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.

Disruption of Circadian Rhythm Genes in Obstructive Sleep Apnea Patients—Possible Mechanisms Involved and Clinical Implication

“…All the protein levels were measured using ELISA assay. Similar outcomes were obtained among diabetes mellitus type 2 patients [ 46 ], patients with hepatocellular carcinoma [ 34 ], or varicose lesions [ 47 ]. However, early reports suggest that one-night effective continuous positive airway pressure (CPAP) treatment does not affect the level of HIF-1α in OSA patients [ 48 , 49 ].…”

“…In an evolutionary sense, it increases energetic efficiency [ 59 ]. The disruption of its function may lead to diabetes mellitus type 2 (T2DM), dyslipidemia, obesity, and metabolic syndrome [ 46 , 67 , 68 , 69 ].…”

Chronic high glucose causes podocyte epithelial-mesenchymal transition through lactate-induced histone lactylation

“…Lactic acid is an important product of glucose metabolism exerting metabolic and non-metabolic functions. Plasma lactate concentration is highest in obese subjects with type 2 diabetes mellitus (T2DM), which is associated with both fasting plasma glucose and glycated haemoglobin concentrations (Y. D. Chen, Varasteh, & Reaven, 1993), and recent studies confirm the results and such a relationship (Higuchi et al, 2020;Lopez-Cano et al, 2020). Moreover, lactates are increased in kidney and urine of T1DM rats (Zhao et al, 2011).…”

“…Li et al, 2008;Yamaguchi et al, 2009). Anaerobic glycolysis and its product lactate are the major energy source of podocytes (Brinkkoetter et al, 2019;Ozawa et al, 2015), and lactate levels are elevated in blood and kidney in diabetic conditions (Y. D. Chen et al, 1993;Higuchi et al, 2020;Lopez-Cano et al, 2020;Zhao et al, 2011). Based on these reports, in the current study, firstly we found that lactate levels were increased in high glucose-stimulated mouse podocytes as well as blood and kidney of diabetic mice, which possibly was due to the upregulated MCT2 in mitochondria and the decreased PDH activity.…”

Discussing the Mechanism of Dahuang Huanglian Xiexin Decoction in the Treatment of Type 2 Diabetes Mellitus via Network Pharmacology and Molecular Docking

“…Some experiments had shown that the activation of HIF-1α could control the weight and blood glucose of the model mice, the insulin sensitivity, lipid metabolism level and albuminuria of the model mice were improved, which might suggest that HIF-1 signaling pathway has a potential impact on diabetes and its complications [32]. Some studies found that HIF-1α gene expression in T2DM patients with poor metabolic control was decreased [33]. However, some studies showed that the level of HIF-1α in T2DM patients was signi cantly higher than that in the control group, and insulin secretion increased when hypoxia was inhibited [34].…”