Maternal low-protein diet (LP) throughout gestation affects pancreatic b-cell fraction of the offspring at birth, thus increasing their susceptibility to metabolic dysfunction and type 2 diabetes in adulthood. The present study sought to strictly examine the effects of LP during the last week of gestation (LP12.5) alone as a developmental window for b-cell programming and metabolic dysfunction in adulthood. Islet morphology analysis revealed normal b-cell fraction in LP12.5 newborns. Normal glucose tolerance was observed in 6- to 8-wk-old male and female LP12.5 offspring. However, male LP12.5 offspring displayed glucose intolerance and reduced insulin sensitivity associated with b-cell dysfunction with aging. High-fat diet exposure of metabolically normal 12-wk-old male LP12.5 induced glucose intolerance due to increased body weight, insulin resistance, and insufficient b-cell mass adaptation despite higher insulin secretion. Assessment of epigenetic mechanisms through microRNAs (miRs) by a real-time PCR-based microarray in islets revealed elevation in miRs that regulate insulin secretion (miRs 342, 143), insulin resistance (miR143), and obesity (miR219). In the islets, overexpression of miR143 reduced insulin secretion in response to glucose. In contrast to the model of LP exposure throughout pregnancy, islet protein levels of mTOR and pancreatic and duodenal homeobox 1 were normal in LP12.5 islets. Collectively, these data suggest that LP diet during the last week of pregnancy is critical and sufficient to induce specific and distinct developmental programming effects of tissues that control glucose homeostasis, thus causing permanent changes in specific set of microRNAs that may contribute to the overall vulnerability of the offspring to obesity, insulin resistance, and type 2 diabetes.
|Original language||English (US)|
|Journal||American Journal of Physiology - Regulatory Integrative and Comparative Physiology|
|State||Published - Oct 2020|
Bibliographical noteFunding Information:
This work was supported by the National Institutes of Health (NIH) Grants R01-DK-084236 and DK-073716 to E. Bernal-Mizrachi; R21-DK-112144, R03-DK-114465, R01-DK-115720, and R21-HD-100840 to E. U. Alejandro; and R24-DK-092759 and RO1-DK-62876 to O. A. MacDougald. The Michigan Mouse Metabolic Phenotyping Center was supported by NIH Grant U2C-DK-110768.
© 2020 American Physiological Society. All rights reserved.
- B-cell function
- Fetal nutrition disorders
- Fetal programming
- Islet biology
- Low-protein diet