Gestational exposure to metformin programs improved glucose tolerance and insulin secretion in adult male mouse offspring

Brigid E. Gregg; Nathalie Botezatu; Joshua D. Brill; Hannah Hafner; Suryakiran Vadrevu; Leslie S. Satin; Emilyn U. Alejandro; Ernesto Bernal-Mizrachi

doi:10.1038/s41598-018-23965-4

Gestational exposure to metformin programs improved glucose tolerance and insulin secretion in adult male mouse offspring

Brigid E. Gregg, Nathalie Botezatu, Joshua D. Brill, Hannah Hafner, Suryakiran Vadrevu, Leslie S. Satin, Emilyn U. Alejandro, Ernesto Bernal-Mizrachi

Physiology

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Abstract

Pancreatic β-cells are exquisitely sensitive to developmental nutrient stressors, and alterations in nutrient sensing pathways may underlie changes observed in these models. Here we developed a mouse model of in utero exposure to the anti-diabetic agent metformin. We have previously shown that this exposure increases offspring pancreatic β-cell mass at birth. We hypothesized that adult offspring would have improved metabolic parameters as a long-term outcome of metformin exposure. Virgin dams were given 5 mg/mL metformin in their water from E0.5 to delivery at E18.5. Body weight, glucose tolerance, insulin tolerance and glucose stimulated insulin secretion were analyzed in the offspring. When male offspring of dams given metformin during gestation were tested as adults they had improved glucose tolerance and enhanced insulin secretion in vivo as did their islets in vitro. Enhanced insulin secretion was accompanied by changes in intracellular free calcium responses to glucose and potassium chloride, possibly mediated by increased L channel expression. Female offspring exhibited improved glucose tolerance at advanced ages. In conclusion, in this model in utero metformin exposure leads to improved offspring metabolism in a gender-specific manner. These findings suggest that metformin applied during gestation may be an option for reprogramming metabolism in at risk groups.

Original language	English (US)
Article number	5745
Journal	Scientific reports
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41598-018-23965-4
State	Published - Dec 1 2018

Bibliographical note

Funding Information:
The authors wish to thank funding agencies for their crucial contribution to this work. E.B.M. supported by the National Institutes of Health (NIH) Grant RO1-DK073716, DK084236, MERIT award IBX002728A and Juvenile Diabetes Research Foundation (JDRF) grant 17-2013-416. This work was supported by National Institutes of Health Grant R01 DK084236. A Career Development Award from NIDDK (K08-DK-102526) supported BG. RO1DK46409 supported Dr. Satin’s research. We would also like to thank the University of Michigan Regional Metabolomics Center for metformin measurements. This work also utilized the Islet Isolation Laboratory and Microscopy Core(s) of the Michigan Diabetes Research Center funded by NIH Grant No. 2P30-DK020572 from the National Institute of Diabetes and Digestive and Kidney Diseases. The tissues used in this study were processed by the Histology/Immunohistochemistry service run by the University of Michigan department of pathology.

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© 2018 The Author(s).

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title = "Gestational exposure to metformin programs improved glucose tolerance and insulin secretion in adult male mouse offspring",

abstract = "Pancreatic β-cells are exquisitely sensitive to developmental nutrient stressors, and alterations in nutrient sensing pathways may underlie changes observed in these models. Here we developed a mouse model of in utero exposure to the anti-diabetic agent metformin. We have previously shown that this exposure increases offspring pancreatic β-cell mass at birth. We hypothesized that adult offspring would have improved metabolic parameters as a long-term outcome of metformin exposure. Virgin dams were given 5 mg/mL metformin in their water from E0.5 to delivery at E18.5. Body weight, glucose tolerance, insulin tolerance and glucose stimulated insulin secretion were analyzed in the offspring. When male offspring of dams given metformin during gestation were tested as adults they had improved glucose tolerance and enhanced insulin secretion in vivo as did their islets in vitro. Enhanced insulin secretion was accompanied by changes in intracellular free calcium responses to glucose and potassium chloride, possibly mediated by increased L channel expression. Female offspring exhibited improved glucose tolerance at advanced ages. In conclusion, in this model in utero metformin exposure leads to improved offspring metabolism in a gender-specific manner. These findings suggest that metformin applied during gestation may be an option for reprogramming metabolism in at risk groups.",

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note = "Funding Information: The authors wish to thank funding agencies for their crucial contribution to this work. E.B.M. supported by the National Institutes of Health (NIH) Grant RO1-DK073716, DK084236, MERIT award IBX002728A and Juvenile Diabetes Research Foundation (JDRF) grant 17-2013-416. This work was supported by National Institutes of Health Grant R01 DK084236. A Career Development Award from NIDDK (K08-DK-102526) supported BG. RO1DK46409 supported Dr. Satin{\textquoteright}s research. We would also like to thank the University of Michigan Regional Metabolomics Center for metformin measurements. This work also utilized the Islet Isolation Laboratory and Microscopy Core(s) of the Michigan Diabetes Research Center funded by NIH Grant No. 2P30-DK020572 from the National Institute of Diabetes and Digestive and Kidney Diseases. The tissues used in this study were processed by the Histology/Immunohistochemistry service run by the University of Michigan department of pathology. Publisher Copyright: {\textcopyright} 2018 The Author(s).",

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AU - Alejandro, Emilyn U.

AU - Bernal-Mizrachi, Ernesto

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N2 - Pancreatic β-cells are exquisitely sensitive to developmental nutrient stressors, and alterations in nutrient sensing pathways may underlie changes observed in these models. Here we developed a mouse model of in utero exposure to the anti-diabetic agent metformin. We have previously shown that this exposure increases offspring pancreatic β-cell mass at birth. We hypothesized that adult offspring would have improved metabolic parameters as a long-term outcome of metformin exposure. Virgin dams were given 5 mg/mL metformin in their water from E0.5 to delivery at E18.5. Body weight, glucose tolerance, insulin tolerance and glucose stimulated insulin secretion were analyzed in the offspring. When male offspring of dams given metformin during gestation were tested as adults they had improved glucose tolerance and enhanced insulin secretion in vivo as did their islets in vitro. Enhanced insulin secretion was accompanied by changes in intracellular free calcium responses to glucose and potassium chloride, possibly mediated by increased L channel expression. Female offspring exhibited improved glucose tolerance at advanced ages. In conclusion, in this model in utero metformin exposure leads to improved offspring metabolism in a gender-specific manner. These findings suggest that metformin applied during gestation may be an option for reprogramming metabolism in at risk groups.

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Gestational exposure to metformin programs improved glucose tolerance and insulin secretion in adult male mouse offspring

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