Metformin reverses hexokinase and phosphofructokinase downregulation and intracellular distribution in the heart of diabetic mice

Silva, Daniel da; Ausina, Priscila; Alencar, Edgard Martins de; Coelho, Wagner Santos; Zancan, Patrícia; Sola‐Penna, Mauro

doi:10.1002/iub.1063

Cited by 41 publications

(19 citation statements)

References 55 publications

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“…The diabetic animal model used in the current work, a single, relatively low, i.p. injection of STZ, shows a low ability to secrete insulin even at high glycemia and also a slight resistance to insulin and has been characterized as a mixed model of DM1 and DM2 . This model is different from the alloxan‐induced diabetic rats described above as the latter is exclusively a DM1 model, normally responsive to insulin.…”

Section: Discussionmentioning

confidence: 99%

Antidiabetic activity of Sedum dendroideum: Metabolic enzymes as putative targets for the bioactive flavonoid kaempferitrin

et al. 2014

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The aim of this study was to evaluate the antidiabetic potential of a leaf extract and flavonoids from Sedum dendroideum (SD). Additionally, our goals were to establish a possible structure/activity relationship between these flavonoids and to assess the most active flavonoid on the glycolytic enzyme 6-phosphofructo-1-kinase (PFK). SD juice (LJ), a flavonoid-rich fraction (BF), and separately five flavonoids were evaluated intraperitoneally for their acute hypoglycemic activity in normal and streptozotocin-induced diabetic mice. First, the major flavonoids kaempferol 3,7-dirhamnoside or kaempferitrin (1), kaempferol 3-glucoside-7-rhamnoside (2), and kaempferol 3-neohesperidoside-7-rhamnoside (3) were tested. Then, the monoglycosides kaempferol 7-rhamnoside (5) and kaempferol 3-rhamnoside (6) were assayed to establish their structure/activity relationship. The effect of 1 on PFK was evaluated in skeletal muscle, liver, and adipose tissue from treated mice. LJ (400 mg/kg), BF (40 mg/kg), and flavonoid 1 (4 mg/kg) reduced glycemia in diabetic mice (120 min) by 52, 53, and 61%, respectively. Flavonoids 2, 3, 5, and 6 were inactive or showed little activity, suggesting that the two rhamnosyl moieties in kaempferitrin are important requirements. Kaempferitrin enhanced the PFK activity chiefly in hepatic tissue, suggesting that it is able to stimulate tissue glucose utilization. This result is confirmed testing kaempferitrin on C2C12 cell line, where it enhanced glucose consumption, lactate production, and the key regulatory glycolytic enzymes. The hypoglycemic activity of kaempferitrin depends on the presence of both rhamnosyl residues in the flavonoid structure when intraperitoneally administered. Our findings show for the first time that a flavonoid is capable of stimulating PFK in a model of diabetes and that kaempferitrin stimulates glucose-metabolizing enzymes. This study contributes to the knowledge of the mechanisms by which this flavonoid exerts its hypoglycemic activity.

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Section: Discussionmentioning

confidence: 99%

Antidiabetic activity of Sedum dendroideum: Metabolic enzymes as putative targets for the bioactive flavonoid kaempferitrin

et al. 2014

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“…These cardioprotective effects may be caused by increased mtHK activity. Metformin treatment reverses the down-regulation in total HK activity and has been shown to increase HK translocation to the mitochondria in diabetic hearts without adversely affecting normal hearts (Da Silva et al, 2012). Whether metformin will increase (mt)HK in hearts during IR to afford protection remains to be examined, but 2 weeks of metformin treatment has previously been demonstrated to increase HK activity in rat white gastrocnemius muscle (Suwa et al, 2006).…”

Section: Metforminmentioning

confidence: 99%

Targeting hexokinase II to mitochondria to modulate energy metabolism and reduce ischaemia‐reperfusion injury in heart

