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Diwekar-Joshi M, Watve M. Driver versus navigator causation in biology: the case of insulin and fasting glucose. PeerJ. 2020;8:e10396doi: 10.7717/peerj.10396.
Diwekar-Joshi, M., & Watve, M. (2020). Driver versus navigator causation in biology: the case of insulin and fasting glucose. PeerJ, 8e10396. https://doi.org/10.7717/peerj.10396
Diwekar-Joshi, Manawa, and Watve, Milind. "Driver versus navigator causation in biology: the case of insulin and fasting glucose." PeerJ vol. 8 (2020): e10396. doi: https://doi.org/10.7717/peerj.10396
Diwekar-Joshi M, Watve M. Driver versus navigator causation in biology: the case of insulin and fasting glucose. PeerJ. 2020 Dec 11;8:e10396. doi: 10.7717/peerj.10396. eCollection 2020. PMID: 33365205; PMCID: PMC7735078.
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PeerJ. 2020 Dec 11;8:e10396. doi: 10.7717/peerj.10396. eCollection 2020.

Driver versus navigator causation in biology: the case of insulin and fasting glucose.

PeerJ

Manawa Diwekar-Joshi, Milind Watve

Affiliations

  1. Biology, Indian Institute of Science Education and Research, Pune, Maharashtra, India.
  2. Deenanath Mangeshkar Hospital and Research Centre, Pune, Maharashtra, India.

PMID: 33365205 PMCID: PMC7735078 DOI: 10.7717/peerj.10396

Abstract

BACKGROUND: In biomedicine, inferring causal relation from experimental intervention or perturbation is believed to be a more reliable approach than inferring causation from cross-sectional correlation. However, we point out here that even in interventional inference there are logical traps. In homeostatic systems, causality in a steady state can be qualitatively different from that in a perturbed state. On a broader scale there is a need to differentiate driver causality from navigator causality. A driver is essential for reaching a destination but may not have any role in deciding the destination. A navigator on the other hand has a role in deciding the destination and the path but may not be able to drive the system to the destination. The failure to differentiate between types of causalities is likely to have resulted into many misinterpretations in physiology and biomedicine.

METHODS: We illustrate this by critically re-examining a specific case of the causal role of insulin in glucose homeostasis using five different approaches (1) Systematic review of tissue specific insulin receptor knock-outs, (2) Systematic review of insulin suppression and insulin enhancement experiments, (3) Differentiating steady state and post-meal state glucose levels in streptozotocin treated rats in primary experiments, (4) Mathematical and theoretical considerations and (5) Glucose-insulin relationship in human epidemiological data.

RESULTS: All the approaches converge on the inference that although insulin action hastens the return to a steady state after a glucose load, there is no evidence that insulin action determines the steady state level of glucose. Insulin, unlike the popular belief in medicine, appears to be a driver but not a navigator for steady state glucose level. It is quite likely therefore that the current line of clinical action in the field of type 2 diabetes has limited success largely because it is based on a misinterpretation of glucose-insulin relationship. The insulin-glucose example suggests that we may have to carefully re-examine causal inferences from perturbation experiments and set up revised norms for experimental design for causal inference.

© 2020 Diwekar-Joshi and Watve.

Keywords: Causality; Glucose homeostasis; Physiology; Steady state

Conflict of interest statement

The authors declare that they have no competing interests.

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