Melatonin and Oxidative Stress in the Diabetic State: Clinical Implications and Potential Therapeutic Applications

All living organisms exhibit circadian rhythms, which govern the majority of biological functions, including metabolic processes. Misalignment of these circadian rhythms increases the risk of developing metabolic diseases. Thus, disruption of the circadian system has been proven to affect the onset of type 2 diabetes mellitus (T2DM). In this context, the pineal indoleamine melatonin is a signaling molecule able to entrain circadian rhythms. There is mounting evidence that suggests a link between disturbances in melatonin production and impaired insulin, glucose, lipid metabolism, and antioxidant capacity. Besides, several genetic association studies have causally associated various single nucleotide polymorphysms (SNPs) of the human MT2 receptor with increased risk of developing T2DM. Taken together, these data suggest that endogenous as well as exogenous melatonin may influence diabetes and associated metabolic disturbances not only by regulating insulin secretion but also by providing protection against reactive oxygen species (ROS) since pancreatic β-cells are very susceptible to oxidative stress due to their low antioxidant capacity.

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Association of the type 2 deiodinase Thr92Ala polymorphism with type 2 diabetes: case–control study and meta-analysis

Acta Endocrinologica ◽

10.1530/eje-10-0419 ◽

2010 ◽

Vol 163 (3) ◽

pp. 427-434 ◽

Cited By ~ 73

Author(s):

José Miguel Dora ◽

Walter Escouto Machado ◽

Jakeline Rheinheimer ◽

Daisy Crispim ◽

Ana Luiza Maia

Keyword(s):

Type 2 Diabetes ◽

Case Control Study ◽

Association Studies ◽

Meta Analysis ◽

Genetic Association Studies ◽

Case Control ◽

Increased Risk ◽

Key Enzyme ◽

Control Study

ObjectiveThe type 2 deiodinase (D2) is a key enzyme for intracellular triiodothyronine (T3) generation. A single-nucleotide polymorphism in D2 (Thr92Ala) has been associated with increased insulin resistance in nondiabetic and type 2 diabetes (DM2) subjects. Our aim was to evaluate whether the D2 Thr92Ala polymorphism is associated with increased risk for DM2.Design and methodsA case–control study with 1057 DM2 and 516 nondiabetic subjects was performed. All participants underwent genotyping of the D2 Thr92Ala polymorphism. Additionally, systematic review and meta-analysis of the literature for genetic association studies of D2 Thr92Ala polymorphism and DM2 were performed in Medline, Embase, LiLacs, and SciELO, and major meeting databases using the terms ‘rs225014’ odds ratio (OR) ‘thr92ala’ OR ‘T92A’ OR ‘dio2 a/g’.ResultsIn the case–control study, the frequencies of D2 Ala92Ala homozygous were 16.4% (n=173) versus 12.0% (n=62) in DM2 versus controls respectively resulting in an adjusted OR of 1.41 (95% confidence intervals (CI) 1.03–1.94, P=0.03). The literature search identified three studies that analyzed the association of the D2 Thr92Ala polymorphism with DM2, with the following effect estimates: Mentuccia (OR 1.40 (95% CI 0.78–2.51)), Grarup (OR 1.09 (95% CI 0.92–1.29)), and Maia (OR 1.22 (95% CI 0.78–1.92)). The pooled effect of the four studies resulted in an OR 1.18 (95% CI 1.03–1.36, P=0.02).ConclusionsOur results indicate that in a case–control study, the homozygosity for D2 Thr92Ala polymorphism is associated with increased risk for DM2. These results were confirmed by a meta-analysis including 11 033 individuals, and support a role for intracellular T3 concentration in skeletal muscle on DM2 pathogenesis.

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Cardiovascular Complications in Patients with Klinefelter’s Syndrome

Current Pharmaceutical Design ◽

10.2174/1381612826666201102105408 ◽

2020 ◽

Vol 26 (43) ◽

pp. 5556-5563

Author(s):

Franz Sesti ◽

Riccardo Pofi ◽

Carlotta Pozza ◽

Marianna Minnetti ◽

Daniele Gianfrilli ◽

...

