Fetal hyperglycemia acutely induces persistent insulin resistance in skeletal muscle

in Journal of Endocrinology
Correspondence should be addressed to A W Norris: andrew-norris@uiowa.edu

(K L Kua is now at Indiana University School of Medicine, Indianapolis, Indiana, USA)

This paper is part of a thematic section on 30 Years of the Developmental Origins of Health and Disease. The guest editors for this section were Sean Limesand, Kent Thornburg and Jane Harding.

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Offspring exposed in utero to maternal diabetes exhibit long-lasting insulin resistance, though the initiating mechanisms have received minimal experimental attention. Herein, we show that rat fetuses develop insulin resistance after only 2-day continuous exposure to isolated hyperglycemia starting on gestational day 18. Hyperglycemia-induced reductions in insulin-induced AKT phosphorylation localized primarily to fetal skeletal muscle. The skeletal muscle of hyperglycemia-exposed fetuses also exhibited impaired in vivo glucose uptake. To address longer term impacts of this short hyperglycemic exposure, neonates were cross-fostered and examined at 21 days postnatal age. Offspring formerly exposed to 2 days late gestation hyperglycemia exhibited mild glucose intolerance with insulin signaling defects localized only to skeletal muscle. Fetal hyperglycemic exposure has downstream consequences which include hyperinsulinemia and relative uteroplacental insufficiency. To determine whether these accounted for induction of insulin resistance, we examined fetuses exposed to late gestational isolated hyperinsulinemia or uterine artery ligation. Importantly, 2 days of fetal hyperinsulinemia did not impair insulin signaling in murine fetal tissues and 21-day-old offspring exposed to fetal hyperinsulinemia had normal glucose tolerance. Similarly, fetal exposure to 2-day uteroplacental insufficiency did not perturb insulin-stimulated AKT phosphorylation in fetal rats. We conclude that fetal exposure to hyperglycemia acutely produces insulin resistance. As hyperinsulinemia and placental insufficiency have no such impact, this occurs likely via direct tissue effects of hyperglycemia. Furthermore, these findings show that skeletal muscle is uniquely susceptible to immediate and persistent insulin resistance induced by hyperglycemia.

 

      Society for Endocrinology

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    Transient fetal hyperglycemia during late gestation. (A) Experimental timeline. Glucose was infused into the left uterine artery for 48 h during late gestation. (B) Maternal blood glucose level before or just before the conclusion of 48 h glucose infusion during late gestation (n = 6). Maternal blood was collected during the awake state. Bars represent the mean ± s.e.m. for these maternal measures. (C) Fetal blood glucose level just before the conclusion of 48 h exposure to euglycemia (EG) or hyperglycemia (HG) (n = 14–15 fetuses/groups from three mothers) *P < 0.05 for difference between groups. Fetal blood was collected during isoflurane and maternal laparotomy. (D) Fetal serum insulin level just before the conclusion of 48 h of infusion (n = 16–24 fetuses/group from four mothers). (C and D) In this and all subsequent plots for fetal measures, bars represent the mean ± s.e.m. across fetuses, with individual points of the same color representing the mean obtained from fetuses originating from a single mother. The data obtained from fetuses of the same mother are also connected by a solid line to aid visualization of this natural pairing and the trend of within-mother changes. The colors between panels are not necessarily conserved and often panels represent different cohorts. The total number of fetuses/offspring examined per group is indicated in each bar. For example, regarding (C) there were 15 EG and 14 HG fetuses examined, obtained from three mothers shown in blue, pink, and green. A full colour version of this figure is available at https://doi.org/10.1530/JOE-18-0455.

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    Effects of transient hyperglycemia on fetal skeletal muscle insulin sensitivity. (A) Experimental timeline. Glucose was infused into the left uterine artery for 48 h during late gestation. The hyperglycemic infusion was discontinued. Two hours later tritiated 2-deoxyglucose (2DG) was administered maternally and fetuses were administered insulin or saline. Fetal tissues were collected 20 min thereafter. (B) Maternal serum scintillation count after 2DG injection (n = four mothers), error bars represent per mother s.e.m. (C) Fetal skeletal muscle insulin-stimulated tritiated 2-deoxyglucose uptake, relative to that in fetal brain, after 48 h exposure to euglycemia or hyperglycemia. (n = 5–9 fetuses/group from three mothers). *P < 0.05 for overall difference between euglycemia and hyperglycemia groups. A full colour version of this figure is available at https://doi.org/10.1530/JOE-18-0455.

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    Effects of transient hyperglycemia on fetal skeletal muscle insulin signaling. (A) Experimental timeline. Glucose was infused into the left uterine artery for 48 h during late gestation. While the infusion was continued, regular insulin or saline was administered to fetuses and fetal tissues were collected 15 min thereafter. (B) Fetal skeletal muscle in vivo insulin (INS) stimulated AKT phosphorylation in fetuses exposed to euglycemia (EG) or hyperglycemia (HG) (n = 27 fetuses/group from 11 mothers). *P < 0.05 for difference between the two groups. Representative western blots shown on right of panel. (C) Tyrosine phosphorylated IRS-1 expression measured using MSD Multiplex Assay (n = 10–14 fetuses/group from six mothers) in saline and insulin-stimulated fetuses. (D) Relative protein expression of signaling molecules proximal to AKT measured using MSD Multiplex Assay. (Total PDK, phospho PDK, total MTOR, phospho-MTOR and total PTEN n = 6–9 fetuses/groups from three mothers, and phospho-PTEN n = 4–6 fetuses/group from two mothers). A full colour version of this figure is available at https://doi.org/10.1530/JOE-18-0455.

