Disruption of Anticipatory Insulin Secretion in Patients with Hyperglycemia and Obesity

Pancreatic beta cells integrate numerous signals in addition to glucose to control insulin secretion rate (ISR). Anticipatory insulin secretion, in which insulin is secreted according to future glucose levels through cephalic and hormonal cues can be effective in minimizing glycemic excursions. We show that in healthy individuals, ISR profile was best correlated with the future blood glucose profile (6+-1 minutes) throughout the postprandial period, demonstrating anticipatory insulin secretion. The glucagon-like peptide-1 (GLP-1) profile was shifted by 9+-3 minutes compared to the blood glucose profile, providing beta cells with information on future glucose levels via a feed forward mechanism. Obesity and pre-diabetes were associated with disruption of anticipatory insulin secretion: The GLP-1 and ISR profiles declined prematurely, contributing to prolonged post-prandial hyperglycemia. Agonism of the GLP-1 Receptor by semaglutide increased ISR and curbed hyperglycemia. However, semaglutide treatment abolished the anticipatory insulin secretion altogether: ISR and glucose profiles overlapped, resulting in a delay between insulin and glucose levels which was associated with higher post-prandial glycemic undershoots. Our data reveal that dysglycaemia disrupts the fine-tuned anticipatory insulin secretion, contributing to glycemic excursions in obesity, prediabetes and type 2 diabetes.