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Model-based hypothesis testing of key mechanisms in initial phase of insulin signaling.

ABSTRACT: Type 2 diabetes is characterized by insulin resistance of target organs, which is due to impaired insulin signal transduction. The skeleton of signaling mediators that provide for normal insulin action has been established. However, the detailed kinetics, and their mechanistic generation, remain incompletely understood. We measured time-courses in primary human adipocytes for the short-term phosphorylation dynamics of the insulin receptor (IR) and the IR substrate-1 in response to a step increase in insulin concentration. Both proteins exhibited a rapid transient overshoot in tyrosine phosphorylation, reaching maximum within 1 min, followed by an intermediate steady-state level after approximately 10 min. We used model-based hypothesis testing to evaluate three mechanistic explanations for this behavior: (A) phosphorylation and dephosphorylation of IR at the plasma membrane only; (B) the additional possibility for IR endocytosis; (C) the alternative additional possibility of feedback signals to IR from downstream intermediates. We concluded that (A) is not a satisfactory explanation; that (B) may serve as an explanation only if both internalization, dephosphorylation, and subsequent recycling are permitted; and that (C) is acceptable. These mechanistic insights cannot be obtained by mere inspection of the datasets, and they are rejections and thus stronger and more final conclusions than ordinary model predictions.

SUBMITTER: Cedersund G

PROVIDER: S-EPMC2424138 | biostudies-literature | 2008 Jun

REPOSITORIES: biostudies-literature

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Model-based hypothesis testing of key mechanisms in initial phase of insulin signaling.

Cedersund Gunnar G Roll Jacob J Ulfhielm Erik E Danielsson Anna A Tidefelt Henrik H Strålfors Peter P

PLoS computational biology 20080620 6

Type 2 diabetes is characterized by insulin resistance of target organs, which is due to impaired insulin signal transduction. The skeleton of signaling mediators that provide for normal insulin action has been established. However, the detailed kinetics, and their mechanistic generation, remain incompletely understood. We measured time-courses in primary human adipocytes for the short-term phosphorylation dynamics of the insulin receptor (IR) and the IR substrate-1 in response to a step increas ...[more]

PMID: 18551197

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Project description:Predicting shifts of species geographical ranges is a fundamental challenge for conservation ecologists given the great complexity of factors involved in setting range limits. Distributional patterns are frequently modelled to "simplify" species responses to the environment, yet the central mechanisms that drive a particular pattern are rarely understood. We evaluated the distributions of two sandhopper species (Crustacea, Amphipoda, Talitridae), Talorchestia capensis and Africorchestia quadrispinosa along the Namibian and South African coasts, encompassing three biogeographic regions influenced by two different oceanographic systems, the Benguela and Agulhas currents. We aimed to test whether the Abundant Centre Hypothesis (ACH) can explain the distributions of these species' abundances, sizes and sex ratios and examined which environmental parameters influence/drive these distributions. Animals were collected during a once-off survey at 29 sites over c.3500 km of coastline. The ACH was tested using a non-parametric constraint space analysis of the goodness of fit of five hypothetical models. Distance Based Linear Modelling (DistLM) was performed to evaluate which environmental traits influenced the distribution data. Abundance, size and sex ratio showed different patterns of distribution. A ramped model fitted the abundance (Ramped North) and size (Ramped South) distribution for A. quadrispinosa. The Inverse Quadratic model fitted the size distribution of T. capensis. Beach slope, salinity, sand temperature and percentage of detritus found on the shore at the time of collection played important roles in driving the abundance of A. quadrispinosa. T. capensis was mainly affected by salinity and the morphodynamic state of the beach. Our results provided only some support for the ACH predictions. The DistLM confirmed that the physical state of the beach is an important factor for sandy beach organisms. The effect of salinity and temperature suggest metabolic responses to local conditions and a role in small to mesoscale shifts in the range of these populations.

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Model-based hypothesis testing of key mechanisms in initial phase of insulin signaling.

Publications

Model-based hypothesis testing of key mechanisms in initial phase of insulin signaling.

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