How Insulin and a Body Switch Can Lead to Health Problems
- Brainz Magazine
- Apr 22
- 6 min read
Dr. Trevor Miller and Jessica Miller, RN, work on foundational health. Their expertise covers a wide birth of topics, giving them the unique ability to recognize unusual patterns. This allows them to be able to pick out issues that others have missed or that previous treatments have uncovered.
Insulin, a critical hormone produced by the pancreas, regulates blood glucose levels by facilitating glucose uptake into cells. Beyond its role in glucose metabolism, insulin is a potent signaling molecule that influences cellular growth, proliferation, and metabolism through pathways like the mechanistic target of rapamycin (mTOR). While mTOR activation is essential for growth and survival, chronic overactivation, often driven by sustained high insulin levels, is implicated in metabolic syndrome and a cascade of related diseases, including fatty liver disease, heart disease, stroke, cancer, Alzheimer’s disease, and mental illness. This article explores why insulin levels should be monitored, how insulin drives mTOR activation, and how chronic mTOR activation contributes to these conditions.
Why insulin should be measured
Insulin levels are a critical biomarker for metabolic health, yet they are often overlooked in routine medical assessments. Unlike blood glucose, which provides a snapshot of current sugar levels, insulin reflects the body’s long-term metabolic state and its ability to manage glucose effectively. Elevated insulin levels, or hyperinsulinemia, often precede hyperglycemia and type 2 diabetes by years, serving as an early warning sign of metabolic dysfunction.
Early detection of insulin resistance: Insulin resistance, where cells become less responsive to insulin, forces the pancreas to produce more insulin to maintain normal glucose levels. Measuring fasting insulin or using tests like the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) can identify insulin resistance before glucose levels rise, allowing for early intervention through lifestyle changes or medical management. Also in the advanced lipid panel, known as an NMR, they will estimate insulin resistance.
Indicator of metabolic syndrome: Hyperinsulinemia is a hallmark of metabolic syndrome, a cluster of conditions including abdominal obesity, high blood pressure, elevated triglycerides, low HDL cholesterol, and insulin resistance. Monitoring insulin can help assess the risk of progressing to metabolic syndrome and its associated diseases.
Personalized treatment: Insulin levels can guide personalized interventions. For instance, individuals with hyperinsulinemia may benefit from a low-carbohydrate, high fiber diet, intermittent fasting, or medications that reduce insulin demand and improve sensitivity.
Prevention of chronic diseases: Sustained high insulin levels drive pathological processes, including inflammation, oxidative stress, and mTOR activation, which contribute to chronic diseases. Regular insulin monitoring can help mitigate these risks by prompting timely interventions.
Insulin and mTOR activation
The mTOR pathway is a central regulator of cellular growth, metabolism, and survival. It exists in two complexes, mTORC1 and mTORC2, with mTORC1 being particularly sensitive to insulin signaling. Insulin activates mTORC1 through the following steps:
Insulin receptor activation: When insulin binds to its receptor on cell membranes, it activates the insulin receptor tyrosine kinase, which phosphorylates insulin receptor substrates (IRS).
PI3K-Akt pathway: Phosphorylated IRS activates phosphoinositide 3-kinase (PI3K), which generates phosphatidylinositol (3,4,5)-trisphosphate (PIP3). PIP3 recruits and activates Akt, a serine/threonine kinase.
mTORC1 activation: Akt phosphorylates and inhibits tuberous sclerosis complex 2 (TSC2), a negative regulator of mTORC1. This allows Rheb, a small GTPase, to activate mTORC1. mTORC1 then promotes protein synthesis, lipid synthesis, and cell growth by phosphorylating downstream targets like S6 kinase (S6K) and 4E-BP1.
While acute mTORC1 activation supports growth and repair (e.g., muscle growth after exercise), chronic activation, driven by persistent hyperinsulinemia, disrupts metabolic homeostasis. Factors like excessive calorie intake, refined carbohydrates, and sedentary lifestyles exacerbate insulin spikes, keeping mTORC1 in a perpetually active state.
Chronic mTOR activation and metabolic syndrome
Metabolic syndrome is characterized by insulin resistance, obesity, dyslipidemia, and hypertension, all of which are linked to chronic mTOR activation. Here’s how sustained mTORC1 activity contributes:
Insulin resistance: Chronic mTORC1 activation creates a feedback loop that worsens insulin resistance. mTORC1 phosphorylates S6K, which in turn phosphorylates IRS-1 at inhibitory sites, reducing insulin signaling efficiency. This forces the pancreas to secrete more insulin, further stimulating mTORC1.
Lipogenesis and obesity: mTORC1 promotes lipid synthesis by activating sterol regulatory element-binding protein 1 (SREBP1), which upregulates genes involved in fatty acid and cholesterol synthesis. This leads to fat accumulation, particularly visceral fat, a key feature of metabolic syndrome.
Inflammation: mTORC1 enhances the production of pro-inflammatory cytokines like IL-6 and TNF-α, contributing to systemic inflammation, a driver of metabolic syndrome.
Dyslipidemia: By promoting lipogenesis and inhibiting lipid breakdown, mTORC1 increases circulating triglycerides and lowers HDL cholesterol, hallmarks of metabolic syndrome.
These effects create a vicious cycle where hyperinsulinemia and mTORC1 activation reinforce each other, accelerating metabolic dysfunction.
mTOR and chronic diseases
Chronic mTOR activation, fueled by hyperinsulinemia and metabolic syndrome, is implicated in several diseases:
1. Non-alcoholic fatty liver disease (NAFLD)
NAFLD, characterized by excessive fat accumulation in the liver, is closely linked to insulin resistance and mTORC1. mTORC1 promotes de novo lipogenesis in hepatocytes via SREBP1, leading to triglyceride accumulation. Chronic activation also impairs autophagy, a process that clears damaged organelles and lipids, exacerbating liver steatosis. Over time, NAFLD can progress to non-alcoholic steatohepatitis (NASH), fibrosis, and cirrhosis.
