Effect of Hyperglycemia on Microvascular Perfusion in Healthy Adults

NCT03520569 | Completed Early Phase 1 Results FDA Drug

• 2 other identifiers: 19948T32DK007646
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

Brief Summary

The investigators are studying the effects of Hyperglycemia on vascular function and insulin sensitivity on healthy adults

Conditions

Vascular Stiffness; Insulin Sensitivity

Outcome Measures

Primary Outcomes (1)

• Change in Flow Mediated Dilation (FMD) Between Baseline and After 2 Hour Insulin Clamp

  Flow mediated dilation measures the change in brachial diameter in response to 5 minutes of ischemia using B-mode ultrasound. It provides an index of nitric oxide generation by the endothelium .

  baseline and after 2 hour insulin clamp

Secondary Outcomes (2)

• Change in Augmentation Index Between Baseline and After 2 Hour Insulin Clamp

  baseline and after 2 hour insulin clamp

• Change in Pulse Wave Velocity (PWV) Between Baseline and After 2 Hour Insulin Clamp

  baseline and after 2 hour insulin clamp

Study Arms (4)

Octreotide- Euglycemia

ACTIVE COMPARATOR

octreotide is 30 ng/kg/min x 240 min insulin 0.15mU/kg/min x 240 min Dextrose 20% at variable rate to maintain euglycemia for 240 min

Drug: Octreotide; Drug: Insulin; Drug: Dextrose 20% solution

Octreotide - Euglycemia- insulin clamp

ACTIVE COMPARATOR

octreotide is 30 ng/kg/min x 330 min insulin 0.15mU/kg/min x 210 min insulin 1.0mU/kg/min x 120 min Dextrose 20% at variable rate to maintain euglycemia for 330 min

Drug: Octreotide; Drug: Insulin; Drug: Dextrose 20% solution

Octreotide- hyperglycemia

ACTIVE COMPARATOR

octreotide is 30 ng/kg/min x 330 min insulin 0.15mU/kg/min x 330 min Dextrose 20% at variable rate to maintain euglycemia for 90 min Dextrose 20% at variable rate to maintain hyperglycemia for 240 min

Drug: Octreotide; Drug: Insulin; Drug: Dextrose 20% solution

Octreotide- hyperglycemia - insulin clamp

ACTIVE COMPARATOR

octreotide is 30 ng/kg/min x 330 min insulin 0.15mU/kg/min x 210 min insulin 1.0mU/kg/min x 120 min Dextrose 20% at variable rate to maintain euglycemia for 90 min Dextrose 20% at variable rate to maintain hyperglycemia for 240 min

Drug: Octreotide; Drug: Insulin; Drug: Dextrose 20% solution

Interventions

Octreotide DRUG

we are using it to block insulin secretion from the pancreas

Octreotide - Euglycemia- insulin clamp; Octreotide- Euglycemia; Octreotide- hyperglycemia; Octreotide- hyperglycemia - insulin clamp

Insulin DRUG

we are using to replace basal insulin and in two protocols to raise insulin concentrations during the insulin clamp

Octreotide - Euglycemia- insulin clamp; Octreotide- Euglycemia; Octreotide- hyperglycemia; Octreotide- hyperglycemia - insulin clamp

Dextrose 20% solution DRUG

We are using dextrose to maintain glycemia level

Octreotide - Euglycemia- insulin clamp; Octreotide- Euglycemia; Octreotide- hyperglycemia; Octreotide- hyperglycemia - insulin clamp

Eligibility Criteria

• Age: 18 Years - 35 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy with no chronic illness
• Age 18-35
• Normal BMI (18-25)
• Normal screening labs or no clinically significant values

You may not qualify if:

• First degree relative with Type 2 Diabetes
• Smoking presently or in the past 6 months
• Medications that affect the vasculature
• Overweight or other indications of insulin resistance
• Elevated LDL cholesterol \> 160
• Elevated BP \> 140/90
• History of congestive heart failure, ischemic heart disease, severe pulmonary disease, liver or kidney disease, bleeding disorders
• Any vascular disease such as myocardial infarction, stroke, peripheral vascular disease
• Presence of an intracardiac or intrapulmonary shunt (we will screen for this by auscultation during the physical exam by PI).
• Pregnant or breastfeeding.
• Known hypersensitivity to perflutren (contained in Definity)

Sponsors & Collaborators

• University of Virginia: lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (1)

University of Virginia

Charlottesville, Virginia, 22908, United States

Location

Related Publications (31)

• Deedwania P, Kosiborod M, Barrett E, Ceriello A, Isley W, Mazzone T, Raskin P. Hyperglycemia and acute coronary syndrome: a scientific statement from the American Heart Association Diabetes Committee of the Council on Nutrition, Physical Activity, and Metabolism. Anesthesiology. 2008 Jul;109(1):14-24. doi: 10.1097/ALN.0b013e31817dced3.

