Developmental programming of neonatal pancreatic β-cells by a maternal low-protein diet in rats involves a switch from proliferation to differentiation

Abstract

Maternal low-protein diets (LP) impair pancreatic β-cell development, resulting in later-life failure and susceptibility to type 2 diabetes (T2D). We hypothesized that intrauterine and/or postnatal developmental programming seen in this situation involve altered β-cell structure and relative time course of expression of genes critical to β-cell differentiation and growth. Pregnant Wistar rats were fed either control (C) 20% or restricted (R) 6% protein diets during pregnancy (1st letter) and/or lactation (2nd letter) in four groups: CC, RR, RC, and CR. At postnatal days 7 and 21, we measured male offspring β-cell fraction, mass, proliferation, aggregate number, and size as well as mRNA level for 13 key genes regulating β-cell development and function in isolated islets. Compared with CC, pre- and postnatal LP (RR) decreased β-cell fraction, mass, proliferation, aggregate size, and number and increased Hnf1a, Hnf4a, Pdx1, Isl1, Rfx6, and Slc2a2 mRNA levels. LP only in pregnancy (RC) also decreased β-cell fraction, mass, proliferation, aggregate size, and number and increased Hnf1a, Hnf4a, Pdx1, Rfx6, and Ins mRNA levels. Postnatal LP offspring (CR) showed decreased β-cell mass but increased β-cell fraction, aggregate number, and Hnf1a, Hnf4a, Rfx6, and Slc2a2 mRNA levels. We conclude that LP in pregnancy sets the trajectory of postnatal β-cell growth and differentiation, whereas LP in lactation has smaller effects. We propose that LP promotes differentiation through upregulation of transcription factors that stimulate differentiation at the expense of proliferation. This results in a decreased β-cell reserve, which can contribute to later-life predisposition to T2D.

Growth arrest specific protein (GAS) 6: a role in the regulation of proliferation and functional capacity of the perinatal rat beta cell

“…1a, b) in accordance with data from previous studies [12,13]. The microarray analysis of the transcriptome from rat pup pancreases revealed several genes as being differentially expressed.…”

“…Despite the GAS6-induced reduction in Mafa observed in this study, the Mafb mRNA content in GAS6-treated neonatal rat islets was unchanged. It was recently reported that a maternal LP diet increases the levels of factors in offspring associated with mature beta cells (among others Slc2a2; a target of MAFA) [13]. Rodriguez-Trejo et al [13] suggested that the maternal LP diet changed the uterine environment to favour maturation of beta cells at the expense of proliferation.…”

“…Rodriguez-Trejo et al [13] suggested that the maternal LP diet changed the uterine environment to favour maturation of beta cells at the expense of proliferation. This hypothesis is supported by our finding of increased Mafa mRNA levels in LP offspring, and a similar insulin mRNA content 2 days after birth despite the reduced beta cell mass in maternal-LPdiet offspring [5,13].…”

“…A maternal LP-diet diminishes proliferation of the fetal beta cells around the time of birth [11,12], and this could partly be caused by premature maturation at the expense of proliferation, thus giving rise to a reduced total beta cell mass [13]. Diet-induced changes in the temporal expression of transcription factors important for beta cell differentiation and maturation, such as v-maf musculoaponeurotic fibrosarcoma oncogene (MAF) homologue A and B and pancreatic duodenal homeobox-1 (PDX1), very likely play a role in development of the phenotype of LP offspring [14][15][16].…”

Low abundance plasma proteins in labour

“…HNF1A may also be involved in metabolic programming of the fetus (Rodriguez-Trejo et al 2012). An interesting finding from this study is the change with parturition in various proteins involved in triglyceride transport and metabolism.…”