2. Cardiovascular disease
mTORC1 contributes to atherosclerosis and heart disease through multiple mechanisms:
Dyslipidemia: Elevated triglycerides and LDL cholesterol, driven by mTORC1-mediated lipogenesis, promote plaque formation in arteries.
Vascular dysfunction: mTORC1 induces endothelial dysfunction by increasing oxidative stress and reducing nitric oxide availability, impairing vasodilation.
Hypertension: Chronic mTORC1 activation promotes vascular smooth muscle proliferation, contributing to arterial stiffness and high blood pressure.
These factors increase the risk of heart attacks and heart failure.
3. Stroke
Stroke risk is elevated in metabolic syndrome due to mTORC1-driven vascular pathology. Atherosclerosis, hypertension, and inflammation—all exacerbated by mTORC1—can lead to ischemic stroke by obstructing cerebral blood flow. Additionally, mTORC1-mediated hyperglycemia impairs cerebral autoregulation, increasing vulnerability to stroke.
4. Cancer
mTORC1 is a master regulator of cell growth and proliferation, making it a key player in cancer. Chronic activation promotes:
Uncontrolled cell growth: mTORC1 enhances protein synthesis and cell cycle progression, driving tumor growth.
Angiogenesis: mTORC1 upregulates vascular endothelial growth factor (VEGF), supporting tumor blood supply.
Metabolic reprogramming: mTORC1 shifts cancer cell metabolism toward glycolysis (the Warburg effect), providing energy and building blocks for rapid proliferation.
Hyperinsulinemia, often present in metabolic syndrome, further amplifies these effects, increasing the risk of cancers like breast, colorectal, and pancreatic cancer.
5. Alzheimer’s disease
Alzheimer’s disease, sometimes called “type 3 diabetes,” is linked to insulin resistance and mTORC1 dysregulation in the brain. Chronic mTORC1 activation:
Impairs autophagy: Reduced autophagy leads to the accumulation of amyloid-beta plaques and tau tangles, hallmarks of Alzheimer’s.
Promotes neuroinflammation: mTORC1-driven cytokine production exacerbates neuronal damage.
Disrupts synaptic plasticity: Hyperactive mTORC1 impairs synaptic function, contributing to cognitive decline.
Hyperinsulinemia also reduces insulin transport across the blood-brain barrier, starving neurons of insulin’s neurotrophic effects.
6. Mental illness
mTORC1 dysregulation is implicated in mental illnesses like depression, anxiety, and schizophrenia. Chronic activation disrupts:
Neurotransmitter balance: mTORC1 affects glutamate and serotonin signaling, altering mood and cognition.
Synaptic plasticity: Excessive mTORC1 activity impairs synaptic pruning and plasticity, contributing to psychiatric disorders.
Neuroinflammation: Inflammatory cytokines, upregulated by mTORC1, are linked to depression and anxiety.
Insulin resistance in the brain may also reduce neurotrophic support, exacerbating mental health issues.
Strategies to mitigate mTOR overactivation
Given the role of chronic mTOR activation in disease, strategies to modulate insulin and mTOR signaling are critical:
1. Dietary interventions
Low-carbohydrate diets: Reducing refined carbohydrates and sugars lowers insulin spikes, decreasing mTORC1 activation.
Intermittent fasting: Fasting periods inhibit mTORC1 and promote autophagy, counteracting chronic activation.
Ketogenic diets: By minimizing insulin secretion, ketogenic diets reduce mTORC1 activity and improve metabolic health.
2. Exercise
Resistance and aerobic exercise enhance insulin sensitivity, reducing hyperinsulinemia. Exercise also activates AMP-activated protein kinase (AMPK), a natural inhibitor of mTORC1.
3. Pharmacological approaches
Metformin: This diabetes drug activates AMPK, inhibiting mTORC1 and improving insulin sensitivity.
Rapamycin: An mTOR inhibitor, rapamycin shows promise in preclinical studies for aging-related diseases, though its clinical use is limited by side effects.
4. Sleep and stress management
Poor sleep and chronic stress elevate cortisol, which worsens insulin resistance. Prioritizing sleep and stress reduction supports metabolic health.
5. Regular monitoring
Routine measurement of fasting insulin, HOMA-IR, and other metabolic markers can guide interventions to prevent mTOR-driven diseases.
Conclusion
Insulin is more than a glucose regulator; it is a powerful driver of the mTOR pathway, which, when chronically activated, contributes to metabolic syndrome and a spectrum of diseases, including fatty liver, heart disease, stroke, cancer, Alzheimer’s, and mental illness. Measuring insulin levels is a proactive step to detect early metabolic dysfunction and guide interventions. By addressing hyperinsulinemia and mTOR overactivation through lifestyle changes, exercise, and targeted therapies, individuals can mitigate the risk of these chronic conditions. As research continues to unravel the insulin-mTOR axis, personalized strategies to modulate this pathway will be key to promoting long-term health.
Read more from Dr. Trevor Miller and Jessica Miller, RN
Dr. Trevor Miller and Jessica Miller, RN, Integrated Health of Indiana
Dr Miller and Nurse Jessica have dedicated their professional lives to helping people live their best lives. Concentrating on healing from the inside out, they use a program to comprehensively address problems with hormones, foundational gut health, the microbiome, and mitochondrial health. Realizing that these are all tied together and addressing them as a whole leads to happier and healthier patients.
