Mode of action of hypoglycemic agents—IV

Cook, David E.; Blair, James B.; Gilfillan, Carol; Lardy, Henry A.

doi:10.1016/0006-2952(73)90111-1

Cited by 17 publications

(10 citation statements)

References 15 publications

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“…Over time, studies on guanidine derivatives began to link inhibition of mitochondrial respiration with reduced gluconeogenesis [30]; however, as already indicated, the poor correlation of the magnitudes of these effects for some drugs led others to conclude that mitochondrial effects were more likely to contribute towards side effects such as lactic acidosis rather than therapeutic effects [19, 21]. In the case of metformin, for example, there is often little impact on cellular ATP levels, even when using concentrations well above those likely to be achieved in vivo.…”

Section: Molecular Action and Target Of Metformin: Lessons And Insighmentioning

confidence: 99%

Molecular mechanism of action of metformin: old or new insights?

2013

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Metformin is the first-line drug treatment for type 2 diabetes. Globally, over 100 million patients are prescribed this drug annually. Metformin was discovered before the era of target-based drug discovery and its molecular mechanism of action remains an area of vigorous diabetes research. An improvement in our understanding of metformin’s molecular targets is likely to enable target-based identification of second-generation drugs with similar properties, a development that has been impossible up to now. The notion that 5' AMP-activated protein kinase (AMPK) mediates the anti-hyperglycaemic action of metformin has recently been challenged by genetic loss-of-function studies, thrusting the AMPK-independent effects of the drug into the spotlight for the first time in more than a decade. Key AMPK-independent effects of the drug include the mitochondrial actions that have been known for many years and which are still thought to be the primary site of action of metformin. Coupled with recent evidence of AMPK-independent effects on the counter-regulatory hormone glucagon, new paradigms of AMPK-independent drug action are beginning to take shape. In this review we summarise the recent research developments on the molecular action of metformin.

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Section: Molecular Action and Target Of Metformin: Lessons And Insighmentioning

confidence: 99%

Molecular mechanism of action of metformin: old or new insights?

2013

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“…This observation implies that the correct cDNA clones of GAPD and NDUFS5 are selected as genes changing their expressions through the processes of the construction and screening of the subtraction library by the suppression subtractive hybridization method in this study. Since the amount of ATP produced in mitochondria was reported to decrease by metformin treatment, [22][23][24][25][26] a part of the reason for this decrease in ATP amount seems to be based on the loss of complex I activity and suppression of the gene expression in complex I by the biguanide. Buformin was also demonstrated to cause a rapid decrease in ATP within 12 h in the present study, even though the expression of NDUFS5 mRNA was observed to decrease gradually.…”

Section: Discussionmentioning

confidence: 99%

Buformin Suppresses the Expression of Glyceraldehyde 3-Phosphate Dehydrogenase

Yano

Kubota

Iguchi

et al. 2006

Biological & Pharmaceutical Bulletin

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Three biguanides, phenformin, buformin, and metformin, were first used clinically for diabetes mellitus in the 1950s. Since phenformin was found to have a lethal side effect, lactic acidosis, in the late of 1970s, 1) its usage decreased rapidly in many countries and was finally withdrawn. Then use of other biguanides declined gradually because of their own adverse effects. Lactic acidosis, hypoglycemia, and digestive organ dysfunction have been found to be adverse effects of biguanides. Lactic acidosis caused by biguanides results in lethal metabolic acidosis, 2) so their use was stopped. Cohen and Woods 3) proposed a classification for lactic acidosis that consisted of types A, B 1 , B 2 , B 3 , and B 4 , and acidosis caused by biguanides belongs to type B 2 according to this classification. Type B is lactic acidosis occurring when clinical evidence of poor tissue perfusion or oxygenation is absent and type B 2 is due to drugs and toxins.Metformin was recently reported to decrease the risk of diabetes-related endpoints in overweight diabetic patients 4) and, therefore, has begun to be widely used again. The following mechanisms of action of biguanides have been proposed 5) : (i) suppression of glucose release from the liver, (ii) increase of glucose intake in peripheral tissues, (iii) decrease of glucose uptake in an alimentary tract, and (iv) suppression of b-oxidation. Metformin was found to improve resistance to insulin in type II diabetes. Zhou et al. 6) postulated that the suppression of SREBP-1 expression through the activation of AMPactivating protein kinase by metformin eliminated the insulin resistance.The following possible mechanism for the side effect of biguanides has been proposed. 7,8) The biguanide binds to the mitochondrial membrane and causes the disruption of oxidative phosphorylation in the mitochondria. This results in an increase in the NADH level, a decrease in pyruvate dehydrogenase activity, and deactivation of the TCA cycle. Furthermore, gluconeogenesis is suppressed and pyruvic acid accumulates in the liver. This leads to an increase in production of lactic acid. However, the molecular mechanisms of the side effects of biguanides are still unclear.When we researched which gene expressions underwent a change in order to clarify the mechanism of biguanides induced lactic acidosis, we found that the gene expression of glyceraldehyde 3-phosphate dehydrogenase (GAPD) in HepG2 cells decreases significantly by buformin treatment. Since GAPD is involved in the glucolytic pathway, we believe the decrease in GAPD may have caused the lactic acidosis. In this study, we demonstrate that expression of the gene for GAPD in HepG2 cells was suppressed by buformin treatment in a time-dependent manner. We also examined the effect of the biguanide on the protein expression of GAPD and determined the levels of NAD + and ATP in HepG2 cells treated with the biguanide to investigate the mechanism of the lactic acidosis side effect. . Therefore, the reaction equilibrium catalyzed by lactate dehydrogenase le...

