Glucoregulatory activity of vesiculin in insulin sensitive and resistant mice

Peptides. 2019 Jun;116:1-7. doi: 10.1016/j.peptides.2019.04.011. Epub 2019 Apr 21.

Abstract

Pancreatic islet-derived peptide hormones play key roles in the maintenance of systemic energy homeostasis and glucose balance and defects in their regulation are strongly implicated in the pathogenesis of obesity and diabetes. Peptides have also been used as lead compounds for therapeutics targeting metabolic disease. It is therefore important to understand the activity and function of islet hormones in both their target tissues and the whole organism. Insulin-like growth factor II (IGF-II) is an insulin homolog secreted by the islet β-cells. Vesiculin is a newly discovered peptide hormone, processed from IGF-II and secreted from islet β-cells in response to glucose. We postulated that vesiculin might act to regulate systemic glucose metabolism. Here we report our original investigations of vesiculin's activity in relation to glucoregulation. Vesiculin and IGF-II displayed similar dose-response relationships for lowering blood glucose in insulin-responsive FVB/n mice. By contrast, the ability of IGF-II to lower blood glucose was blunted in insulin-resistant triprolyl human-amylin transgenic mice, whereas vesiculin's ability to lower blood glucose remained unaffected. We also confirmed the ability of vesiculin to bypass insulin resistance in a second mouse model. In vitro analysis of signalling by vesiculin and IGF-II indicates that, like IGF-II, vesiculin signals through the IR/ IGF1R. Overall, we show that removal of only four amino acids from IGF-II has generated a peptide hormone with different bioactivity relevant to blood-glucose regulation. Investigating the differences among vesiculin, IGF-II and insulin signalling and activity may provide new insights into insulin resistance and potentially inform the design of novel therapeutics.

Keywords: Diabetes; IGF-II; Insulin resistance; Vesiculin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / genetics
  • Diabetes Mellitus / genetics
  • Diabetes Mellitus / metabolism
  • Diabetes Mellitus / pathology
  • Energy Metabolism / genetics
  • Glucose / genetics
  • Glucose / metabolism
  • Humans
  • Insulin / genetics*
  • Insulin Resistance / genetics
  • Insulin-Like Growth Factor II / genetics*
  • Islet Amyloid Polypeptide / genetics
  • Islets of Langerhans / metabolism
  • Islets of Langerhans / pathology
  • Mice
  • Mice, Transgenic
  • Nerve Tissue Proteins / genetics*
  • Obesity / genetics
  • Obesity / metabolism
  • Obesity / pathology
  • Peptide Hormones / genetics
  • Receptor, IGF Type 1 / genetics*

Substances

  • Blood Glucose
  • Igf1r protein, mouse
  • Insulin
  • Islet Amyloid Polypeptide
  • Nerve Tissue Proteins
  • Peptide Hormones
  • vesiculin
  • Insulin-Like Growth Factor II
  • Receptor, IGF Type 1
  • Glucose