Intraislet glucagon signaling is critical for maintaining glucose homeostasis
Lu Zhu, Diptadip Dattaroy, Jonathan Pham, Lingdi Wang, Luiz F. Barella, Yinghong Cui, Kenneth J. Wilkins, Bryan L. Roth, Ute Hochgeschwender, Franz M. Matschinsky, Klaus H. Kaestner, Nicolai M. Doliba, Jürgen Wess
Lu Zhu, Diptadip Dattaroy, Jonathan Pham, Lingdi Wang, Luiz F. Barella, Yinghong Cui, Kenneth J. Wilkins, Bryan L. Roth, Ute Hochgeschwender, Franz M. Matschinsky, Klaus H. Kaestner, Nicolai M. Doliba, Jürgen Wess
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Research Article Metabolism

Intraislet glucagon signaling is critical for maintaining glucose homeostasis

Abstract

Glucagon, a hormone released from pancreatic α cells, plays a key role in maintaining proper glucose homeostasis and has been implicated in the pathophysiology of diabetes. In vitro studies suggest that intraislet glucagon can modulate the function of pancreatic β cells. However, because of the lack of suitable experimental tools, the in vivo physiological role of this intraislet cross-talk has remained elusive. To address this issue, we generated a mouse model that selectively expressed an inhibitory designer GPCR (Gi DREADD) in α cells only. Drug-induced activation of this inhibitory designer receptor almost completely shut off glucagon secretion in vivo, resulting in markedly impaired insulin secretion, hyperglycemia, and glucose intolerance. Additional studies with mouse and human islets indicated that intraislet glucagon stimulates insulin release primarily by activating β cell GLP-1 receptors. These findings strongly suggest that intraislet glucagon signaling is essential for maintaining proper glucose homeostasis in vivo. Our work may pave the way toward the development of novel classes of antidiabetic drugs that act by modulating intraislet cross-talk between α and β cells.

Authors

Lu Zhu, Diptadip Dattaroy, Jonathan Pham, Lingdi Wang, Luiz F. Barella, Yinghong Cui, Kenneth J. Wilkins, Bryan L. Roth, Ute Hochgeschwender, Franz M. Matschinsky, Klaus H. Kaestner, Nicolai M. Doliba, Jürgen Wess

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Figure 5

Glucagon restores normal insulin release in CNO-treated α-GiD islets.

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Glucagon restores normal insulin release in CNO-treated α-GiD islets. Is...
Islets from α-GiD mice were perifused with the indicated glucose concentrations (3 mM and 12 mM; G3 and G12, respectively) in the presence (red curve) or absence (black curve) of CNO (10 μM). At 45 minutes (15 minutes after the addition of AAM), glucagon (10 nM) was added to the perifusion fluid. In the bar graphs, insulin secretion during specific time intervals was expressed as the average of all values measured during a particular perifusion period: G3, 0–15 minutes; G12, 15–30 minutes; G12+AAM, 30–45 minutes; G12+AAM+glucagon, 45–65 minutes. Insulin secretion was normalized to islet DNA content. All islets were prepared from male littermates that were 20–24 weeks old. Data are given as mean ± SEM (4 perifusions with 50 islets per perifusion chamber; islets from 2 mice were pooled per perifusion experiment). *P < 0.05 (2-tailed Student’s t test). AAM, amino acid mixture (see Methods for details).