Keyword(s):

Metabolic Syndrome ◽

Klinefelter Syndrome ◽

Subclinical Atherosclerosis ◽

Cardiovascular Complications ◽

High Risk Population ◽

Metabolic Disturbances ◽

Future Studies ◽

Increased Risk ◽

Chromosome Disorder

More than 70 years have passed since the first description of Klinefelter Syndrome (KS), the most frequent chromosome disorder causing male infertility and hypogonadism. KS is associated with increased cardiovascular (CV) mortality due to several comorbidities, including hypogonadism, as well as metabolic syndrome and type 2 diabetes, which are highly prevalent in these patients. Aside from metabolic disturbances, patients with KS suffer from both acquired and congenital CV abnormalities, cerebrovascular thromboembolic disease, subclinical atherosclerosis and endothelial dysfunction, which may all contribute to increased CV mortality. The mechanisms involved in this increased risk of CV morbidity and mortality are not entirely understood. More research is needed to better characterise the CV manifestations, elucidate the pathophysiological mechanisms and define the contribution of testosterone replacement to restoring CV health in KS patients. This review explores the complex association between KS, metabolic syndrome and CV risk in order to plan future studies and improve strategies to reduce mortality in this high-risk population.

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Effects of MP Polyethylene Microparticles on Microbiome and Inflammatory Response of Larval Zebrafish

Toxics ◽

10.3390/toxics8030055 ◽

2020 ◽

Vol 8 (3) ◽

pp. 55

Author(s):

Nicholas Kurchaba ◽

Bryan J. Cassone ◽

Caleb Northam ◽

Bernadette F. Ardelli ◽

Christophe M. R. LeMoine

Keyword(s):

Oxidative Stress ◽

Inflammatory Markers ◽

Production Cost ◽

Resting Metabolic Rate ◽

Metabolic Disturbances ◽

Microbiome Composition ◽

Larval Zebrafish ◽

Living Organisms ◽

Stress Mediator ◽

And Oxidative Stress

Plastic polymers have quickly become one of the most abundant materials on Earth due to their low production cost and high versatility. Unfortunately, some of the discarded plastic can make its way into the environment and become fragmented into smaller microscopic particles, termed secondary microplastics (MP). In addition, primary MP, purposely manufactured microscopic plastic particles, can also make their way into our environment via various routes. Owing to their size and resilience, these MP can then be easily ingested by living organisms. The effect of MP particles on living organisms is suspected to have negative implications, especially during early development. In this study, we examined the effects of polyethylene MP ingestion for four and ten days of exposure starting at 5 days post-fertilization (dpf). In particular, we examined the effects of polyethylene MP exposure on resting metabolic rate, on gene expression of several inflammatory and oxidative stress linked genes, and on microbiome composition between treatments. Overall, we found no evidence of broad metabolic disturbances or inflammatory markers in MP-exposed fish for either period of time. However, there was a significant increase in the oxidative stress mediator L-FABP that occurred at 15 dpf. Furthermore, the microbiome was disrupted by MP exposure, with evidence of an increased abundance of Bacteroidetes in MP fish, a combination frequently found in intestinal pathologies. Thus, it appears that acute polyethylene MP exposure can increase oxidative stress and dysbiosis, which may render the animal more susceptible to diseases.

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Glucagon-like peptide-1 (GLP-1) Biological Role in Patients of Type 2 Diabetes and Metabolic Syndrome

The Indian Journal of Nutrition and Dietetics ◽

10.21048/ijnd.2019.56.2.20967 ◽

2019 ◽

Vol 56 (2) ◽

pp. 227

Author(s):

Mohammedziyad Abu Awad

Keyword(s):

