Glucose-lowering Effect Of Metformin Research Articles

An update on mode of action of metformin in modulation of meta-inflammation and inflammaging

Type 2 diabetes mellitus (T2DM) is the most common chronic metabolic condition. Several genetic and environmental factors are involved in developing T2DM. Aging, inflammation, and obesity are the main contributors to the initiation of T2DM. They cause chronic sterile meta-inflammation and insulin resistance, thereby making a person more susceptible to developing T2DM. Metformin, a natural cationic biguanide, is widely used as the first-line treatment of T2DM. The exact action mechanism behind the glucose-lowering effect of metformin is not clear, but, presumably, metformin utilizes a broad spectrum of molecular mechanisms to control blood glucose including decreasing intestinal glucose absorption, inhibition of the hepatic gluconeogenesis, decreasing insulin resistance, etc. Recent studies have shown that metformin exerts its effects through the inhibition of mitochondrial respiratory chain complex 1 and the AMP-activated protein kinase (AMPK) activation, but it has been identified in the other studies that AMPK is not the sole hub in metformin mode of action or there are other unknown mechanisms which are involved and yet to be explored. Therefore, here, we discuss the updated findings of the mechanism of action of metformin that contributes to the meta-inflammation and inflammaging action. It is proposed that figuring out the precise mechanism of action of metformin could improve its application in the fields of obesity, inflammation, aging, and inflammaging.

Perfluorooctanesulfonic Acid (PFOS) Thwarts the Beneficial Effects of Calorie Restriction and Metformin.

A combination of calorie restriction (CR), dietary modification, and exercise is the recommended therapy to reverse obesity and nonalcoholic fatty liver disease. In the liver, CR shifts hepatic metabolism from lipid storage to lipid utilization pathways, such as AMP-activated protein kinase (AMPK). Perfluorooctanesulfonic acid (PFOS), a fluorosurfactant previously used in stain repellents and anti-stick materials, can increase hepatic lipids in mice following relatively low-dose exposures. To test the hypothesis that PFOS administration interferes with CR, adult male C57BL/6N mice were fed ad libitum or a 25% reduced calorie diet concomitant with either vehicle (water) or 100 μg PFOS/kg/day via oral gavage for 6 weeks. CR alone improved hepatic lipids and glucose tolerance. PFOS did not significantly alter CR-induced weight loss, white adipose tissue mass, or liver weight over 6 weeks. However, PFOS increased hepatic triglyceride accumulation, in both mice fed ad libitum and subjected to CR. This was associated with decreased phosphorylated AMPK expression in liver. Glucagon (100 nM) treatment induced glucose production in hepatocytes, which was further upregulated with PFOS (2.5 μM) co-treatment. Next, to explore whether the observed changes were related to AMPK signaling, HepG2 cells were treated with metformin or AICAR alone or in combination with PFOS (25 μM). PFOS interfered with glucose-lowering effects of metformin, and AICAR treatment partially impaired PFOS-induced increase in glucose production. In 3T3-L1 adipocytes, metformin was less effective with PFOS co-treatment. Overall, PFOS administration disrupted hepatic lipid and glucose homeostasis and interfered with beneficial glucose-lowering effects of CR and metformin.

M84. METFORMIN FOR EARLY CO-MORBID PREDIABETES OR DIABETES IN SCHIZOPHRENIA SPECTRUM DISORDERS: A DOUBLE BLIND RANDOMIZED PILOT STUDY

BackgroundPatients with severe mental illness (SMI) loose 15–20 years of life due to cardiovascular disease. Much of the metabolic risk, including high rates of type 2 diabetes (T2D) is accrued early on in the illness, highlighting the need for early intervention strategies to target modifiable cardiovascular risk factors. Beyond cardiovascular (CV) risk, metabolic complications have wide-ranging detrimental effects on cognitive performance, medication compliance, and quality of life. There is however an astounding paucity of studies in SMI examining metabolic interventions outside of weight loss. Furthermore, patients with SMI are typically systematically excluded from trials investigating anti-diabetic agents resulting in lack of evidence to guide treatment.MethodsThirty participants with schizophrenia spectrum disorders and co-morbid prediabetes or type 2 diabetes were randomly assigned, in a double-blind fashion to 1500mg/ day of metformin or placebo (2:1 ratio; n=21 metformin and n=9 placebo). Patients had to be overweight or obese, within 5 years of psychosis onset or under the age of 40, and receiving a stable dose of antipsychotics. The primary outcome measures were improvements in glycemia (HbA1c, fasting glucose), and insulin resistance index (Matsuda-derived from glucose tolerance tests and the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)). Secondary outcome measures included changes in weight, fat mass (MRI quantification of hepatic and visceral fat), improvements in cognition, and hippocampal volume (MRI). Data were analyzed using mixed-models methods, and intention to treat analysis.ResultsTwenty-two patients (n=14 metformin; n=8 placebo) completed the 4-month trial. The metformin group had a significant decrease over time in the HOMA-IR (p=0.043), and fasting blood glucose (p=0.007) vs. placebo. There were no differences between treatment groups in the Matsuda index or HBA1c or any secondary outcome measures. Interestingly, weight loss in both groups correlated significantly with decreases in subcutaneous, but not visceral adipose tissue measured by MRI. Controlling for baseline BMI and fasting blood glucose did not change any study findings. Exploratory correlations between change in metabolic indices and change in clinical and cognitive parameters did not reveal any significant associations.DiscussionIndependently of weight loss, metformin is effective in improving dysglycemia and insulin sensitivity in a young, severely mentally ill population at very high risk for early CV mortality. Our preliminary findings, however, fail to find an effect of metformin on weight reduction or tissue specific adiposity measures (which in themselves represent key CV risk factors). Notably, patients in this study had overt glucose dysregulation, a sample routinely excluded in studies examining weight loss interventions in SMI. Moreover, meta-analyses of metformin studies in SMI note greater efficacy early in the illness; possibly weight loss effects are blunted once patients develop prediabetes/T2D. It is also possible that this subgroup of patients may benefit from alternate or combined antidiabetic/obesity therapies.In conclusion, our findings support glucose lowering effects of metformin in SMI patients with early onset prediabetes/T2D, but raise the issue of treatment initiation before the development of overt glucose dysregulation to obtain maximum benefits on adiposity reduction. Given the extremely high rates of T2D in patients with SMI, future adequately powered trials are required to examine metabolic interventions in relation to CV risk factors, and also other related domains such as cognitive function in this highly under-researched population.

The Role of Glucagon-Like Peptide-1 for the Postprandial Effects of Metformin in Type 2 Diabetes

Metformin is the most widely used plasma glucose-lowering drug for the treatment of type 2 diabetes. It has been shown that metformin increases plasma concentrations of glucagon-like peptide-1 (GLP-1), but it remains unknown whether metformin-induced GLP-1 secretion plays any role for the beneficial effects of metformin on postprandial glucose metabolism. We investigated the effect of metformin-induced GLP-1 secretion during meal ingestion in patients with type 2 diabetes using the GLP-1 receptor antagonist exendin[9-39]. In a double-blinded, double dummy, placebo-controlled, randomized, cross-over study, 15 participants with type 2 diabetes (medians: age 71 years, BMI 30.07 kg/m2, HbA1c 50 mmol/mol) were subjected to 14 days’ metformin and placebo treatment, respectively, in randomized order with at least a 2-week washout period between treatments. At the end of each treatment period, two randomized 4-hour mixed meal tests with either concomitant exendin[9-39] (450 pmol/kg/min) or saline infusion, were carried out. Metformin treatment significantly lowered fasting plasma glucose and postprandial plasma glucose excursions compared to placebo. We observed equal metformin-induced reductions in postprandial plasma glucose excursions during saline and exendin[9-39] infusions. Based on postprandial plasma glucose excursions, using the GLP-1 receptor antagonist exendin[9-39], we cannot confirm that GLP-1 secretion is involved in the beneficial postprandial glucose-lowering effects of metformin in patients with type 2 diabetes. Disclosure L.S. Hansen: None. L.S. Gasbjerg: Stock/Shareholder; Self; Antag Therapeutics. A. Brønden: None. N.B. Dalsgaard: None. E. Bahne: None. P.H. Sørensen: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Zealand Pharma A/S. Speaker's Bureau; Self; Merck Sharp & Dohme Corp., AstraZeneca. Research Support; Self; Danish Diabetes Academy, Novo Nordisk Foundation. Other Relationship; Self; Antag Therapeutics. Other Relationship; Spouse/Partner; Antag Therapeutics. T. Vilsbøll: Advisory Panel; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Consultant; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Speaker's Bureau; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Research Support; Self; Eli Lilly and Company, Novo Nordisk A/S. F.K. Knop: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Amgen Inc.. Speaker's Bureau; Self; Merck Sharp & Dohme Corp.. Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Consultant; Self; Amgen Inc.. Advisory Panel; Self; MedImmune, Sanofi. Consultant; Self; Sanofi. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi.

Implication of critical pharmacokinetic gene variants on therapeutic response to metformin in Type 2 diabetes.

Metformin, an oral hypoglycemic drug is the first line of treatment for Type 2 diabetes individuals. We studied the effect of critical gene single nucleotide polymorphisms on the glucose lowering effect of metformin. We performed a prospective study on 221 newly diagnosed, treatment-naive Type 2 diabetes subjects. Individuals were started with metformin monotherapy and followed up for 12 weeks. Our association analysis revealed that SLC22A2 rs316019 and SLC47A2 rs12943590 were significantly associated with metformin drug response across co-dominant and dominant models, respectively. SLC22A2 rs316019 GG and SLC47A2 rs12943590 GA combined genotypes showed maximum average change in HbA1c level. The present study proposes a role of SLC22A2 rs316019 and SLC47A2 rs12943590 in the pharmacokinetic action of metformin.

Pharmacogenetic variation of SLC47A1 gene and metformin response in type2 diabetes patients.

Type 2 diabetes mellitus is a worldwide epidemic disorder with considerable health and economic consequences. Metformin is one of the most commonly prescribed oral antidiabetic drugs. Pharmacogenetic studies showed that variants in genes related to the pharmacokinetics of metformin were associated with glucose-lowering effect of metformin. The aim of this study was to evaluate pharmacogenetic variation in SLC47A1 (rs2289669) and metformin response in type 2 diabetes patients. Seventy one patients with type 2 diabetes were included in the study. The genotypes were determined by Tetra-ARMS-PCR method. There was a significant association between the study polymorphism and the response to metformin treatment with the highest HbA1C reduction in AG genotype. In the dominant model for A allele (AA+AG vs GG), patients with A allele had highest HbA1C reduction in response to metformin.

Involvement of glucagon-like peptide-1 in the glucose-lowering effect of metformin.

Metformin is an oral antihyperglycaemic drug used in the first-line treatment of type 2 diabetes. Metformin's classic and most well-known blood glucose-lowering mechanisms include reduction of hepatic gluconeogenesis and increased peripheral insulin sensitivity. Interestingly, intravenously administered metformin is ineffective and recently, metformin was shown to increase plasma concentrations of the glucose-lowering gut incretin hormone glucagon-like peptide-1 (GLP-1), which may contribute to metformin's glucose-lowering effect in patients with type 2 diabetes. The mechanisms behind metformin-induced increments in GLP-1 levels remain unknown, but it has been hypothesized that metformin stimulates GLP-1 secretion directly and/or indirectly and that metformin prolongs the half-life of GLP-1. Also, it has been suggested that metformin may potentiate the glucose-lowering effects of GLP-1 by increasing target tissue sensitivity to GLP-1. The present article critically reviews the possible mechanisms by which metformin may affect GLP-1 levels and sensitivity and discusses whether such alterations may constitute important and clinically relevant glucose-lowering actions of metformin.

Hepatic glucose and lipid metabolism.

The liver has a central role in the regulation of systemic glucose and lipid fluxes during feeding and fasting and also relies on these substrates for its own energy needs. These parallel requirements are met by coordinated control of carbohydrate and lipid fluxes into and out of the Krebs cycle, which is highly tuned to nutrient availability and heavily regulated by insulin and glucagon. During progression of type 2 diabetes, hepatic carbohydrate and lipid biosynthesis fluxes become elevated, thus contributing to hyperglycaemia and hypertriacylglycerolaemia. Over this interval there are also significant fluctuations in hepatic energy state. To date, it is not known to what extent abnormal glucose and lipid fluxes are causally linked to altered energy states. Recent evidence that the glucose-lowering effects of metformin appear to be mediated by attenuation of hepatic energy generation places an additional spotlight on the interdependence of hepatic biosynthetic and oxidative fluxes. The transition from fasting to feeding results in a significant re-direction of hepatic glucose and lipid fluxes and may also incur a temporary hepatic energy deficit. At present, it is not known to what extent these variables are additionally modified by type 2 diabetes and/or non-alcoholic fatty liver disease. Thus, there is a compelling need to measure fluxes through oxidative, gluconeogenic and lipogenic pathways and determine their relationship with hepatic energy state in both fasting and fed conditions. New magnetic resonance-based technologies allow these variables to be non-invasively studied in animal models and humans. This review summarises a presentation given at the symposium entitled 'The liver in focus' at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Kenneth Cusi, DOI: 10.1007/s00125-016-3952-1 , and by Hannele Yki-Järvinen, DOI: 10.1007/s00125-016-3944-1 ) and a commentary by the Session Chair, Michael Roden (DOI: 10.1007/s00125-016-3911-x ).

Comparison of glucose lowering effect of metformin and acarbose in type 2 diabetes mellitus: a meta-analysis.

BackgroundMetformin is the first-line oral hypoglycemic agent for type 2 diabetes mellitus recommended by international guidelines. However, little information exists comparing it with acarbose which is also commonly used in China. This study expanded knowledge by combining direct and indirect evidence to ascertain the glucose lowering effects of both drugs.MethodsPubMed (1980- December 2013) and China National Knowledge Infrastructure databases (1994-January 2014) were systematically searched for eligible randomized controlled trials from Chinese and English literatures. Meta-analysis was conducted to estimate the glucose lowering effects of metformin vs. acarbose, or either of them vs. common comparators (placebo or sulphonylureas), using random- and fixed-effect models. Bucher method with indirect treatment comparison calculator was applied to convert the summary estimates from the meta-analyses into weighted-mean-difference (WMD) and 95% confidence intervals (CIs) to represent the comparative efficacy between metformin and acarbose.ResultsA total of 75 studies were included in the analysis. In direct comparison (8 trials), metformin reduced glycosylated hemoglobin (HbA1c) by 0.06% more than acarbose, with no significant difference (WMD,-0.06%; 95% CI, -0.32% to 0.20%). In indirect comparisons (67 trials), by using placebo and sulphonylureas as common comparators, metformin achieved significant HbA1c reduction than acarbose, by -0.38% (WMD,-0.38%, 95% CI, -0.736% to -0.024%) and -0.34% (WMD, -0.34%, 95% CI, -0.651% to -0.029%) respectively.ConclusionThe glucose lowering effects of metformin monotherapy and acarbose monotherapy are the same by direct comparison, while metformin is a little better by indirect comparison. This implies that the effect of metformin is at least as good as acarbose's.

Assessment of Pharmacodynamic and Pharmacokinetic Interaction of Aqueous Extract of Cassia auriculata L. and Metformin in Rats.

Background:Cassia auriculata L. (CA) leaf extract might increase the body's production of insulin thereby suppressing the elevated blood glucose and lipid levels in diabetic rats. CA has been used as dietary supplement in India from ancient times.Objective:The present study was to elucidate the synergistic pharmacodynamic (PD) and pharmacokinetic (PK) interaction of metformin (MT) with CA.Materials and Methods:A simple, precise reverse phase high performance liquid chromatography - UV detection mode method was developed to quantify MT in rat plasma. In PD interaction, streptozotocin (45mg/kg, intraperitoneally) induced diabetic Wistar rats weighing 180–250 g of either sex were randomized to receive MT (90 mg/kg, MT-HD), CA (500 mg/kg) separately and in combination of MT (90 mg/kg, MT-HD) + CA (500 mg/kg), and MT (45 mg/kg, MT-LD) + CA (500 mg/kg) (all oral) along with normal and diabetic control groups for 21 days. PK of MT was carried out in normal rats with preadministration of CA (500 mg/kg) for 14 days.Results:PD data showed reasonable blood glucose lowering effect of CA. The reduction of MT dose with combination of CA achieved a similar blood glucose lowering effect of MT alone. PK data showed enhanced time taken to achieve maximum plasma concentration (Cmax), area under the curve (AUC0-t), and Cmax in combination group of MT (90mg/kg) and CA (500mg/kg), and reduction of MT dose in Group III had a reduced Cmax and AUC0-t compared to MT alone treated groups.Conclusion:Co-administration of CA with MT at varying dose showed a synergistic herb-drug interaction. Thus using the synergistic herb-drug interaction, the dose level of MT may be reduced to produce the same therapeutic effect as when taken alone.SUMMARY Elucidating the synergistic pharmacodynamic (PD) and pharmacokinetic (PK) interaction of metformin (MT) with Cassia auriculata L. (CA)PD data showed reasonable blood glucose lowering effect of CA. The reduction of MT dose with combination of CA achieved a similar blood glucose lowering effect of MT alonePK data showed enhanced time taken to achieve maximum plasma concentration (Cmax), area under the curve (AUC0-t), and Cmax in combination group of MT and CA, and reduction of MT dose had a reduced Cmax and AUC0-t compared to MT alone treated groupsCo-administration of CA with MT at varying dose showed a synergistic herb-drug interaction. Thus using the synergistic herb-drug interaction, the dose level of MT may be reduced to produce the same therapeutic effect as when taken alone. Abbreviations used: CA: Cassia auriculata L., PD: Pharmacodynamic, PK: Pharmacokinetic, MT: Metformin, RP-HPLC-UV: Reverse phase High Performance Liquid Chromatography-UV detection mode, Tmax: Time taken to achieve maximum plasma concentration, AUC0-t: Area under the curve, Cmax: Maximum plasma concentration.

The Synergistic Effects of Pioglitazone on the Glucose-Lowering Action of Metformin in Relation to OCT1 and Gluts m-RNA Expression in Healthy Volunteer

Objective: Organic Cation Transporter 1 (OCT1) plays a key role in the disposition of metformin in hepatocytes; a recent non-clinical study reported that the peroxisome-proliferator activated receptor γ agonist pioglitazone increased the expression of Slc22a1 (Oct1) by 3.1-fold as well as its transporting function. We therefore evaluated the effect of pioglitazone on the glucose-lowering effect of metformin in 15 human participants using the Oral Glucose Tolerance Test (OGTT) and measuring the mRNA levels of OCT1, as well as those of Glucose Transporter 1 (GLUT 1) and GLUT4, which are also important in glucose utilization, in peripheral blood cells. Research design and methods: The glucose-lowering effects of metformin were evaluated by the OGTT before and after metformin treatment on Days 1 and 2 of the study and again on Days 18 and 19 after a 14-day course of pioglitazone 30 mg/day. Differences in maximum glucose levels (ΔGmax) and the areas under the glucose-time curve during the first 60 min after glucose ingestion (ΔAUCgluc60) and the entire 180-min test (ΔAUCgluc) caused by metformin treatment were determined before and after pioglitazone administration. Results: Pioglitazone increased ΔGmax by 50.0% (P=0.021), ΔAUCgluc60 by 88.1% (P=0.020), and ΔAUCgluc by 266%. Pioglitazone did not increase OCT1 and GLUT1 mRNA levels in peripheral blood cells. Conclusion: OCT1 induction plays a limited role in the synergistic effect of pioglitazone on the glucose-lowering activity of metformin. However, this synergistic effect lasted 3 days after pioglitazone treatment ended, which warrants further clinical investigation.

Effects of metformin on weight loss: potential mechanisms.

Despite the known glucose-lowering effects of metformin, more recent clinical interest lies in its potential as a weight loss drug. Herein, we discuss the potential mechanisms by which metformin decreases appetite and opposes unfavorable fat storage in peripheral tissues. Many individuals struggle to maintain clinically relevant weight loss from lifestyle and bariatric surgery interventions. Long-term follow-up from the Diabetes Prevention Program demonstrates that metformin produces durable weight loss, and decreased food intake by metformin is the primary weight loss mechanism. Although the effect of metformin on appetite is likely to be multifactorial, changes in hypothalamic physiology, including leptin and insulin sensitivity, have been documented. In addition, novel work in obesity highlights the gastrointestinal physiology and circadian rhythm changes by metformin as not only affecting food intake, but also the regulation of fat oxidation and storage in liver, skeletal muscle, and adipose tissue. Metformin induces modest weight loss in overweight and obese individuals at risk for diabetes. A more detailed understanding of how metformin induces weight loss will likely lead to optimal co-prescription of lifestyle modification with pharmacology for the treatment of obesity independent of diabetes.

The effect of lansoprazole, an OCT inhibitor, on metformin pharmacokinetics in healthy subjects

Gastro-esophageal reflux disease is common in patients with type 2 diabetes. A common treatment is the co-administration of proton-pump inhibitors (PPIs) and metformin. To date, however, the effects of co-administration of PPIs, which inhibit organic cation transporter (OCT) activity, on the action of metformin (a well-known substrate of OCTs) have not been clearly demonstrated. This was a randomized, double-blind, two-way crossover, placebo-controlled trial. Healthy male volunteers (n = 20) received metformin (single dose 1,000 mg on day 1 and single dose 750 mg on day 2, with a 12-h interval) co-administered with placebo or with lansoprazole (30 mg). Plasma concentrations of metformin were measured up to 24 h after the second dose. The glucose-lowering effects of metformin were evaluated by the oral glucose tolerance test before and after each single dose of metformin within the 2-day period. Lansoprazole increased the mean metformin maximum plasma concentration and area under the plasma concentration-time curve from zero to 24 h after the second dosing by 15 and 17 %, respectively (P < 0.05). Moreover, lansoprazole prolonged the metformin elimination half-life from 3.9 to 4.5 h and decreased its renal clearance by 13 % (P < 0.05). However, lansoprazole had no effect on the maximum glucose level and the area under the serum glucose concentration-time curve of metformin. Collectively, we found a modest pharmacokinetic drug interaction between lansoprazole and metformin, which suggests that the concomitant use of these drugs should be appropriately monitored. Further studies are warranted to assess changes in metformin pharmacokinetics in patients with diabetes receiving long-term lansoprazole therapy.

The Effect of Novel Promoter Variants in MATE1 and MATE2 on the Pharmacokinetics and Pharmacodynamics of Metformin

Interindividual variation in response to metformin, first-line therapy for type 2 diabetes, is substantial. Given that transporters are determinants of metformin pharmacokinetics, we examined the effects of promoter variants in both multidrug and toxin extrusion protein 1 (MATE1) (g.-66T → C, rs2252281) and MATE2 (g.-130G → A, rs12943590) on variation in metformin disposition and response. The pharmacokinetics and glucose-lowering effects of metformin were assessed in healthy volunteers (n = 57) receiving metformin. The renal and secretory clearances of metformin were higher (22% and 26%, respectively) in carriers of variant MATE2 who were also MATE1 reference (P < 0.05). Both MATE genotypes were associated with altered post-metformin glucose tolerance, with variant carriers of MATE1 and MATE2 having an enhanced (P < 0.01) and reduced (P < 0.05) response, respectively. Consistent with these results, patients with diabetes (n = 145) carrying the MATE1 variant showed enhanced metformin response. These findings suggest that promoter variants of MATE1 and MATE2 are important determinants of metformin disposition and response in healthy volunteers and diabetic patients.

Pharmacogenomic association between a variant in SLC47A1 gene and therapeutic response to metformin in type 2 diabetes

Pharmacogenetic studies revealed that variants in genes related to the pharmacokinetics of metformin were associated with glucose-lowering effect of metformin. The aim of this study was to investigate possible associations of the variants in genes encoding organic cationic transporters-solute carrier family 22, members A1, A2 (SLC22A1, SLC22A2) and solute carrier family 47, member A1 (SLC47A1) with response to metformin in type 2 diabetes. One hundred forty-eight drug-naive patients with type 2 diabetes were included in the study. Genotyping for SLC22A1 rs622342, SLC22A2 rs316019 and SLC47A1 rs2289669 variants was performed using real-time PCR with subsequent melting-curve analysis. SLC47A1 rs2289669 genotype was significantly associated with the reduction in haemoglobin A1c (HbA1c) after 6 months. Twenty percentage of patients with diabetes that are homozygous for A-allele of SLC47A1 had twofold reduction in HbA1c in comparison with the patients carrying G-allele (GG + GA: 0.55 ± 0.09% vs. AA: 1.10 ± 0.18%, p = 0.018). In conclusion, the results of this study might have in future practical implication in personalised treatment of patients with type 2 diabetes.

Abstract 157: Metabolomic Profiling of AMP-Signaling Stress: Effects of Metformin on Wild Type and Adenylate Kinase AK1-/- Transgenic Mice

Metabolic drugs frequently target mitochondrial functions and AMP signaling. Metformin, one of the most prescribed anti-diabetic medications, exerts its glucose lowering effect through mild interference with mitochondrial energy metabolism triggering homeostatic adenylate kinase (AK)-catalyzed AMP and downstream AMPK signaling. However, metabolomic signature of drug-induced “therapeutic mitochondrial toxicity" and energetic imbalance-induced AMP signaling are poorly understood. This work was aimed to determine metabolomic representation of metformin-induced mitochondrial and AMP signaling stress by comparing wild type and AK1-deficient mice with compromised AMP-signaling. Metabolomic profiling of plasma and urine samples from wild type mice treated with metformin revealed distinct metabolic signature suggesting altered energy, Krebs cycle, lipid and ketone body metabolism, with higher levels of creatinine, malate, α-ketoglutarate, FFA, glycerol, glycerol-3-phosphate, 3-hydroxybutyrate and hypoxanthine. Contrary to expectations glucose lowering effect of metformin was greater in energetically and AMP-signaling compromised AK1-/- mice. Metformin action on AK1 deficient mice was characterized by increased levels of creatinine, lactate, alanine, FFA, phosphoserine, acetoacetate, 3-hydroxybutyrate, malate and α-ketoglutarate indicating broader alterations in energy, glycolytic, Krebs cycle, ketone body, lipid and amino acid metabolism. At baseline, livers from AK1-/- mice had higher AMP/ADP and pAMPKα/AMPKα ratios compared to wild type. There were no significant sustained changes in global nucleotide ratios after metformin treatment. Overall metabolomic profile of AK1-/- mice indicate larger disturbances in energetic and substrate metabolic networks after metformin treatment compared to wild type. Thus, this study revealed specific metabolomic signatures of metformin therapeutic action and mitochondrial toxicity indicating that genetic and metabolic background modulate individual response to metformin treatment.

PS5 - 25. Pharmacogenetics in type 2 diabetes: Genetic variation influences metformin treatment response

The glucose-lowering effect of metformin, the first line treatment for type 2 diabetes, is highly variable between individuals and genetic factors might be involved in this variability. A recent genome wide association study revealed that genetic variation near ATM was associated with metformin treatment success and several studies showed that genetic variation in the metformin transporter genes OCT1, OCT2 and MATE1 influence the response to metformin.

