Demonstration of the mechanism of action of biguanides

Muntoni, Sergio; Tagliamonte, P.; Sirigu, F; Corsini, Giovanni

doi:10.1007/bf02590716

Cited by 5 publications

(4 citation statements)

References 9 publications

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“…The report that metformin stimulates FA oxidation in rat hepatocytes [21] seems at odds with previous papers [30,31,147]. What can be said is that at the concentrations of 0.5 to 2 × 10 –3 M , metformin did not affect total ATP concentrations, but it could produce a subtle decline in the free ATP/ADP ratio as a stimulus for AMP-K activation and hence for increased FA oxidation [21].…”

Section: The Rationale For Treatmentcontrasting

confidence: 52%

“…Yet, various other papers, starting from Randle et al [18], state that β-oxidation of FA, that increases in the same conditions, is the main cause of decreased glucose oxidation and of IR, and that biguanides that are β-oxidation inhibitors, improve IR [30,31,32,33,34,35,36,37,38,39,40,41]. …”

Section: Cellular and Humoral Mechanisms Of Irmentioning

confidence: 99%

“…This is the case because the primary mechanism of action of biguanides consists in selective inhibition of FA oxidation, while leaving unaffected the oxidative capability of mitochondria (ATP generation) and restoring the glucose oxidation depressed by palmitic acid [30,31]. Owing to their molecular structure, biguanides interact with biological membranes, particularly those of mitochondria [145], wherein they accumulate against the concentration gradient [146].…”

Section: The Rationale For Treatmentmentioning

confidence: 99%

“…The main mechanism of action of biguanides is the inhibition of the oxidation of long-chain FA [20,21,22,23,24,25,26,27,28,29,30,31], which are transported into the mitochondria by carnitine [26]. …”

Section: The Rationale For Treatmentmentioning

confidence: 99%

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Insulin Resistance: Pathophysiology and Rationale for Treatment

Muntoni

2011

Ann Nutr Metab

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After binding to its receptor and activating the β-subunit, insulin is faced with two divergent pathways: one is phosphatidylinositol 3-kinase (PI 3-K) dependent, while another is dependent upon activation of mitogen-activated protein kinase (MAP-K). The former is absolutely necessary for mediating most metabolic and antiapoptotic effects; the latter is linked to nonmetabolic, proliferative and mitogenic effects. In obese patients, especially with type 2 diabetes mellitus (DM2), only the PI 3-K, but not the MAP-K, is resistant to insulin stimulation: hence insulin resistance is better defined as metabolic insulin resistance. The resulting ‘compensatory hyperinsulinemia’ is an unsuccessful attempt to overcome the inhibition of the metabolic pathway at the price of unopposed stimulation of the MAP-K pathway, and the administration of exogenous insulin might worsen the metabolic dysfunction. As the preferential activation of the MAP-K pathway in insulin-resistant patients has atherogenic and mitogenic properties, this leads to atherosclerosis and cancer. Metformin may carry out direct protective action on human β cells, inasmuch as it improves both primary and secondary endpoints through selective inhibition of fatty acyl oxidation.

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Section: The Rationale For Treatmentcontrasting

confidence: 52%