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1.
Int J Mol Sci ; 23(5)2022 Feb 23.
Article in English | MEDLINE | ID: covidwho-1715405

ABSTRACT

The abnormal accumulation of methylglyoxal (MG) leading to increased glycation of protein and DNA has emerged as an important metabolic stress, dicarbonyl stress, linked to aging, and disease. Increased MG glycation produces inactivation and misfolding of proteins, cell dysfunction, activation of the unfolded protein response, and related low-grade inflammation. Glycation of DNA and the spliceosome contribute to an antiproliferative and apoptotic response of high, cytotoxic levels of MG. Glyoxalase 1 (Glo1) of the glyoxalase system has a major role in the metabolism of MG. Small molecule inducers of Glo1, Glo1 inducers, have been developed to alleviate dicarbonyl stress as a prospective treatment for the prevention and early-stage reversal of type 2 diabetes and prevention of vascular complications of diabetes. The first clinical trial with the Glo1 inducer, trans-resveratrol and hesperetin combination (tRES-HESP)-a randomized, double-blind, placebo-controlled crossover phase 2A study for correction of insulin resistance in overweight and obese subjects, was completed successfully. tRES-HESP corrected insulin resistance, improved dysglycemia, and low-grade inflammation. Cell permeable Glo1 inhibitor prodrugs have been developed to induce severe dicarbonyl stress as a prospective treatment for cancer-particularly for high Glo1 expressing-related multidrug-resistant tumors. The prototype Glo1 inhibitor is prodrug S-p-bromobenzylglutathione cyclopentyl diester (BBGD). It has antitumor activity in vitro and in tumor-bearing mice in vivo. In the National Cancer Institute human tumor cell line screen, BBGD was most active against the glioblastoma SNB-19 cell line. Recently, potent antitumor activity was found in glioblastoma multiforme tumor-bearing mice. High Glo1 expression is a negative survival factor in chemotherapy of breast cancer where adjunct therapy with a Glo1 inhibitor may improve treatment outcomes. BBGD has not yet been evaluated clinically. Glycation by MG now appears to be a pathogenic process that may be pharmacologically manipulated for therapeutic outcomes of potentially important clinical impact.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Glutathione/analogs & derivatives , Hesperidin/therapeutic use , Lactoylglutathione Lyase/metabolism , Neoplasms, Experimental/drug therapy , Resveratrol/therapeutic use , Animals , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/physiopathology , Drug Therapy, Combination , Enzyme Induction/drug effects , Glutathione/chemistry , Glutathione/therapeutic use , Glycosylation/drug effects , Hesperidin/chemistry , Humans , Insulin Resistance/physiology , Lactoylglutathione Lyase/antagonists & inhibitors , Mice , Molecular Structure , Neoplasms, Experimental/metabolism , Obesity/drug therapy , Obesity/metabolism , Obesity/physiopathology , Pyruvaldehyde/chemistry , Pyruvaldehyde/metabolism , Resveratrol/chemistry
2.
Int J Mol Sci ; 22(18)2021 Sep 17.
Article in English | MEDLINE | ID: covidwho-1448875

ABSTRACT

The metabolic syndrome (MetS) consists of a cluster of metabolic abnormalities including central obesity, insulin resistance, glucose intolerance, hypertension, and atherogenic dyslipidemia [...].


Subject(s)
Metabolic Syndrome/metabolism , Obesity/metabolism , Animals , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/physiopathology , Humans , Insulin Resistance/physiology , Metabolic Syndrome/physiopathology , Obesity/physiopathology
3.
J Endocrinol ; 249(1): 57-70, 2021 04.
Article in English | MEDLINE | ID: covidwho-1314460

ABSTRACT

Vaspin is a novel adipokine mainly expressed in visceral adipose tissue and closely related to obesity and insulin-resistance. Currently, data about its ovarian expression are limited to animal models and its role in human reproduction is largely unexplored. Our study's aims were then to characterise vaspin expression in the human ovary and to study in vitro its effects on granulosa cells physiology. Secondly, we assessed vaspin and its receptor GRP78 variations in granulosa cells and follicular fluid of a cohort of 112 infertile women undergoing an in vitro fertilisation procedure and allocated to three groups, each including normal-weight and obese subjects: 34 PCOS patients, 33 women with isolated polycystic ovary morphology (ECHO group) and 45 controls. Vaspin and GRP78 expression in the ovary was assessed by immunohistochemistry, RT-qPCR and Western blot. Granulosa cells and follicular fluid were analysed by RT-qPCR and ELISA, respectively. In vitro, granulosa cells metabolism was studied after stimulation with recombinant human vaspin, with and without a siRNA directed against GRP78. Vaspin was highly expressed in the human ovary and concentration-dependently enhanced granulosa cells steroidogenesis, proliferation and viability through GRP78 (P < 0.0001). Vaspin levels in both granulosa cells and follicular fluid were significantly higher in obese women (P < 0.0001) and in the normal-weight ECHO group (P < 0.001), which also had the highest expression rates of GRP78 (P < 0.05). Although further investigation is needed, vaspin appears as a novel modulator of human granulosa cells physiology and possibly plays a role in PCOS pathogenesis, notably protecting from insulin-resistance induced complications.


