Metabolic dysfunction and risk of chronic disease

Abdominal obesity is associated with abnormal glucose metabolism, elevated blood pressure, dyslipidemia, and type 2 diabetes mellitus (T2D), which cluster within the Metabolic Syndrome (MetS). Components of MetS may not only be risk factors for cardiovascular disease (CVD), but also for certain cancers, particularly colorectal and liver (Nimptsch & Pischon, Horm Mol Biol Clin Invest 2015). As part of the Helmholtz Portfolio topic "Metabolic Dysfunction" we investigate associations of metabolic factors with chronic disease risk. For colorectal cancer (CRC) we found the association with MetS largely accounted for by abdominal obesity and abnormal glucose metabolism (Aleksandrova et al, Cancer Prev Res 2011). Abdominal obesity is mostly accounted for by visceral fat, which secretes a variety of cytokines and hormones. Within the large European Prospective Investigation into Cancer and Nutrition (EPIC), we evaluated in collaboration with the German Institute of Human Nutrition and other partners the extent to which 11 biomarkers may mediate the association of abdominal adiposity with colon cancer risk (Aleksandrova et al, Int J Cancer 2014). The positive association was mostly accounted for by 3 biomarkers, HDL-cholesterol, non-HMW adiponectin and soluble leptin receptor, suggesting that alterations in levels of these biomarkers may represent a mechanism of action.
Visceral adipose tissue derived cytokines may induce hepatic secretion of acute phase proteins, including C-reactive protein (CRP). We previously found higher CRP levels associated with higher CRC risk (Aleksandrova et al, Am J Epidemiol 2010). In a Mendelian Randomization approach we observed CRP genetic variability leading to raised CRP concentrations associated with higher risk of CRC (Nimptsch et al, Int J Cancer 2015), supporting the hypothesis that circulating CRP may play a causal role.
The liver is central in human metabolism, and obesity is associated with non-alcoholic steatosis, steatohepatitis, liver cirrhosis, and liver cancer. Fetuin-A is a liver protein that inhibits insulin actions, and studies found fetuin-A levels related to risk of T2D and CVD. Hyperinsulinemia is a possible risk factor for CRC, but the role of fetuin-A was unclear. We found higher circulating fetuin-A levels associated with a higher risk of CRC (Nimptsch et al, Int J Cancer 2015). Although fetuin-A genetic
variation explained a large proportion of fetuin-A levels, genetically determined higher fetuin-A was not associated with CRC, suggesting that fetuin-A may not be causally related to CRC.
We also studied prospectively the association of inflammatory and metabolic biomarkers with risks of liver and bilary tract cancers (Aleksandrova et al, Hepatology 2014). Higher concentrations of CRP, IL-6, C-peptide, and non-HMW adiponectin were associated with higher risk of hepatocellular carcinoma (HCC), suggesting that elevated levels of biomarkers of inflammation and hyperinsulinemia are associated with a higher risk of HCC, independent of obesity and established liver cancer risk factors, and may be able to improve risk assessment.
The insulin-like growth factor (IGF) axis mainly regulates cellular proliferation, differentiation and apoptosis, but has also been linked to type 2 diabetes mellitus (T2D). IGF binding protein 3 (IGFBP-3) may increase T2D risk via binding of IGF-1. We investigated together with partners from the German Institute of Human Nutrition serum concentrations of IGF-1, IGFBP-3 and their ratio in relation to T2D incidence within EPIC-Potsdam (Drogan et al, Am J Epidemiol 2016). Our findings did not confirm an association between IGF-1 and risk of T2D, whereas higher IGFBP-3 levels may increase T2D risk independent of IGF-1 levels.
Metabolomics is the simultaneous study of numerous low-molecular weight compounds. We previously identified 14 metabolites independently associated with risk of T2D, including sugar metabolites, amino acids, and choline-containing phospholipids (Floegel et al, Diabetes 2013). We currently investigate to what extent metabolites are associated with risk of cardiovascular disease.
Obesity has also been linked to cognitive impairment, although mechanisms are unclear. Post-operative cognitive dysfunction (POCD) is a frequent condition after surgery among persons within the general elderly population. POCD can also be considered a model to study the influences on cognitive impairment in general. In a meta-analysis, we found only a few studies that have investigated the association of obesity with risk of POCD and the results provide only limited support that obesity increases risk (Feinkohl et al, Diabetes Metab Res Rev 2016). As part of the project "BioCog - Biomarker Development for Postoperative Cognitive Impairment in the Elderly", supported within FP7 by the European Union we investigate associations of obesity and metabolic dysfunction with risk of POCD in detail.

References

Nimptsch K, Pischon T. Body fatness, related biomarkers and cancer risk: an epidemiological perspective. Hormone molecular biology and clinical investigation 2015;22:39-51

Aleksandrova K, Boeing H, Jenab M, Bas Bueno-de-Mesquita H, Jansen E, van Duijnhoven FJ, Fedirko V, Rinaldi S, Romieu I, Riboli E, Romaguera D, Overvad K, Ostergaard JN, Olsen A, Tjonneland A, Boutron-Ruault MC, Clavel-Chapelon F, Morois S, Masala G, Agnoli C, Panico S, Tumino R, Vineis P, Kaaks R, Lukanova A, Trichopoulou A, Naska A, Bamia C, Peeters PH, Rodriguez L, Buckland G, Sanchez MJ, Dorronsoro M, Huerta JM, Barricarte A, Hallmans G, Palmqvist R, Khaw KT, Wareham N, Allen NE, Tsilidis KK, Pischon T. Metabolic syndrome and risks of colon and rectal cancer: the European prospective investigation into cancer and nutrition study. Cancer Prev Res (Phila) 2011;4:1873-83

