Stimulation of the intracellular portion of the human insulin receptor by the antidiabetic drug metformin

Stith, Bradley J.; Woronoff, Keith; Wiernsperger, Nicolas

doi:10.1016/s0006-2952(97)00540-6

Cited by 32 publications

(22 citation statements)

References 13 publications

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“…Indeed, the interest in such reagents and, by inference, suitable assays for their identification, is large. During the past few years, for example, increased efforts were undertaken to find insulin mimetic substances (32)(33)(34), or inhibitors and activators of insulin receptor-regulating phosphatases (35,36). In addition, since it is known that STAT5 activity is dependent on Tyr960, inhibitors which selectively block phosphorylation of this specific part of the IR receptor (37) or block phosphotyrosine-binding domains of interacting proteins (38) could be screened.…”

Section: Resultsmentioning

confidence: 99%

A Cellular Reporter Assay to Monitor Insulin Receptor Kinase Activity Based on STAT 5-Dependent Luciferase Gene Expression

Störz

Döppler

Horn-Müller

et al. 1999

Analytical Biochemistry

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Section: Resultsmentioning

confidence: 99%

A Cellular Reporter Assay to Monitor Insulin Receptor Kinase Activity Based on STAT 5-Dependent Luciferase Gene Expression

Störz

Döppler

Horn-Müller

et al. 1999

Analytical Biochemistry

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“…There is some evidence that metformin might increase glucose uptake by stimulating insulin receptor signaling. For example, in erythrocytes (50,51), monocytes (52), fat cells (53), and Xenopus oocytes (54,55), metformin increases insulin receptor binding (50,52,53) and tyrosine kinase activity (51,54,55). However, because these cells are not the main target of metformin's action, the clinical importance of these findings is uncertain.…”

Section: Discussionmentioning

confidence: 99%

Metformin Increases AMP-Activated Protein Kinase Activity in Skeletal Muscle of Subjects With Type 2 Diabetes

et al. 2002

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Metformin is an effective hypoglycemic drug that lowers blood glucose concentrations by decreasing hepatic glucose production and increasing glucose disposal in skeletal muscle; however, the molecular site of metformin action is not well understood. AMP-activated protein kinase (AMPK) activity increases in response to depletion of cellular energy stores, and this enzyme has been implicated in the stimulation of glucose uptake into skeletal muscle and the inhibition of liver gluconeogenesis. We recently reported that AMPK is activated by metformin in cultured rat hepatocytes, mediating the inhibitory effects of the drug on hepatic glucose production. In the present study, we evaluated whether therapeutic doses of metformin increase AMPK activity in vivo in subjects with type 2 diabetes. Metformin treatment for 10 weeks significantly increased AMPK ␣2 activity in the skeletal muscle, and this was associated with increased phosphorylation of AMPK on Thr172 and decreased acetyl-CoA carboxylase-2 activity. The increase in AMPK ␣2 activity was likely due to a change in muscle energy status because ATP and phosphocreatine concentrations were lower after metformin treatment. Metformin-induced increases in AMPK activity were associated with higher rates of glucose disposal and muscle glycogen concentrations. These findings suggest that the metabolic effects of metformin in subjects with type 2 diabetes may be mediated by the activation of AMPK ␣2.

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“…Although the cellular mechanism of action of dimethylbiguanide remains largely unknown, results from several studies pointed to a connection between dimethylbiguanide and cellular insulin signaling (30,31,(37)(38)(39)(40). Activation of the insulin receptor tyrosine kinase and tyrosine phosphorylation of intracellular substrates are important steps in insulin signaling (41,42).…”

Section: Dimethylbiguanide-induced Effect Does Not Involve Standard Cmentioning

confidence: 99%

Dimethylbiguanide Inhibits Cell Respiration via an Indirect Effect Targeted on the Respiratory Chain Complex I

El-Mir¹,

Nogueira²,

Fontaine³

et al. 2000

Journal of Biological Chemistry

1,217

976

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We report here a new mitochondrial regulation occurring only in intact cells. We have investigated the effects of dimethylbiguanide on isolated rat hepatocytes, permeabilized hepatocytes, and isolated liver mitochondria. Addition of dimethylbiguanide decreased oxygen consumption and mitochondrial membrane potential only in intact cells but not in permeabilized hepatocytes or isolated mitochondria. Permeabilized hepatocytes after dimethylbiguanide exposure and mitochondria isolated from dimethylbiguanide pretreated livers or animals were characterized by a significant inhibition of oxygen consumption with complex I substrates (glutamate and malate) but not with complex II (succinate) or complex IV (N,N,N,N-tetramethyl-1,4-phenylenediamine dihydrochloride (TMPD)/ascorbate) substrates. Studies using functionally isolated complex I obtained from mitochondria isolated from dimethylbiguanidepretreated livers or rats further confirmed that dimethylbiguanide action was located on the respiratory chain complexI.Thedimethylbiguanideeffectwastemperaturedependent, oxygen consumption decreasing by 50, 20, and 0% at 37, 25, and 15°C, respectively. This effect was not affected by insulin-signaling pathway inhibitors, nitric oxide precursor or inhibitors, oxygen radical scavengers, ceramide synthesis inhibitors, or chelation of intra-or extracellular Ca 2؉ . Because it is established that dimethylbiguanide is not metabolized, these results suggest the existence of a new cell-signaling pathway targeted to the respiratory chain complex I with a persistent effect after cessation of the signaling process.Mitochondria are intracellular organelles devoted mainly to energy metabolism (ATP production) that also play a pivotal role in the onset of cell death (1, 2). The regulation of such functions is essential and has been well characterized in isolated mitochondria, whereas much less is known in intact cells. Short term regulation of intact cell respiration has been established with Ca 2ϩ and is related to the Ca 2ϩ -dependent mitochondrial dehydrogenases that regulate the supply of substrates to the respiratory chain (3). It has been reported that lipopolysaccharide plus interferon-␥ can persistently inhibit respiratory chain complex IV in intact astrocytes (4) and that activation of glutamate receptors induces a persistent inhibition of complexes II, III, and IV in intact neurons (5). Both inhibitions can be prevented by nitric-oxide synthase inhibitors. Furthermore, it has been shown that prolonged direct exposure to nitric oxide (NO) 1 in intact J774 cells leads to a persistent inhibition of respiratory chain complex I, whereas inhibition of complex IV was reversible (6).Dimethylbiguanide (metformin) is an oral antihyperglycemic drug widely used in the treatment of type-II diabetes (7-10), the action mechanism of which remains largely unknown (see Refs. 11 and 12 for review). Dimethylbiguanide inhibits hepatic gluconeogenesis, possibly through a decrease in the cytosolic ATP/ADP ratio (13). Although it has been long known that big...

show abstract

Stimulation of the intracellular portion of the human insulin receptor by the antidiabetic drug metformin

Cited by 32 publications

References 13 publications

A Cellular Reporter Assay to Monitor Insulin Receptor Kinase Activity Based on STAT 5-Dependent Luciferase Gene Expression

A Cellular Reporter Assay to Monitor Insulin Receptor Kinase Activity Based on STAT 5-Dependent Luciferase Gene Expression

Metformin Increases AMP-Activated Protein Kinase Activity in Skeletal Muscle of Subjects With Type 2 Diabetes

Dimethylbiguanide Inhibits Cell Respiration via an Indirect Effect Targeted on the Respiratory Chain Complex I

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