Skip to main content

Innovative biomarkers for predicting type 2 diabetes mellitus: relevance to dietary management of frailty in older adults

Biogerontology volume 17, pages 511–527 (2016)Cite this article

Abstract

Type 2 diabetes mellitus (T2DM) increases in prevalence in the elderly. There is evidence for significant muscle loss and accelerated cognitive impairment in older adults with T2DM; these comorbidities are critical features of frailty. In the early stages of T2DM, insulin sensitivity can be improved by a “healthy” diet. Management of insulin resistance by diet in people over 65 years of age should be carefully re-evaluated because of the risk for falling due to hypoglycaemia. To date, an optimal dietary programme for older adults with insulin resistance and T2DM has not been described. The use of biomarkers to identify those at risk for T2DM will enable clinicians to offer early dietary advice that will delay onset of disease and of frailty. Here we have used an in silico literature search for putative novel biomarkers of T2DM risk and frailty. We suggest that plasma bilirubin, plasma, urinary DPP4-positive microparticles and plasma pigment epithelium-derived factor merit further investigation as predictive biomarkers for T2DM and frailty risk in older adults. Bilirubin is screened routinely in clinical practice. Measurement of specific microparticle frequency in urine is less invasive than a blood sample so is a good choice for biomonitoring. Future studies should investigate whether early dietary changes, such as increased intake of whey protein and micronutrients that improve muscle function and insulin sensitivity, affect biomarkers and can reduce the longer term complication of frailty in people at risk for T2DM.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

References

  • Abbasi B, Kimiagar M, Sadeghniiat K, Shirazi MM, Hedayati M, Rashidkhani B (2012) The effect of magnesium supplementation on primary insomnia in elderly: a double-blind placebo-controlled clinical trial. J Res Med Sci 17:1161–1169

    PubMed  PubMed Central  Google Scholar 

  • Agouni A, Lagrue-lak-hal AH, Ducluzeau PH, Mostefai HA, Draunet-busson C, Leftheriotis G, Heymes C, Martinez MC, Andriantsitohaina R (2008) Endothelial dysfunction caused by circulating microparticles from patients with metabolic syndrome. Am J Pathol 173:1210–1219

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Alkhatatbeh M, Enjeti A, Acharya S, Thorne R, Lincz L (2013) The origin of circulating CD36 in type 2 diabetes. Nutr Diabetes 3:e59

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Andersson C, Weeke P, Fosbøl EL, Brendorp B, Køber L, Coutinho W, Sharma AM, Van gaal L, Finer N, James WPT (2009) Acute effect of weight loss on levels of total bilirubin in obese, cardiovascular high-risk patients: an analysis from the lead-in period of the Sibutramine Cardiovascular Outcome trial. Metabolism 58:1109–1115

    CAS  PubMed  Article  Google Scholar 

  • Association AD (2014) Diagnosis and classification of diabetes mellitus. Diabetes Care 37:S81–S90

    Article  Google Scholar 

  • Avogaro A, Fadini GP (2014) The effects of dipeptidyl peptidase-4 inhibition on microvascular diabetes complications. Diabetes Care 37:2884–2894

    CAS  PubMed  Article  Google Scholar 

  • Bakken AF, Schmid R, Thaler MM (1972) Metabolic regulation of heme catabolism and bilirubin production. 1. Hormonal-control of hepatic heme oxygenase activity. J Clin Investig 51:530

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Barañano DE, Rao M, Ferris CD, Snyder SH (2002) Biliverdin reductase: a major physiologic cytoprotectant. Proc Natl Acad Sci 99:16093–16098

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • Barateiro A, Miron VE, Santos SD, Relvas JB, Fernandes A, Brites D (2013) Unconjugated bilirubin restricts oligodendrocyte differentiation and axonal myelination. Mol Neurobiol 47:632–644

    CAS  PubMed  Article  Google Scholar 

  • Bauer JM, Verlaan S, Bautmans I, Brandt K, Donini LM, Maggio M, McMurdo ME, Mets T, Seal C, Wijers SL, Ceda GP, De Vito G, Donders G, Drey M, Greig C, Holmbäck U, Narici M, McPhee J, Poggiogalle E, Power D, Scafoglieri A, Schultz R, Sieber CC, Cederholm T (2015) Effects of a vitamin D and leucine-enriched whey protein nutritional supplement on measures of sarcopenia in older adults, the PROVIDE study: a randomized, double-blind, placebo-controlled trial. J Am Med Dir Assoc 16:740–747

    PubMed  Article  Google Scholar 

  • Becerra SP, Notario V (2013) The effects of PEDF on cancer biology: mechanisms of action and therapeutic potential. Nat Rev Cancer 13:258–271

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Becker J, Semler O, Gilissen C, Li Y, Bolz HJ, Giunta C, Bergmann C, Rohrbach M, Koerber F, Zimmermann K (2011) Exome sequencing identifies truncating mutations in human SERPINF1 in autosomal-recessive osteogenesis imperfecta. Am J Hum Genet 88:362–371

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Bell JA, Volpi E, Fujita S, Cadenas JG, Sheffield-Moore M, Rasmussen BB (2006) Skeletal muscle protein anabolic response to increased energy and insulin is preserved in poorly controlled type 2 diabetes. J Nutr 136:1249–1255

    CAS  PubMed  PubMed Central  Google Scholar 

  • Belo L, Nascimento H, Kohlova M, Bronze-da-rocha E, Fernandes J, Costa E, Catarino C, Aires L, Mansilha HF & Rocha-pereira P (2014) Body fat percentage is a major determinant of total bilirubin independently of UGT1A128 polymorphism in young obese, 9(6):e98467

  • Bernal-mizrachi L, Jy W, Jimenez JJ, Pastor J, Mauro LM, Horstman LL, De marchena E, Ahn YS (2003) High levels of circulating endothelial microparticles in patients with acute coronary syndromes. Am Heart J 145:962–970

    PubMed  Article  Google Scholar 

  • Bernard S, Loffroy R, Sérusclat A, Boussel L, Bonnefoy E, Thévenon C, Rabilloud M, Revel D, Moulin P, Douek P (2009) Increased levels of endothelial microparticles CD144 (VE-Cadherin) positives in type 2 diabetic patients with coronary noncalcified plaques evaluated by multidetector computed tomography (MDCT). Atherosclerosis 203:429–435

    CAS  PubMed  Article  Google Scholar 

  • Bidot L, Jy W, Bidot C, Jimenez J, Fontana V, Horstman L, Ahn Y (2008) Microparticle-mediated thrombin generation assay: increased activity in patients with recurrent thrombosis. J Thromb Haemost 6:913–919

    CAS  PubMed  Article  Google Scholar 

  • Bogan R, Riddle RC, Li Z, Kumar S, Nandal A, Faugere MC, Boskey A, Crawford SE, Clemens TL (2013) A mouse model for human osteogenesis imperfecta type VI. J Bone Miner Res 28:1531–1536

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Borg ML, Andrews ZB, Duh EJ, Zechner R, Meikle PJ, Watt MJ (2011) Pigment epithelium-derived factor regulates lipid metabolism via adipose triglyceride lipase. Diabetes 60:1458–1466

