The main pathogenetic mechanisms of chronic heart failure in patients with coronary heart disease and type 2 diabetes mellitus are considered, in particular, morphological, hemodynamic, metabolic and neurohumoral factors that contribute to the development and progression of chronic heart failure in patients with these comorbid conditions. The purpose of the study was to review the scientific literature and summarize the results of research to study the role of hemodynamic and metabolic factors in the development and progression of chronic heart failure in patients with coronary heart disease and type 2 diabetes. The study emphasizes the leading role of disorders of carbohydrate metabolism (insulin resistance and hyperglycemia) in the occurrence of type 2 diabetes mellitus specific myocardial injury called diabetic cardiomyopathy which leads to disorders of the left ventricular function and the development of chronic heart failure. It is the mechanisms associated with insulin resistance, hyperglycemia and atherogenic dyslipidemia that are responsible for the formation and development of chronic macro- and microvascular complications of type 2 diabetes mellitus, which also include chronic heart failure. The study showed that the increase in myocardial stiffness with the development of its diastolic dysfunction was the earliest sign of myocardial damage in type 2 diabetes mellitus. Hyperfunction and hypertrophy of the left ventricle in terms of mobilization of energy and structural reserves of its myocardium lead to increased dysfunction and clinical manifestations of chronic heart failure. Ultrastructural and morphological changes in the myocardium in diabetic diabetic cardiomyopathy, which are the basis of disorders of cardiomyocyte metabolism, their subsequent hibernation and apoptosis, which ultimately contributes to fibrosis in the myocardium and the development of its systolic and diastolic dysfunction. Conclusion. The peculiarities of cardiovascular remodeling in coronary heart disease, concomitant type 2 diabetes mellitus and the role of these processes in the development of cardiovascular complications, primarily chronic heart failure, are also highlighted. An in-depth understanding of the pathogenetic mechanisms of chronic heart failure development in patients with type 2 diabetes mellitus and coronary heart disease opens new perspectives for the development of more effective pharmacological agents, optimization of drug treatment regimens for chronic heart failure in order to improve the quality and life expectancy of patients.

Keywords: type 2 diabetes mellitus, ischaemic heart disease, chronic heart failure, metabolic, neurohumoral mechanisms

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1. Tronko ND, Zak KP. Sovremennye dostyzhenyya klynycheskoy patofyzyologyy v yzuchenyy patogeneza sakharnogo dyabeta 1-go y 2-go typa u cheloveka [Current advances in clinical pathophysiology in the study of the pathogenesis of type 1 and type 2 diabetes in humans]. Mizhnarodn endokryn zhurn. 2019 Dec 13; 15(6): 422-34. [Russian]. https://doi.org/10.22141/2224-0721.15.6.2019.185403
2. Shkala LV, Myshanich GI, Shkala OV, Cherpak OV, Karapetyan OA, Volkovska TG. Patogenetychni mekhanizmy ta oznaky sertsevo-sudynnykh urazhen pry tsukrovomu diabeti 2-go typu [Pathogenetic mechanisms and signs of cardiovascular lesions in type 2 diabetes mellitus]. Mizhnarodn endokryn zhurn. 2018; 14(3): 235-9. [Ukrainian]. https://doi.org/10.22141/2224-0721.14.3.2018.136418
