Effect of GLP-1 on Microvascular Insulin Responses in Type 1 Diabetes

NCT ID: NCT04133922

Last Updated: 2022-03-22

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: EARLY_PHASE1
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-10-14
• Study Completion Date: 2024-10-31

Brief Summary

GLP-1 increases skeletal and cardiac microvascular perfusion and improves insulin's microvascular responses in human subjects with T1DM, leading to improved metabolic insulin responses, endothelial function, and increased muscle oxygenation

Detailed Description

The proposed study will determine the effect of GLP-1 infusion on microvascular perfusion and microvascular insulin responses in both skeletal and cardiac muscle microvasculature in humans with T1DM. The investigators will study 20 participants with T1DM using a state-of-the-art technology, contrast enhanced ultrasound (CEU), to assess whether GLP-1 augments skeletal and cardiac microvascular blood flow (MBF) as a representation of microvascular perfusion, flow-mediated dilation (FMD) as a measurement of endothelial function, and augmentation index (AI) and pulse wave velocity (PWV) as surrogates for large vessel compliance. The investigators will use the combined CEU and euglycemic-hyperinsulinemic clamp approach to determine if microvascular and metabolic IR improves as a result.

Conditions

Type 1 Diabetes; Insulin Sensitivity/Resistance

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

GLP-1

GLP-1 infusion 1.2 pmol/kg/min for 150 min

Group Type: ACTIVE_COMPARATOR

GLP-1

Intervention Type: DRUG

glucagon-like peptide 1

GLP-1 + Insulin clamp

GLP-1 infusion 1.2 pmol/kg/min for 150 min and insulin 1 mU/kg/min + Dextrose 20% at variable rate to maintain euglycemia for 120 min

Group Type: ACTIVE_COMPARATOR

GLP-1

Intervention Type: DRUG

glucagon-like peptide 1

Insulin

Intervention Type: DRUG

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

Dextrose 20 % in Water

Intervention Type: DRUG

We are using Dextrose to maintain Euglycemia during the insulin clamp

Saline + Insulin clamp

Saline infusion at 30 ml/hr for 150 min and insulin 1 mU/kg/min + Dextrose 20% at variable rate to maintain euglycemia for 120 min.

Group Type: ACTIVE_COMPARATOR

Insulin

Intervention Type: DRUG

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

Dextrose 20 % in Water

Intervention Type: DRUG

We are using Dextrose to maintain Euglycemia during the insulin clamp

Interventions

GLP-1

glucagon-like peptide 1

Intervention Type: DRUG

Insulin

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

Intervention Type: DRUG

Dextrose 20 % in Water

We are using Dextrose to maintain Euglycemia during the insulin clamp

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. History of type 1 diabetes, duration > 1 year

2. Age 18-40 years

3. HbA1c < 8.5%

4. BMI >/=18, <30 kg/m2

5. Using insulin for diabetes treatment only

6. On stable regimen of non-diabetic medications for the last 6 months, excluding oral contraceptives (OCP)

7. All screening labs within normal limits or not clinical significant

Exclusion Criteria

1) Pregnancy or currently breastfeeding 2) Smoking history within 6 months 3) History of microvascular (microalbuminuria, retinopathy, neuropathy) or macrovascular diabetes complications (coronary artery disease, stroke, peripheral vascular disease) 4) Taking vasoactive medications (i.e. calcium channel blockers, angiotensin-converting enzyme or renin inhibitors, angiotensin-receptor blockers, nitrates, alpha-blockers) 5) OCP use within 3 months or 1 month if menses has subsequently occurred 6) Known hypersensitivity to perflutren (contained in Definity© contrast) 7) Screening O2 saturation<90% 8) Anemia (hemoglobin <12 g/dL in women, hemoglobin <13 g/dL in men) 9) Diabetic ketoacidosis (DKA) on presentation to screening visits or study admission days

-

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 40 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