Type 2 Diabetes ◽

Metabolic Syndrome ◽

Glucagon Secretion ◽

Diabetic Patients ◽

Metabolic Disturbances ◽

Cvd Risk ◽

First Line Therapy ◽

Increased Risk ◽

Glucagon Like Peptide 1

<p style="margin: 0in 0in 10pt; text-align: justify; line-height: 200%;">Type2 diabetes is estimated to affect 380 million people worldwide in 2025. Patients of this disease are at increased risk of cardiovascular diseases (CVD).The CVD risk is greater when diabetic patients have metabolic syndrome. Thus, the management of metabolic syndrome and CVD is crucial for diabetic patient’s life progress. GLP-1 has positive biological influences on glucose metabolism control by inhibiting glucagon secretion, enhancing insulin secretion and protecting the effects of cells. GLP-1 was also found to have other positive influences including weight loss, appetite sensation and food intake. These are important factors in metabolic disturbances control and CVD management. The paper reviewed several studies regarding the GLP-1 positive concerns. In conclusion, the paper supports the modern proposal of GLP-1 RAs as a first line therapy in initially diagnosed type 2 diabetes patients.</p>

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Type 2 diabetes-related variants influence the risk of developing multiple myeloma: results from the IMMEnSE consortium

Endocrine Related Cancer ◽

10.1530/erc-15-0029 ◽

2015 ◽

Vol 22 (4) ◽

pp. 545-559 ◽

Cited By ~ 6

Author(s):

Rafael Ríos ◽

Carmen Belén Lupiañez ◽

Daniele Campa ◽

Alessandro Martino ◽

Joaquin Martínez-López ◽

...

Keyword(s):

Type 2 Diabetes ◽

Multiple Myeloma ◽

Prediction Models ◽

Disease Risk ◽

Association Studies ◽

Area Under The Curve ◽

Genome Wide Association Studies ◽

Increased Risk ◽

Stratified Analysis

Type 2 diabetes (T2D) has been suggested to be a risk factor for multiple myeloma (MM), but the relationship between the two traits is still not well understood. The aims of this study were to evaluate whether 58 genome-wide-association-studies (GWAS)-identified common variants for T2D influence the risk of developing MM and to determine whether predictive models built with these variants might help to predict the disease risk. We conducted a case–control study including 1420 MM patients and 1858 controls ascertained through the International Multiple Myeloma (IMMEnSE) consortium. Subjects carrying the KCNQ1rs2237892T allele or the CDKN2A-2Brs2383208G/G, IGF1rs35767T/T and MADDrs7944584T/T genotypes had a significantly increased risk of MM (odds ratio (OR)=1.32–2.13) whereas those carrying the KCNJ11rs5215C, KCNJ11rs5219T and THADArs7578597C alleles or the FTOrs8050136A/A and LTArs1041981C/C genotypes showed a significantly decreased risk of developing the disease (OR=0.76–0.85). Interestingly, a prediction model including those T2D-related variants associated with the risk of MM showed a significantly improved discriminatory ability to predict the disease when compared to a model without genetic information (area under the curve (AUC)=0.645 vs AUC=0.629; P=4.05×10−06). A gender-stratified analysis also revealed a significant gender effect modification for ADAM30rs2641348 and NOTCH2rs10923931 variants (Pinteraction=0.001 and 0.0004, respectively). Men carrying the ADAM30rs2641348C and NOTCH2rs10923931T alleles had a significantly decreased risk of MM whereas an opposite but not significant effect was observed in women (ORM=0.71 and ORM=0.66 vs ORW=1.22 and ORW=1.15, respectively). These results suggest that TD2-related variants may influence the risk of developing MM and their genotyping might help to improve MM risk prediction models.

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Association of Angiotensin Converting Enzyme Insertion-Deletion Polymorphism with Hypertension in Emiratis with Type 2 Diabetes Mellitus and Its Interaction with Obesity Status

Disease Markers ◽

10.1155/2015/536041 ◽

2015 ◽

Vol 2015 ◽

pp. 1-7 ◽

Cited By ~ 6

Author(s):

Habiba Alsafar ◽

Ahmed Hassoun ◽

Shaikha Almazrouei ◽

Wala Kamal ◽

Mustafa Almaini ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Angiotensin Converting Enzyme ◽

