We store calories from our diet in adipocytes. However, excessive calorie intake eventually overwhelms our adipocytes capacity to store energy, resulting in excess energy from our diet being stored in other tissues, generally referred to as ectopic fat. One of the tissues that accumulate ectopic fat is Skeletal Muscle, which store the excess energy from our diet in the form of IntraMyoCellular Lipids (visceral fat is a “proxy” for this ectopic fat).
Normally, Insulin signals Skeletal Muscle to use blood glucose as a source of energy. However, when Skeletal Muscles accumulate IntraMyoCellular Lipids as a source of energy, they resist insulin's signal to uptake blood glucose as a source of energy(become insulin-resistant) because they already have IntraMyoCellular Lipid as a source of energy(among other mechanisms). Because the skeletal muscle becomes insulin-resistant, blood glucose remains elevated, triggering the pancreas to respond with compensatory hyperinsulinemia which may accelerate the onset of age-related disease.
Blood Insulin interacts with virtually every cell in our body by activating the mTOR pathway, which is at the center of regulating the rate of aging. The 3 interventions that most reproducibly extend longevity in virtually all animal models are Calorie Restriction, Rapamycin, and IGF-Receptor Mutations. All these interventions extend longevity by INHIBITING mTOR, however hyperinsulinemia ACTIVATES mTOR, and may explain why hyperinsulinemia is one of the most predictive markers of all-cause mortality (accelerates the rate of aging). Insulin also affects FOXO, the prototypical gene variant associated with longevity in population studies. This may explain why a large percentage of medications proven successful in the Nation Institute of Health "Intervention Testing Program" are Type-II Diabetes medications that reduce blood glucose, which ultimately reduces hyperinsulinemia and mTOR activity. Advanced glycated end products from hyperglycemia play a role in aging, however both ACCORD and UKPDS trials show aggressive hyperglycemia management with insulin or sulfonylureas increase all-cause mortality, but is still recommended (for good reason) because hyperglycemia significantly hurts quality of life (i.g. blindness, amputation). The ideal scenario is lifestyle management to address the root cause of hyperglycemia and hyperinsulinemia. The link below goes into more details on mTORs role in aging
• The Biology of Aging &...
Excessive insulin provides cells with pro-growth signals, enabling PRE-cancerous cells continued cell division and further accumulation of mutations. This is because insulin's “pro-growth” signals blunt the pro-apoptosis signals responding from DNA damage, allowing further cell proliferation and accumulation of DNA mutations in precancerous cells that SHOULD activate apoptosis due to excessive DNA mutation signals. Insulin activates mTOR, which up-regulates mitochondrial HK2, which functions to inhibit BAX, thus effectively preventing upstream DNA damage signals from inducing apoptosis through BAX (AMPK down-regulates HK2, IGF-1 interferes with multiple control points of apoptosis). Also, mouse models genetically modified for the ability to induce high rates of DNA mutations show we’ve evolved remarkably efficient systems designed to prevent accumulation of precancerous cells, however carcinogen exposure coupled with attenuated repair systems designed to activate apoptosis in response to DNA mutations, allow gradual accumulation of DNA mutations that produce a malignancy that becomes unmanageable. Elephants have 4 quadrillion cells but lower cancer rates than humans. They have x20 more copies of p53 than humans (most common mutation in human cancer), as reduced p53 activity permits oncogenesis. Insulin activated mTOR induces MDM2 translation, which inhibits p53. I believe larons syndrome, metformin, and calorie restriction create time-intervals where PRE-cancerous cells are primed for apoptosis and removal, BUT CAN NOT TREAT MATURE MALIGNANCIES WHICH HAVE ALREADY DEVELOPED ONCOGENES THAT WILL CAUSE UNREGULATED CELL PROLIFERATION, IRRESPECTIVE OF ANY DIETARY INTERVENTION THAT AT BEST MAY SLOW THE INEVITABLE CELL GROWTH AND METASTASIS, UNLESS MANAGED WITH CYTOTOXIC INTERVENTION).
There are many factors not related to insulin that influence Coronary Artery Diseases, most importantly ApoB (proxy for LDL and atherogenic particle count). However, Obesity, IMCL, and Hyperinsulinemia affect lipoprotein dynamics and residence time. However, it’s important to emphasize there are many factors contributing to CAD, such as endothelial inflammation, oxLDL and Lp(a) (niacin reduces LP(a) but does NOT improve CVD outcomes).
It’s also possible NAFLD(ectopic fat in liver) produce metabolites that activate enzymes resulting in up-regulating gluconeogenesis, therefore being strong predictor of hyperinsulinemia.
5 янв 2024
