A subclinical inflammatory reaction has been shown to precede the onset of type 2 (non-insulin-dependent) diabetes. We therefore examined prospectively the effects of the central inflammatory cytokines interleukin (IL)-1␤, IL-6, and tumor necrosis factor-␣ (TNF-␣) on the development of type 2 diabetes. We designed a nested case-control study within the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study including 27,548 individuals. Case subjects were defined to be those who were free of type 2 diabetes at baseline and subsequently developed type 2 diabetes during a 2.3-year follow-up period. A total of 192 cases of incident type 2 diabetes were identified and matched with 384 non-disease-developing control subjects. IL-6 and TNF-␣ levels were found to be elevated in participants with incident type 2 diabetes, whereas IL-1␤ plasma levels did not differ between the groups. Analysis of single cytokines revealed IL-6 as an independent predictor of type 2 diabetes after adjustment for age, sex, BMI, waist-to-hip ratio (WHR), sports, smoking status, educational attainment, alcohol consumption, and HbA 1c (4th vs. the 1st quartile: odds ratio [OR] 2.6, 95% CI 1.2-5.5). The association between TNF-␣ and future type 2 diabetes was no longer significant after adjustment for BMI or WHR. Interestingly, combined analysis of the cytokines revealed a significant interaction between IL-1␤ and IL-6. In the fully adjusted model, participants with detectable levels of IL-1␤ and elevated levels of IL-6 had an independently increased risk to develop type 2 diabetes (3.3, 1.7-6.8), whereas individuals with increased concentrations of IL-6 but undetectable levels of IL-1␤ had no significantly increased risk, both compared with the low-level reference group. These results were confirmed in an analysis including only individuals with HbA 1c <5.8% at baseline. Our data suggest that the pattern of circulating inflammatory cytokines modifies the risk for type 2 diabetes. In particular, a combined elevation of IL-1␤ and IL-6, rather than the isolated elevation of IL-6 alone, independently increases the risk of type 2 diabetes. These data strongly support the hypothesis that a subclinical inflammatory reaction has a role in the pathogenesis of type 2 diabetes. Diabetes 52:812-817, 2003

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OBJECTIVE -We aimed to develop a precise risk score for the screening of large populations for individuals at high risk of developing type 2 diabetes based on noninvasive measurements of major risk factors in German study populations. RESEARCH DESIGN AND METHODS -A prospective cohort study (European Prospective Investigation into Cancer and Nutrition [EPIC]-Potsdam study) of 9,729 men and 15,438 women aged 35-65 years was used to derive a risk score predicting incident type 2 diabetes. Multivariate Cox regression model coefficients were used to weigh each variable in the calculation of the score. Data from the EPIC-Heidelberg, the Tü bingen Family Study for Type 2 Diabetes (TÜ F), and the Metabolic Syndrome Berlin Potsdam (MeSyBePo) study were used to validate this score.RESULTS -Information on age, waist circumference, height, history of hypertension, physical activity, smoking, and consumption of red meat, whole-grain bread, coffee, and alcohol formed the German Diabetes Risk Score (mean 446 points [range 118 -983]). The probability of developing diabetes within 5 years in the EPIC-Potsdam study increased from 0.3% for 300 to 23.2% for 750 score points. The area under the receiver-operator characteristic (ROC) curve was 0.84 in the EPIC-Potsdam and 0.82 in the EPIC-Heidelberg studies. Correlation coefficients between the German Diabetes Risk Score and insulin sensitivity in nondiabetic individuals were Ϫ0.56 in the TÜ F and Ϫ0.45 in the MeSyBePo studies. ROC values for undiagnosed diabetes were 0.83 in the TÜ F and 0.75 in the MeSyBePo studies.CONCLUSIONS -The German Diabetes Risk Score (available at www.dife.de) is an accurate tool to identify individuals at high risk for or with undiagnosed type 2 diabetes. Diabetes Care 30:510 -515, 2007R andomized clinical trials have demonstrated that type 2 diabetes can largely be prevented through diet and lifestyle modifications (1-4) or drug treatment (3,5). Personalized primary prevention among high-risk individuals to prevent the transition to overt diabetes is therefore a feasible and attractive alternative to reduce diabetes-related morbidity and mortality. The major challenge is how to identify those high-risk individuals, and, thus, several risk scores have been developed based on data from the San Antonio Heart Study (6), the Finrisk studies (7), the Japanese American Community Diabetes Study (8), the Atherosclerosis Risk in Communities (ARIC) study (9), the Rancho Bernardo Study (10), and a population-based survey in Umea, Sweden (11). Only the Finrisk studies (7) and the ARIC study (9) relied only on factors that are measurable with noninvasive methods and are therefore applicable outside of clinical practice. However, the ARIC risk score demonstrated relatively low validity in the testing sample (9). Furthermore, the Finrisk score recently has been tested in the German Cooperative Health Research in the Region of Augsburg Survey 2000, yielding a low validity to identify undiagnosed diabetic cases (12). Lack of inclusion of important risk factors (e.g., smoki...

