Homeostatic control of β-cell mass in rodents and humans. (a) Control of β-cell mass (the fulcrum of the balance) is based on the relative contribution of processes that result in β-cell gain (replication, hypertrophy, neogenesis) and β-cell loss (death, atrophy, autophagy). A net increase in β-cell mass occurs when mechanisms involved in β-cell gain exceed those of β-cell loss. Improper regulation of this balance is a major contributor to the onset of diabetes. (b) Experimental evidence in rodents and humans of β-cell gain mechanisms (β-cell replication, hypertrophy and neogenesis) during adaptive increases in β-cell mass in response to various increases in metabolic loads (neonatal period, pregnancy, obesity and β-cell recovery after injury). Dark square, evidence for β-cell gain mechanism only in rodent models; white square, only in human autopsy pancreatic samples; striped square, evidence both in rodents and humans; question mark square, no current evidence. This highlights the plasticity of the β-cell’s ability to increase its mass during different physiological and pathological (hyperglycemic) states and the relatively large amount of knowledge that remains to be uncovered, especially with respect to human β-cell biology.

β-cell mass dynamics during pregnancy in the mouse. (a) β-cell mass is increased by both (b) β-cell replication and (c) β-cell hypertrophy during the first two-thirds of gestation. After parturition, maternal β-cell mass returns to non-pregnant levels by (d) β-cell apoptosis, which increases through the end of pregnancy and is still detected 4–6 days after birth. The graphs represent approximate changes in these processes before pregnancy (red, non-pregnant), over the course of pregnancy (light purple) and post-partum (green), and show what is believed to occur during human pregnancy based on rodent studies. Serum lactogenic hormone levels during pregnancy are increased from gestational day 10 to 20, pointing to their key role in the adaptation of the islet to pregnancy [9].

Known mechanisms responsible for β-cell gain during pregnancy. (a) Activation of PRL receptors upon binding of lactogens (PRL or placental lactogen) plays a pivotal role in the adaptation of the β-cell to pregnancy. Downstream signaling pathways of the PRL receptor include STAT5, phosphatidylinositol 3-kinase (PI3K) and MAPK pathways, targets of which have been implicated to lead to increased β-cell proliferation, survival and size. (b) Known transcription factors (listed with their target genes) that regulate the increase in β-cell mass during pregnancy. Red arrow indicates an increase in expression of genes in the islet during pregnancy day 14.5 [10]. (c) Possible PRL receptor independent mechanisms leading to β-cell gain mechanisms. For example, increased HGF levels in the islet endothelium correlates with increased β-cell proliferation in pregnant rats [83]. However, much is still to be discovered, as evidenced by the recent finding that upregulation of the developmental transcription factor MafB in β-cells occurs during pregnancy [84].

β-cell expansion in response to increased metabolic loads. (i) Normally, β-cells in the mouse undergo very little turnover, exhibiting a low basal rate of replication. Pregnancy, obesity and β-cell recovery after injury are examples in which the systemic demand for insulin increases. (ii) To successfully compensate for the relative insulin deficiency that occurs during pregnancy, both proliferative and survival pathways are activated in β-cells, protecting against the onset of diabetes. Recent experimental evidence also suggests the same requirement during obesity and β-cell recovery after injury [10]. An increase in β-cell size also accompanies β-cell expansion occurring during pregnancy and obesity. (iii) If the expanding β-cell mass remains predisposed to β-cell apoptosis resulting from either an increased vulnerability during replication or from byproducts of increased metabolic load, β-cell compensation fails. If β-cell apoptosis overcomes β-cell renewal mechanisms and persists for a prolonged amount of time, diabetes might ensue. Apoptotic β-cells are often organized in pairs in pancreatic tissue sections from type 2 diabetics [57].