Insulin Effects on Cardiac Function in Patients With Diabetes Mellitus

Diabetes Mellitus Clinical Trial

Official title:

Acute Insulin Effects on Cardiac Function in Patients With Diabetes Mellitus

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02962921
• Other study ID #: 1558-RMB-CTIL
• Status: Completed
• Phase: Phase 4
• First received: September 10, 2016
• Last updated: November 9, 2016
• Start date: February 2003
• Est. completion date: November 2004

Study information

• Verified date: November 2016
• Source: Rambam Health Care Campus
• Contact: n/a
• Is FDA regulated: No
• Health authority: Israel: Ethics Commission
• Study type: Interventional

Clinical Trial Summary

Our investigation studies the role of acute insulin administration on the diabetic heart, its corresponding effective blood-insulin level and the time-course applicability of insulin in a routine clinical setting.

A case series of six male (48.1 ± 4.9 y/o) patients with controlled diabetes (HbA1c of 6.6 ± 0.3%, disease duration of 14.4 ± 6.7 yr). Each subject was evaluated for glucose homeostatic, hemodynamic and echocardiographic systolic and diastolic parameters at baseline and following two successive insulin-load steps of a euglycemic hyperinsulinemic clamp study, each 2 h in duration. Results are presented as a mean ± SEM and analysed using the student's t-test.

Description:

Patients:

Six male diabetic (five type 2 and one type 1) patients, 30-65 year old, with an established diagnosis of diabetes mellitus for ≥2 years, who were free of significant valvular heart disease, atrial arrhythmia or cardiac pacing comprised the study population. Patients' characteristics are summarized in table 1.

Each patient served as his or her own control. The study protocol was approved by the ethics committee at Rambam Medical Center, Haifa, Israel. Prior to the study, patients gave written informed consent after receiving a detailed explanation as to the purpose of the study, the technique, its side effects and the study protocol.

Patients were studied within a clinical research facility at the Rambam Medical Center, Haifa, Israel. Baseline evaluation was conducted at 8:00 am after 12 h of fasting, followed by two hyperinsulinemic euglycemic clamp (EHC) steps (2 h each step); The following vital signs were monitored during the study protocol: manual heart rate, systolic blood pressure (SBP), diastolic blood pressure (DBP) and baseline 12-lead electrocardiogram (ECG) recording. Glucose consumption rates against changing insulin levels were measured by the EHC technique. Cardiac function parameters were measured in the last 10 min of each step by tissue Doppler echocardiography. Results are presented as a mean ± SEM.

Clamp technique:

Each patient underwent an EHC study according to the protocol described previously, and implemented in our institute. Baseline measurements of blood insulin and glucose levels were collected. Thereafter, two insulin loads were initiated. The blood glucose level was kept near euglycemia (90 ± 5 mg/dl) throughout 2 h period of each insulin load step. Intravenous (iv) insulin loads were administered by 1- and 10-mU/kg·min at steps 1 and 2 of insulin loading (Lispro Insulin, Eli Lilly, France), respectively. Dexstrose in water 50% (DW50) was infused at variable infusion rates, titrated to maintain euglycemia. Concomitant saline 0.45% was used to dilute the DW50 in order to prevent hypertonicity-induced irritation of the cannuled vein. During the baseline period, saline 0.45% infusion rates were 0.75 ml/min to keep the iv cannule open. Every patient was given a chance to urinate before step 2.

Glucose and insulin homeostatic parameters of the study group were compared to those of healthy controls we studied earlier.

Cardiac function assessment:

Transthoracic echocardiography was performed by a qualified echocardiographer using a General Electric Vivid 3 machine (Tirat HaCarmel, Israel). Parameters were assessed as the mean of three consecutive heart beats.

Systolic echocardiographic parameters:

LV fractional shortening (LVFS) derived from end diastolic and end systolic LV dimensions; LV ejection fraction (LVEF) derived from end diastolic and end systolic LV volumes.

