Department of Biochemistry, Weill Cornell Medical College, New York, NY, 10065, USA.
Weill Center for Metabolic Health and Division of Cardiology, Department of Medicine, Weill Cornell Medicine, New York, NY, 10021, USA.
Mol Metab. 2023 Dec;78:101831. doi: 10.1016/j.molmet.2023.101831. Epub 2023 Nov 2.
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 better understand the impacts of GIPR-Q354 on metabolism, it is necessary to study it in an isogeneic background to the predominant GIPR isoform, E354. To accomplish this objective, we used CRISPR-CAS9 editing to generate mouse models of GIPR-Q354 and GIPR-E354. Here we characterize the metabolic effects of GIPR-Q354 variant in a mouse model (GIPR-Q350).
We generated the GIPR-Q350 mice for in vivo studies of metabolic impact of the variant. We isolated pancreatic islets from GIPR-Q350 mice to study insulin secretion ex vivo. We used a β-cell cell line to understand the impact of the GIPR-Q354 variant on the receptor traffic.
We found that 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).
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.
葡萄糖依赖性胰岛素多肽（GIP）在控制餐后代谢方面发挥作用。在人类中，GIP 受体（GIPR）变体（Q354，rs1800437）与较低的体重指数（BMI）和 2 型糖尿病风险增加有关。为了更好地了解 GIPR-Q354 对代谢的影响，有必要在与主要 GIPR 同工型 E354 同基因背景下研究它。为了实现这一目标，我们使用 CRISPR-CAS9 编辑生成了 GIPR-Q354 和 GIPR-E354 的小鼠模型。在这里，我们在 GIPR-Q350 小鼠模型中描述了 GIPR-Q354 变体对代谢的影响。
我们生成了 GIPR-Q350 小鼠，用于研究变体对代谢的影响。我们从 GIPR-Q350 小鼠中分离胰岛，以研究胰岛素的体外分泌。我们使用β细胞系来了解 GIPR-Q354 变体对受体运输的影响。
我们发现，雌性 GIPR-Q350 小鼠比同窝对照更瘦，雄性 GIPR-Q350 小鼠对饮食诱导的肥胖具有抗性，这与该变体与人类 BMI 降低的关联一致。雌雄两性的 GIPR-Q350 小鼠均对葡萄糖的耐受性更高，并且对 GIP 更敏感。GIPR-Q350 小鼠的餐后 GIP 水平降低，表明反馈调节平衡了肠道内分泌细胞分泌的 GIP 对 GIP 靶组织的敏感性增加。在胰岛葡萄糖刺激胰岛素分泌测定中，GIP 敏感性增加在体外得到了再现。GIPR 激活下游 cAMP 的产生不受 Q354 取代的影响。然而，GIPR-Q354 变体的激活后运输在β细胞中发生改变，表现为细胞内停留时间延长，并且向 Trans-Golgi Network（TGN）的定位增加。
我们的数据将 GIPR-Q354 变体的细胞内运输与 GIP 对代谢的控制联系起来。我们提出，这种时空信号的改变是 GIPR-Q350/4 和 GIPR-E350/4 在小鼠和人类中对葡萄糖稳态的生理影响的基础。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，或许可以利用它来增强 GIPR 的药理学靶向治疗代谢疾病。
