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Spatiotemporal regulation of GIPR signaling impacts glucose homeostasis as revealed in studies of a common GIPR variant
bioRxiv - Physiology Pub Date : 2023-05-03 , DOI: 10.1101/2020.05.12.091025
Lucie Yammine , Belén Picatoste , Nazish Abdullah , David Soares , Rosemary Leahey , Nicolás Gómez-Banoy , Carolina Rosselot , Jennifer Wen , James C. Lo , Adolfo Garcia-Ocaña , Timothy E. McGraw

Glucose-dependent insulinotropic polypeptide (GIP) has a role in controlling postprandial metabolic tone. In humans, a GIP receptor (GIPR) variant (Q354, rs1800437) is associated with a lower body mass index (BMI) and increased risk for Type 2 Diabetes. To isolate the contribution of GIPR in metabolic control, we generated a mouse model of the GIPR-Q354 variant (GIPR-Q350 mice). Female GIPR-Q350 mice are leaner than littermate controls, and male GIPR-Q350 mice are resistant to diet-induced obesity, in line with the association of the variant with reduced BMI in humans. GIPR-Q350 mice of both sexes are more glucose tolerant and exhibit an increased sensitivity to GIP. Postprandial GIP levels are reduced in GIPR-Q350 mice, revealing feedback regulation that balances the increased sensitivity of GIP target tissues to secretion of GIP from intestinal endocrine cells. The increased GIP sensitivity is recapitulated ex vivo during glucose stimulated insulin secretion assays in islets. Generation of cAMP in islets downstream of GIPR activation is not affected by the Q354 substitution. However, post-activation traffic of GIPR-Q354 variant in β-cells is altered, characterized by enhanced intracellular dwell time and increased localization to the Trans-Golgi Network (TGN). Consequently, our data link altered intracellular traffic of the GIPR-Q354 variant with GIP control of metabolism. We propose that this change in spatiotemporal signaling underlies the physiologic effects of GIPR-Q350/4 and GIPR-E350/4 in mice and humans. These findings contribute to a more complete understanding of the impact of GIPR-Q354 variant on glucose homeostasis that could perhaps be leveraged to enhance pharmacologic targeting of GIPR for the treatment of metabolic disease.

中文翻译:

GIPR 信号的时空调节影响葡萄糖稳态,如对常见 GIPR 变体的研究所揭示的那样

葡萄糖依赖性促胰岛素多肽 ( GIP ) 具有控制餐后代谢张力的作用。在人类中,GIP 受体 ( GIPR ) 变体 (Q354, rs1800437) 与较低的体重指数 ( BMI) 和增加患 2 型糖尿病的风险。为了分离 GIPR 在代谢控制中的作用,我们生成了 GIPR-Q354 变体的小鼠模型(GIPR-Q350 小鼠)。雌性 GIPR-Q350 小鼠比同窝对照小鼠更瘦,雄性 GIPR-Q350 小鼠对饮食诱导的肥胖有抵抗力,这与变异与人类 BMI 降低的关联一致。GIPR-Q350 雌性和雌性小鼠对葡萄糖的耐受性更高,并且对 GIP 的敏感性更高。GIPR-Q350 小鼠的餐后 GIP 水平降低,表明反馈调节平衡了 GIP 靶组织对肠道内分泌细胞分泌 GIP 的敏感性增加。增加的 GIP 敏感性在体外得到概括在胰岛中葡萄糖刺激的胰岛素分泌测定中。GIPR 激活下游胰岛中 cAMP 的生成不受 Q354 取代的影响。然而,β 细胞中 GIPR-Q354 变体的激活后流量发生了变化,其特征是细胞内停留时间增加和跨高尔基网络 ( TGN ) 的定位增加). 因此,我们的数据链接改变了 GIPR-Q354 变体的细胞内流量,GIP 控制了新陈代谢。我们提出,时空信号的这种变化是 GIPR-Q350/4 和 GIPR-E350/4 在小鼠和人类中的生理效应的基础。这些发现有助于更全面地了解 GIPR-Q354 变体对葡萄糖稳态的影响,这可能会被用来增强 GIPR 的药理学靶向性以治疗代谢性疾病。
更新日期:2023-05-06
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