A week‑long infusion of the IGF‑1 analog IGF‑1 LR3 in late‑pregnancy sheep lowered the babies' blood insulin and glucose levels and made their pancreas cells release less insulin, even when the cells were studied outside the body. This suggests that high IGF‑1 exposure can directly impair the cells that make insulin.

Insulin and insulin-like growth factor-1 (IGF-1) are fetal hormones critical to establishing normal fetal growth. Experimentally elevated IGF-1 concentrations during late gestation increase fetal weight but lower fetal plasma insulin concentrations. We therefore hypothesized that infusion of an IGF-1 analog for 1 wk into late gestation fetal sheep would attenuate fetal glucose-stimulated insulin secretion (GSIS) and insulin secretion in islets isolated from these fetuses. Late gestation fetal sheep received infusions with IGF-1 LR3 (IGF-1, <i>n</i> = 8), an analog of IGF-1 with low affinity for the IGF binding proteins and high affinity for the IGF-1 receptor, or vehicle control (CON, <i>n</i> = 9). Fetal GSIS was measured with a hyperglycemic clamp (IGF-1, <i>n</i> = 8; CON, <i>n</i> = 7). Fetal islets were isolated, and insulin secretion was assayed in static incubations (IGF-1, <i>n</i> = 8; CON, <i>n</i> = 7). Plasma insulin and glucose concentrations in IGF-1 fetuses were lower compared with CON (<i>P</i> = 0.0135 and <i>P</i> = 0.0012, respectively). During the GSIS study, IGF-1 fetuses had lower insulin secretion compared with CON (<i>P</i> = 0.0453). In vitro, glucose-stimulated insulin secretion remained lower in islets isolated from IGF-1 fetuses (<i>P</i> = 0.0447). In summary, IGF-1 LR3 infusion for 1 wk into fetal sheep lowers insulin concentrations and reduces fetal GSIS. Impaired insulin secretion persists in isolated fetal islets indicating an intrinsic islet defect in insulin release when exposed to IGF-1 LR3 infusion for 1 wk. We speculate this alteration in the insulin/IGF-1 axis contributes to the long-term reduction in &#x3b2;-cell function in neonates born with elevated IGF-1 concentrations following pregnancies complicated by diabetes or other conditions associated with fetal overgrowth.<b>NEW &amp; NOTEWORTHY</b> After a 1-wk infusion of IGF-1 LR3, late gestation fetal sheep had lower plasma insulin and glucose concentrations, reduced fetal glucose-stimulated insulin secretion, and decreased fractional insulin secretion from isolated fetal islets without differences in pancreatic insulin content.