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PubMed2006

[Metformin-associated lactic acidosis].

OBJECTIVE: The aims of this review are to precise the pathophysiological mechanisms leading to biguanide-associated lactic acidosis, to give elements of diagnosis, and to underline the precautionary conditions for prescribing these drugs by an improvement in physicians and patient's education. DATA SOURCES: A PubMed database research in English and French language reports published until December 2005. The keywords were: lactic acidosis, metformin, biguanide, diabetes mellitus. DATA EXTRACTION: Data in selected articles were reviewed, clinical and basic science research relevant informations were extracted. DATA SYNTHESIS: Metformin, which is an oral antidiabetic agent, is the only one biguanide available in France. It acts by enhancing the sensitivity to insulin by a decrease in the hepatic glucose production and an increase in its peripheral use. In term of glycemic control, it has the same efficiency than the other hypoglycemic agents. It represents the treatment of choice for overweight type 2 diabetic patients because of its beneficial effects on the weight loss and on the cardiovascular complications. The incidence of metformin-associated lactic acidosis is very low when contra-indications and appropriate rules for prescribing this drug are respected. The relationship between metformin and lactic acidosis remains largely controversial. In practical, we can distinguish three situations which have different prognosis. In the first case, metformin seems to be responsible for lactic acidosis because of self-poisoning or accidental overdose, and prognosis is good. In the second case, the association between metformin and lactic acidosis is coincidental rather than causal, and may be induced by an underlying organ failure. In the last case there is a cause of lactic acidosis which is worsened by a precipitating factor leading to metformin accumulation. The 2 latter situations are very severe as mortality rate is about 50%. Symptomatic treatments and renal replacement therapy which allows metformin removal are the curative treatment. Prevention is essential. It requires the respect of metformin contraindications and a better education of physicians and patients for a safe prescription. CONCLUSION: Due to its beneficial effects, metformin is the gold standard treatment for overweight type 2 diabetic patients. The essential precautionary conditions for prescribing metformin as well as the respect of its contra-indications permit largely to prevent lactic acidosis. This complication is serious when it is associated with intercurrent illnesses and metformin accumulation. The curative treatment is based on renal replacement therapy. Prevention only rests on the respect of the contra-indications. Education of physicians and patients concerning the rules of prescription remains essential.

Acidosis, Lactic↗
PubMed2004

Effect of metformin treatment on multiple cardiovascular disease risk factors in patients with type 2 diabetes mellitus.

In light of the conflicting results of the recent United Kingdom Prospective Study (UKPDS), where diabetic patients on metformin monotherapy had lower all-cause mortality and the addition of metformin in sulfonylurea-treated patients was associated with an increased risk of diabetes-related death, we sought to compare the effects on cardiovascular disease (CVD) risk factors of metformin monotherapy with metformin treatment when added to a sulfonylurea compound in patients with type 2 diabetes. Thirty-one volunteers with type 2 diabetes mellitus, 16 on dietary therapy and 15 on sulfonylurea monotherapy (SU), were treated with metformin for 12 weeks. Measurements were made of (1) fasting plasma glucose, hemoglobin A(1c) (HbA(1c)), lipid, remnant lipoprotein cholesterol (RLP-C) levels, and low-density lipoprotein (LDL) particle size; (2) daylong plasma glucose, insulin, free fatty acid (FFA), triglyceride (TG), and RLP-C concentrations; and (3) fasting levels of soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), and soluble E-selectin (sE-selectin). Fasting plasma glucose concentrations decreased to a similar degree after treatment with metformin in both the metformin monotherapy group (12.45 +/- 0.48 v 9.46 +/- 0.47 mmol/L, P <.001) and the combined SU and metformin therapy group (14.09 +/- 0.51 v 10.57 +/- 0.85 mmol/L, P =.001). Fasting plasma lipid concentrations and LDL particle size did not significantly change in either treatment group, whereas fasting RLP-C concentrations were significantly lower in the metformin monotherapy group (0.43 +/- 0.09 v 0.34 +/- 0.07 mmol/L, P =.02). Daylong concentrations of plasma glucose, FFA, TG, and RLP-C were lower to a similar degree in both treatment groups, whereas daylong plasma insulin concentrations were unchanged. Fasting plasma sVCAM-1 levels were significantly lower in both the metformin monotherapy group (484 +/- 19 v 446 +/- 18 ng/mL, P =.02) and the combined SU and metformin therapy group (496 +/- 29 v 456 +/- 31 ng/mL, P =.05), whereas fasting plasma sICAM-1 and sE-selectin levels were essentially unchanged. Administration of metformin, either as monotherapy or in combination with a sulfonylurea drug, improved glycemic control and led to a decrease in several CVD risk factors in patients with type 2 diabetes.