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“…When used, 5 pg of glucacon was added to the perfusate at 30 min and 60 min after the start of the perfusion [6]. Perfusate samples (2 ml) were taken at the indicated times, deproteinized, and assayed for glucose and other metabolities as previously described [6,7]. All of the radioactivity in the neutral fraction obtained by this method was found to represent glucose.…”

Section: Methodsmentioning

confidence: 99%

“…All of the radioactivity in the neutral fraction obtained by this method was found to represent glucose. In earlier evaluations of this procedure, it was determined that glucose accounted for more than 90 % of the radioactivity in the neutral fraction [7] and lactate for more than 70 % of the radioactivity in the anionic or 'lactate' fraction [6]. The radioactive anionic or 'lactate' fraction will be referred to as [14C]lactate.…”

Section: Methodsmentioning

confidence: 99%

Gluconeogenesis in the Guinea Pig. Effect of Glucagon on Gluconeogenesis from Lactate by Isolated Perfused Guinea-Pig Liver

Cook

1977

Eur J Biochem

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Gluconeogenesis was stimulated by glucagon in fed but not fasted isolated perfused guinea pig livers. Both the amount and the rate of incorporation of radioactivity into glucose from ~-[U-'~C]lactate were inci-eased in fed livers by the addition of glucagon to the perfusate. The glucagon-stimulated increase in gluconeogenesis was accompanied by an increase in oxygen consumption, an increase in the amount of lactate carbon converted to glucose and a decrease in the amount of lactate carbon converted to COz. The results are interpreted to indicate that glucagon affects gluconeogenesis from lactate in fed livers by redirecting the fate of substrate from other products toward glucose.Much of our knowledge concerning the hormonal control of hepatic gluconeogenesis, especially by glucagon, has been derived from studies with rats, perfused rat livers or isolated hepatocytes prepared from rat livers. The general applicability of such knowledge, however, remains uncertain. For example, Soling et al. [l] have demonstrated that, unlike its positive effect on gluconeogenesis in the rat, glucagon does not stimulate gluconeogenesis in fasted isolated perfused guinea pig liver. In addition, the rat and a few other mammalian species have liver phosphoenolpyruvate carboxykinase activity located almost entirely in the cytosol. Most mammalian species including man and guinea pig, however, have an equal distribution of distinct mitochondria1 and cytosolic phosphoPnolpyruvate carboxykinase activity (cf.[2]). Consequently, the importance of studying the control of hepatic gluconeogenesis in an animal model such as the guinea pig has often been emphasized [I, 3 -51. These and other considerations led to the present investigations on the effects of glucagon on hepatic gluconeogenesis in the guinea pig. MATERIALS AND METHODSMale English short-hair guinea pigs (CAMM Research Institute, Wayne, N.J.) weighing 229 to 349 g Enzyme. Phosphoenolpyruvate carboxykinase (GTP) (EC 4.1. 1.32).were allowed to feed ad lib. or fasted 48 h prior to perfusion. The isolated livers were perfused at 37 "C with a Krebs-Ringer bicarbonate medium containing 3 % fatty-acid-free bovine serum albumin (Miles Laboratories, Elkhart, Ind.) and 20 % washed bovine erythrocytes in a recirculating system as previously described [6]. In this system the livers were perfused for 60 min prior to the addition of substrate. The substrate was 10 mM L-lactate (Schwartz-Mann, Orangeburg, N.J.) containing ~-[U-'~C]lactate (Amersham-Searle, Arlington Heights, Ill.) to give a specific activitity of 1600 dis. min-' pmol-'. Glucagon (a generous gift from Dr William Bromer, Eli Lilly and Co., Indianapolis, Ind.) was prepared in 3 % bovine serum albumin and kept frozen until used. When used, 5 pg of glucacon was added to the perfusate at 30 min and 60 min after the start of the perfusion [6]. Perfusate samples (2 ml) were taken at the indicated times, deproteinized, and assayed for glucose and other metabolities as previously described [6,7]. All of the radioactivity in the neutral fr...

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Mode of action of hypoglycemic agents—IV

Cited by 17 publications

References 15 publications

Molecular mechanism of action of metformin: old or new insights?

Molecular mechanism of action of metformin: old or new insights?

Buformin Suppresses the Expression of Glyceraldehyde 3-Phosphate Dehydrogenase

Gluconeogenesis in the Guinea Pig. Effect of Glucagon on Gluconeogenesis from Lactate by Isolated Perfused Guinea-Pig Liver

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