It says right there in the title – “Is insulin resistance the cause of fibromyalgia? A preliminary report” – it’s a preliminary report, but definitely an interesting one.

In fact, the authors have stated that if the findings are validated, they could lead to a “revolutionary shift” in the way fibromyalgia and related forms of chronic pain (that includes chronic fatigue syndrome (ME/CFS)) are treated. They stated that the new approach “has the potential to save billions of dollars to the health care system and decrease many people’s dependence on opiates”. (Not to mention improve many people’s health and wellbeing :))

Someone is excited…

The study results basically come down to the inability to interpret a rather common lab test correctly.  The findings suggest fibromyalgia could be a form of pre-diabetes that could, in some cases, be treated with readily available diabetes medications. (No wonder they’re excited.)

The Study

Is insulin resistance the cause of fibromyalgia? A preliminary report. Miguel A. Pappolla, Laxmaiah Manchikanti, Clark R. Andersen, Nigel H. Greig, Fawad Ahmed, Xiang Fang, Michael A. Seffinger, Andrea M. Trescot, Published: May 6, 2019, https://doi.org/10.1371/journal.pone.0216079


A small study suggested that metformin – a drug that reduces insulin (pictured here) resistance – might be helpful in fibromyalgia

This small, rather simple retrospective study analyzed insulin resistance (HbA1c test), the use of metformin – a drug used to treat insulin resistance (IR), and pain levels in 23 patients who’d been referred to a pain clinic for widespread myofascial pain (and met the criteria for fibromyalgia).

(Because this was a retrospective study, there was no healthy control group. Instead, the researchers used two independent healthy control populations to get normative values for the HbA1c test.)

Diabetes occurs when the body is unable to metabolize carbohydrates (glucose) properly, leading to high glucose levels in the blood. Insulin, a hormone, allows glucose to enter the cells and produce energy. It also helps break down fats and proteins for energy. When too little insulin is present, or if the insulin receptors on the cells don’t respond to it, glucose will build up in your blood, causing problems.

Over time, insulin resistance and the high glucose levels in diabetes can have nasty effects including eye (retinopathy), kidney (nephropathy), and nerve (neuropathy) problems. Those neuropathy problems include small fiber neuropathy (which is found in fibromyalgia), ME/CFS, GWI, POTS and diabetes.

The authors noted that because their clinic aggressively treats pre-diabetic conditions (HbA1c values of 5.7 or higher), they had data on metformin usage (500 mg twice a day).  In fact, they had quite a bit of data as many of the people with fibromyalgia in this sample were classified as having pre-diabetes. They used the Numeric Pain Rating Scale (NPRS) to assess pain levels every time a patient visited the clinic.



After adapting for age, the HbA1c levels were significantly elevated in the FM patients (green)

The study found highly significant associations between fibromyalgia and increased HbA1c test scores relative to the two test populations (p < 0.0001 and p < 0.0002). That suggested that, at least in this group, the increased HbA1c findings in FM were real, and that insulin resistance or pre-diabetes was present.

The group which received standard treatments, but not metformin, did improve – indicating that the clinic’s pain protocol (consisting generally of norepinephrine reuptake inhibitors (amitriptyline, duloxetine or milnacipran) and/or membrane stabilizing agents (gabapentin or pregabalin)) was helping.

The patients on metformin did much better, though. In fact, the metformin completely resolved the pain of half (8/16) of the FM patients, and some patients only responded to metformin. Plus, the metformin treatment seemed to stick over time.

Misinterpreting HbA1c – A Common Mistake?

metformin fibromyalgia

Pain levels decrease the most when metformin (red) is added to the standard treatment (blue) and compared to baseline (green)

Why hasn’t this simple, rather common test been linked to fibromyalgia before? Possibly because of a mistake the authors propose labs and doctors are regularly making: not accounting for age when assessing HbA1c levels. They noted that the HbA1c values in many of their patients with FM would be considered to be within the normal range.

HbA1c levels, however, rise over time, even in healthy people. Because standard HbA1c norms apparently reflect an older population, the higher values used may understate the extent of pre-diabetes in younger patients. Age-stratifying the clinic’s FM patients indicated that many of them actually had high HbA1c levels. (This was not a particularly young group: just 3 were in their mid-30’s and most were in their 40’s and 50’s).

That’s a pretty important distinction to miss, given that pre-diabetes carries a higher risk for: a) diabetes; b) peripheral neuropathies; c) cardiovascular problems; d) neurological diseases, and, to top it off; e) all-cause mortality…


Metformin is a first line drug for type II diabetes. It has been suggested for FM before, but for its mitochondrial enhancing effects, not its impact on glucose. Numerous studies suggest that mitochondrial problems exist in FM, and several animal studies suggest that metformin may, by increasing mitochondrial and antioxidant activity, reduce pain. One study suggests that FM patients with mitochondrial problems may fare well on metformin. A Canadian metformin FM study has reportedly been completed.

“Patients with FM presenting with low levels of phosphorylated AMPK and inflammasome activation in BMCs, subjected to long-term treatment with metformin, improved both pain and FM-associated symptoms.” Bullon

This same inflammasome, by the way, is found in type 2 diabetes. (Inflammasomes are intracellular immune complexes which respond to pathogens and other stressors by producing inflammatory cytokines.)

Pre-diabetes, Fibromyalgia and Chronic Fatigue Syndrome (ME/CFS) (???)

This isn’t the first study to suggest that insulin resistance might be present in FM and/or ME/CFS. A 2003 study found high rates of fibromyalgia in diabetes. High rates of insulin resistance – associated with cognitive issues – were also found in a 2013 FM study.

