Correlation of Circulating Acid-Labile Subunit Levels with Insulin Sensitivity and Serum LDL Cholesterol in Patients with Type 2 Diabetes: Findings from a Prospective Study with Rosiglitazone.

Ying-Chuen Lai,Ta-Jen Wu,Hung-Yuan Li,Chi-Yuan Jeng,Lee-Ming Chuang

doi:10.1155/2014/917823

Abstract

Silencing of acid-labile subunit (ALS) improved glucose metabolism in animal models. The aim of this study is to evaluate the effects of rosiglitazone (RSG) on ALS levels in individuals with type 2 diabetes. A randomized, double-blind, placebo-controlled trial was conducted. Subjects with type 2 diabetes mellitus were randomly distributed to an RSG-treated (n = 30) or a placebo (n = 31) group. Patients were evaluated prior to treatment at baseline and at 12 and 24 weeks after treatment. At baseline, ALS levels were negatively associated with low-density lipoprotein cholesterol (LDLc) levels and homeostatic model assessment version 2 insulin sensitivity (HOMA2-%S). Over 24 weeks, there was a significantly greater reduction in ALS levels in the nonobese RSG-treated individuals than placebo-treated group. The effect of RSG on ALS was not significant in obese individuals. Fasting plasma glucose and hemoglobin A1c were reduced, but total cholesterol and LDLc were increased, in patients on RSG. Change in ALS levels predicted changes in total cholesterol and HOMA2-%S over time. This study suggested a BMI-dependent effect of RSG treatment on ALS levels. Reduction of ALS by RSG increases the risk of atherosclerosis in individuals with type 2 diabetes.

Highlights

Acid-labile subunit (ALS) is a 63.3 kDa glycoprotein that is encoded by the IGFALS gene at the chromosomal location 16p13.3
To the best of our knowledge, this is the first study to examine the correlation of ALS levels with metabolic phenotypes and the effect of the insulin-sensitizer RSG on ALS levels in subjects with type 2 diabetes
At baseline, ALS levels were highly correlated with age, height, fasting plasma insulin levels, HOMA2-%S, and serum low-density lipoprotein cholesterol (LDLc) concentrations

Summary

Introduction

Acid-labile subunit (ALS) is a 63.3 kDa glycoprotein that is encoded by the IGFALS gene at the chromosomal location 16p13.3. ALS functions to stabilize insulin-like growth factor (IGF) by forming a 150 kDa ternary complex consisting of ALS, IGF-1, and IGF-binding protein (IGFBPs) 3 or 5, resulting in prolonged retention of IGF-1 in the circulation [2]. Growing evidence supports a functional link between ALS and insulin sensitivity and glucose metabolism. Mice lacking the IGFALS gene (ALSKO) were leaner and had an increased percentage of fat mass as compared with wild-type mice. The glucose clearance rate was faster in the ALSKO mice compared with wild-type controls [3, 4]. Drosophilae with silenced dALS, encoding the fly ortholog of vertebrate ALS, were determined to have lower circulating glucose levels [5]

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