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

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.

Keywords: chronodisruption; clock genes; hypoxia; metabolic control; type 2 diabetes.

Figure 1

Relative HIF-1α and HIF-2α gene expression based on the presence of type 2 diabetes. Data are presented as median and interquartile. *** p < 0.001; ns = non-significant. HIF: Hypoxia-Inducible Factor; T2D: type 2 diabetes; mRNA: messenger ribonucleic acid.

Figure 2

Relative gene expression of the clock genes evaluated in the study according to the presence of type 2 diabetes. Data are presented as median and interquartile. *** p < 0.001; ** p < 0.01; * p < 0.05. PER: Period Homolog Proteins; RORA: Retinoid-related Orphan Receptor Alpha; ARNTL: Aryl hydrocarbon Receptor Nuclear Translocator-Like protein-1; CLOCK: Circadian Locomotor Output Cycles Kaput; CRY: Cryptochrome proteins; T2D: type 2 diabetes.

Figure 3

Proposed vicious circle in the relation between nocturnal sleep breathing disorders and disruption of circadian rhythmicity in patients with type 2 diabetes.