Aged↗
PubMed2003

Metformin hydrochloride in the treatment of type 2 diabetes mellitus: a clinical review with a focus on dual therapy.

BACKGROUND: Type 2 diabetes mellitus typically involves abnormal beta-cell function that results in relative insulin deficiency, insulin resistance accompanied by decreased glucose transport into muscle and fat cells, and increased hepatic glucose output, all of which contribute to hyperglycemia. OBJECTIVE: This review examines the pharmacology, pharmacokinetics, drug-interaction potential, adverse effects, and dosing guidelines for metformin hydrochloride, a biguanide agent for the treatment of type 2 diabetes. Clinical trial data are reviewed, including efficacy and tolerability information, with a focus on studies of dual metformin therapy (metformin plus another oral agent or insulin) published from 1998 to the present. Pharmacoeconomic considerations are also discussed. METHODS: Primary research and review articles were identified through a search of MEDLINE (1966-May 2003) and International Pharmaceutical Abstracts (1970-May 2003) using the terms metformin and/or Glucophage. Web of Science (1995-May 2003) was used to search for additional abstracts. The package inserts for metformin and metformin combination products were consulted. All identified articles and abstracts were assessed for relevance, and all relevant information was included. Priority was given to the primary medical literature and clinical trial reports. RESULTS: Metformin is the only currently available oral antidiabetic/hypoglycemic agent that acts predominantly by inhibiting hepatic glucose release. Because patients with type 2 diabetes often have excess hepatic glucose output, use of metformin is effective in lowering glycosylated hemoglobin (HbA1c) by 1 to 2 percentage points when used as monotherapy or in combination with other blood glucose-lowering agents or insulin. Other metabolic variables (eg, dyslipidemia, fibrinolysis) may be improved with the use of metformin. Body weight is often maintained or slightly reduced from baseline. Metformin is well tolerated and is associated with few clinically deleterious adverse events. The most important and potentially life-threatening adverse event associated with its use is lactic acidosis, which occurs very rarely. CONCLUSIONS: Metformin has multiple benefits in patients with type 2 diabetes. It can effectively lower HbA1c values, positively affect lipid profiles, and improve vascular and hemodynamic indices. Adverse effects are generally tolerable and self-limiting. The availability of products combining metformin with a sulfonylurea or rosiglitazone has expanded the array of therapies for the management of type 2 diabetes.

Clinical Trials as Topic↗
PubMed2004

A comparison of the effects of thiazolidinediones and metformin on metabolic control in patients with type 2 diabetes mellitus.

BACKGROUND: Type 2 diabetes mellitus is a condition characterized by impaired insulin secretion and resistance to insulin-mediated glucose uptake and utilization. A number of oral antidiabetic medication are available for its treatment, including metformin and the thiazolidinediones (TZDs). The TZDs have been shown to improve insulin resistance, and it has been suggested that metformin has similar effects. Although both types of agents improve glycemic control, their mechanisms of action and effects on metabolic processes differ. OBJECTIVE: The goal of this review was to compare the effects of TZDs and metformin on metabolic control in patients with type 2 diabetes. METHODS: A search of MEDLINE to March 2004 using the terms metformin and biguanides, and thiazolidinediones and glitazones was conducted to identify preclinical and clinical studies focusing on the mechanisms of action and comparative effects of TZDs and metformin. Also searched were published abstracts from recent major diabetes and endocrinology conferences. RESULTS: In the studies reviewed, both TZDs and metformin demonstrated the ability to improve glycemic control, although long-term monotherapy with TZDs appeared to be more effective than metformin. There continues to be debate about whether metformin is more effective than TZDs in terms of inhibition of hepatic glucose production. However, various studies have found TZDs to be more effective in promoting an increase in whole-body insulin sensitivity. With respect to lipid metabolism, patients who received TZDs had a greater reduction in concentrations of both plasma triglycerides and free fatty acids. Metformin was more effective in promoting weight loss in patients with type 2 diabetes, although TZDs may decrease visceral fat levels. Treatment with either metformin or TZDs was associated with a reduction in the risk of cardiovascular disease, although the mechanisms by which they accomplished this seem to differ. CONCLUSIONS: The evidence suggests that the predominant effect of metformin is inhibition of hepatic glucose production, whereas the primary effects of TZDs is reduction of insulin resistance and promotion of peripheral glucose uptake. TZDs appear to have more positive effects on other metabolic processes and to be associated with greater improvements in cardiovascular risk factors compared with metformin.

Animals↗
PubMed2006

Effect of metformin on survival rate in experimental sepsis.