Diastolic echocardiographic parameters:

1. Mitral valve diastolic flow parameters by pulse wave Doppler: E wave, represents early diastolic filling; A wave, represents late diastolic filling concomitant with the atrial kick, E/A ratio and E wave deceleration time (DT).

2. Tissue Doppler-derived velocities of the mitral annulus: E' represents early diastolic velocity synchronous to the mitral inflow E wave, measured close to the interventricular septum (E' medial) and lateral wall (E' lateral); E' mean, derived from E' lateral and E' medial. A' represents late diastolic velocity to the synchronous mitral inflow A wave, measured close to the septum (A' medial) and lateral wall (A' lateral). A' mean is derived from A' lat. and A' med. A' reflects mitral annulus movement during atrial contraction. The E to E' ratio represents diastolic LV compliance.

Results are presented as mean ± SEM and analyzed using the student's t-test. Statistical significance considered when p value less than 0.05.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 6
• Est. completion date: November 2004
• Est. primary completion date: May 2003
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 30 Years to 65 Years

Eligibility

Inclusion Criteria:

• Diabetes mellitus duration of 2 years and over.

Exclusion Criteria:

• Previous cardiac disease: valvular, Pacing, Arrhythmias, Primary Cardiomyopathy.

Study Design

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetes Mellitus
• Ventricular Dysfunction

Intervention

Drug:
• Insulin LISPRO intravenous loading
intravenous infusion of insulin Lispro.

Locations

Country	Name	City	State
Israel	Rambam Medical Center	Haifa

Sponsors (1)

Lead Sponsor	Collaborator
Rambam Health Care Campus

Country where clinical trial is conducted

Israel, 

References & Publications (23)

Adeghate E. Molecular and cellular basis of the aetiology and management of diabetic cardiomyopathy: a short review. Mol Cell Biochem. 2004 Jun;261(1-2):187-91. Review. — View Citation

Cohen P, Barzilai N, Barzilai D, Karnieli E. Correlation between insulin clearance and insulin responsiveness: studies in normal, obese, hyperthyroid, and Cushing's syndrome patients. Metabolism. 1986 Aug;35(8):744-9. — View Citation

Cohen P, Harel C, Bergman R, Daoud D, Pam Z, Barzilai N, Armoni M, Karnieli E. Insulin resistance and acanthosis nigricans: evidence for a postbinding defect in vivo. Metabolism. 1990 Oct;39(10):1006-11. — View Citation

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. — View Citation

Díaz R, Goyal A, Mehta SR, Afzal R, Xavier D, Pais P, Chrolavicius S, Zhu J, Kazmi K, Liu L, Budaj A, Zubaid M, Avezum A, Ruda M, Yusuf S. Glucose-insulin-potassium therapy in patients with ST-segment elevation myocardial infarction. JAMA. 2007 Nov 28;298 — View Citation

Fein FS, Strobeck JE, Malhotra A, Scheuer J, Sonnenblick EH. Reversibility of diabetic cardiomyopathy with insulin in rats. Circ Res. 1981 Dec;49(6):1251-61. — View Citation

Francis GS. Diabetic cardiomyopathy: fact or fiction? Heart. 2001 Mar;85(3):247-8. — View Citation

Gutierrez C, Blanchard DG. Diastolic heart failure: challenges of diagnosis and treatment. Am Fam Physician. 2004 Jun 1;69(11):2609-16. Review. — View Citation

Hiramatsu K, Ohara N, Shigematsu S, Aizawa T, Ishihara F, Niwa A, Yamada T, Naka M, Momose A, Yoshizawa K. Left ventricular filling abnormalities in non-insulin-dependent diabetes mellitus and improvement by a short-term glycemic control. Am J Cardiol. 19 — View Citation

Iliadis F, Kadoglou N, Didangelos T. Insulin and the heart. Diabetes Res Clin Pract. 2011 Aug;93 Suppl 1:S86-91. doi: 10.1016/S0168-8227(11)70019-5. Review. — View Citation

