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Investigation of SLC2A1 26177A/G gene polymorphism via high resolution melting curve analysis in Malaysian patients with diabetic retinopathy

Ng ZX, Kuppusamy UR, Tajunisah I, Fong KC, Chua KH

J Diabetes Complications, 2012 Sep-Oct;26(5):388-92.
PMID: 22795339 DOI: 10.1016/j.jdiacomp.2012.05.014

PURPOSE:
In this study, we aimed to investigate the possible association between SLC2A1 26177A/G polymorphism and diabetic retinopathy (DR) in Malaysian patients with type 2 diabetes.

METHODS:
Genomic DNA was extracted from 211 Malaysian type 2 diabetic patients (100 without retinopathy [DNR], 111 with retinopathy) and 165 healthy controls. A high resolution melting assay developed in this study was used to detect SLC2A1 26177A/G polymorphism followed by statistical analysis.

RESULTS:
A statistically significant difference in 26177G minor allele frequency between healthy controls (19.7 %) and total patient group (26.1 %) (p<0.05, Odd ratio = 1.437, 95% Confidence interval = 1.015-2.035) as well as between healthy controls (19.7 %) and DNR patients (27.5%) (p<0.05, Odd ratio = 1.546, 95% Confidence interval = 1.024-2.336) was shown in this study. However, when compared between DR and DNR patients, there was no significant difference (p>0.05).

CONCLUSIONS:
This is the first study which shows that SLC2A1 26177G allele is associated with type 2 diabetes in Malaysian population but not with DR.

Matched MeSH terms: Glucose Transporter Type 1/genetics*; Glucose Transporter Type 1/metabolism
Fulltext Evaluation of Anti-proliferative Effects of Barringtonia racemosa and Gallic Acid on Caco-2 Cells

Ho IYM, Abdul Aziz A, Mat Junit S

Sci Rep, 2020 06 19;10(1):9987.
PMID: 32561807 DOI: 10.1038/s41598-020-66913-x

Barringtonia racemosa leaf water extract (BLE) had been shown to have high gallic acid (GA) content and BLE has been postulated to have anti-proliferative effects towards colorectal cancer. This study aims to further investigate the mechanism underlying the anti-proliferative effect of BLE in Caco-2 cells and to determine if GA is responsible for the observed effects. Both BLE and GA inhibited Caco-2 cells in a dose-dependent manner. Cells exposed to IC50 concentration of BLE and GA showed reduced antioxidant activities. GA-treated Caco-2 cells experienced higher oxidative stress compared to cells treated with BLE. Both BLE and GA significantly up-regulated the expression of SLC2A1. BLE but not GA, significantly down-regulated the expression of ADH4. Meanwhile, GA but not BLE, significantly up-regulated AKRIB10 and GLO1 but significantly down-regulated HAGH. Alterations in gene expression were coupled with changes in extracellular glucose and pyruvate levels. While BLE decreased intracellular pyruvate, GA did the opposite. Both intracellular and extracellular D-lactate were not affected by either BLE or GA. GA showed more pronounced effects on apoptosis while BLE irreversibly reduced cell percentage in the G0/G1 phase. In conclusion, this study demonstrates the multiple-actions of BLE against Caco-2 cells, potentially involving various polyphenolic compounds, including GA.

Matched MeSH terms: Glucose Transporter Type 1/metabolism
Fulltext Momordica charantia Suppresses Inflammation and Glycolysis in Lipopolysaccharide-Activated RAW264.7 Macrophages

