Infrapopliteal Transcatheter Interventions for Limb Salvage in Diabetic Patients: Importance of Aggressive Interventional Approach and Role of Transcutaneous Oximetry

AbstractMaturity-onset diabetes of the young, MODY, is an autosomal dominant disease with incomplete penetrance. In a family with multiple generations of diabetes and several early onset diabetic siblings, we found the previously reported P33T PDX1 damaging mutation. Interestingly, this substitution was also present in a healthy sibling. In contrast, a second very rare heterozygous damaging mutation in the necroptosis terminal effector, MLKL, was found exclusively in the diabetic family members. Aberrant cell death by necroptosis is a cause of inflammatory diseases and has been widely implicated in human pathologies, but has not yet been attributed functions in diabetes. Here, we report that the MLKL substitution observed in diabetic patients, G316D, results in diminished phosphorylation by its upstream activator, the RIPK3 kinase, and no capacity to reconstitute necroptosis in two distinct MLKL−/− human cell lines. This MLKL mutation may act as a modifier to the P33T PDX1 mutation, and points to a potential role of impairment of necroptosis in diabetes. Our findings highlight the importance of family studies in unraveling MODY’s incomplete penetrance, and provide further support for the involvement of dysregulated necroptosis in human disease.

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Endothelial Dysfunction in Diabetes Is Aggravated by Glycated Lipoproteins; Novel Molecular Therapies

Biomedicines ◽

10.3390/biomedicines9010018 ◽

2020 ◽

Vol 9 (1) ◽

pp. 18

Author(s):

Laura Toma ◽

Camelia Sorina Stancu ◽

Anca Volumnia Sima

Keyword(s):

Plasma Proteins ◽

Diabetes Complications ◽

Vascular Complications ◽

High Density Lipoproteins ◽

Diabetic Patients ◽

Inflammatory Stress ◽

Glycation End Products ◽

Molecular Therapies ◽

Specific Receptors

Diabetes and its vascular complications affect an increasing number of people. This disease of epidemic proportion nowadays involves abnormalities of large and small blood vessels, all commencing with alterations of the endothelial cell (EC) functions. Cardiovascular diseases are a major cause of death and disability among diabetic patients. In diabetes, EC dysfunction (ECD) is induced by the pathological increase of glucose and by the appearance of advanced glycation end products (AGE) attached to the plasma proteins, including lipoproteins. AGE proteins interact with their specific receptors on EC plasma membrane promoting activation of signaling pathways, resulting in decreased nitric oxide bioavailability, increased intracellular oxidative and inflammatory stress, causing dysfunction and finally apoptosis of EC. Irreversibly glycated lipoproteins (AGE-Lp) were proven to have an important role in accelerating atherosclerosis in diabetes. The aim of the present review is to present up-to-date information connecting hyperglycemia, ECD and two classes of glycated Lp, glycated low-density lipoproteins and glycated high-density lipoproteins, which contribute to the aggravation of diabetes complications. We will highlight the role of dyslipidemia, oxidative and inflammatory stress and epigenetic risk factors, along with the specific mechanisms connecting them, as well as the new promising therapies to alleviate ECD in diabetes.

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What Is Currently the Role of TcPO2 in the Choice of the Amputation Level of Lower Limbs? A Comprehensive Review

Journal of Clinical Medicine ◽

10.3390/jcm10071413 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1413

Author(s):

Judith Catella ◽

Anne Long ◽

Lucia Mazzolai

Keyword(s):

Arterial Disease ◽

Major Amputation ◽

Lower Limbs ◽

Limb Amputation ◽

Quality Of Data ◽

Amputation Level ◽

Increased Risk ◽

Transcutaneous Oximetry ◽

Peripheral Arterial

Some patients still require major amputation for lower extremity peripheral arterial disease treatment. The purpose of pre-operative amputation level selection is to determine the most distal amputation site with the highest healing probability without re-amputation. Transcutaneous oximetry (TcPO2) can detect viable tissue with the highest probability of healing. Several factors affect the accuracy of TcPO2; nevertheless, surgeons rely on TcPO2 values to determine the optimal amputation level. Background about the development of TcPO2, methods of measurement, consequences of lower limb amputation level, and the place of TcPO2 in the choice of the amputation level are reviewed herein. Most of the retrospective studies indicated that calf TcPO2 values greater than 40 mmHg were associated with a high percentage of successful wound healing after below-knee-amputation, whereas values lower than 20 mmHg indicated an increased risk of unsuccessful healing. However, a consensus on the precise cut-off value of TcPO2 necessary to assure healing is missing. Ways of improvement for TcPO2 performance applied to the optimization of the amputation-level are reported herein. Further prospective data are needed to better approach a TcPO2 value that will promise an acceptable risk of re-amputation. Standardized TcPO2 measurement is crucial to ensure quality of data.

