Phosphatases are predicted to govern prolactin-mediated JAK-STAT signaling in pancreatic beta cells

• Published in: bioRxiv
• Main Authors: Simoni, Ariella, Huber, Holly, Georgia, Senta K, Finley, Stacey D
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 15.10.2021
• Subjects: Beta cells; Blood glucose; Cell culture; Cell proliferation; Computer applications; Diabetes; Diabetes mellitus; Insulin; Insulin secretion; Pancreas; Patients; Phosphatase; Pregnancy; Prolactin; Proteins; Regression analysis; Secretion; Signal transduction
• DOI: 10.1101/2021.10.14.464474

Patients with diabetes are unable to produce a sufficient amount of insulin to properly regulate their blood-glucose levels. One potential method of treating diabetes is to increase the number of insulin-secreting beta cells in the pancreas to enhance insulin secretion. It is known that during pregnancy, pancreatic beta cells proliferate in response to the pregnancy hormone, prolactin. Leveraging this proliferative response to prolactin may be a strategy to restore endogenous insulin production for patients with diabetes. To investigate this potential treatment, we previously developed a computational model to represent the prolactin-mediated JAK-STAT signaling pathway in pancreatic beta cells. However, this model does not account for variability in protein expression that naturally occurs between cells. Here, we applied the model to understand how heterogeneity affects the dynamics of JAK-STAT signaling. We simulated a sample of 10,000 heterogeneous cells with varying initial protein concentrations responding to prolactin stimulation. We used partial least squares regression to analyze the significance and role of each of the varied protein concentrations in producing the response of the cell. Our regression models predict that the concentrations of the cytosolic and nuclear phosphatases strongly influence the response of the cell. The model also predicts that increasing prolactin receptor strengthens negative feedback mediated by the inhibitor SOCS. These findings reveal biological targets that can potentially be used to modulate the proliferation of pancreatic beta cells to enhance insulin secretion and beta cell regeneration in the context of diabetes. Competing Interest Statement The authors have declared no competing interest.