Iron Reduction for the Treatment of Diabetes and Nonalcoholic Fatty Liver Disease

Investigators propose that high iron triggers a number of events in different tissues, some of which will predispose to diabetes. Investigators will therefore study normal individuals who have higher than average iron levels in tissues, test your glucose control through standard blood tests like the hemoglobin A1c and by placing a continuous glucose monitor before and after participants have donated blood to determine if decreasing iron levels had any effect.

In addition, iron may also play a role in the progression of fatty liver to scarring and cirrhosis. Since 75% of people with diabetes have some degree of fatty liver, investigators would also like to study how the liver reacts to the lowering of iron.

There will be two optional sub studies conducted only at Wake Forest University Health Sciences they are: 1) Liver substudy that will look at liver complication of diabetes and the role it plays in the progression of fatty liver to scarring and cirrhosis. Investigators will look at how liver reacts to the lowering of iron. 2)Glucose Tolerance Mechanism substudy that will look at the mechanism the body uses to regulate blood sugar levels by insulin, this will require the frequently sample intravenous glucose tolerance test (FSIVGTT).

• Blood Donation (Procedure): Participants in the TREATMENT GROUP will have a Unit of blood (two cups, the same amount you would donate at the Red Cross) drawn. This involves having a needle inserted into a vein in your arm. Prior to taking the blood, staff will measure blood count to be sure participants are not anemic, and blood pressure to be sure there is no dehydration. During or after donation, participants will be given a sports drink to replace the fluid loss. Participants in the CONTROL GROUP will not donate blood, but will have a needle inserted into a vein in your arm. Neither group will not know to which they have been assigned, all will have a sleep mask (like a blindfold, covering the eyes, held on with an elastic band) placed so they will not know whether blood was actually removed.
• Sham Blood Donation (Procedure): Participants will have a needle inserted their arm, however, no blood will be drawn.

Primary outcomes

• HgbA1c Value [Baseline]: HgbA1c measures average blood glucose levels over the past 2-3 months. HgbA1C values from baseline and month 6 will be reported.
• HgbA1c Value [month 6]: HgbA1c measures average blood glucose levels over the past 2-3 months. HgbA1C values from baseline and month 6 will be reported.
• ALT (Alanine Aminotransferase) Value [Baseline]: An ALT test measures a liver enzyme. ALT values from baseline and month 12 will be reported.
• ALT Value [month 12]: An ALT test measures a liver enzyme. ALT values from baseline and month 12 will be reported.
• FSIGTT DI (Frequently Sampled Intravenous Glucose Tolerance Test) Value [Baseline]: Studies often report DI values with a wide range. Normal or reference ranges can vary substantially depending on the study. Higher values indicate better -cell function. The Disposition Index (DI) derived from the Frequently Sampled Intravenous Glucose Tolerance Test (FSIGTT) is a measure of pancreatic -cell function, calculated as the product of insulin sensitivity (S1) and the acute insulin response to glucose (AIRg). It acts as a marker for how well insulin secretion compensates for insulin.
• FSIGTT DI Value [month 6]: Studies often report DI values with a wide range. Normal or reference ranges can vary substantially depending on the study. Higher values indicate better -cell function. The Disposition Index (DI) derived from the Frequently Sampled Intravenous Glucose Tolerance Test (FSIGTT) is a measure of pancreatic -cell function, calculated as the product of insulin sensitivity (S1) and the acute insulin response to glucose (AIRg). It acts as a marker for how well insulin secretion compensates for insulin.

Secondary outcomes

• HgbA1c Value at Month 12 [Month 12]: HgbA1c measures average blood glucose levels over the past 2-3 months.
• Change in Fasting Glucose [Month 6, Month 12]: Fasting glucose measured on glucose machine (Abbott Freestyle Libre Pro system). Difference in values from baseline through month 6 and baseline through month 12 will be reported.
• HOMA-IR (Homeostatic Model Assessment-Insulin Resistance) Score [baseline, month 12]: Insulin sensitivity measured by HOMA-IR (Homeostatic Model Assessment-Insulin Resistance) calculated from fasting glucose and insulin. Values will be reported for Baseline and 12 months. HOMA-IR (Homeostatic Model Assessment of Insulin Resistance) is a calculated score that uses fasting insulin and glucose to measure insulin resistance. An optimal score is generally below 1.0, while values above 1.9 suggest early insulin resistance, and those above 2.9 indicate significant insulin resistance. HOMA-IR (Homeostatic Model Assessment of Insulin Resistance) measures insulin resistance by multiplying fasting insulin and fasting glucose, then dividing by 405. A score below 1.0 indicates optimal insulin sensitivity, while above 1.9-2.0 suggests early resistance, and above 2.9 indicates significant resistance.
• Number of Participants That Discontinued of Oral Antihyperglycemic Agent [Month 12]: The numbers of participants that discontinued of oral antihyperglycemic agents
• Change in Weight [Baseline, Month 12]: The change in weight from baseline to month 12 will be reported
• Change in Systolic Blood Pressure [Baseline, Month 12]: The change in systolic Blood pressure from baseline to month 12 will be reported
• Number of Participants That Converted From Pre-diabetes to Diabetes [Month 12]: Number of participants that converted from pre-Diabetes to Diabetes based on the HbA1C criteria.
• Number of Participants That Converted From Pre-diabetes to Normal Glucose Tolerance [Month 12]: Number of participants that converted from pre-Diabetes to normal glucose tolerance based on the HbA1C criteria.

