Well, I disagree with the fact that metformin would disable GLUT4 hexose transport, on the contraire, it enhances it.Nevertheless, Thiazolidinediones does that also, and have their PRIMARY effect on insulin muscle and fat receptors, while metformin primarily reduces liver glucose output and secondarily acts as insulin receptor enhancer. I will start a HGH 4 UI 5 days on/ 2 off plus pioglitazone 30mg/ day plus ALA 900 mg day, and I think it will be very effective .
Metformin interaction with insulin-regulated glucose uptake, using the Xenopus laevis oocyte model expressing the mammalian transporter GLUT4.
Detaille D - Eur J Pharmacol - 14-Jul-1999; 377(1): 127-36
From NIH/NLM MEDLINE
NLM Citation ID:
10448935 (PubMed}
99376165 (MEDLINE)
Full Source Title:
European Journal of Pharmacology
Publication Type:
Journal Article
Language:
English
Author Affiliation:
Laboratory of Comparative Biochemistry and Physiology, Facultés Universitaires Notre-Dame de la Paix, Namur, Belgium.
[email protected]
Authors:
Detaille D; Wiernsperger N; Devos P
Abstract:
The primary goal of this work was to better define, in molecular terms, the impact of metformin on hexose carriers. The methodology consisted of determining the zero-trans kinetics of 2-deoxy-D-glucose uptake for the mammalian insulin-sensitive glucose transporter (GLUT4) expressed in Xenopus laevis oocytes.
These cells possessed the specialized protein and, when treated with insulin (2 microM) plus metformin (20 microM), showed a markedly enhanced hexose transport activity (2.4-fold increase over basal) as compared to that of cells incubated in the presence of insulin alone (1.8-fold increase over basal)
. Kinetic analysis of this process revealed that insulin induced a similar response to that observed for the native carrier, i.e., a higher Vmax. When metformin was added together with insulin, we mainly recorded a significant decrease in apparent Km for the sugar transported, Vmax being only marginally modified. Parathyroid hormone (PTH), which is known to impair the intrinsic activity of GLUT4, prevented the stimulatory effect of metformin in both kinds of oocytes whereas cytochalasin D, which interferes with the translocation of carriers, was without effect.
These results suggest that metformin combined with insulin can maintain glucose homeostasis by increasing the catalytic activity of some hexose carriers or by improving the affinity of GLUT4 for glucose.
Chronic insulin effects on insulin signalling and GLUT4 endocytosis are reversed by metformin.
Pryor PR - Biochem J - 15-May-2000; 348 Pt 1: 83-91
From NIH/NLM MEDLINE
NLM Citation ID:
10794717 (PubMed}
20256767 (MEDLINE)
Full Source Title:
Biochemical Journal
Publication Type:
Journal Article
Language:
English
Author Affiliation:
Department of Biology and Biochemistry, University of Bath, UK.
Authors:
Pryor PR; Liu SC; Clark AE; Yang J; Holman GD; Tosh D
Abstract:
Decreases in insulin-responsive glucose transport and associated levels of cell surface GLUT4 occur in rat adipocytes maintained in culture for 20 h under hyperinsulinaemic and hyperglycaemic conditions. We have investigated whether this defect is due to reduced signalling from the insulin receptor, GLUT4 expression or impaired GLUT4 trafficking.
The effects of chronic insulin treatment on glucose transport and GLUT4 trafficking were ameliorated by inclusion of metformin in the culture medium.
In comparison with the ic insulin treatment attenuated changes in signalling processes leading to glucose transport. These included insulin receptor tyrosine phosphorylation, phosphoinositide 3-kinase activity and Akt activity, which were all reduced by 60-70%. Inclusion of metformin in the culture medium prevented the effects of the chronic insulin treatment on these signalling processes. In comparison with cells maintained in culture without insulin, the total expression of GLUT4 protein was not significantly altered by chronic insulin treatment, although the level of GLUT1 expression was increased. Trafficking rate constants for wortmannin-induced cell-surface loss of GLUT4 and GLUT1 were assessed by 2-N-4-(1-azi-2, 2,2-trifluoroethyl)benzoyl-1,3-bis(D-mannose-4-yloxy)-2-propyla min e (ATB-BMPA) photolabelling. In comparison with cells acutely treated with insulin, chronic insulin treatment resulted in a doubling of the rate constants for GLUT4 endocytosis. These results suggest that the GLUT4 endocytosis process is very sensitive to the perturbations in signalling that occur under hyperinsulinaemic and hyperglycaemic conditions, and that the resulting elevation of endocytosis accounts for the reduced levels of net GLUT4 translocation observed
Troglitazone not only increases GLUT4 but also induces its translocation in rat adipocytes.
Shintani M - Diabetes - 01-Oct-2001; 50(10): 2296-300
From NIH/NLM MEDLINE
NLM Citation ID:
11574411 (PubMed}
21458369 (MEDLINE)
Full Source Title:
Diabetes
Publication Type:
Journal Article
Language:
English
Author Affiliation:
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Authors:
Shintani M; Nishimura H; Yonemitsu S; Ogawa Y; Hayashi T; Hosoda K; Inoue G; Nakao K
Abstract:
Thiazolidinediones, insulin-sensitizing agents, have been reported to increase glucose uptake along with the expression of glucose transporters in adipocytes and cardiomyocytes. Recently, we have further suggested that the translocation of GLUT4 is stimulated by thiazolidinediones in L6 myocytes. However, the direct effects of thiazolidinediones on translocation of glucose transporters have not yet been determined. In this study, using hemagglutinin epitope-tagged GLUT4 (GLUT4-HA), we provide direct evidence of the effect of troglitazone on the translocation of GLUT4 in rat epididymal adipocytes. Primary cultures of rat adipocytes were transiently transfected with GLUT4-HA and overexpressed eightfold compared with endogenous GLUT4 in transfected cells. A total of 24 h of treatment with troglitazone (10(-4) mol/l) increased the cell surface level of GLUT4-HA by 1.5 +/- 0.03-fold (P < 0.01) without changing the total amount of GLUT4-HA, whereas it increased the protein level of endogenous GLUT4 (1.4-fold) without changing that of GLUT1. Thus, the direct effect on the translocation can be detected apart from the increase in endogenous GLUT4 content using GLUT4-HA. Troglitazone not only increased the translocation of GLUT4-HA on the cell surface in the basal state but also caused a leftward shift in the dose-response relations between GLUT4-HA translocation and insulin concentration in the medium (ED(50): from approximately 0.1 to 0.03 nmol/l). These effects may partly contribute to the antidiabetic activity of troglitazone in patients with obesity and type 2 diabetes.
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