title: 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.
authors.affiliation: Universidad Nacional Autónoma de México. Av. Universidad 3000, Facultad de Química, Mexico City, Mexico.
authors.forename: Adriana
authors.initials: A
authors.lastname: Rodríguez-Trejo
authors.forename: María Guadalupe
authors.initials: MG
authors.lastname: Ortiz-López
authors.forename: Elena
authors.initials: E
authors.lastname: Zambrano
authors.forename: María de Los Ángeles
authors.initials: Mde L
authors.lastname: Granados-Silvestre
authors.forename: Carmen
authors.initials: C
authors.lastname: Méndez
authors.forename: Bertrand
authors.initials: B
authors.lastname: Blondeau
authors.forename: Bernadette
authors.initials: B
authors.lastname: Bréant
authors.forename: Peter W
authors.initials: PW
authors.lastname: Nathanielsz
authors.forename: Marta
authors.initials: M
authors.lastname: Menjivar
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002469:Cell Separation; D004032:Diet; D018753:Diet, Protein-Restricted; D004435:Eating / Q000187:drug effects; D005260:Female; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000187:drug effects; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000187:drug effects*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010179:Pancreas / Q000166:cytology / Q000187:drug effects / Q000254:growth & development; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics
chemical_list: D001786:Blood Glucose; D007328:Insulin; D014157:Transcription Factors