Effect of Type 2 Diabetes Mellitus on the Hypoxia-Inducible Factor 1-Alpha Expression. Is There a Relationship with the Clock Genes?

Carolina López-Cano,Raquel Martí,Liliana Gutiérrez-Carrasquilla,Mireia Dalmases,Rafael Simó,Vicky Ceperuelo-Mallafre,Marta Hernández,Enric Sánchez,Sonia Fernández-Veledo,Cristina Hernández,Albert Lecube,Ferran Barbé,Joan Vendrell

doi:10.3390/jcm9082632

Abstract

Limited reports exist on the relationships between regulation of oxygen homeostasis and circadian clock genes in type 2 diabetes. We examined whether the expression of Hypoxia-Inducible Factor-1α (HIF-1α) and HIF-2α relates to changes in the expression of clock genes (Period homolog proteins (PER)1, PER2, PER3, Retinoid-related orphan receptor alpha (RORA), Aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL), Circadian locomotor output cycles kaput (CLOCK), and Cryptochrome proteins (CRY) 1 and CRY2) in patients with type 2 diabetes. A total of 129 subjects were evaluated in this cross-sectional study (48% with diabetes). The gene expression was measured by polymerase chain reaction. The lactate and pyruvate levels were used as surrogate of the hypoxia induced anaerobic glycolysis activity. Patients with diabetes showed an increased plasma concentration of both lactate (2102.1 ± 688.2 vs. 1730.4 ± 694.4 uM/L, p = 0.013) and pyruvate (61.9 ± 25.6 vs. 50.3 ± 23.1 uM/L, p = 0.026) in comparison to controls. However, this finding was accompanied by a blunted HIF-1α expression (1.1 (0.2 to 5.0) vs. 1.7 (0.4 to 9.2) arbitrary units (AU), p ≤ 0.001). Patients with diabetes also showed a significant reduction of all assessed clock genes’ expression. Univariate analysis showed that HIF-1α and almost all clock genes were significantly and negatively correlated with HbA1c concentration. In addition, positive correlations between HIF-1α and the clock genes were observed. The stepwise multivariate regression analysis showed that HbA1c and clock genes independently predicted the expression of HIF-1α. Type 2 diabetes modifies the expression of HIF-1α and clock genes, which correlates with the degree of metabolic control.

Highlights

In recent years, increasing evidence supports the contribution of type 2 diabetes to the development of sleep breathing disorders [1,2]
Type 2 diabetes appears as an independent risk factor for severe nocturnal hypoxia [5]
Tissues from humans and animals with type 2 diabetes experience an altered cellular response to hypoxia that reduces the relative expression of Hypoxia-Inducible Factor-1α (HIF-1α), modifies glycolytic flux, and affects insulin secretion [8,9]

Summary

Introduction

In recent years, increasing evidence supports the contribution of type 2 diabetes to the development of sleep breathing disorders [1,2]. Hypoxic conditions trigger Hypoxia-Inducible Factor (HIF)-1 gene activation to stimulate angiogenesis and regulate cells to an anaerobic metabolism [6]. This major regulator of oxygen homeostasis is a heterodimer transcription factor that combines a constitutively expressed β-subunit with an oxygen-regulated α-subunit [7]. Tissues from humans and animals with type 2 diabetes experience an altered cellular response to hypoxia that reduces the relative expression of HIF-1α, modifies glycolytic flux, and affects insulin secretion [8,9]

Results

Discussion

Conclusion