title: Phase modulation of insulin pulses enhances glucose regulation and enables inter-islet synchronization.
abstract: Insulin is secreted in a pulsatile manner from multiple micro-organs called the islets of Langerhans. The amplitude and phase (shape) of insulin secretion are modulated by numerous factors including glucose. The role of phase modulation in glucose homeostasis is not well understood compared to the obvious contribution of amplitude modulation. In the present study, we measured Ca2+ oscillations in islets as a proxy for insulin pulses, and we observed their frequency and shape changes under constant/alternating glucose stimuli. Here we asked how the phase modulation of insulin pulses contributes to glucose regulation. To directly answer this question, we developed a phenomenological oscillator model that drastically simplifies insulin secretion, but precisely incorporates the observed phase modulation of insulin pulses in response to glucose stimuli. Then, we mathematically modeled how insulin pulses regulate the glucose concentration in the body. The model of insulin oscillation and glucose regulation describes the glucose-insulin feedback loop. The data-based model demonstrates that the existence of phase modulation narrows the range within which the glucose concentration is maintained through the suppression/enhancement of insulin secretion in conjunction with the amplitude modulation of this secretion. The phase modulation is the response of islets to glucose perturbations. When multiple islets are exposed to the same glucose stimuli, they can be entrained to generate synchronous insulin pulses. Thus, we conclude that the phase modulation of insulin pulses is essential for glucose regulation and inter-islet synchronization.
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk, Korea.
authors.forename: Boah
authors.initials: B
authors.lastname: Lee
authors.affiliation: Asia Pacific Center for Theoretical Physics, Pohang, Gyeongbuk, Korea.
authors.forename: Taegeun
authors.initials: T
authors.lastname: Song
authors.affiliation: School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang, Gyeongbuk, Korea.
authors.forename: Kayoung
authors.initials: K
authors.lastname: Lee
authors.affiliation: The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Jaeyoon
authors.initials: J
authors.lastname: Kim
authors.affiliation: School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang, Gyeongbuk, Korea.
authors.forename: Seungmin
authors.initials: S
authors.lastname: Han
authors.affiliation: School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang, Gyeongbuk, Korea.|The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Per-Olof
authors.initials: PO
authors.lastname: Berggren
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk, Korea.|School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang, Gyeongbuk, Korea.
authors.forename: Sung Ho
authors.initials: SH
authors.lastname: Ryu
authors.affiliation: Asia Pacific Center for Theoretical Physics, Pohang, Gyeongbuk, Korea.|Department of Physics, Pohang University of Science and Technology, Pohang, Gyeongbuk, Korea.
authors.forename: Junghyo
authors.initials: J
authors.lastname: Jo
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D002478:Cells, Cultured; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008810:Mice, Inbred C57BL
chemical_list: D007328:Insulin; D005947:Glucose