Molecular reductions in glucokinase activity increase counter-regulatory responses to hypoglycemia in mice and humans with diabetes.
Molecular reductions in glucokinase activity increase counter-regulatory responses to hypoglycemia in mice and humans with diabetes.
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DOI：
10.1016/j.molmet.2018.08.001
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发表时间：
2018-11
影响因子：
8.1
通讯作者：
Evans ML
中科院分区：
文献类型：
--
作者：
Chakera AJ;Hurst PS;Spyer G;Ogunnowo-Bada EO;Marsh WJ;Riches CH;Yueh CY;Markkula SP;Dalley JW;Cox RD;Macdonald IA;Amiel SA;MacLeod KM;Heisler LK;Hattersley AT;Evans ML
适当的血糖水平对生存至关重要;因此，低血糖的检测和纠正至关重要。低血糖促使综合反应，包括胰岛素释放减少和关键反调节激素胰高血糖素和肾上腺素的分泌减少，这些激素共同促进内源性葡萄糖产生以恢复正常血糖。然而，具体如何协调这一反应仍有待充分澄清。低亲和力己糖激酶葡萄糖激酶存在于参与葡萄糖稳态的葡萄糖敏感细胞中，包括胰腺β细胞和某些脑区。在这里，我们的目的是检查葡萄糖激酶在触发反调节激素对低血糖反应的作用，假设降低葡萄糖激酶活性将导致增加和/或更早触发的反应。进行高胰岛素葡萄糖钳夹以检查对由杂合葡萄糖激酶突变（GCK-MODY）引起的单基因糖尿病患者中产生的受控低血糖挑战的反调节反应。为了研究葡萄糖激酶在不同传感区域中的相对重要性，然后我们研究了分子定义的全身和/或脑葡萄糖激酶破坏的小鼠对钳夹低血糖的反应。与一组血糖匹配的2型糖尿病患者相比，GCK-MODY患者在低血糖期间显示出更早的胰高血糖素反应。与此一致，在葡萄糖激酶突变的I366 F小鼠和链脲佐菌素治疗的β细胞消融糖尿病I366 F小鼠中，胰高血糖素对低血糖的反应也增加。在条件性脑葡萄糖激酶敲除小鼠中，胰高血糖素反应正常，表明低血糖期间胰高血糖素释放受脑外葡萄糖激酶介导的葡萄糖感知控制，但不在β细胞中。对于肾上腺素，我们发现GCK-MODY患者、β细胞消融糖尿病I366 F小鼠和条件性（巢蛋白谱系）脑葡萄糖激酶敲除小鼠的反应增加，支持脑葡萄糖激酶在触发肾上腺素释放中的作用。我们的数据表明，大脑和其他非β细胞外周低血糖传感器中的葡萄糖激酶在葡萄糖稳态中很重要，允许身体检测和响应血糖下降。葡萄糖激酶（GCK）功能降低会增加对低血糖的激素反应。β-细胞GCK负责血糖水平下降时的胰岛素抑制。脑GCK介导的低血糖感知参与肾上腺素释放。GCK介导的胰高血糖素分泌涉及不位于脑或β细胞中的GCK。
Appropriate glucose levels are essential for survival; thus, the detection and correction of low blood glucose is of paramount importance. Hypoglycemia prompts an integrated response involving reduction in insulin release and secretion of key counter-regulatory hormones glucagon and epinephrine that together promote endogenous glucose production to restore normoglycemia. However, specifically how this response is orchestrated remains to be fully clarified. The low affinity hexokinase glucokinase is found in glucose-sensing cells involved in glucose homeostasis including pancreatic β-cells and in certain brain areas. Here, we aimed to examine the role of glucokinase in triggering counter-regulatory hormonal responses to hypoglycemia, hypothesizing that reduced glucokinase activity would lead to increased and/or earlier triggering of responses. Hyperinsulinemic glucose clamps were performed to examine counter-regulatory responses to controlled hypoglycemic challenges created in humans with monogenic diabetes resulting from heterozygous glucokinase mutations (GCK-MODY). To examine the relative importance of glucokinase in different sensing areas, we then examined responses to clamped hypoglycemia in mice with molecularly defined disruption of whole body and/or brain glucokinase. GCK-MODY patients displayed increased and earlier glucagon responses during hypoglycemia compared with a group of glycemia-matched patients with type 2 diabetes. Consistent with this, glucagon responses to hypoglycemia were also increased in I366F mice with mutated glucokinase and in streptozotocin-treated β-cell ablated diabetic I366F mice. Glucagon responses were normal in conditional brain glucokinase-knockout mice, suggesting that glucagon release during hypoglycemia is controlled by glucokinase-mediated glucose sensing outside the brain but not in β-cells. For epinephrine, we found increased responses in GCK-MODY patients, in β-cell ablated diabetic I366F mice and in conditional (nestin lineage) brain glucokinase-knockout mice, supporting a role for brain glucokinase in triggering epinephrine release. Our data suggest that glucokinase in brain and other non β-cell peripheral hypoglycemia sensors is important in glucose homeostasis, allowing the body to detect and respond to a falling blood glucose. Reduced glucokinase (GCK) function increases hormonal responses to hypoglycemia. β-cell GCK is responsible for insulin suppression as blood glucose levels fall. Brain GCK-mediated hypoglycemia-sensing is involved in epinephrine release. GCK-mediated glucagon secretion involves GCK that is not located in brain or β-cells.
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在四种常用的近交小鼠菌株中的体内葡萄糖代谢。
影响因子：
7.7
作者：
Berglund, Eric D.;Li, Candice Y.;Poffenberger, Greg;Ayala, Julio E.;Fueger, Patrick T.;Willis, Shannon E.;Jewell, Marybeth M.;Powers, Alvin C.;Wasserman, David H.
通讯作者：
Wasserman, David H.
影响因子：
7.7
作者：
Levin, Barry E.;Becker, Thomas C.;Dunn-Meynell, Ambrose A.
通讯作者：
Dunn-Meynell, Ambrose A.
影响因子：
4
作者：
CUNNAH, D;JESSOP, DS;REES, LH
通讯作者：
REES, LH
影响因子：
16.6
作者：
Basco D;Zhang Q;Salehi A;Tarasov A;Dolci W;Herrera P;Spiliotis I;Berney X;Tarussio D;Rorsman P;Thorens B
通讯作者：
Thorens B
影响因子：
8.8
作者：
Picard A;Soyer J;Berney X;Tarussio D;Quenneville S;Jan M;Grouzmann E;Burdet F;Ibberson M;Thorens B
通讯作者：
Thorens B