title: A VGF-derived peptide attenuates development of type 2 diabetes via enhancement of islet β-cell survival and function.
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.
authors: Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27704, USA.
authors: Samuel B
authors: SB
authors: Stephens
authors: Jonathan C
authors: JC
authors: Schisler
authors: Hans E
authors: HE
authors: Hohmeier
authors: Jie
authors: J
authors: An
authors: Albert Y
authors: AY
authors: Sun
authors: Geoffrey S
authors: GS
authors: Pitt
authors: Christopher B
authors: CB
authors: Newgard
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019540:Area Under Curve; D001786:Blood Glucose; D002470:Cell Survival / Q000187:drug effects*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology / Q000517:prevention & control*; D005746:Gastric Emptying / Q000187:drug effects; D015870:Gene Expression; D005947:Glucose / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007328:Insulin / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D008297:Male; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology* / Q000502:physiology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D018398:Homeodomain Proteins; D007004:Hypoglycemic Agents; D007328:Insulin; D009479:Neuropeptides; C491327:Nkx6-1 protein, rat; D010446:Peptide Fragments; C522412:TLQP-21 peptide; D015534:Trans-Activators; C522413:VGF peptide; C084010:pancreatic and duodenal homeobox 1 protein; D000242:Cyclic AMP; D005947:Glucose