Assessing the rate dependence of the first phase of glucose-stimulated insulin secretion: dynamic perifusion studies with isolated human pancreatic islets.

Abstract

Insulin released in response to a stepwise increase in glucose (square wave) is biphasic with a transient 5-10 min first-phase peak and a more sustained second phase. Although the first phase is generally assumed to be rate-dependent and the second concentration-dependent, detailed studies of first-phase rate sensitivity are lacking. We performed dynamic perifusion studies with human islets using customizable glucose ramps and established the corresponding insulin secretion time profiles. First-phase release was defined as the excess insulin above that expected from the concentration-dependent second phase, and its dependence on the glucose gradient (rate of increase) was examined. The first-phase insulin release rate calculated this way increased with the gradient and fit well to a Hill-type sigmoid function with a half-maximal value around 1.25 mM/min (<i>n</i>_Hill = 1.8, <i>r</i>² = 0.96). This aligns 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 linear ones as responses are bounded between zero and a maximum. Experimental results were used to slightly recalibrate this local glucose concentration-based computational model resulting in predictions in good agreement with measured first- and second-phase insulin secretions (<i>r</i>² > 0.90). Thus, glucose-stimulated insulin secretion of perifused human islets can be described well as the sum of a mainly rate-sensitive first phase, which is a sigmoid function of the glucose gradient with half-maximal activation around 1.25 mM/min, and a concentration-sensitive second phase, which is a sigmoid function of the glucose concentration with half-maximal activation near 8 mM.<b>NEW & NOTEWORTHY</b> We performed dynamic perifusion studies of human pancreatic islets with customizable glucose ramps that confirmed that the first phase of glucose-stimulated insulin secretion (GSIS) is rate-sensitive. Overall, we found that GSIS of isolated human islets can be described well as the sum of a rate-dependent first phase and a concentration-dependent second phase characterized by Hill-type sigmoid functions with half-maximal activations at a gradient of 1.25 mM/min and a glucose concentration of 8 mM, respectively.