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Somatostatin regulation of beta-cell function in the normal human fetuses and in neonates with persistent
T Otonkoski1, S Andersson, O Simell
1Children's Hospital, University of Helsinki, Finland.
Insights
Human fetal cells show low sensitivity to somatostatin, while cells from infants with persistent hyperinsulinemic hypoglycemia of infancy (PHHI) are effectively inhibited by somatostatin, suggesting a somatostatin deficiency in PHHI.
Area of Science:
- Endocrinology
- Developmental Biology
- Pediatric Endocrinology
Background:
- Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is characterized by defective insulin regulation.
- Somatostatin plays a role in regulating insulin release, but its effects during fetal development and in PHHI are not fully understood.
Purpose of the Study:
- To investigate the insulin-inhibitory effects of somatostatin on human fetal pancreas cells.
- To examine the defective insulin regulation in PHHI and the role of somatostatin in this condition.
Main Methods:
- Perifusion and static incubation experiments using islet-like cell clusters from human fetal pancreases (HFP) and PHHI infants.
- Assessment of insulin release and (pro)insulin biosynthesis in response to somatostatin and glucose.
Main Results:
- Human fetal beta-cells showed marginal suppression of insulin release by somatostatin-14, potentiated by glucagon.
- Somatostatin-14 effectively suppressed insulin release from PHHI cells, more so than from HFP.
- PHHI cells exhibited poor glucose-stimulated insulin release, especially in severe cases.
Conclusions:
- Human fetal beta-cells are relatively insensitive to somatostatin, potentially due to low cellular cAMP levels.
- Insulin release in PHHI is poorly regulated by glucose but effectively inhibited by somatostatin, supporting a somatostatin deficiency hypothesis in PHHI.
Abstract:
To investigate the insulin-inhibitory effects of somatostatin during fetal development, and the defective regulation of insulin release in persistent hyperinsulinemic hypoglycemia of infancy (PHHI), we made perifusion experiments with islet-like cell clusters obtained from 14 human fetal pancreases (HFP) before 20 weeks of gestation and 6 neonates pancreatectomized because of PHHI (5 cases of diffuse and 1 adenomatous islet cell hyperplasia). Somatostatin-14 (600 nmol/L) suppressed insulin release only marginally (20% and 25% suppression in 2 and 20 mmol/L glucose, respectively) in HFP, whereas supplementation of the perifusate with 14 nmol/L glucagon potentiated the suppression to 57%. Somatostatin-28 (600 nmol/L) caused a 35% inhibition in insulin release from the HFP. In static incubation of HFP, somatostatin-14 caused a weak dose-dependent inhibition of insulin release, but had no effect on (pro)insulin biosynthesis. In the PHHI infants, somatostatin infusion suppressed hyperinsulinemia effectively before pancreatectomy. In vitro, 600 nmol/L somatostatin-14 suppressed insulin release clearly better than in the HFP experiments (35-61% inhibition). Glucose (20 mmol/L) induced a 2- to 3-fold increase in insulin release in two clinically mild cases of PHHI, but no response at all in the four others. We conclude that human fetal beta-cells are relatively insensitive to somatostatin, possibly because of low cellular cAMP levels. Furthermore, insulin release from PHHI cells is poorly stimulated by glucose but effectively blocked by somatostatin, supporting the concept of somatostatin deficiency in PHHI.