3. Zheng Y, Ley SH, Hu FB. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol. 2018 Feb; 14(2): 88-98. https://www.ncbi.nlm.nih.gov/pubmed/ 29219149. https://doi.org/10.1038/nrendo.2017.151
4. Shebaldova KO, Komisarenko YuI. Klinichnyy dosvid vykorystannya roslynnogo zasobu Glyutsemedin u kompleksnomu likuvanni khvorykh na tsukrovyy diabet 2-go typu [Clinical experience of using the herbal remedy Glucemedin in the complex treatment of patients with type 2 diabetes mellitus]. Mizhnarodn endokryn zhurn. 2018 Oct 24; 14(5): 462-8. [Ukrainian]. https://doi.org/10.22141/2224-0721.14.5.2018.142681
5. Montazerifar F, Bolouri AA, Mozaffar MM, Karajibani M. The Prevalence of Metabolic Syndrome in Coronary Artery Disease Patients. Cardiol Res. 2016 Dec; 7(6): 202-8. https://www.ncbi.nlm.nih.gov/pubmed/ 28197293. https://www.ncbi.nlm.nih.gov/pmc/articles/5295511. https://doi.org/10.14740/cr507w
6. Prybyla OV, Zynych OV, Melua GA. Oblyteryruyushchyy ateroskleroz arteryy nyzhnykh konechnostey - neotsenennaya opasnost pry sakharnom dyabete [Atherosclerosis obliterans of the lower limb arteries - an underestimated danger in diabetes]. Ukr med chasopys. 2018; 2(2): 42-5. [Russian]. https://doi.org/10.32471/umj.1680-3051.124.124877
7. Zolotukhina YuO. Fibrynolitychna aktyvnist krovi u patsiyentiv z ishemichnoyu khvoroboyu sertsya ta suputnim tsukrovym diabetom 2-go typu. Ukr med chasopys. 2018; 6(2): 40-2. [Ukrainian]. https://doi.org/10.32471/umj.1680-3051.128.134557
8. Rawshani A, Rawshani A, Franzén S, Eliasson B, Svensson A, Miftaraj M, et al. Mortality and cardiovascular disease in type 1 and type 2 diabetes. N Engl J Med. 2017 Apr; 376(15): 1407-18. https://doi.org/10.1056/NEJMoa1608664. https://www.ncbi.nlm.nih.gov/pubmed/28402770
9. Dutka RYa, Chmyr NV. Patogenetychna ta klinichna sporidnenist perebigu tsukrovogo diabetu 2-go typu z metabolichnym syndromom ta khronichnoyu ishemichnoyu khvoroboyu sertsya [Pathogenetic and clinical relationship of type 2 diabetes mellitus with metabolic syndrome and chronic coronary heart disease]. Mizhnarodn endokryn zhurn. 2018; 14(7): 655-60. [Ukrainian]. https://doi.org/10.22141/2224-0721.14.7.2018.148772
10. Krushynska ZG, Yuzvenko TYu, Pankiv VI. Chastota sertsevo-sudynnykh uskladnen u khvorykh na tsukrovyy diabet 2-go typu zalezhno vid vydu antygiperglikemizuyuchoyi terapiyi [Frequency of cardiovascular complications in patients with type 2 diabetes mellitus depending on the type of antihyperglycemic therapy]. Mizhnarodn endokryn zhurn. 2018; 14(6): 570-8. [Ukrainian]. https://doi.org/10.22141/2224-0721.14.6.2018.146067
11. Shah AD, Langenberg C, Rapsomaniki E, Denaxas S, Pujades-Rodriguez M, Gale CP, et al. Type 2 diabetes and incidence of a wide range of cardiovascular diseases: a cohort study in 1,9 million people. Lancet. 2015 Feb 26; 385(1): 86. https://www.ncbi.nlm.nih.gov/pubmed/25466521. https://www.ncbi.nlm.nih.gov/pmc/articles/4303913. https://doi.org/10.1016/S2213-8587(14)70219-0
12. Teljeur C, Smith SM, Paul G, Kelly A, O'Dowd T. Multimorbidity in a cohort of patients with type 2 diabetes. Eur J Gen Pract. 2013 Mar; 19(1): 17-22. https://www.ncbi.nlm.nih.gov/pubmed/23432037. https://doi.org/10.3109/13814788.2012.714768
