The mediation by GLP-1 receptors of glucagon-induced insulin secretion revisited in GLP-1 receptor knockout mice

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The mediation by GLP-1 receptors of glucagon-induced insulin secretion revisited in GLP-1 receptor knockout mice. / Ahrén, Bo; Yamada, Yuichiro; Seino, Yutaka.

In: Peptides, Vol. 135, 170434, 01.2021.

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T1 - The mediation by GLP-1 receptors of glucagon-induced insulin secretion revisited in GLP-1 receptor knockout mice

AU - Ahrén, Bo

AU - Yamada, Yuichiro

AU - Seino, Yutaka

PY - 2021/1

Y1 - 2021/1

N2 - To study whether activation of GLP-1 receptors importantly contributes to the insulinotropic action of exogenously administered glucagon, we have performed whole animal experiments in normal mice and in mice with GLP-1 receptor knockout. Glucagon (1, 3 or 10 μg/kg), the GLP-1 receptor antagonist exendin 9-39 (30 nmol/kg), glucose (0.35 g/kg) or the incretin hormone glucose-dependent insulinotropic polypeptide (GIP; 3 nmol/kg) was injected intravenously or glucose (75 mg) was given orally through gavage. Furthermore, islets were isolated and incubated in the presence of glucose with or without glucagon. It was found that the insulin response to intravenous glucagon was preserved in GLP-1 receptor knockout mice but that glucagon-induced insulin secretion was markedly suppressed in islets from GLP-1 receptor knockout mice. Similarly, the GLP-1 receptor antagonist markedly suppressed glucagon-induced insulin secretion in wildtype mice. These data suggest that GLP-1 receptors contribute to the insulinotropic action of glucagon and that there is a compensatory mechanism in GLP-1 receptor knockout mice that counteracts a reduced effect of glucagon. Two potential compensatory mechanisms (glucose and GIP) were explored. However, neither of these seemed to explain why the insulin response to glucagon is not suppressed in GLP-1 receptor knockout mice. Based on these data we confirm the hypothesis that glucagon-induced insulin secretion is partially mediated by GLP-1 receptors on the beta cells and we propose that a compensatory mechanism, the nature of which remains to be established, is induced in GLP-1 receptor knockout mice to counteract the expected impaired insulin response to glucagon in these mice.

AB - To study whether activation of GLP-1 receptors importantly contributes to the insulinotropic action of exogenously administered glucagon, we have performed whole animal experiments in normal mice and in mice with GLP-1 receptor knockout. Glucagon (1, 3 or 10 μg/kg), the GLP-1 receptor antagonist exendin 9-39 (30 nmol/kg), glucose (0.35 g/kg) or the incretin hormone glucose-dependent insulinotropic polypeptide (GIP; 3 nmol/kg) was injected intravenously or glucose (75 mg) was given orally through gavage. Furthermore, islets were isolated and incubated in the presence of glucose with or without glucagon. It was found that the insulin response to intravenous glucagon was preserved in GLP-1 receptor knockout mice but that glucagon-induced insulin secretion was markedly suppressed in islets from GLP-1 receptor knockout mice. Similarly, the GLP-1 receptor antagonist markedly suppressed glucagon-induced insulin secretion in wildtype mice. These data suggest that GLP-1 receptors contribute to the insulinotropic action of glucagon and that there is a compensatory mechanism in GLP-1 receptor knockout mice that counteracts a reduced effect of glucagon. Two potential compensatory mechanisms (glucose and GIP) were explored. However, neither of these seemed to explain why the insulin response to glucagon is not suppressed in GLP-1 receptor knockout mice. Based on these data we confirm the hypothesis that glucagon-induced insulin secretion is partially mediated by GLP-1 receptors on the beta cells and we propose that a compensatory mechanism, the nature of which remains to be established, is induced in GLP-1 receptor knockout mice to counteract the expected impaired insulin response to glucagon in these mice.

KW - GLP-1

KW - GLP-1 receptor knockout mice

KW - Glucagon

KW - Insulin secretion

U2 - 10.1016/j.peptides.2020.170434

DO - 10.1016/j.peptides.2020.170434

M3 - Article

C2 - 33172827

AN - SCOPUS:85095771364

VL - 135

JO - Peptides

JF - Peptides

SN - 1873-5169

M1 - 170434

ER -