Effect of Postprandial Hyperglycemia on Vasculature in Type 1 Diabetes and Healthy Adults

Type 1 Diabetes Clinical Trial

— WBH001  

Official title:

Effect of Postprandial Hyperglycemia on Vasculature in Type 1 Diabetes and Healthy Adults

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04730882
• Other study ID #: 200216
• Secondary ID: KL2TR003016
• Status: Active, not recruiting
• Start date: April 6, 2021
• Est. completion date: January 2025

Study information

• Verified date: December 2023
• Source: University of Virginia
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

To the investigator's knowledge, there are no data available in the current literature regarding the acute effects of postprandial hyperglycemia and insulin timing on myocardial perfusion in people with type 1 diabetes (T1D). Observational studies using CEU in type 2 diabetes demonstrate that postprandial hyperglycemia determines myocardial perfusion defects. The investigator hypothesizes that the combination of postprandial hyperglycemia and insulin increases pulse wave velocity (i.e., aortic stiffness) and myocardial vasoconstriction, thereby reducing myocardial perfusion in T1D when compared to healthy controls. Furthermore, the investigator hypothesizes in T1D that dosing insulin before meal intake will ameliorate these cardiovascular defects.

Description:

The investigator will compare 17 T1D and 17 age-, sex-, and BMI-matched healthy controls (18-35 yrs) measuring pulse wave velocity (PWV), flow-mediated dilation (FMD) and myocardial perfusion (contrast enhanced ultrasound [CEU]) before and 2 hours after ingesting a mixed meal (40% of each subject's daily estimated caloric need, with 50%, 30%, 20% from carbohydrates, fat and protein, respectively). T1D participants will have 2 study admissions: A) injection of insulin 15 minutes before ingesting a mixed meal. B) injection of insulin 15 min after ingesting a mixed meal.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 36
• Est. completion date: January 2025
• Est. primary completion date: January 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 35 Years

Eligibility

Inclusion Criteria:

• Healthy with no chronic illness
• Age 18-35 years
• BMI = 30 (wt kg/ht m2)
• Normal screening labs or no clinically significant values
• T1D participants must have T1D based on WHO diagnostic criteria for > 1 year
• A fasting plasma glucose level >126 mg/dl (7.0 mmol/l)
• A casual plasma glucose >200 mg/dl (11.1 mmol/l)
• In the absence of unequivocal hyperglycemia, the diagnosis must be confirmed on a subsequent day.
• Subjects using sensor-augmented insulin pump therapy and/or artificial pancreas (closed loop system) will be included

Exclusion Criteria:

• • Smoking presently or have quit < 2 years.
• BP >140/90 mmHg
• BMI >30 (wt kg/ht m2)
• Pulse oximetry <90%
• Elevated LDL cholesterol > 160 mg/dl
• HbA1c = 9 %
• Use of statins, calcium channel blocker, ACE, ARB, nitrates, alpha-beta blockers or diuretics
• History of cardiac, cerebrovascular, gastrointestinal, liver, renal decease or cancer
• Presence of an intracardiac or intrapulmonary shunt (we will screen for this by auscultation during the physical exam by PI).
• Retinopathy (beyond mild non proliferative retinopathy)
• Urine albumin/creatinine ratio > 300 mg per g
• Pregnant or breastfeeding.
• Known hypersensitivity to perflutren (contained in Definity

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 1
• Hyperglycemia
• Hyperglycemia, Postprandial
• Type 1 Diabetes

Intervention

Dietary Supplement:
• Mixed Meal
the meal will be 40% of each subject's daily estimated caloric need, with 50%, 30%, 20% from carbohydrates, fat and protein, respectively

Locations

Country	Name	City	State
United States	University of Virginia	Charlottesville	Virginia

Sponsors (2)

Lead Sponsor	Collaborator
University of Virginia	National Center for Advancing Translational Sciences (NCATS)

Country where clinical trial is conducted

United States, 

References & Publications (72)

Abdelmoneim SS, Hagen ME, Mendrick E, Pattan V, Wong B, Norby B, Roberson T, Szydel T, Basu R, Basu A, Mulvagh SL. Acute hyperglycemia reduces myocardial blood flow reserve and the magnitude of reduction is associated with insulin resistance: a study in nondiabetic humans using contrast echocardiography. Heart Vessels. 2013 Nov;28(6):757-68. doi: 10.1007/s00380-012-0305-y. Epub 2012 Nov 23. — View Citation