AIM: Because "metformin-associated lactic acidosis" refers to metformin and concurrent pathologies as co-precipitating factors, the respective impact in the outcome of metformin therapy, metformin accumulation, and general diseases should be determined. We therefore constructed a model of sepsis in mice treated with metformin at a dose corresponding to clinical practice, or to accumulation. METHODS: 460 mice were separated in 3 groups: no metformin therapy, a 7-day metformin therapy at 50 mg.kg(-1).day(-1) (MET50) or 500 mg.kg(-1).day(-1) (MET500). Blood was drawn on day 7 in 40 metformin-treated animals for determining metformin concentrations. The 420 other mice were divided in 14 subgroups according to the amount of an intra-peritoneal inoculum of E. coli ranging from 5.103 to 1010 CFU/ml in order to construct a lethal dose curve. The survival rate was assessed at 7, 13, 24, 36, 60 and 120 hours thereafter. RESULTS: Plasma metformin concentrations were 0.26 +/- 0.13 mg/l in MET50, and 4.63 +/- 1.92 mg/l in MET500. The comparative analysis of the survival rates at 120 hours showed no difference of mortality, always occurring for an inoculum amount > 10(8) CFU/ml. Comparing the survival rates from time 0 to 120 hours using Kaplan-Meyer curves and the Logrank test, there was no difference between the different groups. CONCLUSION: Metformin, even at a dose mimicking accumulation, does not aggravate the mortality rate in this model of sepsis. Consequently, metformin can not be considered as toxic in such a condition.

Animals↗
PubMed2002

Metformin enhances insulin signalling in insulin-dependent and-independent pathways in insulin resistant muscle cells.

1 Metformin lowers blood glucose levels in type 2 diabetic patients. To evaluate the insulin sensitizing action of metformin on skeletal muscle cells, we have used C2C12 skeletal muscle cells differentiated in chronic presence or absence of insulin. 2 Metformin was added during the last 24 h of differentiation of the C2C12 myotubes. Insulin-stimulated tyrosine phosphorylation of insulin receptor (IR) and insulin receptor substrate-1 (IRS-1) was determined. 3 Chronic insulin treatment resulted in 60 and 40% reduction in insulin-stimulated tyrosine phosphorylation of IR and IRS-1, respectively. Treatment with metformin was able to increase the tyrosine phosphorylation of IR and IRS-1 by 100 and 90% respectively. 4 Chronic insulin treatment drastically reduced (45%) insulin-stimulated phosphatidyl inositol 3-kinase (PI 3-kinase) activity. Metformin treatment restored PI 3-kinase activity in insulin-resistant myotubes. 5 Insulin-stimulated glucose uptake was impaired in chronically insulin-treated myotubes. Metformin increased basal glucose uptake to significant levels (P<0.05), but metformin did not increase insulin-stimulated glucose transport. 6 All the three mitogen-activated protein kinases (MAPK) were activated by insulin in sensitive myotubes. The activation of p38 MAPK was impaired in resistant myotubes, while ERK and JNK were unaffected. Treatment with metformin enhanced the basal activation levels of p38 in both sensitive and resistant myotubes, but insulin did not further stimulate p38 activation in metformin treated cells. 7 Treatment of cells with p38 inhibitor, SB203580, blocked insulin- and metformin-stimulated glucose uptake as well as p38 activation. 8 Since the effect of metformin on glucose uptake corresponded to p38 MAPK activation, this suggests the potential role p38 in glucose uptake. 9 These data demonstrate the direct insulin sensitizing action of metformin on skeletal muscle cells.

Animals↗
PubMed2004

Activation of the AMP-activated protein kinase by the anti-diabetic drug metformin in vivo. Role of mitochondrial reactive nitrogen species.

Metformin, one of the most commonly used drugs for the treatment of type II diabetes, was recently found to exert its therapeutic effects, at least in part, by activating the AMP-activated protein kinase (AMPK). However, the site of its action, as well as the mechanism to activate AMPK, remains elusive. Here we report how metformin activates AMPK. In cultured bovine aortic endothelial cells, metformin dose-dependently activated AMPK in parallel with increased detection of reactive nitrogen species (RNS). Further, either depletion of mitochondria or adenoviral overexpression of superoxide dismutases, as well as inhibition of nitric-oxide synthase, abolished the metformin-enhanced phosphorylations and activities of AMPK, implicating that activation of AMPK by metformin might be mediated by the mitochondria-derived RNS. Furthermore, administration of metformin, which increased 3-nitrotyrosine staining in hearts of C57BL6, resulted in parallel activation of AMPK in the aorta and hearts of C57BL6 mice but not in those of endothelial nitric-oxide synthase (eNOS) knockout mice in which metformin had no effect on 3-nitrotyrosine staining. Because the eNOS knockout mice expressed normal levels of AMPK-alpha that was activated by 5-aminoimidazole-4-carboxamide riboside, an AMPK agonist, these data indicate that RNS generated by metformin is required for AMPK activation in vivo. In addition, metformin significantly increased the co-immunoprecipitation of AMPK and its upstream kinase, LKB1, in C57BL6 mice administered to metformin in vivo. Using pharmacological and genetic inhibitors, we found that inhibition of either c-Src or PI3K abolished AMPK that was enhanced by metformin. We conclude that activation of AMPK by metformin might be mediated by mitochondria-derived RNS, and activation of the c-Src/PI3K pathway might generate a metabolite or other molecule inside the cell to promote AMPK activation by the LKB1 complex.