The pre-diabetes connection may not be as far out as one might suspect. Neil McGregor in Australia and Chris Armstrong of the Open Medicine Foundation have speculated that insulin resistance might be present in ME/CFS.  Ron Davis has suggested that, depending on how the science ends up, ME/CFS could end up in the National Institute of Diabetes and Digestive and Kidney Diseases at the NIH (NIDDK). If these researchers are right, fibromyalgia will probably get there first.

Marco, a patient, latched onto the diabetes question in his 2014 Health Rising blog: “The Energy Disorders: Diabetes, ME/CFS and FM – Can Diabetes Tell Us Anything About Chronic Fatigue Syndrome and Fibromyalgia?”

He pointed out that untreated diabetes is, by definition, “a state of energy deficiency” and that diabetes is a spectrum disorder of which six different types may exist. He related a number of intriguing possible connections between fibromyalgia, ME/CFS and diabetes:

  • People with type II diabetes also suffer from fatigue, early onset of muscle pain, exercise intolerance, and delayed recovery.
  • Similar patterns of reduced oxygen uptake during exercise have been found in ME/CFS patients and in Type II diabetics.
  • Low heart rate variability (HRV) (enhanced sympathetic nervous system activity) has been found in all three diseases.
  • Reduced natural killer cell functioning – a hallmark of ME/CFS – has been found.
  • Cognitively, similar issues of executive functioning are present.
  • Small fiber neuropathy is found in FM, ME/CFS, POTS and diabetes.

Plus, we can now add two more possible commonalities:

  • Poor microcirculation – because insulin interacts with arterioles and precapillary arterioles to increase blood flow to the tissues, insulin resistance could impair the microcirculation, which studies suggest may be impaired in FM and ME/CFS.
  • Poor red blood cell deformability – insulin resistance is also associated with red blood cell deformability problems and increased blood viscosity (thickness) – both of which may be present in ME/CFS. In order for the red blood cells to get through the tiny capillaries and provide oxygen to the tissues, they have to be able to deform. If they can’t do that and/or the blood is too thick, our microcirculation may suffer, resulting in hypoxia (low oxygen levels), high lactate levels (lactic acidosis), and low energy production.

The Energy Disorders: Diabetes, ME/CFS and FM – Can Diabetes Tell Us Anything About Chronic Fatigue Syndrome and Fibromyalgia?

Neil McGregor, an Australian metabolomic’s researcher, reported that while his data suggests that a third of ME/CFS patients have insulin resistance, most actually have a form of hyperinsulinemia, which refers to excess levels of insulin.  While hyperinsulinemia is often found in type II diabetes, it does not cause it, and is more often found in metabolic syndrome. It’s clear that much remains to be learned about the role insulin may play in ME/CFS.

A FM/Type II Diabetes (and Alzheimer’s) Connection?

To make one more potential connection: several studies have linked type II diabetes with (ouch) Alzheimer’s. In fact, some call Alzheimer’s “Diabetes of the Brain” or Type III diabetes.

A 2017 paper hypothesized that problems with red blood cell morphology, deformability, and function and high rates of oxidative stress – that help produce insulin resistance in the brain – tie the two disorders together. That’s an interesting trifecta, given that red blood cell problems and oxidative stress have already been found in ME/CFS and FM, and insulin resistance might be added to the list.  (One study suggests that the rate of dementia may be somewhat increased in FM.)

Is the Fibro-fog in Fibromyalgia a Prelude to Dementia?

Intranasal insulin (a spray) to pump up the insulin levels in the brain is another possibility.  Researchers were awarded $1.7 million to see if intranasal insulin helps with cognitive and other ‘multi-symptom’ problems in Gulf War Illness. Intranasal insulin is also being trialed in Alzheimer’s and Parkinson’s disease.


This was a quite small study and people with ME/CFS, in particular, have become acquainted with the hazards of those. Much larger studies are needed to determine if high levels of age-dependent HbA1c are present in FM (or ME/CFS). Large placebo-controlled, double-blinded studies are needed to assess the effectiveness of metformin in reducing pain.

Physical inactivity and obesity – both of which can be present in FM and ME/CFS – can lead to insulin resistance. (The authors could have but did not assess if BMI made a difference.) Exercise, by the way, if FM patients can handle it, is highly recommended for IR and can ameliorate it.


In a small retrospective study, University of Texas researchers found high rates of age-adjusted HbA1c levels in fibromyalgia, signifying that pre-diabetes may be common, and, if their sample population reflects the population at large, possibly massively underdiagnosed in FM. The authors noted that if the HbA1c values in their patients had not been adjusted for their age, most of them would have been normal.

metformin fibromyalgia

Could metformin work in FM? It looked very good in this preliminary study. Bigger studies will hopefully tell us more.

Treatment with metformin – a first-line drug for type II diabetes – resulted in significant and long term reductions in pain. Half of the cohort (n=16) reportedly completely recovered.  Because metformin also enhances mitochondrial and antioxidant production, it may be helpful in several ways.

Diabetes, FM and ME/CFS do share some interesting commonalities including problems with energy production, small fiber neuropathy, fatigue, exercise intolerance, cognitive issues, red blood cell deformity and possibly problems with the microcirculation.

The results are enticing, but much larger studies are needed to assess the incidence of altered HbA1c levels, metformin’s effects on pain, and the role physical inactivity and/or obesity might play in the IR found in FM.

Have you tried metformin?


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