Hypoxia and hypoxia-inducible factors in diabetes and its complications

Catrina, Sergiu‐Bogdan; Zheng, Xiaowei

doi:10.1007/s00125-021-05380-z

Cited by 215 publications

(176 citation statements)

References 54 publications

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“…The impact of low blood oxygen saturation on diabetes and its complications are still at a very early stage, but studies investigating the role of hypoxia in diabetes are emerging. 34 Some studies suggest that tissue hypoxia may be a central pathogenic factor in the development of diabetic kidney disease. [35][36][37] Indeed, renal hypoxia has been observed in type 2 diabetes with kidney disease, 38 and reduced renal cortical oxygenation has been found to predict a decline in renal function in persons with chronic kidney disease.…”

Section: Impactmentioning

confidence: 99%

Persons with type 1 diabetes have low blood oxygen levels in the supine and standing body positions

Laursen

Clemmensen

Hansen

et al. 2021

BMJ Open Diab Res Care

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IntroductionBlood oxygen saturation is low compared with healthy controls (CONs) in the supine body position in individuals with type 1 diabetes (T1D) and has been associated with complications. Since most of daily life occurs in the upright position, it is of interest if this also applies in the standing body position. In addition, tissue oxygenation in other anatomical sites could show different patterns in T1D. Therefore, we investigated blood, arm and forehead oxygen levels in the supine and standing body positions in individuals with T1D (n=129) and CONs (n=55).Research design and methodsBlood oxygen saturation was measured with pulse oximetry. Arm and forehead mixed tissue oxygen levels were measured with near-infrared spectroscopy sensors applied on the skin.ResultsData are presented as least squares means±SEM and differences (95% CIs). Overall blood oxygen saturation was lower in T1D (CON: 97.6%±0.2%; T1D: 97.0%±0.1%; difference: −0.5% (95% CI −0.9% to −0.0%); p=0.034). In all participants, blood oxygen saturation increased after standing up (supine: 97.1%±0.1%; standing: 97.6%±0.2%; difference: +0.6% (95% CI 0.4% to 0.8%); p<0.001). However, the increase was smaller in T1D compared with CON (CON supine: 97.3%±0.2%; CON standing: 98.0%±0.2%; T1D supine: 96.9%±0.2%; T1D standing: 97.2%±0.1%; difference between groups in the change: −0.4% (95% CI −0.6% to −0.2%); p<0.001). Arm oxygen saturation decreased in both groups after standing and more in those with T1D. Forehead oxygen saturation decreased in both groups after standing and there were no differences between the changes when comparing the groups.ConclusionCompared with CON, individuals with T1D exhibit possible detrimental patterns of tissue oxygen adaptation to standing, with preserved adaptation of forehead oxygenation. Further studies are needed to explore the consequences of these differences.

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Section: Impactmentioning

confidence: 99%

Persons with type 1 diabetes have low blood oxygen levels in the supine and standing body positions

Laursen

Clemmensen

Hansen

et al. 2021

BMJ Open Diab Res Care

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show abstract

“…Diabetic tissue damage leads to hypoxia. However, HIF-1 signaling is impaired in diabetes, which may contribute to the development of diabetic complications ( Catrina and Zheng, 2021 ). ARNT has been implicated in the development and progression of diabetes and is severely downregulated in the liver and pancreas of patients with diabetes ( Gunton et al, 2005 ; Pillai et al, 2011 ).…”

Section: Discussionmentioning

confidence: 99%

Endothelial Aryl Hydrocarbon Receptor Nuclear Translocator Mediates the Angiogenic Response to Peripheral Ischemia in Mice With Type 2 Diabetes Mellitus

Nguyen

Zheng

Knapp

et al. 2021

Front. Cell Dev. Biol.

