Congenital hyperinsulinism caused by hexokinase I expression or glucokinase-activating mutation in a subset of β-cells.
Congenital hyperinsulinism caused by hexokinase I expression or glucokinase-activating mutation in a subset of β-cells.
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作者：
Henquin JC;Sempoux C;Marchandise J;Godecharles S;Guiot Y;Nenquin M;Rahier J
先天性高胰岛素血症会导致新生儿和婴儿持续低血糖。最常见的是，胰岛素分泌不受控制 (IS) 是由于所有 β 细胞或仅可切除病灶内的 β 细胞缺乏功能性 KATP 通道所致。在更罕见的情况下，如果没有 KATP 通道突变，功能亢进的胰岛局限于少数小叶内，而功能低下的胰岛则遍布整个胰腺。他们也可以通过选择性部分胰腺切除术来治愈；然而，与具有 KATP 局灶性病变的患者不同，它们表现出对二氮嗪的临床敏感性。在这里，我们通过来自六个此类病例的病理和邻近正常胰腺的碎片来表征体外IS。正常胰腺的反应不显着。在病理区域，IS 在 1 mmol/L 时升高，并随着 15 mmol/L 葡萄糖进一步升高。二氮嗪抑制 IS，而甲苯磺丁脲拮抗这种抑制作用。最明显的异常是 1 mmol/L 葡萄糖对 IS 的强烈刺激。在 6 例病例中的 5 例中，免疫组织化学显示仅在功能亢进的胰岛 β 细胞中过度存在低 Km 己糖激酶-I。在一个案例中，仅在病理性胰岛中发现了葡萄糖激酶（I211F）的激活突变。这两种异常都归因于体细胞遗传事件，可能是β细胞亚群在低葡萄糖水平下不适当的IS的原因。它们代表了局灶性先天性高胰岛素血症的新原因。
Congenital hyperinsulinism causes persistent hypoglycemia in neonates and infants. Most often, uncontrolled insulin secretion (IS) results from a lack of functional KATP channels in all β-cells or only in β-cells within a resectable focal lesion. In more rare cases, without KATP channel mutations, hyperfunctional islets are confined within few lobules, whereas hypofunctional islets are present throughout the pancreas. They also can be cured by selective partial pancreatectomy; however, unlike those with a KATP focal lesion, they show clinical sensitivity to diazoxide. Here, we characterized in vitro IS by fragments of pathological and adjacent normal pancreas from six such cases. Responses of normal pancreas were unremarkable. In pathological region, IS was elevated at 1 mmol/L and was further increased by 15 mmol/L glucose. Diazoxide suppressed IS and tolbutamide antagonized the inhibition. The most conspicuous anomaly was a large stimulation of IS by 1 mmol/L glucose. In five of six cases, immunohistochemistry revealed undue presence of low-Km hexokinase-I in β-cells of hyperfunctional islets only. In one case, an activating mutation of glucokinase (I211F) was found in pathological islets only. Both abnormalities, attributed to somatic genetic events, may account for inappropriate IS at low glucose levels by a subset of β-cells. They represent a novel cause of focal congenital hyperinsulinism.
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