Sex: All, ages: 40 Years to 75 Years

Inclusion Criteria:

* Ages 40-75
* At least 3 months since diagnosis of prediabetes or diabetes
* HgbA1C value within three months or at screening of 5.7-6.4% for those with prediabetes and 7- 8.5% for those with diabetes (the upper limit of the latter to reduce the likelihood of major changes in glycemic intervention during the trial period, and the lower limit to allow some room for improvement)
* Undiagnosed on no medication HgA1C 6.5-6.9
* C-reactive protein levels up to 11.0
* Aim 2-serum ALT> 1.5 times the upper limit of normal, or; liver stiffness of > 12.5 kPa by Fibroscan transient elastography
* Serum ferritin levels within 1 year or at the time of screening in the upper half of the normal range (>50 ng/mL for women; >100ng/mL for men)

Exclusion Criteria:

* Documented anemia
* Hemoglobin levels within 0.5 g/dL of the lower limit of normal (<12.5 g/dL for women; 13.5 g/dL for men)
* Recent blood loss
* Bleeding diatheses (coagulation abnormalities or treatment with anticoagulants)
* Serious chronic infections or chronic inflammatory conditions that could elevate ferritin as an "acute phase reactant
* C-reactive protein greater than the upper limit of normal to further validate the lack of significant chronic inflammation
* Active cancer diagnosis (excluding skin cell cancers other than melanoma)
* Renal insufficiency (eGFR<60 ml/min)
* History of orthostatic hypotension
* Heavy alcohol use (NIH criteria for men, greater than 4 drinks on any day or 14/week)
* Pregnancy or premenopausal women of childbearing age, unless unable to become pregnant because of oral contraceptive use or surgical loss of ovaries or uterus
* Aim 2 - individuals meeting the additional inclusion criteria for aim 2 will be tested for anti-HAV IgM, HBs Ag, anti-HBc. IgM, anti HCV IgM and IgG. Subjects who prove positive for any of these viral serologies, except for HCV IgG will be excluded. The latter will be tested for HCV RNA by PRC, and if negative they will be eligible for enrollment

Participant flow

Outcome results

• HgbA1c Value (Primary), Mean, percentage of HgbA1c: Treatment Group 6.31 +/- 0.75; Control Group 6.22 +/- 0.57
• HgbA1c Value (Primary), Mean, percentage of HgbA1c: Treatment Group 6.43 +/- 0.77; Control Group 6.32 +/- 0.56
• ALT (Alanine Aminotransferase) Value (Primary), Mean, IU/L: Treatment Group 25.5 +/- 15.7; Control Group 24.1 +/- 12.0
• ALT Value (Primary), Mean, IU/L: Treatment Group 23.0 +/- 12.5; Control Group 27.7 +/- 14.3
• FSIGTT DI (Frequently Sampled Intravenous Glucose Tolerance Test) Value (Primary), Mean, Si*AIRg: Treatment Group 39.6 +/- 9.9; Control Group 40.8 +/- 8.0
• FSIGTT DI Value (Primary), Mean, Si*AIRg: Treatment Group 39.8 +/- 4.4; Control Group 42.5 +/- 9.4
• HgbA1c Value at Month 12 (Secondary), Mean, % of HgbA1c: Treatment Group 6.56 +/- 0.72; Control Group 6.35 +/- 0.83
• Change in Fasting Glucose (Secondary), Mean, mg/dL: Treatment Group -4 +/- 21; Control Group 3.2 +/- 12
• HOMA-IR (Homeostatic Model Assessment-Insulin Resistance) Score (Secondary), Mean, score on a scale: Treatment Group 7.97 +/- 13.7; Control Group 5.28 +/- 5.63
• Number of Participants That Discontinued of Oral Antihyperglycemic Agent (Secondary), Count of participants, Participants: Treatment Group 6; Control Group 1
• Change in Weight (Secondary), Mean, pounds: Treatment Group 0.1 +/- 10.1; Control Group 0.8 +/- 13.4
• Change in Systolic Blood Pressure (Secondary), Mean, mmHG: Treatment Group 2 +/- 11; Control Group 4 +/- 11
• Number of Participants That Converted From Pre-diabetes to Diabetes (Secondary), Count of participants, Participants: Treatment Group 1; Control Group 2
• Number of Participants That Converted From Pre-diabetes to Normal Glucose Tolerance (Secondary), Count of participants, Participants: Treatment Group 1; Control Group 1

Adverse events

Time frame: from baseline through month 12

Serious adverse events by term

Other adverse events by term

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• Study Protocol and Statistical Analysis Plan (PDF, 2025-07-24)
• Informed Consent Form (PDF, 2024-09-19)

• Donald A McClain, MD, PhD, Principal investigator, Wake Forest University Health Sciences

NIH grants: R01DK119913