diaendoСахарный диабетDiabetes mellitus2072-03512072-0378Endocrinology research centre10.14341/DM10376diaendo-10376Research ArticleОбзорыReviewФенотипы предиабета: патогенез и последствия в рамках прогнозирования и профилактики сахарного диабета 2 типа и сердечно-сосудистых заболеванийPhenotypes of prediabetes: pathogenesis and consequences for prediction and prevention of type 2 diabetes and cardiovascular diseasesStefanNorbert

Department of Internal Medicine IV; MD, PhD, Professor

norbert.stefan@med.uni-tuebingen.deUniversity Hospital Tübingen; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen; German Center for Diabetes Research (DZD)Germany201928022020226577581Copyright © Stefan N., 20192019Stefan N.Stefan N.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.dia-endojournals.ru/jour/article/view/10376

Распространенность сахарного диабета 2-го типа (СД2) растет во всем мире. В связи с этим необходимо лучше понимать его патогенез, риск развития осложнений, ассоциированных с СД, и эффективные подходы к лечению. Поскольку СД2 представляет собой очень гетерогенное заболевание, обе стратегии фенотипирования, связанные с его патогенезом и риском осложнений, могут помочь разработать способы профилактики на основе индивидуального риска. Поскольку уже показано, что гипергликемическое состояние при предиабете ассоциировано с повышенным риском метаболического синдрома, необходимо исследовать влияние фенотипов на предсказательные и превентивные исходы уже в этом раннем состоянии гипергликемии. В этой обзорной статье обсуждается, как можно использовать важные фенотипы предиабета, такие как неалкогольная жировая болезнь печени, висцеральное ожирение, нарушение секреции инсулина и инсулинорезистентность, для улучшения прогнозирования и профилактики СД2 и сердечно-сосудистых заболеваний.

The prevalence of type 2 diabetes is increasing world-wide. Thus, it is necessary to better understand its pathogenesis, the risk of diabetes-associated complications and effective treatment strategies. Because type 2 diabetes is a very heterogenous disease, both, related to its pathogenesis and risk of complications, phenotyping strategies in diabetes may help to tailor the preventive strategies based on the individual’s risk. As the the hyperglycemic state of prediabetes is already associated with an increased risk of cardiometabolic diseases it is necessary to investigate the impact of phenotypes for predictive and preventive outcomes already in this early state of hyperglycemia. In this review artice I discuss how important phenotypes of prediabetes, such as nonalcoholic fatty liver disease, visceral obesity, insulin secretion defect and insulin resistance can be used to improve the prediction and prevention of type 2 diabetes and cardiovascular disease.

предиабетсахарный диабет 2 типапрофилактикасердечно-сосудистые заболеванияprediabetesdiabetes mellitus type 2profilacticcardiovascular diseasesПубликация этой статьи была профинансирована Novartis Pharma AG, Базель, Швейцария.The publication of this article was funded by Novartis Pharma AG, Basel, Switzerland.ReferencesMenke A, Casagrande S, Geiss L, Cowie CC. Prevalence of and trends in diabetes among adults in the United States, 1988−2012. JAMA. 2015;314(10):1021−1029. doi: https://doi.org/10.1001/jama.2015.10029Menke A, Casagrande S, Geiss L, Cowie CC. Prevalence of and trends in diabetes among adults in the United States, 1988−2012. JAMA. 2015;314(10):1021−1029. doi: https://doi.org/10.1001/jama.2015.10029Wang