Effect of Iron Reduction by Phlebotomy for Type 2 Diabetes

Iron Reduction by Phlebotomy for the Prevention and Treatment of Type 2 Diabetes

High tissue iron is a risk factor for diabetes even within the broad normal range of normal human values. In order to demonstrate the benefits of reducing iron on glucose homeostasis and to better define the parameters for larger clinical trials, the investigators will subject individuals with prediabetes (impaired glucose tolerance, IGT) or early type 2 diabetes to phlebotomy in order to reduce serum ferritin concentrations and determine the effect on glucose homeostasis as revealed by oral and frequently sampled intravenous glucose tolerance testing.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes Mellitus; Prediabetes
• Intervention / Treatment: Procedure: Phlebotomy

Detailed Description

Male and female subjects aged 35-65 will be recruited from the clinic populations at the Medical Centers of the Universities of Colorado, New Mexico, or Utah who have prediabetes, or diabetes relatively well-controlled (Hemoglobin A1c [HbA1c] ≤ 8.0%) with a single oral agent. Diabetes/prediabetes status is verified by oral glucose tolerance testing (OGTT) using criteria of the American Diabetes Association. Serum ferritin will be determined, and subjects chosen with values in the upper 50% of the normal range, 110-400 ng/mL for males, or 80-240 for females. Exclusion criteria include: hereditary hemochromatosis; cancer (except cases currently with no evidence of disease); serum creatinine >1.5; anemia (Hgb < lower limit of normal); chronic inflammatory conditions (rheumatologic conditions such as rheumatoid arthritis or giant cell arteritis, or chronic infections such as hepatitis B or C) that could affect ferritin; erythrocyte sedimentation rate or C-reactive protein>1.5 times the upper limit of normal (UNL); serum transaminases 2 x UNL; hemophilia, warfarin therapy, or history of GI bleeding; and current glucocorticoid therapy.

After determination of eligibility, subjects are randomized in a 2:1 ratio for treatment and controls arms. In the fasted state, blood is drawn for determination of adiponectin and lipids (HDL, direct LDL, triglycerides). Subjects have the option of participating in a frequently sampled intravenous glucose tolerance test (FSIVGTT). All subjects receive counseling to follow a healthy diet and regular exercise. Phlebotomy occurs at the rate of 500 ml (one Unit) of blood per month over the period of 3-6 months. At two-month intervals, serum ferritin and complete blood counts are determined. When serum ferritin reaches the lowest quartile of normal (<50 ng/mL for females and <70 ng/mL for males, but no sooner than 3 months or later than 6 months after beginning phlebotomy, metabolic status will be reassessed by fasting lipids, adiponectin, OGTT, and optionally, FSIVGTT. Controls are recalled for repeat testing 6-8 months after enrollment.

120 min OGTT and FSIVGTT are performed on separate days after an overnight fast. FSIVGTT data are analyzed using MINMOD Millennium software. Areas under the glucose curve (AUCglucose) are calculated using the trapezoidal method.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 33 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age 35-65
• Prediabetes, or diabetes relatively well-controlled (Hemoglobin A1c [HbA1c] ≤ 8.0%) with a single oral agent as defined by oral glucose tolerance testing (OGTT) using criteria of the American Diabetes Association.
• Serum ferritin values in the upper 50% of the normal range, 110-400 ng/mL for males, or 80-240 for females.

Exclusion Criteria:

• hereditary hemochromatosis;
• cancer (except cases currently with no evidence of disease);
• serum creatinine >1.5;
• anemia (Hgb < lower limit of normal);
• chronic inflammatory conditions (rheumatologic conditions such as rheumatoid arthritis or giant cell arteritis, or chronic infections such as hepatitis B or C) that could affect ferritin;
• erythrocyte sedimentation rate or C-reactive protein>1.5 times the upper limit of normal (UNL);
• serum transaminases 2 x UNL;
• hemophilia,
• warfarin therapy,
• history of GI bleeding;
• current glucocorticoid therapy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phlebotomy; All subjects receive counseling to follow a healthy diet and regular exercise. Phlebotomy occurs at the rate of 500 ml (one Unit) of blood per month over the period of 3-6 months. At two-month intervals, serum ferritin and complete blood counts are determined. When serum ferritin reaches the lowest quartile of normal (<50 ng/mL for females and <70 ng/mL for males, but no sooner than 3 months or later than 6 months after beginning phlebotomy, subjects will be retested for glucose tolerance as described	Procedure: Phlebotomy; Patients donate blood until tissue iron levels are in the lowest quartile of normal.
No Intervention: Control; Subjects receive counseling to follow a healthy diet and regular exercise.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvement in glucose area under the curve.	As determined by oral glucose tolerance testing	6 months after initiation of phlebotomy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvement in insulin sensitivity	As determined by intravenous glucose tolerance testing	6 months after initiation of phlebotomy
Improvement in insulin secretory capacity	As determined by intravenous glucose tolerance testing	6 months after initiation of phlebotomy

Collaborators and Investigators

• Sponsor: University of Utah
• Collaborators: University of Colorado, Denver; University of New Mexico
• Investigators: Principal Investigator: Donald McClain, MD, PhD, University of Utah

Study record dates

Study Major Dates

• Study Start: April 1, 2012
• Primary Completion (Actual): May 1, 2015
• Study Completion (Actual): May 1, 2015

Study Registration Dates

• First Submitted: June 4, 2015
• First Submitted That Met QC Criteria: June 5, 2015
• First Posted (Estimate): June 10, 2015

Study Record Updates

• Last Update Posted (Estimate): June 10, 2015
• Last Update Submitted That Met QC Criteria: June 5, 2015
• Last Verified: June 1, 2015

More Information

Terms related to this study

• Keywords: diabetes; iron; phlebotomy
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2
• Other Study ID Numbers: IRB_00020094