AMP-Activated Protein Kinases↗
PubMed2005

Effects of short-term treatment with metformin on markers of endothelial function and inflammatory activity in type 2 diabetes mellitus: a randomized, placebo-controlled trial.

OBJECTIVES: The UK Prospective Diabetes Study (UKPDS) showed that treatment with metformin decreases macrovascular morbidity and mortality independent of glycaemic control. We hypothesized that metformin may achieve this by improving endothelial function and chronic, low-grade inflammation. Data on this issue are scarce and we therefore tested, in the setting of a randomized, placebo-controlled trial, whether metformin can affect endothelial function and low-grade inflammation. DESIGN: The Hyperinsulinaemia the Outcome of its Metabolic Effects (HOME) trial is a double-blind trial, in which all patients were randomized to receive either metformin or placebo in addition to insulin therapy. At the beginning and the end of a 16-week treatment period fasting blood samples were drawn and a physical examination was carried out. SETTING: The trial was conducted in the outpatient clinics of three nonacademic hospitals (Hoogeveen, Meppel and Coevorden; the Netherlands). SUBJECTS: Patients were included if they were between 30 and 80 years of age; had received a diagnosis of diabetes after the age of 25; had never had an episode of ketoacidosis; and their blood glucose-lowering treatment previously consisted of oral agents but now only consisted of either insulin (n = 345) or insulin and metformin (n = 45). We excluded pregnant women and women trying to become pregnant, patients with a Cockroft-Gault-estimated creatinine clearance <50 mL min(-1), or low plasma cholinesterase (reference value <3.5 units L(-1)), patients with congestive heart failure (New York Heart Association class III/IV), or patients with other serious medical or psychiatric disease. A total of 745 eligible patients were approached; 390 gave informed consent and were randomized (196 metformin, 194 placebo). About 353 patients completed 16 weeks of treatment (171 metformin, 182 placebo). MAIN OUTCOME MEASURES: The HOME trial was designed to study the metabolic and cardiovascular effects of metformin during a follow-up of 4 years. Presented here are the results of an interim analysis after 16 weeks of treatment. RESULTS: When compared with placebo, metformin treatment was associated with an increase in urinary albumin excretion of 21% (-1 to +48; P = 0.06); a decrease in plasma von Willebrand factor of 6% (-10 to -2; P = 0.0007); a decrease in soluble vascular cell adhesion molecule-1 of 4% (-7 to -2; P = 0.0002); a decrease in soluble E-selectin of 6% (-10 to -2; P = 0.008); a decrease in tissue-type plasminogen activator of 16% (-20 to -12; P < 0.0001); and a decrease in plasminogen activator inhibitor-1 of 20% (-27 to -10; P = 0.0001). These changes could not be explained by metformin-associated changes in glycaemic control, body weight or insulin dose. Markers of inflammation, i.e. C-reactive protein and soluble intercellular adhesion molecule-1, did not change with metformin treatment. CONCLUSIONS: In patients with type 2 diabetes treated with insulin, metformin treatment was associated with improvement of endothelial function, which was largely unrelated to changes in glycaemic control, but not with improvement of chronic, low-grade inflammation.

Adult↗
PubMed1992

Effect of metformin on glucose metabolism in the splanchnic bed.

