Pancreatic adaptation in mouse pregnancy has been extensively studied. It is well understood that there is a substantial increase in BCM during gestation in order to compensate for the increased metabolic demand [155,157,158]. In mice, successful adaptation of BCM during pregnancy occurs, in part, due to increased β-cell hypertrophy and proliferation which peak at mid-gestation and are mediated by increased levels of lactogenic hormones [92,155,159]. In mice, placental lactogen-1 is synthesized at early
gestation and peaks on gestational day (GD) 10.5. Mouse placental lactogen-1 is then replaced by mouse placental lactogen 2 which peaks at GD14.5 and remains high throughout the remainder of pregnancy [160]. This is in contrast to humans which only have one placental lactogen (human placental lactogen or human chorionic
somatomammotropin) which gradually increases throughout pregnancy. Furthermore, estrogen levels increase during pregnancy which are associated with decreased β-cell apoptosis, suggesting a protective role for β-cells [161]. Collectively, these changes enable for expansion of BCM which peaks towards the latter portion of gestation
(GD18.5, in mouse comparable to late gestation in human) [159,162]. Increased GSIS, in part due to a decrease in threshold for glucose stimulation, from β-cells further
contributes to the maintenance of euglycemia during the insulin resistant state of
pregnancy [155,163,164]. The adaptive increase in BCM is reversible and returns to pre- pregnancy levels after birth through progesterone-mediated increases in β-cell apoptosis [165], concomitant with decreased levels of placental lactogen reducing β-cell
proliferation. The mechanisms and timing of these changes in mouse pregnancy are well- established. In contrast, due to a scarcity of pancreas samples from pregnant humans, these adaptive mechanisms in human pregnancy remain unclear.
There have only been two studies exploring changes in endocrine pancreas in human pregnancy. Importantly, both studies found an increase in endocrine pancreas mass in pregnancy thus implicating endocrine adaptation to the metabolic changes of pregnancy in both humans and mice. The first study conducted by Van Assche et al. [166] reported a 2.4-fold increase in β-cell fractional area in pregnant women compared to non-pregnant controls. More recently, Butler et al. [96] found a 1.4-fold increase in β-cell fractional area during pregnancy. Differences in the extent of endocrine pancreas adaptation have been postulated to occur due to varying factors between the two studies (such as women who died in car accidents, women with inflammatory diseases, varying pre-pregnancy BMI, wide ranges of gestational ages). Nonetheless, the studies collectively confirm that β-cell expansion occurs in human pregnancy.
The most controversial studied difference between human and mouse compensatory β- cell mechanisms in pregnancy is in regard to β-cell proliferation and neogenesis. In
addition to differences in distribution and composition of islets between mice and humans [28], adult human β-cells are thought to be very stable and rarely divide [167]. The Butler study found that the increased β-cell fractional area was not due to β-cell proliferation, rather there was an increased number of small islets implicating islet neogenesis as the driver of endocrine pancreas adaptation. In contrast, β-cell proliferation has been shown to peak at mid-gestation in mice driving the compensatory adaptations in endocrine pancreas. Nonetheless, prior to concluding islet neogenesis as the sole contributor to BCM expansion in human pregnancy based on the findings of the Butler study it is important to consider that samples were pooled across all gestational ages. Thus, it is plausible that pooling the samples could have diluted an increase in β-cell proliferation if proliferation occurs in a timing-specific manner such as in mice. Furthermore, it is possible that a much lower rate of β-cell proliferation is sufficient to achieve BCM expansion in humans over 9 months of pregnancy vs. 3 weeks in mice which requires a higher rate of proliferation to achieve maximal BCM expansion in a shorter time [154]. Further contributing to the potential difference of β-cell replication as a driver of endocrine pancreas adaptation between humans and mice is the role of lactogenic hormones. In mice, placental lactogen has been shown to drive β-cell replication via signaling through the prolactin receptor (PRLR) in pancreatic β-cells [168]. Signaling via PRLR increases serotonin receptor expression, which upon ligand binding further
regulates β-cell proliferation and insulin secretion [169]. Studies of lactogen treatment in human β-cells have reported conflicting results, with some studies suggesting that
treatment with lactogens increases GSIS and β-cell proliferation [170] in contrast to others which showed a lack of a mitogenic response to lactogens [171]. Differences in humans could be due to lower expression of PRLR on human β-cells than in mice [172]. Evidently there are differences between the behaviour of mouse and human β-cells during pregnancy which require careful consideration when translating animal data to humans. Nonetheless, the scarcity of human pancreas samples in pregnancy poses a challenge to studies in this field.
Although there is evidence to suggest adaptive increases in BCM in pregnancy in both humans and mice, based on current evidence it is likely that the mechanisms leading to
this adaptation differ between mice and humans. Nonetheless, current studies provide clear evidence that both mice and humans rely on compensatory adaptation of β-cells to successfully counter insulin resistance in pregnancy.