The Effect of Metformin on Adipose Tissue Metabolism and Peripheral Blood Flow in Subjects With NIDDM

Jansson, Per‐Anders; Gudbjörnsdottir, H. S.; Ok, Andersson; Lönnroth, Peter

doi:10.2337/diacare.19.2.160

Cited by 32 publications

(30 citation statements)

References 16 publications

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“…To date, information on the direct effect of metformin on adipose lipolysis is scarce and even inconsistent because it was derived from different methodologies. An in vivo study suggested that oral administration of metformin does not affect lipolysis in s.c. adipose tissue of diabetic subjects (Jansson et al 1996), whereas another in vivo microdialysis study confirmed that direct perfusion of highconcentration (1 mM) metformin into abdominal adipose tissue restricted basal and adrenergic-stimulated glycerol release in obese and diabetic patients (Flechtner-Mors et al 1999). In vitro studies indicated that metformin at low concentrations (!25 mM) did not seem to affect the lipolysis response in isolated adipose tissue (Cigolini et al 1984), whereas high-dose metformin (O250 mM) reduced adrenergic-induced lipolysis in primary rat adipocytes (Ren et al 2006) or in C3H10T1/2 preadipocytes (Lenhard et al 1997).…”

Section: Introductionmentioning

confidence: 90%

Mechanisms of metformin inhibiting lipolytic response to isoproterenol in primary rat adipocytes

Zhang¹,

He²,

Xu³

et al. 2008

Journal of Molecular Endocrinology

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The mobilization of free fatty acids (FFA) from adipose tissue to the bloodstream primarily depends on triacylglycerol lipolysis in adipocytes. Catecholamines are major hormones that govern lipolysis through elevating cellular cAMP production and activating protein kinase, cAMP dependent, catalytic, alpha (PKA) and mitogen-activated protein kinase 1/2 (MAPK1/3). Obesity and type 2 diabetes are associated with elevated levels of systemic FFA, which restricts glucose utilization and induces insulin resistance. The biguanide metformin exerts its antihyperglycemic effect by enhancing insulin sensitivity, which is associated with decreased levels of circulating FFA. In this study, we examined the characteristics and basis of the inhibitory effect of metformin on adrenergic-stimulated lipolysis in primary rat adipocytes. We measured the release of FFA and glycerol as an index of lipolysis and examined the major signalings of the lipolytic cascade in primary rat adipocytes. Metformin at 250-500 mM efficiently attenuated FFA and glycerol release from the adipocytes stimulated with 1 mM isoproterenol. To elucidate the basis for this antilipolytic action, we showed that metformin decreased cellular cAMP production, reduced the activities of PKA and MAPK1/3, and attenuated the phosphorylation of perilipin during isoproterenol-stimulated lipolysis. Further, metformin suppressed isoproterenolpromoted lipase activity but did not affect the translocation of lipase, hormone-sensitive from the cytosol to lipid droplets in adipocytes. This study provides evidence that metformin acts on adipocytes to suppress the lipolysis response to catecholamine. This antilipolytic effect could be a cellular basis for metformin decreasing plasma FFA levels and improving insulin sensitivity.

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Section: Introductionmentioning

confidence: 90%

Mechanisms of metformin inhibiting lipolytic response to isoproterenol in primary rat adipocytes

Zhang¹,

He²,

Xu³

et al. 2008

Journal of Molecular Endocrinology

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“…These blots are representative of two independent experiments results showing an anti-lipolytic effect of both metformin and the related biguanide phenformin in rodent adipocytes [8,40], attributed for the latter drug to an activation of AMPK. Moreover, in humans, a perfusion of metformin in microdialysis experiments has an anti-lipolytic effect [22,41].…”

