Nrf2 Balances Excess Energy Management in Cells to Prevent Insulin Resistance Syndrome

I agree with this article.

We mistake metabolic syndrome markers as causes. E.g. Obesity.

The brain reward system leads to more energy rich foods and more efficient power intake at the expense of Nrf2 antioxidant garden foods protectors.

Fortunately we can search for the root cause of metabolic syndrome, insulin resistance initiated by inflammation and oxidative damaging and signaling.

Sufficient energy capital must be balanced with antioxidant expense to prevent insulin resistance causing inflammation.

Recently, I blogged the article on carotid body sensing of insulin excess.  Insulin is a signal of energy excess.  Sympathetic overdrive alerts the brain that Nrf2 anti-aging antioxidant is insufficient and insulin resistance in various organs results as a protection for "Nrf2 anti-aging antioxidant" deficient and vulnerable cells.  In other words, the overwhelmed carotid body insulin sensing cell is itself under oxidative stress and unable to send beta hydroxybutyrate or Nrf2 feedback signals through the nuclear pore to transcribe and translate SOD or glutathione antioxidants needed for homeostasis.  Damage insues that leads first to quiescence and ultimately to apoptosis.  Recovery is ultimately related to burden of senescent cells and stem cell  health and number OR their capacity to regenerate needed cells.

Two solutions for metabolic insulin resistance syndrome 1.  fasting until damage repaired, energy production balanced by endogenous antioxidant status OR 2.  Provide beta hydroxybutyrate or other Nrf2 pathway agonist such as sulforaphane, spermidine.  One could also increase beta hydroxybutyrate indirectly through exercise, MCT oil or PGC1 activation with ursolic acid or a combination of (alpha Lipoic acid and coenzyme Q10.)

One implication of this theory is that insulin resistance syndrome is measurable.
1.  HRV a measure of autonomic nervous system health.
2. The ratio of M1/ M2 macrophages.
3.  The endothelial function tests that measures indirectly telomerase directed NO flow mediated dilation.
4.  Serum telomerase activity.
5. Mannitol Lactulose ratio as a measure of leaky gut endothelial integrity.

It seems obvious that too much energy, too much inflammation or too little antioxidant creates insulin resistance.  Consider localized ischemia reperfusion as a model of localized too much inflammation.

Traumatic brain injury.
Acute kidney injury.
Acute pancreatitis.
Herniated disc with sciatica.
Any infection in a diabetic.

I also believe clock genes reduce Nrf2 translation by reducing spermidine synthesis.  In effect clock genes "slow down" Nrf2 anti-aging antioxidant pathway.  Fortunately spermidine can be supplemented!

https://archpublichealth.biomedcentral.com/articles/10.1186/2049-3258-72-30

Causes of metabolic syndrome and obesity-related co-morbidities Part 1: A composite unifying theory review of human-specific co-adaptations to brain energy consumption
One line summary
Metabolic syndrome and obesity-related co-morbidities are largely explained by co-adaptations to the energy use of the large human brain in the cortico-limbic-striatal and NRF2 systems.
The medical, research and general community is unable to effect significantly decreased rates of central obesity and related type II diabetes mellitus (TIIDM), cardiovascular disease (CVD) and cancer. All conditions seem to be linked by the concept of the metabolic syndrome (MetS), but the underlying causes are not known. MetS markers may have been mistaken for causes, thus many treatments are destined to be suboptimal.
The current paper aims to critique current paradigms, give explanations for their persistence, and to return to first principles in an attempt to determine and clarify likely causes of MetS and obesity related comorbidities. A wide literature has been mined, study concepts analysed and the basics of human evolution and new biochemistry reviewed. A plausible, multifaceted composite unifying theory is formulated.
The basis of the theory is that the proportionately large, energy-demanding human brain may have driven co-adaptive mechanisms to provide, or conserve, energy for the brain. A ‘dual system’ is proposed. 1) The enlarged, complex cortico-limbic-striatal system increases dietary energy by developing strong neural self-reward/motivation pathways for the acquisition of energy dense food, and (2) the nuclear factor-erythroid 2-related factor 2 (NRF2) cellular protection system amplifies antioxidant, antitoxicant and repair activity by employing plant chemicals, becoming highly energy efficient in humans.
The still-evolving, complex human cortico-limbic-striatal system generates strong behavioural drives for energy dense food procurement, including motivating agricultural technologies and social system development. Addiction to such foods, leading to neglect of nutritious but less appetizing ‘common or garden’ food, appears to have occurred. Insufficient consumption of food micronutrients prevents optimal human NRF2 function. Inefficient oxidation of excess energy forces central and non-adipose cells to store excess toxic lipid. Oxidative stress and metabolic inflammation, or metaflammation, allow susceptibility to infectious, degenerative atherosclerotic cardiovascular, autoimmune, neurodegenerative and dysplastic diseases.
Other relevant human-specific co-adaptations are examined, and encompass the unusual ability to store fat, certain vitamin pathways, the generalised but flexible intestine and microbiota, and slow development and longevity.
This theory has significant past and future corollaries, which are explored in a separate article by McGill, A-T, in Archives of Public Health, 72: 31.