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Inhibition of non-canonical pathway of NF8B activation can reduce HbA1c and hepatic ESTEATOSIS in patients with type 2 diabetes mellitus

Grant number: 18/15960-3
Support type:Scholarships abroad - Research
Effective date (Start): February 11, 2019
Effective date (End): February 10, 2020
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Maria Cristina Foss de Freitas
Grantee:Maria Cristina Foss de Freitas
Host: Elif Oral
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Local de pesquisa : University of Michigan, United States  

Abstract

Obesity and type 2 diabetes have reached epidemic proportions and the mechanisms by which obesity leads to insulin resistance and type 2 diabetes remain unsolved. Existing therapies do not effectively cover the needs of all patients and as the energy storage capacity in adipose tissue reaches its limit, it spreads to the liver, causing nonalcoholic fatty liver disease. Our proposal will address this interaction, based on observations that IKKµ and TBK1 pathway are important physiological regulators of energy balance. Thus, there may be great clinical value in modulating these regulators to address these clinical conditions. Recently, it has been described that proteins activated by NFºB, Tbk1 and Ikbke, are increased both in the level of mRNA and in the protein level in adipocytes of mice under high fat diet. Deletion of the Ikbke gene was associated to partially resistance to the development of obesity, insulin resistance, hepatic steatosis and inflammation. It was then identified that the amlexanox drug - previously developed for the treatment of asthma, allergic rhinitis (in Japan) and aphthous ulcers (in the US) - is an inhibitor of the IKKµ / TBK1 pathway. Administration of this drug to obese mice produced reversible weight loss, improved insulin sensitivity, reduced inflammation, reduced glucose, and attenuated hepatic steatosis. More recently, a randomized, double-blind, placebo-controlled clinical study of 42 patients with type 2 diabetes and non-alcoholic fatty liver disease treated for 12 weeks with amlexanox or placebo showed clinically significant reduced hemoglobin A1c (HbA1c) in almost 0.5% in the amlexanox group. In addition, a subgroup that showed a reduction in HbA1c greater than 0.5% were characterized with a distinct transcriptional profile in the gene expression in subcutaneous fat in response to treatment with amlexanox. In addition, the reduction of HbA1c in patients treated with amlexanox correlated with higher levels of C-reactive protein (CRP). Although it was not possible to explore the reduction of hepatic steatosis in this study, preliminary data suggested that patients who responded to the drug had a greater reduction in hepatic fat fraction measured by magnetic resonance imaging (from 16% to 11%). Thus, the main goal of this study is to determine whether amlexanox induces sustained reduction of glucose and improvement of liver fat. We will recruit 120 patients with type 2 diabetes and non-alcoholic fatty liver disease who have inadequate glucose control (HbA1c> 7-9.5%), hepatic steatosis (evaluated with ultrasonography at baseline) and are being treated only with oral agents or lifestyle modification. Patients will be randomized to receive amlexanox 50 mg three times daily or placebo orally for 6 months. Patients will be stratified by sex and CRP (60 will be recruited with elevated CRP). Patients will undergo biopsy of adipose tissue at baseline, 3 months and 6 months, and an MRI of the liver at baseline and 6 months. Adipose tissue biopsy samples and circulating peripheral blood mononuclear cells (PBMCs) will be studied for gene expression by means of Seq RNA analyzes before, during and after exposure to the drug.