Section: Discussionmentioning

confidence: 99%

Biguanides and thiazolidinediones inhibit stimulated lipolysis in human adipocytes through activation of AMP-activated protein kinase

et al. 2009

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Aims/hypothesis In rodent adipocytes, activated AMPactivated protein kinase reduces the lipolytic rate. As the hypoglycaemic drugs metformin and thiazolidinediones activate this enzyme in rodents, we tested the hypothesis that in addition to their known actions they could have an anti-lipolytic effect in human adipocytes. Methods Adipose tissue was obtained from individuals undergoing plastic surgery. Adipocytes were isolated and incubated with lipolytic agents (isoprenaline, atrial natriuretic peptide) and biguanides or thiazolidinediones. Lipolysis was quantified by the glycerol released in the medium. AMPactivated protein kinase activity and phosphorylation state were determined using standard procedures. Results In human adipocytes, isoprenaline and atrial natriuretic peptide stimulated the lipolytic rate three-to fourfold. Biguanides and thiazolidinediones activated AMPactivated protein kinase and inhibited lipolysis by 30-40%, at least in part by inhibiting hormone-sensitive lipase translocation to the lipid droplet. Inhibition of AMPactivated protein kinase by compound C precluded this inhibitory effect on lipolysis. Stimulation of lipolysis also induced an activation of AMP-activated protein kinase concomitant with a drop in ATP concentration. Conclusions/interpretation We show for the first time in human adipocytes that biguanides and thiazolidinediones activate AMP-activated protein kinase, thus counteracting lipolysis induced by lipolytic agents. In addition, β-agonistor ANP-stimulated lipolysis increases AMP-activated protein kinase activity. This is because of an increase in the AMP/ATP ratio, linked to activation of some of the released fatty acids into acyl-CoA. AMP-activated protein kinase activation could represent a physiological means of avoiding a deleterious drain of energy during lipolysis but could be used to restrain pharmacological release of fatty acids.

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“…Furthermore, its ability to improve inflammation and insulin sensitivity, especially over long-term use, may be attenuated by its induction of elevated tissue lactate and blood lactate levels [6,10,11], as lactate possesses proinflammatory properties and can lead to IR [16,17,18,25,28,29,30]. However, OXA can inhibit tissue lactate production and decrease blood lactate levels, thus not only improving inflammation and IR itself but also enhancing the effects of MET.…”

Section: Discussionmentioning

confidence: 99%

“…MET also inhibits complex I of the respiratory chain, thereby inhibiting oxidative metabolism and leading to a shift toward anaerobic metabolism and increased lactate production in hepatocytes [9]. Additionally, it has been observed that MET promotes the production of lactate in rat adipocytes in vitro [10] and increases the release of lactate from adipose tissue in vivo in patients with T2DM [11]. MET also inhibits complex I of the respiratory chain in adipocytes [12].…”

Section: Introductionmentioning

confidence: 99%

Oxamate Enhances the Anti-Inflammatory and Insulin-Sensitizing Effects of Metformin in Diabetic Mice

Ye²,

Zheng³

et al. 2017

Pharmacology

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Metformin (MET) is the first-line drug for treating type 2 diabetes mellitus (T2DM). However, MET increases blood lactate levels in patients with T2DM. Lactate possesses proinflammatory properties and causes insulin resistance (IR). Oxamate (OXA), a lactate dehydrogenase inhibitor, can decrease tissue lactate production and blood lactate levels. This study was conducted to examine the effects of the combination of OXA and MET on inflammation, and IR in diabetic db/db mice. Supplementation of OXA to MET led to lowered tissue lactate production and serum lactate levels compared to MET alone, accompanied with further decreased tissue and blood levels of pro-inflammatory cytokines, along with better insulin sensitivity, beta-cell mass, and glycemic control in diabetic db/db mice. These results show that OXA enhances the anti-inflammatory and insulin-sensitizing effects of MET through the inhibition of tissue lactate production in db/db mice.

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The Effect of Metformin on Adipose Tissue Metabolism and Peripheral Blood Flow in Subjects With NIDDM

Cited by 32 publications

References 16 publications

Mechanisms of metformin inhibiting lipolytic response to isoproterenol in primary rat adipocytes

Mechanisms of metformin inhibiting lipolytic response to isoproterenol in primary rat adipocytes

Biguanides and thiazolidinediones inhibit stimulated lipolysis in human adipocytes through activation of AMP-activated protein kinase

Oxamate Enhances the Anti-Inflammatory and Insulin-Sensitizing Effects of Metformin in Diabetic Mice

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