Angptl4 Does Not Control Hyperglucagonemia or α-cell Hyperplasia Following Glucagon Receptor Inhibition

Proc Natl Acad Sci U S A. 2017 Mar 7;114(10):2747-2752. doi: 10.1073/pnas.1620989114. Epub 2017 Jan 31.


Genetic disruption or pharmacologic inhibition of glucagon signaling effectively lowers blood glucose but results in compensatory glucagon hypersecretion involving expansion of pancreatic α-cell mass. Ben-Zvi et al. recently reported that angiopoietin-like protein 4 (Angptl4) links glucagon receptor inhibition to hyperglucagonemia and α-cell proliferation [Ben-Zvi et al. (2015) Proc Natl Acad Sci USA 112:15498-15503]. Angptl4 is a secreted protein and inhibitor of lipoprotein lipase-mediated plasma triglyceride clearance. We report that Angptl4-/- mice treated with an anti-glucagon receptor monoclonal antibody undergo elevation of plasma glucagon levels and α-cell expansion similar to wild-type mice. Overexpression of Angptl4 in liver of mice caused a 8.6-fold elevation in plasma triglyceride levels, but did not alter plasma glucagon levels or α-cell mass. Furthermore, administration of glucagon receptor-blocking antibody to healthy individuals increased plasma glucagon and amino acid levels, but did not change circulating Angptl4 concentration. These data show that Angptl4 does not link glucagon receptor inhibition to compensatory hyperglucagonemia or expansion of α-cell mass, and that it cannot be given to induce such secretion and growth. The reduction of plasma triglyceride levels in Angptl4-/- mice and increase following Angptl4 overexpression suggest that changes in plasma triglyceride metabolism do not regulate α-cells in the pancreas. Our findings corroborate recent data showing that increased plasma amino acids and their transport into α-cells link glucagon receptor blockage to α-cell hyperplasia.

Keywords: Angptl4; antibody; glucagon receptor; α-cell mass.

MeSH terms

  • Angiopoietin-like 4 Protein / genetics*
  • Animals
  • Blood Glucose / genetics
  • Cell Proliferation / genetics
  • Glucagon / genetics
  • Glucagon / metabolism*
  • Glucagon-Secreting Cells / metabolism
  • Glucagon-Secreting Cells / pathology
  • Humans
  • Hyperplasia / blood
  • Hyperplasia / genetics*
  • Hyperplasia / pathology
  • Lipid Metabolism / genetics*
  • Lipoproteins / blood
  • Liver / metabolism
  • Liver / pathology
  • Mice
  • Mice, Knockout
  • Receptors, Glucagon / genetics
  • Signal Transduction / genetics
  • Triglycerides / blood


  • Angiopoietin-like 4 Protein
  • Angptl4 protein, mouse
  • Blood Glucose
  • Lipoproteins
  • Receptors, Glucagon
  • Triglycerides
  • lipoprotein triglyceride
  • Glucagon