American Diabetes Association

OTHER

Sponsor Role: collaborator

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

NIH

Sponsor Role: collaborator

University of Virginia

OTHER

Sponsor Role: lead

Responsible Party

Zhenqi Liu

Deparment of Medicine, Chief of Div. Endocrinology, University of Virginia

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Zhenqi Liu, MD

Role: PRINCIPAL_INVESTIGATOR

Department of Endocrinology, University of Virginia

Locations

University of Virginia

Charlottesville, Virginia, United States

Countries

United States

References

Secrest AM, Becker DJ, Kelsey SF, Laporte RE, Orchard TJ. Cause-specific mortality trends in a large population-based cohort with long-standing childhood-onset type 1 diabetes. Diabetes. 2010 Dec;59(12):3216-22. doi: 10.2337/db10-0862. Epub 2010 Aug 25.

Reference Type: BACKGROUND

PMID: 20739685 (View on PubMed)

Krolewski AS, Kosinski EJ, Warram JH, Leland OS, Busick EJ, Asmal AC, Rand LI, Christlieb AR, Bradley RF, Kahn CR. Magnitude and determinants of coronary artery disease in juvenile-onset, insulin-dependent diabetes mellitus. Am J Cardiol. 1987 Apr 1;59(8):750-5. doi: 10.1016/0002-9149(87)91086-1.

Reference Type: BACKGROUND

PMID: 3825934 (View on PubMed)

Libby P, Nathan DM, Abraham K, Brunzell JD, Fradkin JE, Haffner SM, Hsueh W, Rewers M, Roberts BT, Savage PJ, Skarlatos S, Wassef M, Rabadan-Diehl C; National Heart, Lung, and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases Working Group on Cardiovascular Complications of Type 1 Diabetes Mellitus. Report of the National Heart, Lung, and Blood Institute-National Institute of Diabetes and Digestive and Kidney Diseases Working Group on Cardiovascular Complications of Type 1 Diabetes Mellitus. Circulation. 2005 Jun 28;111(25):3489-93. doi: 10.1161/CIRCULATIONAHA.104.529651. No abstract available.

Reference Type: BACKGROUND

PMID: 15983263 (View on PubMed)

Soedamah-Muthu SS, Fuller JH, Mulnier HE, Raleigh VS, Lawrenson RA, Colhoun HM. High risk of cardiovascular disease in patients with type 1 diabetes in the U.K.: a cohort study using the general practice research database. Diabetes Care. 2006 Apr;29(4):798-804. doi: 10.2337/diacare.29.04.06.dc05-1433.

Reference Type: BACKGROUND

PMID: 16567818 (View on PubMed)

Peters SAE, Woodward M. Sex Differences in the Burden and Complications of Diabetes. Curr Diab Rep. 2018 Apr 18;18(6):33. doi: 10.1007/s11892-018-1005-5.

Reference Type: BACKGROUND

PMID: 29671082 (View on PubMed)

Huxley RR, Peters SA, Mishra GD, Woodward M. Risk of all-cause mortality and vascular events in women versus men with type 1 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2015 Mar;3(3):198-206. doi: 10.1016/S2213-8587(14)70248-7. Epub 2015 Feb 6.

Reference Type: BACKGROUND

PMID: 25660575 (View on PubMed)

Di Carli MF, Afonso L, Campisi R, Ramappa P, Bianco-Batlles D, Grunberger G, Schelbert HR. Coronary vascular dysfunction in premenopausal women with diabetes mellitus. Am Heart J. 2002 Oct;144(4):711-8.

Reference Type: BACKGROUND

PMID: 12360169 (View on PubMed)

Mendelsohn ME, Karas RH. The protective effects of estrogen on the cardiovascular system. N Engl J Med. 1999 Jun 10;340(23):1801-11. doi: 10.1056/NEJM199906103402306. No abstract available.

Reference Type: BACKGROUND

PMID: 10362825 (View on PubMed)

Bjornstad P, Maahs DM, Duca LM, Pyle L, Rewers M, Johnson RJ, Snell-Bergeon JK. Estimated insulin sensitivity predicts incident micro- and macrovascular complications in adults with type 1 diabetes over 6 years: the coronary artery calcification in type 1 diabetes study. J Diabetes Complications. 2016 May-Jun;30(4):586-90. doi: 10.1016/j.jdiacomp.2016.02.011. Epub 2016 Feb 11.

