Pregnancy is a physiological condition associated with β-cell mass
expansion occurring in response to increased insulin demand. If the insulin resistance is
not compensated by proper augmented insulin production gestational diabetes will
occur. As reviewed herein, pregnancy induced hormonal changes have occupied
scientists since the beginning of the last century where important discoveries of the
hormonal regulation of metabolism during pregnancy have been accomplished. Of the
multiple hormonal and metabolic changes the somatolactogenic hormones, placental
lactogens (PL) and placental growth hormone (GH-V) are the most described and are
found to have dual roles by induction of insulin resistance and promotion of β-cell
function and expansion. More recently, the direct effects on isolated pancreatic islets
and the influence of signaling pathways involved in the adaptation of β-cell growth and
function during pregnancy have been elucidated. This has identified contributions of a
number of known peptide hormones and growth factors (EGF, NGF, HGF, IGFs,
GLP-1) and steroid hormones (progesterone, estrogens, glucocorticoids). In addition,
glucokinase has been found to be essential for the both proliferation and glucose
stimulated insulin secretion during pregnancy. Some transcriptional activators and
repressors (FoxM1, HNF4α, Myc, Bcl6, Men1) have been implicated in β-cell growth
and survival, but also systemic factors like betatrophin, serotonin and osteoprotegerin
have been reported to stimulate β-cell proliferation during pregnancy. Gene expression
studies and proteomics of islets from pregnant rodent have furthermore revealed
upregulation of a number of genes (e.g. cyclophilin B, stathmins, dlk-1, trefoil factor-3
and several others) that may influence β-cell growth and function during pregnancy
although the mechanisms driving these changes are not yet known. Similarly, circulating factors in serum from pregnant women have been identified. Among the
stimulating factors are peptide fragments of alpha-1 antitrypsin, kininogen-1,
apolipoprotein-1, fibrinogen alpha chain and angiotensinogen. An intriguing question
remains about the origin of the increased β-cell mass in pregnancy. In humans, studies
have primarily reported an increase in the number of small islets, suggesting that
neogenesis as the primary driver of β-cell mass expansion in human. In rodents,
however, β-cell replication is believed to be the primary mechanism, although
increased expression the neogenesis marker, neurogenin-3, has also been reported in
pancreas of pregnant rodents. Interestingly, recent studies have suggested that the
apparent loss of β-cells occurring during development of diabetes may be due to dedifferentiation
rather than cell death, suggesting contributions from mechanisms going
beyond neogenesis and replication. In summary, gestational diabetes (GDM) is
associated with lack of appropriate adaptation of the β-cells that may be due to a
reduced pre-pregnancy β-cell mass, lack of stimulating hormones and growth factors or
appearance of β cytotoxic metabolites or factors. This chapter reviews the existing
knowledge of multiple factors and put forward new mechanisms of pregnancy induced
β-cell mass expansion, which are not yet completely understood.
Keywords: Diabetes, Growth hormone, Insulin, Pancreatic β-cells, Pregnancy,
Prolactin.
