Journal
CELL METABOLISM
Volume 16, Issue 1, Pages 33-43Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2012.05.011
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Funding
- National Institutes of Health [DK58398]
- Juvenile Diabetes Research Foundation [17-2007-1026, 3-2007-560]
- American Heart Association [09POST2250151]
- Eli Lilly and Company
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Deterioration of functional islet beta-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 beta-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 beta-cell survival and function.
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