Lactogens protect rodent and human beta cells against glucolipotoxicity-induced cell death through Janus kinase‐2 (JAK2)/signal transducer and activator of transcription-5 (STAT5) signalling

Abstract

Aims/hypothesis A leading cause of type 2 diabetes is a reduction in functional beta cell mass partly due to increased beta cell death, triggered by stressors such as glucolipotoxicity (GLT). This study evaluates the hypothesis that lactogens can protect beta cells against GLT and examines the mechanism behind the pro-survival effect. Methods The effect of exogenous treatment or endogenous expression of lactogens on GLT-induced beta cell death was examined in INS-1 cells, and in rodent and human islets. The mechanism behind the pro-survival effect of lactogens was determined using an inhibitor, siRNAs, a dominant negative (DN) mutant, and Cre-lox-mediated gene deletion analysis. Results Lactogens significantly protect INS-1 and primary rodent beta cells against GLT-induced cell death. The prosurvival effect of lactogens in rodent beta cells is mediated through activation of the Janus kinase-2 (JAK2)/signal transducer and activator of transcription-5 (STAT5) signalling pathway. Lactogen-induced increase in the anti-apoptotic B cell lymphoma-extra large (BCLXL) protein is required to mediate its pro-survival effects in both INS-1 cells and primary rodent beta cells. Most importantly, lactogens significantly protect human beta cells against GLT-induced cell death, and their prosurvival effect is also mediated through the JAK2/STAT5 pathway. Conclusions/interpretation These studies, together with previous work, clearly demonstrate the pro-survival nature of lactogens and identify the JAK2/STAT5 pathway as an important mediator of this effect in both rodent and human beta cells. Future studies will determine the effectiveness of this peptide in vivo in the pathophysiology of type 2 diabetes.

The regulation of pre- and post-maturational plasticity of mammalian islet cell mass

“…Highest rate of beta cell proliferation [21,22] Increased insulin secretion, which is, in part, due to transient insulin resistance [44,45] Doubling of beta cell mass by 5 years of age [22] Several-fold increase in beta cell mass from birth to adulthood [50,51] Increase in beta cells per islet and in islet size [51,52] Evidence of beta cell neogenesis and a regenerative response in diabetes [53] Mature beta cells are sensitive to perturbations in cell cycle control [60] Pro-survival effects of lactogen hormones on beta cells [99,100] but not alpha cells [102] Cytoprotective effect of GLP-1 on beta cells [104] GIP stimulates glucagon secretion [113], while GLP-1 inhibits secretion [112] Increase in beta cell mass reported in obesity [119] Reduction in beta cell mass and relative increase in alpha cell mass in diabetes [74] Decline in beta cell function; decline in beta cell replication Beta cell mass remains relatively constant in healthy humans [121] No major alterations in beta cell size [120] Beta cell apoptosis is low and remains constant throughout life [21] In diabetes: Mitochondrial dysfunction, oxidative stress, ER stress and accumulation of intermediate-sized amyloid particles [127] Neonatal age Puberty Adolescence Adulthood Old age diabetes coupled with high expression of IL-6 receptors on alpha cells suggest that this cytokine could contribute to the increased alpha cell mass observed in diabetes [88]. This notion is supported by fasting hypoglucagonaemia and an inability of mice lacking IL-6 to increase their alpha cell mass.…”

“…These hormones stimulate beta cell proliferation in isolated islets, and beta cell mass is reduced by up to 42% in receptor-deficient mice [98]. It has recently been demonstrated that the pro-survival effects of lactogens are mediated by protection against apoptotic pathways controlled by members of the BCL2 gene family in human beta cells [99] and against glucolipotoxicityinduced cell death via Janus kinase 2 (JAK2)/signal transducer and activator of transcription 5 (STAT5) signalling [100]. While in vitro studies have demonstrated that human somatomammotropin stimulates glucagon release [101], in vivo studies in both rats and humans suggest that pregnancy does not affect alpha cell function [102] and that alpha cells might not be involved in the increased insulin demand in response to insulin resistance during normal human pregnancy [103].…”

CCAAT-enhancer-binding Protein β (C/EBPβ) and Downstream Human Placental Growth Hormone Genes Are Targets for Dysregulation in Pregnancies Complicated by Maternal Obesity

“…3B), which is a characteristic of pregnancies complicated with diabetes that require insulin therapy in humans (53). Mouse placental lactogen (PL) I and PL-II expression were also investigated, as they play a major role in maternal metabolic adaptation in the mouse by regulating pancreatic ␤-cell expansion in pregnancy (54,55); glucose intolerance and diabetes develops when prolactin receptors, for which PL-I/II are ligands, are lacking in pregnancy (56). Maternal obesity in hGH/CS-TG mice resulted in an apparent 55% decrease in PL-I RNA levels (p Ͻ 0.05, n ϭ 9) but no significant change in PL-II (Fig.…”

Human islet preparations distributed for research exhibit a variety of insulin-secretory profiles

“…Studies of human islets have provided insight into human islet morphology, ␤-cell proliferation (2,5,6,12), epigenetics (2, 4 -6, 12, 22), regulation of insulin secretion (9,25,28,29), nutrientinduced toxicity (10,23,36), transcription factor regulation (10,14,16), and transplantation of human islet cells (1,5,26). For example, human ␤-cells proliferate at much lower frequency in vivo than mouse ␤-cells (24,27) and respond to different regulators than mouse ␤-cells (2,18).…”