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Bosma PJ, Chowdhury JR, Bakker C, Gantla S, De boer A, Oostra BA, Lindhout D, Tytgat GN, Jansen PL, Elferink RPO (1995) The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert’s syndrome. N Engl J Med 333:1171–1175

    CAS  PubMed  Article  Google Scholar 

  • Bouzakri K, Plomgaard P, Berney T, Donath MY, Pedersen BK, Halban PA (2011) Bimodal effect on pancreatic β-cells of secretory products from normal or insulin-resistant human skeletal muscle. Diabetes 60:1111–1121

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Breen L, PhillipS SM (2013) Interactions between exercise and nutrition to prevent muscle waste during ageing. Br J Clin Pharmacol 75:708–715

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bulmer AC, Verkade H, Wagner K-H (2013) Bilirubin and beyond: a review of lipid status in Gilbert’s syndrome and its relevance to cardiovascular disease protection. Prog Lipid Res 52:193–205

    CAS  PubMed  Article  Google Scholar 

  • Chavan SS, Hudson LK, Li JH, Ochani M, Harris Y, Patel NB, Katz D, Scheinerman JA, Pavlov VA, Tracey KJ (2012) Identification of pigment epithelium-derived factor as an adipocyte-derived inflammatory factor. Mol Med 18:1161

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chen H, Jia W, Lu J, Bao Y, Li Q, Lu F, Lu W, Yu H, Xiang K (2007) Change and significance of serum pigment epithelium-derived factor in type 2 diabetic nephropathy. Zhonghua yi xue za zhi 87:1230–1233

    CAS  PubMed  Google Scholar 

  • Chen C, Tso AW, Law LS, Cheung BM, Ong K, Wat NM, Janus ED, Xu A, Lam KS (2010a) Plasma level of pigment epithelium-derived factor is independently associated with the development of the metabolic syndrome in Chinese men: a 10-year prospective study. J Clin Endocrinol Metab 95:5074–5081

    CAS  PubMed  Article  Google Scholar 

  • Chen LK, Chen YM, Lin MH, Peng LN, Hwang SJ (2010b) Care of elderly patients with diabetes mellitus: a focus on frailty. Ageing Res Rev 9(Suppl 1):S18–S22

    PubMed  Article  Google Scholar 

  • Chen J, Chen S, Chen Y, Zhang C, Wang J, Zhang W, Liu G, Zhao B, Chen Y (2011) Circulating endothelial progenitor cells and cellular membrane microparticles in db/db diabetic mouse: possible implications in cerebral ischemic damage. Am J Physiol Endocrinol Metab 301:E62–E71

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Chen Y, Feng B, Li X, Ni Y, Luo Y (2012) Plasma endothelial microparticles and their correlation with the presence of hypertension and arterial stiffness in patients with type 2 diabetes. J Clin Hypertens 14:455–460

    CAS  Article  Google Scholar 

  • Chiba Y, Kimbara Y, Kodera R, Tsuboi Y, Sato K, Tamura Y, Mori S, Ito H, Araki A (2015) Risk factors associated with falls in elderly patients with type 2 diabetes. J Diabetes Complicat 29(7):898–902

    PubMed  Article  Google Scholar 

  • Choi KM, Hwang SY, Hong HC, Yang SJ, Choi HY, Yoo HJ, Lee KW, Nam MS, Park YS, Woo JT (2012) C1q/TNF-related protein-3 (CTRP-3) and pigment epithelium-derived factor (PEDF) concentrations in patients with type 2 diabetes and metabolic syndrome. Diabetes 61:2932–2936

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Chung C, Doll JA, Gattu AK, Shugrue C, Cornwell M, Fitchev P, Crawford SE (2008) Anti-angiogenic pigment epithelium-derived factor regulates hepatocyte triglyceride content through adipose triglyceride lipase (ATGL). J Hepatol 48:471–478

    CAS  PubMed  Article  Google Scholar 

  • Crowe S, Wu LE, Economou C, Turpin SM, Matzaris M, Hoehn KL, Hevener AL, James DE, Duh EJ, Watt MJ (2009) Pigment epithelium-derived factor contributes to insulin resistance in obesity. Cell Metab 10:40–47

    CAS  PubMed  Article  Google Scholar 

  • Cruz-Jentoft A, Krznariç Z, Nair KS, Singer P, Teta D, Tipton K, Calder PC (2014) Protein intake and exercise for optimal muscle function with aging: recommendations from the ESPEN Expert Group. Clin Nutr 33:929–936

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • Dawson D, Volpert O, Gillis P, Crawford S, Xu H-J, Benedict W, Bouck N (1999) Pigment epithelium-derived factor: a potent inhibitor of angiogenesis. Science 285:245–248

    CAS  PubMed  Article  Google Scholar 

  • Deatherage BL, Cookson BT (2012) Membrane vesicle release in bacteria, eukaryotes, and archaea: a conserved yet underappreciated aspect of microbial life. Infect Immun 80:1948–1957

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Diabetes U (2014) Diabetes: facts and stats. Diabetes UK, London

    Google Scholar 

  • Djoussé L, Levy D, Cupples LA, Evans JC, D’agostino RB, Ellison RC (2001) Total serum bilirubin and risk of cardiovascular disease in the Framingham offspring study. Am J Cardiol 87:1196–1200

    PubMed  Article  Google Scholar 

  • Doll JA, Stellmach VM, Bouck NP, Bergh AR, Lee C, Abramson LP, Cornwell ML, Pins MR, Borensztajn J, Crawford SE (2003) Pigment epithelium–derived factor regulates the vasculature and mass of the prostate and pancreas. Nat Med 9:774–780

    CAS  PubMed  Article  Google Scholar 

  • Dong H, Huang H, Yun X, Kim D-S, Yue Y, Wu H, Sutter A, Chavin KD, Otterbein LE, Adams DB (2014) Bilirubin increases insulin sensitivity in leptin-receptor deficient and diet-induced obese mice through suppression of ER stress and chronic inflammation. Endocrinology 155:818–828

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Dreyer HC, Strycker LA, Senesac HA, Hocker AD, Smolkowski K, Shah SN, Jewett BA (2013) Essential amino acid supplementation in patients following total knee arthroplasty. J Clin Investig 123:4654–4666

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Duggan C, Xiao L, Wang C-Y, Mctiernan A (2014) Effect of a 12-month exercise intervention on serum biomarkers of angiogenesis in postmenopausal women: a randomized controlled trial. Cancer Epidemiol Biomark Prev 23:648–657

    CAS  Article  Google Scholar 

  • Dullaart RP, Kappelle PJ, De vries R (2012) Lower carotid intima media thickness is predicted by higher serum bilirubin in both non-diabetic and Type 2 diabetic subjects. Clin Chim Acta 414:161–165

    CAS  PubMed  Article  Google Scholar 

  • Dullaart RP, Boersema J, Lefrandt JD, Wolffenbuttel BH, Bakker SJ (2014) The inverse association of incident cardiovascular disease with plasma bilirubin is unaffected by adiponectin. Atherosclerosis 235:380–383

    CAS  PubMed  Article  Google Scholar 

  • Elahy M, Baindur-hudson S, Dass CR (2012) The emerging role of PEDF in stem cell biology. BioMed Res Int 29:167–173

