Mechanisms in the adaptation of maternal β-cells during pregnancy

Ernst, Sara; Demirci, Cem; Valle, Shelley; Velázquez-García, Silvia; Garcı́a-Ocaña, Adolfo

doi:10.2217/dmt.10.24

Cited by 99 publications

(95 citation statements)

References 92 publications

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“…For the maintenance of normal glucose homeostasis in pregnancy, maternal b-cells must compensate for the severe acquired insulin resistance of late gestation by markedly increasing their secretion of insulin. Although the mechanism of this compensation has not been fully elucidated, it is known to involve placental lactogens and prolactin acting through a series of downstream mediators (including the transcription factor FoxMI, the serotonin synthetic enzyme Tph1, and the cell cycle regulator menin), ultimately leading to the expansion of b-cell mass and enhanced insulin secretion (30). In this context, the current findings suggest that male fetus is a previously unrecognized factor that may adversely affect the maternal b-cell compensatory response.…”

Section: Discussionmentioning

confidence: 99%

Fetal Sex and Maternal Risk of Gestational Diabetes Mellitus: The Impact of Having a Boy

et al. 2015

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OBJECTIVERetrospective analyses of perinatal databases have raised the intriguing possibility of an increased risk of gestational diabetes mellitus (GDM) in women carrying a male fetus, but it has been unclear if this was a spurious association. We thus sought to evaluate the relationship between fetal sex and maternal glucose metabolism in a well-characterized cohort of women reflecting the full spectrum of gestational glucose tolerance from normal to mildly abnormal to GDM. RESEARCH DESIGN AND METHODSA total of 1,074 pregnant women underwent metabolic characterization, including oral glucose tolerance test (OGTT), at mean 29.5 weeks' gestation. The prevalence of GDM, its pathophysiologic determinants (b-cell function and insulin sensitivity/ resistance), and its clinical risk factors were compared between women carrying a female fetus (n = 534) and those carrying a male fetus (n = 540). RESULTSWomen carrying a male fetus had lower mean adjusted b-cell function (insulinogenic index divided by HOMA of insulin resistance: 9.4 vs. 10.5, P = 0.007) and higher mean adjusted blood glucose at 30 min (P = 0.025), 1 h (P = 0.004), and 2 h (P = 0.02) during the OGTT, as compared with those carrying a female fetus. Furthermore, women carrying a male fetus had higher odds of developing GDM (odds ratio 1.39 [95% CI 1.01-1.90]). Indeed, male fetus further increased the relative risk of GDM conferred by the classic risk factors of maternal age >35 years and nonwhite ethnicity by 47 and 51%, respectively. CONCLUSIONSMale fetus is associated with poorer b-cell function, higher postprandial glycemia, and an increased risk of GDM in the mother. Thus, fetal sex potentially may influence maternal glucose metabolism in pregnancy.Fetal sex has been associated with differential risks of perinatal outcomes. Specifically, it has long been recognized that the presence of a male fetus carries increased risks of adverse outcomes, including preterm delivery, premature rupture of membranes, umbilical cord prolapse, true umbilical cord knot, failure to progress in the first and second stages of labor, nonreassuring fetal heart rate patterns, cesarean delivery, and lower Apgar scores (1,2). Although the mechanisms by which male sex may contribute to these events are not clearly understood, it seems probable that these outcomes relate primarily to biological factors determined by the fetus. In contrast, however, different pathophysiologic effects would likely need to be

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Section: Discussionmentioning

confidence: 99%

Fetal Sex and Maternal Risk of Gestational Diabetes Mellitus: The Impact of Having a Boy

et al. 2015

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“…Although best known for its lactogenic activity, prolactin is also recognized as a principal determinant of islet adaptation to pregnancy (8)(9)(10)(11). Indeed, a substantial body of evidence from preclinical studies has shown that both prolactin and HPL bind to the prolactin receptor on b-cells and induce the expansion of b-cell mass through a series of downstream intracellular mediators, including tryptophan hydroxylase 1 (the rate-limiting enzyme in serotonin synthesis), cell-cycle regulators, survivin, forkhead proteins, and menin (9,(23)(24)(25)(26).…”

Section: Discussionmentioning

confidence: 99%

“…Normal islet adaptation in pregnancy is believed to be dependent upon a marked expansion of b-cell mass that is stimulated by the circulating hormones prolactin and human placental lactogen (HPL) (8)(9)(10)(11). Preclinical models have demonstrated that prolactin and placentally derived HPL both bind to the prolactin receptor on the b-cells and induce a series of downstream intracellular mediators that ultimately stimulate b-cell growth and proliferation (8)(9)(10)(11).…”

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confidence: 99%

“…Preclinical models have demonstrated that prolactin and placentally derived HPL both bind to the prolactin receptor on the b-cells and induce a series of downstream intracellular mediators that ultimately stimulate b-cell growth and proliferation (8)(9)(10)(11). Indeed, the prolactin receptor has been shown to be essential for the expansion of b-cell mass in pregnancy (12,13).…”

