Hepatic Dysfunction, Vitamin D Status, and Glycemic Control in Diabetes (VDLS)

This study is designed to study the effect of vitamin D intake on the severity of fatty liver and poor glucose control in patients with type 2 diabetes and fatty liver disease.

Study Overview

• Status: Completed
• Conditions: Vitamin D Deficiency; Type 2 Diabetes; Nonalcoholic Fatty Liver Disease
• Intervention / Treatment: Dietary supplement: Ergocalciferol, placebo

Detailed Description

The prevalence of significantly poor glycemic control marked by a hemoglobin A1c (HbA1c) level of ≥ 9.5% in youth with type 2 diabetes (T2D) is 27% 1 and 24.2% in young adults2. Strategies to improve glycemic control in patients with T2D include lifestyle modification, optimization of therapeutic regimens, and correction of comorbid states that impair glycemic control. However, the role of comorbid states on glycemic control in T2D has not been adequately studied. For example, 70% of patients with T2D have nonalcoholic fatty liver disease (NAFLD)3, a potentially serious form of chronic liver disease 4 in which the triad of the development of lipotoxicity-induced mitochondrial dysfunction, activation of inflammatory pathways, and cytokine generation lead to progressive liver damage5. NAFLD is the leading cause of elevated liver enzymes in the US6, and is diagnosed by either liver biopsy or the detection of a hepatic triglyceride content (HTGC) of >5.6% by proton magnetic resonance spectroscopy (1H MRS)2. Despite the high prevalence of NAFLD in T2D, its potential impact on glycemic control through the impairment of hepatic metabolic processes is unclear. This is important because a crucial step in vitamin D metabolism, the hydroxylation of vitamin D at the 25 position, occurs in the liver. The consequence of NAFLD on this critical step in vitamin D metabolism in patients with T2D, and the impact of the resultant 25-hydroxyvitamin D [25(OH)D] deficiency on glycemic control are not well understood. The rationale for this study is that a clear understanding of the role of vitamin D on the pathogenesis of NAFLD is crucial because vitamin D is a prohormone with potent anti-inflammatory properties that inhibit pro-inflammatory cytokines such as tumor necrosis factor- α (TNF-α), interleukin-6, and the activity of macrophages 2 while upregulating the production of anti-inflammatory cytokine, interleukin-10 2which could potentially reverse the effects of insulin resistance (IR) and oxidative stress, the two key components of the 'double hit model' of the pathogenesis of NAFLD. The 'first hit' involves IR-induced hepatocyte lipid accumulation which increases hepatic vulnerability to the components of the 'second hit': oxidative stress and proinflammatory cytokines, leading to mitochondrial dysfunction, inflammation and fibrosis.

The investigators7 previously showed that mild hepatic dysfunction in patients with T2D was associated with a high prevalence (47.5%) of vitamin D deficiency as defined by 25(OH)D level of < 20 ng/mL, as well as poor glycemic control. The investigators further reported a significant inverse relationship between HbA1c and 25(OH)D, and also between 25(OH)D and alanine transaminase. These data suggest that mild hepatic dysfunction could impair vitamin D metabolism and negatively impact glycemic control in patients with T2D. The investigators have also accumulated data 8 to show that 25(OH)D supplementation was associated with a significant reduction in HbA1c in T2D without a significant change in insulin or metformin dose. Histologically, a recent animal study reported significant hepatic steatosis in vitamin D-deficient mice compared to vitamin D-sufficient mice 2.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Worcester, Massachusetts, United States, 01609
      • University of Massachusetts Medical School

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years to 50 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Children: 10 - 17 years
2. Adults: 18 - 50 years
3. Type 2 diabetes > 6 mo duration
4. 25-hydroxyvitamin D [25(OH)D] level of <20 ng/mL
5. Hepatic triglyceride content (HTGC) value of >5.6%
6. HbA1c of > 8%;
7. Ability to take medication by mouth.

Exclusion Criteria:

1. Pregnant or lactating women
2. Mental deficiency (IQ <70)
3. Chronic liver disease
4. Disorders of vitamin D metabolism, kidney, or parathyroid disease;
5. Calcium and/or vitamin D supplementation
6. Mauriac syndrome
7. Malabsorption of fat soluble vitamins
8. Drug toxicity and alcoholism

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Vitamin D supplementation; Ergocalciferol 50,000 IU per week for 6 weeks, then bi-weekly for 6 mo	Dietary supplement: Ergocalciferol, placebo; Ergocalciferol 50000 IU capsules Microcrystalline cellulose; Other Names: Placebo; Vitamin D
Placebo Comparator: Placebo; Placebo capsules, on capsule per week for 6 weeks, then bi-weekly for 6 mo.	Dietary supplement: Ergocalciferol, placebo; Ergocalciferol 50000 IU capsules Microcrystalline cellulose; Other Names: Placebo; Vitamin D

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in hepatic triglyceride content (HTGC)	Change in hepatic triglyceride content (HTGC) as measured by proton magnetic resonance spectroscopy (1H MRS)	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hemoglobin A1c	Change in glycemic control as measured by HbA1c.	6 months

Collaborators and Investigators

• Sponsor: University of Massachusetts, Worcester
• Investigators: Principal Investigator: Benjamin U Nwosu, MD, University of Massachusetts, Worcester

Study record dates

Study Major Dates

• Study Start: March 1, 2014
• Primary Completion (Actual): October 1, 2016
• Study Completion (Actual): October 1, 2016

Study Registration Dates

• First Submitted: May 5, 2014
• First Submitted That Met QC Criteria: May 5, 2014
• First Posted (Estimate): May 7, 2014

Study Record Updates

• Last Update Posted (Estimate): January 10, 2017
• Last Update Submitted That Met QC Criteria: January 7, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Keywords: Adolescents; Children; Type 2 diabetes; Adults; Nonalcoholic fatty liver disease; Vitamin D deficiency
• Additional Relevant MeSH Terms: Digestive System Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Nutrition Disorders; Avitaminosis; Deficiency Diseases; Malnutrition; Liver Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Fatty Liver; Vitamin D Deficiency; Non-alcoholic Fatty Liver Disease; Physiological Effects of Drugs; Micronutrients; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Vitamin D; Ergocalciferols
• Other Study ID Numbers: HSC Docket # H00002866