Zinc, Not Insulin, Regulates the Rat α-Cell Response to Hypoglycemia In Vivo

Abstract

The intraislet insulin hypothesis proposes that the decrement in ␤-cell insulin secretion during hypoglycemia provides an activation signal for ␣-cells to release glucagon. A more recent hypothesis proposes that zinc atoms suppress glucagon secretion via their ability to open ␣-cell ATPsensitive K ؉ channels. Since insulin binds zinc, and zinc is cosecreted with insulin, we tested whether decreased zinc delivery to the ␣-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 ⅐ ml ؊1 ⅐ 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 ⅐ ml ؊1 ⅐ 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 ␤-cell to the ␣-cell to initiate glucagon secretion during hypoglycemia. Diabetes 56:1107-1112, 2007 G lucagon secretion into the hepatic portal circulation is critical for counterregulation of hypoglycemia by virtue of its stimulatory effect on hepatic glycogenolysis, which releases glucose into the systemic circulation to return blood glucose to normal levels. The decrement in insulin release from ␤-cells has been proposed to signal the ␣-cell to release glucagon (1-3). Recently, we demonstrated this phenomenon directly in vivo in streptozotocin-induced diabetic rats and in vitro using isolated islets from these animals. In the in vivo studies, an insulin infusion into the pancreatic artery was switched off when the animals were made hypoglycemic by a jugular-vein infusion of insulin (4).Glucagon secretion, absent in control diabetic animals, was fully restored by this maneuver. Glucagon release was not initiated by this maneuver if saline rather than insulin was used, or if insulin was infused but not switched off. The glucagon response was not observed during normoglycemic or hyperglycemic conditions; the switch-off signal was effective only in the setting of hypoglycemia. We corroborated these findings with in vitro islet perifusion studies (5).Recent work from several laboratories has demonstrated that zinc atoms are capable of suppressing ␣-cell function via activation of rat ␣-cell ATP-sensitive K ϩ (K ATP ) channels (6 -9). Since zinc atoms are bound by and cosecreted with insulin, we hypothesized that zinc might provide the switch-off signal during hypoglycemia. To evaluate this hypothesis, we performed in vivo studies using intrapancreatic artery infusions of zinc-containing insulin, zinc chloride alone, or zinc-free insulin in streptozo...

Glucagon secretion after metabolic surgery in diabetic rodents

“…Impaired pathways with respect to the inhibitory effect of hyperglycemia on glucagon secretion, referred to as a-cell resistance, have been identified in studies of a-cell lines (Xu et al 2006). Interestingly, a switch-off signal from zinc atoms, whether bound to insulin or not, also seems to be involved in the initiation of glucagon release from the a-cell, as could be shown in streptozotocin-induced diabetic Wistar rats (Zhou et al 2007). The removal of somatostatinmediated inhibition of glucagon secretion via pancreatic d-cells by sympathetic activation may further contribute to inadequate glucagon secretion (Hauge-Evans et al 2010).…”

Zinc and diabetes

“…Zinc also has a paracrine effect on neighbouring cells, notably on α cells where it can inhibit glucagon secretion [88]. Thus, the cessation of zinc secretion under hypoglycaemic conditions could act as a trigger for glucagon secretion from α cells at proximity [92,93].…”

Physiology of the pancreatic α-cell and glucagon secretion: role in glucose homeostasis and diabetes

“…On one hand, it has been found that Zn 2C activates K ATP channels and decreases glucagon release in isolated rat a-cells (Ishihara et al 2003, Franklin et al 2005. Zn 2C seems to be the switchoff signal to initiate glucagon secretion during hypoglycaemia in streptozotocin-induced diabetic rats (Zhou et al 2007a). However, these results contrast with the absence of effects on mouse a-cells (Ravier & Rutter 2005).…”