1. Use of the antihyperglycaemic agent, metformin, is often associated with a small rise in circulating lactate. This study investigates the source of the lactate and examines the effect of metformin on glucose metabolism by the intestine and liver of rats. 2. Changes in plasma glucose and lactate were measured in the inferior vena cava (IVC), hepatic portal vein (HPV), hepatic vein (HV) and aorta (A) after intrajejunal administration of metformin (50 and 250 mg kg-1) without and with glucose (2 g kg-1). 3. Metformin 250 mg kg-1 reduced the hyperglycaemic response to a glucose challenge, associated with a greater reduction of glucose concentrations in the HPV (average decrease of 33% at 60 and 120 min) than at other sites. 4. Both doses of metformin increased lactate concentrations in the glucose-loaded state: the highest concentration (2.5 fold increase) was recorded in the HPV 60 min after administration of 250 mg kg-1 metformin, with a high lactate concentration persisting in the HV at 120 min. Metformin 250 mg kg-1 also increased lactate concentrations in the basal state, with highest concentrations (2 fold increase) in the HPV. 5. Two hours after intrajejunal administration of metformin, 50 mg kg-1, rings of tissue from the small intestine showed an average 22% decrease in glucose oxidation ([14C]-glucose conversion to 14CO2) and a 10% increase in lactate production. Since glucose metabolism in the gut is predominantly anaerobic, metformin caused an overall 9.5% increase of intestinal glucose utilization.6. Metformin, 10-6 and I0- mol 1', did not significantly alter glucose oxidation or lactate production by isolated hepatocytes, but a very high concentration of metformin (102 mol 1') increased lactate production by 60%.7. The results support the view that metformin increased intestinal glucose utilization and lactate production by the intestine. Under basal conditions there was net extraction of lactate by the liver but not after an enteral glucose load.

Animals↗
PubMed2006

Metformin increases the PGC-1alpha protein and oxidative enzyme activities possibly via AMPK phosphorylation in skeletal muscle in vivo.

AMP-activated protein kinase (AMPK), which was activated by an antihyperglycemic drug metformin, has been hypothesized to mediate metabolic adaptations. The purposes of the present study were 1) to confirm whether acute metformin administration induced AMPK phosphorylation and 2) to determine whether chronic metformin treatment increased the peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) protein expression, glycolytic and oxidative enzyme activities, and cytochrome c and glucose transporter-4 (GLUT4) protein expressions in the rat soleus and red and white gastrocnemius muscles. The single oral administration of metformin (300 mg/kg body wt) enhanced the AMPK phosphorylation at 5 and/or 6 h after treatment. In the chronic study, rats were fed either normal chow or chow containing 1% metformin for 14 days. Metformin treatment resulted in a mean daily metformin intake of 631 mg.kg body wt(-1).day(-1). Metformin increased the PGC-1alpha content in all three muscles. Metformin increased the hexokinase activity in the white gastrocnemius, the citrate synthase activity in all three muscles, and the beta-hydroxyacyl-CoA dehydrogenase activity in the soleus. The cytochrome c protein content in the soleus muscle also increased. The GLUT4 content was unchanged by metformin. These results suggest that metformin enhances the PGC-1alpha expression and mitochondrial biogenesis possibly at least in part via AMPK phosphorylation in the skeletal muscle. Metformin has thus been proposed to possibly ameliorate insulin resistance, at least partially, by means of such metabolic effects.

AMP-Activated Protein Kinases↗
PubMed2006

Long-term metformin treatment stimulates cardiomyocyte glucose transport through an AMP-activated protein kinase-dependent reduction in GLUT4 endocytosis.

Long-term (18 h) metformin treatment of cardiomyocytes increased glucose transport activity 3- to 5-fold, as measured using the phosphorylated sugar 2-deoxy-D-glucose and the nonphosphorylated sugar 3-O-methyl-D-glucose. The affinity for 3-O-methyl-D-glucose transport was not increased by metformin treatment. Total levels of glucose transporter 4 (GLUT4) were not changed by 18-h culture with or without insulin or metformin treatment. GLUT1 levels were elevated after 18 h in culture, but this increase was not altered by insulin or metformin treatment. Metformin-induced stimulation of transport was not inhibited by treatment with wortmannin and was additive with that of insulin. These data suggest that the metformin effect is mediated by a signaling route independent of phosphatidylinositol 3-kinase and Akt. Surprisingly, however, levels of both phospho-AMP-activated protein kinase and phospho-Akt were increased 4- and 3-fold, respectively, after metformin treatment. Chronic treatment with insulin for 18 h led to down-regulation of insulin-stimulated glucose transport. Cotreatment with metformin bypassed this insulin resistance by maintaining high transport levels. These data also indicate an independent point of convergence of metformin and insulin stimuli on GLUT4 regulatory processes. To test the possibility of altered GLUT4 subcellular trafficking, the kinetics of GLUT4 exocytosis and endocytosis were determined. Metformin treatment markedly slowed endocytosis of GLUT4, but exocytosis was not increased. We conclude that metformin treatment leads to a longer residence time of GLUT4 in the plasma membrane due to an AMP-activated protein kinase-dependent reduction in endocytosis. This accounts for metformin's ability to enhance hexose transport activity above insulin-stimulated and Akt-dependent levels.

AMP-Activated Protein Kinases↗
PubMed1995

Action of metformin on glucose transport and glucose transporter GLUT1 and GLUT4 in heart muscle cells from healthy and diabetic rats.