L, Gao P, Zhang M, et al. Prevalence and ethnic pattern of diabetes and prediabetes in China in 2013. JAMA. 2017;317(24):2515−2523. doi: https://doi.org/10.1001/jama.2017.7596Wang L, Gao P, Zhang M, et al. Prevalence and ethnic pattern of diabetes and prediabetes in China in 2013. JAMA. 2017;317(24):2515−2523. doi: https://doi.org/10.1001/jama.2017.7596Rawshani A, Rawshani A, Franzén S, et al. Mortality and cardiovascular disease in type 1 and type 2 diabetes. N Engl J Med. 2017;376(15):1407−1418. doi: https://doi.org/10.1056/NEJMoa1608664Rawshani A, Rawshani A, Franzén S, et al. Mortality and cardiovascular disease in type 1 and type 2 diabetes. N Engl J Med. 2017;376(15):1407−1418. doi: https://doi.org/10.1056/NEJMoa1608664Avogaro A, Giorda C, Maggini M, et al. Incidence of coronary heart disease in type 2 diabetic men and women: impact of microvascular complications, treatment, and geographic location. Diabetes Care. 2007;30(5):1241–1247. doi: https://doi.org/10.2337/dc06-2558Avogaro A, Giorda C, Maggini M, et al. Incidence of coronary heart disease in type 2 diabetic men and women: impact of microvascular complications, treatment, and geographic location. Diabetes Care. 2007;30(5):1241–1247. doi: https://doi.org/10.2337/dc06-2558Lind M, Svensson AM, Kosiborod M, et al. Glycemic control and excess mortality in type 1 diabetes. N Engl J Med. 2014;371(21):1972−1982. doi: https://doi.org/10.1056/NEJMoa1408214Lind M, Svensson AM, Kosiborod M, et al. Glycemic control and excess mortality in type 1 diabetes. N Engl J Med. 2014;371(21):1972−1982. doi: https://doi.org/10.1056/NEJMoa1408214Bjornstad P, Donaghue KC, Maahs DM. Macrovascular disease and risk factors in youth with type 1 diabetes: time to be more attentive to treatment? Lancet Diabetes Endocrinol. 2018;6(10):809−820. doi: https://doi.org/10.1016/S2213-8587(18)30035-4Bjornstad P, Donaghue KC, Maahs DM. Macrovascular disease and risk factors in youth with type 1 diabetes: time to be more attentive to treatment? Lancet Diabetes Endocrinol. 2018;6(10):809−820. doi: https://doi.org/10.1016/S2213-8587(18)30035-4Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348(5):383−393. doi: https://doi.org/10.1056/NEJMoa021778Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348(5):383−393. doi: https://doi.org/10.1056/NEJMoa021778Rawshani A, Rawshani A, Franzén S, et al. Risk factors, mortality, and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2018;379(7):633−644. doi: https://doi.org/10.1056/NEJMoa1800256Rawshani A, Rawshani A, Franzén S, et al. Risk factors, mortality, and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2018;379(7):633−644. doi: https://doi.org/10.1056/NEJMoa1800256Piller C. Dubious diagnosis. Science. 2019;363(6431):1026−1031. doi: https://doi.org/10.1126/science.363.6431.1026Piller C. Dubious diagnosis. Science. 2019;363(6431):1026−1031. doi: https://doi.org/10.1126/science.363.6431.1026Ali MK, Bullard KM, Saydah S, et al. Cardiovascular and renal burdens of prediabetes in the USA: analysis of data from serial cross-sectional surveys, 1988−2014. Lancet Diabetes Endocrinol. 2018;6(5):392−403. doi: https://doi.org/10.1016/S2213-8587(18)30027-5Ali MK, Bullard KM, Saydah S, et al. Cardiovascular and renal burdens of prediabetes in the USA: analysis of data from serial cross-sectional surveys, 1988−2014. Lancet Diabetes Endocrinol. 