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    Effects of transient hyperglycemia on fetal brown adipose tissue (BAT) insulin action. (A) See Fig. 2A for experimental timeline. Fetal BAT insulin-stimulated 2DG uptake in fetuses exposed to euglycemia or hyperglycemia (n = 5–9 fetuses/group from three mothers). (B) See Fig. 3A for experimental timeline. Fetal BAT insulin (INS) stimulated AKT phosphorylation in fetuses exposed to euglycemia (EG) or hyperglycemia (HG) (n = 27–28 fetuses/group from 11 mothers). Representative western blots shown to right of panel. A full colour version of this figure is available at https://doi.org/10.1530/JOE-18-0455.

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    Effects of transient hyperglycemia on fetal liver insulin signaling. See Fig. 3A for relevant experimental timeline. (A) Fetal liver insulin-stimulated AKT phosphorylation measured by MSD multiplex panel (n = 10–14 fetuses/group, six mothers) just before the conclusion of exposure to euglycemia or hyperglycemia. The increase induced by insulin was significant for each group (euglycemia and hyperglycemia). *P < 0.05 for increase induced by insulin across experimental groups. (B) Fetal liver insulin-stimulated GSK phosphorylation measured by MSD multiplex panel (n = 10–14 fetuses/group, six mothers). The increase induced by insulin was significant for each group (euglycemia and hyperglycemia). Lower *: P < 0.05 for increase induced by insulin across experimental groups. Upper *: P < 0.05 for overall difference between euglycemia and hyperglycemia-exposed fetuses. A full colour version of this figure is available at https://doi.org/10.1530/JOE-18-0455.

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    Impact of fetal hyperinsulinemia on acute insulin signaling. (A) Experimental timeline. Detemir, a long-acting insulin, or control diluent, was administered to fetuses during late gestation to induce chronic hyperinsulinemia (HI). Forty-eight hours later, regular insulin (short acting) or saline was administered to the fetuses, and fetal blood/tissues collected 15 min thereafter to assess insulin signaling. (B) Fetal blood glucose in response to exogenous insulin stimulation (n = 9–15 fetuses/group, eight mothers) after 48 h exposure to long-acting insulin (detemir) or control (diluent). *P < 0.05 for decrease in glucose induced by insulin across groups. (C) In vivo insulin-stimulated AKT phosphorylation in fetal skeletal muscle (n = 15–18 fetuses/group from six mothers), (D) fetal brown adipose tissue (n = 14 fetuses/group, seven mothers), and (E) fetal liver (n = 11–14 fetuses/group, five mothers). Representative western blots shown adjacent to panels. A full colour version of this figure is available at https://doi.org/10.1530/JOE-18-0455.

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    Acute fetal effects of 48 h placental insufficiency. (A) Experimental timeline. One uterine artery was ligated during late gestation while the contralateral artery was left intact (control). Forty-eight hours later, insulin or saline was administered to fetuses, and fetal tissues harvested 15 min thereafter. (B) Fetal weight 48 h after induction of placental insufficiency by uterine artery ligation (‘ligate’ group) (n = 43–44 fetuses/group from seven mothers). *P < 0.05 for difference between groups. (C) Fetal skeletal muscle insulin-stimulated AKT phosphorylation 48 h after ligation (n = 12 fetuses/group from six mothers). Representative western blot shown below panel. A full colour version of this figure is available at https://doi.org/10.1530/JOE-18-0455.

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    Offspring insulin signaling and glucose tolerance after late gestation fetal exposure to hyperglycemia. (A) Experimental timeline. Glucose was infused for 48 h into the left uterine artery. Pups were delivered by C-section and cross-fostered to surrogate mothers. Twenty-one days later insulin signaling and glucose tolerance were interrogated. (B, C and D) Insulin (INS) stimulated AKT phosphorylation in 21 day old weanlings assessing (B) soleus muscle (11–12 offspring/group, from five mothers) *P < 0.05 for difference between groups, (C) BAT (n = 9–13 offspring/group, five mothers), and (D) liver (n = 10–12 offspring/group, five mothers) in offspring exposed as fetuses to euglycemia (EG) or hyperglycemia (HG). Representative western blots shown below panels. (E) Intraperitoneal glucose tolerance test (GTT) of weanling offspring exposed in utero to euglycemia (EG) vs hyperglycemia (HG) (all genders included, 19–28 offspring/group from six mothers) and (F) corresponding glucose area under the curve (AUC) (n = 19–28 offspring/group from six mothers) *P < 0.05 for difference between groups. For all offspring measures, bars represent the mean ± s.e.m. across offspring. A full colour version of this figure is available at https://doi.org/10.1530/JOE-18-0455.

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    Offspring insulin signaling and glucose tolerance after late gestation fetal exposure to hyperinsulinemia. (A) Experimental timeline. Hyperinsulinemia was induced in fetuses using detemir, whereas controls received diluent. Forty-eight hours thereafter, pups were delivered and raised by their mothers. Twenty-one days later insulin signaling and glucose tolerance were interrogated. (B and C) Insulin (INS) stimulated AKT phosphorylation in 21 day old weanlings assessing insulin-stimulated AKT phosphorylation in (B) skeletal muscle (18–20 fetuses/group, seven mothers) and (C) liver (18–20 fetuses/group, seven mothers), *P < 0.05 for difference between groups, in offspring exposed as fetuses to hyperinsulinemia (detemir) vs control (diluent). Representative western blots shown below panels. (D) Intraperitoneal glucose tolerance test (GTT) of weanling offspring exposed in utero to hyperinsulinemia (detemir) vs control (diluent) (n = 23–28 offspring/group from eight mothers), and (E) corresponding glucose area AUC (n = 23–28 offspring/group from eight mothers). A full colour version of this figure is available at https://doi.org/10.1530/JOE-18-0455.

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