BACKGROUND The AMP-activated protein kinase (AMPK) cascade is a sensor of cellular energy charge that acts as a 'metabolic master switch' and inhibits cell proliferation. Activation requires phosphorylation of Thr172 of AMPK within the activation loop by upstream kinases (AMPKKs) that have not been identified. Recently, we identified three related protein kinases acting upstream of the yeast ho...

The patient; a 64-year-old housewife, had been known to suffer from maturity-onset diabetes for four years. She was treated with chlorpropamide for 18 months, and then with a 1,000-calorie diet (130 g. of carbohydrate) alone for three months. She remained more than a stone (6.4 kg.) above the standard weight for her height and was therefore started on phenformin in May 1964 in order to treat he...

Compounds containing guanidine-related molecules have been used since medieval times to relieve symptoms of diabetes mellitus. Guanidine itself was too toxic but two linked guanidine rings (biguanides) were useful and generally safer. For 20 years, phenformin was used before adverse effects led to removal from the US and European markets. Metformin continues to be widely prescribed for diabetes...

Biguanides are a class of drugs widely used as oral antihyperglycemic agents for the treatment of type 2 diabetes mellitus, but they are associated with lactic acidosis, a lethal side effect. We reported previously that biguanides are good substrates of rat organic cation transporter 1 (Oct1; Slc22a1) and, using Oct1(-/-) mice, that mouse Oct1 is responsible for the hepatic uptake of a biguanid...

Pyruvate kinase (EC 2.7.1.40) is inhibited by phenethylbiguanide. The kinetics of inhibition are competitive between biguanide and divalent, but not monovalent, metal cation activators of the enzyme; biguanide inhibition thus resembles inhibition by Ca(++). Alteration of either the polar or nonpolar portion of the phenethylbiguanide molecule quantitatively reduces its effectiveness as an inhibi...