2018;6(5):392−403. doi: https://doi.org/10.1016/S2213-8587(18)30027-5Perreault L, Faerch K, Gregg EW. Can cardiovascular epidemiology and clinical trials close the risk management gap between diabetes and prediabetes? Curr Diab Rep. 2017;17(9):77. doi: https://doi.org/10.1007/s11892-017-0899-7Perreault L, Faerch K, Gregg EW. Can cardiovascular epidemiology and clinical trials close the risk management gap between diabetes and prediabetes? Curr Diab Rep. 2017;17(9):77. doi: https://doi.org/10.1007/s11892-017-0899-7Lillioja S, Mott DM, Spraul M, et al. Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus. Prospective studies of Pima Indians. N Engl J Med. 1993;329(27):1988−1992. doi: https://doi.org/10.1056/NEJM199312303292703Lillioja S, Mott DM, Spraul M, et al. Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus. Prospective studies of Pima Indians. N Engl J Med. 1993;329(27):1988−1992. doi: https://doi.org/10.1056/NEJM199312303292703Weyer C, Bogardus C, Mott DM, Pratley RE. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest. 1999;104(6):787−794. doi: https://doi.org/10.1172/JCI7231Weyer C, Bogardus C, Mott DM, Pratley RE. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest. 1999;104(6):787−794. doi: https://doi.org/10.1172/JCI7231Neeland IJ, Ross R, Després JP, et al.; International Atherosclerosis Society; International Chair on Cardiometabolic Risk Working Group on Visceral Obesity. Visceral and ectopic fat, atherosclerosis, and cardiometabolic disease: a position statement. Lancet Diabetes Endocrinol. 2019;7(9):715−725. doi: https://doi.org/10.1016/S2213-8587(19)30084-1Neeland IJ, Ross R, Després JP, et al.; International Atherosclerosis Society; International Chair on Cardiometabolic Risk Working Group on Visceral Obesity. Visceral and ectopic fat, atherosclerosis, and cardiometabolic disease: a position statement. Lancet Diabetes Endocrinol. 2019;7(9):715−725. doi: https://doi.org/10.1016/S2213-8587(19)30084-1Stefan N, Häring HU, Cusi K. Non-alcoholic fatty liver disease: causes, diagnosis, cardiometabolic consequences, and treatment strategies. Lancet Diabetes Endocrinol. 2019;7(4):313−324. doi: https://doi.org/10.1016/S2213-8587(18)30154-2Stefan N, Häring HU, Cusi K. Non-alcoholic fatty liver disease: causes, diagnosis, cardiometabolic consequences, and treatment strategies. Lancet Diabetes Endocrinol. 2019;7(4):313−324. doi: https://doi.org/10.1016/S2213-8587(18)30154-2Stefan N, Ramsauer M, Jordan P, et al. Inhibition of 11β-HSD1 with RO5093151 for non-alcoholic fatty liver disease: a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2014;2(5):406−416. doi: https://doi.org/10.1016/S2213-8587(13)70170-0Stefan N, Ramsauer M, Jordan P, et al. Inhibition of 11β-HSD1 with RO5093151 for non-alcoholic fatty liver disease: a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2014;2(5):406−416. doi: https://doi.org/10.1016/S2213-8587(13)70170-0Stefan N, Kantartzis K, Machann J, et al. Identification and characterization of metabolically benign obesity in humans. Arch Intern Med. 2008;168(15):1609−1616. doi: https://doi.org/10.1001/archinte.168.15.1609Stefan N, Kantartzis K, Machann J, et al. Identification and characterization of metabolically benign obesity in humans. Arch Intern Med. 2008;168(15):1609−1616. doi: https://doi.org/10.1001/archinte.168.15.1609Fabbrini E, Magkos F, Mohammed BS, et al. Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity. Proc Natl Acad Sci U S A. 2009;106(36):15430−15435. doi: https://doi.org/10.1073/pnas.0904944106Fabbrini E, Magkos F, Mohammed BS, et al. Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity. Proc Natl Acad Sci U S A. 2009;106(36):15430−15435. doi: https://doi.org/10.1073/pnas.0904944106Stefan N, Häring HU, Hu FB, Schulze MB. Divergent associations of height with cardiometabolic disease and cancer: epidemiology, pathophysiology, and global implications. Lancet Diabetes Endocrinol. 2016;4(5):457−467. doi: https://doi.org/10.1016/S2213-8587(15)00474-XStefan N, Häring HU, Hu FB, Schulze MB. Divergent associations of height with cardiometabolic disease and cancer: epidemiology, pathophysiology, and global implications. Lancet Diabetes Endocrinol. 2016;4(5):457−467. doi: https://doi.org/10.1016/S2213-8587(15)00474-XKantartzis K, Machann J, Schick F, et al. The impact of liver fat vs visceral fat in determining categories of prediabetes. Diabetologia. 2010;53(5):882−889. doi: https://doi.org/10.1007/s00125-010-1663-6Kantartzis K, Machann J, Schick F, et al. The impact of liver fat vs visceral fat in determining categories of prediabetes. Diabetologia. 2010;53(5):882−889. doi: https://doi.org/10.1007/s00125-010-1663-6Stefan N, Fritsche A, Schick F, Häring HU. Phenotypes of prediabetes and stratification of cardiometabolic risk. Lancet Diabetes Endocrinol. 2016;4(9):789−798. doi: https://doi.org/10.1016/S2213-8587(16)00082-6Stefan N, Fritsche A, Schick F, Häring HU. Phenotypes of prediabetes and stratification of cardiometabolic risk. Lancet Diabetes Endocrinol. 2016;4(9):789−798. doi: https://doi.org/10.1016/S2213-8587(16)00082-6Stefan N, Häring HU, Hu FB, Schulze MB. Metabolically healthy obesity: epidemiology, mechanisms, and clinical implications. Lancet Diabetes Endocrinol. 2013;1(2):152−162. doi: https://doi.org/10.1016/S2213-8587(13)70062-7Stefan N, Häring HU, Hu FB, Schulze MB. Metabolically healthy obesity: epidemiology, mechanisms, and clinical implications. Lancet Diabetes Endocrinol. 2013;1(2):152−162. doi: https://doi.org/10.1016/S2213-8587(13)70062-7Stefan N, Häring HU, Schulze MB. Metabolically healthy obesity: the low-hanging fruit in obesity treatment? Lancet Diabetes Endocrinol. 2018;6(3):249−258. doi: https://doi.org/10.1016/S2213-8587(17)30292-9Stefan N, Häring HU, Schulze MB. Metabolically healthy obesity: the low-hanging fruit in obesity treatment? Lancet Diabetes Endocrinol. 2018;6(3):249−258. doi: https://doi.org/10.1016/S2213-8587(17)30292-9Stefan N, Schick F, Häring HU. Causes, characteristics, and consequences of metabolically unhealthy normal weight in humans. Cell Metab. 2017;26(2):292−300. doi: https://doi.org/10.1016/j.cmet.2017.07.008Stefan N, Schick F, Häring HU. Causes, characteristics, and consequences of metabolically unhealthy normal weight in humans. Cell Metab. 2017;26(2):292−300. doi: https://doi.org/10.1016/j.cmet.2017.07.008Tchernof A, Després JP. Pathophysiology of human visceral obesity: an update. Physiol Rev. 2013;93(1):359−404. doi: https://doi.org/10.1152/physrev.00033.2011Tchernof A, Després JP. Pathophysiology of human visceral obesity: an update. Physiol Rev. 2013;93(1):359−404. doi: https://doi.org/10.1152/physrev.00033.2011Fasshauer M, Blüher M. Adipokines in health and disease. Trends Pharmacol Sci. 2015;36(7):461−470. doi: https://doi.org/10.1016/j.tips.2015.04.014Fasshauer M, Blüher M. Adipokines in health and disease. Trends Pharmacol Sci. 2015;36(7):461−470. doi: https://doi.org/10.1016/j.tips.2015.04.014Scherer PE. The many secret lives of adipocytes: implications for diabetes. Diabetologia. 2019;62(2):223−232. doi: https://doi.org/10.1007/s00125-018-4777-xScherer PE. The many secret lives of adipocytes: implications for diabetes. Diabetologia. 