Gestational Diabetes Is Characterized by Reduced Mitochondrial Protein Expression and Altered Calcium Signaling Proteins in Skeletal Muscle

Kristen E Boyle,Linda A Barbour,Rachel C Janssen,James M Devente,Jacob E Friedman,Martha Lappas,Hyonson Hwang,Teri L Hernandez,Lawrence J Mandarino

doi:10.1371/journal.pone.0106872

Abstract

The rising prevalence of gestational diabetes mellitus (GDM) affects up to 18% of pregnant women with immediate and long-term metabolic consequences for both mother and infant. Abnormal glucose uptake and lipid oxidation are hallmark features of GDM prompting us to use an exploratory proteomics approach to investigate the cellular mechanisms underlying differences in skeletal muscle metabolism between obese pregnant women with GDM (OGDM) and obese pregnant women with normal glucose tolerance (ONGT). Functional validation was performed in a second cohort of obese OGDM and ONGT pregnant women. Quantitative proteomic analysis in rectus abdominus skeletal muscle tissue collected at delivery revealed reduced protein content of mitochondrial complex I (C-I) subunits (NDUFS3, NDUFV2) and altered content of proteins involved in calcium homeostasis/signaling (calcineurin A, α1-syntrophin, annexin A4) in OGDM (n = 6) vs. ONGT (n = 6). Follow-up analyses showed reduced enzymatic activity of mitochondrial complexes C-I, C-III, and C-IV (−60–75%) in the OGDM (n = 8) compared with ONGT (n = 10) subjects, though no differences were observed for mitochondrial complex protein content. Upstream regulators of mitochondrial biogenesis and oxidative phosphorylation were not different between groups. However, AMPK phosphorylation was dramatically reduced by 75% in the OGDM women. These data suggest that GDM is associated with reduced skeletal muscle oxidative phosphorylation and disordered calcium homeostasis. These relationships deserve further attention as they may represent novel risk factors for development of GDM and may have implications on the effectiveness of physical activity interventions on both treatment strategies for GDM and for prevention of type 2 diabetes postpartum.

Highlights

Gestational diabetes mellitus (GDM) is a rapidly growing public health concern
Several proteins involved in calcium homeostasis and calcium-dependent cellular signaling were altered in skeletal muscle of women with obese pregnant women with GDM (OGDM), including calmodulin-dependent calcineurin A b (PPP3CB), which was increased by over 2-fold in women with OGDM compared with obese pregnant women with normal glucose tolerance (ONGT) women (P,0.05)
In this hypothesis-generating analysis we found that several proteins of the mitochondrial electron transport system (ETS) were downregulated in the women with GDM, a factor that was corroborated by reduced activity of several enzyme complexes of the ETS in a similar, larger cohort of both OGDM and ONGT women

Summary

Introduction

Gestational diabetes mellitus (GDM) is a rapidly growing public health concern. Adoption of new diagnostic criteria recommended by the American Diabetes Association (ADA) [1,2] estimates a global prevalence of nearly one in five women (,18%) who are considered at risk for GDM. Obesity occurs in ,one in three women of child-bearing age [1,3] and is a driving force accelerating the prevalence of GDM. GDM diagnosis identifies a population of women at markedly increased risk for future diabetes [8,9], in part due to abnormal skeletal muscle signaling. Understanding the pathogenesis of GDM is extremely important from a public health perspective for both maternal and child health

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