Are We Missing a Major Driver of Chronic Immune Inflammation?
Dr. Greg Fors, Chief Science Officer, BioSpec Nutritionals
Autoimmune disease is becoming one of the major chronic health problems of our time. Hashimoto's thyroiditis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, multiple sclerosis and other autoimmune disorders affect millions of people, and evidence shows that the burden of autoimmunity is increasing in many parts of the world.[1,2] Why?
Our genes have not changed in a few generations. Our environment has. Our food has. Our metabolism has.
At the same time that autoimmune disease has increased, we have developed an enormous epidemic of obesity, visceral adiposity, insulin resistance and metabolic dysfunction. I believe we are missing an important connection.
What if insulin resistance isn't simply occurring alongside autoimmune disease? What if it is helping create the biological environment that allows autoimmune inflammation to persist?
That question becomes even more important when we consider the treatments many autoimmune patients eventually require.
WHY THIS MATTERS: AUTOIMMUNE DRUGS ARE NO EASY RIDE
Modern medications have transformed the treatment of severe autoimmune disease. Biologics, conventional disease-modifying drugs, corticosteroids and newer targeted therapies can control destructive inflammation and, in some patients, prevent serious disability and organ damage.
But powerful drugs can come with powerful biological consequences. Many of these medications intentionally alter or suppress portions of the immune response. Depending upon the drug, important adverse effects can include serious infections, reactivation of latent infections, liver abnormalities, blood-cell abnormalities and other systemic complications. Certain agents and classes also carry warnings concerning malignancies.
That doesn't mean these drugs should not be used. Sometimes they are absolutely necessary.
But wouldn't it be better if we could also reduce the biological forces helping drive the patient's inflammatory disease?
I have spent decades working with chronically ill patients, and I have seen what can happen when we aggressively address diet, metabolic dysfunction, gastrointestinal health, nutritional deficiencies, inflammation, sleep, exercise and other contributors to the patient's total biological burden. Some patients improve enough that their prescribing physicians are eventually able to discontinue or at least reduce medication requirements. In selected patients with sustained disease control, medication tapering is already part of conventional rheumatologic management.[10]
That is an important goal. The goal is not to tell patients to stop their medications. They should never discontinue a biologic, corticosteroid or disease-modifying drug without working with the clinician managing that medication.
The goal is to make the patient healthier.
But there is another group of patients where I believe we may have an even greater opportunity: the patient who has not yet developed a diagnosable autoimmune disease.
THE POSITIVE ANA PATIENT: A WINDOW OF OPPORTUNITY?
In my practice, I routinely include an antinuclear antibody ANA panel as part of my broader evaluation. When I find an elevated ANA, I don't automatically tell that patient they have lupus, rheumatoid arthritis or another autoimmune disease. A positive ANA is not a diagnosis.
But I don't automatically ignore it either. I look harder. Does the patient have unexplained fatigue, migrating aches, joint or muscle pain, rashes, dry eyes or mouth, thyroid abnormalities, gastrointestinal problems, neurological symptoms or other patterns suggesting immune dysregulation?
Then I look carefully at the family history. Is there lupus? Multiple sclerosis? Hashimoto's disease? Rheumatoid arthritis? Sjögren's? Psoriasis? Inflammatory bowel disease? Another autoimmune condition in a parent, sibling, grandparent or child?
Then I look at the rest of the biological terrain. Is hs-CRP elevated? Is the sedimentation rate elevated? What does fibrinogen look like? Is there insulin resistance? Visceral adiposity? Dyslipidemia? Dysbiosis? Intestinal permeability? Poor sleep? Chronic stress? Nutritional insufficiency? Significant environmental burden? Now the ANA begins to have context.
THIS MAY BE PRECLINICAL AUTOIMMUNITY
What I have observed clinically actually fits an established concept in immunology: preclinical autoimmunity. Autoimmunity does not necessarily begin the day someone receives a diagnosis.
In diseases such as systemic lupus erythematosus, Sjögren's syndrome and rheumatoid arthritis, autoantibodies can be detectable years before the patient develops enough symptoms and tissue involvement to meet diagnostic criteria. In SLE, autoantibodies have been documented more than nine years before diagnosis in some patients.[14-17] This is critically important.
It means there can be a biological period between normal immune tolerance and established autoimmune disease.