Low plasma levels of the anti-inflammatory factor adiponectin characterize obesity and insulin resistance. To elucidate the relationship between plasma levels of adiponectin, adiponectin gene expression in adipose tissue, and markers of inflammation, we obtained blood samples, anthropometric measures, and subcutaneous adipose tissue samples from 65 postmenopausal healthy women. Adiponectin plasma levels and adipose-tissue gene expression were significantly lower in obese subjects and inversely correlated with obesity-associated variables, including high-sensitive C-reactive protein (hs-CRP) and interleukin-6 (IL-6). Despite adjustment for obesity-associated variables, plasma levels of adiponectin were significantly correlated to adiponectin gene expression (partial r ‫؍‬ 0.38, P < 0.05). Furthermore, the inverse correlation between plasma levels of hs-CRP and plasma adiponectin remained significant despite correction for obesity-associated variables (partial r ‫؍‬ ؊0.32, P < 0.05), whereas the inverse correlation between adiponectin plasma levels or adiponectin gene expression in adipose tissue with plasma IL-6 were largely dependent on the clustering of obesity-associated variables. In conclusion, our data suggest a transcriptional mechanism leading to decreased adiponectin plasma levels in obese women and demonstrate that low levels of adiponectin are associated with higher levels of hs-CRP and IL-6, two inflammatory mediators and markers of increased cardiovascular risk. Diabetes 52:942-947, 2003

Adiponectin affects lipid metabolism and insulin sensitivity. However, adiponectin circulates in three different oligomers that may also have distinct biological functions. We aimed to analyze the role of these oligomers in obesity and lipid metabolism after weight reduction. A total of 17 obese volunteers (15 women and 2 men) participated in a weight reduction program. Individuals were characterized before and after 6 months of a balanced diet. Adiponectin was determined by enzyme-linked immunosorbent assay, and oligomers were detected by nondenaturating Western blot. BMI decreased (35.1 ؎ 1.2 to 32.8 ؎ 1.1 kg/m 2 , P < 0.001), which was associated with an improved metabolite profile. Total adiponectin increased from 5.3 ؎ 0.5 to 6.1 ؎ 0.6 g/ml (P ‫؍‬ 0.076). High (HMW) and medium molecular weight (MMW) adiponectin oligomers significantly increased during weight reduction (HMW: 0.37 ؎ 0.07 to 0.4 ؎ 0.08 g/ml, P ‫؍‬ 0.042; MMW: 2.3 ؎ 0.2 to 2.9 ؎ 0.3 g/ml, P ‫؍‬ 0.007), while low molecular weight (LMW) did not significantly change. Body weight inversely correlated with HMW (r ‫؍‬ ؊0.695, P ‫؍‬ 0.002) and positively with LMW (r ‫؍‬ 0.579, P ‫؍‬ 0.015). Interestingly, HDL cholesterol and HMW were strongly correlated (r ‫؍‬ 0.665, P ‫؍‬ 0.007). Indeed, HMW and free fatty acids before weight reduction predicted ϳ60% of HDL changes during intervention. In conclusion, weight reduction results in a relative increase of HMW/MMW adiponectin and a reduction of LMW adiponectin. Total adiponectin and especially HMW adiponectin are related to circulating HDL cholesterol. Diabetes 54: 2712-2719, 2005