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• Brouwers O, Niessen PM, Haenen G, Miyata T, Brownlee M, Stehouwer CD, De Mey JG, Schalkwijk CG. Hyperglycaemia-induced impairment of endothelium-dependent vasorelaxation in rat mesenteric arteries is mediated by intracellular methylglyoxal levels in a pathway dependent on oxidative stress. Diabetologia. 2010 May;53(5):989-1000. doi: 10.1007/s00125-010-1677-0. Epub 2010 Feb 26.

  PMID: 20186387 BACKGROUND

• Ceriello A, Taboga C, Tonutti L, Quagliaro L, Piconi L, Bais B, Da Ros R, Motz E. Evidence for an independent and cumulative effect of postprandial hypertriglyceridemia and hyperglycemia on endothelial dysfunction and oxidative stress generation: effects of short- and long-term simvastatin treatment. Circulation. 2002 Sep 3;106(10):1211-8. doi: 10.1161/01.cir.0000027569.76671.a8.

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• Suzuki K, Watanabe K, Futami-Suda S, Yano H, Motoyama M, Matsumura N, Igari Y, Suzuki T, Nakano H, Oba K. The effects of postprandial glucose and insulin levels on postprandial endothelial function in subjects with normal glucose tolerance. Cardiovasc Diabetol. 2012 Aug 14;11:98. doi: 10.1186/1475-2840-11-98.

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• Ceriello A, Novials A, Ortega E, Canivell S, La Sala L, Pujadas G, Esposito K, Giugliano D, Genovese S. Glucagon-like peptide 1 reduces endothelial dysfunction, inflammation, and oxidative stress induced by both hyperglycemia and hypoglycemia in type 1 diabetes. Diabetes Care. 2013 Aug;36(8):2346-50. doi: 10.2337/dc12-2469. Epub 2013 Apr 5.

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• Perkins JM, Joy NG, Tate DB, Davis SN. Acute effects of hyperinsulinemia and hyperglycemia on vascular inflammatory biomarkers and endothelial function in overweight and obese humans. Am J Physiol Endocrinol Metab. 2015 Jul 15;309(2):E168-76. doi: 10.1152/ajpendo.00064.2015. Epub 2015 May 26.

  PMID: 26015434 BACKGROUND

• Giugliano D, Marfella R, Coppola L, Verrazzo G, Acampora R, Giunta R, Nappo F, Lucarelli C, D'Onofrio F. Vascular effects of acute hyperglycemia in humans are reversed by L-arginine. Evidence for reduced availability of nitric oxide during hyperglycemia. Circulation. 1997 Apr 1;95(7):1783-90. doi: 10.1161/01.cir.95.7.1783.

  PMID: 9107164 BACKGROUND

• Cuypers MH, Kasanardjo JS, Polak BC. Retinal blood flow changes in diabetic retinopathy measured with the Heidelberg scanning laser Doppler flowmeter. Graefes Arch Clin Exp Ophthalmol. 2000 Dec;238(12):935-41. doi: 10.1007/s004170000207.

  PMID: 11196354 BACKGROUND

• Horova E, Mazoch J, Hiigertova J, Kvasnicka J, Skrha J, Soupal J, Prazny M. Acute hyperglycemia does not impair microvascular reactivity and endothelial function during hyperinsulinemic isoglycemic and hyperglycemic clamp in type 1 diabetic patients. Exp Diabetes Res. 2012;2012:851487. doi: 10.1155/2012/851487. Epub 2012 Jan 4.

  PMID: 22262970 BACKGROUND

• Burgansky-Eliash Z, Barak A, Barash H, Nelson DA, Pupko O, Lowenstein A, Grinvald A, Rubinstein A. Increased retinal blood flow velocity in patients with early diabetes mellitus. Retina. 2012 Jan;32(1):112-9. doi: 10.1097/IAE.0b013e31821ba2c4.

  PMID: 21878846 BACKGROUND

• Rattigan S, Clark MG, Barrett EJ. Hemodynamic actions of insulin in rat skeletal muscle: evidence for capillary recruitment. Diabetes. 1997 Sep;46(9):1381-8. doi: 10.2337/diab.46.9.1381.

  PMID: 9287035 BACKGROUND

• Chai W, Zhang X, Barrett EJ, Liu Z. Glucagon-like peptide 1 recruits muscle microvasculature and improves insulin's metabolic action in the presence of insulin resistance. Diabetes. 2014 Aug;63(8):2788-99. doi: 10.2337/db13-1597. Epub 2014 Mar 21.

  PMID: 24658303 BACKGROUND

• 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.

  PMID: 11756321 BACKGROUND

• Clerk LH, Vincent MA, Jahn LA, Liu Z, Lindner JR, Barrett EJ. Obesity blunts insulin-mediated microvascular recruitment in human forearm muscle. Diabetes. 2006 May;55(5):1436-42. doi: 10.2337/db05-1373.