    Google Scholar 

  • Evans WJ (2010) Skeletal muscle loss: cachexia, sarcopenia, and inactivity. Am J Clin Nutr 91:1123S–1127S

    CAS  PubMed  Article  Google Scholar 

  • Evans WJ, Paolisso G, Abbatecola AM, Corsonello A, Bustacchini S, Strollo F, Lattanzio F (2010) Frailty and muscle metabolism dysregulation in the elderly. Biogerontology 11:527–536

    CAS  PubMed  Article  Google Scholar 

  • Felsher BF, Rickard D, Redeker AG (1970) Reciprocal Relation between Caloric Intake and Degree of Hyperbilirubinemia in Gilberts Syndrome. N Engl J Med 283:170

    CAS  PubMed  Article  Google Scholar 

  • Feng B, Chen Y, Luo Y, Chen M, Li X, Ni Y (2010) Circulating level of microparticles and their correlation with arterial elasticity and endothelium-dependent dilation in patients with type 2 diabetes mellitus. Atherosclerosis 208:264–269

    CAS  PubMed  Article  Google Scholar 

  • Filleur S, Nelius T, De Riese W, Kennedy R (2009) Characterization of PEDF: a multi-functional serpin family protein. J Cell Biochem 106:769–775

    CAS  PubMed  Article  Google Scholar 

  • Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, Seeman T, Tracy R, Kop WJ, Burke G, McBurnie MA (2001) Frailty in older adults: evidence for a phenotype. J Gerontol A 56:M146–M156

    CAS  Article  Google Scholar 

  • Fu YY, Kang KJ, Ahn JM, Kim H-R, Na KY, Chae D-W, Kim S, Chin HJ (2010) Hyperbilirubinemia reduces the streptozotocin-induced pancreatic damage through attenuating the oxidative stress in the Gunn rat. Tohoku J Exp Med 222:265–273

    CAS  PubMed  Article  Google Scholar 

  • Fujii M, Inoguchi T, Sasaki S, Maeda Y, Zheng J, Kobayashi K, Takayanagi R (2010) Bilirubin and biliverdin protect rodents against diabetic nephropathy by downregulating NAD (P) H oxidase. Kidney Int 78:905–919

    CAS  PubMed  Article  Google Scholar 

  • Fujita S, Glynn EL, Timmerman KL, Rasmussen BB, Volpi E (2009) Supraphysiological hyperinsulinaemia is necessary to stimulate skeletal muscle protein anabolism in older adults: evidence of a true age-related insulin resistance of muscle protein metabolism. Diabetologia 52:1889–1898

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Fukui M, Tanaka M, Shiraishi E, Harusato I, Hosoda H, Asano M, Hasegawa G, Nakamura N (2008) Relationship between serum bilirubin and albuminuria in patients with type 2 diabetes. Kidney Int 74:1197–1201

    CAS  PubMed  Article  Google Scholar 

  • Gaetano C, Colussi C, Capogrossi MC (2007) PEDF, PPAR-δ, p53: deadly circuits arise when worlds collide. Cardiovasc Res 76:195–196

    CAS  PubMed  Article  Google Scholar 

  • Gao D, Griffiths HR, Bailey CJ (2009) Oleate protects against palmitate-induced insulin resistance in L6 myotubes. Br J Nutr 102:1557–1563

    CAS  PubMed  Article  Google Scholar 

  • Gao D, Pararasa C, Dunston CR, Bailey CJ, Griffiths HR (2012) Palmitate promotes monocyte atherogenicity via de novo ceramide synthesis. Free Radic Biol Med 53:796–806

    CAS  PubMed  Article  Google Scholar 

  • Gattu AK, Swenson ES, Iwakiri Y, Samuel VT, Troiano N, Berry R, Church CD, Rodeheffer MS, Carpenter TO, Chung C (2013) Determination of mesenchymal stem cell fate by pigment epithelium-derived factor (PEDF) results in increased adiposity and reduced bone mineral content. FASEB J 27:4384–4394

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Gattu AK, Birkenfeld AL, Iwakiri Y, Jay S, Saltzman M, Doll J, Protiva P, Samuel VT, Crawford SE, Chung C (2014) Pigment epithelium-derived factor (PEDF) suppresses IL-1β-mediated c-Jun N-terminal kinase (JNK) activation to improve hepatocyte insulin signaling. Endocrinology 155:1373–1385

    PubMed  Article  CAS  Google Scholar 

  • Greenspan SL, Perera S, Ferchak MA, Nace DA, Resnick NM (2015) Efficacy and safety of single-dose zoledronic Acid for osteoporosis in frail elderly women: a randomized clinical trial. JAMA Intern Med 175:913–921

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • Guzek M, Jakubowski Z, Bandosz P, Wyrzykowski B, Smoczyński M, Jabloiska A, Zdrojewski T (2011) Inverse association of serum bilirubin with metabolic syndrome and insulin resistance in Polish population. Przegl Epidemiol 66:495–501

    Google Scholar 

  • Han SS, Na KY, Chae D-W, Kim YS, Kim S, Chin HJ (2010) High serum bilirubin is associated with the reduced risk of diabetes mellitus and diabetic nephropathy. Tohoku J Exp Med 221:133–140

    CAS  PubMed  Article  Google Scholar 

  • He X, Cheng R, Benyajati S, Ma J-X (2015) PEDF and its roles in physiological and pathological conditions: implication in diabetic and hypoxia-induced angiogenic diseases. Clin Sci 128:805–823

    PubMed  PubMed Central  Article  Google Scholar 

  • Hopkins PN, Wu LL, Hunt SC, James BC, Vincent GM, Williams RR (1996) Higher serum bilirubin is associated with decreased risk for early familial coronary artery disease. Arterioscler Thromb Vasc Biol 16:250–255

    CAS  PubMed  Article  Google Scholar 

  • Hruby A, O’donnell CJ, Jacques PF, Meigs JB, Hoffmann U, Mckeown NM (2014) Magnesium intake is inversely associated with coronary artery calcification: the Framingham Heart Study. JACC Cardiovasc Imaging 7:59–69

    PubMed  PubMed Central  Article  Google Scholar 

  • Hulsmans M & Holvoet P (2013) MicroRNA-containing microvesicles regulating inflammation in association with atherosclerotic disease. Cardiovasc Res, cvt161

  • Ingelfinger JR, Watchko JF, Tiribelli C (2013) Bilirubin-induced neurologic damage—mechanisms and management approaches. N Engl J Med 369:2021–2030

    Article  CAS  Google Scholar 

  • Inoguchi T, Sasaki S, Kobayashi K, Takayanagi R, Yamada T (2007) Relationship between Gilbert syndrome and prevalence of vascular complications in patients with diabetes. JAMA 298:1396–1400

    Article  Google Scholar 

  • Ishikawa K, Navab M, Leitinger N, Fogelman AM, Lusis AJ (1997) Induction of heme oxygenase-1 inhibits the monocyte transmigration induced by mildly oxidized LDL. J Clin Investig 100:1209

