The role of reduced glucose transporter content and glucose metabolism in the immature secretory responses of fetal rat pancreatic islets

Abstract

Isolated fetal islets show an immature or poor secretory response to nutrient secretagogues which may result from impaired mitochondrial oxidative processes. Insulin secretion, glucose metabolism and detection of metabolic enzymes by radiolabelling and immunoprecipitation were compared in islets isolated from neonatal (aged 5 days) and fetal rats (at 20 days gestation). The insulin secretory dynamics of fetal islets were abnormal in response to stimulation by glucose (10 mmol/l); a rapid release of insulin reaching a maximum 6 min after stimulation was observed with no rising second phase release. However, when the data were expressed as percentage of islet insulin content released, fetal islets released significantly more insulin than neonatal islets in response to glucose (4.86 +/- 0.45% vs 1.81 +/- 0.62%, p < 0.01) or 100 nmol/l glibenclamide (2.49 +/- 0.17% vs 0.25 +/- 0.06%, p < 0.001). Fetal islets however, failed to release insulin in response to stimulation by glyceraldehyde (10 mmol/l) unlike neonatal islets. Both glucose utilisation (as measured by the formation of [3H] H2O from 5-[3H] glucose) and glucose oxidation (as measured by the formation of [14C] CO2 from U-[14C] glucose) did not increase significantly in response to increasing the medium glucose concentration to 10 mmol/l whereas in neonatal islets, glucose utilisation and glucose oxidation were significantly increased 2.5- and 2.7-fold, respectively. When islets were incubated with both radiolabelled glucoses simultaneously, the rate of glucose oxidation was shown to be directly proportional to the rate of glucose utilisation. The relationship between glucose utilisation and glucose oxidation was similar in fetal and neonatal islets.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of NADH Shuttles in Glucose-Induced Insulin Secretion From Fetal β-Cells

“…tion, even though the V max of glucokinase increased and hence glucose utilization was also significantly increased (5). Our results are in agreement with those from Rorsman et al (8) but disputed by those of Hughes (4). However, as shown by Eto et al (13), the supply of NADH to the mitochondria is more crucial to ATP synthesis and glucosestimulated insulin secretion than total glucose utilization and oxidation.…”

“…lucose is the major physiological stimulus for insulin secretion in adult ␤-cells (1-3) but is unable to cause a similar response in fetal ␤-cells (4,5). The secretion of insulin from an adult ␤-cell involves the transport of glucose into the ␤-cell via the GLUT2 transporter, followed by the production of ATP, as a result of glucose metabolism in the glycolytic pathway, the tricarboxylic acid (TCA) cycle, and the mitochondrial electron transport chain.…”

“…The increase in intracellular Ca 2ϩ triggers insulin secretion. It is hypothesized that the failure of fetal ␤-cells to respond to glucose is due to an immaturity in one or more of the above steps (4).…”

Foxa2 regulates multiple pathways of insulin secretion

“…However, when we compared the expression profile of P8 mutant islets with that of controls, we found that the transcriptional programs were very similar, excluding the possibility of a pervasive developmental delay. In addition, fetal islets have a 50% reduction in protein and mRNA levels of Glut2 (42), which conceivably contributes to the lack of glucose sensitivity in fetal islets. However, both our previous studies (7) and real-time PCR from our study here revealed no difference in Glut2 mRNA expression between Foxa2 loxP/loxP ;Ins.Cre and control mice at P8.…”

Different Regulated Expression of the Tyrosine Phosphatase-Like Proteins IA-2 and Phogrin by Glucose and Insulin in Pancreatic Islets

“…Poor secretory responses appear not to be a consequence of inadequate insulin content of ␤-cells. Low levels of expression or activity of glucose transporters and metabolic enzymes may contribute (31,32), but other components of the secretory machinery may also be deficient in fetal and early neonatal life. The present study demonstrates that development of regulated insulin secretion after birth is accompanied by an increase in islet levels of IA-2, a tyrosine phosphatase-like protein that is proposed to mediate interactions of secretory granules with the islet cytoskeleton (12).…”