Biomedical Research Service, John D. Dingell VA Medical Center and Department of Pharmaceutical Sciences and Medicine, Wayne State University, Detroit, MI, USA.
Small GTPases. 2021 Sep-Nov;12(5-6):323-335. doi: 10.1080/21541248.2020.1815508. Epub 2020 Aug 31.
A growing body of evidence implicates requisite roles for GTP and its binding proteins (Rho GTPases) in the cascade of events leading to physiological insulin secretion from the islet beta cell. Interestingly, chronic exposure of these cells to hyperglycaemic conditions appears to result in sustained activation of specific Rho GTPases (e.g. Rac1) leading to significant alterations in cellular functions including defects in mitochondrial function and nuclear collapse culminating in beta cell demise. One of the objectives of this review is to highlight our current understanding of the regulatory roles of GTP and Rho GTPases in normal islet function (e.g. proliferation and insulin secretion) as well potential defects in these signalling molecules and metabolic pathways that could contribute islet beta cell dysfunction and loss of functional beta cell mass leading to the onset of diabetes. Potential knowledge gaps in this field and possible avenues for future research are also highlighted. ARNO: ADP-ribosylation factor nucleotide binding site opener; CML: carboxyl methylation; Epac: exchange protein directly activated by cAMP; ER stress: endoplasmic reticulum stress; FTase: farnesyltransferase; GAP: GTPase activating protein; GDI: GDP dissociation inhibitor; GEF: guanine nucleotide exchange factor; GGTase: geranylgeranyltransferase; GGpp: geranylgeranylpyrophosphate; GGPPS: geranylgeranyl pyrophosphate synthase; GSIS: glucose-stimulated insulin secretion; HGPRTase: hypoxanthine-guanine phosphoribosyltransferase; IMPDH: inosine monophosphate dehydrogenase; α-KIC: α-ketoisocaproic acid; MPA: mycophenolic acid; MVA: mevalonic acid; NDPK: nucleoside diphosphate kinase; NMPK: nucleoside monophosphate kinase; Nox2: phagocyte-like NADPH oxidase; PAK-I: p21-activated kinase-I; β-PIX: β-Pak-interacting exchange factor; PRMT: protein arginine methyltransferase; Rac1: ras-related C3 botulinum toxin substrate 1; Tiam1: T-cell lymphoma invasion and metastasis-inducing protein 1; Trx-1: thioredoxin-1; Vav2: vav guanine nucleotide exchange factor 2.
越来越多的证据表明，GTP 及其结合蛋白（Rho GTPases）在导致胰岛β细胞生理性胰岛素分泌的级联反应中发挥必要作用。有趣的是，这些细胞长期暴露于高血糖环境似乎会导致特定 Rho GTPases（如 Rac1）的持续激活，从而导致细胞功能发生重大变化，包括线粒体功能缺陷和核崩溃，最终导致β细胞死亡。本文的一个目标是强调我们目前对 GTP 和 Rho GTPases 在正常胰岛功能（如增殖和胰岛素分泌）中的调节作用的理解，以及这些信号分子和代谢途径中的潜在缺陷如何导致胰岛β细胞功能障碍和功能性β细胞质量损失，从而导致糖尿病的发生。还强调了该领域的潜在知识空白和未来研究的可能途径。ARNO：ADP-核糖基化因子核苷酸结合位点 opener；CML：羧基甲基化；Epac：cAMP 直接激活的交换蛋白；ER 应激：内质网应激；FTase：法尼基转移酶；GAP：GTPase 激活蛋白；GDI：GDP 解离抑制剂；GEF：鸟嘌呤核苷酸交换因子；GGTase：香叶基香叶基转移酶；GGpp：香叶基香叶基焦磷酸；GGPPS：香叶基焦磷酸合酶；GSIS：葡萄糖刺激的胰岛素分泌；HGPRTase：次黄嘌呤鸟嘌呤磷酸核糖基转移酶；IMPDH：肌苷单磷酸脱氢酶；α-KIC：α-酮异己酸；MPA：霉酚酸；MVA：甲羟戊酸；NDPK：核苷二磷酸激酶；NMPK：核苷一磷酸激酶；Nox2：吞噬细胞样 NADPH 氧化酶；PAK-I：p21 激活激酶-I；β-PIX：β-Pak 相互作用交换因子；PRMT：蛋白质精氨酸甲基转移酶；Rac1：ras 相关 C3 肉毒梭菌毒素底物 1；Tiam1：T 细胞淋巴瘤侵袭和转移诱导蛋白 1；Trx-1：硫氧还蛋白-1；Vav2：vav 鸟嘌呤核苷酸交换因子 2。
