Elevated C-Reactive Protein Levels in the Development of Type 1 Diabetes

H. Peter Chase; Sonia Cooper; Iris Osberg; Lars C. Stene; Katherine Barriga; Jill Norris; George S. Eisenbarth; Marian Rewers


Diabetes. 2004;53(10) 

In This Article


Type 1 diabetes is now accepted to be a chronic immunoinflammatory disorder. Because it is a disease of inflammation—both of the innate and adaptive immune systems—it is perhaps not surprising that elevated CRP levels were found. It is important to note that the elevated CRP levels were found before elevated glucose levels, so that this marker of inflammation is not related to hyperglycemia. This observation is impossible to study in people who already have type 1 diabetes.

CRP was more likely to be positive in children progressing to type 1 diabetes. CRP production is stimulated by inflammatory cytokines such as interleukin (IL)-6. Higher levels of IL-6 have been described in young adults with type 1 diabetes compared with control subjects.[19] Mendall et al.[20] showed that elevated CRP levels were positively associated with elevated serum levels of the IL-6 cytokine.

Children with either one or two or more positive IAs were more likely to have elevated CRP concentrations than IA- children. Being positive for only one IA only predicts a slightly increased risk of type 1 diabetes.[15] A total of 15 of the 16 children who developed type 1 diabetes in this study had two or more positive IAs before the diagnosis of diabetes. The children were still young at the time of the last sample (mean age 7.6 years), and the peak time of diabetes onset (11-12 years) had not yet been reached for the majority of the children in our study. It is therefore possible that some of the children who had only one positive IA at the last testing will develop further antibodies and type 1 diabetes with time. Further follow-up of the DAISY cohort and other longitudinal studies will help to further elucidate the role of CRP and other markers of inflammation in the development of type 1 diabetes.

Elevated levels of inflammatory cytokines and inflammatory prostaglandins[9,10] and of prostaglandin synthase 2 (COX2)[11] have been described in children before or after the onset of type 1 diabetes. A study in adults with type 2 diabetes demonstrated that treatment with aspirin, a COX2 inhibitor, resulted in reduced CRP, insulin resistance, and serum triglycerides despite a lack of change in body weight.[21] If inhibitors of the COX2 enzyme are used to try to prevent type 1 diabetes in humans, monitoring levels of CRP may be helpful. Elevated CRP levels are now described before the onset of type 1 diabetes and have previously been described before the onset of type 2 diabetes[12] and gestational diabetes.[3] Inflammation may be a common factor in the development of these various types of diabetes.

CRP has previously been shown to be elevated in adults with known type 1 diabetes.[7,8] In the study by Kilpatrick et al.,[7] the CRP levels were related to age, BMI, HbA1c, female sex, and a history of coronary heart disease in a first-degree relative. In the study by Schalkwijk et al.,[8] the CRP levels were higher in 40 subjects with type 1 diabetes in comparison with control subjects. They demonstrated a relationship with chronic hepatic inflammation. Although the mechanism of the CRP elevation is unknown, they suggest it might be related to activation of macrophages, increased oxidative stress, or induction of cytokines. There is evidence that all three of these may be factors in the etiology of type 1 diabetes. Our report is the first description of elevated CRP levels in infants and young children before the onset of type 1 diabetes.

Bohmer et al.[22] followed the immune activation state looking for a final "immunologic burst" in five patients with "high-normal blood glucose" and low insulin production (<2.5 percentile) on intravenous glucose tolerance tests. They found tumor necrosis factor-α elevated in four of five patients, with no change during the study, and normal levels of serum β2 microglobulin and CRP. (The high-sensitivity CRP assay was not yet available.) They concluded that "no evidence exists for an accelerated loss of islet β-cell function or increased immunologic activity immediately before the diagnosis of insulin dependency." Although their patients were studied in the 6 months before diagnosis of type 1 diabetes and our last CRP levels were an average of 7.8 months before diagnosis, we also did not detect a rise in CRP levels from the first to the final sample in the children who developed type 1 diabetes (Fig. 1).

The inability to suppress the inflammation, or to allow it to affect islet tissue, may be influenced by genetics, by an accelerated immune response, by nutritional or other environmental factors, or by a combination of these mechanisms. It is of note that the incidence of type 1 diabetes in children has increased concurrently with avoidance of aspirin use because of the fear of Reyes syndrome. Similarly, the incidence has increased as we have decreased our consumption of the anti-inflammatory ω-3 fatty acids and increased our consumption of the proinflammatory ω-6 fatty acids.[23] Future studies addressing the prevention of diabetes should consider the use of anti-inflammatory agents.


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