[Comparative studies of the effect of N1-n-butylbiguanide hydrochloride (Buformin) and N1-n-butylbiguanide tosylate (Buformin retard)].
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Short-term effect of buformin, a biguanide, on insulin sensitivity, soluble fraction of tumor necrosis factor receptor and serum lipids in overweight patients with type 2 diabetes mellitus.
AIMS/HYPOTHESIS: The UK Prospective Diabetes Study (UKPDS) showed that biguanide therapy in overweight patients reduced the risk for any diabetes-related endpoint and all-cause mortality. Biguanides lower the blood glucose values without stimulation of insulin release. We have investigated the short-term effect of buformin on insulin sensitivity, solved tumor necrosis factor receptors (sTNFRs), and serum lipids in overweight subjects with type 2 diabetes mellitus (DM). METHOD: Thirteen overweight subjects with type 2 DM were examined. The subjects who were fed 20 kcal/kg body weight were divided into two subgroups according to whether they were treated by buformin (Buformin group), or dietary therapy alone (Diet group). Six patients were in Buformin group and seven patients were in Diet group. We calculated insulin-mediated glucose uptake by the liver and peripheral tissues using euglycemic hyperinsulinemic clamp combined with an oral glucose load before and after buformin treatment or diet therapy for 2 weeks. RESULTS: Fasting plasma glucose, total cholesterol (T-chol), LDL-cholesterol (LDL-chol), and sTNFR2 were significantly decreased, and hepatic glucose uptake significantly increased from 32 +/- 7 to 42 +/- 7% (P < 0.05) in Buformin group but did not changed significantly in Diet group. However, the glucose infusion rate thought to express insulin sensitivity in peripheral tissue, TNF-alpha, sTNFR1, fasting plasma insulin, C-peptide, and NEFA levels did not change significantly in both the groups after treatment. CONCLUSION/INTERPRETATION: Buformin improved insulin sensitivity in the liver and decreased T-chol, LDL-chol, and sTNFR2. The mechanism of action for buformin likely involves inhibition of TNF-alpha. Buformin lowers insulin resistance and risk factors for cardiovascular disease including serum lipid and will therefore, be useful in management of overweight type 2 DM patients.
Buformin↗
Effect of buformin on splanchnic carbohydrate and substrate metabolism in healthy man.
The effect of buformin (100 mg b.i.d. for 5 days) on carbohydrate metabolism, both splanchnic glucose output (SGO) and net substrate exchange were studied in 6 healthy male volunteers in the basal state and following glucose ingestion (100 g). Control studies without buformin were also performed in 5 men. Splanchnic glucose and substrate exchange was determined by means of the hepatic venous catheter technique. SGO was 154 +/- 18 (SEM) mg/min in the postabsorptive state and increased 33.3 +/- 2.8 g above the basal level during the 150 min period following glucose ingestion. Buformin administration did not alter basal SGO (157 +/- 26 mg/min), nor the splanchnic exchange of pyruvate, alanine, glycerol, OH-butyrate and acetoacetate. Splanchnic lactate balance was altered by buformin and net lactate output occurred. Following glucose ingestion the rise in splanchnic lactate output was increased, whereas no change in SGO (32.9 +/- 3.5 g/150 min) and splanchnic exchange of the other substrates was observed. The increase in arterial blood glucose concentration following oral glucose loading was reduced by buformin pretreatment (p less than 0.005). The insulin production rate (basal, 16 +/- 2 mU/min; following oral glucose, 13 +/- 2 U/150 min) as calculated from C-peptide release from the splanchnic area was unchanged by buformin. Except for a marked rise in splanchnic lactate production, buformin did not alter splanchnic carbohydrate metabolism after orally ingested glucose in healthy man. The diminished increase in arterial blood glucose concentration associated with unaltered insulin production suggests that buformin facilitates glucose utilization by peripheral tissues.
Adult↗
Buformin suppresses the expression of glyceraldehyde 3-phosphate dehydrogenase.