Some researchers have described an early stage as "benign autoimmunity" or "latent autoimmunity." The person has developed measurable autoreactivity, but clinical autoimmune disease has not yet emerged.[14-17]
Even more interesting, research comparing ANA-negative healthy individuals, ANA-positive healthy individuals and patients with lupus has demonstrated progressive differences in immune signaling. Several inflammatory cytokines, including TNF, IL-17 and interferon-γ, showed a stepwise increase from ANA-negative controls to ANA-positive healthy individuals and finally to patients with SLE.[18] In other words:
ANA positive does not necessarily mean autoimmune disease, but it may mean something biologically important is already happening.
Family history adds another piece of information. Healthy relatives of patients with autoimmune diseases have increased rates of autoantibody positivity, and investigators have identified clinically unaffected relatives who remain in a state of latent autoimmunity without progressing to diagnosable disease.[19] That fits what I have repeatedly observed in clinical practice.
I have seen patients with positive ANA testing who have no diagnosable autoimmune disease but have a striking family history of autoimmunity. I have seen the same pattern within families across generations.
Does that mean every ANA-positive patient with a family history of an autoimmune disease is destined to develop autoimmune disease? Of course not.
That is precisely what makes this so interesting. Some people apparently maintain this state of immune autoreactivity for decades without progressing to tissue-destructive autoimmune disease. Others move from autoantibody production to additional immune abnormalities, symptoms, inflammation and eventually diagnosable disease.
The clinically important question is: what determines which direction that patient goes?
We don't completely know. But this is where personalized lifestyle medicine becomes extraordinarily interesting.
If I have an ANA-positive patient with a strong family history of autoimmunity who is overweight, insulin resistant, metabolically inflamed, sleeping poorly, eating an ultra-processed diet, experiencing chronic stress and showing additional inflammatory abnormalities, I am not waiting for that patient to develop lupus, Hashimoto's disease or rheumatoid arthritis before I start improving their physiology.
That patient has just given me a window of opportunity. I cannot promise that changing their lifestyle will prevent an autoimmune disease. Nobody can.
But I can reduce the biological burden that may be pushing a genetically susceptible immune system in the wrong direction.
That is prevention.
And this is exactly where the metabolic evaluation becomes so important.
INSULIN IS MORE THAN A BLOOD-SUGAR HORMONE
We commonly evaluate glucose while paying far less attention to insulin. That is a mistake.
A patient can maintain a relatively normal fasting glucose and even a reasonable hemoglobin A1c for years by producing progressively larger amounts of insulin. The glucose looks acceptable because the pancreas is working overtime.
By the time glucose becomes obviously abnormal, metabolic dysfunction may have been developing for years, even decades.
This matters in autoimmune disease because insulin resistance rarely travels alone. It commonly travels with visceral adiposity, altered adipokines, elevated free fatty acids, oxidative stress, mitochondrial dysfunction and chronic inflammatory signaling. The result is not simply a glucose problem.
It is an altered immunometabolic environment.
THE METABOLIC-IMMUNE FEEDBACK LOOP
Immune cells require enormous amounts of energy when activated. Their metabolism influences their behavior and inflammatory signaling.
At the same time, insulin-resistant adipose tissue is not simply stored fat. Enlarged and dysfunctional adipocytes become metabolically and immunologically active. They attract macrophages and other immune cells and generate inflammatory mediators. Cytokines such as TNF-α and IL-6 can then further interfere with insulin signaling. Now we have a vicious cycle:
Insulin resistance → metabolic dysfunction → inflammatory signaling → worsening insulin resistance → additional immune activation.
Autoimmune inflammation can worsen metabolic dysfunction, while metabolic dysfunction can help maintain an inflammatory environment. This is why I do not look at these disorders as isolated diseases.
The immune system, metabolism, gut, mitochondria, endocrine system and nervous system are talking to one another continuously.
Treating one while ignoring the others can mean missing much of the physiology.
BLOOD-SUGAR SPIKES MATTER TOO
It is not only fasting glucose. Large glucose spikes increase oxidative stress, mitochondrial reactive oxygen and nitrogen species, endothelial dysfunction and inflammatory signaling. Repeated glucose excursions can generate significant oxidative and inflammatory stress.[3,4] In other words, tissue damage!
One high-carbohydrate meal does not cause Hashimoto's disease, rheumatoid arthritis or lupus. That is not the point. Remember:
Genetics loads the gun. Environment pulls the trigger.
The better clinical question is:
What happens when a genetically susceptible person experiences large glucose and insulin excursions several times a day, seven days a week, year after year, while simultaneously carrying visceral fat, sleeping poorly, eating ultra-processed foods, experiencing chronic stress, developing intestinal dysbiosis and encountering environmental toxicants?
Each factor can add another log to the fire. Eventually there may be enough logs burning that the body's regulatory systems can no longer keep the fire under control.