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Serum Amyloid Beta42 Is Not Eliminated by the Cirrhotic Liver: A Pilot Study

Journal of Clinical Medicine ◽

10.3390/jcm10122669 ◽

2021 ◽

Vol 10 (12) ◽

pp. 2669

Author(s):

Reiner Wiest ◽

Thomas S. Weiss ◽

Lusine Danielyan ◽

Christa Buechler

Keyword(s):

Liver Cirrhosis ◽

Hepatic Clearance ◽

Protective Role ◽

Tissue Growth ◽

Cirrhotic Liver ◽

Diabetic Patients ◽

Peripheral Clearance ◽

End Stage ◽

The Brain

Amyloid-beta (Aβ) deposition in the brain is the main pathological hallmark of Alzheimer disease. Peripheral clearance of Aβ may possibly also lower brain levels. Recent evidence suggested that hepatic clearance of Aβ42 is impaired in liver cirrhosis. To further test this hypothesis, serum Aβ42 was measured by ELISA in portal venous serum (PVS), systemic venous serum (SVS), and hepatic venous serum (HVS) of 20 patients with liver cirrhosis. Mean Aβ42 level was 24.7 ± 20.4 pg/mL in PVS, 21.2 ± 16.7 pg/mL in HVS, and 19.2 ± 11.7 pg/mL in SVS. Similar levels in the three blood compartments suggested that the cirrhotic liver does not clear Aβ42. Aβ42 was neither associated with the model of end-stage liver disease score nor the Child–Pugh score. Patients with abnormal creatinine or bilirubin levels or prolonged prothrombin time did not display higher Aβ42 levels. Patients with massive ascites and patients with large varices had serum Aβ42 levels similar to patients without these complications. Serum Aβ42 was negatively associated with connective tissue growth factor levels (r = −0.580, p = 0.007) and a protective role of Aβ42 in fibrogenesis was already described. Diabetic patients with liver cirrhosis had higher Aβ42 levels (p = 0.069 for PVS, p = 0.047 for HVS and p = 0.181 for SVS), which is in accordance with previous reports. Present analysis showed that the cirrhotic liver does not eliminate Aβ42. Further studies are needed to explore the association of liver cirrhosis, Aβ42 levels, and cognitive dysfunction.

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Erythrocytes: Central Actors in Multiple Scenes of Atherosclerosis

International Journal of Molecular Sciences ◽

10.3390/ijms22115843 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5843

Author(s):

Chloé Turpin ◽

Aurélie Catan ◽

Olivier Meilhac ◽

Emmanuel Bourdon ◽

François Canonne-Hergaux ◽

...

Keyword(s):

Iron Homeostasis ◽

The Body ◽

Diabetic Patients ◽

Special Focus ◽

Plaque Progression ◽

Cell Dysfunction ◽

Circulating Cells ◽

The Impact ◽

Progression Of Atherosclerosis

The development and progression of atherosclerosis (ATH) involves lipid accumulation, oxidative stress and both vascular and blood cell dysfunction. Erythrocytes, the main circulating cells in the body, exert determinant roles in the gas transport between tissues. Erythrocytes have long been considered as simple bystanders in cardiovascular diseases, including ATH. This review highlights recent knowledge concerning the role of erythrocytes being more than just passive gas carriers, as potent contributors to atherosclerotic plaque progression. Erythrocyte physiology and ATH pathology is first described. Then, a specific chapter delineates the numerous links between erythrocytes and atherogenesis. In particular, we discuss the impact of extravasated erythrocytes in plaque iron homeostasis with potential pathological consequences. Hyperglycaemia is recognised as a significant aggravating contributor to the development of ATH. Then, a special focus is made on glycoxidative modifications of erythrocytes and their role in ATH. This chapter includes recent data proposing glycoxidised erythrocytes as putative contributors to enhanced atherothrombosis in diabetic patients.

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Transporters, TBC1D4, and ARID5B Variants to Explain Glycated Hemoglobin Variability in Patients with Type 2 Diabetes

Pharmacology ◽

10.1159/000517462 ◽

2021 ◽

pp. 1-9

Author(s):

Vanessa Gonzalez-Covarrubias ◽

Héctor Sánchez-Ibarra ◽

Karla Lozano-Gonzalez ◽

Sergio Villicaña ◽

Tomas Texis ◽

...

Keyword(s):

Genetic Variants ◽

Glucose Control ◽

Plasma Levels ◽

Prediction Models ◽

Glycated Hemoglobin ◽

Clinical Chemistry ◽

Diabetic Patients ◽

Genetic Associations ◽

Hemoglobin Variability

Introduction: Genetic variants could aid in predicting antidiabetic drug response by associating them with markers of glucose control, such as glycated hemoglobin (HbA1c). However, pharmacogenetic implementation for antidiabetics is still under development, as the list of actionable markers is being populated and validated. This study explores potential associations between genetic variants and plasma levels of HbA1c in 100 patients under treatment with metformin. Methods: HbA1c was measured in a clinical chemistry analyzer (Roche), genotyping was performed in an Illumina-GSA array and data were analyzed using PLINK. Association and prediction models were developed using R and a 10-fold cross-validation approach. Results: We identified genetic variants on SLC47A1, SLC28A1, ABCG2, TBC1D4, and ARID5B that can explain up to 55% of the interindividual variability of HbA1c plasma levels in diabetic patients under treatment. Variants on SLC47A1, SLC28A1, and ABCG2 likely impact the pharmacokinetics (PK) of metformin, while the role of the two latter can be related to insulin resistance and regulation of adipogenesis. Conclusions: Our results confirm previous genetic associations and point to previously unassociated gene variants for metformin PK and glucose control.

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