Different mechanisms operating during different critical time-windows reduce rat fetal beta cell mass due to a maternal low-protein or low-energy diet

Abstract

Aims/hypothesis Adverse events during intra-uterine life may programme organ growth and favour disease later in life. In animals, protein or energy restriction during gestation alters the development of the endocrine pancreas, even though the duration of malnutrition is different. Here, we evaluate the specific effects of both diets during different periods of gestation and the mechanisms underlying the decreased beta cell mass. Methods Pregnant Wistar rats were fed either a low-protein or a low-energy diet during the last week of gestation or throughout gestation. Fetuses and their pancreases were analysed at days 15 and 21 of gestation. Results The low-energy diet reduced the beta cell mass from 21-day-old fetuses by 33 or 56% when administered during the last week or throughout gestation, respectively. Fetal corticosterone levels were increased. At 15 days of fetal age, the number of cells producing neurogenin 3 (NEUROG3) or pancreatic and duodenal homeobox gene 1 (PDX-1) was reduced. Neither islet vascularisation nor beta cell proliferation was affected. The low-protein diet, in contrast, was more efficient in decreasing the fetal beta cell mass when given during the last week of gestation (−53%) rather than throughout gestation (−33%). Beta cell proliferation was decreased by 50% by the low-protein diet, independently of its duration, and islet vascularisation was reduced. This diet did not affect NEUROG3-or PDX-1-positive cell numbers. Conclusion/interpretation Although both diets reduced the fetal beta cell mass, the cellular mechanisms and the sensitivity windows were different. Early alteration of neogenesis due to elevated corticosterone levels is likely to be responsible for the decreased beta cell mass in low-energy fetuses, whereas impaired beta cell proliferation and islet vascularisation at later stages are implicated in low-protein fetuses. Keywords

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.…”

“…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].…”

The intrauterine metabolic environment modulates the gene expression pattern in fetal rat islets: prevention by maternal taurine supplementation

“…In contrast, many genes involved in cell cycle and cell proliferation were changed by the LP diet and their expression restored by taurine. This may fit in with the lengthening of the beta cell cycle and the lower proliferation rate that we previously described in fetuses from dams fed an LP diet [8,13,37]. Evidence for the involvement of the IGF gene/protein family in beta cell development is abundant.…”

Reduced pancreatic β-cell mass is associated with decreased FoxO1 and Erk1/2 protein phosphorylation in low-protein malnourished rats

“…Malnourishment induces functional and structural alterations in the endocrine pancreas in fetal, neonatal (1)(2)(3)(4) and adult rats (5)(6)(7)(8)(9). We have shown that malnutrition caused by a low-protein diet increases insulin sensitivity in peripheral tissues of adult rats (6,7).…”

“…Other studies have reported alterations in pancreatic islet structure in models of undernutrition. Among these alterations, reduction in β-cell mass and proliferation has been reported, as well as diminished islet vascularization (1)(2)(3)(4). Changes in peripheral insulin sensitivity are compensated by reciprocal alterations in islet mass and function (10)(11)(12)(13).…”