Uncommon Forms of Insulin Resistance Often Hide in Plain Sight

Uncommon forms of insulin resistance with unusual root causes often hide in plain sight.

Learn how to detect and treat them, and you can have a profound positive impact on your patients’ lives, often saving them months, even years of frustration, said Heba Elnazer, MD, at the 2018 Integrative Healthcare Symposium.

Heba Elnazer IHS2018“Almost anything can cause insulin resistance. It is not just overweight and obesity. Inflammation causes it, aging causes it, PCOS and high androgen states, pituitary tumors and high prolactin levels, chronic liver or kidney disease…. all of these things can lead to states of insulin resistance,” said Dr. Elnazer, director of the Revive Medical Center, a membership-based functional medicine practice in Al Qahirah, Egypt.

These other less obvious causes are easily overlooked, especially in today’s clinical world of 10-minute office visits and high volume practice. But even in holistic and functional medicine practices, clinicians can fall prey to a sort of tunnel vision that precludes them from seeing the problem in patients that don’t fit the typical “metabolic syndrome” profile.

Three Subtypes

In the simplest of terms, insulin resistance is a state in which a greater than normal amount of insulin is required to elicit a quantitatively normal response to a glucose load. Dr. Elnazer defined three subtypes, differentiated by the particular factors underlying the blunted insulin response.

Type A is characterized by defects of the insulin receptors themselves. In these cases, insulin binding is impaired, thus diminishing the transport of glucose.

Type B reflects autoimmune attack on the insulin receptors, via autoantibodies. The net result—attenuation of glucose absorption and hyperglycemia—is the same as in Type A, but the cause is different.

Type C is caused by defects of tyrosine kinase or glucose transport molecules. In these cases, the insulin receptors may be normal, and insulin binding proceeds properly, but the downstream intracellular signal is impaired. 

To manage insulin resistance well, you need to figure out where in the signal chain the problem occurs, Dr. Elnazer told the IHS attendees. “If you don’t actively look for these types, you will likely miss them.”

Pre-receptor defects might reflect abnormal insulin mutations, abnormalities of insulin production, or the development of anti-insulin antibodies.

Receptor abnormalities may result from reduced numbers of insulin receptors, reduced insulin binding capacity, mutations resulting in abnormal receptor morphology, or autoantibodies to the otherwise normal receptors.

Post-receptor problems are related to defective signal transduction or mutations of the GLUT-4 (glucose transporter type 4) vesicles within the cells.

These distinctions may seem academic or theoretical, but Dr. Elnazer contends that they have great clinical significance, because they will affect a patient’s likelihood of responding to the most common treatment modalities.

The typical functional medicine approach–dietary changes (low glycemic index, low fructose, low carb, high vegetable intake), supplementation to enhance glucose metabolism and raise beneficial lipid and fatty acid levels, treatments aimed at lowering triglycerides–will usually work for simple, uncomplicated forms of insulin resistance.

But it wont work well for Type A or B, in which there are defects of the insulin receptors or there are autoantibodies to insulin.  

IR in Normal Weight Patients

In contrast to the “classic” insulin resistance in an overweight person, people with Type A insulin resistance (characterized by receptor defects) are usually normal weight or even lean. This form disproportionately affects adolescent and young adult women. Roughly 3% have polycystic ovary syndrome or some other form of hyperandrogenism. In males, hypoglycemia may be the only manifestation.

Dr. Elnazer said that Type A is very easy to miss, because most clinicians are not cued to think about insulin resistance in lean people. And even in young women who show obvious signs of PCOS, many clinicians become narrowly focused on the hyperandrogenism and miss the insulin abnormalities.

Patients with Type B (anti-receptor antibodies) usually show signs of other autoimmune conditions such as lupus, Hashimoto’s thyroiditis, or rheumatoid arthritis. They are likely to be overweight or obese, with low fasting blood glucose levels but high hemoglobin A1c levels. They frequently experience episodes of hypoglycemia that range from mild to extreme.

Paradoxically, Type B is easy to miss as well. Because these patients are usually overweight, some physicians focus narrowly on that aspect of the condition and miss the autoimmune problem, especially if the patient is young and the autoimmune process is in a fairly early stage. With standard protocols, these patients might lose weight but the insulin resistance persists because the underlying driver—the autoimmune condition—remains unchecked.

The diagnostic picture is further complicated by the fact that there are many overlapping signs and symptoms common to both Type A and B: Sweating, tremors, fatigue, lightheadedness, and proneness to fainting.

Pay Attention to Prolactin

“Be on the lookout for prolactinomas,” Dr. Elnazer stressed. Prolactin-related issues should be high on your suspicion list in any patient who shows insulin resistance but does not fit the classic pattern of metabolic syndrome.

