[PDF][PDF] A VGF-derived peptide attenuates development of type 2 diabetes via enhancement of islet β-cell survival and function

SB Stephens, JC Schisler, HE Hohmeier, J An, AY Sun… - Cell metabolism, 2012 - cell.com
SB Stephens, JC Schisler, HE Hohmeier, J An, AY Sun, GS Pitt, CB Newgard
Cell metabolism, 2012cell.com
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 …
Summary
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.
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