Garvey W T, Revers R R, Kolterman O G, Rubenstein A H, Olefsky J M
J Clin Endocrinol Metab. 1985 Mar;60(3):559-68. doi: 10.1210/jcem-60-3-559.
We studied the dose-response characteristics of insulin's ability to modulate its own secretion in normal and type II diabetic (NIDDM) subjects by measuring suppression of serum C-peptide levels during insulin infusions with the plasma glucose level held constant. In normal subjects at euglycemia, primed continuous insulin infusion rates of 15, 40, 120, and 240 mU/M2 X min acutely raised serum insulin to steady state levels of 37 +/- 2 (+/- SE), 96 +/- 6, 286 +/- 17, and 871 +/- 93 microU/ml, respectively. During each infusion, maximal suppression of C-peptide to 30% of basal levels occurred by 130 min. At the higher insulin levels (greater than or equal to 100 microU/ml), C-peptide levels fell rapidly, with an apparent t1/2 of 13 min, which approximates estimates for the t1/2 of circulating C-peptide in man. This is consistent with an immediate 70% inhibition of the basal rate of insulin secretion. At the lower insulin level (37 +/- 2 microU/ml), C-peptide levels fell to 30% of basal values less rapidly (apparent t1/2, 33 min), suggesting that 70% inhibition of basal insulin secretion rates was achieved more slowly. In NIDDM subjects, primed continuous insulin infusion rates of 15, 40, 120, and 1200 mU/M2 X min acutely raised serum insulin to steady state levels of 49 +/- 7, 93 +/- 11,364 +/- 31, and 10,003 +/- 988 microU/ml. During studies at basal hyperglycemia, only minimal C-peptide suppression was found, even at pharmacological insulin levels (10,003 +/- 988 microU/ml). However, if plasma glucose was allowed to fall during the insulin infusions, there was a rapid decrease in serum C-peptide to 30% of basal levels, analogous to that in normal subjects. Three weeks of intensive insulin therapy did not alter C-peptide suppression under conditions of hyperinsulinemia and falling plasma glucose. The following conclusions were reached. 1) In normal subjects, insulin (40-1000 microU/ml) inhibits its own secretion in a dose-responsive manner; more time is required to achieve maximal 70% suppression at the lower insulin level (40 microU/ml). 2) In NIDDM studied at basal hyperglycemia, insulin has minimal ability to suppress its own secretion. Thus, impaired feedback inhibition could contribute to basal hyperinsulinemia. 3) Under conditions of hyperinsulinemia and falling plasma glucose, insulin secretion is rapidly suppressed in NIDDM (analogous to that in normal subjects studied during euglycemia.
我们通过在血浆葡萄糖水平保持恒定的情况下测量胰岛素输注期间血清C肽水平的抑制情况，研究了正常和II型糖尿病（NIDDM）受试者中胰岛素调节自身分泌能力的剂量反应特性。在正常受试者处于血糖正常状态时，15、40、120和240 mU/M2×min的负荷连续胰岛素输注率分别使血清胰岛素急性升高至稳态水平37±2（±SE）、96±6、286±17和871±93 μU/ml。在每次输注期间，到130分钟时C肽最大抑制至基础水平的30%。在较高胰岛素水平（≥100 μU/ml）时，C肽水平迅速下降，表观半衰期为13分钟，这与人体循环C肽半衰期的估计值相近。这与基础胰岛素分泌率立即受到70%的抑制相一致。在较低胰岛素水平（37±2 μU/ml）时，C肽水平下降至基础值的30%的速度较慢（表观半衰期为33分钟），表明基础胰岛素分泌率70%的抑制作用实现得较慢。在NIDDM受试者中，15、40、120和1200 mU/M2×min的负荷连续胰岛素输注率分别使血清胰岛素急性升高至稳态水平49±7、93±11、364±31和10003±988 μU/ml。在基础高血糖状态下的研究中，即使在药理胰岛素水平（10003±988 μU/ml）时，也仅发现最小程度的C肽抑制。然而，如果在胰岛素输注期间允许血浆葡萄糖下降，则血清C肽会迅速下降至基础水平的30%，这与正常受试者中的情况类似。强化胰岛素治疗三周并未改变高胰岛素血症和血浆葡萄糖下降情况下的C肽抑制情况。得出以下结论。1）在正常受试者中，胰岛素（40 - 1000 μU/ml）以剂量反应方式抑制自身分泌；在较低胰岛素水平（40 μU/ml）时需要更多时间才能实现最大70%的抑制。2）在基础高血糖状态下研究的NIDDM中，胰岛素抑制自身分泌的能力最小。因此，反馈抑制受损可能导致基础高胰岛素血症。3）在高胰岛素血症和血浆葡萄糖下降的情况下，NIDDM中的胰岛素分泌迅速受到抑制（类似于血糖正常时研究的正常受试者中的情况）。
