AT WPC 2016

PORTLAND, ORE. (FRONTLINE MEDICAL NEWS) – More than half of overweight, nondiabetic people with Parkinson’s disease were insulin resistant even though most had normal fasting glucose and insulin levels in a prospective, observational study, raising concerns about the potential role of insulin resistance in accelerating the progression of neurodegenerative diseases, including certain features of Parkinson’s disease.

Researchers at Cedars-Sinai Medical Center in Los Angeles tested 93 patients with Parkinson’s disease to determine the prevalence of undiagnosed insulin resistance (IR). They used the homeostatic model assessment of insulin resistance (HOMA-IR) formula, with a HOMA-IR index of 2.0 as a cut-off for abnormal insulin sensitivity. The index is a measure of how much insulin is needed to control blood sugar and uses just blood fasting insulin and glucose levels for the calculation.

Speaking at his poster presentation at the World Parkinson Congress, lead researcher Elliot Hogg, MD, said, “A very high percentage of those that were overweight or obese were actually insulin resistant, and these patients would have been missed by normal screening techniques potentially,” which would be fasting glucose or glycated hemoglobin levels. “It would be rare for [clinicians] to actually look at insulin.”

Of the 93 patients (71 men), with an average age of 66 years, 9 were diabetic. Of the 84 nondiabetic patients, 49 (58%) had an abnormal HOMA-IR index, ranging from 2.01 to 9.92, which is consistent with IR. Of the 84, 63 were overweight (body mass index [BMI] greater than 25 kg/m2), and 60.3% had IR. Among the 27 nondiabetic, obese patients (BMI greater than 30 kg/m2), 96% had IR. Only 19% of patients with normal BMI had IR. All the nondiabetic subjects with abnormal HOMA-IR who had values available (n = 22) had normal fasting glucose and glycated hemoglobin levels.

The vast majority of subjects with IR had normal fasting glucose and insulin levels. “They’re using too much insulin to control the amount of glucose that they have even though their glucose itself is not abnormal,” Dr. Hogg said. “The relevance of this could be that this may promote some of the degenerative processes that are inherent to Parkinson’s and, more importantly, could potentially offer a reversible target, because if you can identify patients who are insulin resistant, you could, through diet and exercise and lifestyle changes or medications, potentially reverse this and potentially change their path from heading to Parkinson’s or worsening Parkinson’s to something else. That would be the ultimate hope for this research.”

Although overweight is a well known risk factor for insulin resistance, it may be particularly relevant in Parkinson’s disease “because it seems to promote aspects of the disease that could impact not just the motor features of Parkinson’s but also the nonmotor features. We’re most concerned about cognition. … one of the most feared complications of Parkinson’s and something that we have very little to offer for right now,” Dr. Hogg explained.

He said he plans to look at brain glucose metabolism in Parkinson’s patients without insulin resistance and compare it to similar patients with insulin resistance using PET scanning to see if “these brains are potentially starved of energy.” He cited a British study that showed that exenatide, a glucagonlike peptide-1 (GLP-1) agonist used in diabetes, improved cognition in a treated group. He plans to test liraglutide, another GLP-1 agonist, to see if it will improve or at least stabilize motor or nonmotor symptoms of Parkinson’s disease in insulin-resistant patients.

He suggested that physicians may want to look at insulin and not just measures of blood glucose in appropriate patients.

Jori Fleisher, MD, a movement disorders neurologist at New York University Langone Medical Center in New York, commented that the study indicates that there may be a cohort of patients who are seen routinely but have an undiagnosed risk factor. “Potentially, if we could address it and get their insulin resistance under control, perhaps with weight loss, then we might be able to potentially affect the progression of the Parkinson’s disease,” she said.

As for a mechanism of the effect, she said it is known that there is a “huge role of oxidative stress and apoptosis in the progression of Parkinson’s disease,” and insulin resistance may contribute to it.

She said she would like to see the study replicated in a much larger cohort before routinely adopting insulin measures in clinical practice. If the findings are sufficiently validated, “this is something that seems fairly easy and innocuous to test for.”

Richard Smeyne, PhD, director of the Jefferson Comprehensive Parkinson’s Center at Thomas Jefferson University in Philadelphia, speculated that insulin may also have functions in the brain aside from its metabolic effects, specifically, promoting or maintaining neurons through neurotropic effects mediated through the insulinlike growth factor-1 receptors. Still, he cautioned that he would be “hesitant to look at insulin resistance peripherally and make some sort of comment about its relationship to Parkinson’s disease.”

The study was investigator initiated and had no commercial support. Dr. Hogg, Dr. Fleisher, and Dr. Smeyne reported having no financial disclosures.