Reference Type: BACKGROUND

PMID: 26936306 (View on PubMed)

Baron AD. Hemodynamic actions of insulin. Am J Physiol. 1994 Aug;267(2 Pt 1):E187-202. doi: 10.1152/ajpendo.1994.267.2.E187.

Reference Type: BACKGROUND

PMID: 8074198 (View on PubMed)

Millstein RJ, Pyle LL, Bergman BC, Eckel RH, Maahs DM, Rewers MJ, Schauer IE, Snell-Bergeon JK. Sex-specific differences in insulin resistance in type 1 diabetes: The CACTI cohort. J Diabetes Complications. 2018 Apr;32(4):418-423. doi: 10.1016/j.jdiacomp.2018.01.002. Epub 2018 Jan 10.

Reference Type: BACKGROUND

PMID: 29449137 (View on PubMed)

DeFronzo RA, Hendler R, Simonson D. Insulin resistance is a prominent feature of insulin-dependent diabetes. Diabetes. 1982 Sep;31(9):795-801. doi: 10.2337/diab.31.9.795. No abstract available.

Reference Type: BACKGROUND

PMID: 6761214 (View on PubMed)

Kaul K, Apostolopoulou M, Roden M. Insulin resistance in type 1 diabetes mellitus. Metabolism. 2015 Dec;64(12):1629-39. doi: 10.1016/j.metabol.2015.09.002. Epub 2015 Sep 11.

Reference Type: BACKGROUND

PMID: 26455399 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 29139080 (View on PubMed)

Gao F, Gao E, Yue TL, Ohlstein EH, Lopez BL, Christopher TA, Ma XL. Nitric oxide mediates the antiapoptotic effect of insulin in myocardial ischemia-reperfusion: the roles of PI3-kinase, Akt, and endothelial nitric oxide synthase phosphorylation. Circulation. 2002 Mar 26;105(12):1497-502. doi: 10.1161/01.cir.0000012529.00367.0f.

Reference Type: BACKGROUND

PMID: 11914261 (View on PubMed)

Clark MG. Impaired microvascular perfusion: a consequence of vascular dysfunction and a potential cause of insulin resistance in muscle. Am J Physiol Endocrinol Metab. 2008 Oct;295(4):E732-50. doi: 10.1152/ajpendo.90477.2008. Epub 2008 Jul 8.

Reference Type: BACKGROUND

PMID: 18612041 (View on PubMed)

Baron AD, Brechtel-Hook G, Johnson A, Cronin J, Leaming R, Steinberg HO. Effect of perfusion rate on the time course of insulin-mediated skeletal muscle glucose uptake. Am J Physiol. 1996 Dec;271(6 Pt 1):E1067-72. doi: 10.1152/ajpendo.1996.271.6.E1067.

Reference Type: BACKGROUND

PMID: 8997227 (View on PubMed)

Baron AD, Laakso M, Brechtel G, Edelman SV. Mechanism of insulin resistance in insulin-dependent diabetes mellitus: a major role for reduced skeletal muscle blood flow. J Clin Endocrinol Metab. 1991 Sep;73(3):637-43. doi: 10.1210/jcem-73-3-637.

Reference Type: BACKGROUND

PMID: 1874938 (View on PubMed)

Laakso M, Edelman SV, Brechtel G, Baron AD. Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man. A novel mechanism for insulin resistance. J Clin Invest. 1990 Jun;85(6):1844-52. doi: 10.1172/JCI114644.

Reference Type: BACKGROUND

PMID: 2189893 (View on PubMed)

Barrett EJ, Wang H, Upchurch CT, Liu Z. Insulin regulates its own delivery to skeletal muscle by feed-forward actions on the vasculature. Am J Physiol Endocrinol Metab. 2011 Aug;301(2):E252-63. doi: 10.1152/ajpendo.00186.2011. Epub 2011 May 24.

