Abstract
The detailed characterization and quantification of the kinetics of glucose-stimulated insulin secretion (GSIS) by normal pancreatic islets is of considerable interest for characterizing β-cell dysfunction, assessing the quality of isolated islets, and improving the design of artificial pancreas devices. Here, we performed dynamic evaluation of GSIS by human and mouse islets at high temporal resolution (every minute) in response to different glucose steps using an automated multichannel perifusion instrument. In both species, insulin responses were biphasic (a transient first-phase peak followed by a sustained second-phase), and the amount of insulin released showed a sigmoid-type dependence on glucose concentration. However, compared to murine islets, human islets have (1) a less pronounced first-phase response, (2) a flat secretion rate during second-phase response, (3) a left-shifted concentration response (reaching half-maximal response at 7.9 ± 0.4 vs. 13.7 ± 0.6 mM), and (4) an ~3-fold lower maximal secretion rate (8.3 ± 2.3 vs. 23.9 ± 5.1 pg/min/islet at 30 mM glucose). These results can be used to establish a more informative protocol for the calculation of the stimulation index, which is widely used for islet assessment in both research and clinical applications, but without an accepted standard or clear evidence as to what low- to high-glucose steps can provide better characterization of islet function. Data obtained here suggest that human islet functionality might be best characterized with a dynamic stimulation index obtained with a glucose step from a low of 4–5 to a high of 14–17 mM (e.g., G4 → G16).
Highlights
In normal healthy subjects, blood glucose levels are maintained in a relatively narrow range between 3.0 and 9.0 mM (54–162 mg/dL), an observation well-documented by continuous glucose monitoring (CGM) systems [1, 2]
Human pancreatic islet samples were procured from the Integrated Islet Distribution Program (IIDP) at City of Hope or from isolations performed at the Human Islet Cell Processing Facility at the Diabetes Research Institute (University of Miami, Miller School of Medicine, Miami, FL, USA)
A first illustration is provided by the average curves shown in Figure 1 obtained from a large number of perifusions (n = 25 and 34) following our standard protocol (G3 → G11 → G3)
Summary
Blood glucose levels are maintained in a relatively narrow range between 3.0 and 9.0 mM (54–162 mg/dL), an observation well-documented by continuous glucose monitoring (CGM) systems [1, 2] This is mainly achieved via a finely tuned control system that relies on insulin producing β-cells located in pancreatic islets to adjust their insulin secretion depending on the blood glucose levels. It could help to better understand the process, assess β-cell function, and quantify progress toward disease onset in prospective patients. It is of critical importance for the development of improved artificial (e.g., closed loop) and bioartificial pancreas systems (e.g., encapsulated islets)
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