13. Malyar KYu, Anisimova OS, Drishlyuk OI, Bykovska LYu, Filipova YeV. Efektyvnist preparatu Vazonat u skladi kompleksnoyi terapiyi patsiyentiv iz tsukrovym diabetom 2-go typu na tli sertsevo-sudynnoyi patologiyi [The effectiveness of the drug Vasonate in the complex therapy of patients with type 2 diabetes mellitus on the background of cardiovascular pathology]. Mizhnarodn endokryn zhurn. 2018; 14(1): 86-92. [Ukrainian]. https://doi.org/10.22141/2224-0721.14.1.2018.127098
14. Sokolova LK, Pushkaryov VM, Kovzun EY, Pushkaryov VV, Tronko ND. Sakharnyy dyabet y ateroskleroz: epygenetycheskye mekhanyzmy patogeneza. Obzor lyteratury [Diabetes mellitus and atherosclerosis: epigenetic mechanisms of pathogenesis. Literature review]. Ukr kardiol zhurn. 2017; 6: 104-17. [Russian]
15. Gerush YV, Tarallo VL. Systemnye podkhody k prognozyrovanyyu rasprostranennosty sakharnogo dyabeta [Systemic approaches to predicting the prevalence of diabetes]. Mizhnarodn endokryn zhurn. 2018; 14(5): 469-75. [Russian] https://doi.org/10.22141/2224-0721.14.5.2018.142682
16. Pankiv VI. Novi rekomendatsiyi Amerykanskoyi diabetychnoyi asotsiatsiyi 2018 roku z diagnostyky ta likuvannya tsukrovogo diabetu [New recommendations of the American Diabetes Association 2018 on the diagnosis and treatment of diabetes]. Mizhnarodn endokryn zhurn. 2018; 14(1): 93-8. [Ukrainian]. https://doi.org/10.22141/2224-0721.14.1.2018.127099
17. American Diabetes Association's Standards of Medical Care in Diabetes - 2018. Diabetes Care. 2018; 41(1): 1-159. https://www.ncbi.nlm.nih.gov/pubmed/29382975. https://www.ncbi.nlm.nih.gov/pmc/articles/5775000. https://doi.org/10.2337/cd17-0119
18. Garnytska AV. Molekulyarni ta epigenetychni mekhanizmy metabolichnykh efektiv zasobiv, yaki zastosovuyutsya v likuvanni patsiyentiv iz tsukrovym diabetom 2-go typu ta yogo uskladnen [Molecular and epigenetic mechanisms of metabolic effects of drugs used in the treatment of patients with type 2 diabetes mellitus and its complications]. Endokrynologia. 2018; 23(3): 281-8. [Ukrainian]
19. Malachkova NV, Komarovskaya YV, Kyrylyuk ML. Uroven glykemyy y ynsulynorezystentnosty u bolnykh s sakharnym dyabetom 2-go typa, dyabetycheskoy retynopatyey y ozhyrenyem [The level of glycemia and insulin resistance in patients with type 2 diabetes mellitus, diabetic retinopathy and obesity]. Mezhdunarodn endokryn zhurn. 2017; 13(3): 129-34. [Russian]. https://doi.org/10.22141/2224-0721.13.3.2017.104108
20. Schneider AL, Kalyani RR, Golden S, Stearns SC, Wruck L, Yeh HC, et al. Diabetes and Prediabetes and Risk of Hospitalization: The Atherosclerosis Risk in Communities (ARIC) Study. Diabetes Care. 2016 May; 39(5): 772-9. https://doi.org/10.2337/dc15-1335. https://www.ncbi.nlm.nih.gov/pubmed/26953170. https://www.ncbi.nlm.nih.gov/pmc/articles/4839170
21. Piddubna AA, Vivsyannyk VV, Sazhyn NI, Vyshnevska LT, Boyko LD. Korektsiya lipidnogo spektra krovi ta metabolichni porushennya u khvorykh na tsukrovyy diabet 2-go typu z ishemichnoyu khvoroboyu sertsya [Correction of blood lipid spectrum and metabolic disorders in patients with type 2 diabetes mellitus with coronary heart disease]. Mizhnarodn endokryn zhurn. 2018; 14(4): 428. [Ukrainian]. https://doi.org/10.22141/2224-0721.14.4.2018.140222
22. Mahbuba S, Mohsin F, Rahat F, Nahar J, Begum T, Nahar N. Descriptive epidemiology of metabolic syndrome among obese adolescent population. Diabetes Metab Syndr. 2018 May; 12(3): 369-74. https://doi.org/10.1016/j.dsx.2017.12.026. https://www.ncbi.nlm.nih.gov/pubmed/29358036