2019;62(2):223−232. doi: https://doi.org/10.1007/s00125-018-4777-xStefan N, Häring HU. The role of hepatokines in metabolism. Nat Rev Endocrinol. 2013;9(3):144−152. doi: https://doi.org/10.1038/nrendo.2012.258Stefan N, Häring HU. The role of hepatokines in metabolism. Nat Rev Endocrinol. 2013;9(3):144−152. doi: https://doi.org/10.1038/nrendo.2012.258Stefan N, Fritsche A, Weikert C, et al. Plasma fetuin-A levels and the risk of type 2 diabetes. Diabetes. 2008;57(10):2762−2767. doi: https://doi.org/10.2337/db08-0538Stefan N, Fritsche A, Weikert C, et al. Plasma fetuin-A levels and the risk of type 2 diabetes. Diabetes. 2008;57(10):2762−2767. doi: https://doi.org/10.2337/db08-0538Ix JH, Wassel CL, Kanaya AM, et al.; Health ABC Study. Fetuin-A and incident diabetes mellitus in older persons. JAMA. 2008;300(2):182−188. doi: https://doi.org/10.1001/jama.300.2.182Ix JH, Wassel CL, Kanaya AM, et al.; Health ABC Study. Fetuin-A and incident diabetes mellitus in older persons. JAMA. 2008;300(2):182−188. doi: https://doi.org/10.1001/jama.300.2.182Weikert C, Stefan N, Schulze MB, et al. Plasma fetuin-a levels and the risk of myocardial infarction and ischemic stroke. Circulation. 2008;118(24):2555−2562. doi: https://doi.org/10.1161/CIRCULATIONAHA.108.814418Weikert C, Stefan N, Schulze MB, et al. Plasma fetuin-a levels and the risk of myocardial infarction and ischemic stroke. Circulation. 2008;118(24):2555−2562. doi: https://doi.org/10.1161/CIRCULATIONAHA.108.814418Pal D, Dasgupta S, Kundu R, et al. Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance. Nat Med. 2012;18(8):1279−1285. doi: https://doi.org/10.1038/nm.2851Pal D, Dasgupta S, Kundu R, et al. Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance. Nat Med. 2012;18(8):1279−1285. doi: https://doi.org/10.1038/nm.2851Stefan N, Häring HU. Circulating fetuin-A and free fatty acids interact to predict insulin resistance in humans. Nat Med. 2013;19(4):394−395. doi: https://doi.org/10.1038/nm.3116Stefan N, Häring HU. Circulating fetuin-A and free fatty acids interact to predict insulin resistance in humans. Nat Med. 2013;19(4):394−395. doi: https://doi.org/10.1038/nm.3116Stefan N, Schick F, Häring HU. Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease. N Engl J Med. 2014;371(23):2236−2237. doi: https://doi.org/10.1056/NEJMc1412427Stefan N, Schick F, Häring HU. Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease. N Engl J Med. 2014;371(23):2236−2237. doi: https://doi.org/10.1056/NEJMc1412427Gerst F, Wagner R, Kaiser G, et al. Metabolic crosstalk between fatty pancreas and fatty liver: effects on local inflammation and insulin secretion. Diabetologia. 2017;60(11):2240−2251. doi: https://doi.org/10.1007/s00125-017-4385-1Gerst F, Wagner R, Kaiser G, et al. Metabolic crosstalk between fatty pancreas and fatty liver: effects on local inflammation and insulin secretion. Diabetologia. 2017;60(11):2240−2251. doi: https://doi.org/10.1007/s00125-017-4385-1Stefan N, Staiger H, Wagner R, et al. A high-risk phenotype associates with reduced improvement in glycaemia during a lifestyle intervention in prediabetes. Diabetologia. 2015;58(12):2877−2884. doi: https://doi.org/10.1007/s00125-015-3760-zStefan N, Staiger H, Wagner R, et al. A high-risk phenotype associates with reduced improvement in glycaemia during a lifestyle intervention in prediabetes. Diabetologia. 2015;58(12):2877−2884. doi: https://doi.org/10.1007/s00125-015-3760-z

The authors declare that there are no conflicts of interest present.