Abstract
There is evidence that post-load/post-meal hyperglycemia is a stronger risk factor for cardiovascular disease than fasting hyperglycemia. The underlying mechanism remains to be elucidated. The current study aimed to compare the metabolic profiles of post-load hyperglycemia and fasting hyperglycemia. All subjects received an oral glucose tolerance test (OGTT) and were stratified into fasting hyperglycemia (FH) or post-load hyperglycemia (PH). Forty-six (FH, n = 23; PH, n = 23) and 40 patients (FH, n = 20; PH, n = 20) were recruited as the exploratory and the validation set, respectively, and underwent metabolic profiling. Eighty-seven subjects including normal controls (NC: n = 36; FH: n = 22; PH: n = 29) were additionally enrolled and assayed with enzyme-linked immunosorbent assay (ELISA). In the exploratory set, 10 metabolites were selected as differential metabolites of PH (vs. FH). Of them, mannose and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) were confirmed in the validation set to be significantly higher in FH than in PH. In the 87 subjects measured with ELISA, FH had numerically higher mannose (466.0 ± 179.3 vs. 390.1 ± 140.2 pg/ml) and AICAR (523.5 ± 164.8 vs. 512.1 ± 186.0 pg/ml) than did PH. In the pooled dataset comprising 173 subjects, mannose was independently associated with FPG (β = 0.151, P = 0.035) and HOMA-IR (β = 0.160, P = 0.026), respectively. The associations of AICAR with biochemical parameters did not reach statistical significance. FH and PH exhibited distinct metabolic profiles. The perturbation of mannose may be involved in the pathophysiologic disturbances in diabetes.
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References
Kannel WB, McGee DL. Diabetes and cardiovascular risk factors: the Fra-mingham study. Circulation. 1979;59:8–13.
Laakso M. Hyperglycemia and cardiovascular disease in type 2 diabetes. Diabetes. 1999;48:937–42.
International Diabetes Federation Guideline Development Group. Guideline for management of postmeal glucose in diabetes. Diabetes Res Clin Pract. 2014;103:256–68.
Hanefeld M, Fischer S, Julius U, Schulze J, Schwanebeck U, Schmechel H, et al. Risk factors for myocardial infarction and death in newly detected NIDDM: the Diabetes Intervention Study, 11-year follow-up. Diabetologia. 1996;39:1577–83.
Cavalot F, Pagliarino A, Valle M, Di Martino L, Bonomo K, Massucco P, et al. Postprandial blood glucose predicts cardiovascular events and all-cause mortality in type 2 diabetes in a 14-year follow-up: lessons from the San Luigi Gonzaga Diabetes Study. Diabetes Care. 2011;34:2237–43.
Coutinho M, Gerstein HC, Wang Y, Yusuf S. The relationship between glucose and incident cardiovascular events. A metaregression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years. Diabetes Care. 1999;22:233–40.
Nicholson JK, Lindon JC, Holmes E. ‘Metabonomics’: understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. Xenobiotica. 1999;29:1181–9.
Newgard CB, An J, Bain JR, Muehlbauer MJ, Stevens RD, Lien LF, et al. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab. 2009;9:311–26.
Qiu Y, Cai G, Su M, Chen T, Zheng X, Xu Y, et al. Serum metabolite profiling of human colorectal cancer using GC-TOFMS and UPLC-QTOFMS. J Proteome Res. 2009;8:4844–50.
Wang TJ, Larson MG, Vasan RS, Cheng S, Rhee EP, McCabe E, et al. Metabolite profiles and the risk of developing diabetes. Nat Med. 2011;17:448–53.
Cederholm J, Wibell L. Insulin release and peripheral sensitivity at the oral glucose tolerance test. Diabetes Res Clin Pract. 1990;10:167–75.
Kind T, Wohlgemuth G, Lee DY, Lu Y, Palazoglu M, Shahbaz S, et al. FiehnLib: mass spectral and retention index libraries for metabo-lomics based on quadrupole and time-of-flight gas chromatography/mass spectrometry. Anal Chem. 2009;81:10038–48.
Lee S, Zhang C, Kilicarslan M, Piening BD, Bjornson E, Hallstrom BM, et al. Integrated network analysis reveals an association between plasma mannose levels and insulin resistance. Cell Metab. 2016;24:172–84.
