Buchwald Peter, Chuang Sung-Ting, Watts Brandon, Alcazar Oscar
Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, Florida, USA.
Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, Florida, USA.
bioRxiv. 2025 Jul 4:2025.07.01.662581. doi: 10.1101/2025.07.01.662581.
Insulin released in response to a stepwise increase in glucose (square wave) is biphasic with a transient first-phase peak of 5-10 min and a more sustained second phase. While it is usually assumed that the first phase is rate- and the second is concentration-dependent, there are no detailed investigations into the rate-sensitivity of the first phase. We performed dynamic perifusion studies with isolated human pancreatic islets in a system that allowed fully customizable glucose ramps and established the corresponding insulin secretion time-profiles with high (once-a-minute) time-resolution. We considered the first-phase release to be the excess amount of insulin in addition to what would be expected from the glucose concentration-dependent second-phase release and examined its dependence on the glucose gradient (rate of increase). The average first-phase insulin release rate calculated this way increased with the gradient and could be fitted well with a Hill-type sigmoid function having a half-maximal value around 1.25 mM/min ( ). This agrees well with our previously introduced glucose-insulin control system built on a general framework of a sigmoid proportional-integral-derivative (σPID) controller, a generalized PID controller more suitable for biological systems than classic linear ones as biological responses are always limited between zero and a possible maximum. Experimental results obtained here were used to slightly readjust the parameters of this local glucose concentration-based computational model resulting in predictions in good agreement with measured first- and second-phase insulin secretions ( ). Thus, glucose-stimulated insulin secretion (GSIS) of perifused human islets can be described well as the sum of a rate-sensitive first phase, which is a sigmoid function of the glucose gradient with half-maximal value around 1.25 mM/min, and a concentration-sensitive second phase, which is a sigmoid function of the glucose concentration with half-maximal value around 8 mM.
响应葡萄糖逐步增加（方波）而释放的胰岛素是双相的，有一个5 - 10分钟的短暂第一相峰值和一个更持久的第二相。虽然通常认为第一相是速率依赖性的，第二相是浓度依赖性的，但尚未对第一相的速率敏感性进行详细研究。我们在一个允许完全可定制葡萄糖斜坡的系统中对分离的人胰岛进行了动态灌流研究，并以高（每分钟一次）时间分辨率建立了相应的胰岛素分泌时间曲线。我们将第一相释放视为除了葡萄糖浓度依赖性第二相释放所预期的胰岛素量之外的过量胰岛素，并研究了其对葡萄糖梯度（增加速率）的依赖性。以这种方式计算的平均第一相胰岛素释放速率随梯度增加，并且可以很好地拟合为具有约1.25 mM/分钟半最大值的希尔型S形函数（ ）。这与我们之前基于S形比例积分微分（σPID）控制器的通用框架构建的葡萄糖 - 胰岛素控制系统非常吻合，σPID控制器是一种比经典线性控制器更适合生物系统的广义PID控制器，因为生物反应总是限制在零和可能的最大值之间。这里获得的实验结果用于稍微调整这个基于局部葡萄糖浓度的计算模型的参数，从而得到与测量的第一相和第二相胰岛素分泌高度一致的预测结果（ ）。因此，灌流人胰岛的葡萄糖刺激胰岛素分泌（GSIS）可以很好地描述为速率敏感的第一相（是葡萄糖梯度的S形函数，半最大值约为1.25 mM/分钟）和浓度敏感的第二相（是葡萄糖浓度的S形函数，半最大值约为8 mM）之和。