Lee SY, Wong WF, Dong J, Cheng KK

Molecules, 2020 Aug 20;25(17).
PMID: 32825228 DOI: 10.3390/molecules25173783

Macrophage activation is a key event that triggers inflammatory response. The activation is accompanied by metabolic shift such as upregulated glucose metabolism. There are accumulating evidences showing the anti-inflammatory activity of Momordica charantia. However, the effects of M. charantia on inflammatory response and glucose metabolism in activated macrophages have not been fully established. The present study aimed to examine the effect of M. charantia in modulating lipopolysaccharide (LPS)-induced inflammation and perturbed glucose metabolism in RAW264.7 murine macrophages. The results showed that LPS-induced NF-κB (p65) nuclear translocation was inhibited by M. charantia treatment. In addition, M. charantia was found to reduce the expression of inflammatory genes including IL6, TNF-α, IL1β, COX2, iNOS, and IL10 in LPS-treated macrophages. Furthermore, the data showed that M. charantia reduced the expression of GLUT1 and HK2 genes and lactate production (-28%), resulting in suppression of glycolysis. Notably, its effect on GLUT1 gene expression was found to be independent of LPS-induced inflammation. A further experiment also indicated that the bioactivities of M. charantia may be attributed to its key bioactive compound, charantin. Taken together, the study provided supporting evidences showing the potential of M. charantia for the treatment of inflammatory disorders.

Matched MeSH terms: Glucose Transporter Type 1/biosynthesis
Fulltext Development of a novel in vitro insulin resistance model in primary human tenocytes for diabetic tendinopathy research

Tan HY, Tan SL, Teo SH, Roebuck MM, Frostick SP, Kamarul T

PeerJ, 2020;8:e8740.
PMID: 32587790 DOI: 10.7717/peerj.8740

Background: Type 2 diabetes mellitus (T2DM) had been reported to be associated with tendinopathy. However, the underlying mechanisms of diabetic tendinopathy still remain largely to be discovered. The purpose of this study was to develop insulin resistance (IR) model on primary human tenocytes (hTeno) culture with tumour necrosis factor-alpha (TNF-α) treatment to study tenocytes homeostasis as an implication for diabetic tendinopathy.
Methods: hTenowere isolated from human hamstring tendon. Presence of insulin receptor beta (INSR-β) on normal tendon tissues and the hTeno monolayer culture were analyzed by immunofluorescence staining. The presence of Glucose Transporter Type 1 (GLUT1) and Glucose Transporter Type 4 (GLUT4) on the hTeno monolayer culture were also analyzed by immunofluorescence staining. Primary hTeno were treated with 0.008, 0.08, 0.8 and 8.0 µM of TNF-α, with and without insulin supplement. Outcome measures include 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-d-glucose (2-NBDG) assay to determine the glucose uptake activity; colourimetric total collagen assay to quantify the total collagen expression levels; COL-I ELISA assay to measure the COL-I expression levels and real-time qPCR to analyze the mRNA gene expressions levels of Scleraxis (SCX), Mohawk (MKX), type I collagen (COL1A1), type III collagen (COL3A1), matrix metalloproteinases (MMP)-9 and MMP-13 in hTeno when treated with TNF-α. Apoptosis assay for hTeno induced with TNF-α was conducted using Annexin-V FITC flow cytometry analysis.
Results: Immunofluorescence imaging showed the presence of INSR-β on the hTeno in the human Achilles tendon tissues and in the hTeno in monolayer culture. GLUT1 and GLUT4 were both positively expressed in the hTeno. TNF-α significantly reduced the insulin-mediated 2-NBDG uptake in all the tested concentrations, especially at 0.008 µM. Total collagen expression levels and COL-I expression levels in hTeno were also significantly reduced in hTeno treated with 0.008 µM of TNF-α. The SCX, MKX and COL1A1 mRNA expression levels were significantly downregulated in all TNF-α treated hTeno, whereas the COL3A1, MMP-9 and MMP-13 were significantly upregulated in the TNF-α treated cells. TNF-α progressively increased the apoptotic cells at 48 and 72 h.
Conclusion: At 0.008 µM of TNF-α, an IR condition was induced in hTeno, supported with the significant reduction in glucose uptake, as well as significantly reduced total collagen, specifically COL-I expression levels, downregulation of candidate tenogenic markers genes (SCX and MKX), and upregulation of ECM catabolic genes (MMP-9 and MMP-13). Development of novel IR model in hTeno provides an insight on how tendon homeostasis could be affected and can be used as a tool for further discovering the effects on downstream molecular pathways, as the implication for diabetic tendinopathy.

