Kerstin Kempf, German Diabetes Clinic, German Diabetes Center, Leibniz Institute at Heinrich-Heine-University Düsseldorf, Auf'm Hennekamp 65, 40225 Düsseldorf, Germany, Tel: +49-211-3382-647, Fax: +49-211-3382-603, E-mail: Kerstin.Kempf@ddz.uni-duesseldorf.de

Low-Grade Inflammation in Obesity and Type 2 Diabetes Mellitus

It is now accepted that "adiposities" (macrophage infiltration and inflammation of adipose tissue in obesity) and systemic low grade inflammation affect the pathogenesis of type 2 diabetes mellitus (T2DM). To date, a number of systemic indicators of inflammation have been found abnormal in patients with T2DM. These include acute-phase proteins, cytokines, chemokines, and mediators associated with endothelial activation. Prospective studies have demonstrated the presence of low grade inflammation already in the metabolic syndrome (MetS) or impaired glucose tolerance (IGT) years or even decades before diagnosis of T2DM. Further arguments in favor of a pathogenetic role of low grade inflammation are associations of several immune gene alleles with risk of T2DM and studies with genetically modified animals (see [1-3] for a comprehensive review). Therefore, modern weight-reduction programs additionally focus on strategies to attenuate the proinflammatory state.

The Impact of Exercise on T2DM and Inflammation

Recent studies emphasized the value of exercise in both reducing the incidence of T2DM and attenuating inflammation. The efficacy of exercise and diet-based intervention to delay or prevent the progression to T2DM in individuals at high risk (IGT and/or overweight) was clearly demonstrated in the Finnish Diabetes Prevention Study [4], the Diabetes Prevention Program in the U.S.A [5], the Da Qing IGT and Diabetes Study in China [6], the Indian Diabetes Prevention Programme [7], and other randomized controlled trials [8] with relative risk reductions of up to 58%. Interestingly, nearly almost the same risk reduction was seen for the rosiglitazone group in the DREAM trial [9]. This similarity in outcome suggests that the same subset of individuals with dysglycemia may be responsive to either intense lifestyle change or rosiglitazone. If so, the effects of lifestyle changes or of rosiglitazone on diabetes risk would be mediated by the same mechanism, and genes regulated by peroxisome-proliferator-activated receptor ? (PPAR?) would be common targets [10]. The relative importance of exercise in most of these studies has not been investigated, but data from the Finnish and Chinese studies indicate a diet-independent beneficial effect of physical activity [6,11]. Immunmodulatory effects of exercise are supported by similarly beneficial effects of dietary changes. In this context, glucose is the most extensively studied nutrient and a lot of effort is made to investigate the effects of postprandial hyperglycemia.

Postprandial Hyperglycemia as Risk Factor for Cardiovascular Disease

Besides the rapidly increasing prevalence of overweight and obesity due to chronic overnutrition combined with a lack of exercise, many people in developed countries are in a postprandial state throughout most of the day. This seems to be problematic as recent studies (e.g. the Honolulu Heart Study [12], the Chicago Heart Study [13], the Hoorn Study [14], and the DECODE Study [15]) demonstrated that, in addition to T2DM and inflammation, postprandial hyperglycemia is an independent risk factor for cardiovascular disease (CVD). Moreover, the STOP-NIDDM trial [16] showed that the development of hypertension and cardiovascular events can be reduced if postprandial hyperglycemia is treated. But why is postprandial hyperglycemia so detrimental?

Glucose-Mediated Inflammation in Metabolically Dysregulated Subjects

Answers to this question have been given by recent studies which investigated the regulation of pro-inflammatory immune mediators in response to the uptake of glucose and test meals. In non-diabetic individuals, fasting plasma glucose concentrations generally range from 70 to 110 mg/dl. Glucose concentrations begin to rise ~10 minutes after the start of a meal as a result of the absorption of dietary carbohydrates and peak after ~60 minutes, rarely exceed 140 mg/dl, and return to preprandial levels due to insulin action within 2-3 hours. In T2DM patients, peak insulin levels are delayed and the magnitude and duration of postprandial glucose peaks are higher [17].

A comparable development can be seen for the regulation of immune mediators. Our data demonstrates that in vivo, oral glucose tolerance tests (OGTT; 75 g glucose) increased the expression of cytokines in peripheral blood cells in normal weight and normal glucose tolerant (NGT) subjects with a maximal increase 90 minutes after glucose challenge and decrease thereafter [1]. Moreover, we could show that in control subjects immune mediator expression in circulating blood cells has returned to baseline levels 2 hours after oral glucose load, while in MetS subject the expression of TNF-a, ICAM-1, and IL-6 is significantly elevated [18]. These results we confirmed by in vitro stimulation of blood cells from MetS and control subjects demonstrating a significant increase in immune mediator expression only in MetS subjects combined with induced immune mediator secretion [18]. Further studies demonstrated increased plasma levels of cytokines, chemokines, adhesion molecules, or reactive oxygen species in NGT subjects [19] and patients with IGT or T2DM after glucose challenge by OGTT or glucose clamps. Nevertheless, in NGT subjects plasma levels normalized within 2-3 hours, whereas in individuals with disturbed metabolic regulation glucose-induced inflammation is stronger or lasts longer [20-23]. Thus, metabolic dysregulation may support peripheral inflammation by sensitizing leukocytes to up-regulate pro-inflammatory markers in response to glucose, which in turn increases the risk for atherosclerosis and CVD.

Potential Mechanisms for Glucose-Mediated Damage

Taken together, we and others saw induction of pro-inflammatory reactions mainly in metabolically dysregulated subjects, which indicates that the glucose-mediated effects might be modulated by other metabolic factors. Promising candidates may be triglycerides and oxidative stress: postprandial levels of triglycerides, free fatty acids, and the inflammation marker complement component 3 (C3) increase more strongly in MetS subjects compared to controls with significant associations between fasting C3 and triglycerides levels as well as numbers of MetS components [24]. Glucose peaks during postprandial periods have been shown to especially increase oxidative stress markers [25] and to increase monocyte adhesion to endothelial cells [26]. Long-term lipid-lowering treatment with simvastatin was shown to reduce the postprandial triglyceride increase paralleled by lower induction of inflammation and oxidative stress markers [20], and also antioxidants like glutathione and vitamin E and C prevented postprandial increase of inflammation markers [21,27].

Conclusion

Postprandial hyperglycemia is an important risk factor for CVD and the underlying mechanisms include glucose-mediated inflammation and oxidative stress. Moreover, the potential of glucose to induce upregulation of immune parameters in vivo and in vitro seems to be more pronounced when metabolic dysregulation (i.e. MetS, IGT, or T2DM) is already present. Therefore, there is an urgent need for improved understanding and awareness of the role of metabolic dysregulation in glucose-mediated activation of inflammatory pathways, which subsequently may suggest novel treatment options to prevent the development of arteriosclerosis and CVD.

References

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