Reduced glucose-stimulated insulin secretion following a 1-wk IGF-1 infusion in late gestation fetal sheep is due to an intrinsic islet defect

Abstract

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 one week 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, n=8), an analogue of IGF-1 with low affinity for the IGF binding proteins and high affinity for the IGF-1 receptor, or vehicle control (CON, n=9). Fetal GSIS was measured with a hyperglycemic clamp (IGF-1, n=8; CON, n=7). Fetal islets were isolated, and insulin secretion was assayed in static incubations (IGF-1, n=8; CON, n=7). Plasma insulin and glucose concentrations in IGF-1 fetuses were lower compared to CON (P=0.0135 and P=0.0012, respectively). During the GSIS study, IGF-1 fetuses had lower insulin secretion compared to CON (P=0.0453). In vitro, glucose-stimulated insulin secretion remained lower in islets isolated from IGF-1 fetuses (P=0.0447). In summary, IGF-1 LR3 infusion for one week 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 one week. We speculate this alteration in the insulin/IGF-1 axis contributes to the long-term reduction in β-cell function in neonates born with elevated IGF-1 concentrations following pregnancies complicated by diabetes or other conditions associated with fetal overgrowth.

Sheep recombinant IGF-1 promotes organ-specific growth in fetal sheep

“…In this study, we demonstrated that oIGF-1, like LR3 IGF-1 ( Stremming et al, 2021 ), increased in vitro myoblast proliferation, in vivo myoblast proliferation, and selective fetal organ weight, but it did not increase fetal body weight. Similar to infusion of LR3 IGF-1, fetal oIGF-1 infusion for 1 week also attenuated fetal insulin concentrations, which has been previously reported ( Liechty et al, 1996 ; Lok et al, 1996 ; Boyle et al, 1998 ; White et al, 2018 ; Stremming et al, 2021 ; White et al, 2021 ); however, fetal glucose concentrations in oIGF-1 are maintained similar to control animals. Fetal plasma amino acid concentrations were also lower after infusion of oIGF-1, which is consistent with infusion of LR3 IGF-1 ( Stremming et al, 2021 ).…”

“…At the end of the infusion period, fetal IGF-1 concentrations were 3.5-fold higher in oIGF-1 infused fetuses compared to saline infused fetuses ( Figure 3B ). Because IGF-1 infusion decreases fetal insulin concentrations ( Liechty et al, 1996 ; Lok et al, 1996 ; Boyle et al, 1998 ; White et al, 2018 ; Stremming et al, 2021 ; White et al, 2021 ), plasma insulin concentrations were obtained. At the end of the infusion period, fetal plasma insulin concentrations were 89% lower in oIGF-1 infused fetuses compared to fetuses that received a saline infusion ( Figure 3C ).…”

“…One possibility may involve concurrent downregulation of insulin concentrations and potential synergy with amino acid supply and metabolism. LR3 IGF-1 infusion decreases fetal insulin and amino acid concentrations ( Liechty et al, 1996 ; Lok et al, 1996 ; Boyle et al, 1998 ; White et al, 2018 ; Stremming et al, 2021 ; White et al, 2021 ), which may limit fetal growth potential. Consistent with previous studies, we also demonstrated that fetal insulin concentrations were reduced after infusion of oIGF-1 for 1 week.…”

“…Fetal plasma was used to measure glucose and lactate concentrations (YSI 2900, YSI Inc., Yellow Springs, OH). Plasma insulin, IGF-1, and cortisol concentrations were measured by ELISA as previously described ( White et al, 2021 ). Plasma amino acid and norepinephrine concentrations were measured using HPLC as previously described ( Limesand et al, 2006 ).…”

“…Fetal plasma was used to measure glucose and lactate concentrations (YSI 2900, YSI Inc., Yellow Springs, OH). Plasma insulin, IGF-1, and cortisol concentrations were measured by ELISA as previously described (White et al, 2021).…”