Fetal hyperglycemia acutely induces persistent insulin resistance in skeletal muscle

Abstract

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.

Maternal Obesity and Western-style Diet Impair Fetal and Juvenile Offspring Skeletal Muscle Insulin-Stimulated Glucose Transport in Nonhuman Primates

“…Further, IRS1-PI3K activity, but not IRS1 phosphorylation, was reduced in fetal muscle in offspring of obese sheep (34); although, these measures in fetal sheep were made in fasted, and not insulin-stimulated tissues, it provides additional evidence that IRS1-PI3K may be a critical node regulated by maternal obesity in the fetal muscle. Lastly, reduced insulin-stimulated glucose uptake in fetal muscle has also been found in a rat model of fetal hyperglycemia with impairments in insulin signaling occurring at the level of Akt and not IRS1 (35).…”

SDC3 acts as a timekeeper of myogenic differentiation by regulating the insulin/AKT/mTOR axis in muscle stem cell progeny

“…Moreover, it has been shown that fetal hyperglycemia caused by gestational diabetes of the mother causes insulin resistance in developing skeletal muscle (Kua et al, 2019), suggesting that targeting of SDC3 during gestational diabetes might be beneficial to both mother and fetus.…”

“…Changes in SDC3 expression have been linked to metabolic syndrome, regulation of energy balance and obesity, all risk factors predisposing to development of type 2 diabetes mellitus (Chang et al, 2018; Strader et al, 2004). Moreover, it has been shown that fetal hyperglycemia caused by gestational diabetes of the mother causes insulin resistance in developing skeletal muscle (Kua et al, 2019). Further work to investigate the role of SDC3/INSR/AKT signaling in a diabetic model would be advantageous to elucidate any protective effects from targeting this pathway on diabetic myopathy as well as on regulation of glucose levels.…”

Offspring of Obese Dams Exhibit Sex-Differences in Pancreatic Heparan Sulfate Glycosaminoglycans and Islet Insulin Secretion

“…The body composition of female dams, P21 offspring, and 8W young adult offspring were measured using EchoMRI (EchoMRI LLC, Houston, TX) ( 14 ). Intraperitoneal glucose tolerance testing (GTT) and intraperitoneal insulin tolerance testing (ITT) were performed as published previously ( 14 , 42 ). Briefly, animals were fasted for 5-6 hours prior to GTT, and 2 hours prior to ITT.…”