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Published online February 22, 2007
Diabetes 56:1107-1112, 2007
DOI: 10.2337/db06-1454
© 2007 by the American Diabetes Association
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Zinc, Not Insulin, Regulates the Rat {alpha}-Cell Response to Hypoglycemia In Vivo

Huarong Zhou1, Tao Zhang1, Jamie S. Harmon1, Joseph Bryan2, and R. Paul Robertson1,3,4

1 Pacific Northwest Research Institute, Seattle, Washington
2 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
3 Department of Medicine, University of Washington, Seattle, Washington
4 Department of Pharmacology, University of Washington, Seattle, Washington

Address correspondence and reprint requests to R. Paul Robertson, MD, PNRI, 720 Broadway, Seattle, WA 98122. E-mail: rpr{at}pnri.org

Abbreviations: AUC, area under the curve; ATCC, American Type Culture Collection; FBS, fetal bovine serum; KATP, ATP-sensitive K+; M199, Medium 199; STZ, streptozotocin

The intraislet insulin hypothesis proposes that the decrement in ß-cell insulin secretion during hypoglycemia provides an activation signal for {alpha}-cells to release glucagon. A more recent hypothesis proposes that zinc atoms suppress glucagon secretion via their ability to open {alpha}-cell ATP-sensitive K+ channels. Since insulin binds zinc, and zinc is cosecreted with insulin, we tested whether decreased zinc delivery to the {alpha}-cell activates glucagon secretion. In streptozotocin-induced diabetic Wistar rats, we observed that switching off intrapancreatic artery insulin infusions in vivo during hypoglycemia greatly improved glucagon secretion (area under the curve [AUC]: control group 240 ± 261 and experimental group 4,346 ± 1,259 pg · ml–1 · 90 min–1; n = 5, P < 0.02). Switching off pancreatic artery infusions of zinc chloride during hypoglycemia also improved the glucagon response (AUC: control group 817 ± 107 and experimental group 3,445 ± 573 pg · ml–1 · 90 min–1; n = 6, P < 0.01). However, switching off zinc-free insulin infusions had no effect. Studies of glucose uptake in muscle and liver cell lines verified that the zinc-free insulin was biologically active. We conclude that zinc atoms, not the insulin molecule itself, provide the switch-off signal from the ß-cell to the {alpha}-cell to initiate glucagon secretion during hypoglycemia.


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