Insulin within islets is a physiologic glucagon release inhibitor.

Maruyama, Hiroshi; Hisatomi, Akitaka; Orci, Lelio; Grodsky, G M; Unger, Roger H

doi:10.1172/jci111658

Cited by 301 publications

(240 citation statements)

References 14 publications

(6 reference statements)

Supporting

Mentioning

216

Contrasting

Unclassified

Order By: Relevance

“…The decrement in insulin release from ␤-cells has been proposed to signal the ␣-cell to release glucagon (1)(2)(3). Recently, we demonstrated this phenomenon directly in vivo in streptozotocin-induced diabetic rats and in vitro using isolated islets from these animals.…”

mentioning

confidence: 69%

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

et al. 2007

View full text Add to dashboard Cite

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...

show abstract

mentioning

confidence: 69%

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

et al. 2007

View full text Add to dashboard Cite

show abstract

“…Stagner and Samols (21) ported that retrograde perfusion of a constant glucose concentration increased mean glucagon secretion from dog pancreas and explained this phenomenon by suggesting that it was due to the prevention of insulin in the islet portal circulation from reaching the ␣-cell downstream. Maruyama et al (22) perfused anti-insulin serum in rat pancreas and observed a significant rise in glucagon secretion, whereas nonimmune guinea pig serum had no effect. They concluded that insulin maintains an ongoing restraint on ␣-cell secretion and that loss of this inhibition by insulin may account for the hyperglucagonemia observed in insulin-deficient states.…”

Section: Discussionmentioning

confidence: 99%

Regulation of α-Cell Function by the β-Cell in Isolated Human and Rat Islets Deprived of Glucose: the “Switch-off” Hypothesis

et al. 2004

View full text Add to dashboard Cite

The "switch-off" hypothesis to explain ␤-cell regulation of ␣-cell function during hypoglycemia has not been assessed previously in isolated islets, largely because they characteristically do not respond to glucose deprivation by secreting glucagon. We examined this hypothesis using normal human and Wistar rat islets, as well as islets from streptozotocin (STZ)-administered ␤-celldeficient Wistar rats. As expected, islets perifused with glucose and 3-isobutryl-1-methylxanthine did not respond to glucose deprivation by increasing glucagon secretion. However, if normal rat islets were first perifused with 16.7 mmol/l glucose to increase endogenous insulin secretion, followed by discontinuation of the glucose perifusate, a glucagon response to glucose deprivation was observed (peak change within 10 min after switch off ‫؍‬ 61 ؎ 15 pg/ml [mean ؎ SE], n ‫؍‬ 6, P < 0.01). A glucagon response from normal human islets using the same experimental design was also observed. A glucagon response (peak change within 7 min after switch off ‫؍‬ 31 ؎ 1 pg/ml, n ‫؍‬ 3, P < 0.01) was observed from ␤-cell-depleted, STZ-induced diabetic rats whose islets still secreted small amounts of insulin. However, when these islets were first perifused with both exogenous insulin and 16.7 mmol/l glucose, followed by switching off both the insulin and glucose perifusate, a significantly larger (P < 0.05) glucagon response was observed (peak change within 7 min after switch off ‫؍‬ 71 ؎ 11 pg/ml, n ‫؍‬ 4, P < 0.01). This response was not observed if the insulin perifusion was not switched off when the islets were deprived of glucose or when insulin was switched off without glucose deprivation. These data uniquely demonstrate that both normal, isolated islets and islets from STZ-administered rats can respond to glucose deprivation by releasing glucagon if they are first provided with increased endogenous or exogenous insulin. These results fully support the ␤-cell switch-off hypothesis as a key mechanism for the ␣-cell response to hypoglycemia.

show abstract

“…One intriguing aspect is also whether the changes in glucagon secretion are secondary to insulin resistance in the glucagon-producing alpha cells. It is known that insulin inhibits glucagon secretion [24,25] and, therefore, resistance in the alpha cells to insulin would augment glucagon secretion [26], which would explain the higher glucagon response to arginine in the arginine test. On the other hand, insulin secretion is increased in insulin resistance, which would counterbalance a defective insulin action also in the alpha cells.…”

Section: Discussionmentioning

confidence: 99%

Glucagon secretion in relation to insulin sensitivity in healthy subjects

Åhrén

2005

Diabetologia

View full text Add to dashboard Cite

Aims/hypothesis: The study evaluated whether glucagon secretion is regulated by changes in insulin sensitivity under normal conditions. Materials and methods: A total of 155 healthy women with NGT (aged 53-70 years) underwent a glucose-dependent arginine-stimulation test for evaluation of glucagon secretion. Arginine (5 g) was injected i.v. under fasting conditions (plasma glucose 4.8±0.1 mmol/l) and after raising blood glucose concentrations to 14.8±0.1 and 29.8±0.2 mmol/l. The acute glucagon response (AGR) to arginine during the three glucose levels (AGR 1 , AGR 2 , AGR 3 ) was estimated, as was the suppression of baseline glucagon by the increased glucose. All women also underwent a 2-h euglycaemic-hyperinsulinaemic clamp study for estimation of insulin sensitivity. Results: Insulin sensitivity was normally distributed, with a mean of 73.2±29.3 (SD) nmol glucose kg −1 min −1 /pmol insulin l −1 . When relating the variables obtained from the arginine test to insulin sensitivity, insulin resistance was associated with increased AGR and with increased suppression of glucagon levels by glucose. For example, the regression between insulin sensitivity and AGR 2 was r=−0.38 (p<0.001) and between insulin sensitivity and suppression of glucagon levels by 14.8 mmol/l glucose r=0.36 (p<0.001). Insulin sensitivity also correlated negatively with insulin secretion; multivariate analysis revealed that changes in insulin sensitivity and insulin secretion were independently related to changes in glucagon secretion. Conclusions/ interpretation: The body adapts to insulin resistance by increasing the glucagon response to arginine and by increasing the suppression of glucagon levels by glucose. Hence, not only the islet beta cells but also the alpha cells seem to undergo compensatory changes during the development of insulin resistance.

show abstract

Insulin within islets is a physiologic glucagon release inhibitor.

Cited by 301 publications

References 14 publications

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

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

Regulation of α-Cell Function by the β-Cell in Isolated Human and Rat Islets Deprived of Glucose: the “Switch-off” Hypothesis

Glucagon secretion in relation to insulin sensitivity in healthy subjects

Contact Info

Product

Resources

About