Cardiotrophin 1 protects beta cells from apoptosis and prevents streptozotocin-induced diabetes in a mouse model

Abstract

Aims/hypothesis Cardiotrophin 1 (CT-1) is a recently described cytokine originally isolated from the heart where it has been shown to play an important role in apoptotic protection of cardiomyocytes and heart hypertrophy. Its beneficial properties have also been described in other organs such as liver and neuromuscular tissue. In the present study, we investigated whether CT-1 can confer protection against pro-apoptotic stimuli in pancreatic beta cells, and its role in insulin secretion and diabetes development.Methods The effects of CT-1 on apoptosis and function were studied using MIN6B1 cells and freshly isolated murine pancreatic islets. The impact on the development of diabetes was evaluated in Ct1-null (Ct1 −/− ) mice (the gene Ct1 is also known as Ctf1) using two streptozotocin (STZ)-induced models of diabetes. Results CT-1 has a protective effect in MIN6B1 cells and murine islets under the pro-apoptotic stimulus of serum deprivation, which correlates with the expression of B cell lymphoma-extra large, or following exposure to a mixture of cytokines. In addition, CT-1 enhances glucose-stimulated insulin secretion in MIN6B1 cells and this was repressed by inhibitors of phospholipase C. Furthermore, Ct1 −/− mice were more prone to develop diabetes, and their glucose tolerance test showed impaired plasma glucose clearance which correlated with decreased pancreatic insulin secretion. Conclusions/interpretation The results obtained from both in vitro and in vivo experiments show that CT-1 improves beta cell function and survival, and protects mice against STZ-induced diabetes.

Cardiotrophin-1: A multifaceted cytokine

“…An interesting finding of our group is that the glucose-lowering properties of CT-1 are also observed in mice with streptozotocin (STZ)-induced insulin deficiency, demonstrating an insulin-independent effect of CT-1 on glucose homeostasis [52]. In line with this, the study of Jimé nez-Gonzá lez et al [107] found that CT-1 has a protective effect from apoptosis in MIN6B1 cells and murine islets, and that CT-1 enhances glucose-stimulated insulin secretion in MIN6B1 cells. Studies in vitro and in vivo support the insulin-sensitizing effect of CT-1 in muscle [52].…”

Prediction of type 1 diabetes in Sardinian schoolchildren using islet cell autoantibodies: 10-year follow-up of the Sardinian schoolchildren type 1 diabetes prediction study

“…These data give a solid rationale to continue multiple autoantibody screening among young Sardinians. It could identify individuals potentially eligible for enrolment in clinical trials aimed at reducing the risk of progression from islet autoimmunity towards clinical T1DM [38][39][40][41].…”

Common Genetic Variation in the Human CTF1 Locus, Encoding Cardiotrophin-1, Determines Insulin Sensitivity

“…Beside regenerative and anti-apoptotic functions in several tissues, e.g. motoneurons and hepatocytes [7], [8], in a recent study, CT-1 was reported to protect beta cells from apoptosis and to enhance glucose-stimulated insulin secretion, and additionally, to prevent streptozotocin-induced diabetes in a mouse model [9].…”

“…For this reason, and because of its high expression in tissues that play a pivotal role in the pathogenesis of type 2 diabetes like beta-cells, skeletal muscle and liver [6], [8], [9], the CT-1 gene ( CTF1) would be a promising candidate to associate with diabetes, insulin secretion and insulin sensitivity. Thus, we asked whether genetic variation within or near CTF1 has an impact on insulin secretion and insulin sensitivity in humans.…”