Center for Metabolic Research, Veterans Affairs San Diego Healthcare System, San Diego, California 92161, USA.
J Clin Endocrinol Metab. 2013 Aug;98(8):3446-53. doi: 10.1210/jc.2013-1771. Epub 2013 Jun 3.
Pasireotide (SOM230) is a somatostatin analog with affinity for somatostatin receptor subtypes sst₁₋₃ and sst₅. Clinical trials have demonstrated the efficacy of pasireotide in treating Cushing's disease and acromegaly but have also shown adverse effects on glucose metabolism.
The aim of the study was to evaluate the mechanism of pasireotide-associated hyperglycemia.
We conducted a randomized, single-center, open-label study.
Forty-five healthy male volunteers were randomized to pasireotide 600 (n = 19), 900 (n = 19), or 1200 μg (n = 7) sc twice a day for 7 days. Randomization to 1200 μg was discontinued because of increased severity of gastrointestinal adverse events in this arm. An oral glucose tolerance test (OGTT), a hyperglycemic clamp test, and a hyperinsulinemic-euglycemic clamp test were performed on 3 consecutive days at baseline and treatment end.
The effect of pasireotide on insulin secretion and hepatic/peripheral insulin sensitivity was measured. The secondary objective was to evaluate the effects of pasireotide on oral glucose absorption.
Pasireotide treatment resulted in significant decreases in insulin AUC0-180 min during both the hyperglycemic clamp test (-77.5%; P < .001 in both dose groups) and the OGTT (-61.9%; P < .001 in both dose groups). Suppression of glucagon levels was less pronounced. No significant changes in hepatic or peripheral insulin sensitivity were found during the hyperinsulinemic-euglycemic clamp test. Additionally, significant increases in glucose AUC₀₋₁₈₀ min (+67.4%) and decreases in AUC₀₋₁₈₀ min glucagon-like peptide-1 (-46.7%) and glucose-dependent insulinotropic polypeptide levels (-69.8%) were observed during the OGTT. No dose dependency or unexpected adverse events were observed.
Pasireotide-associated hyperglycemia is related to decreases in insulin secretion and incretin hormone responses, without changes in hepatic/peripheral insulin sensitivity.
帕瑞肽（SOM230）是一种生长抑素类似物，对生长抑素受体亚型 sst₁₋₃ 和 sst₅ 具有亲和力。临床试验已经证明了帕瑞肽在治疗库欣病和肢端肥大症方面的疗效，但也显示了对葡萄糖代谢的不良影响。
本研究旨在评估帕瑞肽相关高血糖的发生机制。
我们进行了一项随机、单中心、开放标签研究。
45 名健康男性志愿者随机分为帕瑞肽 600（n = 19）、900（n = 19）或 1200 μg（n = 7）sc，每天两次，共 7 天。由于该组胃肠道不良事件的严重程度增加，随机分配至 1200 μg 组的患者被排除。在基线和治疗结束时连续 3 天进行口服葡萄糖耐量试验（OGTT）、高血糖钳夹试验和高胰岛素-正常血糖钳夹试验。
帕瑞肽对胰岛素分泌和肝/外周胰岛素敏感性的影响。次要目标是评估帕瑞肽对口服葡萄糖吸收的影响。
帕瑞肽治疗导致高血糖钳夹试验（剂量组 -77.5%；P <.001）和 OGTT（剂量组 -61.9%；P <.001）中胰岛素 AUC0-180 min 显著降低。胰高血糖素水平的抑制作用则不那么明显。高胰岛素-正常血糖钳夹试验中未发现肝或外周胰岛素敏感性的显著变化。此外，OGTT 中观察到葡萄糖 AUC0-180 min 显著增加（+67.4%），GLP-1（-46.7%）和葡萄糖依赖性胰岛素释放肽（GIP）水平降低（-69.8%）。未观察到剂量依赖性或意外的不良事件。
帕瑞肽相关的高血糖与胰岛素分泌和肠降血糖素激素反应减少有关，而与肝/外周胰岛素敏感性无关。
