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

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.

• Authors: Daniel Oropeza, Nathalie Jouvet, Lionel Budry, Jonathan E Campbell, Khalil Bouyakdan, Julie Lacombe, Gabrielle Perron, Valerie Bergeron, Joshua C Neuman, Harpreet K Brar, Rachel J Fenske, Clemence Meunier, Sarah Sczelecki, Michelle E Kimple, Daniel J Drucker, Robert A Screaton, Vincent Poitout, Mathieu Ferron, Thierry Alquier, Jennifer L Estall
• Journal: Diabetes (Diabetes) Vol. 64 Issue 11 Pg. 3798-807 (Nov 2015) ISSN: 1939-327X [Electronic] United States
• PMID: 26153246 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Chemical References

• Blood Glucose
• Insulin
• Human Growth Hormone

Topics

• Animals
• Blood Glucose (metabolism)
• Diabetes Mellitus, Experimental (genetics, metabolism)
• Homeostasis (physiology)
• Human Growth Hormone (genetics, metabolism)
• Humans
• Hyperglycemia (genetics, metabolism)
• Insulin (blood)
• Insulin-Secreting Cells (metabolism)
• Male
• Mice
• Mice, Transgenic
• Phenotype