Drugs online research references
Br J Pharmacol. 2002 Oct;137(3):329-36.
Metformin enhances insulin signalling in insulin-dependent and-independent pathways in insulin resistant muscle cells.
Kumar N, Dey CS.
Signal Transduction Research Laboratory, Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Punjab, India.
1 Metformin lowers blood glucose levels in type 2 diabetic patients. To evaluate the insulin sensitizing action of metformin on skeletal muscle cells, we have used C2C12 skeletal muscle cells differentiated in chronic presence or absence of insulin. 2 Metformin was added during the last 24 h of differentiation of the C2C12 myotubes. Insulin-stimulated tyrosine phosphorylation of insulin receptor (IR) and insulin receptor substrate-1 (IRS-1) was determined. 3 Chronic insulin treatment resulted in 60 and 40% reduction in insulin-stimulated tyrosine phosphorylation of IR and IRS-1, respectively. Treatment with metformin was able to increase the tyrosine phosphorylation of IR and IRS-1 by 100 and 90% respectively. 4 Chronic insulin treatment drastically reduced (45%) insulin-stimulated phosphatidyl inositol 3-kinase (PI 3-kinase) activity. Metformin treatment restored PI 3-kinase activity in insulin-resistant myotubes. 5 Insulin-stimulated glucose uptake was impaired in chronically insulin-treated myotubes. Metformin increased basal glucose uptake to significant levels (P<0.05), but metformin did not increase insulin-stimulated glucose transport. 6 All the three mitogen-activated protein kinases (MAPK) were activated by insulin in sensitive myotubes. The activation of p38 MAPK was impaired in resistant myotubes, while ERK and JNK were unaffected. Treatment with metformin enhanced the basal activation levels of p38 in both sensitive and resistant myotubes, but insulin did not further stimulate p38 activation in metformin treated cells. 7 Treatment of cells with p38 inhibitor, SB203580, blocked insulin- and metformin-stimulated glucose uptake as well as p38 activation. 8 Since the effect of metformin on glucose uptake corresponded to p38 MAPK activation, this suggests the potential role p38 in glucose uptake. 9 These data demonstrate the direct insulin sensitizing action of metformin on skeletal muscle cells.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12237252&dopt=Abstract
J Clin Invest. 1992 Oct;90(4):1386-95.
Glucose transport in human skeletal muscle cells in culture. Stimulation by insulin and metformin.
Sarabia V, Lam L, Burdett E, Leiter LA, Klip A.
Division of Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada.
Primary human muscle cell cultures were established and the regulation of glucose transport was investigated. Primary cultures were allowed to proceed to the stage of myotubes through fusion of myoblasts or were used for clonal selection based on fusion potential. In clonally selected cultures, hexose (2-deoxy-glucose) uptake into myotubes was linear within the time of study and inhibitable by cytochalasin B (IC50 = 400 nM). Cytochalasin B photolabeled a protein(s) of 45,000-50,000 D in a D-glucose-protectable manner, suggesting identity with the glucose transporters. In the myotube stage, the cells expressed both the GLUT1 and GLUT4 glucose transporter protein isoforms at an average molar ratio of 7:1. Preincubation in media of increasing glucose concentrations (range 5-25 mM) progressively decreased the rate of 2-deoxyglucose uptake. Insulin elevated 2-deoxyglucose uptake in a dose-dependent manner, with half maximal stimulation achieved at 3.5 nM. Insulin also stimulated the transport of the nonmetabolizable hexose 3-O-methylglucose, as well as the activity of glycogen synthase, responsible for nonoxidative glucose metabolism. The oral antihyperglycemic drug metformin stimulated the cytochalasin B-sensitive component of both 2-deoxyglucose and 3-O-methylglucose uptake. Maximal stimulation was observed at 8 h of exposure to 50 microM metformin, and this effect was not prevented by incubation with the protein-synthesis inhibitor cycloheximide. The relative effect of metformin was higher in cells incubated in 25 mM glucose than in 5 mM glucose, consistent with its selective action in hyperglycemic conditions in vivo. Metformin (50 microM for 24 h) was more effective than insulin (1 microM for 1 h) in stimulating hexose uptake and the hormone was effective on top of the stimulation caused by the biguanide, suggesting independent mechanisms of action.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1401073&dopt=Abstract
Diabete Metab. 1976 Dec;2(4):187-90.
Vitamin B 12 and folic acid serum levels in diabetics under various therapeutic regimens.
Carpentier JL, Bury J, Luyckx A, Lefebvre P.
The aim of the present study was to reconsider the problem of the haematological consequences of biguanide treatment by evaluating serum vitamin B 12 and folic acid levels as well as classical haematological parameters in 30 diabetics treated by metformin. For purpose of comparison, similar evaluations were done in diabetics treated with insulin (27 patients) or sulfonylureas (13 patients). Results indicated that mean serum levels of vitamin B 12 were significantly lower in patients receiving metformin than in both other groups. In the metformin-treated group, five patients had serum levels of vitamin B 12 below 270 pg/ml and five had borderline values. No difference was found in the mean serum folic acid levels between the three groups. Similarly, there were no differences in the red blood cell counts, volumes or haemoglogin concentrations nor in the mean values of serum iron and lacticodeshydrogenase levels between the three groups. Since the haematologic and neurologic complications of vitamin B 12 deficiency may only appear after the deficiency had existed for 10-15 years, the lack of haematological alteration may be explained by the fact that the vitamin B 12 deficiency was not present for a sufficient period of time. We conclude that it may be wise to monitor the haematological values as well as vitamin B 12 levels at regular intervals in diabetic patients treated with metformin so that B 12 hypovitaminosis and its complications can be prevented.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1017538&dopt=Abstract
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