Faulty Insulin Secretion Key to Glucose Dysregulation in PD?

Pauline Anderson

June 18, 2018

LISBON, Portugal — Glucose dysregulation in patients with advanced Parkinson's disease (PD) is related to impaired adaptive insulin secretion due to dysautonomia, new research suggests.

"Dysautonomia and blood glucose dysregulation should be screened for in PD patients with moderate to advanced disease, to prevent metabolic syndrome in these patients but also because diabetes in Parkinson's appears to be associated with a more aggressive phenotype," said Ana Marques, MD, Clermont Auvergne University, Clermont-Ferrand, France

The study was presented here at the Congress of the European Academy of Neurology (EAN) 2018.

Contradictory Studies

Epidemiological studies show contradictory results regarding a link between diabetes and PD, said Marques. "Sometimes PD appears like a risk factor for diabetes and sometimes diabetes appears like a risk factor for PD, and sometimes there is no link."

However, said Marques, biological studies show a strong association, although the link is not well understood.

Marquis and colleagues previously found that fasting plasma glucose concentrations in patients with PD who have deep-brain stimulators were higher than in matched healthy controls, and that those glucose concentrations normalized when the device was turned on.

Deep-brain stimulation improves autonomic nervous system activity, so researchers hypothesize that normalization of glucose concentrations could be due to normalization of autonomous activity, said Marques.

She also noted that insulin production and secretion are modulated by the autonomic nervous system.

"So it could be that blood glucose dysregulation in PD could be linked with the severity of dysautonomia."

For this new study, participants with diabetes were excluded, as were those with dementia and those who drank alcohol and smoked over a certain limit. Also excluded were those with advanced heart failure, cirrhosis, chronic kidney disease, untreated thyroid disease, and metabolic and biologic dysfunction because these conditions could be confounding factors, Marques explained. 

The study included 50 patients with moderate to advanced PD (31 men and 18 women; mean age, about 61 years; mean body mass index [BMI], 25.27) who had been living with the condition for more than 5 years and 50 healthy controls matched for age, sex, and BMI.

Fasting plasma glucose and fasting plasma insulin levels did not significantly differ between groups. The fasting urine glucose levels were lower in the PD group, "but in both groups, the levels were considered abnormal," said Marques.

The patients with PD had no modification of dopaminergic treatment during the month before assessment. As well, none of the patients with PD had received subthalamic nucleus deep-brain stimulation.

During the month before the study, none of the participants could take medications that might interfere with metabolism, including antibiotics and anti-inflammatory drugs.

Glucose Tolerance

Study participants underwent a 75-g oral glucose tolerance test. The total area under the time curve (AUC) for blood glucose concentrations was higher in patients with PD than in controls at 90 minutes and at 150 minutes (P = .05).

However, when participants were tested for plasma insulin response, AUC did not differ between the PD and control groups (P = .57 for insulin concentrations up to 180 minutes)

"So PD patients appear to have higher blood glucose following oral glucose intake compared to healthy controls without presenting the rise in insulin levels that you are supposed to observe when glucose levels start to increase," said Marques.

Researchers also evaluated autonomic function.

When they looked at independent associations between glucose and various clinical parameters, they found that higher blood glucose levels were related to higher score of dysautonomia, as well as to longer duration of PD.  

This, said Marques, suggests that sympathetic denervation might be leading to β-cell dysfunction. In the general population, when glucose levels start to rise, β cells quickly respond by increasing the secretion of the stored insulin while at the same time increasing its production, she explained.

"Here, the glucose dysregulation of PD could be due to a β-cell failure," as the patients with PD could not increase their insulin production in response to higher glucose levels.

Higher blood glucose levels were also related to higher BMI, they found. Conversely, male sex and higher levodopa equivalent doses were associated with lower glucose levels.

Patients with moderate to severe PD should be screened for dysautonomia and blood glucose dysregulation, Marques concluded.

If glucose dysregulation becomes the new therapeutic target in PD, "we suggest that insulin-releasing drugs should possibly be preferred over insulin-sensitizer drugs in PD patients with diabetes" because the problem does not seem to lie with insulin resistance but rather with insulin secretion, said Marques.

In response to a query from a delegate, Marques said the results would be expected to be similar in patients with multiple system atrophy.

She also clarified that patients with diabetes were excluded but those with prediabetes conditions, such as glucose intolerance, were not.

"There were indeed more patients with glucose intolerance in the PD group compared to healthy controls," she said.

Asked by another meeting attendee if the researchers controlled for physical activity, Marques said they didn't, but that future studies should do so because patients with PD are very sedentary compared to healthy controls and physical activity can affect metabolism.

The investigators have disclosed no relevant financial relationships.

Congress of the European Academy of Neurology (EAN) 2018. Oral session O107. Presented June 16, 2018.

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