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Diabetes. 2015 Nov;64(11):3798-807. doi: 10.2337/db15-0272. Epub 2015 Jul 7.

Phenotypic Characterization of MIP-CreERT1Lphi Mice With Transgene-Driven Islet Expression of Human Growth Hormone.

Author information

1
Institut de recherches cliniques de Montréal, Montreal, QC, Canada Department of Anatomy and Cell Biology, McGill University, Montreal, QC, Canada.
2
Institut de recherches cliniques de Montréal, Montreal, QC, Canada Division of Experimental Medicine, McGill University, Montreal, QC, Canada.
3
Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, QC, Canada.
4
Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
5
Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, QC, Canada Département de Médecine, Université de Montréal, Montreal, QC, Canada.
6
Institut de recherches cliniques de Montréal, Montreal, QC, Canada.
7
Department of Medicine and Interdisciplinary Graduate Program in Nutritional Sciences, University of Wisconsin-Madison, Madison, WI.
8
Division of Experimental Medicine, McGill University, Montreal, QC, Canada.
9
Department of Cellular and Molecular Medicine, Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada.
10
Institut de recherches cliniques de Montréal, Montreal, QC, Canada Division of Experimental Medicine, McGill University, Montreal, QC, Canada Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, QC, Canada.
11
Institut de recherches cliniques de Montréal, Montreal, QC, Canada Department of Anatomy and Cell Biology, McGill University, Montreal, QC, Canada Division of Experimental Medicine, McGill University, Montreal, QC, Canada Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, QC, Canada Département de Médecine, Université de Montréal, Montreal, QC, Canada jennifer.estall@ircm.qc.ca.

Abstract

There is growing concern over confounding artifacts associated with β-cell-specific Cre-recombinase transgenic models, raising questions about their general usefulness in research. The inducible β-cell-specific transgenic (MIP-CreERT(1Lphi)) mouse was designed to circumvent many of these issues, and we investigated whether this tool effectively addressed concerns of ectopic expression and disruption of glucose metabolism. Recombinase activity was absent from the central nervous system using a reporter line and high-resolution microscopy. Despite increased pancreatic insulin content, MIP-CreERT mice on a chow diet exhibited normal ambient glycemia, glucose tolerance and insulin sensitivity, and appropriate insulin secretion in response to glucose in vivo and in vitro. However, MIP-CreERT mice on different genetic backgrounds were protected from high-fat/ streptozotocin (STZ)-induced hyperglycemia that was accompanied by increased insulin content and islet density. Ectopic human growth hormone (hGH) was highly expressed in MIP-CreERT islets independent of tamoxifen administration. Circulating insulin levels remained similar to wild-type controls, whereas STZ-associated increases in α-cell number and serum glucagon were significantly blunted in MIP-CreERT(1Lphi) mice, possibly due to paracrine effects of hGH-induced serotonin expression. These studies reveal important new insight into the strengths and limitations of the MIP-CreERT mouse line for β-cell research.

PMID:
26153246
PMCID:
PMC4613972
DOI:
10.2337/db15-0272
[Indexed for MEDLINE]
Free PMC Article

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