OBESITY IS AN IMMUNE CONDITION AS WELL AS A METABOLIC CONDITION
This connection has become increasingly difficult to ignore. A 2026 systematic review and meta-analysis found obesity associated with a 41% higher incidence of autoimmune disease overall compared with normal weight. Significant associations were also reported for rheumatoid arthritis, psoriasis, multiple sclerosis and Crohn's disease/ulcerative colitis.[5]
Earlier research has similarly connected obesity with several autoimmune disorders, including Hashimoto's thyroiditis.[6] Autoimmune disease is multifactorial. There is rarely one cause.
But we should stop treating metabolic dysfunction as an unrelated side issue in the autoimmune patient.
If the patient is insulin resistant, metabolically inflamed and carrying excessive visceral fat, that physiology deserves treatment.
DON'T JUST CHECK GLUCOSE, CHECK INSULIN
One of the simplest clinical changes we can make is to identify metabolic dysfunction earlier. I routinely consider:
Fasting glucose • Fasting insulin • Hemoglobin A1c • HOMA-IR • Triglycerides • HDL • Triglyceride/HDL ratio • Waist circumference/visceral adiposity • Postprandial glucose when appropriate
HOMA-IR
HOMA-IR is easily calculated:
HOMA-IR = Fasting glucose mg/dL × fasting insulin µIU/mL ÷ 405
For example:
Glucose = 90 mg/dL
Insulin = 5 µIU/mL
90 × 5 ÷ 405 = HOMA-IR 1.11
In my functional medicine practice, I am not waiting until the patient crosses a laboratory threshold for obvious insulin resistance. I want to identify metabolic dysfunction while it is developing. As practical optimization targets, I generally like to see:
Fasting insulin: around ≤5 µIU/mL
HOMA-IR: approximately 1.0 or below
Everyone is an individual, and these are clinical optimization targets rather than universal diagnostic cutoffs. But they give us useful goals when we are looking for early metabolic dysfunction.
TRIGLYCERIDES AND THE TRIGLYCERIDE/HDL RATIO
Here is another early metabolic clue that is sitting on almost every standard lipid panel. Watch the triglycerides.
When fasting triglycerides begin pushing toward 150 mg/dL, I immediately become concerned about insulin resistance and carbohydrate intolerance. In metabolic optimization, I would much rather see fasting triglycerides closer to 100 mg/dL or below.
But triglycerides become even more informative when we look at them alongside HDL. One of the classic patterns of insulin resistance is:
Triglycerides go UP while HDL goes DOWN.
That is why I pay close attention to the triglyceride-to-HDL cholesterol ratio (TG/HDL-C). As a practical clinical guide:
Around 2/1 TG/HDL or below: metabolically favorable.
2-3: start paying attention, particularly when fasting insulin, waist circumference, blood pressure or glucose is also moving in the wrong direction.
Above approximately 3: increasingly suspicious for insulin resistance and atherogenic dyslipidemia, particularly when accompanied by elevated triglycerides, low HDL, visceral adiposity or elevated fasting insulin.
The exact threshold varies by sex, ethnicity and population, so I do not diagnose insulin resistance from this ratio alone. I use it as another piece of the metabolic fingerprint.
A patient can have a "normal" fasting glucose while fasting insulin, HOMA-IR, triglycerides, TG/HDL ratio and waist circumference are already telling a very different story. That is the patient I want to identify before diabetes develops.
THE ENVIRONMENT ADDS MORE LOGS TO THE FIRE
Metabolism is only one piece of the story.
Diet. Insulin resistance. Visceral adiposity. Dysbiosis. Increased intestinal permeability. Micronutrient deficiencies. Oxidative stress. Poor sleep. Chronic psychological stress. Smoking. Infections. Environmental chemicals. Pesticides and other occupational exposures. They do not occur independently inside the patient. They accumulate.
Research has associated certain pesticide exposures with autoimmune disease, including an association between insecticide exposure and rheumatoid arthritis.[9]
But clinically, I am interested in the larger question:
What is the patient's total biological burden?
I sometimes describe this as the biological soup or milieu surrounding the patient's cells. The body can compensate for an enormous amount of physiological stress, until it cannot.
Again, genetics loads the gun; environment pulls the trigger.
When enough factors accumulate, the total biological burden may exceed that individual's ability to maintain normal metabolic and immune regulation. Again:
Each factor can add another log to the fire.
THE FUNCTIONAL MEDICINE OPPORTUNITY
This changes how I look at an autoimmune patient. Yes, identify the autoimmune disease. Yes, use appropriate conventional treatment when necessary.