Action to Control Cardiovascular Risk in Diabetes Study Group; Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB, Cushman WC, Genuth S, Ismail-Beigi F, Grimm RH Jr, Probstfield JL, Simons-Morton DG, Friedewald WT. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008 Jun 12;358(24):2545-59. doi: 10.1056/NEJMoa0802743. Epub 2008 Jun 6. — View Citation

Alessa T, Szeto A, Chacra W, Mendez A, Goldberg RB. High HDL-C prevalence is common in type 1 diabetes and increases with age but is lower in Hispanic individuals. J Diabetes Complications. 2015 Jan-Feb;29(1):105-7. doi: 10.1016/j.jdiacomp.2014.08.011. Epub 2014 Sep 6. — View Citation

Aryangat AV, Gerich JE. Type 2 diabetes: postprandial hyperglycemia and increased cardiovascular risk. Vasc Health Risk Manag. 2010 Mar 24;6:145-55. doi: 10.2147/vhrm.s8216. — View Citation

Bagi Z, Broskova Z, Feher A. Obesity and coronary microvascular disease - implications for adipose tissue-mediated remote inflammatory response. Curr Vasc Pharmacol. 2014 May;12(3):453-61. doi: 10.2174/1570161112666140423221843. — View Citation

Barletta G, Del Bene MR. Myocardial perfusion echocardiography and coronary microvascular dysfunction. World J Cardiol. 2015 Dec 26;7(12):861-74. doi: 10.4330/wjc.v7.i12.861. — View Citation

Bonke FC, Donnachie E, Schneider A, Mehring M. Association of the average rate of change in HbA1c with severe adverse events: a longitudinal evaluation of audit data from the Bavarian Disease Management Program for patients with type 2 diabetes mellitus. Diabetologia. 2016 Feb;59(2):286-93. doi: 10.1007/s00125-015-3797-z. Epub 2015 Oct 30. — View Citation

Breton MD, Patek SD, Lv D, Schertz E, Robic J, Pinnata J, Kollar L, Barnett C, Wakeman C, Oliveri M, Fabris C, Chernavvsky D, Kovatchev BP, Anderson SM. Continuous Glucose Monitoring and Insulin Informed Advisory System with Automated Titration and Dosing of Insulin Reduces Glucose Variability in Type 1 Diabetes Mellitus. Diabetes Technol Ther. 2018 Aug;20(8):531-540. doi: 10.1089/dia.2018.0079. Epub 2018 Jul 6. — View Citation

Cavalot F, Petrelli A, Traversa M, Bonomo K, Fiora E, Conti M, Anfossi G, Costa G, Trovati M. Postprandial blood glucose is a stronger predictor of cardiovascular events than fasting blood glucose in type 2 diabetes mellitus, particularly in women: lessons from the San Luigi Gonzaga Diabetes Study. J Clin Endocrinol Metab. 2006 Mar;91(3):813-9. doi: 10.1210/jc.2005-1005. Epub 2005 Dec 13. — View Citation

Ceriello A, Esposito K, Piconi L, Ihnat MA, Thorpe JE, Testa R, Boemi M, Giugliano D. Oscillating glucose is more deleterious to endothelial function and oxidative stress than mean glucose in normal and type 2 diabetic patients. Diabetes. 2008 May;57(5):1349-54. doi: 10.2337/db08-0063. Epub 2008 Feb 25. — View Citation

Ceriello A, Hanefeld M, Leiter L, Monnier L, Moses A, Owens D, Tajima N, Tuomilehto J. Postprandial glucose regulation and diabetic complications. Arch Intern Med. 2004 Oct 25;164(19):2090-5. doi: 10.1001/archinte.164.19.2090. — View Citation

Ceriello A. The emerging role of post-prandial hyperglycaemic spikes in the pathogenesis of diabetic complications. Diabet Med. 1998 Mar;15(3):188-93. doi: 10.1002/(SICI)1096-9136(199803)15:33.0.CO;2-V. No abstract available. — View Citation

