A mathematical model of the impact of insulin secretion dynamics on selective hepatic insulin resistance.

Zhao, Gang; Wirth, Dagmar; Schmitz, Ingo; Meyer-Hermann, Michael

dc.contributor.author	Zhao, Gang
dc.contributor.author	Wirth, Dagmar
dc.contributor.author	Schmitz, Ingo
dc.contributor.author	Meyer-Hermann, Michael
dc.date.accessioned	2017-12-13T09:08:17Z
dc.date.available	2017-12-13T09:08:17Z
dc.date.issued	2017-11-08
dc.identifier.citation	A mathematical model of the impact of insulin secretion dynamics on selective hepatic insulin resistance. 2017, 8 (1):1362 Nat Commun	en
dc.identifier.issn	2041-1723
dc.identifier.pmid	29118381
dc.identifier.doi	10.1038/s41467-017-01627-9
dc.identifier.uri	http://hdl.handle.net/10033/621204
dc.description.abstract	Physiological insulin secretion exhibits various temporal patterns, the dysregulation of which is involved in diabetes development. We analyzed the impact of first-phase and pulsatile insulin release on glucose and lipid control with various hepatic insulin signaling networks. The mathematical model suggests that atypical protein kinase C (aPKC) undergoes a bistable switch-on and switch-off, under the control of insulin receptor substrate 2 (IRS2). The activation of IRS1 and IRS2 is temporally separated due to the inhibition of IRS1 by aPKC. The model further shows that the timing of aPKC switch-off is delayed by reduced first-phase insulin and reduced amplitude of insulin pulses. Based on these findings, we propose a sequential model of postprandial hepatic control of glucose and lipid by insulin, according to which delayed aPKC switch-off contributes to selective hepatic insulin resistance, which is a long-standing paradox in the field.
dc.language.iso	en	en
dc.rights.uri	http://creativecommons.org/licenses/by-nc-sa/4.0/	*
dc.title	A mathematical model of the impact of insulin secretion dynamics on selective hepatic insulin resistance.	en
dc.type	Article	en
dc.contributor.department	Braunschweiger Zentrum für Systembiologie, Rebenring 56, 38106, Germany.	en
dc.identifier.journal	Nature communications	en
refterms.dateFOA	2018-05-23T10:16:34Z
html.description.abstract	Physiological insulin secretion exhibits various temporal patterns, the dysregulation of which is involved in diabetes development. We analyzed the impact of first-phase and pulsatile insulin release on glucose and lipid control with various hepatic insulin signaling networks. The mathematical model suggests that atypical protein kinase C (aPKC) undergoes a bistable switch-on and switch-off, under the control of insulin receptor substrate 2 (IRS2). The activation of IRS1 and IRS2 is temporally separated due to the inhibition of IRS1 by aPKC. The model further shows that the timing of aPKC switch-off is delayed by reduced first-phase insulin and reduced amplitude of insulin pulses. Based on these findings, we propose a sequential model of postprandial hepatic control of glucose and lipid by insulin, according to which delayed aPKC switch-off contributes to selective hepatic insulin resistance, which is a long-standing paradox in the field.