Doctor of Philosophy
Dr. David Hill
Effects of a low protein (LP) diet during gestation on the metabolism of rat offspring have been well characterized and leads to glucose intolerance in adulthood. It is unknown how LP impacts endocrine pancreas development in the mouse, or whether this affects future β-cell plasticity. Streptozotocin (STZ) – induced β-cell injury has been demonstrated to be followed by β-cell regeneration in young animals, but the mechanism(s) of regeneration are not clear. Our objective was to characterize a mouse model of maternal LP, in addition to identifying factors that contribute to the long term development of glucose intolerance and the mechanism of β-cell regeneration.
We hypothesized that protein restriction during gestation in mice will alter development, leading to long term glucose impairments and a failure to regenerate β-cell mass after STZ.
Pregnant Balb/c mice were placed on a control (C; 20% protein) or an isocaloric LP (8% protein) diet throughout gestation and C thereafter. Offspring were injected with multiple low doses of STZ or vehicle at postnatal day 1 for each dietary treatment. The offspring were examined to assess β-cell mass, glucose homeostasis and potential sources of regenerated β-cells. Additionally, differential gene expression was analyzed by cDNA microarray to identify candidate genes involved in β-cell regeneration.
LP-fed offspring had a reduced birth weight, and females developed glucose intolerance at d130, confirming previous studies in rat. LP offspring had a reduced capacity for β-cell regeneration following STZ compared to C-fed offspring. LP+STZ mice were observed to have an increased presence of putative precursor β-cells within islets, assessed by the frequency of cells containing the transcription factor Pdx-1, but not insulin. This suggests that such cells may fail to differentiate and contribute to new β-cell formation following exposure to LP. Additionally, female LP+STZ mice had a reduced presence of the trophic islet peptide, regenerating islet-derived 1 (Reg1), when compared to the C+STZ animals.
In conclusion, these studies have developed a mouse model of nutrition-induced fetal programming of metabolism, have shown that prior LP exposure compromised future β-cell plasticity, and have identified key genes relevant to β-cell regeneration whose expression is altered in LP-treated animals.
Cox, Aaron R., "The Effects of Low Protein during Gestation on Mouse Pancreas Development and Beta Cell Regeneration" (2011). Electronic Thesis and Dissertation Repository. 169.