Chai W, Liu J, Jahn LA, Fowler DE, Barrett EJ, Liu Z. Salsalate attenuates free fatty acid-induced microvascular and metabolic insulin resistance in humans. Diabetes Care. 2011 Jul;34(7):1634-8. doi: 10.2337/dc10-2345. Epub 2011 May 26. — View Citation

Chan A, Barrett EJ, Anderson SM, Kovatchev BP, Breton MD. Muscle microvascular recruitment predicts insulin sensitivity in middle-aged patients with type 1 diabetes mellitus. Diabetologia. 2012 Mar;55(3):729-36. doi: 10.1007/s00125-011-2402-3. Epub 2011 Dec 14. — View Citation

Coggins M, Lindner J, Rattigan S, Jahn L, Fasy E, Kaul S, Barrett E. Physiologic hyperinsulinemia enhances human skeletal muscle perfusion by capillary recruitment. Diabetes. 2001 Dec;50(12):2682-90. doi: 10.2337/diabetes.50.12.2682. — View Citation

Corbin KD, Driscoll KA, Pratley RE, Smith SR, Maahs DM, Mayer-Davis EJ; Advancing Care for Type 1 Diabetes and Obesity Network (ACT1ON). Obesity in Type 1 Diabetes: Pathophysiology, Clinical Impact, and Mechanisms. Endocr Rev. 2018 Oct 1;39(5):629-663. doi: 10.1210/er.2017-00191. — View Citation

Currie CJ, Peters JR, Tynan A, Evans M, Heine RJ, Bracco OL, Zagar T, Poole CD. Survival as a function of HbA(1c) in people with type 2 diabetes: a retrospective cohort study. Lancet. 2010 Feb 6;375(9713):481-9. doi: 10.1016/S0140-6736(09)61969-3. Epub 2010 Jan 26. — View Citation

Danne T, Nimri R, Battelino T, Bergenstal RM, Close KL, DeVries JH, Garg S, Heinemann L, Hirsch I, Amiel SA, Beck R, Bosi E, Buckingham B, Cobelli C, Dassau E, Doyle FJ 3rd, Heller S, Hovorka R, Jia W, Jones T, Kordonouri O, Kovatchev B, Kowalski A, Laffel L, Maahs D, Murphy HR, Norgaard K, Parkin CG, Renard E, Saboo B, Scharf M, Tamborlane WV, Weinzimer SA, Phillip M. International Consensus on Use of Continuous Glucose Monitoring. Diabetes Care. 2017 Dec;40(12):1631-1640. doi: 10.2337/dc17-1600. — View Citation

Davis SN, Duckworth W, Emanuele N, Hayward RA, Wiitala WL, Thottapurathu L, Reda DJ, Reaven PD; Investigators of the Veterans Affairs Diabetes Trial. Effects of Severe Hypoglycemia on Cardiovascular Outcomes and Death in the Veterans Affairs Diabetes Trial. Diabetes Care. 2019 Jan;42(1):157-163. doi: 10.2337/dc18-1144. Epub 2018 Nov 19. — View Citation

de Ferranti SD, de Boer IH, Fonseca V, Fox CS, Golden SH, Lavie CJ, Magge SN, Marx N, McGuire DK, Orchard TJ, Zinman B, Eckel RH. Type 1 diabetes mellitus and cardiovascular disease: a scientific statement from the American Heart Association and American Diabetes Association. Diabetes Care. 2014 Oct;37(10):2843-63. doi: 10.2337/dc14-1720. Epub 2014 Aug 11. No abstract available. — View Citation

Gerbaud E, Darier R, Montaudon M, Beauvieux MC, Coffin-Boutreux C, Coste P, Douard H, Ouattara A, Catargi B. Glycemic Variability Is a Powerful Independent Predictive Factor of Midterm Major Adverse Cardiac Events in Patients With Diabetes With Acute Coronary Syndrome. Diabetes Care. 2019 Apr;42(4):674-681. doi: 10.2337/dc18-2047. Epub 2019 Feb 6. — View Citation