23. Chernyavskaya Y, Zemlyanytsyna OV, Romanova YP, Kravchun NA. Effektyvnyy varyant lechenyya sakharnogo dyabeta 2-go typa [An effective treatment for type 2 diabetes]. Mizhnarodn endokryn zhurn. 2018; 14(2): 194-8. [Russian]. https://doi.org/10.22141/2224-0721.14.2.2018.130566
24. McCracken E, Monaghan M, Sreenivasan S. Pathophysiology of the metabolic syndrome. Clinics in Dermatology. 2018 Jan-Feb; 36(1): 14-20. https://doi.org/10.1016/j.clindermatol.2017.09.004. https://www.ncbi.nlm.nih.gov/pubmed/29241747
25. Bayanova EG. Vzaymosvyaz mezhdu komponentamy metabolycheskogo syndroma u bolnykh ozhyrenyem [The relationship between the components of the metabolic syndrome in obese patients]. Mizhnarodn endokryn zhurn. 2017; 13(2): 209-12. [Russian]. https://doi.org/10.22141/2224-0721.13.2.2017.100615
26. Masik NP, Kalandey KYa. Poshyrenist metabolichnogo syndromu u khvorykh terapevtychnogo statsionaru z gipertonichnoyu khvoroboyu [Prevalence of metabolic syndrome in patients of therapeutic hospital with hypertension]. Ukr terapevt zhurn. 2017; 4: 40-5. [Ukrainian]
27. Despres JP, Lamarche В, Mauriege Р, Cantin B, Dagenais GR, Moorjani S, et al. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med. 2006; 348: 952-7. https://www.ncbi.nlm.nih.gov/pubmed/8596596. doi: 10.1056/nejm1996041133 41504
28. Marott SC, Nordestgaard BG, Tybjærg-Hansen А, Benn M. Components of the metabolic syndrome and risk of type 2 diabetes. The Journal of Clinical Endocrinology & Metabolism. 2016 Aug 1; 101(8): 3212-21. https://doi.org/10.1210/jc.2015-3777. https://www.ncbi.nlm.nih.gov/pubmed/27285293
29. Naito R, Kasai T. Coronary artery disease in type 2 diabetes mellitus: Recent treatment strategies and future perspectives. World J Cardiol. 2015 Mar 26; 7(3): 119-24. https://doi.org/10.4330/wjc.v7.i3.119. https://www.ncbi.nlm.nih.gov/pubmed/25810811. https://www.ncbi.nlm.nih.gov/pmc/articles/4365308
30. Osadchyy OI. Sertseva nedostatnist i komorbidnist. Suchasnyy stan ta perspektyvy likuvannya [Heart failure and comorbidity. Current state and prospects of treatment]. Ukr med chasopys. 2018; 2(2): 4-6. [Ukrainian]
31. Arror AR, Mandavia CH, Sowers JR. Insulin resistance and heart failure : molecular mechanisms. Heart Fail Clin. 2012 Oct 1; 8(4): 609-17. https://doi.org/10.1016/j.hfc.2012.06.005. https://www.ncbi.nlm.nih.gov/pubmed/22999243. https://www.ncbi.nlm.nih.gov/pmc/articles/3457065
32. Palmer SC, Mavridis D, Nicolucci A, Johnson DW, Tonelli M, Craig JC, et al. Comparison of clinical outcomes and adverse events associated with glucose-lowering drugs in patients with type 2 diabetes: a meta-analysis. JAMA. 2016 Jul 19; 316(3): 313-24. https://doi.org/10.1001/jama.2016.9400. https://www.ncbi.nlm.nih.gov/pubmed/27434443
33. Chernyavska IV. Profil chynnykiv ryzyku sertsevo-sudynnykh zakhvoryuvan pry ishemichniy khvorobi sertsya v osib iz normalnym i porushenym vuglevodnym obminom [Profile of risk factors for cardiovascular disease in coronary heart disease in individuals with normal and impaired carbohydrate metabolism]. Mizhnarodn endokryn zhurn. 2015; 8(72): 83-7. [Ukrainian] https://doi.org/10.22141/2224-0721.8.72.2015.72416