Matched MeSH terms: Glucose Transporter Type 1
Fulltext Animal Models of Metabolic Epilepsy and Epilepsy Associated Metabolic Dysfunction: A Systematic Review

Kundap UP, Paudel YN, Shaikh MF

Pharmaceuticals (Basel), 2020 May 26;13(6).
PMID: 32466498 DOI: 10.3390/ph13060106

Epilepsy is a serious neurological disorder affecting around 70 million people globally and is characterized by spontaneous recurrent seizures. Recent evidence indicates that dysfunction in metabolic processes can lead to the alteration of neuronal and network excitability, thereby contributing to epileptogenesis. Developing a suitable animal model that can recapitulate all the clinical phenotypes of human metabolic epilepsy (ME) is crucial yet challenging. The specific environment of many symptoms as well as the primary state of the applicable neurobiology, genetics, and lack of valid biomarkers/diagnostic tests are the key factors that hinder the process of developing a suitable animal model. The present systematic review summarizes the current state of available animal models of metabolic dysfunction associated with epileptic disorders. A systematic search was performed by using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) model. A range of electronic databases, including google scholar, Springer, PubMed, ScienceDirect, and Scopus, were scanned between January 2000 and April 2020. Based on the selection criteria, 23 eligible articles were chosen and are discussed in the current review. Critical analysis of the selected literature delineated several available approaches that have been modeled into metabolic epilepsy and pointed out several drawbacks associated with the currently available models. The result describes available models of metabolic dysfunction associated with epileptic disorder, such as mitochondrial respiration deficits, Lafora disease (LD) model-altered glycogen metabolism, causing epilepsy, glucose transporter 1 (GLUT1) deficiency, adiponectin responsive seizures, phospholipid dysfunction, glutaric aciduria, mitochondrial disorders, pyruvate dehydrogenase (PDH) α-subunit gene (PDHA1), pyridoxine dependent epilepsy (PDE), BCL2-associated agonist of cell death (BAD), Kcna1 knock out (KO), and long noncoding RNAs (lncRNA) cancer susceptibility candidate 2 (lncRNA CASC2). Finally, the review highlights certain focus areas that may increase the possibilities of developing more suitable animal models and underscores the importance of the rationalization of animal models and evaluation methods for studying ME. The review also suggests the pressing need of developing precise robust animal models and evaluation methods for investigating ME.

Matched MeSH terms: Glucose Transporter Type 1
Fulltext Amelioration of mitochondrial dysfunction-induced insulin resistance in differentiated 3T3-L1 adipocytes via inhibition of NF-κB pathways

Bakar MH, Sarmidi MR, Kai CK, Huri HZ, Yaakob H

Int J Mol Sci, 2014 Dec 02;15(12):22227-57.
PMID: 25474091 DOI: 10.3390/ijms151222227

A growing body of evidence suggests that activation of nuclear factor kappa B (NF-κB) signaling pathways is among the inflammatory mechanism involved in the development of insulin resistance and chronic low-grade inflammation in adipose tissues derived from obese animal and human subjects. Nevertheless, little is known about the roles of NF-κB pathways in regulating mitochondrial function of the adipose tissues. In the present study, we sought to investigate the direct effects of celastrol (potent NF-κB inhibitor) upon mitochondrial dysfunction-induced insulin resistance in 3T3-L1 adipocytes. Celastrol ameliorates mitochondrial dysfunction by altering mitochondrial fusion and fission in adipocytes. The levels of oxidative DNA damage, protein carbonylation and lipid peroxidation were down-regulated. Further, the morphology and quantification of intracellular lipid droplets revealed the decrease of intracellular lipid accumulation with reduced lipolysis. Moreover, massive production of the pro-inflammatory mediators tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were markedly depleted. Insulin-stimulated glucose uptake activity was restored with the enhancement of insulin signaling pathways. This study signified that the treatments modulated towards knockdown of NF-κB transcription factor may counteract these metabolic insults exacerbated in our model of synergy between mitochondrial dysfunction and inflammation. These results demonstrate for the first time that NF-κB inhibition modulates mitochondrial dysfunction induced insulin resistance in 3T3-L1 adipocytes.