The biguanides metformin and buformin, which are clinically used for diabetes mellitus, are known to improve resistance to insulin in patients. Biguanides were reported to cause lactic acidosis as a side effect. Since the mechanism of the side effect still remains obscure, we have examined genes whose expression changes by treating HepG2 cells with buformin in order to elucidate the mechanisms of the side effect. A subtraction cDNA library was constructed by the method of suppressive subtractive hybridization and the screening of the library was performed with cDNA probes prepared from HepG2 cells treated with or without buformin for 12 h. The expression of the gene and the protein obtained by the screening was monitored by real-time RT-PCR with specific primers and Western blotting with specific antibody. The amounts of ATP and NAD+ were determined with luciferase and alcohol dehydrogenase, respectively. We found that expression of the glyceraldehyde 3-phosphate dehydrogenase (GAPD) gene was suppressed by treating HepG2 cells with 0.25 mM buformin for 12 h as a result of the library screening. The decrease in the expression depended on the treatment period. The amount of GAPD protein also decreased simultaneously with the suppression of the gene expression by the treatment with buformin. The amount of ATP and NAD+ in the HepG2 cells treated with buformin decreased to 10 and 20% of the control, respectively. These observations imply that the biguanide causes deactivation of the glycolytic pathway and subsequently the accumulation of pyruvate and NADH and a decrease in NAD+. Therefore, the reaction equilibrium catalyzed by lactate dehydrogenase leans towards lactate production and this may result in lactic acidosis.
Acidosis, Lactic↗
Treatment of reactive hypoglycemia with buformin.
The therapeutic effect of short-term buformin (l-butylbiguanide) treatment was investigated in 12 patients with reactive hypoglycemia. Eleven of them were classified as having idiopathic reactive hypoglycemia, nine obese and two nonobese. None of these patients had a degree of hyperglycemia during glucose tolerance tests which would indicate diabetes mellitus. In one patient reactive hypoglycemia was related to chemical diabetes. The diagnosis of reactive hypoglycemia was established on the basis of patient's hypoglycemic reaction and low blood glucose levels during 6-hour oral glucose tolerance tests. The patient's received 200 mg of buformin daily for 7 days and its therapeutic effectiveness was assessed by repeat testing. Buformin treatment resulted in significant increase of blood glucose values between 180 and 360 min after oral glucose challenge and in considerable improvement of hypoglycemia in nine obese patients with idiopathic reactive hypoglycemia and in the patient with chemical diabetes. Buformin also significantly reduced maximal insulin response and incremental insulin areas. In two nonobese patients hypoglycemic reaction was deteriorated after buformin therapy.
Adult↗
[The effect of combined therapy with buformin and dichloracetate on blood lactate concentrations in diabetics].
In animals, dichloroacetate (DCA) which activates pyruvate dehydrogenase has been shown to diminish increased blood lactate concentrations due to biguanide treatment. In 10 maturity onset diabetics, therefore, the effect of a combined therapy with buformin and DCA (200 mg b.i.d.) was studied on blood lactate concentrations and compared with an analogous pre- and postinvestigation period of 6 days with buformin treatment alone (100 mg b.i.d.). Mean blood glucose concentrations remained the same during all 3 investigation periods. Also, neither fasting nor postprandially significant differences were found in blood lactate and ketones. In association with a standardized ergometer test, however, the rise in blood lactate was significantly smaller (p less than 0.05) while the patients were on buformin plus DCA, compared to the periods when only buformin was given. Furthermore, less ketone bodies appeared to be utilized by the exercising muscle under the influence of the combined treatment (p less than 0.05). These results are in good agreement with animal studies and suggest that DCA might be as effective in decreasing enhanced blood lactate concentrations in biguanide treated man as in animals.
Acetates↗
The inhibitory action of buformin, a biguanide on gluconeogenesis from alanine and its transport system in rat livers.
The effect of buformin, a biguanide, on gluconeogenesis from 10 mM alanine in the presence of 143 nM glucagon were studied using isolated rat liver perfusions. In addition, to investigate possible mechanisms of biguanide action, alanine utilization in isolated rat liver perfusion and [3H]alanine uptake in isolated hepatocytes were observed. Buformin (1.85 mM) strongly inhibited gluconeogenesis from alanine in the presence of glucagon in both normal and streptozocin-induced diabetic rat livers. This inhibition was followed by a decrease in alanine utilization. Both of these inhibitory effects of buformin were dose-dependent. [3H]Alanine uptake was significantly inhibited by buformin. The effect of this agent was similar to but weaker than that of ouabain. However, tolbutamide failed to reduce either alanine utilization or [3H]alanine uptake, although this drug significantly inhibited gluconeogenesis from alanine. These data suggest that biguanides may reduce hepatic alanine utilization via the inhibition of Na+/L-alanine transport activity as one possible mechanism, resulting the inhibition of gluconeogenesis from alanine in the presence of glucagon.