Mardinoglu A, Stancakova A, Lotta LA, Kuusisto J, Boren J, Bluher M, et al. Plasma mannose levels are associated with incident type 2 diabetes and cardiovascular disease. Cell Metab. 2017;26:281–3.
Yoshimura K, Hirano S, Takata H, Funakoshi S, Ohmi S, Amano E, et al. Plasma mannose level, a putative indicator ofglycogenolysis, and glucose tolerance in Japanese individuals. J Diabetes Investig. 2017;8:489–95.
Turner RC, Holman RR. Pathophysiology of diabetes. Lancet. 1976;2:856.
Sone H, Shimano H, Ebinuma H, Takahashi A, Yano Y, Iida KT, et al. Physiological changes in circulating mannose levels in normal, glucose-intolerant, and diabetic subjects. Metabolism. 2003;52:1019–27.
Taguchi T, Miwa I, Mizutani T, Nakajima H, Fukumura Y, Kobayashi I, et al. Determination of D-mannose in plasma by HPLC. Clin Chem. 2003;49:181–3.
Davis JA, Freeze HH. Studies of mannose metabolism and effects of long-term mannose ingestion in the mouse. Biochim Biophys Acta. 2001;1528:116–26.
Caro JF, Cecchin F, Sinha MK. Is glycosylation in the liver needed for insulin binding, processing, and action? Evidence for heterogeneity. J Biol Chem. 1984;259:12810–6.
Abdul-Ghani MA, Jenkinson CP, Richardson DK, Tripathy D, DeFronzo RA. Insulin secretion and action in subjects with impaired fasting glucose and impaired glucose tolerance: results from the Veterans Administration Genetic Epidemiology Study. Diabetes. 2006;55:1430–5.
Abdul-Ghani MA, Tripathy D, DeFronzo RA. Contributions of beta-cell dysfunction and insulin resistance to the pathogenesis of impaired glucose tolerance and impaired fasting glucose. Diabetes Care. 2006;29:1130–9.
Basu R, Barosa C, Jones J, Dube S, Carter R, Basu A, et al. Pathogenesis of prediabetes: role of the liver in isolated fasting hyperglycemia and combined fasting and postprandial hyperglycemia. J Clin Endocrinol Metab. 2013;98:E409–17.
Sabina RL, Holmes EW, Becker MA. The enzymatic synthesis of 5-amino-4-imidazolecarboxamide riboside triphosphate (ZTP). Science. 1984;223:1193–5.
Pold R, Jensen LS, Jessen N, Buhl ES, Schmitz O, Flyvbjerg A, et al. Long-term AICAR administration and exercise prevents diabetes in ZDF rats. Diabetes. 2005;54:928–34.
Buhl ES, Jessen N, Pold R, Ledet T, Flyvbjerg A, Pedersen SB, et al. Long-term AICAR administration reduces metabolic disturbances and lowers blood pressure in rats displaying features of the insulin resistance syndrome. Diabetes. 2002;51:2199–206.
Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care. 1999;22:1462–70.
Acknowledgements
This work was funded by the National Natural Science Foundation of China (81300666), Natural Science Foundation of Shanghai (17ZR1421300), the Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support (20161430), and the innovation foundation of translational medicine of Shanghai Jiao Tong University School of Medicine and Shanghai SJTUSM Biobank (15ZH4006). We would like to thank all of the involved clinicians, nurses, and technicians at each of the participating centers for dedicating their time and skill to the completion of this study.
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J.-y.L., J.-h.P. and J.Z. contributed to study design, data analysis, and writing the paper. Y.-n.Z. contributed to data analysis. W.Z., X.-x.H. and L.-w.Y. contributed to conduction of study and data collection. X.-j.M. contributed to study design, data analysis, and interpretation of data. Y.-q.B. and W.-p.J. contributed to interpretation of data and revision of the manuscript.
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Lu, Jy., Peng, Jh., Ma, Xj. et al. Metabolic perturbations of post-load hyperglycemia vs. fasting hyperglycemia. Acta Pharmacol Sin 40, 216–221 (2019). https://doi.org/10.1038/s41401-018-0018-6
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DOI: https://doi.org/10.1038/s41401-018-0018-6
