Functional and Molecular Adaptations of Enteroendocrine L-Cells in Male Obese Mice Are Associated With Preservation of Pancreatic α-Cell Function and Prevention of Hyperglycemia.

Abstract

Glucose homeostasis depends on the coordinated secretion of glucagon, insulin, and Glucagon-like peptide (GLP)-1 by pancreas and intestine. Obesity, which is associated with an increased risk of developing insulin resistance and type 2 diabetes, affects the function of these organs. Here, we investigate the functional and molecular adaptations of proglucagon-producing cells in obese mice to better define their involvement in type 2 diabetes development. We used GLU-Venus transgenic male mice specifically expressing Venus fluorochrome in proglucagon-producing cells. Mice were subjected to 16 weeks of low-fat diet or high-fat diet (HFD) and then subdivided by measuring glycated hemoglobin (HbA1c) in 3 groups: low-fat diet mice and I-HFD (glucose-intolerant) mice with similar HbA1c and H-HFD (hyperglycemic) mice, which exhibited higher HbA1c. At 16 weeks, both HFD groups exhibited similar weight gain, hyperinsulinemia, and insulin resistance. However, I-HFD mice exhibited better glucose tolerance compared with H-HFD mice. I-HFD mice displayed functional and molecular adaptations of enteroendocrine L-cells resulting in increased intestinal GLP-1 biosynthesis and release as well as maintained pancreatic α- and β-cell functions. By contrast, H-HFD mice exhibited dysfunctional L, α- and β-cells with increased β- and L-cell numbers. Administration of the GLP-1R antagonist Exendin9-39 in I-HFD mice led to hyperglycemia and alterations of glucagon secretion without changes in insulin secretion. Our results highlight the cross-talk between islet and intestine endocrine cells and indicate that a compensatory adaptation of L-cell function in obesity plays an important role in preserving glucose homeostasis through the control of pancreatic α-cell functions.

• Authors: Rodolphe Dusaulcy, Sandra Handgraaf, Svetlana Skarupelova, Florian Visentin, Christian Vesin, Mounia Heddad-Masson, Frank Reimann, Fiona Gribble, Jacques Philippe, Yvan Gosmain
• Journal: Endocrinology (Endocrinology) Vol. 157 Issue 10 Pg. 3832-3843 (Oct 2016) ISSN: 1945-7170 [Electronic] United States
• PMID: 27547850 (Publication Type: Journal Article)

Chemical References

• Peptide Fragments
• exendin (9-39)
• Glucagon-Like Peptide 1
• Glucagon

Topics

• Animals
• Diabetes Mellitus, Type 2 (etiology, metabolism)
• Diet, High-Fat
• Enteroendocrine Cells (metabolism)
• Glucagon (metabolism)
• Glucagon-Like Peptide 1 (metabolism)
• Glucagon-Secreting Cells (metabolism)
• Hyperglycemia (etiology, metabolism)
• Insulin-Secreting Cells (metabolism)
• Male
• Mice, Inbred C57BL
• Mice, Transgenic
• Obesity (complications, metabolism)
• Peptide Fragments
• Phenotype