Cardiovascular Risk Factors After Single Pancreas Transplantation (Diamant)

Assessment of Cardiovascular Risk Factors, Including Endothelial Function, After Restoration of Normoglycemia Following Single Pancreas Transplantation

Patients accepted for the waiting list for single pancreas transplantation suffer from severe glucose instability with hyperglycemia due to diabetes type 1, but do not have significant diabetes-related complications. Pancreas transplantation restores normoglycemia in diabetes type 1 patients with unstable control of glycemia. Both hypo- and hyperglycemic events are abolished, and 70-80 % of the patients obtain satisfactory HbA1c levels (HbA1c 5.0-6.0 %) without the need of exogenous insulin. Endothelial dysfunction is considered as an early and potentially reversible stage in the atherosclerotic process. The endothelium is involved in homeostasis, leucocyte adhesion and vasomotor activity. Reduced endothelium-dependent vasodilation is associated with increments in cardiovascular risk factors, and endothelial dysfunction is a predictor for future cardiovascular disease. It has also been hypothesized that endothelial dysfunction may be involved in the impaired glycemic control by reducing the availability of glucose in peripheral muscles.Establishing normoglycemia by pancreas transplantation alone in previously diabetic type 1 patients has recently been shown to improve left ventricular ejection fraction, assessed by Doppler echocardiographic examination. In diabetic patients receiving a new pancreas it is possible to assess the effect of changing blood glucose excursions on cardiovascular risk factors, including endothelial function, without the use of antidiabetic drugs (exclude pleiotropic effects).

The primary objective of the present study is to assess if endothelial function (assessed by flow-mediated dilatation of arteria brachialis) is improved when hyperglycemia is reversed by single pancreas transplantation in patients with type 1 diabetes.

Secondary objectives are to investigate the changes in the following parameters by reversal of hyperglycemia by pancreas transplantation; Peripheral arterial tonometry, serum/plasma concentrations of endothelial dysfunction markers, blood pressure, lipid and lipoprotein concentrations.

Study Overview

• Status: Completed
• Conditions: Diabetes Type 1; Endothelial Dysfunction
• Intervention / Treatment: Procedure: Single pancreas transplantation

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Norway
  • Oslo, Norway, N-0424
    • Oslo University Hospital, Rikshospitalet

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients with type 1 diabetes accepted for the waiting list for single pancreas transplantation
• Healthy volunteers (non-diabetic, non-transplanted)
• Over 18 years of age
• Signed informed consent

Exclusion Criteria:

• Non-functioning pancreas graft (defined as HbA1c ≥ 6.5 % with the need of insulin injections and fasting C-peptide concentration < 300 pmol/L).
• Active infection
• Active autoimmune disease other than diabetes
• Severe liver disease

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Single pancreas transplantation; This is an explorative analysis to assess the impact of establishing normoglycemia in previously hyperglycemic patients, without using antidiabetic drugs, by investigating patients before and after single pancreas transplantation. Active patients on the waiting list for single pancreas transplantation will be investigated while on the waiting list and subsequently 8 weeks and 1 year after transplantation if they have a functioning pancreas graft. A control group of healthy volunteers (non-diabetic, non-transplanted), frequency-matched for age and gender with regards to the pancreas transplanted patients, will be investigated once.

Procedure: Single pancreas transplantation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Endothelial function	This is an explorative analysis to assess the impact of establishing normoglycemia in previously hyperglycemic patients, without using antidiabetic drugs, by investigating patients before and after single pancreas transplantation. Active patients on the waiting list for single pancreas transplantation will be investigated while on the waiting list and subsequently 8 weeks and 1 year after transplantation if they have a functioning pancreas graft. Flow-mediated dilatation (FMD) of large vessels (arteria brachialis) will be assessed by measuring vessel diameter by ultrasound and the FMD of micro vessels in the finger tip will be assessed by Endo-PAT (PAT=Peripheral Arterial Tonus) following reactive hyperperfusion induced by occlusion of the artery by a sphygmomanometer cuff.	1 year post-transplant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peripheral arterial tonometry		1 year post-transplant
Changes in cardiac performance	An echocardiographic examination will be performed to assess changes in cardiac performance, such as left ventricular ejection fraction	1 year post-transplant
Pulse wave velocity (arterial stiffness)	Pulse wave velocity, using a SphygmoCor device, measuring arterial stiffness will be performed in addition to pulse wave analysis evaluating the shape and amplitude of the aortic pulse wave.	1 year post-transplant
Heart rate variability	Heart rate variability will be assessed, using a Vagus device, analyzing short-term electrocardiogram recordings.	1 year post-transplant
Plasma concentrations of endothelial dysfunction markers	Fasting plasma samples (6 mL EDTA vacutainer) will be drawn for determination of relevant markers for endothelial dysfunction, such as von Willebrand factors (vWF) and vascular cell adhesion molecule-1 (VCAM-1).	1 year post-transplant
Blood pressure	Blood pressure will be measured seated after ten minutes rest by Dyna Map (Tuff.-Cuff, CAS Medical system Inc.) and the mean of the lower two out of three measurements will be used.	1 year post-transplant
Lipid and lipoprotein concentrations		1 year post-transplant
Bone mineral density and body composition	Measurement of bone mineral density, using low dosage radiation (dual-energy X-ray absorptiometry (DEXA) scan) to assess the amount (grams) of mineral that are packed into a segment of bone. In addition a body composition (visceral fat, metabolic measurement) will be determined using the DEXA scan.	1 year post-transplant
Glomerular filtration rate	Renal function, defined as glomerular filtration rate, will be evaluated by measuring iohexol clearance. The concentration of iohexol (Omnipaque), a low dose non-ionic x-ray contrast medium of low osmolality, extensively used in clinical radiology and considered essentially free from side effects, will be measured 2 hours and 5 hours after iv injection of iohexol. Like other iodine-containing contrast media, it is completely eliminated from the body by excretion in the urine, thus it is an ideal marker for kidney function. It will be quantitated by chemical measurement based on the determination of iodine.	1 year post-transplant
Oral glucose tolerance test	Measurements of plasma glucose, C-peptide and serum insulin before, 30 and 120 minutes following an oral administration of 75 g glucose.	1 year post-transplant

Collaborators and Investigators

• Sponsor: Oslo University Hospital
• Investigators: Principal Investigator: Trond G Jenssen, Professor, Oslo University Hospital

Study record dates

Study Major Dates

• Study Start: January 1, 2014
• Primary Completion (Actual): February 1, 2017
• Study Completion (Actual): February 1, 2017

Study Registration Dates

• First Submitted: February 14, 2014
• First Submitted That Met QC Criteria: February 17, 2014
• First Posted (Estimate): February 19, 2014

Study Record Updates

• Last Update Posted (Actual): March 16, 2017
• Last Update Submitted That Met QC Criteria: March 15, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Keywords: Endothelial dysfunction; Diabetes type 1; Pancreas transplantation
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Gastrointestinal Agents; Pancrelipase
• Other Study ID Numbers: 2013/1062; 2013047 (Other Grant/Funding Number: South-Eastern Norway Regional Health Authority)