Matched MeSH terms: Glucose Transporter Type 1/metabolism
Metformin mitigates impaired testicular lactate transport/utilisation and improves sexual behaviour in streptozotocin-induced diabetic rats

Nna VU, Abu Bakar AB, Ahmad A, Mohamed M

Arch Physiol Biochem, 2021 Feb;127(1):51-60.
PMID: 31072137 DOI: 10.1080/13813455.2019.1610778

CONTEXT: Lactate is the preferred energy substrate for developing testicular germ cells. Diabetes is associated with impaired testicular lactate transport/utilisation, and poor sexual behaviour.
OBJECTIVE: To examine the effects of metformin on parameters involved in testicular lactate production, transport/utilisation, and sexual behaviour in diabetic state.
METHODS: Male Sprague-Dawley rats were assigned into normal control (NC), diabetic control (DC), and metformin-treated diabetic group (n = 6/group). Metformin (300 mg/kg b.w./day) was administrated orally for 4 weeks.
RESULTS: Intra-testicular glucose and lactate levels, and lactate dehydrogenase (LDH) activity increased, while the mRNA transcript levels of genes responsible for testicular glucose and lactate transport/utilisation (glucose transporter 3, monocarboxylate transporter 4 (MCT4), MCT2, and LDH type C) decreased in DC group. Furthermore, penile nitric oxide increased, while cyclic guanosine monophosphate decreased, with impaired sexual behaviour in DC group. Treatment with metformin improved these parameters.
CONCLUSIONS: Metformin increases testicular lactate transport/utilisation and improves sexual behaviour in diabetic state.

Matched MeSH terms: Glucose Transporter Type 1/biosynthesis
Lauric acid alleviates insulin resistance by improving mitochondrial biogenesis in THP-1 macrophages

Tham YY, Choo QC, Muhammad TST, Chew CH

Mol Biol Rep, 2020 Dec;47(12):9595-9607.
PMID: 33259010 DOI: 10.1007/s11033-020-06019-9

Mitochondrial dysfunction plays a crucial role in the central pathogenesis of insulin resistance and type 2 diabetes mellitus. Macrophages play important roles in the pathogenesis of insulin resistance. Lauric acid is a 12-carbon medium chain fatty acid (MCFA) found abundantly in coconut oil or palm kernel oil and it comes with multiple beneficial effects. This research objective was to uncover the effects of the lauric acid on glucose uptake, mitochondrial function and mitochondrial biogenesis in insulin-resistant macrophages. THP-1 monocytes were differentiated into macrophages and induce insulin resistance, before they were treated with increasing doses of lauric acid (5 μM, 10 μM, 20 μM, and 50 μM). Glucose uptake assay, cellular ROS and ATP production assays, mitochondrial content and membrane potential assay were carried out to analyse the effects of lauric acid on insulin resistance and mitochondrial biogenesis in the macrophages. Quantitative RT-PCR (qRT-PCR) and western blot analysis were also performed to determine the expression of the key regulators. Insulin-resistant macrophages showed lower glucose uptake, GLUT-1 and GLUT-3 expression, and increased hallmarks of mitochondrial dysfunction. Interestingly, lauric acid treatment upregulated glucose uptake, GLUT-1 and GLUT-3 expressions. The treatment also restored the mitochondrial biogenesis in the insulin-resistant macrophages by improving ATP production, oxygen consumption, mitochondrial content and potential, while it promoted the expression of mitochondrial biogenesis regulator genes such as TFAM, PGC-1α and PPAR-γ. We show here that lauric acid has the potential to improve insulin sensitivity and mitochondrial dysregulation in insulin-resistant macrophages.

Matched MeSH terms: Glucose Transporter Type 1/genetics; Glucose Transporter Type 1/metabolism