But don't stop there.
Ask why this patient's genetic susceptibility is now being expressed in this moment, in this biological environment.
If fasting insulin is 15 µIU/mL, HOMA-IR is elevated, triglycerides are climbing, HDL is falling, the patient carries substantial visceral adiposity and every meal produces a large glucose excursion, I do not consider those findings incidental because the diagnosis happens to be Hashimoto's or rheumatoid arthritis.
Those are therapeutic targets.
Lifestyle remains the foundation. Remove ultra-processed foods, added sugars and refined/ground carbohydrate products. Emphasize nutrient-dense whole foods, adequate protein, non-starchy vegetables, nuts and seeds. Build and maintain skeletal muscle. Move after meals. Improve sleep. Address chronic stress. Restore gastrointestinal health when necessary. Correct nutrient deficiencies. Reduce unnecessary environmental exposures.
Remove the logs from the fire.
TARGETED NUTRITIONAL SUPPORT: SUPPORT THE PHYSIOLOGY
Nutraceuticals should not be presented as replacements for appropriate autoimmune medical care, and they cannot compensate for a destructive lifestyle. They can, however, provide targeted physiological support while we change that lifestyle.
For a patient with insulin resistance, botanical compounds such as berberine, mulberry leaf, Gymnema sylvestre, cinnamon extract and banaba can support glucose and insulin metabolism. These are among the metabolic botanicals incorporated into Biospec Glucose-IR.
BioSpec Glucose-IR provides structure-function support for healthy glucose metabolism and insulin activity.
For the inflammatory component, curcumin and Boswellia serrata have human evidence supporting effects on inflammatory pathways and biomarkers. Curcumin research, including randomized trials and meta-analyses, has reported reductions in inflammatory markers including CRP and TNF-α.[11-13] These botanicals form part of the rationale behind Biospec Inflam-95.
BioSpec Inflam-95 provides structure-function support for healthy inflammatory pathways and a balanced inflammatory response.
Oxidative stress and mitochondrial dysfunction are another part of the biological terrain. Nutrients including N-acetylcysteine, R-alpha-lipoic acid, acetyl-L-carnitine and CoQ10 can be used to support antioxidant defense and mitochondrial physiology. These are combined in Biospec Mito-Detox III.
BioSpec Mito-Detox III provides structure-function support for antioxidant defenses, mitochondrial energy production, and cellular detoxification pathways.
Notice the sequence:
Lifestyle first. Targeted nutrition second. Nutraceutical support layered onto the physiology.
We are not looking for a supplement that "cures autoimmunity." We are trying to create a healthier human being.
CHANGE THE TERRAIN
Autoimmune disease is not simply an immune-system problem. For most patients it is occurring in the middle of metabolic dysfunction, chronic inflammation, gastrointestinal dysfunction, oxidative stress, mitochondrial stress, environmental burden and poor lifestyle. The personal environment that pulls the trigger!
These systems interact. That is why measuring glucose alone isn't enough.
Look at insulin. Calculate HOMA-IR. Look at triglycerides and HDL. Look at visceral adiposity. Look at the patient's diet. Look at the gut. Look at inflammation. Look at sleep. Look at stress. Look at the environment.
Then start changing what you can change. The patient may still require medication. Some absolutely will.
But our therapeutic ambition should extend beyond controlling symptoms with increasingly powerful drugs.
Improve the terrain. Reduce the inflammatory burden. Improve metabolic health. Give the body's regulatory systems a better environment in which to function.
And when a patient achieves sustained disease control, their prescribing physician can determine whether medication requirements can safely be reduced.
That is a far different goal than simply watching the disease progress and adding another medication.
Each factor can add another log to the fire.
Our job is to start taking the logs away.
Bottom Line
Insulin resistance should be evaluated as part of the broader immunometabolic environment rather than treated as an isolated glucose problem. For clinicians, assessing insulin, HOMA-IR, lipid patterns, visceral adiposity, inflammation, sleep, stress, gut health, and mitochondrial physiology may provide a more complete picture of the patient's biological terrain. Lifestyle remains foundational, while targeted nutritional support can be considered as part of a broader, clinician-guided plan.
Comprehensive Medical Disclaimer
This article is for educational purposes only and is not medical advice, diagnosis, or treatment. It is not a substitute for evaluation and care from a qualified healthcare professional. Do not start, stop, or change prescribed medication or treatment without consulting the clinician managing your care. Dietary supplements are not intended to diagnose, treat, cure, or prevent any disease. Individual results vary.
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