Physiological development of insulin secretion, calcium channels, and GLUT2 expression of pancreatic rat β-cells

Abstract

Insulin secretion in mature β-cells increases vigorously when extracellular glucose concentration rises. Glucose-stimulated insulin secretion depends on Ca2+ influx through voltage-gated Ca2+ channels. During fetal development, this structured response is not well established, and it is after birth that β-cells acquire glucose sensitivity and a robust secretion. We compared some elements of glucose-induced insulin secretion coupling in β-cells obtained from neonatal and adult rats and found that neonatal cells are functionally immature compared with adult cells. We observed that neonatal cells secrete less insulin and cannot sense changes in extracellular glucose concentrations. This could be partially explained because in neonates Ca2+ current density and synthesis of mRNA α1 subunit Ca2+ channel are lower than in adult cells. Interestingly, immunostaining for α1B, α1C, and α1D subunits in neonatal cells is similar in cytoplasm and plasma membrane, whereas it occurs predominantly in the plasma membrane in adult cells. We also observed that GLUT2 expression in adult β-cells is mostly located in the membrane, whereas in neonatal cells glucose transporters are predominantly in the cytoplasm. This could explain, in part, the insensitivity to extracellular glucose in neonatal β-cells. Understanding neonatal β-cell physiology and maturation contributes toward a better comprehension of type 2 diabetes physiopathology, where alterations in β-cells include diminished L-type Ca2+ channels and GLUT2 expression that results in an insufficient insulin secretion.

Beta cell coupling and connexin expression change during the functional maturation of rat pancreatic islets

“…We further document that, during development, the levels of Cx36 expression correlate with those of the insulin gene, as recently reported in humans [29]. Beta cells of neonatal islets express significantly less insulin mRNA than those of adult rats [8], a difference that cannot be explained merely by developmental changes in beta cell number/volume [3]. Our data indicate that increased CX36 signalling may be required to achieve proper insulin expression, an essential landmark of beta cell maturation, a consideration which, in turn, raises the intriguing possibility that the CX36 and beta cell maturation events may not only be coincidental but Fig.…”

“…M, molecular weight markers; F, fetus; N, neonatal; Y, young; A, adult. *p<0.05 vs neonatal and fetal values depolarisation and Ca +2 handling [1,2,4,7,8,24], it is conceivable that their modest expression of Cx36, gap junctions and beta cell coupling could account for their poor glucose-induced insulin secretion. Consistent with this view, we now show that a postnatal increase in the levels of the CX36 protein, the abundance of gap junctions and the extent of beta cell coupling accompanies the in vivo acquisition of glucose responsiveness, as previously suggested by preliminary in vitro experiments [9].…”

“…It has long been known that this glucose responsiveness is normally established in the few days that follow birth, even though beta cells are already equipped in the late prenatal period with most of their adult features [3][4][5][6][7][8]. Several events occurring during the early neonatal period, including changes in K + membrane permeability, production of GLUT2, protein kinase C-alpha, Ca 2+ channels and key enzymes of the NADH shuttles, are implicated in the maturation of beta cell function [1,2,[4][5][6][7][8][23][24][25]. We now show that gap junction/CX36 signalling, which contributes significantly to the proper function of adult beta cells [17, Fig.…”

“…When compared with adult islets, fetal and neonatal islets from different species exhibit a reduced secretory response to glucose and other secretagogues [1][2][3][4][5][6][7][8]. The nature of this poor responsiveness is not fully understood, and has been variably attributed to many factors, including fuel metabolites, intracellular signals, hormones and other environmental conditions [1][2][3][8][9][10][11].…”

“…The nature of this poor responsiveness is not fully understood, and has been variably attributed to many factors, including fuel metabolites, intracellular signals, hormones and other environmental conditions [1][2][3][8][9][10][11].…”