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Jenkins A, Zhang SX, Gosmanova A, Aston C, Dashti A, Baker MZ, Lyons T, Ma J-X (2008) Increased serum pigment epithelium derived factor levels in Type 2 diabetes patients. Diabetes Res Clin Pract 82:e5–e7

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Jenkins AJ, Fu D, Azar M, Stoner JA, Kaufman DG, Zhang S, Klein RL, Lopes-virella MF, Ma J-X, Lyons TJ (2014) Clinical correlates of serum pigment epithelium-derived factor in type 2 diabetes patients. J Diabetes Complic 28:353–359

    Article  Google Scholar 

  • Joham AE, Teede HJ, Hutchison SK, Stepto NK, Harrison CL, Strauss BJ, Paul E, Watt MJ (2012) Pigment epithelium-derived factor, insulin sensitivity, and adiposity in polycystic ovary syndrome: impact of exercise training. Obesity 20:2390–2396

    CAS  PubMed  Article  Google Scholar 

  • Johnston SS, Conner C, Aagren M, Ruiz K, Bouchard J (2012) Association between hypoglycaemic events and fall-related fractures in Medicare-covered patients with type 2 diabetes. Diabetes Obes Metab 14:634–643

    CAS  PubMed  Article  Google Scholar 

  • Jung K-H, Chu K, Lee S-T, Bahn J-J, Kim J-H, Kim M, Lee SK, Roh J-K (2011) Risk of macrovascular complications in type 2 diabetes mellitus: endothelial microparticle profiles. Cerebrovasc Diseases 31:485–493

    Article  Google Scholar 

  • Jung CH, Lee MJ, Kang YM, Hwang JY, Jang JE, Leem J, Park J-Y, Kim H-K, Lee WJ (2014) Higher serum bilirubin level as a protective factor for the development of diabetes in healthy Korean men: a 4 year retrospective longitudinal study. Metabolism 63:87–93

    CAS  PubMed  Article  Google Scholar 

  • Kalousova M, Novotny L, Zima T, Braun M, Vitek L (2005) Decreased levels of advanced glycation end-products in patients with Gilbert syndrome. Cell Mol Biol 51:387–392

    CAS  PubMed  Google Scholar 

  • Kang SJ, Lee C, Kruzliak P (2014) Effects of serum bilirubin on atherosclerotic processes. Ann Med 46:138–147

    CAS  PubMed  Article  Google Scholar 

  • Kao T, Chou C, Wang C, Chou C, Hu J, Chen W (2012) Associations between serum total bilirubin levels and functional dependence in the elderly. Internal Med J 42:1199–1207

    CAS  Article  Google Scholar 

  • Katakami N, Kaneto H, Yamasaki Y, Matsuhisa M (2008) Increased serum pigment epithelium-derived factor levels in type 1 diabetic patients with diabetic retinopathy. Diabetes Res Clin Pract 81:e4–e7

    CAS  PubMed  Article  Google Scholar 

  • Kawamura K, Ishikawa K, Wada Y, Kimura S, Matsumoto H, Kohro T, Itabe H, Kodama T, Maruyama Y (2005) Bilirubin from heme oxygenase-1 attenuates vascular endothelial activation and dysfunction. Arterioscler Thromb Vasc Biol 25:155–160

    CAS  PubMed  Google Scholar 

  • Kim F, Pham M, Luttrell I, Bannerman DD, Tupper J, Thaler J, Hawn TR, Raines EW, Schwartz MW (2007) Toll-like receptor-4 mediates vascular inflammation and insulin resistance in diet-induced obesity. Circ Res 100:1589–1596

    CAS  PubMed  Article  Google Scholar 

  • Kimm H, Yun JE, Jo J, Jee SH (2009) Low serum bilirubin level as an independent predictor of stroke incidence a prospective study in Korean men and women. Stroke 40:3422–3427

    CAS  PubMed  Article  Google Scholar 

  • Ko GT, Chan JC, Woo J, Lau E, Yeung VT, Chow C-C, Li JK, So W-Y, Cockram CS (1996) Serum bilirubin and cardiovascular risk factors in a Chinese population. J Cardiovasc Risk 3:459–463

    CAS  PubMed  Article  Google Scholar 

  • Kobayashi S, Satoh M, Namikoshi T, Haruna Y, Fujimoto S, Arakawa S, Komai N, Tomita N, Sasaki T, Kashihara N (2008) Blockade of serotonin 2A receptor improves glomerular endothelial function in rats with streptozotocin-induced diabetic nephropathy. Clin Exp Nephrol 12:119–125

    CAS  PubMed  Article  Google Scholar 

  • Koga H, Sugiyama S, Kugiyama K, Watanabe K, Fukushima H, Tanaka T, Sakamoto T, Yoshimura M, Jinnouchi H, Ogawa H (2005) Elevated levels of VE-cadherin-positive endothelial microparticles in patients with type 2 diabetes mellitus and coronary artery disease. J Am Coll Cardiol 45:1622–1630

    CAS  PubMed  Article  Google Scholar 

  • Kurtzman N, Zhang L, French B, Jonas R, Bantly A, Rogers WT, Moore JS, Rickels MR, Mohler ER (2013) Personalized cytomic assessment of vascular health: evaluation of the vascular health profile in diabetes mellitus. Cytom Part B 84:255–266

    Article  CAS  Google Scholar 

  • Lee M, Jung C, Kang Y, Hwang J, Jang J, Leem J, Park J-Y, Kim H-K, Lee W (2014) Serum bilirubin as a predictor of incident metabolic syndrome: a 4-year retrospective longitudinal study of 6205 initially healthy Korean men. Diabetes Metab 40:305–309

    CAS  PubMed  Article  Google Scholar 

  • Leroyer A, Tedgui A, Boulanger C (2008) Microparticles and type 2 diabetes. Diabetes & metabolism 34:27–32

    Article  Google Scholar 

  • Li P, Qin C (2015) Elevated circulating VE-cadherin+CD144+ endothelial microparticles in ischemic cerebrovascular disease. Thromb Res 135:375–381

    CAS  PubMed  Article  Google Scholar 

  • Li F, Song N, Tombran-tink J, Niyibizi C (2013) pigment epithelium-derived factor enhances differentiation and mineral deposition of human mesenchymal stem cells. Stem Cells 31:2714–2723

    CAS  PubMed  Article  Google Scholar 

  • Li F, Song N, Tombran‐tink J, Niyibizi C (2015) Pigment epithelium derived factor suppresses expression of Sost/sclerostin by osteocytes: implication for its role in bone matrix mineralization. J Cell Physiol 230:1243–1249

    CAS  PubMed  Article  Google Scholar 

  • Little KM, Smalley DM, Harthun NL, Ley K (2010) The plasma microparticle proteome. Semin Thromb Hemost 36:845–856

    CAS  PubMed  Article  Google Scholar 

  • Liu M-L, Williams KJ (2012) Microvesicles: potential markers and mediators of endothelial dysfunction. Curr Opin Endocrinol Diabetes Obes 19:121–127

    CAS  PubMed  Article  Google Scholar 

  • Liu J, Wang L, Tian XY, Liu L, Wong WT, Zhang Y, Han Q-B, Ho H-M, Wang N, Wong SL (2015) Unconjugated bilirubin mediates heme oxygenase-1–induced vascular benefits in diabetic mice. Diabetes 64:1564–1575

