Hepatic Dysfunction, Vitamin D Status, and Glycemic Control in Diabetes
Condition: Type 2 Diabetes; Nonalcoholic Fatty Liver Disease; Vitamin D Deficiency
MeSH terms: Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Diabetes Mellitus; Diabetes Mellitus, Type 2; Vitamin D Deficiency
Study type: Interventional
Phase: Phase 3

Summary: 
      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.
    

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.
    

Intervention name(s): Ergocalciferol, placebo
Intervention type(s): Dietary Supplement
Intervention description(s): Ergocalciferol 50000 IU capsules Microcrystalline cellulose
Other intervention name(s): Vitamin D; Placebo
Intervention MeSH terms: Vitamin D; Ergocalciferols
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Children; Adolescents; Adults; Type 2 diabetes; Nonalcoholic fatty liver disease; Vitamin D deficiency