Ghouse J, Skov MW, Kanters JK, Lind B, Isaksen JL, Blanche P, Haunso S, Kober L, Svendsen JH, Olesen MS, Holst AG, Gerds TA, Nielsen JB. Visit-to-Visit Variability of Hemoglobin A1c in People Without Diabetes and Risk of Major Adverse Cardiovascular Events and All-Cause Mortality. Diabetes Care. 2019 Jan;42(1):134-141. doi: 10.2337/dc18-1396. Epub 2018 Oct 23. — View Citation

Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria. The DECODE study group. European Diabetes Epidemiology Group. Diabetes Epidemiology: Collaborative analysis Of Diagnostic criteria in Europe. Lancet. 1999 Aug 21;354(9179):617-21. — View Citation

Gorst C, Kwok CS, Aslam S, Buchan I, Kontopantelis E, Myint PK, Heatlie G, Loke Y, Rutter MK, Mamas MA. Long-term Glycemic Variability and Risk of Adverse Outcomes: A Systematic Review and Meta-analysis. Diabetes Care. 2015 Dec;38(12):2354-69. doi: 10.2337/dc15-1188. — View Citation

Goto A, Goto M, Terauchi Y, Yamaguchi N, Noda M. Association Between Severe Hypoglycemia and Cardiovascular Disease Risk in Japanese Patients With Type 2 Diabetes. J Am Heart Assoc. 2016 Mar 9;5(3):e002875. doi: 10.1161/JAHA.115.002875. Erratum In: J Am Heart Assoc. 2016 Jun;5(6). pii: e002075. doi: 10.1161/JAHA.116.002075. — View Citation

Haas AV, Rosner BA, Kwong RY, Rao AD, Garg R, Di Carli MF, Adler GK. Sex Differences in Coronary Microvascular Function in Individuals With Type 2 Diabetes. Diabetes. 2019 Mar;68(3):631-636. doi: 10.2337/db18-0650. Epub 2018 Nov 8. — View Citation

Horvath EM, Benko R, Kiss L, Muranyi M, Pek T, Fekete K, Barany T, Somlai A, Csordas A, Szabo C. Rapid 'glycaemic swings' induce nitrosative stress, activate poly(ADP-ribose) polymerase and impair endothelial function in a rat model of diabetes mellitus. Diabetologia. 2009 May;52(5):952-61. doi: 10.1007/s00125-009-1304-0. Epub 2009 Mar 5. — View Citation

Jahn LA, Hartline L, Rao N, Logan B, Kim JJ, Aylor K, Gan LM, Westergren HU, Barrett EJ. Insulin Enhances Endothelial Function Throughout the Arterial Tree in Healthy But Not Metabolic Syndrome Subjects. J Clin Endocrinol Metab. 2016 Mar;101(3):1198-206. doi: 10.1210/jc.2015-3293. Epub 2016 Jan 12. — View Citation

Jamiolkowska M, Jamiolkowska I, Luczynski W, Tolwinska J, Bossowski A, Glowinska Olszewska B. Impact of Real-Time Continuous Glucose Monitoring Use on Glucose Variability and Endothelial Function in Adolescents with Type 1 Diabetes: New Technology--New Possibility to Decrease Cardiovascular Risk? J Diabetes Res. 2016;2016:4385312. doi: 10.1155/2016/4385312. Epub 2015 Nov 16. — View Citation

Kovatchev B, Cobelli C. Glucose Variability: Timing, Risk Analysis, and Relationship to Hypoglycemia in Diabetes. Diabetes Care. 2016 Apr;39(4):502-10. doi: 10.2337/dc15-2035. — View Citation

Kuruvilla S, Janardhanan R, Antkowiak P, Keeley EC, Adenaw N, Brooks J, Epstein FH, Kramer CM, Salerno M. Increased extracellular volume and altered mechanics are associated with LVH in hypertensive heart disease, not hypertension alone. JACC Cardiovasc Imaging. 2015 Feb;8(2):172-80. doi: 10.1016/j.jcmg.2014.09.020. Epub 2015 Jan 7. — View Citation

Larghat AM, Swoboda PP, Biglands JD, Kearney MT, Greenwood JP, Plein S. The microvascular effects of insulin resistance and diabetes on cardiac structure, function, and perfusion: a cardiovascular magnetic resonance study. Eur Heart J Cardiovasc Imaging. 2014 Dec;15(12):1368-76. doi: 10.1093/ehjci/jeu142. Epub 2014 Aug 12. — View Citation

