Inhibition of IL-1beta improves Glycaemia in a Mouse Model for Gestational Diabetes.

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. We established a mouse model for GDM on the basis of its two major risk factors, obesity and aging. In these GDM mice, we observed increased Interleukin-1ß (IL-1ß) expression in the uterus and the placenta along with elevated circulating IL-1ß concentrations compared to normoglycemic pregnant mice. Treatment with an anti-IL-1ß antibody improved glucose-tolerance of GDM mice without apparent deleterious effects for the fetus. Finally, IL-1ß antagonism showed a tendency for reduced plasma corticosterone concentrations, possibly explaining the metabolic improvement. We conclude that IL-1ß is a causal driver of impaired glucose tolerance in GDM.

Pancreatic α Cell-Derived Glucagon-Related Peptides Are Required for ß Cell Adaptation and Glucose Homeostasis.

Pancreatic α cells may process proglucagon not only to glucagon but also to glucagon-like peptide-1 (GLP-1). However, the biological relevance of paracrine GLP-1 for ß cell function remains unclear. We studied effects of locally derived insulin secretagogues on ß cell function and glucose homeostasis using mice with α cell ablation and with α cell-specific GLP-1 deficiency. Normally, intestinal GLP-1 compensates for the lack of α cell-derived GLP-1. However, upon aging and metabolic stress, glucose tolerance is impaired. This was partly rescued with the DPP-4 inhibitor sitagliptin, but not with glucagon administration. In isolated islets from these mice, glucose-stimulated insulin secretion was heavily impaired and exogenous GLP-1 or glucagon rescued insulin secretion. These data highlight the importance of α cell-derived GLP-1 for glucose homeostasis during metabolic stress and may impact on the clinical use of systemic GLP-1 agonists versus stabilizing local α cell-derived GLP-1 by DPP-4 inhibitors in type 2 diabetes.