34. Kyyak YuG, Kyyak GYu, Barnett OYu. Spetsyfichnist diabetychnoyi kardiomiopatiyi nayavnosti komorbidnykh sertsevo-sudynnykh zakhvoryuvan: kliniko-ultrastrukturni doslidzhennya [Specificity of diabetic cardiomyopathy in the presence of comorbid cardiovascular diseases: clinical and ultrastructural studies]. Mizhnarodn endokryn zhurn. 2016 5(77): 33-8. [Ukrainian]. https://doi.org/10.22141/2224-0721.5.77.2016.78751
35. Shah MS, Brownlee M. Molecular and cellular mechanisms of cardiovascular disorders diabetes. Circ Res.2016 May 27; 118(11): 1808-29. https://doi.org/10.1161/CIRCRESAHA.116.306923. https://www.ncbi.nlm.nih.gov/pubmed/27230643. https://www.ncbi.nlm.nih.gov/pmc/articles/4888901
36. Pham I, Cosson Е, Nguyen M, Banu I, Genevois I, Poignard P, et al. Evidence for a Specific Diabetic Cardiomyopathy: An Observational Retrospective Echocardiography Study in 656 Asymptomatic Type 2 Diabetic Patients. Int J Endocrinol. 2015 May 13; 2015: 1-8. https://doi.org/10.1155/2015/743503. https://www.ncbi.nlm.nih.gov/pubmed/26074964. https://www.ncbi.nlm.nih.gov/pmc/articles/4444596
37. Guha A, Harmancey R, Taegtmeyer H. Nonischemic heart failure in diabetes mellitus. Curr Opin Cardiol. 2008 May; 23(3): 241-8. https://doi.org/10.1097/HCO.0b013e3282fcc2fa. https://www.ncbi.nlm.nih.gov/pubmed/18382213. https://www.ncbi.nlm.nih.gov/pmc/articles/3625426
38. Babik B, Peták F, Agócs S, Blaskovics I, Alács E, Bodó K, et al. Diabetes mellitus: endothelial dysfunction and changes in hemostasis. Orv Hetil. 2018 Aug; 159(33): 1335-45. https://doi.org/10.1556/650.2018.31130. https://www.ncbi.nlm.nih.gov/pubmed/30099904
39. Bugger H, Abel ED. Molecular mechanisms of diabetic cardiomyopathy. Diabetologia. 2014 Apr; 57(4): 660-71. https://doi.org/10.1007/s00125-014-3171-6. https://www.ncbi.nlm.nih.gov/pubmed/24477973. https://www.ncbi.nlm.nih.gov/pmc/articles/3969857
40. Jia G, DeMarco VG, Sowers JR. Insulin resistance and hyperinsulinaemia in diabetic cardiomyopathy. Nat Rev Endocrinol. 2016 Mar; 12(3): 144-53. https://doi.org/10.1038/nrendo.2015.216. https://www.ncbi.nlm.nih.gov/pubmed/26678809. https://www.ncbi.nlm.nih.gov/pmc/articles/4753054
41. Babyy LN, Stroganova NP, Khomenko YuO. Dyastolycheskaya dysfunktsyya levogo zheludochka serdtsa y eyo rol v razvytyy serdechnoy nedostatochnosty u bolnykh yshemycheskoy boleznyu serdtsa [Diastolic dysfunction of the left ventricle of the heart and its role in the development of heart failure in patients with coronary heart disease]. Ukr kardiol zhurn. 2017; 3: 20-6. [Russian]
42. Yena LM, Yarosh VO, Artemenko VO, Khrystoforova GM. Gormonalnyy gomeostaz ta yogo vzayemozv'yazok iz morfofunktsionalnym stanom sertsevo-sudynnoyi systemy u khvorykh na khronichnu sertsevu nedostatnist zi zberezhenoyu fraktsiyeyu vykydu [Hormonal homeostasis and its relationship with the morphofunctional state of the cardiovascular system in patients with chronic heart failure with preserved ejection fraction]. Sertseva nedostatnist ta komorbidni stany. 2017; 3: 42-6. [Ukrainian]
43. Kravchun NO, Chernyayeva AO. Remodelyuvannya miokarda v patsiyentiv iz tsukrovym diabetom 2-go typu v poyednanni z nealkogolnoyu zhyrovoyu khvoroboyu pechinky [Myocardial remodeling in patients with type 2 diabetes mellitus in combination with nonalcoholic fatty liver disease]. Mizhnarodn endokryn zhurn. 2015; 8(72): 88-94. [Ukrainian] https://doi.org/10.22141/2224-0721.8.72.2015.72417