Reference Type: BACKGROUND

PMID: 21610226 (View on PubMed)

Miller KM, Foster NC, Beck RW, Bergenstal RM, DuBose SN, DiMeglio LA, Maahs DM, Tamborlane WV; T1D Exchange Clinic Network. Current state of type 1 diabetes treatment in the U.S.: updated data from the T1D Exchange clinic registry. Diabetes Care. 2015 Jun;38(6):971-8. doi: 10.2337/dc15-0078.

Reference Type: BACKGROUND

PMID: 25998289 (View on PubMed)

Ratner R, Whitehouse F, Fineman MS, Strobel S, Shen L, Maggs DG, Kolterman OG, Weyer C. Adjunctive therapy with pramlintide lowers HbA1c without concomitant weight gain and increased risk of severe hypoglycemia in patients with type 1 diabetes approaching glycemic targets. Exp Clin Endocrinol Diabetes. 2005 Apr;113(4):199-204. doi: 10.1055/s-2005-837662.

Reference Type: BACKGROUND

PMID: 15891954 (View on PubMed)

Kim S, Jeong J, Jung HS, Kim B, Kim YE, Lim DS, Kim SD, Song YS. Anti-inflammatory Effect of Glucagon Like Peptide-1 Receptor Agonist, Exendin-4, through Modulation of IB1/JIP1 Expression and JNK Signaling in Stroke. Exp Neurobiol. 2017 Aug;26(4):227-239. doi: 10.5607/en.2017.26.4.227. Epub 2017 Aug 31.

Reference Type: BACKGROUND

PMID: 28912645 (View on PubMed)

Mazidi M, Karimi E, Rezaie P, Ferns GA. Treatment with GLP1 receptor agonists reduce serum CRP concentrations in patients with type 2 diabetes mellitus: A systematic review and meta-analysis of randomized controlled trials. J Diabetes Complications. 2017 Jul;31(7):1237-1242. doi: 10.1016/j.jdiacomp.2016.05.022. Epub 2016 May 30.

Reference Type: BACKGROUND

PMID: 28479155 (View on PubMed)

Dai Y, Mehta JL, Chen M. Glucagon-like peptide-1 receptor agonist liraglutide inhibits endothelin-1 in endothelial cell by repressing nuclear factor-kappa B activation. Cardiovasc Drugs Ther. 2013 Oct;27(5):371-80. doi: 10.1007/s10557-013-6463-z.

Reference Type: BACKGROUND

PMID: 23657563 (View on PubMed)

Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, Steinberg WM, Stockner M, Zinman B, Bergenstal RM, Buse JB; LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016 Jul 28;375(4):311-22. doi: 10.1056/NEJMoa1603827. Epub 2016 Jun 13.

Reference Type: BACKGROUND

PMID: 27295427 (View on PubMed)

Nystrom T, Gutniak MK, Zhang Q, Zhang F, Holst JJ, Ahren B, Sjoholm A. Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease. Am J Physiol Endocrinol Metab. 2004 Dec;287(6):E1209-15. doi: 10.1152/ajpendo.00237.2004. Epub 2004 Sep 7.

Reference Type: BACKGROUND

PMID: 15353407 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 24658303 (View on PubMed)

Chai W, Fu Z, Aylor KW, Barrett EJ, Liu Z. Liraglutide prevents microvascular insulin resistance and preserves muscle capillary density in high-fat diet-fed rats. Am J Physiol Endocrinol Metab. 2016 Sep 1;311(3):E640-8. doi: 10.1152/ajpendo.00205.2016. Epub 2016 Jul 19.

Reference Type: BACKGROUND

PMID: 27436611 (View on PubMed)

Basu A, Charkoudian N, Schrage W, Rizza RA, Basu R, Joyner MJ. Beneficial effects of GLP-1 on endothelial function in humans: dampening by glyburide but not by glimepiride. Am J Physiol Endocrinol Metab. 2007 Nov;293(5):E1289-95. doi: 10.1152/ajpendo.00373.2007. Epub 2007 Aug 21.

Reference Type: BACKGROUND

PMID: 17711996 (View on PubMed)

Other Identifiers

5R01DK102359-03

Identifier Type: NIH

Identifier Source: secondary_id

View Link

21590

Identifier Type: -

Identifier Source: org_study_id