Temporal Coding of Insulin Action through Multiplexing of the AKT Pathway

Konishi, Hiroyuki; Noguchi, Rei; Toyoshima, Yu; Ozaki, Yu Ichi; Uda, Shinsuke; Watanabe, Kanako; Ogawa, Wataru; Kuroda, Shinya

doi:10.1016/j.molcel.2012.04.018

Cited by 108 publications

(178 citation statements)

References 36 publications

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“…A precedent for differential effects of transient and prolonged insulin exposure comes from insulin's known mitogenic effects (20). Prolonged insulin exposure initiates signal transduction events that are distinct from transient incubation in cultured hepatocytes (29). However, the time scale in our in vivo experiments (2 vs. 8 h) is very CA expression in unfed larvae.…”

Section: Discussionmentioning

confidence: 91%

Overnutrition induces β-cell differentiation through prolonged activation of β-cells in zebrafish larvae

Maddison

Page-McCaw

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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Insulin from islet ␤-cells maintains glucose homeostasis by stimulating peripheral tissues to remove glucose from circulation. Persistent elevation of insulin demand increases ␤-cell number through selfreplication or differentiation (neogenesis) as part of a compensatory response. However, it is not well understood how a persistent increase in insulin demand is detected. We have previously demonstrated that a persistent increase in insulin demand by overnutrition induces compensatory ␤-cell differentiation in zebrafish. Here, we use a series of pharmacological and genetic analyses to show that prolonged stimulation of existing ␤-cells is necessary and sufficient for this compensatory response. In the absence of feeding, tonic, but not intermittent, pharmacological activation of ␤-cell secretion was sufficient to induce ␤-cell differentiation. Conversely, drugs that block ␤-cell secretion, including an ATP-sensitive potassium (KATP) channel agonist and an L-type Ca 2ϩ channel blocker, suppressed overnutrition-induced ␤-cell differentiation. Genetic experiments specifically targeting ␤-cells confirm existing ␤-cells as the overnutrition sensor. First, inducible expression of a constitutively active K ATP channel in ␤-cells suppressed the overnutrition effect. Second, inducible expression of a dominant-negative K ATP mutant induced ␤-cell differentiation independent of nutrients. Third, sensitizing ␤-cell metabolism by transgenic expression of a hyperactive glucokinase potentiated differentiation. Finally, ablation of the existing ␤-cells abolished the differentiation response. Taken together, these data establish that overnutrition induces ␤-cell differentiation in larval zebrafish through prolonged activation of ␤-cells. These findings demonstrate an essential role for existing ␤-cells in sensing overnutrition and compensating for their own insufficiency by recruiting additional ␤-cells.

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Section: Discussionmentioning

confidence: 91%

Overnutrition induces β-cell differentiation through prolonged activation of β-cells in zebrafish larvae

Maddison

Page-McCaw

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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“…The mechanism may be related to the differential dose response relationship between pAkt and its various downstream substrates [48], or the temporal pattern of the insulin signal shown in modelling studies [51]. Insulin sensitivity by clamp was highly correlated with liver fat, adiponectin and Akt phosphorylation (R 0.53, 0.55 and 0.54, respectively [ESM Table 1]).…”

Section: Discussionmentioning

confidence: 99%

Impaired Akt phosphorylation in insulin-resistant human muscle is accompanied by selective and heterogeneous downstream defects

Tonks

Miller

et al. 2013

Diabetologia

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Aims/hypothesis Muscle insulin resistance, one of the earliest defects associated with type 2 diabetes, involves changes in the phosphoinositide 3-kinase/Akt network. The relative contribution of obesity vs insulin resistance to perturbations in this pathway is poorly understood. Methods We used phosphospecific antibodies against targets in the Akt signalling network to study insulin action in muscle from lean, overweight/obese and type 2 diabetic individuals before and during a hyperinsulinaemic-euglycaemic clamp. Results Insulin-stimulated Akt phosphorylation at Thr309 and Ser474 was highly correlated with whole-body insulin sensitivity. In contrast, impaired phosphorylation of Akt substrate of 160 kDa (AS160; also known as TBC1D4) was associated with adiposity, but not insulin sensitivity. Neither insulin sensitivity nor obesity was associated with defective insulin-dependent phosphorylation of forkhead box O (FOXO) transcription factor. In view of the resultant basal hyperinsulinaemia, we predicted that this selective response within the Akt pathway might lead to hyperactivation of those processes that were spared. Indeed, the expression of genes targeted by FOXO was downregulated in insulin-resistant individuals. Conclusions/interpretation These results highlight nonlinearity in Akt signalling and suggest that: (1) the pathway from Akt to glucose transport is complex; and (2) pathways, particularly FOXO, that are not insulin-resistant, are likely Electronic supplementary material The online version of this article (doi:10.1007/s00125-012-2811-y) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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“…Signal transduction pathways utilise temporal signalling patterns, such as oscillations, to encode information of a greater complexity, with enhanced specificity for downstream substrates and processes (Cheong and Levchenko, 2010;Kubota et al, 2012). Self-organising oscillatory behaviour in PIP3 generation, facilitated by PI3K, has been described for amoeboid cells expressing the PH domain of Akt during random cell migration (Arai et al, 2010); however, such oscillations have not yet been demonstrated in response to insulin.…”

Section: Insulin Stimulation Induces Self-organising Oscillations In mentioning

confidence: 99%

An improved Akt reporter reveals intra- and inter-cellular heterogeneity and oscillations in signal transduction

Norris

Yang

Krycer

et al. 2017

Journal of Cell Science

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Akt is a key node in a range of signal transduction cascades and play a critical role in diseases such as cancer and diabetes. Fluorescentlytagged Akt reporters have been used to discern Akt localisation, yet it has not been clear how well these tools recapitulate the behaviour of endogenous Akt proteins. Here, we observed that fusion of eGFP to Akt2 impaired both its insulin-stimulated plasma membrane recruitment and its phosphorylation. Endogenous-like responses were restored by replacing eGFP with TagRFP-T. The improved response magnitude and sensitivity afforded by TagRFP-T-Akt2 over eGFP-Akt2 enabled monitoring of signalling outcomes in single cells at physiological doses of insulin with subcellular resolution and revealed two previously unreported features of Akt biology. In 3T3-L1 adipocytes, stimulation with insulin resulted in recruitment of Akt2 to the plasma membrane in a polarised fashion. Additionally, we observed oscillations in plasma membrane localised Akt2 in the presence of insulin with a consistent periodicity of 2 min. Our studies highlight the importance of fluorophore choice when generating reporter constructs and shed light on new Akt signalling responses that may encode complex signalling information.This article has an associated First Person interview with the first author of the paper.

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Temporal Coding of Insulin Action through Multiplexing of the AKT Pathway

Cited by 108 publications

References 36 publications

Overnutrition induces β-cell differentiation through prolonged activation of β-cells in zebrafish larvae

Overnutrition induces β-cell differentiation through prolonged activation of β-cells in zebrafish larvae

Impaired Akt phosphorylation in insulin-resistant human muscle is accompanied by selective and heterogeneous downstream defects

An improved Akt reporter reveals intra- and inter-cellular heterogeneity and oscillations in signal transduction

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