Altered Expression of Hexokinase Isoforms May Mediate a Reduced Glucose Threshold for Insulin Secretion in the Perinatal Period

Presentation Number: SUN 593
Date of Presentation: April 2nd, 2017

Daphne Yau*1, Lane Jaeckle Santos2, Changhong Li3, Yu-Chin Lien2, Rebecca A Simmons2 and Charles A Stanley4
1Children's Hospital of Philadelphia, Philadelphia, PA, 2University of Pennsylvania, Philadelphia, PA, 3The Children’s Hospital of Philadelphia, Philadelphia, PA, 4The Children's Hospital of Philadelphia, Philadelphia, PA

Abstract

Hypoglycemia is common in the first 24-48 hours of life in normal newborns. Most infants are asymptomatic but seizures and permanent neurologic injury can occur. The underlying mechanism is poorly understood although limited data suggests a reduced threshold for glucose-stimulated insulin secretion (GSIS). To determine the differences in the regulation of insulin secretion during the transition from fetal to post-natal life, we examined insulin responses to fuels in perifused rat pancreas and isolated islets. The glucose threshold for insulin release was markedly lower in the fetal pancreas at gestational day 21 of 23, with clear stimulation of insulin secretion at a glucose concentration of 3 mmol/L vs 10 mmol/L in adult islets. The maximal GSIS was also lower in the fetal versus adult pancreas (2.4-fold vs. 13.5-fold basal, p<0.01). However, the insulin response to ketoisocaproate, a fuel directly feeding into the tricarboxylic acid cycle, was similar. Quantitative PCR analysis of islet mRNA revealed a reduction in glucokinase expression in fetal versus adult islets, while the expression of high affinity (low Km) hexokinase isoforms was significantly increased compared to adult islets (p<0.01). These data show that transitional neonatal hypoglycemia involves a reduced threshold for GSIS in the fetal and early postnatal period mediated by increased expression of high affinity hexokinase isoforms combined with lowered glucokinase expression. Future pharmacological targeting of these different hexokinase isoforms in the beta-cell represents a unique way in which to treat neonatal hypoglycemia. 

 

Nothing to Disclose: DY, LJ, CL, YCL, RAS, CAS