Insulin Resistance

Hypo-responsiveness to the hormone insulin. The literature strongly suggests that it is an adaptive function that mediates energy-partitioning between different cells and tissues. A cell expressing an insulin resistant phenotype diverts incoming resources, primarily glucose towards cells with intact insulin signalling or with non-insulin-dependent glucose uptake.

This happens naturally in response to cellular energy-saturation to preserve intracellular homeostasis, in pregnancy to divert maternal nutrients to the fetus, and in fasting/starvation to spare glucose for vital-functions. Insulin resistance (IR) also happens as a response to pro-inflammatory stimuli as a mechanism to up-regulate glucose-availability for immune-cells, which chiefly uses passive diffusion for glucose internalisation. On a systemic level this co-occurs with increased hepatic glucose production for the same purpose. Systemic IR mostly involves muscle, adipose tissue and the liver, while the main benefiters are neural tissue, erythrocytes, leukocytes and thrombocytes. Grossly, IR can be said to mediate shift in glucose-partitioning away from metabolic pathways related to the locomotor-system in favour of neural- and immune-functions, and in pathological contexts it is mostly a downstream response to inflammation mediated by leukocyte-derived cytokines. It increases the glucose concentration-threshold needed to supply musculoskeletal tissues, necessitating an above-normal level of glucose-intake to preserve normal tissue-energetics which might explain hypherphagia in metabolic dissorders.

Supporting Evidence

• IR is not a fault but a feature.¹⁾https://www.jlr.org/content/early/2018/07/27/jlr.R087510.full.pdf
• IR can act as a mechanism to divert energy towards immune-function²⁾https://www.nature.com/articles/nature11862
• IR can act as a protection mechanism against intracellular nutrient overload.³⁾https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2764908/
• Hibernating animals enter a state of systemic IR that is reversed on arousal ⁴⁾https://www.ncbi.nlm.nih.gov/pubmed/23314346
• IR occur during sleep, sparing glucose in the favour of fat-metabolism⁵⁾https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5583684/
• During pregnancy there is a progressive rise in IR⁶⁾https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4290225/
• Short- and longterm fasting cause IR ⁷⁾https://www.ncbi.nlm.nih.gov/pubmed/6341773⁸⁾https://www.ncbi.nlm.nih.gov/pubmed/16185788
• In development of DM2, glucose consumption by the brain is increased, while decreasing in muscle.⁹⁾https://diabetes.diabetesjournals.org/content/67/Supplement_1/1790-P
• Study showing an association between IR and the phenomenon known as leptin-resistance.¹⁰⁾https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5590380/

Conflicting Evidence

• Increased expression of insulin receptors in cells of the spinal disc i a DM-model of DDD.¹¹⁾https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4408867/

Association with Disease

• Inflammatory cytokines and LPS increase GLUT-1 and IR in skeletal muscle in vitro.¹²⁾https://www.ncbi.nlm.nih.gov/pubmed/9230132
• Diabetic patients with OA has more severe synovitis than non-diabetic OA-patients¹³⁾https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3554306/
• Synovial insulin resistance is evident in diabetic patients, and might explain the increased OA severity¹⁴⁾https://www.sciencedirect.com/science/article/abs/pii/S0168822716308701¹⁵⁾https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5371020/
• Diabetic patients report muskuloskeletal pain 1.7-2.1 times more frequently than non-diabetics ¹⁶⁾https://www.ncbi.nlm.nih.gov/pubmed/22244365/
• Higher prevalence of muskuloskeletal pain, OA and RA among diabetic patients¹⁷⁾https://www.ncbi.nlm.nih.gov/pubmed/31886282
• Increased resistance to insulin in tendon tissue has been observed in a DM-model of TP.¹⁸⁾https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6003963/
• Experimentally induced DM caused histopathological change in Achilles-tendon similar to TP.¹⁹⁾https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3794027/
• Increased expression of GLUT-1 relative to GLUT-4 in RA synovial tissue.²⁰⁾https://onlinelibrary.wiley.com/doi/abs/10.1002/art.41190
• Endothelial insulin resistance was detected in patients cardiovascular disease and correlated with arterial stiffness.²¹⁾https://www.ahajournals.org/doi/10.1161/JAHA.118.010816