44. Vaduganathan М, Claggett BL, Chatterjee NA. Raptova smert sered patsiyentiv iz SN zi zberezhenoyu FV: analiz doslidzhennya TORSAT [Sudden death in patients with HF with preserved PV: an analysis of the TORSAT study]. Sertseva nedostatnist ta komorbidni stany. 2018; 1: 46. [Ukrainian]
45. Degtyar NY, Gerasymenko ND., Rasyn MS. Endotelyy y systemnoe vospalenye rol yadernykh transkryptsyonnykh faktorov y terapevtycheskye vozmozhnosty (obzor lyteratury) [Endothelium and systemic inflammation, the role of nuclear transcription factors and therapeutic options (literature review)]. Arteryalnaya gypertenzyya. 2016; 4(48): 21-5. [Russian]. https://doi.org/10.22141/2224-1485.4.48.2016.76991
46. Zyablitsev SV, Chernobryvtsev OP, Zyablitsev DS. Pokaznyky endotelialnoyi dysfunktsiyi pry tsukrovomu diabeti 2-go typu yak vyznachalni chynnyky rozvytku uskladnen [Indicators of endothelial dysfunction in type 2 diabetes mellitus as determining factors in the development of complications]. Mizhnarodn endokryn zhurn. 2018; 14(7): 661-7. [Ukrainian]. https://doi.org/10.22141/2224-0721.14.7.2018.148773
47. Carrizzo A, Izzo C, Oliveti M, Alfano A,Virtuoso N, Capunzo M, et al. The Main Determinants of Diabetes Mellitus Vascular Complications: Endothelial Dysfunction and Platelet Hyperaggregation. Int J Mol Sci. 2018 Oct; 19(10): 2968. https://doi.org/10.3390/ijms19102968. https://www.ncbi.nlm.nih.gov/pubmed/30274207. https://www.ncbi.nlm.nih.gov/pmc/articles/6212935
48. Blum A, Socea D, Sirchan R. Vascular responsiveness in type 2 diabetes mellitus. QJM. 2016 Dec; 109(12): 791-6. https://doi.org/10.1093/qjmed/hcw081. https://www.ncbi.nlm.nih.gov/pubmed/27289111
49. Low Wang CC, Hess C., Hiatt WR, Goldfine AB. Atherosclerotic Cardiovascular Disease and Heart Failure in Type 2 Diabetes Mellitus - Mechanisms, Management, and Clinical Consideration. Circulation. 2016 Jun 14; 133(24): 2459-502. https://doi.org/10.1161/CIRCULATIONAHA.116.022194. https://www.ncbi.nlm.nih.gov/pubmed/27297342. https://www.ncbi.nlm.nih.gov/pmc/articles/4910510
50. Radchenko OM, Korolyuk OYa. Osoblyvosti perebigu ta likuvannya ishemichnoyi khvoroby sertsya u khvorykh z porushennyamy metabolizmu glyukozy ta tsukrovym diabetom [Features of the course and treatment of coronary heart disease in patients with impaired glucose metabolism and diabetes]. Mizhnarodn endokryn zhurn. 2015; 6(70): 11-6. [Ukrainian] https://doi.org/10.22141/2224-0721.6.70.2015.72632
51. Martyshyn OO. Metabolichni, endokrynni ta sertsevo-sudynni zakhvoryuvannya: mizhdystsyplinarnyy pidkhid do diagnostyky ta likuvannya [Metabolic, endocrine and cardiovascular diseases: an interdisciplinary approach to diagnosis and treatment]. Ukr med chasopys. 2017; 6(122): 57-60. [Ukrainian]
52. Rodriguez-Poncelas A, Coll-de-Tuero G, Saez M, Garrido-Martín JM, Millaruelo-Trillo JM, de-la-Puente JB, et al. Comparison of different vascular risk engines in the identification of type 2 diabetes patients with high cardiovascular risk. BMC Cardiovasc Disord. 2015; 15: 121. https://doi.org/10.1186/s12872-015-0120-3. https://www.ncbi.nlm.nih.gov/pubmed/26464076. https://www.ncbi.nlm.nih.gov/pmc/articles/4605091
53. Davies MJ, D'Alessio DA, Fradkin J, Kernan WN, Mathieu C, Mingrone G, Management Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018 Dec; 41(12): 2669-701. https://doi.org/10.2337/dci18-0033. https://www.ncbi.nlm.nih.gov/pubmed/30291106. https://www.ncbi.nlm.nih.gov/pmc/articles/6245208