Lee AK, Warren B, Lee CJ, McEvoy JW, Matsushita K, Huang ES, Sharrett AR, Coresh J, Selvin E. The Association of Severe Hypoglycemia With Incident Cardiovascular Events and Mortality in Adults With Type 2 Diabetes. Diabetes Care. 2018 Jan;41(1):104-111. doi: 10.2337/dc17-1669. Epub 2017 Nov 10. — View Citation

Lee CL, Sheu WH, Lee IT, Lin SY, Liang WM, Wang JS, Li YF. Trajectories of fasting plasma glucose variability and mortality in type 2 diabetes. Diabetes Metab. 2018 Mar;44(2):121-128. doi: 10.1016/j.diabet.2017.09.001. Epub 2017 Oct 9. — View Citation

Lind M, Bounias I, Olsson M, Gudbjornsdottir S, Svensson AM, Rosengren A. Glycaemic control and incidence of heart failure in 20,985 patients with type 1 diabetes: an observational study. Lancet. 2011 Jul 9;378(9786):140-6. doi: 10.1016/S0140-6736(11)60471-6. Epub 2011 Jun 24. — View Citation

Lind M, Svensson AM, Kosiborod M, Gudbjornsdottir S, Pivodic A, Wedel H, Dahlqvist S, Clements M, Rosengren A. Glycemic control and excess mortality in type 1 diabetes. N Engl J Med. 2014 Nov 20;371(21):1972-82. doi: 10.1056/NEJMoa1408214. — View Citation

Liu J, Jahn LA, Fowler DE, Barrett EJ, Cao W, Liu Z. Free fatty acids induce insulin resistance in both cardiac and skeletal muscle microvasculature in humans. J Clin Endocrinol Metab. 2011 Feb;96(2):438-46. doi: 10.1210/jc.2010-1174. Epub 2010 Nov 3. — View Citation

Livingstone SJ, Looker HC, Hothersall EJ, Wild SH, Lindsay RS, Chalmers J, Cleland S, Leese GP, McKnight J, Morris AD, Pearson DW, Peden NR, Petrie JR, Philip S, Sattar N, Sullivan F, Colhoun HM. Risk of cardiovascular disease and total mortality in adults with type 1 diabetes: Scottish registry linkage study. PLoS Med. 2012;9(10):e1001321. doi: 10.1371/journal.pmed.1001321. Epub 2012 Oct 2. — View Citation

Martin-Timon I, Sevillano-Collantes C, Segura-Galindo A, Del Canizo-Gomez FJ. Type 2 diabetes and cardiovascular disease: Have all risk factors the same strength? World J Diabetes. 2014 Aug 15;5(4):444-70. doi: 10.4239/wjd.v5.i4.444. — View Citation

Mavrogeni S, Bratis K, Gavra P, Fousteris E, Markussis V, Kolovou G, van Wijk K, Hautemann D, Reiber JH, Melidonis A. Stress cardiac magnetic resonance reveals myocardial perfusion impairment in asymptomatic diabetes mellitus type I, missed by the routine non-invasive evaluation. Int J Cardiol. 2013 Sep 10;167(6):e167-9. doi: 10.1016/j.ijcard.2013.04.170. Epub 2013 May 9. No abstract available. — View Citation

Miller RG, Costacou T, Orchard TJ. Risk Factor Modeling for Cardiovascular Disease in Type 1 Diabetes in the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study: A Comparison With the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC). Diabetes. 2019 Feb;68(2):409-419. doi: 10.2337/db18-0515. Epub 2018 Nov 8. — View Citation

Monnier L, Colette C, Owens DR. Glycemic variability: the third component of the dysglycemia in diabetes. Is it important? How to measure it? J Diabetes Sci Technol. 2008 Nov;2(6):1094-100. doi: 10.1177/193229680800200618. — View Citation

Monnier L, Colette C, Wojtusciszyn A, Dejager S, Renard E, Molinari N, Owens DR. Toward Defining the Threshold Between Low and High Glucose Variability in Diabetes. Diabetes Care. 2017 Jul;40(7):832-838. doi: 10.2337/dc16-1769. Epub 2016 Dec 30. — View Citation

