Increased Percentage of Neutrophils Linked to Greater Diabetes Risk
People with Cushing’s syndrome who have an increased percentage of a specific type of white blood cells, called neutrophils — which are involved in inflammation and act as the first line of defense against bacteria and other organisms — are at greater risk of developing diabetes mellitus, according to a recent study.
The study found that patients with the highest percentages of these white blood cells had a more than eightfold greater risk of diabetes as compared with those with the lowest values of neutrophils.
Thus, the percentage of neutrophils “may be referred to as a new predictor for diabetes in Cushing’s syndrome patients,” the researchers wrote.
Conducted by researchers at Zhongshan Hospital, Fudan University, Shanghai, in China, the study was titled “Association between Neutrophilic Granulocyte Percentage and Diabetes Mellitus in Cushing’s Syndrome Patients: A Cross-Sectional Study” and published in the International Journal of Endocrinology.
Cushing’s syndrome is characterized by high levels of cortisol — the stress hormone responsible for the body’s flight or fight response — and can be caused by long-term exposure to excess glucocorticoids, a type of anti-inflammatory medication.
Another complication of chronic exposure to glucocorticoids is diabetes mellitus, in which the body’s ability to produce and respond appropriately to insulin is impaired. Insulin is the hormone that controls glucose uptake into cells, and its impairment leads to increased blood glucose (sugar) levels.
“Glucose intolerance and diabetes mellitus are widespread in Cushing’s syndrome patients,” the researchers wrote, noting that, in this study, the prevalence of diabetes mellitus was 38.7% among patients.
The investigators also noted that these two conditions can contribute to worse prognoses in this patient population. However, the exact physiological processes that cause diabetes in Cushing’s syndrome patients are elusive.
There is some indication that white blood cells may be involved in the disease process. According to the researchers, “The more severe the symptoms of Cushing’s disease, the higher the WBC [white blood cell] count.”
Now, to investigate the potential association between inflammation, diabetes, and Cushing’s disease, the team looked at data from 150 patients diagnosed with Cushing’s syndrome, and followed at the Zhongshan Hospital between 2017 and 2019. Of these, 58 patients — the 38.7% — also were diagnosed with diabetes.
The patients’ mean age was 50.7 most (119, or about 80%) were women. Among them, the average body mass index or BMI, a calculation used to assess obesity, was 25.0 kg/m2, which is considered overweight.
Overall, the Cushing’s patients who also had diabetes tended to be older and to have higher levels of triglyceride, a type of fat.
Additionally, diabetic patients had higher fasting blood glucose levels — sugar levels in the bloodstream after an overnight fast for 12 hours, not eating — and higher 2-hour postprandial blood glucose, which is a measure of a person’s blood sugar levels two hours after eating. Patients with diabetes also had higher HbA1c, or glycated hemoglobin levels, indicative of blood sugar levels over the last couple of months. Of note, all of these parameters are typically used to diagnose diabetes.
Higher cortisol levels during various daily measurements also were found among the diabetic patients, specifically at the 8 am, 4 pm, and midnight cortisol assessments.
Furthermore, Cushing’s patients with diabetes had higher total white blood cells counts (7.8 vs. 6.7), as well as higher neutrophil counts (5.86 vs. 4.6). They also had a higher percentage of neutrophils percent — as compared with all the white blood cells in the sample, and known as NEUT% — at 73.6% versus 65.2%, when compared with Cushing’s patients without diabetes.
Those with diabetes also were found to have a lower percent of lymphocytes, another type of white blood cells, as those without diabetes —18.8% vs. 25.6% — although there was no significant difference in the total lymphocyte count among these patients.
Given the finding of a possible link between white blood cells and glucose levels in Cushing’s patients, the researchers created a model to illustrate the possible correlation between NEUT% and glucose levels.
They found that NEUT% is positively correlated to various blood glucose parameters, including the fasting blood glucose level, the 2-hour postprandial glucose level, and HbA1c, meaning that as NEUT% rises so do these glucose parameters.
Additionally, the researchers found that white blood cell counts were positively correlated with both fasting blood glucose level and the 2-hour postprandial glucose level.
Total neutrophil count also was positively correlated with fasting blood glucose level, the 2-hour postprandial glucose level, and HbA1c, similar to %NEUT.
However, the correlations between blood lymphocyte parameters and both fasting blood glucose level and the 2-hour postprandial glucose level were negative, meaning that as total lymphocyte counts decrease, those two glucose parameters rise.
The researchers also looked at the connection between cortisol levels and blood glucose parameters, given the considerably higher cortisol levels in Cushing’s patients with diabetes.
They found that the 8 am, 4 pm, and midnight cortisol levels were positively correlated with fasting blood glucose level and the 2-hour postprandial glucose level. 8 am cortisol levels also were associated with HbA1c.
“These data demonstrate that blood glucose levels and cortisol levels are mutually influential,” the researchers wrote.
Then, to determine independent risk factors for diabetes development in Cushing’s patients, the researchers used multiple analysis models. When adjusting for gender, age, BMI, and triglyceride levels, %NEUT remained a significant risk factor, with patients with the highest values having an 8.45 times higher risk, as compared with those with the lowest %NEUT.
In another model also taking into account the midnight cortisol level, the increased risk associated with higher %NEUT remained high, at 6.49 times increased risk.
Older patients or those with higher triglyceride levels also were more at risk of developing diabetes than patients who were younger or had lower triglyceride levels.
Overall, “these results suggest that NEUT% is an independent risk factor for DM [diabetes mellitus] in [Cushing’s] patients,” the team concluded. The researchers believe that the results may offer new insights into the disease processes of white blood cell parameters on the regulation of diabetes.
“Neutrophils appear to be the immune cells involved in the proinflammation procedure that underlies insulin resistance,” the researchers wrote, further supporting their findings that the increased white blood cells seen in Cushing’s patients with worsening disease may play a role in the increased risk of diabetes.