Greater changes in insulin sensitivity after intake of an isoenergetic HCF than after intake of an HP diet might help to explain the diverse effects of these diets on diabetes risk. This trial is registered at clinicaltrials.gov as NCT00579657.

Aims/hypothesis:

OBJECTIVE -Cereal fiber intake is linked to reduced risk of type 2 diabetes in epidemiological observations. The pathogenic background of this phenomenon is unknown. Based on recent findings, we hypothesized that intake of purified insoluble oat fiber may improve wholebody insulin sensitivity. RESEARCH DESIGN AND METHODS-A randomized, controlled, single-blind, cross-over study was performed, and 17 overweight or obese subjects with normal glucose metabolism were analyzed. After consumption of nine macronutrient-matched portions of fiberenriched bread (white bread enriched with 31.2 g insoluble fiber/day) or control (white bread) over a time period of 72 h, whole-body insulin sensitivity was assessed by euglycemichyperinsulinemic clamp. Energy intake was individually adjusted by providing standardized liquid meals. Hydrogen breath tests were performed to control for dietary adherence.RESULTS -When analyzing the entire cohort, whole-body glucose disposal was improved after fiber consumption (M value 6.56 Ϯ 0.32 vs. 6.07 Ϯ 0.27 mg ⅐ min Ϫ1 ⅐ kg Ϫ1 ; P ϭ 0.043). Thirteen subjects had increased hydrogen breath test concentrations after fiber consumption, indicating probable dietary adherence. Restricting analysis to these subjects, improvements in M value (6.85 Ϯ 0.34 vs. 6.06 Ϯ 0.32 mg ⅐ min Ϫ1 ⅐ kg Ϫ1 ; P ϭ 0.003) and insulin sensitivity, expressed as M/I ratio (M value divided by mean serum insulin at steady state: 3.73 Ϯ 0.23 vs. 3.21 Ϯ 0.27; P ϭ 0.02), after fiber consumption were more pronounced. Plasma lipids, serum magnesium, ghrelin, and adiponectin concentrations, as well as substrate utilization and body weight, were not significantly changed by fiber intake (P Ͼ 0.15).CONCLUSIONS -Increased insoluble dietary fiber intake for 3 days significantly improved whole-body insulin sensitivity. These data suggest a potential mechanism linking cereal fiber intake and reduced risk of type 2 diabetes. Diabetes Care 29:775-780, 2006T he epidemic of obesity-associated insulin resistance and type 2 diabetes is a major burden in modern societies. In population studies, cereal fiber intake is linked, by unknown mechanisms, to reduced risk of developing type 2 diabetes and cardiovascular disease (rev. in 1). Insoluble fibers are nonviscous with negligible effects on gastric emptying, macronutrient absorption from the gut, postprandial glucose responses, and blood lipids (1). In contrast, consumption of soluble viscous fibers reduces postprandial glucose responses and positively influences certain serum lipids (2). Surprisingly, epidemiological studies clearly show that principally insoluble cereal fibers appear to offer protection from cardiovascular disease and diabetes (1). Beneficial effects of cereal fibers are frequently discussed in the context of wholegrain consumption. Fruit, vegetables, unrefined whole grains, and bran products are highly complex substances, containing both soluble and insoluble dietary fibers as well as other biologically active substances, e.g., polyphenols, antioxidants, vitamins, trace mineral...