title: Zinc, not insulin, regulates the rat alpha-cell response to hypoglycemia in vivo.
abstract: The intra-islet insulin hypothesis proposes that the decrement in beta-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 co-secreted 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 x ml(-1) x 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 x ml(-1) x 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 beta-cell to the alpha-cell to initiate glucagon secretion during hypoglycemia.
authors.affiliation: Pacific Northwest Research Institute, 720 Broadway, Seattle, WA 98122, USA.
authors.forename: Huarong
authors.initials: H
authors.lastname: Zhou
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.forename: Jamie S
authors.initials: JS
authors.lastname: Harmon
authors.forename: Joseph
authors.initials: J
authors.lastname: Bryan
authors.forename: R Paul
authors.initials: RP
authors.lastname: Robertson
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002096:C-Peptide / Q000097:blood; D005934:Glucagon / Q000097:blood; D050416:Glucagon-Secreting Cells / Q000187:drug effects / Q000502:physiology*; D006943:Hyperglycemia / Q000139:chemically induced; D007003:Hypoglycemia / Q000503:physiopathology*; D007328:Insulin / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013311:Streptozocin; D015032:Zinc / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; D007328:Insulin; D013311:Streptozocin; D005934:Glucagon; D015032:Zinc