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Nephron 2017Like other biguanide agents, metformin is an anti-hyperglycemic agent with lower tendency towards hypoglycemia compared to other anti-diabetic drugs. Given its favorable...
Like other biguanide agents, metformin is an anti-hyperglycemic agent with lower tendency towards hypoglycemia compared to other anti-diabetic drugs. Given its favorable effects on serum lipids, obese body habitus, cardiovascular disease, and mortality, metformin is recommended as the first-line pharmacologic agent for type 2 diabetes in the absence of contraindications. However, as metformin accumulation may lead to type B non-hypoxemic lactic acidosis, especially in the setting of kidney injury, chronic kidney disease, and overdose, regulatory agencies such as the United States Food and Drug Administration (FDA) have maintained certain restrictions regarding its use in kidney dysfunction. Case series have demonstrated a high fatality rate with metformin-associated lactic acidosis (MALA), and the real-life incidence of MALA may be underestimated by observational studies and clinical trials that have excluded patients with moderate-to-advanced kidney dysfunction. A recent study of advanced diabetic kidney disease patients in Taiwan in Lancet Endocrinology and Diabetes has provided unique insight into the potential consequences of unrestricted metformin use, including a 35% higher adjusted mortality risk that was dose-dependent. This timely study, as well as historical data documenting the toxicities of other biguanides, phenformin and buformin, suggest that the recent relaxation of FDA recommendations to expand metformin use in patients with kidney dysfunction (i.e., those with estimated glomerular filtration rates ≥30 instead of our recommended ≥45 ml/min/1.73 m2) may be too liberal. In this article, we will review the history of metformin use; its pharmacology, mechanism of action, and potential toxicities; and policy-level changes in its use over time.
Topics: Acidosis, Lactic; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Humans; Hypoglycemic Agents; Metformin; Practice Guidelines as Topic; Renal Insufficiency, Chronic; Risk Factors; Taiwan; United States
PubMed: 27760420
DOI: 10.1159/000450862 -
Internal Medicine (Tokyo, Japan) 2009We report a case of diabetic mastopathy in a man with type 2 diabetes. The patient was a 62-year-old man who had been diagnosed with type 2 diabetes at the age of 46... (Review)
Review
We report a case of diabetic mastopathy in a man with type 2 diabetes. The patient was a 62-year-old man who had been diagnosed with type 2 diabetes at the age of 46 years. He had been treated with oral hypoglycemic agents. He noticed a mass in his left breast in February 2007, when HbA(1)c was 7.6% with the treatment using oral hypoglycemic agents, including acarbose, glimepiride, buformine, and pioglitazone. Mammography of the breast showed increased density, and ultrasonography showed a regular-shaped hypoechoic mass. Core needle biopsy was performed, and diabetic mastopathy was confirmed pathologically. Diabetic mastopathy usually occurs in women with type 1 diabetes. This case, a man with type 2 diabetes, is very rare.
Topics: Diabetes Mellitus, Type 2; Fibrocystic Breast Disease; Humans; Male; Middle Aged; Rare Diseases
PubMed: 19483361
DOI: 10.2169/internalmedicine.48.1834 -
RSC Advances Apr 2021A bar micro-solid phase (bar μ-SPE) extraction method using either graphene or zeolite or their mixtures as an adsorbent, coupled with high-performance liquid...
A bar micro-solid phase (bar μ-SPE) extraction method using either graphene or zeolite or their mixtures as an adsorbent, coupled with high-performance liquid chromatography (using a C1 column) was developed for the simultaneous determination of pharmaceutical compounds (metformin (MET), buformin (BUF), phenformin (PHEN) and propranolol (PROP)) of diverse polarity (log from -1.82 to 3.10). Parameters influencing the extraction, such as conditioning solvents, pH of the sample, sample volume, amount of adsorbent, stirring rate, time of extraction, type and volume of desorption solvent and time of desorption were investigated. Under the optimized conditions, the extraction method using graphene (extraction efficiency, % EE, ∼6-15%) resulted in the least amount of extracted drugs. However, the use of zeolite and zeolite/graphene mixtures improves the % EE significantly, 30% for PHEN and 42% for PROP using zeolite; 22% for MET and 18% for BUF using the adsorbent mixture. Under similar conditions, enrichment factors for these drugs range from 11-15. The validated method was performed for the determination of the drugs that were spiked to urine samples. Good recoveries ranging from 72.8 to 116% were achieved.
PubMed: 35479128
DOI: 10.1039/d1ra01569a -
IScience Feb 2024Metformin is the first-line treatment for type 2 diabetes, yet its mechanism of action is not fully understood. Recent studies suggest metformin's interactions with gut...
