Pancreatic islets, the islets of Langerhans, mature and become competent in regulating blood glucose levels after birth. This process coincides with a transient high density of pancreatic macrophages which interact closely with pancreatic islet β cells. Here we explore if and how these macrophages contribute to the postnatal islet maturation important for the formation of healthy islets that produce and secrete hormones that regulate glucose homeostasis. Previous preliminary observations demonstrate that neonatal infections deplete the pancreas of the macrophages, leading to β cell failure and insulin resistance. Dysregulated blood glucose levels resulting in hyperglycemia are early signs of type 2 diabetes, a metabolic disorder characterized by failure of β cells to clear excess blood glucose levels. In this study, the effect of transient neonatal infections combined with exposure to high fat diet on glucose and insulin tolerance was investigated in mice in order to investigate if these individuals were more susceptible to type 2 diabetes development. In parallel, human monocytes were differentiated into macrophages and co-cultured with stem cell-derived islets of Langerhans to investigate the mechanisms by which macrophages contribute to pancreatic islet maturation.