Anti-Insulin Receptor Antibodies Improve Hyperglycemia in a Mouse Model of Human Insulin Receptoropathy.
Anti-Insulin Receptor Antibodies Improve Hyperglycemia in a Mouse Model of Human Insulin Receptoropathy.
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作者：
Brierley GV;Webber H;Rasijeff E;Grocott S;Siddle K;Semple RK
人胰岛素受体基因（INSR）的两个等位基因的功能丧失突变导致极端的胰岛素抵抗（IR），通常在儿童期死亡，几乎没有有效的治疗选择。二价抗受体抗体可以通过培养细胞中的突变型INSR引发胰岛素样信号传导，但这是否转化为体内有意义的代谢益处尚不清楚，其中胰岛素信号传导和受体再循环的动力学更复杂。为了解决这一问题，我们采用了一种策略来模拟小鼠中的人胰岛素受体病，在腺病毒介导的野生型（WT）或突变型人INSR的加回之前，使用腺相关病毒递送的Cre重组酶来急性敲除floxed Insr小鼠中的内源性肝Insr（肝胰岛素受体敲除[L-IRKO] + GFP）。两种鼠抗INSR单克隆抗体，先前被证明是突变型INSR的替代激动剂，然后通过腹膜内注射进行测试。正如预期的，L-IRKO + GFP小鼠显示葡萄糖耐受不良和严重的高胰岛素血症。这通过加回WT而不是D 734 A或S350 L突变体INSR完全校正。抗体注射改善了D 734 A INSR表达小鼠的葡萄糖耐量，并降低了S350 L和D 734 A INSR表达动物的高胰岛素血症。在表达WT INSR的小鼠中未引起低血糖。抗体处理还下调WT和突变型INSR蛋白，减弱其有益的代谢作用。因此，抗INSR抗体改善了胰岛素受体病急性模型中的IR，但这些发现意味着由抗体刺激受体并诱导其下调的竞争效应决定的狭窄治疗窗口。
Loss-of-function mutations in both alleles of the human insulin receptor gene (INSR) cause extreme insulin resistance (IR) and usually death in childhood, with few effective therapeutic options. Bivalent antireceptor antibodies can elicit insulin-like signaling by mutant INSR in cultured cells, but whether this translates into meaningful metabolic benefits in vivo, wherein the dynamics of insulin signaling and receptor recycling are more complex, is unknown. To address this, we adopted a strategy to model human insulin receptoropathy in mice, using Cre recombinase delivered by adeno-associated virus to knockout endogenous hepatic Insr acutely in floxed Insr mice (liver insulin receptor knockout [L-IRKO] + GFP), before adenovirus-mediated add back of wild-type (WT) or mutant human INSR. Two murine anti-INSR monoclonal antibodies, previously shown to be surrogate agonists for mutant INSR, were then tested by intraperitoneal injections. As expected, L-IRKO + GFP mice showed glucose intolerance and severe hyperinsulinemia. This was fully corrected by add back of WT but not with either D734A or S350L mutant INSR. Antibody injection improved glucose tolerance in D734A INSR-expressing mice and reduced hyperinsulinemia in both S350L and D734A INSR-expressing animals. It did not cause hypoglycemia in WT INSR-expressing mice. Antibody treatment also downregulated both WT and mutant INSR protein, attenuating its beneficial metabolic effects. Anti-INSR antibodies thus improve IR in an acute model of insulin receptoropathy, but these findings imply a narrow therapeutic window determined by competing effects of antibodies to stimulate receptors and induce their downregulation.
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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：
11.4
作者：
OBRIEN, RM;SOOS, MA;SIDDLE, K
通讯作者：
SIDDLE, K
DOI：
10.1124/jpet.115.229690
发表时间：
2016-02-01
影响因子：
3.5
作者：
Bezwada, Padma;Zhao, Jingsong;Johnson, Kirk
通讯作者：
Johnson, Kirk
影响因子：
16
作者：
Michael, MD;Kulkarni, RN;Kahn, CR
通讯作者：
Kahn, CR
影响因子：
4.8
作者：
Krook, A;Moller, DE;ORahilly, S
通讯作者：
ORahilly, S