Modern Tech May Shed Light on Hypoglycemia in Absence of Diabetes

Miriam E. Tucker

August 28, 2019

Use of continuous glucose monitoring (CGM) may detect clinically hypoglycemic blood glucose values that correlate with reported hypoglycemic symptoms in individuals without diabetes, a small pilot study has found. 

The study is believed to be the first to use modern CGM technology to address the long-controversial phenomenon of hypoglycemia as a condition unto itself in people without diabetes.

The findings were published online in the Journal of Clinical & Translational Endocrinology by Morgana Mongraw-Chaffin, PhD, assistant professor of epidemiology and prevention at Wake Forest School of Medicine, Winston-Salem, North Carolina, and colleagues.

Hypoglycemia in the absence of diabetes, also known as reactive, postprandial, or idiopathic hypoglycemia, is a common complaint among people — often young women — who present to medical settings. A 2006 UK study estimated 38% of women without diabetes experience hypoglycemic symptoms.

Yet there are no standard diagnostic criteria or management guidelines for the phenomenon. In fact, the very existence of the condition has been debated for decades and it was blatantly dubbed a "nondisease" in an article published in 1974 in the New England Journal of Medicine.

The new study evaluated just eight patients — all young women who reported symptoms such as shakiness, dizziness, headache, and irritability that they attributed to low blood glucose — and had no control group, so it's far from conclusive.

However, while wearing a blinded CGM for a week, all participants experienced glucose values below 70 mg/dL, and in half values actually dropped below 54 mg/dL, correlating with reported symptoms.

In 2017, the 54 mg/dL cutoff for hypoglycemia was chosen for reporting in clinical trials by the International Hypoglycemia Study Group both because it presents "immediate and long-term danger to the individual" and because, that group said, values below 54 mg/dL "do not occur under physiological conditions in nondiabetic individuals," Mongraw-Chaffin and colleagues note.

Symptoms Lead to Obesogenic Behaviors

Of concern, all study participants also reported obesogenic behavior to avoid symptoms.

"Regardless if these symptoms are linking to glucose values — and we're finding that they are — these women are snacking between meals and avoiding exercise in order to prevent symptoms. In light of the ongoing obesity epidemic, if we can help any group of people in our population avoid obesity, that would be very useful," Mongraw-Chaffin told Medscape Medical News in an interview.   

Moreover, she pointed out, "Some doctors don't believe this exists and tell patients there's nothing wrong, so those patients are turning to other sources for information and guidance, and those sources may not be evidence-based."

New data using CGM are important, Mongraw-Chaffin said, because previous studies of the phenomenon are decades old and typically used oral glucose tolerance tests performed in laboratories, rather than in real-world settings.

"It's amazing the insights we can get when we revisit an old question with newer technology," she noted.  

How Common Is Hypoglycemia in People Without Symptoms (or Diabetes)?

"It’s an interesting study, but I don't think it's definitive," said M. Sue Kirkman, MD, professor of medicine and medical director of the Diabetes Care Center Clinical Trials Unit, University of North Carolina School of Medicine, Chapel Hill, when asked for comment.

She cited the older studies using laboratory glucose levels in age- and sex-matched people with and without hypoglycemic symptoms that showed no difference in glucose levels.

"This doesn't mean the symptoms are 'in the head,' but that maybe people are reacting to something else besides the absolute glucose level. [The new study]...would have been a stronger study had they also studied a control group of young women without symptoms. They might have found similar glucose levels," Kirkman said.  

She added that blood glucose values below 70 mg/dL and even down into the 50s "can be found in normal people, particularly in young women. When we are looking for an insulinoma and do a 72-hour fast, for example, we don't stop the fast and draw the labs until the blood glucose by the lab is below 55 mg/dL in men, and some protocols say it should be below 45 mg/dL in women."

She agreed that these symptoms can reduce quality of life but said "some of it is fear that something terrible is going on or that they are going to have life-threatening hypoglycemia. Dietary changes — not the obesogenic and often vicious-cycle snacking they mention — and reassurance are often really helpful."

"This study, with no control group, doesn't prove that there is pathology in terms of glucose levels."

"It's more likely that these women have glucose levels that are within the spread of what is normal and that what we really need to do is help them with symptoms and anxiety and to recognize that normal is a broader range than what we define in people with diabetes," she explained.

Measured Hypoglycemia Correlated With Symptoms

The eight women studied were between the ages of 18 and 35 years (mean 29 years) without diabetes. Six were white and two were African American. Six were of normal weight and two were obese.

In the enrollment survey, the most common symptoms reported — at a minimum of 3 hours since last eating — were fatigue and irritability, followed by weakness, dizziness, and palpitations. Difficulty concentrating, blurred vision, tremor, and shakiness were also reported.

Five of the eight women said that the symptoms limited their ability to do things they wanted to do or lowered their quality of life. All eight reported having changed their behavior in response to symptoms, including altering the timing of meals or snacking between meals when not hungry. Three of the eight said they avoided exercise because of symptoms or to prevent them.

They wore a blinded Dexcom G4 CGM for 7 days, with an average of 1994 (1767-2799) glucose values measured per participant. Hypoglycemia was classified as values < 70 mg/dL, or < 54 mg/dL persisting for at least 15 minutes, or three consecutive continuous glucose readings.

During the study, three participants reported experiencing symptoms daily, two reported symptoms four times during the week, and two had symptoms twice during the week.

All participants had minimum glucose readings below 70 mg/dL and half (four participants) had a minimum glucose reading lower than 50 mg/dL, "the value considered to be 'the generic nondiabetic glycemic threshold for impairment of cognitive function,'" the authors say, again quoting the International Hypoglycemia Study Group.

Participants who had hypoglycemia defined as < 54 mg/dL had an average of 1.75 days with at least one episode of a minimum glucose below that level. The average number of days with minimum readings lower than 70 mg/dL was 3.4 days. The average time between last meal and symptom onset was 4.4 hours.

The odds ratio for symptom occurrence was 1.15 (P = .001) for every 5 mg/dL lower glucose value, adjusted for age, race, and body mass index.

Insulin levels were not measured, but it's unlikely any of these women had insulinomas given the rarity of that condition (about 1-4 cases per million people) and the fact that fasting hypoglycemia is more characteristic of insulinomas, the authors say.

"A Starting Point, Not an Ending Point"

Mongraw-Chaffin told Medscape Medical News that she and her colleagues plan to study this in a larger and more diverse population — including men — and to enroll a control group to obtain normative data. They also want to develop preliminary diagnostic criteria and follow participants to track their health outcomes over time.

They currently have two new grants under review on the topic. "We're very aware of the criticisms about this study. This is a starting point, not an ending point," she said.

The study was supported by a Wake Forest Clinical and Translational Science Institute Ignition Fund Pilot Award by the National Center for Advancing Translational Sciences, National Institutes of Health. Kirkman's institution receives research support from Novo Nordisk, Theracos, and Bayer.

J Clin Transl Endocrinol. Published online July 24, 2019. Full text

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