    CAS  PubMed  Article  Google Scholar 

  • Lourenco dos santos S, Baraibar MA, Lundberg S, Eeg-olofsson O, Larsson L, Friguet B (2015) Oxidative proteome alterations during skeletal muscle ageing. Redox Biol 5:267–274

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Lu CL, Hsu PC, Shen HN, Chang YH, Chen HF, Li CY (2015) Association between history of severe hypoglycemia and risk of falls in younger and older patients with diabetes. Medicine 94:e1339

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Maggio M, De vita F, Lauretani F, Butto V, Bondi G, Cattabiani C, Nouvenne A, Meschi T, Dall’aglio E, Ceda GP (2013) IGF-1, the cross road of the nutritional, inflammatory and hormonal pathways to frailty. Nutrients 5:4184–4205

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Maggio M, De vita F, Lauretani F, Nouvenne A, Meschi T, Ticinesi A, Dominguez LJ, Barbagallo M, Dall’aglio E, Ceda GP (2014) The Interplay between Magnesium and testosterone in modulating physical function in men. Int J Endocrinol 2014:525249

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • Martin S, Tesse A, Hugel B, Martínez MC, Morel O, Freyssinet J-M, Andriantsitohaina R (2004) Shed membrane particles from T lymphocytes impair endothelial function and regulate endothelial protein expression. Circulation 109:1653–1659

    PubMed  Article  Google Scholar 

  • Matsuyama K, Ogata N, Matsuoka M, Shima C, Wada M, Jo N, Matsumura M (2008) Relationship between pigment epithelium-derived factor (PEDF) and renal function in patients with diabetic retinopathy. Mol Vision 14:992

    CAS  Google Scholar 

  • Mazzone GL, Rigato I, Ostrow JD, Bossi F, Bortoluzzi A, Sukowati CH, Tedesco F, Tiribelli C (2009) Bilirubin inhibits the TNFα-related induction of three endothelial adhesion molecules. Biochem Biophys Res Commun 386:338–344

    CAS  PubMed  Article  Google Scholar 

  • Mölzer C, Huber H, Diem K, Wallner M, Bulmer AC, Wagner K-H (2013) Extracellular and intracellular anti-mutagenic effects of bile pigments in the Salmonella typhimurium reverse mutation assay. Toxicol Vitro 27:433–437

    Article  CAS  Google Scholar 

  • Morita T, Imai T, Yamaguchi T, Sugiyama T, Katayama S, Yoshino G (2003) Induction of heme oxygenase-1 in monocytes suppresses angiotensin II-elicited chemotactic activity through inhibition of CCR2: role of bilirubin and carbon monoxide generated by the enzyme. Antioxid Redox Signal 5:439–447

    CAS  PubMed  Article  Google Scholar 

  • Muller MJ, Geisler C, Pourhassan M, Gluer CC, Bosy-westphal A (2014) Assessment and definition of lean body mass deficiency in the elderly. Eur J Clin Nutr 68:1220–1227

    CAS  PubMed  Article  Google Scholar 

  • Nakamura K, Yamagishi SI, Adachi H, Kurita-NAKAMURA Y, Matsui T, Inoue H (2009) Serum levels of pigment epithelium-derived factor (PEDF) are positively associated with visceral adiposity in Japanese patients with type 2 diabetes. Diabetes 25:52–56

    CAS  Google Scholar 

  • Nakamura K, Yamagishi S-I, Adachi H, Matsui T, Kurita Y, Imaizumi T (2010) Serum levels of pigment epithelium-derived factor (PEDF) are an independent determinant of insulin resistance in patients with essential hypertension. Int J Cardiol 143:96–98

    PubMed  Article  Google Scholar 

  • Nomura S, Shouzu A, Omoto S, Nishikawa M, Iwasaka T (2004) Effects of losartan and simvastatin on monocyte-derived microparticles in hypertensive patients with and without type 2 diabetes mellitus. Clin Appl Thrombosis 10:133–141

    CAS  Article  Google Scholar 

  • Nomura S, Shouzu A, Omoto S, Nishikawa M, Iwasaka T (2005) Benidipine improves oxidized LDL-dependent monocyte and endothelial dysfunction in hypertensive patients with type 2 diabetes mellitus. J Hum Hypertens 19:551–557

    CAS  PubMed  Article  Google Scholar 

  • Nomura S, Shouzu A, Omoto S, Nishikawa M, Fukuhara S, Iwasaka T (2006) Effect of valsartan on monocyte/endothelial cell activation markers and adiponectin in hypertensive patients with type 2 diabetes mellitus. Thrombosis Res 117:385–392

    CAS  Article  Google Scholar 

  • Nomura S, Inami N, Kimura Y, Omoto S, Shouzu A, Nishikawa M, Iwasaka T (2007) Effect of nifedipine on adiponectin in hypertensive patients with type 2 diabetes mellitus. J Hum Hypertens 21:38–44

    CAS  PubMed  Article  Google Scholar 

  • Nomura S, Inami N, Shouzu A, Urase F, Maeda Y (2009) Correlation and association between plasma platelet-, monocyte-and endothelial cell-derived microparticles in hypertensive patients with type 2 diabetes mellitus. Platelets 20:406–414

    CAS  PubMed  Article  Google Scholar 

  • Notari L, Arakaki N, Mueller D, Meier S, Amaral J, Becerra SP (2010) Pigment epithelium-derived factor binds to cell-surface F1-ATP synthase. FEBS J 277:2192–2205

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Oberbach A, Blüher M, Wirth H, Till H, Kovacs P, Kullnick Y, Schlichting N, Tomm JM, Rolle-kampczyk U, Murugaiyan J (2011) Combined proteomic and metabolomic profiling of serum reveals association of the complement system with obesity and identifies novel markers of body fat mass changes. J Proteome Res 10:4769–4788

    CAS  PubMed  Article  Google Scholar 

  • Ogata N, Imaizumi M, Nomura S, Shozu A, Arichi M, Matsuoka M, Matsumura M (2005) Increased levels of platelet-derived microparticles in patients with diabetic retinopathy. Diabetes Res Clin Pract 68:193–201

    CAS  PubMed  Article  Google Scholar 

  • Ogata N, Nomura S, Shouzu A, Imaizumi M, Arichi M, Matsumura M (2006) Elevation of monocyte-derived microparticles in patients with diabetic retinopathy. Diabetes Res Clin Pract 73:241–248

    CAS  PubMed  Article  Google Scholar 

  • Ogata N, Matsuoka M, Matsuyama K, Shima C, Tajika A, Nishiyama T, Wada M, Jo N, Higuchi A, Minamino K (2007) Plasma concentration of pigment epithelium-derived factor in patients with diabetic retinopathy. J Clin Endocrinol Metab 92:1176–1179

    CAS  PubMed  Article  Google Scholar 

  • Omoto S, Nomura S, Shouzu A, Nishikawa M, Fukuhara S, Iwasaka T (2002) Detection of monocyte-derived microparticles in patients with Type II diabetes mellitus. Diabetologia 45:550–555