Odds Ratio ◽

Association Studies ◽

Converting Enzyme ◽

Obesity Status ◽

Increased Risk

The association of Angiotensin Converting Enzyme (ACE) insertion-deletion (I/D) polymorphism with Type 2 Diabetes Mellitus (T2DM) and hypertension has been extensively studied throughout various ethnic populations but largely with inconsistent findings. We investigated these associations in Emirati population and their interaction with obesity status. Saliva samples were collected from a total of 564 Emiratis (277 T2DM and 297 healthy). DNA was extracted and the samples were genotyped forACEI/D polymorphism by a PCR based method followed by gel electrophoresis. Upon evaluation of theACEI/D polymorphism amongst all T2DM, hypertensive patients, and respective controls regardless of obesity status,ACEDD genotype was not found to be associated with either T2DM [odds ratio (OR) = 1.34,p=0.086] or hypertension [odd ratio (OR) = 1.02,p=0.93]. When the genetic variants amongst the nonobese and obese population were analyzed separately, the risk genotypeACEDD conferred significantly increased risk of hypertension in nonobese population [odds ratio (OR) = 1.80,p=0.02] but was found to be protective against the hypertension in the obese group ((OR) = 0.54,p=0.01). However, there was no effect of obesity status on the association ofACEgenotypes with T2DM. The risk of hypertension associated withACEDD is modulated by obesity status and hence future genetic association studies should take obesity into account for the interpretation of data. We also confirmed thatACEI/D polymorphism is not associated with T2DM risk in Emirati population.

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The Essential Element Manganese, Oxidative Stress, and Metabolic Diseases: Links and Interactions

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/7580707 ◽

2018 ◽

Vol 2018 ◽

pp. 1-11 ◽

Cited By ~ 51

Author(s):

Longman Li ◽

Xiaobo Yang

Keyword(s):

Oxidative Stress ◽

Metabolic Diseases ◽

Essential Element ◽

Ros Generation ◽

Oxygen Species ◽

Mitochondrial Oxidative Stress ◽

Nonalcoholic Fatty Liver ◽

The Past ◽

The Relationship

Manganese (Mn) is an essential element that is involved in the synthesis and activation of many enzymes and in the regulation of the metabolism of glucose and lipids in humans. In addition, Mn is one of the required components for Mn superoxide dismutase (MnSOD) that is mainly responsible for scavenging reactive oxygen species (ROS) in mitochondrial oxidative stress. Both Mn deficiency and intoxication are associated with adverse metabolic and neuropsychiatric effects. Over the past few decades, the prevalence of metabolic diseases, including type 2 diabetes mellitus (T2MD), obesity, insulin resistance, atherosclerosis, hyperlipidemia, nonalcoholic fatty liver disease (NAFLD), and hepatic steatosis, has increased dramatically. Previous studies have found that ROS generation, oxidative stress, and inflammation are critical for the pathogenesis of metabolic diseases. In addition, deficiency in dietary Mn as well as excessive Mn exposure could increase ROS generation and result in further oxidative stress. However, the relationship between Mn and metabolic diseases is not clear. In this review, we provide insights into the role Mn plays in the prevention and development of metabolic diseases.

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Oxidative Stress Applied in Diabetes Mellitus-A New Paradigm

Proceedings ◽

10.3390/proceedings2019011007 ◽

2019 ◽

Vol 11 (1) ◽

pp. 7

Author(s):

Pantea Stoian ◽

Mitrofan ◽

Colceag ◽

Serafinceanu ◽

Eftimie Totu ◽

...

Keyword(s):

Oxidative Stress ◽

Alternative Methods ◽

Biological Processes ◽

New Paradigm ◽

Medical Practitioners ◽

Complex Systems Theory ◽

Network Concept ◽

Living Organisms ◽

Pathogenic Process

Although obesity and a sedentary lifestyle are well-known risk factors for type 2 diabetes, at molecular level, the oxidative stress is regarded as the primary contributor to the pathogenic process. Our work intends to evidence how the thinking models influence the way that medical practitioners understand the pathogenic mechanisms. Some research groups focused lately on the system’s dynamics and Complex Systems Theory. The living organisms as a complex system could be analyzed applying the network concept. Alternative methods for characterizing biological processes or phenomena based on feedback node structure have been developed [1].

