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Human glucagon gene promoter sequences regulating tissue-specific versus nutrient-regulated gene expression
Min Nian1, Jun Gu, David M Irwin
1Department of Laboratory Medicine and Pathobiology, Banting and Best Diabetes Centre, Toronto General Hospital, University of Toronto, Toronto, Canada M5G 2C4.
Summary
Human proglucagon gene regulation by nutrients differs from rodents. Specific human gene sequences in mice did not respond to feeding cues, indicating distinct nutrient sensing mechanisms for glucagon-like peptide biosynthesis.
Area of Science:
- Endocrinology
- Molecular Biology
- Genetics
Background:
- Glucagon-like peptides (GLPs) are crucial for nutrient homeostasis.
- Rodent GLP synthesis is nutrient-dependent, but human regulation is less understood.
- Investigating human proglucagon gene expression control by nutrients is essential.
Purpose of the Study:
- To elucidate the regulatory mechanisms of human proglucagon gene expression in response to nutrients.
- To compare nutrient-induced regulation of human and murine proglucagon gene expression in vivo.
- To determine if human proglucagon gene promoter elements confer nutrient responsiveness in a mouse model.
Main Methods:
- Utilized human glucagon-GH transgenic mice to study human proglucagon promoter-hGH transgene expression.
- Administered fasting-refeeding and high-fiber diets to assess nutrient effects.
- Measured circulating hGH, insulin, and endogenous mouse proglucagon RNA levels in various tissues.
Main Results:
- Fasting-refeeding altered mouse insulin and proglucagon RNA but not transgene hGH levels.
- High-fiber diet increased mouse proglucagon RNA and glucose-stimulated hGH.
- The human proglucagon promoter-hGH transgene did not respond to fasting-refeeding or high-fiber diets.
Conclusions:
- Human proglucagon gene regulatory sequences are not sufficient to confer nutrient responsiveness in vivo.
- Murine enteroendocrine cells recognize energy-derived signals differently than human gene regulatory elements.
- Significant differences exist in nutrient sensing pathways controlling GLP biosynthesis between humans and rodents.