The blood glucose level of DM_V rats was significantly reduced, while the glucose transporter 4 (GLUT4) expression and blood microcirculation of DM_V rats were significantly enhanced in comparison to those of DM rats.
The goal of the present study is to develop a cell-based assay for identifying negative regulators of GLUT4 translocation as potential targets for the treatment of Type 2 diabetes.
However, it is currently unknown how insulin signaling targeting WNK1 regulates GLUT4 trafficking in skeletal muscle, and whether this regulation is perturbed in T2D.
Solute carrier family 2 member 4- (SLC2A4-) retinol binding protein-4- (RBP4-) phosphoenolpyruvate carboxykinase 1 (PCK1)/phosphoinositide 3-kinase (PI3K) is an adipocyte derived "signalling pathway" that may contribute to the pathogenesis of type 2 diabetes mellitus (T2DM).
To elucidate whether structural defects in the IR and/or GLUT-4 could be a primary cause of insulin resistance in NIDDM, we have sequenced the entire coding region of the GLUT-4 gene from DNA of six NIDDM patients.
The potential contributions of genetic mutation and disruption of short- or long-term regulation of glucose transporters, particularly GLUT4, in insulin-sensitive tissues to the etiology of NIDDM are examined.
Expression of the glucose transporter GLUT4, encoded by Slc2a4 gene, is reduced in both type 1 and type 2 diabetes (T1D and T2D), contributing to glycemic impairment.
The expressions of phosphatidylinositol-3-kinase (PI-3K), protein kinase B (Akt), glucose transporters-4 (GLUT4) Mrna, and p-PI-3K, p-Akt, GLUT4 protein involved in the PI-3K/Akt signaling pathway of T2DM were markedly up-regulated.
The downregulation of phosphorylation-AKT (p-AKT) and glucose transporter-4 (GLUT4) in skeletal muscle of T2DM rats was restored and abnormal pathological changes in pancreas tissues were also improved.
The aim of this study was the estimation of insulin resistance indicators and the quantitative expression of GLUT-1, GLUT-3 and GLUT-4 on peripheral blood lymphocytes in prediabetic subjects and persons with a positive family history of type 2 diabetes during 24 months of observation.
Since the insulin receptor substrate-1 (IRS-1) is the major substrate of the insulin receptor tyrosine kinase and has been shown to activate phosphatidylinositol (PI) 3-kinase and promote GLUT4 translocation, the IRS-1 gene is a potential candidate for development of non-insulin-dependent diabetes mellitus (NIDDM).
The possibility that the insulin receptor and GLUT4 may be candidate genes for inherited insulin resistance in NIDDM has been addressed with the aid of genetic screening techniques such as SSCP.
Haplotype analysis revealed that two common haplotypes H1 (111, P = 0.001, OR 1.23[1.08-1.40]) and H2 (222, P = 0.002 OR 0.73[0.59-0.89]) in STRA6, H6 (2121, P = 0.006, OR 1.69[1.51-2.48]) in RBP4 and H4 (2121, P = 0.01 OR 1.41[1.07-1.85]) in GLUT4 were associated with type 2 diabetes.
Type 2 diabetes mellitus and obesity are associated with impaired regulation of GLUT4 gene expression and elevated levels of free fatty acids and proinflammatory factors.
However, in vastus lateralis, relative amounts of GLUT4 per milligram membrane protein were similar (NS) among lean (1.0 +/- 0.2) and obese (1.5 +/- 0.3) subjects and patients with IGT (1.4 +/- 0.2) and NIDDM (1.2 +/- 0.2).
All 11 exons of the GLUT4 gene from 30 British white subjects with NIDDM were amplified using the polymerase chain reaction and screened for nucleotide sequence variation using the single-stranded conformation polymorphism (SSCP) method.
Defects in translocation of the glucose transporter GLUT4 are associated with peripheral insulin resistance, preclinical diabetes, and progression to type 2 diabetes.
Adaptation to states of enhanced metabolic demand is associated with increased glucose metabolism and GLUT4 gene expression, whereas states of insulin resistance such as type 2 diabetes mellitus (DM2), obesity, and aging are associated with impaired regulation of GLUT4 gene expression and function.
In conclusion, the uncoupling of insulin action on Akt/AS160 signaling and glucose transport implicates defective GLUT4 trafficking as an early event in the pathogenesis of type 2 diabetes.
All our results have thus highlighted the potential of Rut as both a valuable lead compound for anti-T2DM drug discovery and a promising chemical probe for GLUT4 associated pathways exploration.
In the late 1980s, when GLUT4, the major insulin-regulated glucose transporter, was identified, my lab observed that it was downregulated in adipocytes but not in skeletal muscle in insulin-resistant states, such as obesity and type 2 diabetes, in humans and rodents.