Aleksandrova K, Drogan D, Boeing H, Jenab M, Bas Bueno-de-Mesquita H, Jansen E, van Duijnhoven FJ, Rinaldi S, Fedirko V, Romieu I, Kaaks R, Riboli E, Gunter MJ, Romaguera D, Westhpal S, Overvad K, Tjonneland A, Halkjaer J, Boutron-Ruault MC, Clavel-Chapelon F, Lukanova A, Trichopoulou A, Trichopoulos D, Vidalis P, Panico S, Agnoli C, Palli D, Tumino R, Vineis P, Buckland G, Sanchez-Cruz JJ, Dorronsoro M, Diaz MJ, Barricarte A, Ramon Quiros J, Peeters PH, May AM, Hallmans G, Palmqvist R, Crowe FL, Khaw KT, Wareham N, Pischon T. Adiposity, mediating biomarkers and risk of colon cancer in the European prospective investigation into cancer and nutrition study. Int J Cancer 2014;134:612-21

Aleksandrova K, Jenab M, Boeing H, Jansen E, Bueno-de-Mesquita HB, Rinaldi S, Riboli E, Overvad K, Dahm CC, Olsen A, Tjonneland A, Boutron-Ruault MC, Clavel-Chapelon F, Morois S, Palli D, Krogh V, Tumino R, Vineis P, Panico S, Kaaks R, Rohrmann S, Trichopoulou A, Lagiou P, Trichopoulos D, van Duijnhoven FJ, Leufkens AM, Peeters PH, Rodriguez L, Bonet C, Sanchez MJ, Dorronsoro M, Navarro C, Barricarte A, Palmqvist R, Hallmans G, Khaw KT, Wareham N, Allen NE, Spencer E, Romaguera D, Norat T, Pischon T. Circulating C-reactive protein concentrations and risks of colon and rectal cancer: a nested case-control study within the European Prospective Investigation into Cancer and Nutrition. Am J Epidemiol 2010;172:407-18

Nimptsch K, Aleksandrova K, Boeing H, Janke J, Lee YA, Jenab M, Bueno-de-Mesquita HB, Jansen EH, Tsilidis KK, Trichopoulou A, Weiderpass E, Wu C, Overvad K, Tjonneland A, Boutron-Ruault MC, Dossus L, Racine A, Kaaks R, Canzian F, Lagiou P, Trichopoulos D, Palli D, Agnoli C, Tumino R, Vineis P, Panico S, Johansson A, Van Guelpen B, Khaw KT, Wareham N, Peeters PH, Quiros JR, Vencesla Garcia A, Molina-Montes E, Dorronsoro M, Chirlaque MD, Barricarte Gurrea A, Key TJ, Duarte-Salles T, Stepien M, Gunter MJ, Riboli E, Pischon T. Association of CRP genetic variants with blood concentrations of C-reactive protein and colorectal cancer risk. Int J Cancer 2015;136:1181-92

Nimptsch K, Aleksandrova K, Boeing H, Janke J, Lee YA, Jenab M, Kong SY, Tsilidis KK, Weiderpass E, Bueno-De-Mesquita HB, Siersema PD, Jansen EH, Trichopoulou A, Tjonneland A, Olsen A, Wu C, Overvad K, Boutron-Ruault MC, Racine A, Freisling H, Katzke V, Kaaks R, Lagiou P, Trichopoulos D, Severi G, Naccarati A, Mattiello A, Palli D, Grioni S, Tumino R, Peeters PH, Ljuslinder I, Nystrom H, Brandstedt J, Sanchez MJ, Gurrea AB, Bonet CB, Chirlaque MD, Dorronsoro M, Quiros JR, Travis RC, Khaw KT, Wareham N, Riboli E, Gunter MJ, Pischon T. Plasma fetuin-A concentration, genetic variation in the AHSG gene and risk of colorectal cancer. Int J Cancer 2015;137:911-20

Aleksandrova K, Boeing H, Nothlings U, Jenab M, Fedirko V, Kaaks R, Lukanova A, Trichopoulou A, Trichopoulos D, Boffetta P, Trepo E, Westhpal S, Duarte-Salles T, Stepien M, Overvad K, Tjonneland A, Halkjaer J, Boutron-Ruault MC, Dossus L, Racine A, Lagiou P, Bamia C, Benetou V, Agnoli C, Palli D, Panico S, Tumino R, Vineis P, Bueno-de-Mesquita B, Peeters PH, Gram IT, Lund E, Weiderpass E, Quiros JR, Agudo A, Sanchez MJ, Gavrila D, Barricarte A, Dorronsoro M, Ohlsson B, Lindkvist B, Johansson A, Sund M, Khaw KT, Wareham N, Travis RC, Riboli E, Pischon T. Inflammatory and metabolic biomarkers and risk of liver and biliary tract cancer. Hepatology 2014;60:858-71

Drogan D, Schulze MB, Boeing H, Pischon T. Insulin-Like Growth Factor 1 and Insulin-Like Growth Factor-Binding Protein 3 in Relation to the Risk of Type 2 Diabetes Mellitus: Results From the EPIC-Potsdam Study. Am J Epidemiol 2016;183:553-60

Floegel A, Stefan N, Yu Z, Muhlenbruch K, Drogan D, Joost HG, Fritsche A, Haring HU, Hrabe de Angelis M, Peters A, Roden M, Prehn C, Wang-Sattler R, Illig T, Schulze MB, Adamski J, Boeing H, Pischon T. Identification of serum metabolites associated with risk of type 2 diabetes using a targeted metabolomic approach. Diabetes 2013;62:639-48

Feinkohl I, Winterer G, Pischon T. Obesity and post-operative cognitive dysfunction: a systematic review and meta-analysis. Diabetes Metab Res Rev 2016