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Molecular adaptations in islets from neonatal rats reared artificially on a high carbohydrate milk formula
M Srinivasan1, F Song, R Aalinkeel
1Department of Biochemistry, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, 14214, Buffalo, NY, USA
Insights
High carbohydrate formula in neonatal rats causes lasting hyperinsulinemia. Molecular changes in pancreatic islets, including increased insulin production and transcription factors like PDX-1, contribute to this condition.
Area of Science:
- Endocrinology
- Molecular Biology
- Developmental Biology
Background:
- Neonatal exposure to high carbohydrate (HC) diets can induce hyperinsulinemia.
- This condition persists into adulthood, suggesting early molecular programming.
- Understanding islet adaptations is crucial for metabolic disease research.
Purpose of the Study:
- To investigate the molecular mechanisms underlying hyperinsulinemia in neonatal rats fed a HC formula.
- To examine changes in pancreatic islet gene expression and protein activity.
- To identify key factors contributing to persistent hyperinsulinemia.
Main Methods:
- Isolation of pancreatic islets from neonatal rats fed HC formula or mother-fed (MF) diet.
- Quantification of preproinsulin mRNA levels.
- Assessment of Pancreatic duodenal homeobox factor-1 (PDX-1) mRNA, DNA binding activity, and protein content.
- Measurement of mRNA levels for stress-activated protein kinase-2, phosphatidylinositol 3-kinase, and upstream stimulatory factor.
Main Results:
- HC diet significantly increased preproinsulin mRNA and insulin biosynthesis in neonatal islets.
- PDX-1 mRNA, DNA binding activity, and protein content were elevated in HC islets.
- mRNA levels of stress-activated protein kinase-2, phosphatidylinositol 3-kinase, and upstream stimulatory factor were increased in HC islets.
Conclusions:
- Early-life high carbohydrate nutrition induces molecular adaptations in pancreatic islets.
- Upregulation of preproinsulin gene expression, PDX-1, and associated kinases contributes to HC-induced hyperinsulinemia.
- These findings highlight the role of developmental programming in metabolic disorders.
Abstract:
Four day-old rat pups artificially raised on a high carbohydrate (HC) milk formula during their suckling period immediately develop hyperinsulinemia which persists into adulthood despite weaning onto lab chow on day 24. The present study investigates the molecular adaptations in islets isolated from neonatal rats in response to this dietary treatment during their suckling period. There is a significant increase in the level of preproinsulin mRNA and insulin biosynthesis in 12 day-old HC islets compared to islets from age-matched mother-fed (MF) control rats. Pancreatic duodenal homeobox factor-1 (PDX-1) modulates pancreatic ontogeny as well as preproinsulin gene expression in islets from neonatal rats. The mRNA level, DNA binding activity and protein content of PDX-1 are significantly increased in HC islets. The stress-activated protein kinase-2 and phosphatidylinositol 3-kinase have been reported to modulate PDX-1 activity in islets. The mRNA levels of these kinases are increased in HC islets. The mRNA level of upstream stimulatory factor (a modulator of PDX-1 gene expression) is also significantly increased in HC islets. These results indicate that the upregulation of several molecular events, including increases in the gene expression of preproinsulin, transcription factors and kinases may contribute to the chronic hyperinsulinemic state in the HC rats.