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Hypoxia-inducible factors (HIFs) are the master regulators of angiogenesis, a process that is impaired in patients with diabetes mellitus (DM). The transcription factor aryl hydrocarbon receptor nuclear translocator (ARNT, also known as HIF1β) has been implicated in the development and progression of diabetes. Angiogenesis is driven primarily by endothelial cells (ECs), but both global and EC-specific loss of ARNT-cause are associated with embryonic lethality. Thus, we conducted experiments in a line of mice carrying an inducible, EC-specific ARNT-knockout mutation (ArntΔEC, ERT2) to determine whether aberrations in ARNT expression might contribute to the vascular deficiencies associated with diabetes. Mice were first fed with a high-fat diet to induce diabetes. ArntΔEC, ERT2 mice were then adminstrated with oral tamoxifen to disrupt Arnt and peripheral angiogenesis was evaluated by using laser-Doppler perfusion imaging to monitor blood flow after hindlimb ischemia. The ArntΔEC, ERT2 mice had impaired blood flow recovery under both non-diabetic and diabetic conditions, but the degree of impairment was greater in diabetic animals. In addition, siRNA-mediated knockdown of ARNT activity reduced measurements of tube formation, and cell viability in human umbilical vein endothelial cells (HUVECs) cultured under high-glucose conditions. The ArntΔEC, ERT2 mutation also reduced measures of cell viability, while increasing the production of reactive oxygen species (ROS) in microvascular endothelial cells (MVECs) isolated from mouse skeletal muscle, and the viability of ArntΔEC, ERT2 MVECs under high-glucose concentrations increased when the cells were treated with an ROS inhibitor. Collectively, these observations suggest that declines in endothelial ARNT expression contribute to the suppressed angiogenic phenotype in diabetic mice, and that the cytoprotective effect of ARNT expression in ECs is at least partially mediated by declines in ROS production.

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“…A number of reports have suggested that disturbed hypoxic sensitivity may be responsible for impaired wound healing. [2][3][4][5][6][7] Cellular adaptive responses to hypoxia are mediated by the hypoxia-inducible factor (HIF). Stabilization of HIF-1α may be critical to improving wound healing.…”

Section: Introductionmentioning

confidence: 99%

Differentiation of Diabetic Foot Ulcers Based on Stimulation of Myogenic Oscillations by Transient Ischemia

Los-Stegienta

Katarzyńska

Borkowska

et al. 2021

VHRM

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Purpose: Diabetic foot ulceration is a chronic complication characterized by impaired wound healing. There is a great demand for a diagnostic tool that is able to monitor and predict wound healing. Patients and Methods: Oscillations in the microcirculation, known as flowmotion, can be monitored very distinctly and precisely using the Flow Mediated Skin Fluorescence (FMSF) technique. The flowmotion response to hypoxia was measured quantitatively in 42 patients with diabetic foot ulcers. Results: The flowmotion response to hypoxia parameters FM(R) and HS were used to differentiate the diabetic foot ulcers and correlate them with clinical status. In some cases, FMSF measurements were continued over the period of a year in order to monitor disease progress. The clinical status of the quarter of patients with the highest HS values (group A, HS = 50.2±18.3) was compared to the quarter with the lowest HS values (group B, HS = 4.3±1.7). The patients in the group B were identified as having low prognosis for healing and were characterized by higher incidences of hypertension, hyperlipidemia, prevalent CVD, neuropathy and nephropathy. Conclusion: Impaired flowmotion responses to hypoxia induced by transient ischemia can be used for differentiation of diabetic foot ulcers and identification of cases with low prognosis for healing.

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Hypoxia and hypoxia-inducible factors in diabetes and its complications

Cited by 215 publications

References 54 publications

Persons with type 1 diabetes have low blood oxygen levels in the supine and standing body positions

Persons with type 1 diabetes have low blood oxygen levels in the supine and standing body positions

Endothelial Aryl Hydrocarbon Receptor Nuclear Translocator Mediates the Angiogenic Response to Peripheral Ischemia in Mice With Type 2 Diabetes Mellitus

Differentiation of Diabetic Foot Ulcers Based on Stimulation of Myogenic Oscillations by Transient Ischemia

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