Beta-Cell Adaptation to Pregnancy - Role of Calcium Dynamics

Abstract

During pregnancy, the mother develops insulin resistance to shunt nutrients to the growing fetus. As a result, the maternal islets of Langerhans undergo several changes to increase insulin secretion in order to maintain glucose homeostasis and prevent the development of gestational diabetes. These changes include an increase in β-cell proliferation and β-cell mass, upregulation of insulin synthesis and insulin content, enhanced cell-to-cell communication, and a lowering of the glucose threshold for insulin secretion, all of which resulting in an increase in glucose-stimulated insulin secretion. Emerging data suggests that a change in intracellular calcium dynamics occurs in the β-cell during pregnancy as part of the adaptive process. Influx of calcium into β-cells is crucial in the regulation of glucose-stimulated insulin secretion. Calcium fluxes into and out of the cytosol, endoplasmic reticulum, and mitochondria are also important in controlling β-cell function and survival. Here, we review calcium dynamics in islets in response to pregnancy-induced changes in hormones and signaling molecules, and how these changes may enhance insulin secretion to stave off gestational diabetes.

Keywords: apoptosis; beta-cell; calcium; endoplasmic reticulum; insulin secretion; islets; pregnancy.

Figure 1

Glucose is transported into the cytoplasm through glucose transporters (GLUT2 in rodents). Once inside, glucose are metabolized in the mitochondria to generate ATP. An increase in ATP to ADP ratio will cause the closure of ATP-sensitive potassium channel (K_ATP), resulting in membrane depolarization. This leads to the opening of the L-type voltage-dependent Ca²⁺ channels (VDCC) and an influx of Ca²⁺. To maintain [Ca²⁺]_m, Ca²⁺ enters through the MCU or the VDACs and escapes through the NCLX. Ca²⁺ is pumped into the ER through ATP-dependent SERCA, and is released back into the cytosol through the IP3R or RyR calcium channels. Calcium can also flow from the ER to the mitochondria. During pregnancy, placental hormones bind to PrlR, inducing a signal cascade that results in up regulation of several genes to increase insulin production and secretion. These include Lrrc55 and SERCA to maintain [Ca²⁺]_ER, MCU to maintain [Ca²⁺]_m, and INS1/2 to increase insulin expression. VDAC, voltage-dependent anion channels; MCU, mitochondrial Ca²⁺ uniporter; PRLR, prolactin receptor; Prl/PL, prolactin/placental lactogen. The dashed line arrow indicates that influx of calcium induces insulin secretion. Created with BioRender.com.