Polyol accumulation in muscle and liver in a mouse model of type 2 diabetes

Gallagher, Emily J.; LeRoith, Derek; Stasinopoulos, Marilyn; Zelenko, Zara; Shiloach, Joseph

doi:10.1016/j.jdiacomp.2016.04.019

Cited by 19 publications

(10 citation statements)

References 43 publications

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“…A reduction in available NADPH, due to the overutilization of the Polyol Pathway, significantly decreases GSH levels and thus limits the ROS-scavenging activity of GSH, and further increases ROS levels [14]. A diabetic mouse model (MKR) vs. control study performed in 2010 revealed sorbitol levels 2.5 times higher in MKR when compared to a control Also found was 1.7 times lower levels of the reduced glutathione (rGSH) in skeletal muscle [15]. Therefore, it is understood that the overutilization of the polyol pathway due to glucose excess is a major source of oxidative stress, by limiting the recycling of GSH via GSR induced by diabetes.…”

Section: Pathogenesis In T2dmmentioning

confidence: 99%

Type 2 Diabetes Mellitus and Altered Immune System Leading to Susceptibility to Pathogens, Especially Mycobacterium tuberculosis

Ferlita

Yegiazaryan

Noori

et al. 2019

JCM

117

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There has been an alarming increase in the incidence of Type 2 Diabetes Mellitus (T2DM) worldwide. Uncontrolled T2DM can lead to alterations in the immune system, increasing the risk of susceptibility to infections such as Mycobacterium tuberculosis (M. tb). Altered immune responses could be attributed to factors such as the elevated glucose concentration, leading to the production of Advanced Glycation End products (AGE) and the constant inflammation, associated with T2DM. This production of AGE leads to the generation of reactive oxygen species (ROS), the use of the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) via the Polyol pathway, and overall diminished levels of glutathione (GSH) and GSH-producing enzymes in T2DM patients, which alters the cytokine profile and changes the immune responses within these patients. Thus, an understanding of the intricate pathways responsible for the pathogenesis and complications in T2DM, and the development of strategies to enhance the immune system, are both urgently needed to prevent co-infections and co-morbidities in individuals with T2DM.

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Section: Pathogenesis In T2dmmentioning

confidence: 99%

Type 2 Diabetes Mellitus and Altered Immune System Leading to Susceptibility to Pathogens, Especially Mycobacterium tuberculosis

Ferlita

Yegiazaryan

Noori

et al. 2019

JCM

117

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“…During this course of non-diffusive behavior of sorbitol, intra-cellular accumulation of sorbitol initiates, leading to occurrences of osmotic stress [67,116]. Further, with the exhaustive analysis of early studies it was revealed that sorbitol is converted to fructose via sorbitol dehydrogenase, with NAD+ getting reduced to NADH.…”

Section: Retinopathy and Candidate Genesmentioning

confidence: 99%

Genetic and epigenetic modifications in the pathogenesis of diabetic retinopathy: a molecular link to regulate gene expression

