Placental insufficiency is a primary cause of intrauterine growth restriction (IUGR). IUGR increases the risk of developing type 2 diabetes mellitus (T2DM) throughout life, which indicates that insults from placental insufficiency impair β-cell development during the perinatal period because β-cells have a central role in the regulation of glucose tolerance. The severely IUGR fetal pancreas is characterized by smaller islets, less β-cells, and lower insulin secretion. Because of the important associations among impaired islet growth, β-cell dysfunction, impaired fetal growth, and the propensity for T2DM, significant progress has been made in understanding the pathophysiology of IUGR and programing events in the fetal endocrine pancreas. Animal models of IUGR replicate many of the observations in severe cases of human IUGR and allow us to refine our understanding of the pathophysiology of developmental and functional defects in islet from IUGR fetuses. Almost all models demonstrate a phenotype of progressive loss of β-cell mass and impaired β-cell function. This review will first provide evidence of impaired human islet development and β-cell function associated with IUGR and the impact on glucose homeostasis including the development of glucose intolerance and diabetes in adulthood. We then discuss evidence for the mechanisms regulating β-cell mass and insulin secretion in the IUGR fetus, including the role of hypoxia, catecholamines, nutrients, growth factors, and pancreatic vascularity. We focus on recent evidence from experimental interventions in established models of IUGR to understand better the pathophysiological mechanisms linking placental insufficiency with impaired islet development and β-cell function.

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.

Fetal insulin is critical for regulation of growth. Insulin concentrations are partly determined by the amount of β‐cells present and their insulin content. Insulin‐like growth factor‐1 (IGF‐1) is a fetal anabolic growth factor which also impacts β‐cell mass in models of β‐cell injury and diabetes. The extent to which circulating concentrations of IGF‐1 impact fetal β‐cell mass and pancreatic insulin content is unknown. We hypothesized that an infusion of an IGF‐1 analog for 1 week into the late gestation fetal sheep circulation would increase β‐cell mass, pancreatic islet size, and pancreatic insulin content. After the 1‐week infusion, pancreatic insulin concentrations were 80% higher than control fetuses (P < 0.05), but there were no differences in β‐cell area, β‐cell mass, or pancreatic vascularity. However, pancreatic islet vascularity was 15% higher in IGF‐1 fetuses and pancreatic VEGFA,HGF,IGF1, and IGF2 mRNA expressions were 70–90% higher in IGF‐1 fetuses compared to control fetuses (P < 0.05). Plasma oxygen, glucose, and insulin concentrations were 25%, 22%, and 84% lower in IGF‐1 fetuses, respectively (P < 0.05). The previously described role for IGF‐1 as a β‐cell growth factor may be more relevant for local paracrine signaling in the pancreas compared to circulating endocrine signaling.

Fall-calving Angus cows were used to evaluate the effect of ambient temperature on duration of gestation. In Exp. 1, cows were AI and calved in August (n = 14) or October (n = 10). Cows grazed native prairie pasture in Oklahoma and had a BCS of 6.0 ± 0.5 (1 = emaciated, and 9 = obese) at parturition. Commencing 2 wk before the expected calving date, blood samples were taken from the coccygeal vein every 2 to 3 d until calving. Cows that calved in August tended to have shorter gestations (P = 0.07) compared with cows that calved in October. Maximum daily ambient temperature during the last 14 d of gestation was greater for August-calving cows (P < 0.001) compared with October cows. Concentrations of cortisol in plasma during the last 4 d of gestation were greater in cows that calved in August (P < 0.04) compared with cows that calved in October. In Exp. 2, cows were AI and calved in either mid-August (n = 7), late-August (n = 6), September (n = 6), or October (n = 8) to evaluate the effects of elevated ambient temperature on duration of gestation, ruminal temperature at parturition, and plasma cortisol, progesterone, and estradiol. Temperature boluses (SmartStock, LLC, Pawnee, OK) programmed to transmit temperature every hour were place in the rumen at 255 d of gestation. Cows grazed native prairie pasture in Oklahoma and had a BCS of 6.5 ± 0.4 at calving. Maximum ambient temperatures during d 263 to 273 of gestation were influenced by month of calving × day (P < 0.001). Duration of gestation was shorter for mid-August cows (P < 0.05) compared with October cows, but did not differ compared with late-August (P = 0.29) and September (P = 0.50) cows. Ruminal temperature during the 4 d before calving was not influenced by month of calving (P = 0.76). Ruminal temperature was decreased during the 24 h before parturition for cows in all months (P < 0.01) compared with 2 to 4 d before parturition. Concentrations of cortisol in plasma during d 271 to 276 of gestation were less (P < 0.05) for late-August compared with cows that calved during the other months. Concentrations of progesterone were greater during 7 d before parturition in October compared with cows that calved in September. Estradiol in plasma of cows during late gestation was not affected by month of calving (P = 0.76). Exposure of beef cows to elevated ambient temperature resulted in shorter gestations. Ruminal temperature in cows decreased ≥ 0.3°C the day before parturition.

A nine-day infusion of leucine into fetal sheep potentiates fetal glucose-stimulated insulin secretion (GSIS). However, there were accompanying pancreatic structural changes that included a larger proportion of β-cells and increased vascularity. Whether leucine can acutely potentiate fetal GSIS in vivo before these structural changes develop is unknown. The mechanisms by which leucine acutely potentiates GSIS in adult islets and insulin secreting cell lines are well known. These mechanisms involve leucine metabolism including leucine oxidation. However, it is not clear if leucine-stimulated metabolic pathways are active in fetal islets. We hypothesized that leucine would acutely potentiate GSIS in fetal sheep and that isolated fetal islets are capable of oxidizing leucine. We also hypothesized that leucine would stimulate other metabolic pathways associated with insulin secretion. In pregnant sheep we tested in vivo GSIS with and without an acute leucine infusion. In isolated fetal sheep islets we measured leucine oxidation with a [1-14C]L-leucine tracer. We also measured concentrations of other amino acids, glucose, and analytes associated with cellular metabolism following incubation of fetal islets with leucine. In vivo, a leucine infusion resulted in glucose stimulated insulin concentrations that were over 50% higher than controls (P<0.05). Isolated fetal islets oxidized leucine. Leucine supplementation of isolated fetal islets also resulted in significant activation of metabolic pathways involving leucine and other amino acids. In summary, acute leucine supplementation potentiates fetal GSIS in vivo, likely through pathways related to the oxidation of leucine and catabolism of other amino acids.