Clinical trial NCT00230087: Iron Depletion Therapy for Type 2 DM and NAFLD
Official title: Iron Depletion Therapy for Patients With Type 2 Diabetes Mellitus and Non-Alcoholic Fatty Liver Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Non-Alcoholic Fatty Liver Disease
Diabetes Mellitus
Keywords: diabetes
nafld
nash
phlebotomy
Lead sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Sponsor class: NIH
First posted: 2005-09-30
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to find out whether lowering the amount of iron in the body will result in less resistance to insulin and improved liver function in patients with type 2 diabetes mellitus and non-alcoholic fatty liver disease. This may result in better diabetes control and/or a decrease in the amount of liver fat.

Detailed description: Nonalcoholic fatty liver disease (NAFLD) is a common liver disease in the United States. NAFLD can lead to severe liver disease in some patients. Patients with NAFLD develop resistance to the normal action of insulin. Insulin is important for processing sugar and fat and increased resistance to insulin leads to fat in the liver. There is a correlation between the amount of iron in a person's body and the ability of insulin to work properly. Several small studies suggest that removal of iron may improve both diabetes and NAFLD by lowering insulin resistance.

The goal of this pilot study is to determine the effect of iron depletion on insulin sensitivity in patients with type 2 diabetes mellitus and non-alcoholic fatty liver disease. This study will be performed as an ancillary P\&F study to the NASH CRN; all participants will be recruited from the NASH CRN Database Study. Secondary outcome measures will include the effect of iron depletion on hepatic necroinflammation, markers of oxidative stress and intrahepatic fat content. Insulin resistance will be directly measured using a two-step hyperinsulinemic euglycemic clamp procedure, before and after iron depletion by phlebotomy. Oral glucose tolerance tests will also be performed in order to evaluate the efficacy of using the indirect, but less cumbersome, HOMA model to derive values of insulin resistance in this patient cohort. This study will advance our understanding of the role of body iron stores in the pathophysiology of type 2 diabetes mellitus and non-alcoholic fatty liver disease. If iron depletion results in improved insulin sensitivity, reduced hepatic necroinflammation and/or intrahepatic fat content, a large scale, randomized, controlled trial of iron depletion in patients with type 2 diabetes mellitus and non-alcoholic fatty liver disease will be planned.

Eligibility criteria: Inclusion Criteria

* Histological evidence of NAFLD and enrollment in NASH CRN Database Study
* Type 2 DM treated with diet or a stable dose of non-insulin sensitizing oral hypoglycemic agents for \> 3 mo.
* Hemoglobin HbA1c level ≤ 8 %
* Serum ALT levels ≥1.3 x ULN
* Between 18-65 years of age

Exclusion Criteria

* Hereditary hemochromatosis or hepatic iron overload defined as any of the following:

  * 2+ iron on hepatic iron staining
  * Hepatic Iron Index ≥ 1.9
  * C282Y homozygous or C282Y/H63D compound heterozygous HFE genotype
* Use of insulin or thiazolidinediones for the treatment of diabetes
* Use of anti-NASH drugs (thiazolidinediones, vitamin E, UDCA, SAM-e, betaine, milk thistle, gemfibrozil, anti-TNF therapies, probiotics)
* Serum ferritin \<50μg/L
* Serum transferrin-iron saturation \<10 %
* Hemoglobin \<10 mg/L
* Hematocrit \<38 %
* Voluntary blood donation or therapeutic phlebotomy within the previous twelve months (except routine lab tests)
* Pregnant or lactating women
* Prior history of coronary artery disease, myocardial infarction, exertional dyspnea or chronic chest pain at rest.
* Evidence of myocardial infarction as determined by an ECG

Primary outcomes:
measure: Improved insulin sensitivity as determined by:(1) hyperinsulinemic euglycemic clamp method
timeFrame: one year
measure: (2) HOMA model- determined by the OGTT method
timeFrame: one year
Secondary outcomes:
measure: Change in serum aminotransferase levels Change in levels of serum, plasma and urinary markers of oxidative stress
timeFrame: one year
measure: Changes in intrahepatic and intraabdominal fat content as determined by CT scan
timeFrame: one year
measure: Change in serum levels of proinflammatory cytokines (ie IL-6, TnF-αR2)
timeFrame: one year
Other outcomes:
Locations:
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
Study officials:
affiliation: University of Washington
name: Kris V Kowdley, MD
role: PRINCIPAL_INVESTIGATOR
References: