The pharmacogenetics of metformin and its impact on plasma metformin steady-state levels and glycosylated hemoglobin A1c

Christensen, Mette Marie Hougaard; Brasch‐Andersen, Charlotte; Gréen, Henrik; Nielsen, Flemming; Damkier, Per; Beck‐Nielsen, Henning

doi:10.1097/fpc.0b013e32834c0010

Cited by 235 publications

(235 citation statements)

References 43 publications

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“…As described above, neither the EGP nor any of the other variables were affected by the OCT1 allele status. This is in contrast to previous studies [12,13,38] and in agreement with others [14,39]. Most studies differ with respect to dosing of metformin (not only in amount but also single dose vs steady state) or participant population (type 2 diabetic patients vs healthy individuals) and may not be directly comparable.…”

Section: Discussionsupporting

confidence: 87%

“…Genetic variation in all of the above-mentioned transporters has been linked to altered pharmacokinetic and pharmacodynamic response to metformin [9]. In OCT1 (also known as SLC22A1), there are four known genetic variations (rs12208357 [R61C], rs34130495 [G401S], rs34059508 [G465R] and rs72552763 [M420del]), which encode an OCT1-transporter protein with reduced function and hence, have been linked to reduced-response metformin response in humans [12][13][14].…”

Section: Introductionmentioning

confidence: 99%

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Endogenous glucose production increases in response to metformin treatment in the glycogen-depleted state in humans: a randomised trial

et al. 2015

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Aims/hypothesis Metformin is believed to reduce glucose levels primarily by inhibiting hepatic glucose production. Recent data indicate that metformin antagonises glucagondependent glucose output, suggesting that compensatory mechanisms protect against hypoglycaemia. Here, we examined the effect of metformin on glucose metabolism in humans after a glycogen-depleting fast and the role of reducedfunction alleles in OCT1 (also known as SLC22A1). Methods In a randomised, crossover trial, healthy individuals with or without reduced-function alleles in OCT1 were fasted for 42 h twice, either with or without prior treatment with 1 g metformin twice daily. Participants were recruited from the Pharmacogenomics Biobank of the University of Southern Denmark. Treatment allocation was generated by the Good Clinical Practice Unit, Odense University Hospital, Denmark. Variables of whole-body glucose metabolism were assessed using [3-3 H]glucose, indirect calorimetry and measurement of substrates and counter-regulatory hormones. The primary outcome was endogenous glucose production (EGP). Results Thirty-seven individuals were randomised. Thirty-four completed the study (12 had none, 13 had one and nine had two reduced-function alleles in OCT1). Three were excluded from the analysis because of early dropout. Metformin significantly stimulated glucose disposal rates and non-oxidative glucose metabolism with no effect on glucose oxidation. This increase in glucose utilisation was explained by a concomitant increase in glycolytic flux and accompanied by increased EGP, most likely mediated by increased plasma lactate, glucagon and cortisol levels. There was no effect of reduced-function OCT1 alleles on any of these measures. All individuals completed the glycogendepleting fast without hypoglycaemia. Conclusions/interpretation Metformin stimulates glycolytic glucose utilisation and lactate production in the glycogendepleted state. This may trigger a rise in glucose counterregulatory hormones and subsequently an increase in EGP, which protects against hypoglycaemia.

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Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Endogenous glucose production increases in response to metformin treatment in the glycogen-depleted state in humans: a randomised trial

et al. 2015

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“…A possible direct effect of another medication, metformin, was also investigated. Metformin added to plasma ex vivo at a concentration of 1.2 μg/ml [25] did not affect cholesterol efflux (3.6±0.2% vs 3.5±0.5% p00.9).…”

