Plasma Protein Biomarkers Correlated with the Development of Diet-Induced Type 2 Diabetes in Mice

Abstract

INTRODUCTION: Early detection, assessment of disease progression, and application of an appropriate therapeutic intervention are all important for the care of patients with type 2 diabetes. Currently, however, there is no simple test for early detection of type 2 diabetes. Established diagnostic tests for the disease including oral glucose tolerance, fasting blood glucose, and hemoglobin A1c are relatively late markers where the disease has already progressed. Since blood is in direct contact with many tissues, we hypothesized that pathological tissue changes are likely to be reflected in proteomic profiles of plasma. METHODS: Mice were reared either on regular chow or a high-fat diet at weaning and several physiological responses (i.e., weight, fasting plasma glucose and insulin, and glucose tolerance) were monitored at regular time intervals. Plasma was collected at regular intervals for proteomic analysis by two-dimensional gel electrophoresis and subsequent mass spectrometry. RESULTS: Onset of hyperinsulinemia with corresponding glucose intolerance was observed in 2 weeks and fasting blood glucose levels rose significantly after 4 weeks on the high-fat diet. Many proteins were found to exist in multiple forms (isoforms). Levels of some isoforms including plasma retinol binding protein, transthyretin, Apolipoprotein A1, and kininogen showed significant changes as early as 4 weeks which coincided with the very early development of glucose intolerance. CONCLUSIONS: These results show that a proteomic approach to study the development of type 2 diabetes may uncover unknown early post-translationally modified diagnostic and/or therapeutic protein targets.