    CAS  PubMed  Article  Google Scholar 

  • Oosterwerff MM, Eekhoff EM, van Schoor NM, Boeke AJP, Nanayakkara P, Meijnen R, Knol DL, Kramer MH, Lips P (2014) Effect of moderate-dose vitamin D supplementation on insulin sensitivity in vitamin D–deficient non-Western immigrants in the Netherlands: a randomized placebo-controlled trial. Am J Clin Nutr 100:152–160

    CAS  PubMed  Article  Google Scholar 

  • Pararasa C, Bailey CJ, Griffiths HR (2015) Ageing, adipose tissue, fatty acids and inflammation. Biogerontology 16:235–248

    CAS  PubMed  Article  Google Scholar 

  • Perlstein TS, Pande RL, Creager MA, Weuve J, Beckman JA (2008) Serum total bilirubin level, prevalent stroke, and stroke outcomes: NHANES 1999–2004. Am J Med 121(781–788):e1

    PubMed  Google Scholar 

  • Perry IJ, Wannamethee SG, Walker MK, Thomson A, Whincup PH, Shaper AG (1995) Prospective study of risk factors for development of non-insulin dependent diabetes in middle aged British men. BMJ 310:560–564

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Peters SA, Huxley RR, Woodward M (2014) Diabetes as a risk factor for stroke in women compared with men: a systematic review and meta-analysis of 64 cohorts, including 775 385 individuals and 12 539 strokes. Lancet 383:1973–1980

    PubMed  Article  Google Scholar 

  • Piccin A, Murphy WG, Smith OP (2007) Circulating microparticles: pathophysiology and clinical implications. Blood Rev 21:157–171

    CAS  PubMed  Article  Google Scholar 

  • Pirro M, Schillaci G, Paltriccia R, Bagaglia F, Menecali C, Mannarino MR, Capanni M, Velardi A, Mannarino E (2006) Increased ratio of CD31+/CD42− microparticles to endothelial progenitors as a novel marker of atherosclerosis in hypercholesterolemia. Arterioscler Thrombosis Vascu Biol 26:2530–2535

    CAS  Article  Google Scholar 

  • Puddu P, Puddu GM, Cravero E, Muscari S, Muscari A (2010) The involvement of circulating microparticles in inflammation, coagulation and cardiovascular diseases. Can J Cardiol 26:e140–e145

    PubMed Central  Article  Google Scholar 

  • Qaisiya M, Zabetta CDC, Bellarosa C, Tiribelli C (2014) Bilirubin mediated oxidative stress involves antioxidant response activation via Nrf2 pathway. Cell Signal 26:512–520

    CAS  PubMed  Article  Google Scholar 

  • Quan GM, Ojaimi J, Li Y, Kartsogiannis V, Zhou H, Choong PF (2005) Localization of pigment epithelium-derived factor in growing mouse bone. Calcif Tissue Int 76:146–153

    CAS  PubMed  Article  Google Scholar 

  • Rana KS, Arif M, Hill EJ, Aldred S, Nagel DA, Nevill A, Randeva HS, Bailey CJ, Bellary S, Brown JE (2014) Plasma irisin levels predict telomere length in healthy adults. Age 36:995–1001

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Raschke S, Eckardt K, Holven KB, Jensen J & Eckel J (2013) Identification and validation of novel contraction-regulated myokines released from primary human skeletal muscle cells

  • Rockwood K, Song X, Macknight C, Bergman H, Hogan DB, Mcdowell I, Mitnitski A (2005) A global clinical measure of fitness and frailty in elderly people. CMAJ 173:489–495

    PubMed  PubMed Central  Article  Google Scholar 

  • Rodríguez-mañas L, Féart C, Mann G, Viña J, Chatterji S, Chodzko-zajko W, Gonzalez-Colaço Harmand M, Bergman H, Carcaillon L, Nicholson C, Scuteri A, Sinclair A, Pelaez M, van der Cammen T, Beland F, Bickenbach J, Delamarche P, Ferrucci L, Fried LP, Gutiérrez-robledo LM, Rockwood K, Rodríguez Artalejo F, Serviddio G, Vega E, Behalf ON, ON Behalf OF THE, F. O. D. C. C. G (2013) Searching for an operational definition of frailty: a delphi method based consensus statement. the frailty operative definition-consensus conference project. J GerontolSer A 68:62–67

    Article  Google Scholar 

  • Rotter I, Kosik-Bogacka D, Dolegowska B, Safranow K, Lubkowska A, Laszczynska M (2015) Relationship between the concentrations of heavy metals and bioelements in aging men with metabolic syndrome. Int J Environ Res Public Health 12:3944–3961

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Russell WR, Baka A, Bjorck I, Delzenne N, Gao D, Griffiths HR, Hadjilucas E, Juvonen K, Lahtinen S, Lansink M, van Loon L, Mykkanen H, Ostman E, Riccardi G, Vinoy S, Weickert MO (2013) Impact of diet composition on blood glucose regulation. Crit Rev Food Sci Nutr. doi:10.1080/10408398.2013.792772

    Google Scholar 

  • Saarela RK, Soini H, Hiltunen K, Muurinen S, Suominen M, Pitkälä K (2014) Dentition status, malnutrition and mortality among older service housing residents. J Nutr Health Aging 18:34–38

    CAS  PubMed  Article  Google Scholar 

  • Sabater M, Moreno-navarrete JM, José Or Tega F, Pardo G, Salvador J, Ricart W, Fruhbeck G, Fernández-real J (2010) Circulating pigment epithelium-derived factor levels are associated with insulin resistance and decrease after weight loss. J Clin Endocrinol Metab 95:4720–4728

    CAS  PubMed  Article  Google Scholar 

  • Sacheck JM, Ohtsuka A, McLary SC, Goldberg AL (2004) IGF-I stimulates muscle growth by suppressing protein breakdown and expression of atrophy-related ubiquitin ligases, atrogin-1 and MuRF1. Am J Physiol Endocrinol Metab 287:E591–E601

    CAS  PubMed  Article  Google Scholar 

  • Sandri M, Barberi L, Bijlsma AY, Blaauw B, Dyar KA, Milan G, Mammucari C, Meskers CG, Pallafacchina G, Paoli A, Pion D, Roceri M, Romanello V, Serrano AL, Toniolo L, Larsson L, Maier AB, Muñoz-Cánoves P, Musarò A, Pende M, Reggiani C, Rizzuto R, Schiaffino S (2013) Signalling pathways regulating muscle mass in ageing skeletal muscle: the role of the IGF1-Akt-mTOR-FoxO pathway. Biogerontology 14:303–323

    CAS  PubMed  Article  Google Scholar 

  • Sato H, Adachi Y, Koiwai O (1996) The genetic basis of Gilbert’s syndrome. Lancet 347:557–558

    CAS  PubMed  Article  Google Scholar 

  • Schwartz AV, Schafer AL, Grey A, Vittinghoff E, Palermo L, Lui LY, Wallace RB, Cummings SR, Black DM, Bauer DC, Reid IR (2013) Effects of antiresorptive therapies on glucose metabolism: results from the FIT, HORIZON-PFT, and FREEDOM trials. J Bone Miner Res 28:1348–1354

