A VGF-derived Peptide Attenuates Development of Type 2 Diabetes via Enhancement of Islet β-cell Survival and Function

Cell Metab. 2012 Jul 3;16(1):33-43. doi: 10.1016/j.cmet.2012.05.011.

Abstract

Deterioration of functional islet β-cell mass is the final step in progression to Type 2 diabetes. We previously reported that overexpression of Nkx6.1 in rat islets has the dual effects of enhancing glucose-stimulated insulin secretion (GSIS) and increasing β-cell replication. Here we show that Nkx6.1 strongly upregulates the prohormone VGF in rat islets and that VGF is both necessary and sufficient for Nkx6.1-mediated enhancement of GSIS. Moreover, the VGF-derived peptide TLQP-21 potentiates GSIS in rat and human islets and improves glucose tolerance in vivo. Chronic injection of TLQP-21 in prediabetic ZDF rats preserves islet mass and slows diabetes onset. TLQP-21 prevents islet cell apoptosis by a pathway similar to that used by GLP-1, but independent of the GLP-1, GIP, or VIP receptors. Unlike GLP-1, TLQP-21 does not inhibit gastric emptying or increase heart rate. We conclude that TLQP-21 is a targeted agent for enhancing islet β-cell survival and function.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Area Under Curve
  • Blood Glucose
  • Cell Survival / drug effects*
  • Cells, Cultured
  • Cyclic AMP / metabolism
  • Diabetes Mellitus, Type 2 / pathology
  • Diabetes Mellitus, Type 2 / prevention & control*
  • Gastric Emptying / drug effects
  • Gene Expression
  • Glucose / physiology
  • Heart Rate / drug effects
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Hyperglycemia / prevention & control
  • Hypoglycemic Agents / pharmacology*
  • Hypoglycemic Agents / therapeutic use
  • Insulin / blood
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / physiology*
  • Male
  • Neuropeptides / genetics
  • Neuropeptides / metabolism
  • Peptide Fragments / pharmacology*
  • Peptide Fragments / physiology
  • Peptide Fragments / therapeutic use
  • Rats
  • Rats, Wistar
  • Trans-Activators / genetics
  • Trans-Activators / metabolism

Substances

  • Blood Glucose
  • Homeodomain Proteins
  • Hypoglycemic Agents
  • Insulin
  • Neuropeptides
  • Nkx6-1 protein, rat
  • Peptide Fragments
  • TLQP-21 peptide
  • Trans-Activators
  • VGF peptide
  • pancreatic and duodenal homeobox 1 protein
  • Cyclic AMP
  • Glucose