Pradhan¹,

Upadhyay²,

Tiwari³

et al. 2016

New Front Ophthalmol

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Intensification in the frequency of diabetes and the associated vascular complications has been a root cause of blindness and visual impairment worldwide. One such vascular complication which has been the prominent cause of blindness; retinal vasculature, neuronal and glial abnormalities is diabetic retinopathy (DR), a chronic complicated outcome of Type 1 and Type 2 diabetes. It has also become clear that “genetic” variations in population alone can’t explain the development and progression of diabetes and its complications including DR. DR experiences engagement of foremost mediators of diabetes such as hyperglycemia, oxidant stress, and inflammatory factors that lead to the dysregulation of “epigenetic” mechanisms involving histone acetylation and histone and DNA methylation, chromatin remodeling and expression of a complex set of stress-regulated and disease-associated genes. In addition, both elevated glucose concentration and insulin resistance leave a robust effect on epigenetic reprogramming of the endothelial cells too, since endothelium associated with the eye aids in maintaining the vascular homeostasis. Furthermore, several studies conducted on the disease suggest that the modifications of the epigenome might be the fundamental mechanism(s) for the proposed metabolic memory’ resulting into prolonged gene expression for inflammation and cellular dysfunction even after attaining the glycemic control in diabetics. Henceforth, the present review focuses on the aspects of genetic and epigenetic alterations in genes such as vascular endothelial growth factor and aldose reductase considered being associated with DR. In addition, we discuss briefly the role of the thioredoxin-interacting protein TXNIP, which is strongly induced by high glucose and diabetes, in cellular oxidative stress and mitochondrial dysfunction potentially leading to chromatin remodeling and ocular complications of diabetes. The identification of disease-associated genes and their epigenetic regulations will lead to potential new drugs and gene therapies as well as personalized medicine to prevent or slow down the progression of DR.

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“…Subsequently, sorbitol may convert to fructose by sorbitol dehydrogenase [77]. A similar spill-over effect of glycolysis has been established as an ancillary pathway in type 2 diabetes mellitus [77][78][79][80]. Increased activity of the polyol pathway was also reported in other liver diseases such as Wilson's disease that is characterized by copper accumulation in the liver and other organs [81].…”

Section: Discussionmentioning

confidence: 75%

Sugar Alcohols Have a Key Role in Pathogenesis of Chronic Liver Disease and Hepatocellular Carcinoma in Whole Blood and Liver Tissues

Ismail

Fiehn

Elfert

et al. 2020

Cancers

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The major risk factors for hepatocellular carcinoma (HCC) are hepatitis C and B viral infections that proceed to Chronic Liver Disease (CLD). Yet, the early diagnosis and treatment of HCC are challenging because the pathogenesis of HCC is not fully defined. To better understand the onset and development of HCC, untargeted GC-TOF MS metabolomics data were acquired from resected human HCC tissues and their paired non-tumor hepatic tissues (n = 46). Blood samples of the same HCC subjects (n = 23) were compared to CLD (n = 15) and healthy control (n = 15) blood samples. The participants were recruited from the National Liver Institute in Egypt. The GC-TOF MS data yielded 194 structurally annotated compounds. The most strikingly significant alteration was found for the class of sugar alcohols that were up-regulated in blood of HCC patients compared to CLD subjects (p < 2.4 × 10−12) and CLD compared to healthy controls (p = 4.1 × 10−7). In HCC tissues, sugar alcohols were the most significant (p < 1 × 10−6) class differentiating resected HCC tissues from non-malignant hepatic tissues for all HCC patients. Alteration of sugar alcohol levels in liver tissues also defined early-stage HCC from their paired non-malignant hepatic tissues (p = 2.7 × 10−6). In blood, sugar alcohols differentiated HCC from CLD subjects with an ROC-curve of 0.875 compared to 0.685 for the classic HCC biomarker alpha-fetoprotein. Blood sugar alcohol levels steadily increased from healthy controls to CLD to early stages of HCC and finally, to late-stage HCC patients. The increase in sugar alcohol levels indicates a role of aldo-keto reductases in the pathogenesis of HCC, possibly opening novel diagnostic and therapeutic options after in-depth validation.

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Polyol accumulation in muscle and liver in a mouse model of type 2 diabetes

Cited by 19 publications

References 43 publications

Type 2 Diabetes Mellitus and Altered Immune System Leading to Susceptibility to Pathogens, Especially Mycobacterium tuberculosis

Type 2 Diabetes Mellitus and Altered Immune System Leading to Susceptibility to Pathogens, Especially Mycobacterium tuberculosis

Genetic and epigenetic modifications in the pathogenesis of diabetic retinopathy: a molecular link to regulate gene expression

Sugar Alcohols Have a Key Role in Pathogenesis of Chronic Liver Disease and Hepatocellular Carcinoma in Whole Blood and Liver Tissues

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