The effects of the antidiabetic drug metformin on glucose transport were investigated in freshly isolated heart muscle cells from healthy and streptozotocin-diabetic rats. In vivo treatment of diabetic rats with metformin failed to affect the basal and insulin-stimulated rate of glucose transport measured in isolated cells. In vitro exposure to therapeutic concentrations (< or = 10(-4) M) of metformin did not influence glucose transport, even upon incubation times up to 5 h or in the presence of high glucose (20 nM). In contrast, higher metformin concentrations produced an 8- to 12-fold increase in glucose uptake (with a lag of 90 min, and a maximum at 180 min and approximately 5 mM). In the presence of submaximal insulin concentrations (< or = 3.10(-10) M), the effects of metformin (5 mM) and of insulin were more than additive, whereas, at saturating insulin concentrations (10(-8) M), partial additivity was observed. Like insulin, metformin caused an approximately 1.6-fold increase in the content of both glucose transporter isoforms GLUT1 and GLUT4 in the plasma membrane of cardiac myocytes, with a corresponding decrease in an intracellular membrane fraction. cAMP-elevating treatments depressed the metformin-, but not the insulin-dependent glucose uptake, by 20-30%. In myocytes from diabetic rats, the rate of metformin-activated glucose transport was similar to that of cells from control animals, whereas basal and insulin-stimulated transport were substantially diminished. Finally, metformin (5 mM) induced a slight depression of oxygen consumption and energy metabolism of myocytes (as determined by measuring their level of energy-rich phosphates) comparable to the effects of hypoxia in rat hearts. In conclusion, these data do not provide evidence in favor of the hypothesis that glucose uptake by muscle tissue represents the site of metformin's therapeutic action in vivo. On the other hand, the large, insulin-independent effect of metformin at high concentrations (approximately mM) in vitro may be related to the action of hypoxia and occurs through a redistribution of glucose carriers from an intracellular locus to the plasma membrane. The mechanism (or signal) involved in metformin's action is likely to differ from that triggered by insulin and is not impaired in the diabetic state.

Animals↗
PubMed1996

Metabolic effects of metformin on glucose and lactate metabolism in noninsulin-dependent diabetes mellitus.

Metformin is a biguanide that has been shown to effectively lower plasma glucose levels in subjects with noninsulin-dependent diabetes mellitus (NIDDM). However, its mechanism of action remains unknown. Studies that have examined the effect of metformin on hepatic glucose production (HGP) and muscle glucose utilization in NIDDM have yielded conflicting results, and little information is available about the action of metformin on lactate turnover and gluconeogenesis from lactate in humans. We studied 20 NIDDM subjects and 8 nondiabetic controls in a randomized, double blind, placebo-controlled trial to determine the effect of 15 weeks of treatment with metformin or placebo on glucose and lactate metabolism. Before and after treatment, all participants received a 7-h infusion of [6-3H]glucose and [3-14C]lactate in combination with indirect calorimetry and estimation of lactate central vein specific activity. A euglycemic insulin clamp (20 mU/m2.min) was performed during the last 3 h of the tracer infusions. The study design allowed us to evaluate the effects of metformin vs. placebo treatment on glycemic control, plasma lipid profile, HGP, insulin-mediated glucose uptake, oxidative and nonoxidative glucose metabolism, and lactate turnover. Metformin treatment significantly reduced fasting plasma glucose (196 +/- 18 vs. 152 +/- 12 mg/dL; P < 0.01), hemoglobin A1 (12.5 +/- 0.6 vs. 9.2 +/- 0.3%; P < 0.01), and plasma triglyceride and low density lipoprotein cholesterol concentrations. When diabetics were compared to nondiabetic controls, basal HGP was higher (12.9 +/- 1.0 vs. 9.8 +/- 1.2 mumol/kg.min; P < 0.01) despite the presence of fasting hyperinsulinemia and insulin-mediated total body glucose disposal (10.9 +/- 0.9 vs. 20.2 +/- 3.3 mumol/kg.min; P < 0.01) was decreased. Metformin significantly reduced fasting HGP (from 12.9 +/- 0.7 to 11.0 +/- 0.5 mumol/kg.min; P < 0.01), but did not enhance total body glucose disposal during insulin stimulation (10.9 +/- 0.9 vs. 11.0 +/- 0.5 mumol/kg.min; P = NS). Neither oxidative nor nonoxidative glucose disposal was improved by metformin treatment. The fasting plasma lactate concentration (1.1 +/- 0.1 vs. 0.6 +/- 0.1 mmol/L) and lactate turnover (14.0 +/- 0.8 vs. 10.3 +/- 0.6 mumol/kg.min) were significantly increased in diabetics and strongly correlated (r = 0.68; P < 0.001). The percent gluconeogenesis derived from lactate was similar in diabetic and control subjects (17 +/- 2% vs. 15 +/- 2%; P = NS), but the estimated rate of gluconeogenesis from lactate was increased in the diabetic group (P < 0.01). Despite the significant reduction in HGP after metformin treatment, the percentage of gluconeogenesis from lactate and the rate of lactate-derived gluconeogenesis were unchanged from baseline. Basal lactate turnover (15.4 +/- 1.4 vs. 14.8 +/- 1.4 mumol/kg.min) and lactate oxidation (7.9 +/- 0.7 vs. 8.1 +/- 0.9 mumol/ kg.min) as well as total lactate turnover and lactate oxidation during the insulin clamp were similar before and after metformin treatment. There were no changes in any of the above metabolic parameters in the placebo-treated group. In poorly controlled NIDDM subjects, the primary mechanism by which metformin improves glycemic control is related to the suppression of accelerated basal HGP, and this most likely is secondary to an inhibition of hepatic glycogenolysis. Metformin has no effect on the rate of lactate turnover or gluconeogenesis from lactate in either the basal or insulin-stimulated states.

Blood Glucose↗
PubMed2000

Uptake and dispersion of metformin in the isolated perfused rat liver.

Although metformin is a widely used oral antihyperglycaemic, the exact mechanisms of its cellular uptake and action remain obscure. In this study the hepatic extraction and disposition kinetics of metformin were investigated by use of an isolated in-situ rat liver preparation. The liver was perfused in single-pass mode with protein-free Krebs bicarbonate medium at a flow rate of 20 mL min(-1). During constant infusion with 1 mg L(-1) metformin hydrochloride the hepatic uptake of metformin approached equilibrium within 10 min. The steady-state availability, F, determined from the ratio of outflow concentration to input concentration, was 0.99+/-0.02 (mean +/- s.d., n = 4). The outflow profile of metformin resulting from a bolus injection of 25 microg into the portal vein, had a sharp peak then a slower declining terminal phase. The mean transit time (MTT; 49.5+/-14.5, n = 6) and normalized variance (CV2; 4.13+/-0.05) of the hepatic transit times of metformin were estimated by numerical integration from the statistical moments of the outflow data. The volume of distribution of metformin in the liver (1.58+/-0.28 mL (g liver)(-1)) was estimated from its MTT. The volume of distribution is greater than the water space of liver, indicating that metformin enters the hepatic aqueous space and becomes distributed among cellular components. The magnitude of CV2 for metformin is greater than for the vascular marker sucrose, suggesting that distribution of metformin into hepatic tissue is not instantaneous. In conclusion, hepatic uptake of metformin is rate-limited by a permeability barrier. Although metformin is accumulated in the liver, the organ does not extract it.

Animals↗
PubMed1983

Pharmacologic effects of metformin in relation to its disposition in alloxan diabetic rats.

The purpose of this investigation is to elucidate the relationship between the time course of pharmacologic effects and drug disposition after administration of metformin, an oral antidiabetic drug of biguanides. Alloxan diabetic rats and normal rats were used in the experiments. After administration of metformin, plasma glucose levels, blood pyruvate levels, blood lactate levels, plasma pancreatic glucagon immunoreactivity (pancreatic GI) and plasma gut glucagon like immunoreactivity (gut GLI) were determined as well as serum concentrations of metformin. In alloxan diabetic rats, gut GLI levels were significantly correlated to the logarithm of tissue metformin levels, calculated from serum metformin levels. The blood lactate, pyruvate and plasma glucose levels were also linearly related to gut GLI levels, after metformin administration. It was also clarified that metformin did not inhibit the intestinal absorption of glucose and that metformin presumably inhibited the hepatic gluconeogenesis. It is reasonable to consider that the effect of metformin on the gut GLI level is the primal effect, and that other pharmacologic effects such as plasma glucose lowering, blood lactate and pyruvate increasing effects are the consequences of the primal effect, at least in alloxan diabetic rats. While in normal rats, plasma gut GLI levels were not significantly related to metformin tissue levels, however, plasma glucose levels were considerably correlated with the logarithm of the plasma or tissue metformin levels. These results indicated that the effect of gut GLI was entirely masked by endogeneous insulin, which might be secreted by metformin administration.

Administration, Oral↗
PubMed1994

Internalization of metformin is necessary for its action on potentiating the insulin-induced Xenopus laevis oocyte maturation.

