Pagano G, Cavallo-Perin P, Cassader M, Bruno A, Ozzello A, Masciola P, Dall'omo A M, Imbimbo B
J Clin Invest. 1983 Nov;72(5):1814-20. doi: 10.1172/JCI111141.
Prednisone-induced insulin resistance may depend on either reduced sensitivity (receptor defect) or reduced response to insulin (postreceptor defect). To clarify the mechanism of prednisone-induced insulin resistance, a [3H]glucose infusion (1 microCi/min) was performed for 120 min before and during a euglycemic clamp repeated at approximately 100, approximately 1,000, and approximately 10,000 microU/ml steady state plasma insulin concentration in 10 healthy, normal weight subjects, aged 35 +/- 7 yr. Each test was repeated after 7-d administration of placebo or prednisone (15 plus 15 mg/d per subject), in a randomized sequence with an interval of 1 mo between the two tests. Mean fasting blood glucose (89.5 +/- 2.1 vs. 83.7 +/- 1.9 mg/dl) and mean fasting plasma insulin values (17.8 +/- 1.2 vs. 14.3 +/- 0.8 microU/ml) were significantly higher (P less than 0.01) after prednisone. The insulin sensitivity index (glucose metabolic clearance rate in ml/kg per min) was significantly lower (P less than 0.001) after prednisone at all three steady state plasma insulin levels: 2.8 +/- 0.3 vs. 7.4 +/- 1.1 at approximately 100 microU/ml; 6.0 +/- 0.5 vs. 12.2 +/- 1.1 at approximately 1,000 microU/ml; 7.4 +/- 0.6 vs. 14.4 +/- 0.5 at approximately 10,000 microU/ml. Fasting glucose production (in mg/kg per min) was significantly higher after prednisone: 3.7 +/- 0.2 vs. 2.9 +/- 0.2, P less than 0.001. Suppression of glucose production at steady state plasma insulin level of approximately 100 microU/ml was less after prednisone (1.01 +/- 0.35 vs. 0.14 +/- 0.13, NS), and total at approximately 1,000 and approximately 10,000 microU/ml after both prednisone and placebo. The metabolic kinetic parameters of insulin after prednisone were not significantly different from those after placebo. In addition, insulin binding and 3-ortho-methyl-glucose transport were studied in vitro on fat cells from 16 normal-weight surgical candidates aged 40 +/- 8 yr (10 treated with placebo and 6 with prednisone as above). No significant difference was observed with regard to specific insulin binding (tested with 1 ng/ml hormone only), whereas significant transport differences were noted at the basal level (0.40 +/- 0.10 vs. 0.54 +/- 0.12 pmol/10(5) cells, P less than 0.05), and at increasing concentrations up to the maximum stimulation values (5 ng/ml): 0.59 +/- 0.04 vs. 0.92 +/- 0.12 pmol/10(5) cells, P less than 0.005. These results suggest that (a) administration of an anti-inflammatory dose of prednisone for 7 d induces insulin resistance in man; (b) this is more dependent on depressed peripheral glucose utilization than on increased endogenous production; (c) total insulin binding on isolated adipocytes is not significantly affected; (d) insulin resistance is primarily the outcome of postreceptor defect (impaired glucose transport).
泼尼松诱导的胰岛素抵抗可能取决于敏感性降低（受体缺陷）或对胰岛素的反应降低（受体后缺陷）。为了阐明泼尼松诱导胰岛素抵抗的机制，在10名年龄为35±7岁的健康、体重正常的受试者中，于正常血糖钳夹试验前和试验期间进行了120分钟的[3H]葡萄糖输注（1微居里/分钟），正常血糖钳夹试验以约100、约1000和约10000微单位/毫升的稳态血浆胰岛素浓度重复进行。在给予安慰剂或泼尼松（每位受试者每天15 + 15毫克）7天后，以随机顺序重复每项试验，两次试验之间间隔1个月。服用泼尼松后，平均空腹血糖（89.5±2.1对83.7±1.9毫克/分升）和平均空腹血浆胰岛素值（17.8±1.2对14.3±0.8微单位/毫升）显著更高（P＜0.01）。在所有三个稳态血浆胰岛素水平下，服用泼尼松后的胰岛素敏感性指数（葡萄糖代谢清除率，毫升/千克/分钟）均显著降低（P＜0.001）：在约100微单位/毫升时为2.8±0.3对7.4±1.1；在约1000微单位/毫升时为6.0±0.5对12.2±1.1；在约10000微单位/毫升时为7.4±0.6对14.4±0.5。服用泼尼松后空腹葡萄糖生成（毫克/千克/分钟）显著更高：3.7±0.2对2.9±0.2，P＜0.001。在稳态血浆胰岛素水平约100微单位/毫升时，服用泼尼松后对葡萄糖生成的抑制作用较小（1.01±0.35对0.14±0.13，无显著性差异），而在服用泼尼松和安慰剂后，在约1000和约10000微单位/毫升时葡萄糖生成完全被抑制。服用泼尼松后胰岛素的代谢动力学参数与服用安慰剂后无显著差异。此外，在体外对16名年龄为40±8岁的正常体重手术候选者（10名用安慰剂治疗，6名用上述泼尼松治疗）的脂肪细胞进行了胰岛素结合和3 - 邻 - 甲基 - 葡萄糖转运研究。在特异性胰岛素结合方面（仅用1纳克/毫升激素检测）未观察到显著差异，而在基础水平（0.40±0.10对0.54±0.12皮摩尔/10⁵个细胞，P＜0.05）以及浓度增加至最大刺激值（5纳克/毫升）时观察到显著的转运差异：0.59±0.04对0.92±0.12皮摩尔/10⁵个细胞，P＜0.005。这些结果表明：（a）给予抗炎剂量的泼尼松7天可诱导人体胰岛素抵抗；（b）这更多地取决于外周葡萄糖利用降低而非内源性生成增加；（c）分离的脂肪细胞上的总胰岛素结合未受到显著影响；（d）胰岛素抵抗主要是受体后缺陷（葡萄糖转运受损）的结果。
