Changes in metabolism via modulation of the Interleukin-1 pathway

Abstract

1.1 Inhibition of IL-1β Improves Glycaemia in a Mouse Model for Gestational Diabetes Aims: Gestational diabetes mellitus (GDM) is one of the most common diseases associated with pregnancy. However, the underlying mechanisms remain unclear. Based on the well-documented role of inflammation in type 2 diabetes, the aim was to investigate the role of inflammation in GDM. Methods: We established a mouse model for GDM based on its two major risk factors, obesity and aging. Results: In these GDM mice, we observed increased IL-1β expression in the uterus and the placenta, along with elevated circulating IL-1β concentrations compared to normoglycaemic pregnant mice. Treatment with an anti-IL-1β antibody improved glucose tolerance of GDM mice without apparent deleterious effects for the fetuses. Finally, IL-1β antagonism showed a tendency for reduced plasma corticosterone concentrations, possibly explaining the metabolic improvement. Conclusions: We conclude that IL-1β is a causal driver of impaired glucose tolerance in GDM. 1.2 β-Cell-Specific Overexpression of pro-IL-1β as a Mouse Model for Human Type 2 Diabetes Aim: Impaired islet function is a key element of impaired glucose homeostasis in type 2 diabetes. Chronic local low-grade inflammation driven by Interleukin-1β (IL-1β) in the islets was associated with impaired islet function. However, the source and the importance of islet driven IL-1β remains unclear. The aim was to increase β-cell-derived IL-1β in mice to identify a causal role of local IL-1β on glucose homeostasis. Methods: We generated an inducible knock-in mouse to overexpress pro-IL-1β and crossed it with two Cre-driver mouse lines containing either the inducible Pdx1ER or the constitutive Rip promoter driving Cre recombinase expression, to obtain two mouse lines overexpressing pro-IL-1β in β cells. Mice were fed standard chow diet or high-fat diet to investigate the effect of the pro-IL-1β overexpression in lean and obese mice. We developed a bioassay to detect biologically active IL-1β. Results: Both strains had increased islet-derived active IL-1β as indicated by increased islet mRNA expression of Il1b and IL-1β-dependent cytokines, as well as by increased IL-1β bioactivity. When fed a high-fat diet, insulin secretion was impaired in both transgenic lines compared to their littermate controls. However, only Pdx1ER Cre-driven pro-IL-1β overexpressor mice had impaired glucose tolerance along with decreased islet size and function. Treatment of these mice with an anti-IL-1β antibody rescued the deterioration of islet function. Conclusion: β-cell-specific overexpression of pro-IL-1β results in local, biologically active IL-1β production with subsequent inflammation and impairment of insulin secretion. 1.3 Overexpression of pro-IL-1β in Myeloid Cells Induces Insulin Resistance and Impairs Insulin Secretion in Mice Aim: Chronic low-grade inflammation is observed in obese patients and is associated with defective insulin production and action with subsequent type 2 diabetes (T2D). The aim was to induce a subtle systemic, IL-1β-driven inflammation in mice to generate a model of IL-1β-dependent aspects of chronic-low-grade inflammation. Methods: We generated a Lyz2 Cre recombinase-driven pro-IL-1β overexpressing mouse to specifically overexpress pro-IL-1β in myeloid cells. We confirmed the overexpression in various myeloid cells-containing tissues. We assessed glucose tolerance and insulin secretion and insulin tolerance at various ages. Results: Myeloid cells-specific overexpression of pro-IL-1β resulted in a subtle increase of baseline IL-1β protein in morning serum and in peritoneal macrophages as well as in islets in chow-fed animals. Glucose tolerance was transiently impaired and insulin resistance was increased in chow-fed myeloid cells-specific pro-IL-1β overexpressor mice at the age of 23 weeks compared to littermate controls. Upon high-fat diet feeding, insulin secretion but not glucose tolerance was impaired in myeloid cells-specific pro-IL-1β overexpressor mice at the age of 52 weeks compared to littermate controls. Conclusion: Myeloid cells-specific overexpression of pro-IL-1β impairs glucose tolerance and increases insulin resistance and mimics aspects of human T2D.