Monnier L, Mas E, Ginet C, Michel F, Villon L, Cristol JP, Colette C. Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. JAMA. 2006 Apr 12;295(14):1681-7. doi: 10.1001/jama.295.14.1681. — View Citation

Ng AC, Auger D, Delgado V, van Elderen SG, Bertini M, Siebelink HM, van der Geest RJ, Bonetti C, van der Velde ET, de Roos A, Smit JW, Leung DY, Bax JJ, Lamb HJ. Association between diffuse myocardial fibrosis by cardiac magnetic resonance contrast-enhanced T(1) mapping and subclinical myocardial dysfunction in diabetic patients: a pilot study. Circ Cardiovasc Imaging. 2012 Jan;5(1):51-9. doi: 10.1161/CIRCIMAGING.111.965608. Epub 2011 Dec 1. Erratum In: Circ Cardiovasc Imaging. 2012 Mar;5(2):e25. — View Citation

Norgaard K, Feldt-Rasmussen B, Borch-Johnsen K, Saelan H, Deckert T. Prevalence of hypertension in type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1990 Jul;33(7):407-10. doi: 10.1007/BF00404089. — View Citation

Ohkuma T, Komorita Y, Peters SAE, Woodward M. Diabetes as a risk factor for heart failure in women and men: a systematic review and meta-analysis of 47 cohorts including 12 million individuals. Diabetologia. 2019 Sep;62(9):1550-1560. doi: 10.1007/s00125-019-4926-x. Epub 2019 Jul 18. — View Citation

Piconi L, Quagliaro L, Assaloni R, Da Ros R, Maier A, Zuodar G, Ceriello A. Constant and intermittent high glucose enhances endothelial cell apoptosis through mitochondrial superoxide overproduction. Diabetes Metab Res Rev. 2006 May-Jun;22(3):198-203. doi: 10.1002/dmrr.613. — View Citation

Priya G, Kalra S. A Review of Insulin Resistance in Type 1 Diabetes: Is There a Place for Adjunctive Metformin? Diabetes Ther. 2018 Feb;9(1):349-361. doi: 10.1007/s13300-017-0333-9. Epub 2017 Nov 14. — View Citation

Quagliaro L, Piconi L, Assaloni R, Martinelli L, Motz E, Ceriello A. Intermittent high glucose enhances apoptosis related to oxidative stress in human umbilical vein endothelial cells: the role of protein kinase C and NAD(P)H-oxidase activation. Diabetes. 2003 Nov;52(11):2795-804. doi: 10.2337/diabetes.52.11.2795. — View Citation

Rana O, Byrne CD, Kerr D, Coppini DV, Zouwail S, Senior R, Begley J, Walker JJ, Greaves K. Acute hypoglycemia decreases myocardial blood flow reserve in patients with type 1 diabetes mellitus and in healthy humans. Circulation. 2011 Oct 4;124(14):1548-56. doi: 10.1161/CIRCULATIONAHA.110.992297. Epub 2011 Sep 12. — View Citation

Risso A, Mercuri F, Quagliaro L, Damante G, Ceriello A. Intermittent high glucose enhances apoptosis in human umbilical vein endothelial cells in culture. Am J Physiol Endocrinol Metab. 2001 Nov;281(5):E924-30. doi: 10.1152/ajpendo.2001.281.5.E924. — View Citation

Saisho Y. Glycemic variability and oxidative stress: a link between diabetes and cardiovascular disease? Int J Mol Sci. 2014 Oct 13;15(10):18381-406. doi: 10.3390/ijms151018381. — View Citation

Scognamiglio R, Negut C, de Kreutzenberg SV, Tiengo A, Avogaro A. Effects of different insulin regimes on postprandial myocardial perfusion defects in type 2 diabetic patients. Diabetes Care. 2006 Jan;29(1):95-100. — View Citation

Scognamiglio R, Negut C, De Kreutzenberg SV, Tiengo A, Avogaro A. Postprandial myocardial perfusion in healthy subjects and in type 2 diabetic patients. Circulation. 2005 Jul 12;112(2):179-84. doi: 10.1161/CIRCULATIONAHA.104.495127. Epub 2005 Jul 5. — View Citation