3-Hydroxybutyric Acid↗
Effect of buformin and metformin on formation of advanced glycation end products by methylglyoxal.
BACKGROUND: The formation and accumulation of advanced glycation end products (AGE) in various tissues are known to be involved in the aging process and complications of long-term diabetes. Aminoguanidine as AGE inhibitors was first studied, and metformin as biguanide compounds have been reported to react with reactive dicarbonyl precursors such as methylglyoxal. METHODS: We studied the effects of the biguanides of buformin and metformin on AGE formation by the methods of specific fluorescence, and enzyme-linked immunosorbent assay and a Western blot analysis using the anti-AGE antibody after incubating BSA or RNase with methylglyoxal. RESULTS: Buformin is a more potent inhibitor of AGE formation than metformin, and suggests that the amino group of buformin trap the carbonyl group of methylglyoxal to suppress formation of AGE. CONCLUSION: In addition to that of metformin, buformin may be clinically useful to prevent diabetic complications.
Animals↗
Effect of buformin on the regulation of glycogen metabolism in the skeletal muscle of normal rats.
In view of the experience that after short- or long-term oral administration of biguanides to rats no glycogenolysis in the muscle tissue occurs or even an increase of the muscle glycogen content and a high rate of incorporation of radioglucose into the muscle glycogen, the glycogen synthetase activity of skeletal muscle in a concentrated muscle homogenate and the effect of isoproterenol on glycogenolysis were investigated in normal rats after short-term oral administration of 1-butylbiguanide (buformin). The basal synthetase activity and the ATP inhibition of the enzyme were not affected by buformin, but the cyclic AMP mediated inactivation was significantly inhibited after buformin pretreatment. This inhibition was reversed by running the assay in the presence of Mg2+. Buformin also inhibited the isoproterenol induced glycogenolysis of the skeletal muscle tissue. From our results we suppose that biguanides may influence the regulation of glycogen metabolism by inhibiting the inactivating synthetase kinase and the activating phosphorylase kinase. It is possible that divalent cations like Mg2+ as an activator of kinase reactions are concerned.
Animals↗
[Inhibition of the blastomogenic effect of 7,12-dimethylbenz(a)anthracene in female rats by buformin, diphenin, a polypeptide pineal extract and L-DOPA].
Female rats were treated with buformin, phenytoin, polypeptide pineal extract, L-DOPA or buformin combined with L-DOPA during 3 weeks before intravenous injections of DMBA (1.5 mg 6 times with one-week intervals) over a period of carcinogen injections and after it till the animals' death. The overall tumour incidence in the control group was 97%, while in buformin, phenytoin, pineal extract, L-DOPA and buformin + L-DOPA treated groups it amounted to 55, 71, 80, 50 and 62%, respectively (P < 0.05). The incidence of mammary adenocarcinoma amounted to 81, 36, 55, 26, 25 and 19%, respectively (P < 0.05). The mechanisms of the similar effects the drugs belonging to different classes produce on chemical carcinogenesis are discussed.
9,10-Dimethyl-1,2-benzanthracene↗
A new method for determination of buformin in plasma and urine by ion-paired reversed-phase HPLC with ultraviolet detection.
Buformin is a widely used as an antidiabetic agent but its renal excretion is still controversial. A new HPLC method with ultraviolet (UV) detection for the determination of buformin in plasma and urine has been developed. After protein precipitation or dilution, buformin and internal standard phenformin were resolved on an octadecyl silica column and detected by UV detection at 233 nm. Intra- and inter-day coefficients of variation were <9%. The limit of quantification was around 0.05 micro g/ml for plasma and 2.5 micro g/ml for urine.
Buformin↗
A validated HPLC method with ultraviolet detection for the determination of buformin in plasma.
