(2), P < 0.05, and pancreatic and duodenal homeobox 1 expression in ductal cells of Px+G: 1.21 ± 0.38% vs. Px+V: 0.23 ± 0.10%, P < 0.05) and replication (Px+G: 1.65 ± 0.26% vs. S+V: 0.64 ± 0.14%; P < 0.05). In addition, reduced β-cell apoptosis contributed to the increased β-cell mass in gastrin-treated rats (Px+G: 0.07 ± 0.02%, Px+V: 0.23 ± 0.05%; P < 0.05). Gastrin action on β-cell regeneration and survival increased β-cell mass and improved glucose tolerance in 95% Px rats, supporting a potential role of gastrin in the treatment of diabetes

Heterozygous inactivation of the Na/Ca exchanger increases glucose-induced insulin release, b-cell proliferation, and mass

Objective: we have previously shown that overexpression of the Na-Ca exchanger (NCX1), a protein responsible for Ca2+ extrusion from cells, increases β-cell programmed cell death (apoptosis) and reduces β-cell proliferation. To further characterize the role of NCX1 in β-cells under in vivo conditions, we developed and characterized mice deficient for NCX1. Research design and methods: biologic and morphologic methods (Ca2+ imaging, Ca2+ uptake, glucose metabolism, insulin release, and point counting morphometry) were used to assess β-cell function in vitro. Blood glucose and insulin levels were measured to assess glucose metabolism and insulin sensitivity in vivo. Islets were transplanted under the kidney capsule to assess their performance to revert diabetes in alloxan-diabetic mice. Results: heterozygous inactivation of Ncx1 in mice induced an increase in glucose-induced insulin release, with a major enhancement of its first and second phase. This was paralleled by an increase in β-cell proliferation and mass. The mutation also increased β-cell insulin content, proinsulin immunostaining, glucose-induced Ca2+ uptake, and β-cell resistance to hypoxia. In addition, Ncx1+/− islets showed a two- to four-times higher rate of diabetes cure than Ncx1+/+ islets when transplanted into diabetic animals. Conclusions: downregulation of the Na/Ca exchanger leads to an increase in β-cell function, proliferation, mass, and resistance to physiologic stress, namely to various changes in β-cell function that are opposite to the major abnormalities seen in type 2 diabetes. This provides a unique model for the prevention and treatment of β-cell dysfunction in type 2 diabetes and after islet transplantation