A second-generation glucagon-like peptide-1 receptor agonist mitigates vomiting and anorexia while retaining glucoregulatory potency in lean diabetic and emetic mammalian models.
A second-generation glucagon-like peptide-1 receptor agonist mitigates vomiting and anorexia while retaining glucoregulatory potency in lean diabetic and emetic mammalian models.
复制标题
DOI：
10.1111/dom.14089
复制
发表时间：
2020-10
期刊：
影响因子：
--
通讯作者：
De Jonghe BC
中科院分区：
文献类型：
--
作者：
Borner T;Shaulson ED;Tinsley IC;Stein LM;Horn CC;Hayes MR;Doyle RP;De Jonghe BC
开发维生素B12与胰高血糖素样肽-1受体（GLP-1 R）激动剂exendin-4（Ex 4）结合的缀合物，该缀合物显示出对中枢神经系统的渗透率降低，同时维持外周葡萄糖调节功能。我们评估了Ex 4的维生素B12缀合物（B12-Ex 4）是否改善Goto-Kakizaki（GK）大鼠的葡萄糖耐量而不诱导厌食症，GK大鼠是一种未充分研究但医学上受损的需要GLP-1 R激动剂的葡萄糖调节作用而不引起厌食症的患者群体的瘦型2型糖尿病模型。我们还利用了麝香鼩（Suncus murinus），一种能够呕吐的哺乳动物模型，来测试B12-Ex 4对血液动力学特征、进食和呕吐的影响。在两种模型中，天然Ex 4和B12-Ex 4在葡萄糖耐量试验期间等效地减弱血糖水平的升高。在GK大鼠和鼩中，急性Ex 4给药降低了摄食量，导致体重减轻;相比之下，等摩尔B12-Ex 4给药对摄食和体重无影响。与Ex 4产生的可靠呕吐相反，在全身给予B12-Ex 4的鼩中几乎不存在呕吐。当集中给药时，B12-Ex 4和Ex 4诱导相似的呕吐效力，表明B12-Ex 4的脑渗透是诱导呕吐所必需的。这些发现突出了B12-Ex 4作为2型糖尿病的新型治疗的潜在治疗价值，其没有体重减轻，不良反应减少，耐受性更好，但与当前GLP-1 R激动剂的葡萄糖调节相似。
To develop a conjugate of vitamin B12 bound to the glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 (Ex4) that shows reduced penetrance into the central nervous system while maintaining peripheral glucoregulatory function. We evaluated whether a vitamin B12 conjugate of Ex4 (B12-Ex4) improves glucose tolerance without inducing anorexia in Goto-Kakizaki (GK) rats, a lean type 2 diabetes model of an understudied but medically compromised population of patients requiring the glucoregulatory effects of GLP-1R agonists without anorexia. We also utilized the musk shrew (Suncus murinus), a mammalian model capable of emesis, to test B12-Ex4 on glycaemic profile, feeding and emesis. In both models, native Ex4 and B12-Ex4 equivalently blunted the rise in blood glucose levels during a glucose tolerance test. In both GK rats and shrews, acute Ex4 administration decreased food intake, leading to weight loss; by contrast, equimolar administration of B12-Ex4 had no effect on feeding and body weight. There was a near absence of emesis in shrews given systemic B12-Ex4, in contrast to reliable emesis produced by Ex4. When administered centrally, both B12-Ex4 and Ex4 induced similar potency of emesis, suggesting that brain penetrance of B12-Ex4 is required for induction of emesis. These findings highlight the potential therapeutic value of B12-Ex4 as a novel treatment for type 2 diabetes devoid of weight loss and with reduced adverse effects and better tolerance, but similar glucoregulation to current GLP-1R agonists.
登录
查看更多内容
影响因子：
2.2
作者：
GOTO, Y;KAKIZAKI, M;MASAKI, N
通讯作者：
MASAKI, N
影响因子：
4.9
作者：
Grill, H. J.;Hayes, M. R.
通讯作者：
Hayes, M. R.
影响因子：
7.7
作者：
Krieger, Jean-Philippe;Arnold, Myrtha;Lee, Shin J.
通讯作者：
Lee, Shin J.
影响因子：
81.5
作者：
Green, Ralph;Allen, Lindsay H.;Yajnik, Chittaranjan
通讯作者：
Yajnik, Chittaranjan
DOI：
10.1111/dom.13143
发表时间：
2018-03
期刊：
Diabetes, obesity & metabolism
影响因子：
--
作者：
Caspard H;Jabbour S;Hammar N;Fenici P;Sheehan JJ;Kosiborod M
通讯作者：
Kosiborod M