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.
Highlights
Physiological insulin secretion exhibits various temporal patterns, the dysregulation of which is involved in diabetes development
MTORC1, and its effector kinase S6K, limit insulin signaling by threonine/serine phosphorylating IRS1
Considering that impaired first-phase insulin indiabetes is associated with impaired glucose tolerance, we investigated the effects of different dynamic features of first-phase insulin, including the peak level and the slope of the increase (Fig. 5a)
Summary
Physiological insulin secretion exhibits various temporal patterns, the dysregulation of which is involved in diabetes development. Pulsatile infusion of exogenous insulin directly into the pre-hepatic vein showed enhanced effects in the activation of key signaling molecules, transcription factors, and in the suppression of hepatic glucose production, as compared to constant insulin infusion or to a pattern mimicking T2D18. Insulin has both direct and indirect effects in suppressing hepatic glucose production[19]. Phosphorylated IRS proteins activate multiple signaling pathways, among which Akt and atypical protein kinase C ζ/λ (aPKC) are two key metabolic effectors of insulin[21] Insulin regulates both carbohydrate and lipid metabolisms in the liver. Recent results point to a more prominent role of altered nutrient delivery to the liver[28], defects in insulin signaling might contribute to the development of hepatic selective insulin resistance[29,30,31,32]
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