Nederlof

Eerbeek

Hollmann

et al. 2014

British J Pharmacology

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Mitochondrially bound hexokinase II (mtHKII) has long been known to confer cancer cells with their resilience against cell death. More recently, mtHKII has emerged as a powerful protector against cardiac cell death. mtHKII protects against ischaemia‐reperfusion (IR) injury in skeletal muscle and heart, attenuates cardiac hypertrophy and remodelling, and is one of the major end‐effectors through which ischaemic preconditioning protects against myocardial IR injury. Mechanisms of mtHKII cardioprotection against reperfusion injury entail the maintenance of regulated outer mitochondrial membrane (OMM) permeability during ischaemia and reperfusion resulting in stabilization of mitochondrial membrane potential, the prevention of OMM breakage and cytochrome C release, and reduced reactive oxygen species production. Increasing mtHK may also have important metabolic consequences, such as improvement of glucose‐induced insulin release, prevention of acidosis through enhanced coupling of glycolysis and glucose oxidation, and inhibition of fatty acid oxidation. Deficiencies in expression and distorted cellular signalling of HKII may contribute to the altered sensitivity of diabetes to cardiac ischaemic diseases. The interaction of HKII with the mitochondrion constitutes a powerful endogenous molecular mechanism to protect against cell death in almost all cell types examined (neurons, tumours, kidney, lung, skeletal muscle, heart). The challenge now is to harness mtHKII in the treatment of infarction, stroke, elective surgery and transplantation. Remote ischaemic preconditioning, metformin administration and miR‐155/miR‐144 manipulations are potential means of doing just that. Linked Articles This article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2014.171.issue-8

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“…Metformin (one of the most commonly prescribed drugs) improves peripheral sensitivity to insulin, promotes hyperglycemic control, and acts as an anti-inflammatory agent 92,117,118. Glucagon-like peptide (GLP)-1 is an incretin hormone that stimulates postprandial insulin secretion and improves insulin sensitivity.…”

Section: Antidiabetic Drugs For Treatment Of Dcmmentioning

confidence: 99%

Predictors and prevention of diabetic cardiomyopathy

Chavali¹,

Tyagi²,

Mishra³

2013

DMSO

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Despite our cognizance that diabetes can enhance the chances of heart failure, causes multiorgan failure,and contributes to morbidity and mortality, it is rapidly increasing menace worldwide. Less attention has been paid to alert prediabetics through determining the comprehensive predictors of diabetic cardiomyopathy (DCM) and ameliorating DCM using novel approaches. DCM is recognized as asymptomatic progressing structural and functional remodeling in the heart of diabetics, in the absence of coronary atherosclerosis and hypertension. The three major stages of DCM are: (1) early stage, where cellular and metabolic changes occur without obvious systolic dysfunction; (2) middle stage, which is characterized by increased apoptosis, a slight increase in left ventricular size, and diastolic dysfunction and where ejection fraction (EF) is <50%; and (3) late stage, which is characterized by alteration in microvasculature compliance, an increase in left ventricular size, and a decrease in cardiac performance leading to heart failure. Recent investigations have revealed that DCM is multifactorial in nature and cellular, molecular, and metabolic perturbations predisposed and contributed to DCM. Differential expression of microRNA (miRNA), signaling molecules involved in glucose metabolism, hyperlipidemia, advanced glycogen end products, cardiac extracellular matrix remodeling, and alteration in survival and differentiation of resident cardiac stem cells are manifested in DCM. A sedentary lifestyle and high fat diet causes obesity and this leads to type 2 diabetes and DCM. However, exercise training improves insulin sensitivity, contractility of cardiomyocytes, and cardiac performance in type 2 diabetes. These findings provide new clues to diagnose and mitigate DCM. This review embodies developments in the field of DCM with the aim of elucidating the future perspectives of predictors and prevention of DCM.

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Metformin reverses hexokinase and phosphofructokinase downregulation and intracellular distribution in the heart of diabetic mice

Cited by 41 publications

References 55 publications

Antidiabetic activity of Sedum dendroideum: Metabolic enzymes as putative targets for the bioactive flavonoid kaempferitrin

Antidiabetic activity of Sedum dendroideum: Metabolic enzymes as putative targets for the bioactive flavonoid kaempferitrin

Targeting hexokinase II to mitochondria to modulate energy metabolism and reduce ischaemia‐reperfusion injury in heart

Predictors and prevention of diabetic cardiomyopathy

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