Altered pancreatic morphology in the offspring of pregnant rats given reduced dietary protein is time and gender specific

Abstract

Restriction of dietary protein during gestation and lactation in the rat results in a reduction in b cell mass, insulin content and release in the offspring, and glucose intolerance when the offspring reach adulthood. The present study was designed to identify if a particular developmental window existed during prenatal development when endocrine pancreatic development was most susceptible to nutritional insult. Pregnant rats received a low-protein (8%, LP), but isocalorific diet from conception to parturition, during the first 2 weeks of gestation (LP (1-2)), the second week only (LP (2)), or the third week (LP (3)). At other times, they received a 20% protein (C) diet, while control animals received this diet continuously. When the offspring were examined at 130 days age, animals that had received LP diet had a significantly impaired glucose tolerance compared with control-fed animals. Pancreatic morphology was examined in the offspring on postnatal days 1 and 21. The LP diet resulted in a significant decrease in the numbers of large (more than 10 000 mm 2 ) and medium (between 5000 and 10 000 mm 2 ) sized islets present at postnatal day 1 for all LP treatments. Consequently, mean islet area and the mean number of b cells were reduced. The impact of LP diet was most pronounced in LP (2) for females and in LP (3) for males, and this was greater than for continuous LP exposure. Insulin and Glut-2 mRNA expression were impacted negatively by LP in early and late gestation, but increased following administration in midgestation. Total pancreatic insulin content was not altered by LP treatment. Pdx-1, a transcription factor associated with both b cell development and insulin gene transcription, was decreased in female offspring following LP (1-2) and LP (3), but not in males. Pancreatic expression of nestin mRNA, and the abundance of nestin-immunoreactive cells within islets, was decreased by all LP treatments. By postnatal day 21, the mean islet area and number of b cells had largely recovered. However, insulin and Glut-2 mRNAs were elevated in offspring exposed to LP diet, particularly in females. The studies show that LP dietary insult in early, middle, or late gestation, all result in a relative deficiency of b cells following birth, due to a failure to develop larger islets, but that females were particularly susceptible in mid-gestation and males in late gestation.

Regulation of postnatal pancreatic Pdx1 and downstream target genes after gestational exposure to protein restriction in rats

“…Administration of a LP diet during pregnancy in rats has been studied extensively and leads to low birth weight in offspring with an important impairment in pancreatic development within the endocrine compartment (Snoeck et al 1990, Petrik et al 1999, Holemans et al 2003, Heywood et al 2004, Chamson-Reig et al 2006). In addition, the effect of protein restriction depended on the timing or the critical period when the food insult was given during pregnancy.…”

“…Group 1 C were fed with C diet until day 130, Group 2 LP1 received LP diet until day 130, Group 3 LP2 were fed LP diet during gestation and lactation (day 21), and Group 4 LP3 received LP diet during gestation only. The 130 day time point was chosen based on our previous published work, which demonstrated that male LP2 offspring first exhibit glucose intolerance at this age (Chamson-Reig et al 2006). The offspring at birth were restricted to eight pups to maintain uniform neonatal growth.…”

“…In addition, we have shown that this LP diet given during pregnancy at different windows of fetal development results in a relative deficiency of b cells following birth, due to a failure to develop larger islets. These developmental changes in the pancreas affect male and female fetuses differently (Chamson-Reig et al 2006). Interestingly, if the LP diet was extended into neonatal life, the pancreas showed reduced b-cell mass, islet area and pancreatic vascularity with increased b-cell apoptosis and decreased rate of b-cell duplication and reduction in IGF2 expression (Petrik et al 1999).…”

Increased islet neogenesis without increased islet mass precedes autoimmune attack in diabetes-prone rats

“…49 A recent study also showed decreased area of large islets in offspring of Wistar rats fed a low-protein diet. 50 Whether or not very large islets seen in BBc rats are a common feature of islet size distribution in humans remains unclear.…”

Transgenerational metabolic outcomes associated with uteroplacental insufficiency

“…Three sections of equal distance apart were immunostained for insulin-positive b-cells using a guinea pig polyclonal anti-insulin antibody (1:200 dilution, Dako, Kingsgrove, NSW, Australia; nZ5-8/group; Siebel et al 2010, Laker et al 2011, Tran et al 2012. Pancreatic islet number and area per sectional area (per mm 2 ) were averaged across the three sections, with islet area arbitrarily divided into small (!5000 mm 2 ), medium (5000-10 000 mm 2 ), and large (O10 000 mm 2 ) (Chamson-Reig et al 2006).…”