Common prolactinoma signals include: Amenorrhea or menstrual irregularities; Galactorrhea; Osteopenia or osteoporosis in a young person (female or male); Low libido and erectile dysfunction; Headaches; Recurrent visual problems; and Low levels of thyroid stimulating hormone (TSH), growth hormone (GH), and/or adrenocorticotrophic hormone (ACTH).

“Measure prolactin levels repeatedly over time, especially if the initial levels are only mildly elevated,” she advised. “You need to monitor this closely.”

She also suggested keeping a close watch on thyroid function, especially TSH, which is a prolactin-releasing factor.

In some cases, it makes sense to order an MRI to exclude prolactinomas or other causes of prolactin elevation.

PCOS Pitfalls

The relationship between PCOS and insulin resistance is complex, and the picture is further complicated by the fact that while PCOS is the most common cause of hyperandrogenism, it is by no means the only one.

Dr. Elnazer explained that adrenal insufficiency leads over time to hyperplasia of the pituitary cells, which ultimately results in hyperandrogenism. But it is easy to miss this. Likewise, it is easy to overlook prolactinomas, or thyroid-related causes for hirsutism and menstrual irregularities.

For all women with signs of PCOS, she recommends measuring free testosterone, and obtaining a thorough hormonal assay that includes TSH, HCG, prolactin, FSH, LH and the LH / FSH ratio.

“You also want to get a glucose, fasting insulin, or HOMA IR measurement, as well as a full metabolic profile. An ultrasound exam is also a very good idea,” she added.

Treating Atypical Insulin Resistance

There is no simple cookbook for treating the atypical forms of insulin resistance. The conditions are inherently complex, and treatment needs to be personalized.

“There is no specific consensus on treating Type A, Type B or Type C insulin resistance syndromes from the perspective of Evidence Based Medicine,” Dr. Elnazer cautioned.

That said, she offered a host of tips drawn from her own clinical experience.

For patients with Type A, in which insulin binding is impaired, it is essential to focus on establishing a low-glycemic diet and careful meal planning. She strongly urges patients to eliminate fructose as much as possible. This includes many fruits and fruit juices. “High-fructose foods are very detrimental to these people with Type A,” she said.

Smoothies can be problematic. “People who are into smoothies end up getting very high fructose loads in each meal. Fruits are made to be eaten, not juiced and drunk. Smoothies are not a great thing for insulin-resistant people in general.”

She also recommends that patients eliminate gluten and dairy.

Many patients with atypical insulin resistance will benefit from metformin, and Dr. Elnazer does not hesitate to use the drug when appropriate. Some patients may also need statins. When they are necessary, she prefers alternate day dosing regimens, to minimize risk of side effects, and always advises patients to take a CoQ10 supplement as well.

There are many nutraceuticals that can be helpful in managing these cases, including:

Alpha lipoic acid: “This is one of my favorite supplements for insulin resistance and prediabetes.” She sometimes starts a patient on metformin for two or three days, then introduces ALA (usually at 600 mg/d) and gradually tapers the metformin. In addition to improving insulin sensitivity, ALA also has anti-inflammatory effects.

Melatonin: “It’s not just for sleep,” she said. Melatonin is also a great antioxidant, and can help with weight loss in patients who need to lose weight.

N-Acetylcysteine: NAC is another of Dr. Elnazer’s go-to nutraceutical tools. It converts into glutathione, and it is very important for supporting hepatic detoxification pathways. It is also a good mucolytic.

Chromium (to improve insulin responsiveness), Turmeric (to reduce inflammation) and Valerian (for relaxation and sleep) can also be helpful.

She strongly suggested looking closely at each patient’s nutrient profile, and supplementing to correct obvious deficiencies. Suboptimal levels of vitamin D3, B vitamins, and iron are common in patients with insulin resistance.

For those with Type B autoimmune-related forms of insulin resistance, she offered the following general supplementation suggestions:

  • Vitamin C 1,000 mg/d
  • Chromium 1,000 mg/d
  • Magnesium 400 mg/d
  • Echinacea 100 mg/d
  • Vitamin A 10,000 IU/d
  • Vitamin D 5,000 IU/d
  • Probiotics (combination strains, ~50 billion CFU)

It is vital that patients understand that there’s no single magic fix for insulin resistance. It requires a comprehensive lifestyle shift. “The thing about metabolic syndrome and insulin resistance is that once you get it under control with lifestyle change, you need to keep that lifestyle. If you deviate, the symptoms come back very quickly.”

Physical activity is an essential part of the equation. “Everything improves with exercise. We encourage it, especially in our aging patients.”

Register now for the 15th Annual Integrative Healthcare Symposium, Feb 21-23, 2019, at the New York Hilton Midtown, in New York City. Connect, learn, collaborate, and return to your practice with insights and clinical pearls you can immediately incorporate into the care of your patients. Use code HPC219 before Nov 27 and receive a discount.




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