Pdx1- and Ngn3-Cre-Mediated PLAG1 Expression in the Pancreas Leads to Endocrine Hormone Imbalances That Affect Glucose Metabolism

Abstract

Pleomorphic adenoma gene-like 1 (PLAGL1) has been linked to transient neonatal diabetes mellitus. Here, we investigated the role of the related pleomorphic adenoma gene 1 (PLAG1) in glucose homeostasis. PLAG1 transgenic mice in which expression of the PLAG1 transgene can be targeted to different organs by Cre-mediated modulation were crossed with Pdx1-Cre or Ngn3-Cre mice, resulting in double transgenic P1-Pdx1Cre or P1-Ngn3Cre mice, respectively. P1-Pdx1Cre and P1-Ngn3Cre mice developed hyperplasia of pancreatic islets due to increased β-and δ-but not α-cell proliferation. In young P1-Pdx1Cre mice (less than 15 weeks) there was a balanced increase in the pancreatic content of insulin and somatostatin, which was associated with normoglycemia. In older P1-Pdx1Cre mice the pancreatic somatostatin content far exceeded that of insulin, leading to the progressive development of severe hypoglycemia beyond 30 weeks. In contrast, in older P1-Ngn3Cre mice the relative increase of the pancreatic insulin content exceeded that of somatostatin and these mice remained normoglycemic. In conclusion, forced expression of PLAG1 under the control of the Pdx1 or Ngn3 promoter in murine pancreas induces different degrees of endocrine hormone imbalances within the pancreas, which is associated with hypoglycemia in P1-Pdx1Cre mice but not P1-Ngn3Cre mice. These results suggest that once stem cell-derived islet transplantations become possible, the appropriate balance between different hormone-producing cells will need to be preserved to prevent deregulated glucose metabolism.

Methylation and Expression of FTO and PLAG1 Genes in Childhood Obesity: Insight into Anthropometric Parameters and Glucose–Lipid Metabolism

“…In mouse model studies performed by Declercq et al PLAG1 overexpression in pancreatic ꞵ-cells led to hyperplasia of the islets resulting in hyperinsulinemia, which in turn caused compensatory hepatic insulin resistance reflected by increased HOMA-IR values. Glucose levels in the studied mice were decreased or remained normal [ 81 , 82 ]. In humans, PLAG1 expression was found to be increased in blood samples of children with pre-type 1 diabetes [ 83 , 84 , 85 ].…”

The Combined Expression of Pdx1 and MafA with Either Ngn3 or NeuroD Improves the Differentiation Efficiency of Mouse Embryonic Stem Cells into Insulin-Producing Cells

“…The observation is in line with other studies which demonstrated the immaturity of differentiated cells (1, 32). More efforts are needed to promote the terminal differentiation of β-cells with secretory functions (6, 8).…”

Replenishing a Balanced Mixture of Hormone Producing Cells: A Necessary Component in the Stem Cell Based Therapy for Diabetes?

“…It might be important to take the balance of the different endocrine cells present in the transplant into account. Indeed, transgenic mouse models over expressing PLAG1 in different compartments of the pancreas differentially affect the hormone balance and have a different impact on the glucose homeostasis [9]. The Creinducible PLAG1 transgenic mouse model was intercrossed with Pdx1-Cre, Ngn3-Cre and Rip-Cre transgenic to target PLAG1 expression to different compartments of the pancreas (the whole pancreas, the endocrine cells and the β-cells, respectively).…”