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Total Antioxidant Capacity and Malondialdehyde in Depressive Rotational Shift Workers

Journal of Environmental and Public Health ◽

10.1155/2013/150693 ◽

2013 ◽

Vol 2013 ◽

pp. 1-5 ◽

Cited By ~ 4

Author(s):

Farahnaz Khajehnasiri ◽

Seyed Bagher Mortazavi ◽

Abdolamir Allameh ◽

Shahin Akhondzadeh ◽

Hassan Hashemi

Keyword(s):

Oxidative Stress ◽

Standard Deviation ◽

Antioxidant Capacity ◽

Shift Work ◽

Work Experience ◽

Total Antioxidant Capacity ◽

Depression Score ◽

Shift Workers ◽

Increased Risk ◽

Total Antioxidant

Shift work is associated with sleep deprivation, occupational stress, and increased risk of depression. Depressed patients show increased oxidative stress. During excessive oxidative stress, Malondialdehyde (MDA) increases and total antioxidant capacity (TAC) decreases in body. This cross-sectional study was conducted to determine the serum level of TAC and MDA among depressed rotational shift workers in Shahid Tondooyan Tehran Oil Refinery. 21-item Beck Depression Inventory was used to measure depression level. The level of TAC and MDA was measured by 8 mL fasting blood sample. MDA was determined by thiobarbituric acid reaction. Serum total antioxidants were measured using the ABTS. Results of this study showed that TAC mean and standard deviation concentration was 2.451 (±0.536) mg/dL and MDA was 3.725 (±1.098) mic·mol/L, and mean and standard deviation of depression score and BMI were 14.07 (±3.84) and 24.92 (±3.65) kg/m2, respectively. Depression score had a positive correlation with rotational shift work experience and work experience (r=0.218andr=0.212), respectively, (P<0.05).

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The Niemann-Pick C1 Like 1 (NPC1L1) Inhibitor Ezetimibe Improves Metabolic Disease Via Decreased Liver X Receptor (LXR) Activity in Liver of Obese Male Mice

Endocrinology ◽

10.1210/en.2013-2143 ◽

2014 ◽

Vol 155 (8) ◽

pp. 2810-2819 ◽

Cited By ~ 20

Author(s):

Taichi Sugizaki ◽

Mitsuhiro Watanabe ◽

Yasushi Horai ◽

Nao Kaneko-Iwasaki ◽

Eri Arita ◽

...

Keyword(s):

Oxidative Stress ◽

Metabolic Syndrome ◽

Insulin Signaling ◽

Metabolic Diseases ◽

In Vitro Study ◽

Liver X Receptor ◽

Gene Expressions ◽

The Metabolic Syndrome ◽

Increased Risk

Dyslipidemic patients with diabetes mellitus, including metabolic syndrome, are at increased risk of coronary heart disease. It has been reported that ezetimibe, a cholesterol absorption inhibitor, improves metabolic diseases in mice and humans. However, the underlying mechanism has been unclear. Here we explored the effects of ezetimibe on lipid and glucose homeostasis. Male KK-Ay mice were fed a high-fat diet, which is the mouse model of metabolic syndrome, with or without ezetimibe for 14 weeks. Ezetimibe improved dyslipidemia, steatosis, and insulin resistance. Ezetimibe decreased hepatic oxysterols, which are endogenous agonists of liver X receptor (LXR), to decrease hepatic lipogenic gene expressions, especially in stearoyl-CoA desaturase-1 (SCD1), leading to a remarkable reduction of hepatic oleate content that would contribute to the improvement of steatosis by reducing triglycerides and cholesterol esters. Simultaneously, hepatic β-oxidation, NADPH oxidase and cytochrome P450 2E1 (CYP2E1) were reduced, and thus reactive oxygen species (ROS) and inflammatory cytokines were also decreased. Consistent with these changes, ezetimibe diminished c-Jun N-terminal kinase (JNK) phosphorylation and improved insulin signaling in the liver. In vitro study using primary hepatocytes obtained from male SD rats, treated with oleate and LXR agonist, showed excess lipid accumulation, increased oxidative stress and impaired insulin signaling. Therefore, in obese subjects, ezetimibe reduces hepatic LXR activity by reducing hepatic oxysterols to lower hepatic oleate content. This improves steatosis and reduces oxidative stress, and this reduction improves insulin signaling in the liver. These results provide insight into pathogenesis and strategies for treatment of the metabolic syndrome.

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