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

• Published in: Cell metabolism 2012-07, Vol.16 (1), p.33-43
• Main Authors: Stephens, Samuel B., Schisler, Jonathan C., Hohmeier, Hans E., An, Jie, Sun, Albert Y., Pitt, Geoffrey S., Newgard, Christopher B.
• Format: Article
• Language: English
• Subjects: 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
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2012.05.011

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. [Display omitted] ► Nkx6.1 overexpression in rat islets strongly upregulates the prohormone VGF ► VGF peptide TLQP-21 potentiates glucose-stimulated insulin secretion ► TLQP-21 treatment of ZDF rats improves glycemic control and preserves islet mass ► Antiapoptotic action of TLQP-21 occurs via a PKA, IGF1R, PI3K-dependent pathway