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 beta-cell. During fetal life, the beta-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 beta-cell. In late fetal life, glucose is also a strong stimulus to beta-cell replication, and metabolism of glucose is a prerequisite for this process. Glucose stimulates proliferation by recruiting beta-cells from a resting state into a proliferative compartment composed of cells in an active cell cycle. The proliferative compartment comprises less than 10% of the total islet cell population even at maximal stimulation. The proliferation of fetal beta-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 beta-cell explains the intrauterine hyperinsulinemia and beta-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 beta-cell growth.

Functional characteristics of neonatal rat β cells with distinct markers

“…It has been known for decades that fetal and neonatal b cells, both in rodents and humans, secrete less insulin when stimulated with glucose (Asplund et al 1969, Grill et al 1981, Hellerstrom & Swenne 1991. This glucose unresponsiveness was attributed to an impartial differentiation, in particular relating to specialized features of glucose-sensing b cells such as NADH shuttles (Tan et al 2002), K C ATP channels (Rorsman et al 1989) or general immaturity with expression of disallowed genes (Aye et al 2010, Jermendy et al 2011.…”

“…Here, we studied the b cell in the neonatal pancreas (2-3 days after birth): during the first months of postnatal rat life, the total b cell number expands more than tenfold mainly due to b cell division (Hellmann 1959, Hellman et al 1961, McEvoy 1981, Kaung 1994. Fetal and neonatal b cells have also been reported to have a lower glucose-stimulated insulin secretion (GSIS) than adult b cells (Asplund et al 1969, Grill et al 1981, Hellerstrom & Swenne 1991. Both their higher propensity to proliferate and their lower functional glucose responsiveness are generally considered as two sides of a same coin: both properties are assumed to reflect an incompletely differentiated b cell phenotype that has, on the one hand, not yet assumed full expression of all genes that are quintessential for the specialized glucose--sensing function of a mature b cell (Rorsman et al 1989, Tan et al 2002, Jermendy et al 2011 and, on the other hand, likely maintains expression of protein markers typically encountered in developing tissues.…”

Expressing urine from a gel disposable diaper for biomonitoring using phthalates as an example

“…Weeks 10-14 during the fetal period, when differentiation is occurring and alpha, beta, and delta cells of the endocrine pancreas appear, constitute another period of susceptibility during the development of the pancreas (Sadler, 2000) (Figure 8). The formation of distinct islets of endocrine cells occurs during the later fetal period, but the islets continue to grow and rearrange until about four years of age (Hellerstrom & Swenne, 1991). Similar stages of pancreatic development occur in mice during equivalent developmental periods, and much has been learned in recent years about the genes that control pancreatic development from knockout mice that have disruption of these genes (Figure 8).…”

“…The transcription factors SOX17, PDX1, HLXB9, and PTF1a are known to be essential for normal pancreatic development based on knockout mouse models (Murtaugh & Melton, 2003). It is during the second half of gestation that the endocrine cells begin to differentiate into the specialized cell types containing a single hormone (Hellerstrom & Swenne, 1991). By term, the islets have the appearance of adult tissue, but there are still considerable changes in size and arrangement of the islets for four or more years in humans.…”

Whole-body fuel selection: ‘reproduction’

“…For example, growth of the endocrine pancreas is enhanced in overweight infants of diabetic mothers and decreased in infants that are small-for-dates (Fowden, 1989). This response is likely to be mediated via changes in fetal glucose supply as glucose is a potent stimulator of pancreatic p-cell replication (Hellerstrom & Swenne, 1991), although it should be noted that the insulin secretory response to glucose is much lower during fetal than postnatal life (Bassett et al 1973).…”