2068-P: Beta-Cell Compensation to Pubertal Insulin Resistance Is Compromised in High-Fat Fed Rats and Impairs Glucose Homeostasis Later in Life

Puberty is a time of hormonal changes associated with insulin resistance (IR). Although insulin sensitivity is restored at the end of puberty in healthy youth, it does not resolve in obese adolescents leading to an increased risk of metabolic disease such as T2D. During pregnancy-induced IR, pancreatic β cells increase their functional mass to maintain glucose homeostasis. During puberty, however, the mechanism of β-cell compensation to IR and its role in glucose metabolism in adulthood have not been established. In this study we characterized pancreatic β-cell adaptation to pubertal IR in rats and evaluated the effect of metabolic stress during puberty on glucose homeostasis in adult animals. Methods: Wistar rats were fed a chow or high fat diet (HFD) during puberty. Fasted plasma insulin and glucose tolerance were determined from weaning to adulthood. β-cell proliferation was assessed by immunostaining of pancreatic cryosections for Ki67 and insulin or Nkx6.1. β-cell mass was measured by morphometric analysis of insulin staining. Isolated islets from Wistar rats were exposed during 72h to the serum of prepubertal, pubertal, or postpubertal animals and β-cell proliferation was evaluated by flow cytometry using insulin and EdU antibodies. Results: During puberty, glucose intolerance was associated with an increase in insulin levels, suggestive of IR. Accordingly, puberty was characterized by a pulse in β-cell proliferation and a rise in β-cell mass. Pubertal but not pre or post pubertal rat serum induced β-cell proliferation in isolated islets. HFD led to a decrease in β-cell proliferation during puberty with impaired glucose tolerance and defective insulin secretion in adult animals. Conclusion: During puberty in rats, β cells proliferate to compensate for IR. Metabolic stress during puberty impairs glucose homeostasis later in life. Future studies will identify the circulating factor(s) that trigger β-cell expansion during puberty. Disclosure A. Castell: None. G. Fergusson: None. M. Ethier: None. C. Tremblay: None. J. Ghislain: None. V. Poitout: None.