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Inflammatory Marker Profile Shifts As Type 2 Develops

A large, population-based, observational study identified different profiles of inflammatory and immune biomarkers in people with no diabetes, prediabetes, or type 2 diabetes…

Findings revealed an increase in the median concentrations of white blood cells, monocytes, granulocytes, interleukin-18, IL-1 receptor antagonist and fibrinogen in patients with diabetes and prediabetes compared with those without diabetes.

The study may provide a better understanding of the pathophysiology underlying type 2 diabetes, as shown by changes in levels of 12 biomarkers — white blood cells (WBCs), granulocytes, lymphocytes, monocytes, platelets, C-reactive protein (CRP), albumin, fibrinogen, hematocrit, interleukin-18 (IL-18), IL-1 receptor antagonist (IL-1RA), and neopterin — in three groups of individuals: those with no diabetes or subclinical disease or clinical disease.

Dr. Vera Grossmann, University Medical Center Mainz, Germany, and colleagues write, “This is one of the largest single-center population-based cohort studies…profiling the inflammatory and immune response in subjects with prediabetes, diabetes, and its disease-specific complications.”

Previous research has shown that chronic low-grade inflammation precedes the onset of type 2 diabetes, and levels of CRP, WBCs, IL-IRA, IL-18, and fibrinogen, for example, are increased years before the onset of the disease.

The researchers analyzed data from the Gutenberg Health Study, a single-center representative cohort in Germany that includes people aged 35 to 74, with equal numbers of men and women and urban and rural dwellers. All participants had blood tests to determine levels of HbA1c and biomarkers. Individuals with type 1 diabetes or diabetes of unknown type were excluded, leaving a cohort of about 7500 men and 7500 women.

Participants were classified into three groups, based on their HbA1c levels:

  • 12,152 participants (81%) had no diabetes (HbA1c < 6.0%).
  • 1,425 participants (9.5%) had prediabetes (HbA1c 6.0% to 6.4%).
  • 1,299 participants (8.7%) had type 2 diabetes (HbA1c > 6.5%).

The researchers identified four ways that biomarkers changed in the progression from no diabetes to prediabetes to diabetes:

  1. The median concentrations of WBCs, granulocytes, monocytes, IL-1RA, IL-18, and fibrinogen increased going from normoglycemia to prediabetes to diabetes.
  2. The median concentrations of lymphocytes and CRP were increased in prediabetes compared with normoglycemia, but they were not further elevated in diabetes.
  3. The median concentration of neopterin was the same in normoglycemia and prediabetes but was increased in diabetes.
  4. The hematocrit was unchanged in normoglycemia, prediabetes, and diabetes.

Interestingly, the two cytokines that have opposing mechanisms of action — the anti-inflammatory cytokine IL-1RA and the potent proinflammatory cytokine IL-18 — both increased substantially from prediabetes to diabetes. The study also reported how similarities and differences in CRP and fibrinogen patterns might help explain part of the pathophysiology of diabetes.

CRP is one of the best-investigated epidemiological biomarkers for prediabetes, diabetes, and type 2 diabetes–associated cardiovascular disease, the authors note.

In this study, the median concentration of CRP was much higher in prediabetes than in normoglycemia (2.3 mg/L vs 1.4 mg/L), but it was only slightly higher in diabetes vs prediabetes (2.4 mg/L vs 2.3 mg/L), “reflecting a very early activation of the immune system,” according to the results.

Similarly, the median concentration of fibrinogen was much higher in prediabetes than in normoglycemia (345 mg/L vs 315 mg/L) and was only slightly higher in diabetes vs prediabetes (359 mg/L vs 345 mg/L).

However, “in contrast to CRP, [fibrinogen] was strongly associated with prediabetes and diabetes independently of cardiovascular risk factors and cardiovascular disease and may therefore point to an important role in the pathophysiology of type 2 diabetes,” the authors suggest.

Nevertheless, “markers of inflammation and immunity enable differentiation between the early preclinical and clinical phases of the disease, disease complications, and progression,” they conclude.

Practice Pearls:

  • In this study, the median concentration of CRP was much higher in prediabetes than in normoglycemia.
  • Similarly, the median concentration of fibrinogen was much higher in prediabetes than in normoglycemia (345 mg/L vs 315 mg/L) and was only slightly higher in diabetes vs prediabetes (359 mg/L vs 345 mg/L).
  • This study, will help provide a better understanding of the pathophysiology underlying type 2 diabetes, as shown by changes in levels of 12 biomarkers.

Diabetes Care. Published online April 15, 2015. Profile of the Immune and Inflammatory Response in Individuals With Prediabetes and Type 2 Diabetes. Abstract.