Metformin and Exercise in Type 2 Diabetes

OBJECTIVETo determine the effect of metformin on the acute metabolic response to submaximal exercise, the effect of exercise on plasma metformin concentrations, and the interaction between metformin and exercise on the subsequent response to a standardized meal.RESEARCH DESIGN AND METHODSTen participants with type 2 diabetes were recruited for this randomized crossover study. Metformin or placebo was given for 28 days, followed by the alternate condition for 28 days. On the last 2 days of each condition, participants were assessed during a nonexercise and a subsequent exercise day. Exercise took place in the morning and involved a total of 35 min performed at three different submaximal intensities.RESULTSMetformin increased heart rate and plasma lactate during exercise (both P ≤ 0.01) but lowered respiratory exchange ratio (P = 0.03) without affecting total energy expenditure, which suggests increased fat oxidation. Metformin plasma concentrations were greater at several, but not all, time points on the exercise day compared with the nonexercise day. The glycemic response to a standardized meal was reduced by metformin, but the reduction was attenuated when exercise was added (metformin × exercise interaction, P = 0.05). Glucagon levels were highest in the combined exercise and metformin condition.CONCLUSIONSThis study reveals several ways by which metformin and exercise therapies can affect each other. By increasing heart rate, metformin could lead to the prescription of lower exercise workloads. Furthermore, under the tested conditions, exercise interfered with the glucose-lowering effect of metformin.

Interaction between polymorphisms in the OCT1 and MATE1 transporter and metformin response

Metformin is transported into the hepatocyte by organic cation transporter 1 (OCT1) and out of the hepatocyte by multidrug and toxin extrusion 1 (MATE1). Recently, we discovered that polymorphisms rs622342 A>C in the SLC22A1 gene, coding for OCT1, and rs2289669 G>A in the SLC47A1 gene, coding for MATE1, are associated with the degree of glucose lowering by metformin. In this study, we assessed whether there exists an interaction between these two polymorphisms. We identified all incident metformin users in the Rotterdam Study, a population-based cohort study. Multiplicative interaction between the polymorphisms and change in HbA1c levels was analyzed in 98 incident metformin users. In incident metformin users with the OCT1 rs622342 AA genotype, genetic variation at the MATE1 rs2289669 polymorphism was not associated with change in HbA1c levels [-0.10; 95% confidence interval (CI): -0.35 to 0.14; P=0.39]. In users with the OCT1 rs622342 AC genotype, there was a tendency between rs2289669 polymorphisms and change in HbA1c (-0.31; 95% CI: -0.65 to 0.03; P=0.070) and in users with the OCT1 rs622342 CC genotype there was a significant association with change in HbA1c levels (-0.68; 95% CI: -1.06 to -0.30; P=0.005). The multiplicative interaction between these two genotypes was statistically significant (-0.52; 95% CI: -0.94 to -0.11; P=0.015). The effect of the MATE1 rs2289669 polymorphism on the glucose lowering effect of metformin is larger in incident users with the OCT1 rs622342 CC genotype than in incident users with the AA genotype. The effect in incident users with the OCT1 rs622342 AC genotype is in between.

Metformin primarily decreases plasma glucose not by gluconeogenesis suppression but by activating glucose utilization in a non-obese type 2 diabetes Goto-Kakizaki rats

Metformin is an anti-diabetic agent that has been reported to decrease plasma glucose by multiple mechanisms, such as decreasing hepatic glucose production and activating peripheral glucose utilization. In order to elucidate the primary glucose-lowering mechanism of metformin, the present study focused on a comparison of the acute effect between metformin and CS-917 as a direct gluconeogenesis inhibitor. We examined the effect of metformin and CS-917 on glucose turnover in intravenous glucose-loaded Goto-Kakizaki (GK) rats, and on gluconeogenesis and glucose utilization in rat hepatocytes. Moreover, the glucose-lowering effect of metformin and CS-917 was compared in a fed and a fasted state in GK rats. In intravenous glucose-loaded GK rats, metformin and CS-917 lowered plasma glucose by increasing the glucose disappearance rate and by decreasing the glucose appearance rate, respectively. In rat hepatocytes, CS-917 but not metformin suppressed gluconeogenesis (IC 50 = 0.136 µM). Instead, metformin dose-dependently increased glucose uptake and the following lactate production at 30 to 100 µM. Metformin decreased plasma glucose more in a fed state than in a fasted state in GK rats. CS-917, however, decreased plasma glucose more in a fasted state. These results confirm that metformin primarily decreases plasma glucose not by gluconeogenesis inhibition but by activating glucose utilization in GK rats. Moreover, metformin and CS-917 have different glucose-lowering effects depending on the nutrient state, which may be related to differences in their mechanisms of action. Such differences in action may have implications for metformin and CS-917 in the treatment of type 2 diabetes patients.