Henquin Jean-Claude, Nenquin Myriam, Stiernet Patrick, Ahren Bo
Unité d'Endocrinologie et Métabolisme, Brussels, Belgium.
Diabetes. 2006 Feb;55(2):441-51. doi: 10.2337/diabetes.55.02.06.db05-1051.
The mechanisms underlying biphasic insulin secretion have not been completely elucidated. We compared the pattern of plasma insulin changes during hyperglycemic clamps in mice to that of glucose-induced insulin secretion and cytosolic calcium concentration (Ca(2+)) changes in perifused mouse islets. Anesthetized mice were infused with glucose to clamp blood glucose at 8.5 (baseline), 11.1, 16.7, or 30 mmol/l. A first-phase insulin response consistently peaked at 1 min, and a slowly ascending second phase occurred at 16.7 and 30 mmol/l glucose. Glucose-induced insulin secretion in vivo is thus biphasic, with a similarly increasing second phase in the mouse as in humans. In vitro, square-wave stimulation from a baseline of 3 mmol/l glucose induced similar biphasic insulin secretion and Ca(2+) increases, with sustained and flat second phases. The glucose dependency (3-30 mmol/l) of both changes was sigmoidal with, however, a shift to the right of the relation for insulin secretion compared with that for Ca(2+). The maximum Ca(2+) increase was achieved by glucose concentrations, causing half-maximum insulin secretion. Because this was true for both phases, we propose that contrary to current concepts, amplifying signals are also implicated in first-phase glucose-induced insulin secretion. To mimic in vivo conditions, islets were stimulated with high glucose after being initially perifused with 8.5 instead of 3.0 mmol/l glucose. First-phase insulin secretion induced by glucose at 11.1, 16.7, and 30 mmol/l was decreased by approximately 50%, an inhibition that could not be explained by commensurate decreases in Ca(2+) or in the pool of readily releasable granules. Also unexpected was the gradually ascending pattern of the second phase, now similar to that in vivo. These observations indicated that variations in prestimulatory glucose can secondarily affect the magnitude and pattern of subsequent glucose-induced insulin secretion.
双相胰岛素分泌的潜在机制尚未完全阐明。我们将小鼠高血糖钳夹期间血浆胰岛素变化模式与葡萄糖诱导的胰岛素分泌以及灌注小鼠胰岛中细胞溶质钙浓度(Ca(2+))变化模式进行了比较。对麻醉的小鼠输注葡萄糖,将血糖钳夹在8.5(基线)、11.1、16.7或30 mmol/l。第一相胰岛素反应始终在1分钟时达到峰值,在葡萄糖浓度为16.7和30 mmol/l时出现缓慢上升的第二相。因此,体内葡萄糖诱导的胰岛素分泌是双相的,小鼠中的第二相增加情况与人类相似。在体外,从3 mmol/l葡萄糖基线开始的方波刺激诱导了类似的双相胰岛素分泌和Ca(2+)增加,第二相持续且平稳。两种变化的葡萄糖依赖性(3 - 30 mmol/l)呈S形,但与Ca(2+)相比,胰岛素分泌关系向右偏移。通过导致半数最大胰岛素分泌的葡萄糖浓度实现了最大Ca(2+)增加。由于两个阶段均如此,我们提出与当前概念相反,放大信号也参与了第一相葡萄糖诱导的胰岛素分泌。为模拟体内条件,胰岛在最初用8.5而非3.0 mmol/l葡萄糖灌注后用高葡萄糖刺激。在11.1、16.7和30 mmol/l葡萄糖浓度下,葡萄糖诱导的第一相胰岛素分泌降低了约50%,这种抑制无法用Ca(2+)或易释放颗粒池的相应降低来解释。同样出乎意料的是第二相逐渐上升的模式,现在与体内相似。这些观察结果表明,刺激前葡萄糖的变化可继而影响随后葡萄糖诱导的胰岛素分泌的幅度和模式。