EFFECT OF SUSTAINED PHYSIOLOGICAL HYPERINSULINEMIA AND HYPERGLYCEMIA ON INSULIN-SECRETION AND INSULIN SENSITIVITY IN MAN
EFFECT OF SUSTAINED PHYSIOLOGICAL HYPERINSULINEMIA AND HYPERGLYCEMIA ON INSULIN-SECRETION AND INSULIN SENSITIVITY IN MAN
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DOI：
10.1007/bf00400466
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发表时间：
1994-10-01
期刊：
影响因子：
8.2
通讯作者：
DEFRONZO, RA
中科院分区：
文献类型：
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作者：
DELPRATO, S;LEONETTI, E;DEFRONZO, RA
在 15 名健康年轻受试者中进行了两项研究方案，以检查慢性（72-96 小时）生理性正常血糖高胰岛素血症（+ 72 pmol/l）和慢性高血糖（+ 1.4 mmol/l）高胰岛素血症（+ 78 pmol/l）对胰岛素敏感性和胰岛素分泌的影响。受试者在慢性胰岛素或葡萄糖输注之前和之后接受三步正常血糖胰岛素（胰岛素输注速率= 1.5、3和6 nmol.kg(-1).min(-1)）钳夹和高血糖（6.9 mmol/l）钳夹。持续正常血糖高胰岛素血症4天后，全身葡萄糖处理量下降20-40%。在每个胰岛素钳步骤中，胰岛素作用缺陷是由于非氧化葡萄糖处理受损造成的（p < 0.01）。慢性正常血糖高胰岛素血症不会改变胰岛素介导的肝葡萄糖生成抑制。胰岛素输注后，高血糖刺激胰岛素分泌的能力显着减弱。慢性葡萄糖输注 72 小时（合并高血糖高胰岛素血症）后，全身葡萄糖处理没有变化。然而，每个胰岛素钳步骤期间的葡萄糖氧化显着增加，并且非氧化葡萄糖处理相应下降 25-39% (p < 0.01)；慢性高血糖性高胰岛素血症不会改变胰岛素对肝葡萄糖产生的抑制作用。慢性葡萄糖输注使血浆胰岛素对急性高血糖的反应增加两倍以上。这些结果表明，慢性生理性高胰岛素血症，无论是通过外源性胰岛素输注还是通过刺激内源性胰岛素分泌引起，都会导致胰岛素抵抗的发展，其特征是非氧化（糖原合成）途径中的特定缺陷。这些发现表明，高胰岛素血症不仅应被视为对胰岛素抵抗的代偿反应，而且也是胰岛素作用缺陷的一个自我延续的原因。
Two study protocols to examine the effects of chronic (72-96 h) physiologic euglycaemic hyperinsulinaemia (+ 72 pmol/l) and chronic hyperglycaemic (+ 1.4 mmol/l) hyperinsulinaemia (+ 78 pmol/l) on insulin sensitivity and insulin secretion were performed in 15 healthy young subjects. Subjects received a three-step euglycaemic insulin (insulin infusion rates = 1.5, 3, and 6 nmol.kg(-1).min(-1)) clamp and a hyperglycaemia (6.9 mmol/l) clamp before and after chronic insulin or glucose infusion. Following 4 days of sustained euglycaemic hyperinsulinaemia whole body glucose disposal decreased by 20-40%. During each insulin clamp step, the defect in insulin action was accounted for by impaired non-oxidative glucose disposal (p < 0.01). Chronic euglycaemic hyperinsulinaemia did not alter insulin-mediated suppression of hepatic glucose production. Following insulin infusion the ability of hyperglycaemia to stimulate insulin secretion was significantly diminished. Following 72 h of chronic glucose infusion (combined hyperglycaemic hyperinsulinaemia), there was no change in whole body glucose disposal. However, glucose oxidation during each insulin clamp step was significantly increased and there was a reciprocal decline in non-oxidative glucose disposal by 25-39% (p < 0.01); suppression of hepatic glucose production by insulin was unaltered by chronic hyperglycaemic hyperinsulinaemia. Chronic glucose infusion increased the plasma insulin response to acute hyperglycaemia more than twofold. These results demonstrate that chronic, physiologic hyperinsulinaemia, whether created by exogenous insulin infusion or by stimulation of endogenous insulin secretion, leads to the development of insulin resistance, which is characterized by a specific defect in the non-oxidative (glycogen synthetic) pathway. These findings indicate that hyperinsulinaemia should be considered, not only as a compensatory response to insulin resistance, but also as a self-perpetuating cause of the defect in insulin action.