Jonassen AK, Sack MN, Mjøs OD, Yellon DM. Myocardial protection by insulin at reperfusion requires early administration and is mediated via Akt and p70s6 kinase cell-survival signaling. Circ Res. 2001 Dec 7;89(12):1191-8. — View Citation

Kahn JK, Zola B, Juni JE, Vinik AI. Radionuclide assessment of left ventricular diastolic filling in diabetes mellitus with and without cardiac autonomic neuropathy. J Am Coll Cardiol. 1986 Jun;7(6):1303-9. — View Citation

Khankirawatana B, Khankirawatana S, Peterson B, Mahrous H, Porter TR. Peak atrial systolic mitral annular velocity by Doppler tissue reliably predicts left atrial systolic function. J Am Soc Echocardiogr. 2004 Apr;17(4):353-60. — View Citation

Khouri SJ, Maly GT, Suh DD, Walsh TE. A practical approach to the echocardiographic evaluation of diastolic function. J Am Soc Echocardiogr. 2004 Mar;17(3):290-7. Review. — View Citation

Kitzman DW, Gardin JM, Gottdiener JS, Arnold A, Boineau R, Aurigemma G, Marino EK, Lyles M, Cushman M, Enright PL; Cardiovascular Health Study Research Group.. Importance of heart failure with preserved systolic function in patients > or = 65 years of age — View Citation

Mak GS, Sawaya H, Khan AM, Arora P, Martinez A, Ryan A, Ernande L, Newton-Cheh C, Wang TJ, Scherrer-Crosbie M. Effects of subacute dietary salt intake and acute volume expansion on diastolic function in young normotensive individuals. Eur Heart J Cardiova — View Citation

Mamas MA, Neyses L, Fath-Ordoubadi F. A meta-analysis of glucose-insulin-potassium therapy for treatment of acute myocardial infarction. Exp Clin Cardiol. 2010 Summer;15(2):e20-4. — View Citation

McMurray JJ, Stewart S. Epidemiology, aetiology, and prognosis of heart failure. Heart. 2000 May;83(5):596-602. Review. — View Citation

Poornima IG, Parikh P, Shannon RP. Diabetic cardiomyopathy: the search for a unifying hypothesis. Circ Res. 2006 Mar 17;98(5):596-605. Review. — View Citation

Rizza RA, Mandarino LJ, Gerich JE. Dose-response characteristics for effects of insulin on production and utilization of glucose in man. Am J Physiol. 1981 Jun;240(6):E630-9. — View Citation

Rubler S, Dlugash J, Yuceoglu YZ, Kumral T, Branwood AW, Grishman A. New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am J Cardiol. 1972 Nov 8;30(6):595-602. — View Citation

Sasso FC, Carbonara O, Cozzolino D, Rambaldi P, Mansi L, Torella D, Gentile S, Turco S, Torella R, Salvatore T. Effects of insulin-glucose infusion on left ventricular function at rest and during dynamic exercise in healthy subjects and noninsulin depende — View Citation

Whitlow PL, Rogers WJ, Smith LR, McDaniel HG, Papapietro SE, Mantle JA, Logic JR, Russell RO Jr, Rackley CE. Enhancement of left ventricular function by glucose-insulin-potassium infusion in acute myocardial infarction. Am J Cardiol. 1982 Mar;49(4):811-20 — View Citation

* Note: There are 23 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Blood insulin levels (µU/ml: micro international unit per milliliter)		1 year	No
Other	Left ventricle fractioning shortening (%)		1 year	No
Other	E wave (centimeter per second)		1 year	No
Other	A wave (centimeter per second)		1 year	No
Other	E deceleration time (seconds)		1 year	No
Other	E' (centimeters)		1 year	No
Other	A' (centimeters)		1 year	No
Primary	Left ventricle ejection fraction (%)		1 year	No
Secondary	Time needed to exert insulin effect on myocardial function (hour)	Describe the shortest time required for insulin to change myocardial function.	1 year	No