Metformin

´ https://www.youtube.com/watch?v=c4JYVdK5oqU

´ Metformin, which is also sold under the trade names Glucophage, Fortamet,

Glumetza, and Riomet, is of the class of drugs called biguanides.
´ Metformin's major effect is to decrease hepatic glucose output by inhibiting
gluconeogenesis.
´ In addition, metformin increases insulin-mediated glucose utilization in peripheral
tissues (such as muscle), particularly after meals.
´ Metformin does not increase insulin levels in the body
´ Antilipolytic effect that lowers serum free fatty acid concentrations, thereby reducing
substrate availability for gluconeogenesis

Metformin- Gluconeogenesis
´ Metformin suppresses gluconeogenesis by inhibiting a specific mitochondrial isoform of
glycerophosphate dehydrogenase (mGPD).
´ This enzyme is responsible for converting glycerophosphate to dihydroxyacetone
phosphate, thereby preventing glycerol from contributing to the gluconeogenic
pathway
´ Inhibition of mGPD leads to accumulation of cytoplasmic NADH and a decrease in the
conversion of lactate to pyruvate, limiting contributions to hepatic gluconeogenesis
´ Metformin inhibits the mitochondrial respiratory chain in the liver, lowering cAMP, thus
reducing the expression of gluconeogenic enzymes. 
Metformin- Fatty Acid Synthesis
´ Metformin also activates the enzyme AMP-activated protein kinase (AMPK) in
hepatocytes, which appears to be the mechanism by which metformin lowers serum
lipid concentrations
´ Activation of AMPK involves AMP binding to regulatory sites on the γ subunits.
This causes conformational changes that allosterically activate the enzyme and
inhibit dephosphorylation
 ´ AMPK-dependent inhibitory phosphorylation of acetyl-CoA carboxylases Acc1 and Acc2
suppresses lipogenesis and lowers cellular fatty acid synthesis in liver and muscle
´ Metformin works through, LKB1, to regulate AMPK.
´ LKB1 is a tumor suppressor, and activation of AMPK through LKB1 may play a role in
inhibiting cell growth

\
Metformin- Catabolic vs. Anabolic Regulation

´ Once activated by increases in AMP:ATP, AMPK acts to restore energy homeostasis by

switching on catabolic pathways generating ATP, while switching off cellular processes
consuming ATP.
´ Metformin has the following effects:
´ Improves Insulin sensitivity
´ Enhances peripheral glucose uptake
´ Increased peripheral utilization of glucose may be due to improved
insulin binding to insulin receptors.
´ AMPK is known to cause glucose transporter GLUT4 deployment to the
plasma membrane
´ Decreases absorption of glucose from the gastrointestinal tract.
 ´
´ Metformin – Candidates, Dosing, and Contraindications
´ Candidates for treatment with Metformin are centered around those with
hyperglycemia in Type 2 diabetes.
´ Used in combination with diet and exercise
´ Metformin Dosing:
´ Immediate Release: Metformin is available as 500, 850, or 1000 mg tablets and
should be taken with meals twice daily.
´ Extended Release: Typically taken once daily with the evening meal, is available
in 500 and 750 mg tablets
´ Metformin is contraindicated lactic acidosis. The following factors may
predispose someone to lactic acidosis:
´ Impaired renal function 
´ Active or progressive liver disease
´ Active alcohol abuse
´ Past history of lactic acidosis