    CAS  PubMed  Article  Google Scholar 

  • Schwertner HA, Fischer JR Jr (2000) Comparison of various lipid, lipoprotein, and bilirubin combinations as risk factors for predicting coronary artery disease. Atherosclerosis 150:381–387

    CAS  PubMed  Article  Google Scholar 

  • Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS (2006) TLR4 links innate immunity and fatty acid–induced insulin resistance. J Clin Investig 116:3015

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Shouzu A, Nomura S, Hayakawa T, Omoto S, Shimizu H, Miyake Y, Yonemoto T, Fukuhara S, Iwasaka T, Nishikawa M (2000) State-of-the-art review: effect of sarpogrelate hydrochloride on platelet-derived microparticles and various soluble adhesion molecules in diabetes mellitus. Clin Appl Thromb/Hemost 6:139–143

    CAS  Article  Google Scholar 

  • Shouzu A, Nomura S, Omoto S, Hayakawa T, Nishikawa M, Iwasaka T (2004) Effect of ticlopidine on monocyte-derived microparticles and activated platelet markers in diabetes mellitus. Clin Appl Thrombosis 10:167–173

    CAS  Article  Google Scholar 

  • Signorovitch JE, Macaulay D, Diener M, Yan Y, Wu EQ, Gruenberger JB, Frier BM (2013) Hypoglycaemia and accident risk in people with type 2 diabetes mellitus treated with non-insulin antidiabetes drugs. Diabetes Obes Metab 15:335–341

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Sinclair AJ, Conroy SP, Bayer AJ (2008) Impact of diabetes on physical function in older people. Diabetes Care 31:233–235

    PubMed  Article  Google Scholar 

  • Sinclair A, Dunning T, Rodriguez-manas L (2015) Diabetes in older people: new insights and remaining challenges. Lancet Diabetes Endocrinol 3:275–285

    PubMed  Article  Google Scholar 

  • Sinning J-M, Losch J, Walenta K, Böhm M, Nickenig G & Werner N (2010) Circulating CD31+/Annexin V+ microparticles correlate with cardiovascular outcomes. Eur Heart J, ehq478

  • Soares MP, Seldon MP, Gregoire IP, Vassilevskaia T, Berberat PO, Yu J, Tsui T-Y, Bach FH (2004) Heme oxygenase-1 modulates the expression of adhesion molecules associated with endothelial cell activation. J Immunol 172:3553–3563

    CAS  PubMed  Article  Google Scholar 

  • Soe K, Sacerdote A, Karam J, Bahtiyar G (2011) Management of type 2 diabetes mellitus in the elderly. Maturitas 70:151–159

    CAS  PubMed  Article  Google Scholar 

  • Sorrentino D, Stump DD, Zhou SL, Vanness K, Isola LM, Berk PD (1994) the hepatocellular uptake of free fatty-acids is selectively preserved during starvation. Gastroenterology 107:1415–1424

    CAS  PubMed  Article  Google Scholar 

  • Stocker R, Yamamoto Y, McDonagh AF, Glazer AN, Ames BN (1987) Bilirubin is an antioxidant of possible physiological importance. Science 235:1043–1046

    CAS  PubMed  Article  Google Scholar 

  • Sun A-L, Deng J-T, Guan G-J, Chen S-H, Liu Y-T, Cheng J, Li Z-W, Zhuang X-H, Sun F-D, Deng H-P (2012) Dipeptidyl peptidase-IV is a potential molecular biomarker in diabetic kidney disease. Diabetes Vasc Disease Res 9:301–308

    Article  Google Scholar 

  • Sunderland KL, Tryggestad JB, Wang JJ, Teague AM, Pratt LV, Zhang SX, Thompson DM, Short KR (2012) Pigment epithelium-derived factor (PEDF) varies with body composition and insulin resistance in healthy young people. J Clin Endocrinol Metab 97:E2114–E2118

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Tahara N, Yamagishi S-I, Tahara A, Nitta Y, Kodama N, Mizoguchi M, Mohar D, Ishibashi M, Hayabuchi N, Imaizumi T (2011) Serum level of pigment epithelium-derived factor is a marker of atherosclerosis in humans. Atherosclerosis 219:311–315

    CAS  PubMed  Article  Google Scholar 

  • Ter borg S, Verlaan S, Hemsworth J, Mijnarends DM, Schols JM, Luiking YC, De groot LC (2015) Micronutrient intakes and potential inadequacies of community-dwelling older adults: a systematic review. Br J Nutr 113:1195–1206

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Terrisse A, Puech N, Allart S, Gourdy P, Xuereb J, Payrastre B, Sie P (2010) Internalization of microparticles by endothelial cells promotes platelet/endothelial cell interaction under flow. J Thrombosis Haemost 8:2810–2819

    CAS  Article  Google Scholar 

  • Theron L, Gueugneau M, Coudy C, Viala D, Bijlsma A, Butler-browne G, Maier A, Bechet D, Chambon C (2014) Label-free quantitative protein profiling of vastus lateralis muscle during human aging. Mol Cell Proteomics 13:283–294

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Théry C, Ostrowski M, Segura E (2009) Membrane vesicles as conveyors of immune responses. Nat Rev Immunol 9:581–593

    PubMed  Article  CAS  Google Scholar 

  • Tombran-tink J, Barnstable C (2004) Osteoblasts and osteoclasts express PEDF, VEGF-A isoforms, and VEGF receptors: possible mediators of angiogenesis and matrix remodeling in the bone. Biochem Biophys Res commun 316:573–579

    CAS  PubMed  Article  Google Scholar 

  • Tombran-tink J, Mazuruk K, Rodriguez IR, Chung D, Linker T, Englander E, Chader GJ (1996) Organization, evolutionary conservation, expression and unusual Alu density of the human gene for pigment epithelium-derived factor, a unique neurotrophic serpin. Mol Vis 2:774–780

    Google Scholar 

  • Trommelen J, Groen BB, Hamer HM, de Groot LC, van Loon LJ (2015) Mechanisms in Endocrinology: exogenous insulin does not increase muscle protein synthesis rate when administered systemically: a systematic review. Eur J Endocrinol 2015(173):R25–R34

    Article  CAS  Google Scholar 

  • Tryggestad JB, Wang JJ, Zhang SX, Thompson DM & Short KR (2014) Elevated plasma pigment epithelium‐derived factor in children with type 2 diabetes mellitus is attributable to obesity. Pediatr Diabetes

  • Tschoner A, Sturm W, Ress C, Engl J, Kaser S, Laimer M, Laimer E, Klaus A, Tilg H, Patsch JR (2011) Effect of weight loss on serum pigment epithelium-derived factor levels. Eur J Clin Investig 41:937–942

    CAS  Article  Google Scholar 

  • Turan GA, Eskicioglu F, Sivrikoz ON, Cengiz H, Gur EB, Tatar S, Sahin N, Yilmaz O (2015) Prophylactic vitamin D supplementation in ovarian hyperstimulation syndrome: an animal study. Archives Gynecol Obstet 292:421–427

    CAS  Article  Google Scholar 

  • Van der Pols-Vijlbrief R, Wijnhoven HA, Schaap LA, Terwee CB, Visser M (2015) Determinants of protein-energy malnutrition in community-dwelling older adults: a systematic review of observational studies. Ageing Res Rev 18:112–131