  PMID: 16644702 BACKGROUND

• Clerk LH, Vincent MA, Barrett EJ, Lankford MF, Lindner JR. Skeletal muscle capillary responses to insulin are abnormal in late-stage diabetes and are restored by angiotensin-converting enzyme inhibition. Am J Physiol Endocrinol Metab. 2007 Dec;293(6):E1804-9. doi: 10.1152/ajpendo.00498.2007. Epub 2007 Oct 2.

  PMID: 17911341 BACKGROUND

• 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.

  PMID: 26756115 BACKGROUND

• Inyard AC, Chong DG, Klibanov AL, Barrett EJ. Muscle contraction, but not insulin, increases microvascular blood volume in the presence of free fatty acid-induced insulin resistance. Diabetes. 2009 Nov;58(11):2457-63. doi: 10.2337/db08-1077. Epub 2009 Aug 12.

  PMID: 19675134 BACKGROUND

• 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.

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• Marfella R, Nappo F, De Angelis L, Siniscalchi M, Rossi F, Giugliano D. The effect of acute hyperglycaemia on QTc duration in healthy man. Diabetologia. 2000 May;43(5):571-5. doi: 10.1007/s001250051345.

  PMID: 10855531 BACKGROUND

• Glaser N, Ngo C, Anderson S, Yuen N, Trifu A, O'Donnell M. Effects of hyperglycemia and effects of ketosis on cerebral perfusion, cerebral water distribution, and cerebral metabolism. Diabetes. 2012 Jul;61(7):1831-7. doi: 10.2337/db11-1286. Epub 2012 Apr 12.

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• Wei K, Jayaweera AR, Firoozan S, Linka A, Skyba DM, Kaul S. Quantification of myocardial blood flow with ultrasound-induced destruction of microbubbles administered as a constant venous infusion. Circulation. 1998 Feb 10;97(5):473-83. doi: 10.1161/01.cir.97.5.473.

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• 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.

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• 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.

  PMID: 15998667 BACKGROUND

• 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.

  PMID: 23180239 BACKGROUND

• Eggleston EM, Jahn LA, Barrett EJ. Hyperinsulinemia rapidly increases human muscle microvascular perfusion but fails to increase muscle insulin clearance: evidence that a saturable process mediates muscle insulin uptake. Diabetes. 2007 Dec;56(12):2958-63. doi: 10.2337/db07-0670. Epub 2007 Aug 24.

  PMID: 17720897 BACKGROUND

• DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol. 1979 Sep;237(3):E214-23. doi: 10.1152/ajpendo.1979.237.3.E214.

  PMID: 382871 BACKGROUND

• Cardillo C, Nambi SS, Kilcoyne CM, Choucair WK, Katz A, Quon MJ, Panza JA. Insulin stimulates both endothelin and nitric oxide activity in the human forearm. Circulation. 1999 Aug 24;100(8):820-5. doi: 10.1161/01.cir.100.8.820.

  PMID: 10458717 BACKGROUND

• Horton WB, Jahn LA, Hartline LM, Aylor KW, Patrie JT, Barrett EJ. Insulin increases central aortic stiffness in response to hyperglycemia in healthy humans: A randomized four-arm study. Diab Vasc Dis Res. 2021 Mar-Apr;18(2):14791641211011009. doi: 10.1177/14791641211011009.

  PMID: 33908285 DERIVED

• Horton WB, Jahn LA, Hartline LM, Aylor KW, Patrie JT, Barrett EJ. Acute hyperglycaemia enhances both vascular endothelial function and cardiac and skeletal muscle microvascular function in healthy humans. J Physiol. 2022 Feb;600(4):949-962. doi: 10.1113/JP281286. Epub 2021 Feb 2.

  PMID: 33481251 DERIVED

MeSH Terms

Conditions

Insulin Resistance

Interventions

Octreotide; Insulin; Glucose; Solutions

Condition Hierarchy (Ancestors)

Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides; Amino Acids, Peptides, and Proteins; Proinsulin; Insulins; Pancreatic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Hexoses; Monosaccharides; Sugars; Carbohydrates; Pharmaceutical Preparations

Results Point of Contact

• Title: Eugene Barrett
• Organization: University of Virginia

EJB8X@VIRGINIA.EDU

434-924-1263

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prinicipal Investigator

Model Details: Each subject is studied 4 times in a randomized sequential order

Study Record Dates

• First Submitted: March 8, 2018
• First Posted: May 9, 2018
• Study Start: February 4, 2019
• Primary Completion: April 1, 2021
• Study Completion: April 1, 2021
• Last Updated: May 13, 2022
• Results First Posted: May 13, 2022

Record last verified: 2022-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)