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confidence: 99%

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Maternal Serum Prolactin and Prediction of Postpartum β-Cell Function and Risk of Prediabetes/Diabetes

Retnakaran

Kramer

et al. 2016

Diabetes Care

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OBJECTIVEThe insulin resistance of mid-to late pregnancy poses a physiologic stress test for the pancreatic b-cells, which must respond by markedly increasing their secretion of insulin. This response is achieved through an expansion of b-cell mass induced by the hormones prolactin and human placental lactogen (HPL). Conversely, the furan fatty acid metabolite 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) has recently emerged as a negative regulator of b-cell function in pregnancy. Given their respective roles in the b-cell response to the stress test of gestation, we hypothesized that antepartum prolactin, HPL, and CMPF may relate to a woman's underlying glucoregulatory physiology and hence to her metabolic status after pregnancy. RESEARCH DESIGN AND METHODSThree hundred and sixty-seven women underwent measurement of fasting serum prolactin, HPL, and CMPF in the late-2nd/early-3rd trimester, followed by an oral glucose tolerance test (OGTT) at 3 months postpartum that enabled assessment of glucose tolerance, insulin sensitivity/resistance, and b-cell function (Insulin Secretion-Sensitivity Index-2 [ISSI-2]). RESULTSThe postpartum OGTT identified 301 women with normal glucose tolerance (NGT) and 66 with prediabetes or diabetes. Serum prolactin in pregnancy was higher in women with postpartum NGT compared with those with postpartum prediabetes/ diabetes (mean 98.2 vs. 80.2 ng/mL, P = 0.0003), whereas HPL and CMPF did not differ between the groups. On multiple linear regression analyses, antepartum prolactin was an independent determinant of postpartum ISSI-2 (b = 0.0016, t = 2.96, P = 0.003). Furthermore, higher serum prolactin in pregnancy independently predicted a lower risk of postpartum prediabetes/diabetes (odds ratio 0.50, 95% CI 0.35-0.72, P = 0.0002). CONCLUSIONSSerum prolactin in pregnancy predicts postpartum b-cell function and risk of prediabetes/diabetes.

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“…To maintain normoglycaemia during pregnancy, an increase in insulin secretion is needed to compensate for the increased insulin resistance (2). The precise mechanisms of b-cells mass expansion during human pregnancy have only partially been elucidated, but reports indicate that there is an adaptive increase in b-cell numbers (23,24,25). From early to 28 weeks of gestation, the women from South Asia were not able to increase their b-cell function mutual to the insulin resistance.…”

Section: Discussionmentioning

confidence: 99%

Failure to increase insulin secretory capacity during pregnancy-induced insulin resistance is associated with ethnicity and gestational diabetes

Mørkrid

Jenum

Sletner

et al. 2012

European Journal of Endocrinology

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Objective: To assess changes in insulin resistance and b-cell function in a multiethnic cohort of women in Oslo, Norway, from early to 28 weeks' gestation and 3 months post partum and relate the findings to gestational diabetes mellitus (GDM). Method: Population-based cohort study of 695 healthy pregnant women from Western Europe (41%), South Asia (25%), Middle East (15%), East Asia (6%) and elsewhere (13%). Blood samples and demographics were recorded at mean 15 (V1) and 28 (V2) weeks' gestation and 3 months post partum (V3). Universal screening was by 75 g oral glucose tolerance test at V2, GDM with modified IADPSG criteria (no 1-h measurement): fasting plasma glucose (PG) R5.1 or 2-h PG R8.5 mmol/l. Homeostatic model assessment (HOMA)-b (b-cell function) and HOMA-IR (insulin resistance) were calculated from fasting glucose and C-peptide. Result: Characteristics were comparable across ethnic groups, except age (South Asians: younger, P!0.001) and prepregnant BMI (East Asians: lower, PZ0.040). East and South Asians were more insulin resistant than Western Europeans at V1. From V1 to V2, the increase in insulin resistance was similar across the ethnic groups, but the increase in b-cell function was significantly lower for the East and South Asians compared with Western Europeans. GDM women compared with non-GDM women were more insulin resistant at V1; from V1 to V2, their b-cell function increased significantly less and the percentage increase in b-cell function did not match the change in insulin resistance. Conclusion: Pregnant women from East Asia and South Asia were more insulin resistant and showed poorer HOMA-b-cell function than Western Europeans.

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Mechanisms in the adaptation of maternal β-cells during pregnancy

Cited by 99 publications

References 92 publications

Fetal Sex and Maternal Risk of Gestational Diabetes Mellitus: The Impact of Having a Boy

Fetal Sex and Maternal Risk of Gestational Diabetes Mellitus: The Impact of Having a Boy

Maternal Serum Prolactin and Prediction of Postpartum β-Cell Function and Risk of Prediabetes/Diabetes

Failure to increase insulin secretory capacity during pregnancy-induced insulin resistance is associated with ethnicity and gestational diabetes

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