Inflammatory Marker Profile Shifts as Type 2 Diabetes Develops

Marlene Busko

May 01, 2015

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

This study, published online April 15 in Diabetes Care, may help 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.

"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," Dr Vera Grossmann (University Medical Center Mainz, Germany) and colleagues write.

The findings "underline the importance of inflammation and immunity in development of type 2 diabetes" and show that the inflammatory biomarker profile changes as type 2 diabetes develops and progresses, senior author Dr Philipp S Wild (University Medical Center Mainz) told Medscape Medical News.

"Although the study findings do not have a direct impact on clinical practice now, they might contribute to…improvement in the diagnosis of early disease states, the optimization of risk assessment of patients, and potentially the development of new interventions and therapeutic strategies [for type 2 diabetes]," he said.

Changing Levels of Biomarkers as Diabetes Progresses

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.

However, little is known about the changes in inflammatory and immune biomarkers across the spectrum of type 2 diabetes, Dr Grossmann and colleagues write.

They 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:

  • The median concentrations of WBCs, granulocytes, monocytes, IL-1RA, IL-18, and fibrinogen increased going from normoglycemia to prediabetes to diabetes.

  • The median concentrations of lymphocytes and CRP were increased in prediabetes compared with normoglycemia, but they were not further elevated in diabetes.

  • The median concentration of neopterin was the same in normoglycemia and prediabetes but was increased in diabetes.

  • 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 concentration of neopterin, a sensitive indicator of cell-mediated immune activation, was inversely associated with subclinical disease but was positively associated with the prevalence of established disease. The implications of these findings remain to be determined, the researchers say.

CRP, Fibrinogen, and Pathophysiology of 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 Dr Grossmann and colleagues.

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.

In the subgroup of patients with diabetes, the researchers also identified how elevated levels of biomarkers were linked with diabetes-related complications.

Higher concentrations of WBCs in general and granulocytes in particular were associated with the prevalence of retinopathy, and higher concentrations of lymphocytes and CRP were linked with the prevalence of neuropathy. Higher hematocrit values were associated with a lower prevalence of proteinuria.

Since it was an observational study, this research cannot show a causal relationship between inflammation and type 2 diabetes, Dr Grossman and colleagues caution.

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

The Gutenberg Health Study is funded by the government of Rhineland-Palatinate, the research programs Wissen schafft Zukunft and Center for Translational Vascular Biology of the Johannes Gutenberg-University of Mainz and its contract with Boehringer Ingelheim and Philips Medical Systems. The authors have reported no relevant financial relationships.

Diabetes Care. Published online April 15, 2015. Abstract

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