Functional Maturation and Proliferation of Fetal Pancreatic β-Cells

Abstract

We review some key aspects of the maturation of stimulus-secretion coupling and the regulation of DNA replication in the fetal β-cell. During fetal life, the β-cell shows a poor insulin response to glucose, although it responds to several other nonnutrient stimuli. However, chronic exposure to glucose in excess of basal levels can induce maturation of the stimulus-secretion coupling. Studies of glucose metabolism and the transmembrane flow of K⁺ and Ca²⁺ indicate that the attenuated glucose-stimulated insulin release is due to an immature glucose metabolism resulting in impaired regulation of ATP-sensitive K⁺ channels in the plasma membrane of the fetal β-cell. In late fetal life, glucose is also a strong stimulus to β-cell replication, and metabolism of glucose is a prerequisite for this process. Glucose stimulates proliferation by recruiting β-cells from a resting state into a proliferative compartment composed of cells in an active cell cycle. The proliferative compartment comprises <10% of the total islet cell population even at maximal stimulation. The proliferation of fetal β-cells is also regulated by several peptide growth factors such as growth hormone, insulinlike growth factor I, and platelet-derived growth factor. The observation that glucose can both induce precocious maturation of the stimulus-secretion coupling and stimulate proliferation of the fetal β-cell explains the intrauterine hyperinsulinemia and β-cell hyperplasia of the offspring of diabetic mothers with relatively mild hyperglycemia. However, severe hyperglycemia, at least when induced in rats, seems to retard rather than stimulate β-cell growth.