A sensitive and rapid high-performance liquid chromatographic assay is developed and validated for the determination of buformin in plasma. After addition of metformin as the internal standard, the analytes were deproteinated with acetonitrile, washed with dichloromethane, and the resulting supernatant injected. Chromatography was performed at ambient temperature by pumping a mobile phase of 0.03 m diammonium hydrogen phosphate buffer (pH 7, 250 mL) in methanol (750 mL) at a fl ow rate of 1 mL/min through a silica column. Buformin and metformin were detected at 236 nm, and eluted 9.8 and 15.4 min, respectively. No endogenous substances were found to interfere. Calibration curves were linear over the concentration range of 20-2000 ng/mL. The limit of quantitation was 20 ng/mL. The intra- and inter-day relative standard deviation (RSD) was 8.3%, or less, and the accuracy was within 10.1% of the relative error (RE). The method is suitable in pharmacokinetic investigation of buformin.
Animals↗
Buformin concentrations in a case of fatal lactic acidosis.
A fatal case of lactic acidosis in a 84 year old diabetic woman taking buformin is reported. Buformin concentrations in serum, other body fluids and tissues were measured by gas chromatography. Serum buformin concentration at admission was 5.5 mg/l. Postmortem concentrations were: in serum 3.2 mg/l; in lung 2.8 mg/kg wet weight; in heart 3.0 mg/kg; in pericardial fluid 3.5 mg/l; in liver 5.2 mg/kg; in bile 6.3 mg/l; and in kidney 98 mg/kg.
Acidosis↗
[Vitamin B12-level in serum of diabetics receiving long-term buformin therapy].
Disturbances of the vitamin B12 resorption by the therapy with biguanides above all metformin are known from literature. In 59 patients with Buformin retard-monotherapy we determined in 18.7% slight reductions of the vitamin B12 level in the serum, in one patient the serum concentration was lower than 50 pg/ml. That means that also under therapy with Buformin can be reckoned with easy disturbances of resorption for vitamin B12. Occasional controls of Hb and anamnestic establishment of neurological symptoms are to be recommended during a therapy with Buformin, in order not to overlook the clinical signs of a vitamin B12 hypovitaminosis.
Biguanides↗
[Levels of lactic acid in type II diabetics treated with buformin].
The objective of the work was to assess the blood lactate levels in type 2 diabetics selected at random, treated for prolonged periods with buformin. 77% of the investigated group of diabetics (N = 70) had elevated blood lactate levels and 16% of them had hyperlactataemia (more than 5.0 mmol/l). In 33% patients with an originally elevated lactataemia after 12 weeks of discontinued buformin treatment the lactic acid blood levels reached normal values. The lactate levels declined significantly (by more than 25% of the original value) after 6 weeks without buformin treatment in another 45% of the diabetic patients. In 18% of the investigated patients, who had high lactate levels even after discontinuation of treatment, in two-thirds neither impaired function of the kidneys and liver nor cardiac disease or alcoholism were detected.
Adult↗
Effects of buformin on the metabolsim of the isolated haemoglobin-free perfused hindlimb of normal rats.
Using the isolated, haemoglobin-free, perfused resting hindlimb of normal rats buformin neither had a direct insulin-like effect on glucose uptake by muscle tissue nor potentiated the effect of insulin on glucose uptake after oral pretreatment for one or several days with low and high doses (30 mg-350 mg/kg). Effects on glycogenolysis could not be detected. Glycerol release was inhibited after several days of pretreatment with low and high doses of buformin. The utilization of added oleate was also partly inhibited. The level of energy rich phosphates in the muscle tissue and oxygen consumption were not affected under any of the conditions used in these experiments.
Animals↗
Gas chromatographic determination of buformin in body fluids and tissues, using a nitrogen phosphorus detector: application to a postmortem case.
A specific method is described for the quantitation of the oral hypoglycemic biguanide buformin in biological material by gas chromatography. Phenformin, another biguanide derivative, is used as internal standard. Both compounds are converted to the corresponding s-triazine derivatives by reacting with acetic anhydride prior to gas chromatography with nitrogen-specific detection. The described procedure has been applied to the quantitative assay of buformin in body fluids and tissues, obtained from a postmortem case. The results of these toxicological investigations are discussed.
Acidosis↗
Effect of a biguanide (buformin) on carnitine palmitoyltransferase activity.
Buformin at a concentration of 1--2.5 mM stimulates solubilized carnitine palmitoyltransferase by reducing the inhibitory effect of palmitoyl-CoA. Neither buformin nor metformin inhibits the solubilized carnitine palmitoyltransferase.
Acyltransferases↗