Cellular Mechanism Of Action

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For almost 40 years of research, the precise cellular mechanism of metformin action has been a mystery. While depending on the researcher's background, the experimental system used or the available assay, a great many cellular mechanisms have been described but a single unifying site of action such as a receptor, an enzyme, or a transcription factor, had stubbornly escaped detection. Throughout this quest it was generally undisputed that metformin had no effect on the pancreatic beta cell in stimulating insulin secretion (8) and its main site of action had to be on the insulin action end.

The enzyme AMP-activated protein kinase (AMPK) is considered a cellular masterswitch in the control of whole-body energy and substrate metabolism. It plays a major role in the control of hepatic metabolism by integrating nutritional and hormonal signals. AMPK maintains energy balance by switching on catabolic pathways and switching off ATP-consuming pathways, both by short-term effects on phosphorylation of regulatory proteins and by long-term effects on gene expression. Activation of AMPK in the liver leads to the stimulation of fatty acid oxidation and inhibition of lipogenesis, glucose production, and protein synthesis. Metformin, like adiponectin and exercise is a potent stimulator of AMPK activity (17). Activation of AMPK results in many of the well-known cellular effects of metformin: inhibition of key enzymes of gluconeogenesis and glycogen synthesis in hepatocytes, and stimulation of insulin signaling and glucose transport in muscle cells (18).

Guanidine Biguanide Metformin

Guanidine i

Biguantdine FIGURE 1 Chemical structure of biguanides.

One important upstream kinase of the AMPK cascade is the tumor suppressor LKB1, which was originally identified for its role in Peutz-Jegher's syndrome (19). Interestingly, deletion of the gene-encoding LKB1 in the liver leads to marked hyperglycemia as a consequence of increased gluconeogenic gene expression and hepatic glucose output. More importantly, the absence of LKB1 in the liver abolishes the effect of lowering glucose level caused by metformin (20). These findings establish LKB1 as the molecular target of metformin by which it increases AMPK activity which in turn regulates the key metabolic pathways of metformin action (Fig. 3).

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Supplements For Diabetics

Supplements For Diabetics

All you need is a proper diet of fresh fruits and vegetables and get plenty of exercise and you'll be fine. Ever heard those words from your doctor? If that's all heshe recommends then you're missing out an important ingredient for health that he's not telling you. Fact is that you can adhere to the strictest diet, watch everything you eat and get the exercise of amarathon runner and still come down with diabetic complications. Diet, exercise and standard drug treatments simply aren't enough to help keep your diabetes under control.

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