Increased alpha and beta cell mass during mouse pregnancy is not dependent on transdifferentiation

Abstract

Maternal pancreatic beta-cell mass (BCM) increases during pregnancy to compensate for relative insulin resistance. If BCM expansion is suboptimal, gestational diabetes mellitus can develop. Alpha-cell mass (ACM) also changes during pregnancy, but there is a lack of information about α-cell plasticity in pregnancy and whether α- to β-cell transdifferentiation can occur. To investigate this, we used a mouse model of gestational glucose intolerance induced by feeding low-protein (LP) diet from conception until weaning and compared pregnant female offspring to control diet-fed animals. Control and LP pancreata were collected for immunohistochemical analysis and serum glucagon levels were measured. In order to lineage trace α- to β-cell conversion, we utilized transgenic mice expressing yellow fluorescent protein behind the proglucagon gene promoter (Gcg-Cre/YFP) and collected pancreata for histology at various gestational timepoints. Alpha-cell proliferation increased significantly at gestational day (GD) 9.5 in control pregnancies resulting in an increased ACM at GD18.5, and this was significantly reduced in LP animals. Despite these changes, serum glucagon was higher in LP mice at GD18.5. Pregnant Gcg-Cre/YFP mice showed no increase in the abundance of insulin+YFP+glucagon– cells (phenotypic β-cells). A second population of insulin+YFP+glucagon+ cells was identified which also did not alter during pregnancy. However, there was an altered anatomical distribution within islets with fewer insulin+YFP+glucagon– cells but more insulin+YFP+glucagon+ cells being present in the islet mantle at GD18.5. These findings demonstrate that dynamic changes in ACM occur during normal pregnancy and were altered in glucose-intolerant pregnancies.

Adaptive Changes in Glucose Homeostasis and Islet Function During Pregnancy: A Targeted Metabolomics Study in Mice

“…Szlapinski et al. showed a significantly increased alpha-cell proliferation at GD 9.5 in mouse pregnancies, resulting in an increased alpha-cell mass at GD 18.5 ( 41 ). Beta-cell proliferation and beta-cell mass were also observed to increase dramatically during the pregnancy ( 39 ).…”

Acetone Ingestion Mimics a Fasting State to Improve Glucose Tolerance in a Mouse Model of Gestational Hyperglycemia

“…These findings are in agreement with those observed following transient fasting of non-pregnant mice, where a greater number of transitional α- to β-cells were observed upon re-feeding [ 31 ], resulting in β-cell regeneration and a rescue from diabetes. However, we previously found that α- to β-cell trans-differentiation did not contribute to the increased BCM that normally occurs during mouse pregnancy [ 32 ]. It is possible that the bihormonal cells represent an intermediate stage in the functional maturation of resident β-cell progenitors, which we previously showed to contribute to the increased BCM of pregnancy in mice [ 11 ].…”

Beta-cell compensation and gestational diabetes

“…There is emerging evidence that pregnancy is accompanied by α-cell mass expansion ( 98 , 99 , 100 ). This effect results from increased α-cell replication but not from transdifferentiation of exocrine cell types ( 100 ).…”

“…There is emerging evidence that pregnancy is accompanied by α-cell mass expansion ( 98 , 99 , 100 ). This effect results from increased α-cell replication but not from transdifferentiation of exocrine cell types ( 100 ). However, despite a 2-fold increment of α-cell mass at gestational day 18.5, plasma glucagon levels remain unchanged in pregnant mice ( 98 , 99 , 100 ).…”

“…This effect results from increased α-cell replication but not from transdifferentiation of exocrine cell types ( 100 ). However, despite a 2-fold increment of α-cell mass at gestational day 18.5, plasma glucagon levels remain unchanged in pregnant mice ( 98 , 99 , 100 ). To understand the underlying physiology of α-cell adaptation to pregnancy, Qiao et al.…”