    Article  Google Scholar 

  • Venkat VL, Shneider BL, Magee JC, Turmelle Y, Arnon R, Bezerra JA, Hertel PM, Karpen SJ, Kerkar N, Loomes KM, Molleston J, Murray KF, Ng VL, Raghunathan T, Rosenthal P, Schwartz K, Sherker AH, Sokol RJ, Teckman J, Wang K, Whitington PF, Heubi JE, Educ CLDR (2014) Total serum bilirubin predicts fat-soluble vitamin deficiency better than serum bile acids in infants with biliary atresia. J Pediatr Gastroenterol Nutr 59:702–707

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Venturi G, Gandini A, Monti E, Carbonare LD, Corradi M, Vincenzi M, Valenti MT, Valli M, Pelilli E, Boner A (2012) Lack of expression of SERPINF1, the gene coding for pigment epithelium-derived factor, causes progressively deforming osteogenesis imperfecta with normal type I collagen. J Bone Mineral Res 27:723–728

    CAS  Article  Google Scholar 

  • Vitek L (2012) The role of bilirubin in diabetes, metabolic syndrome, and cardiovascular diseases. Front Pharmacol 3:65–81

    Article  Google Scholar 

  • Vítek L (2005) Impact of serum bilirubin on human diseases. Pediatrics 115:1411–1412

    PubMed  Article  Google Scholar 

  • Vitek L, Ostrow JD (2009) Bilirubin chemistry and metabolism; harmful and protective aspects. Curr Pharm Design 15:2869–2883

    CAS  Article  Google Scholar 

  • Vitek L, Schwertner HA (2007) The heme catabolic pathway and its protective effects on oxidative stress-mediated diseases. Adv Clin Chem 43:1–57

    CAS  PubMed  Article  Google Scholar 

  • Wallner M, Blassnigg S, Marisch K, Pappenheim M, Müllner E, Mölzer C, Nersesyan A, Marculescu R, Doberer D, Knasmüller S (2012) Effects of unconjugated bilirubin on chromosomal damage in individuals with Gilberts syndrome measured with the micronucleus cytome assay. Mutagenesis 27:731–735

    CAS  PubMed  Article  Google Scholar 

  • Wang ZC, Wong T, Hashizume T, Dickmann LZ, Scian M, Koszewski NJ, Goff JP, Horst RL, Chaudhry AS, Schuetz EG, Thummel KE (2014) Human UGT1A4 and UGT1A3 conjugate 25-hydroxyvitamin D-3: metabolite structure, Kinetics, inducibility, and interindividual variability. Endocrinology 155:2052–2063

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • Waterlow JC (1972) Classification and definition of protein-calorie malnutrition. Br Med J 5826:566–569

    Article  Google Scholar 

  • Wei Y, Liu X-M, Peyton KJ, Wang H, Johnson FK, Johnson RA, Durante W (2009) Hypochlorous acid-induced heme oxygenase-1 gene expression promotes human endothelial cell survival. Am J Phys-Cell Physiol 297:C907–C915

    CAS  Article  Google Scholar 

  • Wilhelm-leen ER, Hall YN, Deboer IH, Chertow GM (2010) Vitamin D deficiency and frailty in older Americans. J Intern Med 268:171–180

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Wolf P (1967) The nature and significance of platelet products in human plasma. Br J Haematol 13:269–288

    CAS  PubMed  Article  Google Scholar 

  • Wu T-W, Fung K-P, Yang C-C (1994) Unconjugated bilirubin inhibits the oxidation of human low density lipoprotein better than Trolox. Life Sci 54:PL477–PL481

    Google Scholar 

  • Xiang H, Huang R, Zhou Y (2010) Influences of hypertension and diabetes on arterial compliances and endothelial microparticle level. Nan fang yi ke da xue xue bao 30:2387–2389

    PubMed  Google Scholar 

  • Yamagishi S-I, Matsui T (2011) Advanced glycation end products (AGEs), oxidative stress and diabetic retinopathy. Curr Pharm Biotechnol 12:362–368

    CAS  PubMed  Article  Google Scholar 

  • Yamagishi S-I, Adachi H, Abe A, Yashiro T, Enomoto M, Furuki K, Hino A, Jinnouchi Y, Takenaka K, Matsui T (2006) Elevated serum levels of pigment epithelium-derived factor in the metabolic syndrome. J Clin Endocrinol Metab 91:2447–2450

    CAS  PubMed  Article  Google Scholar 

  • Yang J, Duh EJ, Caldwell RB, Behzadian MA (2010) Antipermeability function of PEDF involves blockade of the MAP kinase/GSK/β-catenin signaling pathway and uPAR expression. Investig Ophthalmol Vis Sci 51:3273

    Article  Google Scholar 

  • Yang S, Li Q, Zhong L, Song Y, Tian B, Cheng Q, Qing H, Xia W, Luo M, Mei M (2011) Serum pigment epithelium-derived factor is elevated in women with polycystic ovary syndrome and correlates with insulin resistance. J Clin Endocrinol Metab 96:831–836

    CAS  PubMed  Article  Google Scholar 

  • Yang S, Luo T, Zhou H, Lv Q, Liu L, Zhang W, Gao R, Chen S, Xia W, Luo M (2014) Rosiglitazone Inhibits expression and secretion of PEDF in adipose tissue and liver of male SD rats Via a PPAR-γ independent mechanism. Endocrinology 155:941–950

    PubMed  Article  CAS  Google Scholar 

  • Yasuda M, Kiyohara Y, Wang JJ, Arakawa S, Yonemoto K, Doi Y, Ninomiya T, Ishibashi T (2011) High serum bilirubin levels and diabetic retinopathy: the Hisayama study. Ophthalmology 118:1423–1428

    PubMed  Google Scholar 

  • Yoshida Y, Yamagishi SI, Matsui T, Jinnouchi Y, Fukami K, Imaizumi T, Yamakawa R (2009) Protective role of pigment epithelium-derived factor (PEDF) in early phase of experimental diabetic retinopathy. Diabetes 25:678–686

    CAS  Google Scholar 

  • Zhou Y, Xu F, Deng H, Bi Y, Sun W, Zhao Y, Chen Z & Weng J (2013) PEDF expression is inhibited by insulin treatment in adipose tissue via suppressing 11β-HSD1

  • Zittermann A (2013) Magnesium deficit ? overlooked cause of low vitamin D status? BMC Med 11:229

    PubMed  PubMed Central  Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Life & Health Sciences and Aston Research Centre for Healthy Ageing, Aston University, Birmingham, B4 7ET, UK

    John Ikwuobe, Srikanth Bellary & Helen R. Griffiths

Authors
  1. John Ikwuobe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Srikanth Bellary
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Helen R. Griffiths
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Helen R. Griffiths.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ikwuobe, J., Bellary, S. & Griffiths, H.R. Innovative biomarkers for predicting type 2 diabetes mellitus: relevance to dietary management of frailty in older adults. Biogerontology 17, 511–527 (2016). https://doi.org/10.1007/s10522-016-9634-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10522-016-9634-z

Keywords

  • Insulin resistance
  • Ageing
  • Falls
  • Obesity