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Review
. 2023 Dec;299(12):105405.
doi: 10.1016/j.jbc.2023.105405. Epub 2023 Oct 29.

Beta-cell compensation and gestational diabetes

Taofeek O Usman  1 , Goma Chhetri  1 , Hsuan Yeh  1 , H Henry Dong  2
Affiliations
Review

Beta-cell compensation and gestational diabetes

Taofeek O Usman et al. J Biol Chem. 2023 Dec.

Abstract

Gestational diabetes mellitus (GDM) is characterized by glucose intolerance in pregnant women without a previous diagnosis of diabetes. While the etiology of GDM remains elusive, the close association of GDM with increased maternal adiposity and advanced gestational age implicates insulin resistance as a culpable factor for the pathogenesis of GDM. Pregnancy is accompanied by the physiological induction of insulin resistance in the mother secondary to maternal weight gain. This effect serves to spare blood glucose for the fetus. To overcome insulin resistance, maternal β-cells are conditioned to release more insulin into the blood. Such an adaptive response, termed β-cell compensation, is essential for maintaining normal maternal metabolism. β-cell compensation culminates in the expansion of β-cell mass and augmentation of β-cell function, accounting for increased insulin synthesis and secretion. As a result, a vast majority of mothers are protected from developing GDM during pregnancy. In at-risk pregnant women, β-cells fail to compensate for maternal insulin resistance, contributing to insulin insufficiency and GDM. However, gestational β-cell compensation ensues in early pregnancy, prior to the establishment of insulin resistance in late pregnancy. How β-cells compensate for pregnancy and what causes β-cell failure in GDM are subjects of investigation. In this mini-review, we will provide clinical and preclinical evidence that β-cell compensation is pivotal for overriding maternal insulin resistance to protect against GDM. We will highlight key molecules whose functions are critical for integrating gestational hormones to β-cell compensation for pregnancy. We will provide mechanistic insights into β-cell decompensation in the etiology of GDM.

Keywords: gestational diabetes; insulin resistance; β-cell compensation; β-cell mass.

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Conflict of interest statement

Conflict of interest The authors have no conflicts of interest with the content of this article.

Figures

Figure 1
Figure 1
Gestational β-cell compensation. Pregnancy begets maternal β-cell compensation, an adaptive mechanism by which β-cells evolve to release more insulin into the blood. Gestational β-cell compensation culminates in β-cell mass expansion, increased insulin synthesis and secretion, enhanced glucose sensing, and augmented antioxidative function in maternal islets. Gestational β-cell compensation is instrumental for overcoming maternal insulin resistance to maintain normal glucose homeostasis in women during pregnancy.
Figure 2
Figure 2
β-cell compensation for maternal insulin resistance during pregnancy. Pregnancy is accompanied by enhanced insulin sensitivity in the first trimester, followed by a progressive decline in maternal insulin sensitivity, resulting in overt insulin resistance in the third trimester. This effect is due to a combination of maternal weight gain and placental growth hormone, whose paracrine action contributes to insulin resistance in peripheral tissues in the mother. Gestational β-cell compensation, characterized by increased insulin secretion, initiates at the beginning of the second trimester and increases progressively to a peak level in the third trimester.
Figure 3
Figure 3
Mechanism of β-cell compensation for pregnancy. β-cells compensate for maternal insulin resistance in multiple mechanisms. First, PRL- and PL-mediated activation of PRLR signaling stimulates STAT5 phosphorylation by JAK2. This effect promotes STAT5 translocation from the cytoplasm to the nucleus and augments STAT5 activity in stimulating β-cell proliferation. Second, HGF-mediated activation of C-Met signaling functions via PI3K to enhance AKT and PKCζ activities. This effect promotes β-cell production of mTOR, GSK3, and FOXM1, key proteins in stimulating β-cell proliferation. Third, PRL- and PL-mediated activation of PRLR signaling is associated with increased β-cell production of serotonin, whose autocrine action via HTR2B contributes to β-cell mass expansion during pregnancy. The question mark denotes the signaling pathway to be delineated. AKT, serine/threonine protein kinase; CDK4, cyclin-dependent kinase 4; C-Met, mesenchymal-epithelial transition factor; FoxM1, forkhead box M1; FoxD3, forkhead box D3; GSK3, glycogen synthase kinase 3; HGF, hepatocyte growth factor; JAK2, Janus kinase 2, mTOR, mammalian target of rapamycin; PI3K, phosphoinositide 3-kinase; PKCζ, protein kinase C ζ; PL, placenta lactogen; PRLR, prolactin receptor; PRL, prolactin; STAT5, signal transducer and activator of transcription five; TPH-1, tryptophan hydrolase-1; TPH-2, tryptophan hydrolase-2.
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