Abstract
BackgroundComprehensive proteomics profiling may offer new insights into the dysregulated metabolic milieu of type 2 diabetes, and in the future, serve as a useful tool for personalized medicine. This calls for a better understanding of circulating protein patterns at the early stage of type 2 diabetes as well as the dynamics of protein patterns during changes in metabolic status.MethodsTo elucidate the systemic alterations in early-stage diabetes and to investigate the effects on the proteome during metabolic improvement, we measured 974 circulating proteins in 52 newly diagnosed, treatment-naïve type 2 diabetes subjects at baseline and after 1 and 3 months of guideline-based diabetes treatment, while comparing their protein profiles to that of 94 subjects without diabetes.FindingsEarly stage type 2 diabetes was associated with distinct protein patterns, reflecting key metabolic syndrome features including insulin resistance, adiposity, hyperglycemia and liver steatosis. The protein profiles at baseline were attenuated during guideline-based diabetes treatment and several plasma proteins associated with metformin medication independently of metabolic variables, such as circulating EPCAM.InterpretationThe results advance our knowledge about the biochemical manifestations of type 2 diabetes and suggest that comprehensive protein profiling may serve as a useful tool for metabolic phenotyping and for elucidating the biological effects of diabetes treatments.FundingThis work was supported by the Swedish Heart and Lung Foundation, the Swedish Research Council, the Erling Persson Foundation, the Knut and Alice Wallenberg Foundation, and the Swedish state under the agreement between the Swedish government and the county councils (ALF-agreement).
Highlights
Type 2 diabetes, characterized by hyperglycemia on account of chronic insulin resistance and impaired pancreatic b-cell function, is a complex systemic disease with dysregulated metabolic pathways and complications in several organ systems
The results indicated that weight change and metformin medication had the largest importance, each explaining 14% of the proteome variance during treatment, whereas change in hemoglobin A1c (HbA1c) and homeostatic model assessment of insulin resistance (HOMA-IR) only accounted for 4.8% and 1.1%, respectively
Results from the present study show that subjects with screening detected early type 2 diabetes, void of classic diabetes symptoms, display wide-ranging alterations in the plasma proteome as compared to non-diabetic controls, to the extent that diabetes status can be predicted with high accuracy from the protein signature
Summary
Type 2 diabetes, characterized by hyperglycemia on account of chronic insulin resistance and impaired pancreatic b-cell function, is a complex systemic disease with dysregulated metabolic pathways and complications in several organ systems. The early stage of the disease frequently goes undiagnosed for many years because hyperglycemia develops gradually and is often not severe enough for the patient to notice the classic symptoms of diabetes [1]. Comprehensive proteomics profiling may offer new insights into the dysregulated metabolic milieu of type 2 diabetes, and in the future, serve as a useful tool for personalized medicine. This calls for a better understanding of circulating protein patterns at the early stage of type 2 diabetes as well as the dynamics of protein patterns during changes in metabolic status.
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