Section: Resultsmentioning

confidence: 89%

Advanced glycation end-products (AGEs) and functionality of reverse cholesterol transport in patients with type 2 diabetes and in mouse models

et al. 2012

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Aims/hypothesis We investigated the contribution of AGEs to the impairment of reverse cholesterol transport (RCT) variables in diabetic individuals and in two animal models of diabetic obesity and of renal impairment. Methods The capacity of plasma and HDL from 26 individuals with moderately controlled type 2 diabetes to support cholesterol efflux was compared with 26 age-and sexmatched individuals without diabetes. We also compared the rates of RCT in vivo in two animal models: db/db mice and mice with chronic renal failure. Results Diabetic individuals had characteristic dyslipidaemia and higher levels of plasma AGEs. The capacity of whole plasma, ApoB-depleted plasma and isolated HDL to support cholesterol efflux was greater for diabetic patients compared with controls despite their lower HDL-cholesterol levels. The capacity of plasma to support cholesterol efflux correlated with plasma levels of cholesteryl ester transfer protein and levels of ApoB, but not with levels of AGE. RCT was severely impaired in db/db mice despite elevated HDL-cholesterol levels and no change in AGE concentration, whereas RCT in uraemic mice was unaffected despite elevated AGE levels. Conclusions/interpretation AGEs are unlikely to contribute significantly to the impairment of RCT in type 2 diabetes.

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“…Moreover, genetic variation in the genes coding OCT1, OCT2, MATE1, and MATE2 (membrane transporters of metformin) have been linked to an altered pharmacodynamic and pharmacokinetic response to metformin; the genetic component to the variation in renal metformin clearance has been estimated to be approximately 90% [23]. Thus, the non-significant differences in the correlations between plasma steady-state concentrations of metformin with glycemic control and insulin resistance reported here most likely reflect a combination of variation in the renal excretion of metformin, volume of distribution, and in the bioavailability of the drug [20]. The lowering of blood glucose by metformin develops over at least 10 days [8] indicating that metformin has a long residence time in the liver or other effect compartments.…”

Section: Discussionmentioning

confidence: 74%

“…Accordingly, the suggested reason for such finding is the variation and inconsistent pharmacokinetics of metformin in diabetic patients. Mette et al demonstrate huge interindividual variations in trough steady-state metformin plasma levels in type 2 diabetics which may be attributed to the OCT1 transporter activity under trough steady-state conditions [20]. Moreover, Yasmin et al reported that there is no benefit from increased doses of metformin in females with PCOS, but reduction of insulin resistance is more significant in those patients with lower insulin sensitivity at baseline [21]; such condition is not clearly manifested in the present study due to relatively short duration of treatment, but at least impart support the idea of avoiding dose escalation without monitoring clinical improvement.…”

Section: Discussionmentioning

confidence: 99%

Dose-dependent relationship between serum metformin levels and glycemic control, insulin resistance and leptin levels in females newly diagnosed with type 2 diabetes mellitus

Kadhim¹,

Ismael²,

Khalaf³

et al. 2012

JDM

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Despite the extensive clinical experience with the use of metformin worldwide, no formal doseranging study has been conducted because the current dosing strategy of metformin was determined empirically, rather than by an understanding of its dose-response relationship in patients with type 2 diabetes. The present study was designed to evaluate the correlation between serum metformin levels and glycemic control, insulin resistance and leptin levels in females newly diagnosed with type 2 diabetes. Sixty type 2 diabetic females were recruited for the study and were allocated into 3 groups; each receiving metformin 1000, 1500 and 2000 mg/day respectively for 3 months. Blood samples withdrawn from each patient at zero time and after 3 months is used to evaluate serum levels of HbA1c, glucose, leptin and insulin, in addition, the measurement of serum level of metformin in blood after 3 months by HPLC. The results demonstrated that all the treated groups with different doses of metformin showed significant improve in all parameters; the use of increased metformin doses was only correlated with plasma leptin levels in the highest dose. In conclusion, serum metformin levels are not good predictors for correlating improvement in clinical and biochemical parameters with increasing the dose in newly diagnosed non-insulin resistant females with type 2 diabetes.

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The pharmacogenetics of metformin and its impact on plasma metformin steady-state levels and glycosylated hemoglobin A1c

Cited by 235 publications

References 43 publications

Endogenous glucose production increases in response to metformin treatment in the glycogen-depleted state in humans: a randomised trial

Endogenous glucose production increases in response to metformin treatment in the glycogen-depleted state in humans: a randomised trial

Advanced glycation end-products (AGEs) and functionality of reverse cholesterol transport in patients with type 2 diabetes and in mouse models

Dose-dependent relationship between serum metformin levels and glycemic control, insulin resistance and leptin levels in females newly diagnosed with type 2 diabetes mellitus

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