Snell-Bergeon JK, Roman R, Rodbard D, Garg S, Maahs DM, Schauer IE, Bergman BC, Kinney GL, Rewers M. Glycaemic variability is associated with coronary artery calcium in men with Type 1 diabetes: the Coronary Artery Calcification in Type 1 Diabetes study. Diabet Med. 2010 Dec;27(12):1436-42. doi: 10.1111/j.1464-5491.2010.03127.x. — View Citation

Strojek K, Raz I, Jermendy G, Gitt AK, Liu R, Zhang Q, Jacober SJ, Milicevic Z. Factors Associated With Cardiovascular Events in Patients With Type 2 Diabetes and Acute Myocardial Infarction. J Clin Endocrinol Metab. 2016 Jan;101(1):243-53. doi: 10.1210/jc.2015-1962. Epub 2015 Nov 23. — View Citation

Su G, Mi SH, Tao H, Li Z, Yang HX, Zheng H, Zhou Y, Tian L. Impact of admission glycemic variability, glucose, and glycosylated hemoglobin on major adverse cardiac events after acute myocardial infarction. Diabetes Care. 2013 Apr;36(4):1026-32. doi: 10.2337/dc12-0925. Epub 2013 Jan 24. — View Citation

Su MY, Lin LY, Tseng YH, Chang CC, Wu CK, Lin JL, Tseng WY. CMR-verified diffuse myocardial fibrosis is associated with diastolic dysfunction in HFpEF. JACC Cardiovasc Imaging. 2014 Oct;7(10):991-7. doi: 10.1016/j.jcmg.2014.04.022. Epub 2014 Sep 17. — View Citation

Subaran SC, Sauder MA, Chai W, Jahn LA, Fowler DE, Aylor KW, Basu A, Liu Z. GLP-1 at physiological concentrations recruits skeletal and cardiac muscle microvasculature in healthy humans. Clin Sci (Lond). 2014 Aug;127(3):163-70. doi: 10.1042/CS20130708. — View Citation

Sundell J, Knuuti J. Insulin and myocardial blood flow. Cardiovasc Res. 2003 Feb;57(2):312-9. doi: 10.1016/s0008-6363(02)00718-6. — View Citation

Tam CS, Xie W, Johnson WD, Cefalu WT, Redman LM, Ravussin E. Defining insulin resistance from hyperinsulinemic-euglycemic clamps. Diabetes Care. 2012 Jul;35(7):1605-10. doi: 10.2337/dc11-2339. Epub 2012 Apr 17. — View Citation

Tang X, Li S, Wang Y, Wang M, Yin Q, Mu P, Lin S, Qian X, Ye X, Chen Y. Glycemic variability evaluated by continuous glucose monitoring system is associated with the 10-y cardiovascular risk of diabetic patients with well-controlled HbA1c. Clin Chim Acta. 2016 Oct 1;461:146-50. doi: 10.1016/j.cca.2016.08.004. Epub 2016 Aug 5. — View Citation

Tromp J, Lim SL, Tay WT, Teng TK, Chandramouli C, Ouwerkerk W, Wander GS, Sawhney JPS, Yap J, MacDonald MR, Ling LH, Sattar N, McMurray JJV, Richards AM, Anand I, Lam CSP; ASIAN-HF Investigators. Microvascular Disease in Patients With Diabetes With Heart Failure and Reduced Ejection Versus Preserved Ejection Fraction. Diabetes Care. 2019 Sep;42(9):1792-1799. doi: 10.2337/dc18-2515. Epub 2019 Jul 10. — View Citation

Turkbey EB, Backlund JY, Genuth S, Jain A, Miao C, Cleary PA, Lachin JM, Nathan DM, van der Geest RJ, Soliman EZ, Liu CY, Lima JA, Bluemke DA; DCCT/EDIC Research Group. Myocardial structure, function, and scar in patients with type 1 diabetes mellitus. Circulation. 2011 Oct 18;124(16):1737-46. doi: 10.1161/CIRCULATIONAHA.111.022327. Epub 2011 Sep 26. — View Citation

