Intra-islet glucagon confers β-cell glucose competence for first-phase insulin secretion and favors GLP-1R stimulation by exogenous glucagon.
Intra-islet glucagon confers β-cell glucose competence for first-phase insulin secretion and favors GLP-1R stimulation by exogenous glucagon.
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DOI：
10.1016/j.jbc.2021.101484
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Holz GG
中科院分区：
文献类型：
--
作者：
Cabrera O;Ficorilli J;Shaw J;Echeverri F;Schwede F;Chepurny OG;Leech CA;Holz GG
我们报告说，从α细胞分泌的胰岛内胰高血糖素通过β细胞胰高血糖素和GLP-1受体（GcgR和GLP-1 R）发出信号，从而赋予大鼠胰岛表现出第一相葡萄糖刺激的胰岛素分泌（GSIS）的能力。因此，在未用外源性胰高血糖素或GLP-1处理的胰岛中，GcgR拮抗剂（LY 2786890）或GLP-1 R拮抗剂（Ex[9-39]）消除了第一时相GSIS。在机制上，响应于胰岛内胰高血糖素的葡萄糖能力取决于β细胞cAMP信号传导，因为它被cAMP拮抗剂前药RP-8-Br-cAMPS-pAB阻断。在其作为旁分泌激素的作用中，胰岛内胰高血糖素以高亲和力与GcgR结合，同时还发挥“溢出”效应以低亲和力与GLP-1 R结合。这导致外源性胰高血糖素增强GSIS的浓度-反应关系右移。因此，如果类似浓度的胰岛内胰高血糖素已经占据GcgR，则0.3 nM胰高血糖素未能增强GSIS，正如预期的那样。然而，10至30 nM胰高血糖素有效地结合β细胞GLP-1 R以增强GSIS，Ex[9-39]而非LY 2786890阻断了该作用。最后，我们报告说，胰岛内胰高血糖素支持胰岛素分泌的作用需要葡萄糖浓度逐步增加，以触发第一阶段GSIS。当GSIS受到葡萄糖浓度梯度增加的刺激时，其不可测量，如在体内口服葡萄糖耐量试验期间发生的。总的来说，如果胰岛内胰高血糖素作用缺陷导致静脉葡萄糖耐量试验中第一时相GSIS的特征性丧失，即在临床环境中诊断2型糖尿病，则这些发现是可以理解的。
We report that intra-islet glucagon secreted from α-cells signals through β-cell glucagon and GLP-1 receptors (GcgR and GLP-1R), thereby conferring to rat islets their competence to exhibit first-phase glucose-stimulated insulin secretion (GSIS). Thus, in islets not treated with exogenous glucagon or GLP-1, first-phase GSIS is abolished by a GcgR antagonist (LY2786890) or a GLP-1R antagonist (Ex[9–39]). Mechanistically, glucose competence in response to intra-islet glucagon is conditional on β-cell cAMP signaling because it is blocked by the cAMP antagonist prodrug Rp-8-Br-cAMPS-pAB. In its role as a paracrine hormone, intra-islet glucagon binds with high affinity to the GcgR, while also exerting a “spillover” effect to bind with low affinity to the GLP-1R. This produces a right shift of the concentration-response relationship for the potentiation of GSIS by exogenous glucagon. Thus, 0.3 nM glucagon fails to potentiate GSIS, as expected if similar concentrations of intra-islet glucagon already occupy the GcgR. However, 10 to 30 nM glucagon effectively engages the β-cell GLP-1R to potentiate GSIS, an action blocked by Ex[9–39] but not LY2786890. Finally, we report that the action of intra-islet glucagon to support insulin secretion requires a step-wise increase of glucose concentration to trigger first-phase GSIS. It is not measurable when GSIS is stimulated by a gradient of increasing glucose concentrations, as occurs during an oral glucose tolerance test in vivo. Collectively, such findings are understandable if defective intra-islet glucagon action contributes to the characteristic loss of first-phase GSIS in an intravenous glucose tolerance test, that is, diagnostic of type 2 diabetes in the clinical setting.
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DOI：
10.1038/nrm.2017.89
发表时间：
2018-01
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Haeusler RA;McGraw TE;Accili D
通讯作者：
Accili D
影响因子：
4.8
作者：
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通讯作者：
Nenquin, Myriam
影响因子：
4.8
作者：
Chepurny, Oleg G.;Leech, Colin A.;Holz, George G.
通讯作者：
Holz, George G.
影响因子：
8.1
作者：
Campbell, Scott A.;Golec, Dominic P.;Light, Peter E.
通讯作者：
Light, Peter E.
影响因子：
3.5
作者：
GROMADA, J;RORSMAN, P;WULFF, BS
通讯作者：
WULFF, BS