Subject(s)
Granulosa Cells/physiology , Heat-Shock Proteins/physiology , Polycystic Ovary Syndrome/physiopathology , Serpins/physiology , Adult , Cell Line, Tumor , Cell Proliferation/drug effects , Female , Fertilization in Vitro , Follicular Fluid/chemistry , France , Gene Expression , Granulosa Cells/chemistry , Granulosa Cells/drug effects , Heat-Shock Proteins/analysis , Heat-Shock Proteins/genetics , Humans , Infertility, Female/therapy , Insulin Resistance/physiology , Obesity/metabolism , Ovary/chemistry , Ovary/metabolism , RNA, Messenger/analysis , Serpins/genetics , Serpins/pharmacology , Steroids/biosynthesis
4.
Islets ; 13(3-4): 66-79, 2021 07 04.
Article in English | MEDLINE | ID: covidwho-1310869

ABSTRACT

The link between COVID-19 infection and diabetes has been explored in several studies since the start of the pandemic, with associations between comorbid diabetes and poorer prognosis in patients infected with the virus and reports of diabetic ketoacidosis occurring with COVID-19 infection. As such, significant interest has been generated surrounding mechanisms by which the virus may exert effects on the pancreatic ß cells. In this review, we consider possible routes by which SARS-CoV-2 may impact ß cells. Specifically, we outline data that either support or argue against the idea of direct infection and injury of ß cells by SARS-CoV-2. We also discuss ß cell damage due to a "bystander" effect in which infection with the virus leads to damage to surrounding tissues that are essential for ß cell survival and function, such as the pancreatic microvasculature and exocrine tissue. Studies elucidating the provocation of a cytokine storm following COVID-19 infection and potential impacts of systemic inflammation and increases in insulin resistance on ß cells are also reviewed. Finally, we summarize the existing clinical data surrounding diabetes incidence since the start of the COVID-19 pandemic.


Subject(s)
Insulin-Secreting Cells/physiology , SARS-CoV-2/physiology , Bystander Effect/physiology , COVID-19/complications , COVID-19/epidemiology , COVID-19/metabolism , COVID-19/physiopathology , Cytokine Release Syndrome/complications , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/metabolism , Cytokine Release Syndrome/virology , Diabetes Mellitus/immunology , Diabetes Mellitus/metabolism , Diabetes Mellitus/virology , Humans , Inflammation/complications , Inflammation/metabolism , Inflammation/virology , Insulin Resistance/physiology , Insulin-Secreting Cells/virology , Pandemics , SARS-CoV-2/pathogenicity
5.
Mol Metab ; 53: 101262, 2021 11.
Article in English | MEDLINE | ID: covidwho-1253402

ABSTRACT

OBJECTIVE: Obesity, in particular visceral obesity, and insulin resistance emerged as major risk factors for severe coronavirus disease 2019 (COVID-19), which is strongly associated with hemostatic alterations. Because obesity and insulin resistance predispose to thrombotic diseases, we investigated the relationship between hemostatic alterations and body fat distribution in participants at risk for type 2 diabetes. SUBJECTS: Body fat distribution (visceral and subcutaneous abdominal adipose tissue) and liver fat content of 150 participants - with impaired glucose tolerance and/or impaired fasting glucose - were determined using magnetic resonance imaging and spectroscopy. Participants underwent precise metabolic characterization and major hemostasis parameters were analyzed. RESULTS: Procoagulant factors (FII, FVII, FVIII, and FIX) and anticoagulant proteins (antithrombin, protein C, and protein S) were significantly associated with body fat distribution. In patients with fatty liver, fibrinogen (298 mg/dl vs. 264 mg/dl, p = 0.0182), FVII (99% vs. 90%, p = 0.0049), FVIII (114% vs. 90%, p = 0.0098), protein C (124% vs. 111%, p = 0.0006), and protein S (109% vs. 89%, p < 0.0001) were higher than in controls. In contrast, antithrombin (97% vs. 102%, p = 0.0025) was higher in control patients. In multivariate analyses controlling for insulin sensitivity, body fat compartments, and genotype variants (PNPLA3I148MM/MI/TM6SF2E167kK/kE), only protein C and protein S remained significantly increased in fatty liver. CONCLUSIONS: Body fat distribution is significantly associated with alterations of procoagulant and anticoagulant parameters. Liver fat plays a key role in the regulation of protein C and protein S, suggesting a potential counteracting mechanism to the prothrombotic state in subjects with prediabetes and fatty liver.