Vincent MA, Clerk LH, Lindner JR, Price WJ, Jahn LA, Leong-Poi H, Barrett EJ. Mixed meal and light exercise each recruit muscle capillaries in healthy humans. Am J Physiol Endocrinol Metab. 2006 Jun;290(6):E1191-7. doi: 10.1152/ajpendo.00497.2005. — View Citation

Vincent MA, Dawson D, Clark AD, Lindner JR, Rattigan S, Clark MG, Barrett EJ. Skeletal muscle microvascular recruitment by physiological hyperinsulinemia precedes increases in total blood flow. Diabetes. 2002 Jan;51(1):42-8. doi: 10.2337/diabetes.51.1.42. — View Citation

Waden J, Forsblom C, Thorn LM, Gordin D, Saraheimo M, Groop PH; Finnish Diabetic Nephropathy Study Group. A1C variability predicts incident cardiovascular events, microalbuminuria, and overt diabetic nephropathy in patients with type 1 diabetes. Diabetes. 2009 Nov;58(11):2649-55. doi: 10.2337/db09-0693. Epub 2009 Aug 3. — View Citation

Wan EY, Fung CS, Fong DY, Lam CL. Association of variability in hemoglobin A1c with cardiovascular diseases and mortality in Chinese patients with type 2 diabetes mellitus - A retrospective population-based cohort study. J Diabetes Complications. 2016 Sep-Oct;30(7):1240-7. doi: 10.1016/j.jdiacomp.2016.05.024. Epub 2016 May 31. — View Citation

Wightman SS, Sainsbury CAR, Jones GC. Visit-to-visit HbA1c variability and systolic blood pressure (SBP) variability are significantly and additively associated with mortality in individuals with type 1 diabetes: An observational study. Diabetes Obes Metab. 2018 Apr;20(4):1014-1017. doi: 10.1111/dom.13193. Epub 2018 Jan 18. — View Citation

Zinman B, Marso SP, Christiansen E, Calanna S, Rasmussen S, Buse JB; LEADER Publication Committee on behalf of the LEADER Trial Investigators. Hypoglycemia, Cardiovascular Outcomes, and Death: The LEADER Experience. Diabetes Care. 2018 Aug;41(8):1783-1791. doi: 10.2337/dc17-2677. Epub 2018 Jun 14. — View Citation

Zorach B, Shaw PW, Bourque J, Kuruvilla S, Balfour PC Jr, Yang Y, Mathew R, Pan J, Gonzalez JA, Taylor AM, Meyer CH, Epstein FH, Kramer CM, Salerno M. Quantitative cardiovascular magnetic resonance perfusion imaging identifies reduced flow reserve in microvascular coronary artery disease. J Cardiovasc Magn Reson. 2018 Feb 22;20(1):14. doi: 10.1186/s12968-018-0435-1. — View Citation

* Note: There are 72 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Myocardial Microvascular Perfusion (measured by contrast-enhanced ultrasound)	Measurement of change in myocardial microvascular perfusion	baseline and 2 hours after a meal
Secondary	Skeletal Muscle Microvascular Perfusion (measured by contrast-enhanced ultrasound)	Measurement of change in microvascular perfusion of skeletal muscle	baseline and 2 hours after a meal
Secondary	Flow Mediated Dilation	Vascular measure of change in conduit artery stiffness	baseline and 2 hours after a meal
Secondary	Pulse Wave Velocity ( PWV)	Measurement of change in central artery stiffness	baseline and 2 hours after a meal
Secondary	Tumor Necrosis Factor-Alpha (TNF-alpha)	Inflammatory biomarker (plasma sample) specific specific to patients with type 1 diabetes	baseline and 2 hours after a meal
Secondary	Interleukin 6 (IL-6)	Inflammatory biomarker (plasma sample) specific specific to patients with type 1 diabetes	baseline and 2 hours after a meal
Secondary	high sensitivity C-reactive protein (hsCRP)	Inflammatory biomarker (plasma sample) specific specific to patients with type 1 diabetes	baseline and 2 hours after a meal
Secondary	Intercellular Adhesion Molecule 1 (ICAM-1)	Biomarker (plasma sample) of endothelial dysfunction	baseline and 2 hours after a meal
Secondary	E-selectin	Biomarker (plasma sample) of endothelial dysfunction	baseline and 2 hours after a meal