In this study, metformin (N, N1 dimethylbiguanide) was found to potentiate insulin-induced Xenopus laevis oocyte maturation, a phenomenon of transition from late G2 to M phase of the cell cycle. These cells also accumulated exogenous metformin (130 +/- 6.5 nmol/oocyte). Metformin covalently-coupled to Sepharose 4B beads failed to potentiate the insulin-induced oocyte maturation which suggests that these cells did not take up metformin from the extracellular medium. Addition of metformin alone to Xenopus laevis oocytes did not induce the maturation process, though these cells took up exogenous metformin. Micro-injection of metformin (120 nmol/oocyte) to oocytes accelerated the insulin-induced maturation, but it was lower than in cells which were incubated with free metformin together with insulin. Interestingly, insulin had no effect on metformin uptake by the oocytes. Methylglyoxal-bis(guanylhydrazone), MGBG, an apparent analogue of metformin, induced oocyte maturation. Addition of metformin, either free or Sepharose-bound, did not influence the MGBG-induced 60% maturation of Xenopus laevis oocytes. These results suggest that the internalization of metformin is necessary for its action and its effects are specific on insulin activity.

Animals↗
PubMed1995

Metformin. A review of its pharmacological properties and therapeutic use in non-insulin-dependent diabetes mellitus.

The biguanide metformin (dimethylbiguanide) is an oral antihyperglycaemic agent used in the management of non-insulin-dependent diabetes mellitus (NIDDM). It reduces blood glucose levels, predominantly by improving hepatic and peripheral tissue sensitivity to insulin without affecting the secretion of this hormone. Metformin also appears to have potentially beneficial effects on serum lipid levels and fibrinolytic activity, although the long term clinical implications of these effects are unclear. Metformin possesses similar antihyperglycaemic efficacy to sulphonylureas in obese and nonobese patients with NIDDM. Additionally, interim data from the large multicentre United Kingdom Prospective Diabetes Study (UKPDS) indicated similar antihyperglycaemic efficacy for metformin and insulin in newly diagnosed patients with NIDDM. Unlike the sulphonylureas and insulin, however, metformin treatment is not associated with increased bodyweight. Addition of metformin to existing antidiabetic therapy confers enhanced antihyperglycaemic efficacy. This may be of particular use in improving glycaemic control in patients with NIDDM not adequately controlled with sulphonylurea monotherapy, and may serve to reduce or eliminate the need for daily insulin injections in patients with NIDDM who require this therapy. The acute, reversible gastrointestinal adverse effects seen with metformin may be minimised by administration with or after food, and by using lower dosages, increased slowly where necessary. Lactic acidosis due to metformin is rare, and the risk of this complication may be minimised by observance of prescribing precautions and contraindications intended to avoid accumulation of the drug or lactate in the body. Unlike the sulphonylureas, metformin does not cause hypoglycaemia. Thus, metformin is an effective antihyperglycaemic agent which appears to improve aberrant plasma lipid and fibrinolytic profiles associated with NIDDM. Possible long term clinical benefits of this drug with regard to cardiovascular mortality and morbidity are not yet established but are being assessed in a major ongoing study. Since metformin does not promote weight gain or hypoglycaemia it should be considered first-line pharmacotherapy in obese patients with NIDDM inadequately controlled by nonpharmacological measures. Metformin appears similarly effective for the pharmacological management of NIDDM in nonobese patients.

Clinical Trials as Topic↗
PubMed2006

Efficacy, tolerability, and safety of a novel once-daily extended-release metformin in patients with type 2 diabetes.

OBJECTIVE: The purpose of this study was to determine the efficacy and safety of a novel extended-release metformin in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Adults with type 2 diabetes (newly diagnosed, treated with diet and exercise only, or previously treated with oral diabetic medications) were randomly assigned to receive one of three extended-release metformin treatment regimens (1,500 mg/day q.d., 1,500 mg/day twice daily, or 2,000 mg/day q.d.) or immediate-release metformin (1,500 mg/day twice daily) in a double-blind 24-week trial. RESULTS: Significant decreases (P < 0.001) in mean HbA(1c) (A1C) levels were observed by week 12 in all treatment groups. The mean changes from baseline to end point in the two groups given 1,500 mg extended-release metformin (-0.73 and -0.74%) were not significantly different from the change in the immediate-release metformin group (-0.70%), whereas the 2,000-mg extended-release metformin group showed a greater decrease in A1C levels (-1.06%; mean difference [2,000 mg extended-release metformin - immediate-release metformin]: -0.36 [98.4% CI -0.65 to -0.06]). Rapid decreases in fasting plasma glucose levels were observed by week 1, which continued until week 8, and were maintained for the duration of the study. The overall incidence of adverse events was similar for all treatment groups, but fewer patients in the extended-release metformin groups discontinued treatment due to nausea during the initial dosing period than in the immediate-release metformin group. CONCLUSIONS: Once- or twice-daily extended-release metformin was as safe and effective as twice-daily immediate-release metformin and provided continued glycemic control for up to 24 weeks of treatment.

Adolescent↗