Subject(s)
Body Fat Distribution , COVID-19/complications , Diabetes Mellitus, Type 2/epidemiology , Fatty Liver/epidemiology , Hemostasis/physiology , Aged , COVID-19/blood , COVID-19/physiopathology , Cohort Studies , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/physiopathology , Fatty Liver/blood , Fatty Liver/diagnosis , Fatty Liver/physiopathology , Female , Humans , Insulin Resistance/physiology , Liver/diagnostic imaging , Magnetic Resonance Imaging , Male , Middle Aged , Protein C/analysis , Protein C/metabolism , Protein S/analysis , Protein S/metabolism , Randomized Controlled Trials as Topic , Risk Factors , SARS-CoV-2/pathogenicity
6.
Metabolism ; 113: 154401, 2020 12.
Article in English | MEDLINE | ID: covidwho-856999

ABSTRACT

BACKGROUND & AIMS: Angiotensin converting enzyme (ACE)-2 is a modulator of adipose tissue metabolism. However, human data of adipose ACE-2 is rarely available. Considering that, ACE-2 is believed to be the receptor responsible for cell entry of SARS-CoV-2, a better understanding of its regulation is desirable. We therefore characterized the modulation of subcutaneous adipose ACE-2 mRNA expression during weight loss and the impact of ACE-2 expression on weight loss induced short- and long-term improvements of glucose metabolism. METHODS: 143 subjects (age > 18; BMI ≥ 27 kg/m2) were analyzed before and after a standardized 12-week dietary weight reduction program. Afterwards subjects were randomized to a 12-month lifestyle intervention or a control group (Maintain-Adults trial). Insulin sensitivity (IS) was estimated by HOMA-IR (as an estimate of liver IS) and ISIClamp (as an estimate of skeletal muscle IS). ACE-2 mRNA expression (ACE-2AT) was measured in subcutaneous adipose tissue before and after weight loss. RESULTS: ACE-2AT was not affected by obesity, but was reduced in insulin resistant subjects. Weight loss resulted in a decline of ACE-2AT (29.0 (20.0-47.9) vs. 21.0 (13.0-31.0); p = 1.6 ∗ 10-7). A smaller reduction of ACE-2 AT (ΔACE-2AT) was associated with a larger improvement of ISIClamp (p = 0.013) during weight reduction over 3 months, but not with the extend of weight loss. The degree of changes in insulin resistance were preserved until month 12 and was also predicted by the weight loss induced degree of ΔACE-2AT (p = 0.011). CONCLUSIONS: Our data indicate that subcutaneous adipose ACE-2 expression correlates with insulin sensitivity. Weight loss induced decline of subcutaneous adipose ACE-2 expression might affect short- and long-term improvement of myocellular insulin sensitivity, which might be also relevant in the context of ACE-2 downregulation by SARS-CoV-2. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT00850629, https://clinicaltrials.gov/ct2/show/NCT00850629, date of registration: February 25, 2009.


Subject(s)
Adipose Tissue/metabolism , Angiotensin-Converting Enzyme 2/genetics , COVID-19/prevention & control , Weight Loss/physiology , Weight Reduction Programs , Adipose Tissue/enzymology , Adult , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/epidemiology , Caloric Restriction , Combined Modality Therapy , Exercise Therapy , Female , Gene Expression Regulation, Enzymologic , Humans , Insulin Resistance/physiology , Male , Middle Aged , Obesity/therapy , Overweight/therapy , Pandemics , SARS-CoV-2/pathogenicity
7.
J Diabetes Res ; 2020: 8205261, 2020.
Article in English | MEDLINE | ID: covidwho-852770

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic continues to cause havoc to many countries of the globe, with no end in sight, due to nonavailability of a given vaccine or treatment regimen. The pandemic has so far had a relatively limited impact on the African continent, which contributes more than 93% of global malaria burden. However, the limited burden of COVID-19 pandemic on the African region could have long-term implications on the health and wellbeing of affected inhabitants due to its malaria-endemic status. Malaria causes recurrent insulin resistance with episodes of infection at relatively low parasitaemia. Angiotensin-converting enzyme 2 (ACE2) which is widely distributed in the human body is implicated in the pathogenesis of malaria, type 2 diabetes mellitus (T2DM), and COVID-19. Use of ACE2 by the COVID-19 virus induces inflammation and oxidative stress, which can lead to insulin resistance. Although COVID-19 patients in malaria-endemic African region may not exhibit severe signs and symptoms of the disease, their risk of exhibiting heightened insulin resistance and possible future development of T2DM is high due to their prior exposure to malaria. African governments must double efforts at containing the continued spread of the virus without neglecting existing malarial control measures if the region is to avert the plausible long-term impact of the pandemic in terms of future development of T2DM.


Subject(s)
Coronavirus Infections/epidemiology , Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 2/pathology , Endemic Diseases , Malaria/epidemiology , Pneumonia, Viral/epidemiology , Africa/epidemiology , Angiotensin-Converting Enzyme 2 , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Betacoronavirus/physiology , COVID-19 , Coronavirus Infections/complications , Diabetes Mellitus, Type 2/complications , Disease Progression , Humans , Insulin Resistance/physiology , Malaria/complications , Pandemics , Peptidyl-Dipeptidase A/physiology , Pneumonia, Viral/complications , Prediabetic State/epidemiology , Prediabetic State/pathology , Prediabetic State/virology , Renin-Angiotensin System/drug effects , Renin-Angiotensin System/physiology , SARS-CoV-2
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