Mechanism of action The molecular mechanism of<unk>  is not completely understood. Multiple potential mechanisms of action have been proposed: inhibition of the mitochondrial respiratory chain (complex I), activation of AMP-activated protein kinase (AMPK), inhibition of glucagon-induced elevation of cyclic adenosine monophosphate (cAMP) with reduced activation of protein kinase A (PKA), complex IV–mediated inhibition of the GPD2 variant of mitochondrial glycerol-3-phosphate dehydrogenase (thereby reducing glycerol-derived hepatic gluconeogenesis), and an effect on gut microbiota.<unk>  also exerts an anorexiant effect in most people, decreasing caloric intake.<unk>  decreases gluconeogenesis (glucose production) in the liver.<unk>  inhibits basal secretion from the pituitary gland of growth hormone, adrenocorticotropic hormone, follicle stimulating hormone, and expression of proopiomelanocortin, which in part accounts for its insulin-sensitizing effect with multiple actions on tissues including the liver, skeletal muscle, endothelium, adipose tissue, and the ovaries. The average patient with type 2 diabetes has three times the normal rate of gluconeogenesis;<unk>  treatment reduces this by over one-third. Activation of AMPK was required for<unk> 's inhibitory effect on liver glucose production. AMPK is an enzyme that plays an important role in insulin signalling, whole-body energy balance, and the<unk> abolism of glucose and fats. AMPK activation was required for an increase in the expression of small heterodimer partner, which in turn inhibited the expression of the hepatic gluconeogenic genes phosphoenolpyruvate carboxykinase and glucose 6-phosphatase.<unk>  is frequently used in research along with AICA ribonucleotide as an AMPK agonist. The mechanism by which biguanides increase the activity of AMPK remains uncertain; however,<unk>  increases the concentration of cytosolic adenosine monophosphate (AMP) (as opposed to a change in total AMP or total AMP/adenosine triphosphate).<unk>  inhibits cyclic AMP production, blocking the action of glucagon, and thereby reducing fasting glucose levels.<unk>  also induces a profound shift in the faecal microbial community profile in diabetic mice, and this may contribute to its mode of action possibly through an effect on glucagon-like peptide-1 secretion. In addition to suppressing hepatic glucose production,<unk>  increases insulin sensitivity, enhances peripheral glucose uptake (by inducing the phosphorylation of GLUT4 enhancer factor), decreases insulin-induced suppression of fatty acid oxidation, and decreases the absorption of glucose from the gastrointestinal tract. Increased peripheral use of glucose may be due to improved insulin binding to insulin receptors. The increase in insulin binding after<unk>  treatment has also been demonstrated in patients with diabetes mellitus type 2. AMPK probably also plays a role in increased peripheral insulin sensitivity, as<unk>  administration increases AMPK activity in skeletal muscle. AMPK is known to cause GLUT4 deployment to the plasma membrane, resulting in insulin-independent glucose uptake. Some<unk> abolic actions of<unk>  do appear to occur by AMPK-independent mechanisms.<unk>  has indirect antiandrogenic effects in women with insulin resistance, such as those with PCOS, due to its beneficial effects on insulin sensitivity. It may reduce testosterone levels in such women by as much as 50%. A Cochrane review, though, found that<unk>  was only slightly effective for decreasing androgen levels in women with PCOS.<unk>  also has significant effects on the gut microbiome, such as its effect on increasing agmatine production by gut bacteria, but the relative importance of this mechanism compared to other mechanisms is uncertain. Pharmacokinetics<unk>  has an oral bioavailability of 50–60% under fasting conditions, and is absorbed slowly. Peak plasma concentrations (Cmax) are reached within 1–3 hours of taking immediate-release<unk>  and 4–8 hours with extended-release formulations. The plasma protein binding of<unk>  is negligible, as reflected by its very high apparent volume of distribution (300–1000 l after a single dose). Steady state is usually reached in 1–2 days.<unk>  has acid dissociation constant values (pKa) of 2.8 and 11.5, so it exists very largely as the hydrophilic cationic species at physiological pH values. The<unk>  pKa values make it a stronger base than most other basic medications with less than 0.01% nonionized in blood. Furthermore, the lipid solubility of the nonionized species is slight as shown by its low logP value (log(10) of the distribution coefficient of the nonionized form between octanol and water) of −1.43. These chemical parameters indicate low lipophilicity and, consequently, rapid passive diffusion of<unk>  through cell membranes is unlikely. As a result of its low lipid solubility it requires the transporter SLC22A1 in order for it to enter cells. The logP of<unk>  is less than that of phenformin (−0.84) because two<unk> hyl substituents on<unk>  impart lesser lipophilicity than the larger phenylethyl side chain in phenformin. More lipophilic derivatives of<unk>  are presently under investigation with the aim of producing prodrugs with superior oral absorption than<unk> .<unk>  is not<unk> abolized. It is cleared from the body by tubular secretion and excreted unchanged in the urine; it is undetectable in blood plasma within 24 hours of a single oral dose. The average elimination half-life in plasma is 6.2 hours.<unk>  is distributed to (and appears to accumulate in) red blood cells, with a much longer elimination half-life: 17.6 hours (reported as ranging from 18.5 to 31.5 hours in a single-dose study of nondiabetics). Some evidence indicates that liver concentrations of<unk>  in humans may be two to three times higher than plasma concentrations, due to portal vein absorption and first-pass uptake by the liver in oral administration.
Metformin
Rosiglitazone
Pioglitazone
Glibenclamide
Liraglutide
Miglitol
Exenatide
Glipizide