High glucagon, low growth: unveiling fetal hyperglucagonaemia's impact on adult metabolic health

Glucagon is a peptide hormone that was identified by Charles Kimball and John Murlin in 1922, during the characterization of a pancreatic factor capable of increasing blood glucose concentrations. It was initially called a ‘glucose agonist’ and later received the name glucagon (Wewer Albrechtsen et al., 2023). It is known that glucagon is secreted by pancreatic alpha cells, playing a fundamental role with insulin in glycaemic homeostasis (Zhang et al., 2021). On the other hand, glucagon can exert effects on different metabolic processes, including amino acid metabolism. At high concentrations this hormone is known to intensify the oxidation of amino acids and inhibit protein synthesis, leading to hypoaminoacidaemia and a decrease in body lean mass, as observed in individuals with glucagonomas (Cilvik et al., 2021; Wewer Albrechtsen et al., 2023). In a recent study published in The Journal of Physiology, Cilvik et al. (2024) gathered evidence supporting that high glucagon concentrations compromise fetal growth through the impact on amino acid metabolism. The authors sought to investigate the effect of chronic hyperglucagonaemia in late gestation and its impacts on pancreatic islets. Fetuses from singleton and late gestation sheep were used and received continuous infusions of three different solutions: the control group (vehicle, bovine serum albumin), the low-dose group (5 ng/kg/min glucagon) and the high-dose group (50 ng/kg/min glucagon). Observations were made during acute (3 h) and chronic (8–10 days) exposure to glucagon administration. Arterial blood samples were collected periodically to measure insulin, glucagon, glucose and amino acid concentrations, while histological analyses were performed to evaluate pancreatic structure. The results showed a reduction in both basal insulin secretion and glucose-stimulated insulin, at both doses of 5 ng/kg/min (GCG-5) and 50 ng/kg/min (GCG-50), with a more pronounced effect in the chronic phase in sheep fetuses exposed to high doses (GCG-50) (Fig. 1). Previous studies in mice suggest that under normal conditions, glucagon stimulates insulin secretion through activation of the glucagon receptor. However, chronic exposure to excess glucagon can result in the exhaustion of pancreatic beta cells due to overproduction of insulin, thus reducing its secretion (Zhang et al., 2021). This finding further corroborates the results obtained by Cilvik and collaborators regarding the effects of glucagon on insulin secretion. Regarding the structure of the pancreas, there was a significant reduction in the area of pancreatic islets and the proliferation of alpha and beta cells (Fig. 1), suggesting that excess glucagon can compromise the endocrine function of the pancreas. Furthermore, it was observed that fetuses exposed to glucagon presented significant alterations in amino acid and glucose concentrations. Studies carried out in pregnant sheep demonstrate the beneficial potential of chronic administration of amino acids in fetuses with intrauterine growth restriction, promoting the improvement of insulin secretion and functional recovery of the endocrine pancreas (Brown et al., 2016). Together, these results highlight that the imbalance in glucagon concentrations harms the fetus, due to the inadequate response of pancreatic beta cells. Meanwhile, increased amino acid concentrations contribute to healthy fetal growth (Brown et al., 2016; Cilvik et al., 2021, 2024). Additionally, recent evidence from the same group Cilvik et al. (2021) shows that fetal hyperglucagonaemia can inhibit the secretion of chorionic somatomammotropin (CSH), a hormone that appears to be essential for fetal metabolism and growth. This inhibition is associated with a reduction in insulin secretion and low birth weight. Furthermore, low concentrations of CSH and excess glucagon may contribute to reduced placental blood flow, and consequently limit the delivery of nutrients and oxygen to the fetus (Cilvik et al., 2021). The results presented here are promising and relevant to the scientific community. However, there are some limitations to be considered. It is not yet clear whether the structural changes observed in the pancreas are reversible or whether they persist throughout life. Furthermore, it is not clear whether the reduced proliferation of pancreatic beta and alpha cells is related to low amino acid concentrations or the direct effect of glucagon. These questions are relevant and require further investigation. In conclusion, the study by Cilvik et al. (2024) highlights the implications of metabolic imbalance in fetal development, evidencing the complex relationship between glucagon, amino acid metabolism and insulin secretion. These findings emphasize the need for further studies to better understand the mechanisms underlying excess glucagon in fetuses and its association with the development of metabolic diseases in the future. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. None declared. T.S.: Conception or design of the work; Drafting the work or revising it critically for important intellectual content; Final approval of the version to be published; Agreement to be accountable for all aspects of the work. R.B.: Conception or design of the work; Drafting the work or revising it critically for important intellectual content; Final approval of the version to be published; Agreement to be accountable for all aspects of the work. Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP): Renata Braga, 2019/21171-4. The authors would like to thank Dr Eduardo Ropelle for his support and guidance.