Metformin is the first-line treatment for type 2 diabetes, yet its mechanism of action is not fully understood. Recent studies suggest metformin's interactions with gut microbiota are responsible for exerting therapeutic effects. In this study, we report that metformin targets the gut microbial enzyme agmatinase, as a competitive inhibitor, which may impair gut agmatine catabolism. The metformin inhibition constant (K) of agmatinase is 1 mM and relevant in the gut where the drug concentration is 1-10 mM. Metformin analogs phenformin, buformin, and galegine are even more potent inhibitors of agmatinase (K = 0.6, 0.1, and 0.007 mM, respectively) suggesting a shared mechanism. Agmatine is a known effector of human host metabolism and has been reported to augment metformin's therapeutic effects for type 2 diabetes. This gut-derived inhibition mechanism gives new insights on metformin's action in the gut and may lead to significant discoveries in improving metformin therapy.
PubMed: 38318350
DOI: 10.1016/j.isci.2024.108900 -
Journal of Pharmaceutical Analysis Dec 2012Glassy carbon electrode, which is used to electrochemically determine the content of buformin, is modified with an electropolymerized film of -aminobenzoic acid in pH...
Glassy carbon electrode, which is used to electrochemically determine the content of buformin, is modified with an electropolymerized film of -aminobenzoic acid in pH 7.0 acetate buffer solution (ABS). The polymer showed an excellent electrocatalytic activity for the reduction of buformin. In pH 7.0 ABS, the cathodic peak current increased linearly over three concentration intervals of buformin, and the detection limit (S/N=3) was 2.0×10 g/mL. The method was successfully applied to directly determine buformin in tablets with standard addition recoveries of 95.8-102.5%. The proposed method is simple, cheap and highly efficient.
PubMed: 29403783
DOI: 10.1016/j.jpha.2012.05.005 -
Drug Metabolism and Pharmacokinetics Dec 2007Nateglinide is an antidiabetic agent metabolized by CYP2C9 and CYP3A4; hence inhibitors of these CYP isozymes may interact with nateglinide. There are, however, only...
Nateglinide is an antidiabetic agent metabolized by CYP2C9 and CYP3A4; hence inhibitors of these CYP isozymes may interact with nateglinide. There are, however, only limited in vitro data on how to predict drug-drug interactions in vivo. We examined the effects of 18 drugs that may be prescribed together with nateglinide (metformin, buformin, aspirin, gemfibrozil, simvastatin, pioglitazone, rosiglitazone, carbamazepine, clarithromycin, gliclazide, clofibrate, fluconazole, bezafibrate, phenylbutazone, nifedipine, famotidine, ibuprofen and miconazole) on the conversion of nateglinide to its major metabolite (N-[trans-4-(1-hydroxy-1-methylethyl)-cyclohexanecarbonyl]-D-phenylalanine) using human liver microsomes. Eight compounds showed a<50% inhibitory effect and we estimated the K(i) values for the remaining 10 compounds. Except for fluconazole and miconazole, 1+I(in, max, u)/K(i) calculated from the K(i) values, was approximately 1 and thus the possibility of a drug-drug interaction was considered low. The value for fluconazole suggested the risk of interaction and agreed with the results of clinical studies in which the AUC of nateglinide increased by 48% when it was co-administered with fluconazole. The present study showed that nateglinide metabolism would hardly be affected by the drugs used in this study, except for miconazole and fluconazole that are potent inhibitors of multiple isoforms of CYPs.
Topics: Aryl Hydrocarbon Hydroxylases; Biotransformation; Cyclohexanes; Cytochrome P-450 CYP2C9; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; Humans; Hypoglycemic Agents; In Vitro Techniques; Kinetics; Microsomes, Liver; Models, Biological; Nateglinide; Phenylalanine
PubMed: 18159128
DOI: 10.2133/dmpk.22.409 -
Biological & Pharmaceutical Bulletin Jul 2009Biguanides are known to have a serious side effect, lactic acidosis. We previously reported that buformin suppressed the expression of glyceraldehyde 3-phosphate...
Biguanides are known to have a serious side effect, lactic acidosis. We previously reported that buformin suppressed the expression of glyceraldehyde 3-phosphate dehydrogenase (GAPD) and suggested that this decrease was one of the causes of lactic acidosis. In this study, we examined the signaling pathway and regulatory factors for the expression of the GAPD gene triggered by metformin in HepG2 cells. The mRNA and protein expression of GAPD, detected by real-time reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting, respectively, decreased upon treatment of the cells with 10 mM metformin for 24 h. Under the conditions, metformin induced phosphorylation of AMP-activated protein kinase (AMPK). The expression of GAPD mRNA decreased on treatment with an activator for AMPK, 5-amino-imidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR). Inhibitors for signal transducers, Compound C, H-89, and MDL-12,330A, restored the level of GAPD mRNA. A luciferase reporter plasmid containing bp -1795 to +57 of the 5'-flanking region of the GAPD gene was constructed for a reporter gene assay. The luciferase activity in transfectants decreased on incubation with metformin. A mutant reporter plasmid with an altered cAMP-response element (CRE) counteracted the metformin-mediated repression of GAPD transcription. These results suggest that signal transducers, adenylate cyclase (AC), protein kinase A (PKA), and AMPK, are involved in the signaling pathway triggered by metformin and CRE-binding protein is one of the transcription factors for the GAPD gene down-regulated by metformin.
Topics: Blotting, Western; Cell Line, Tumor; Gene Expression Regulation, Enzymologic; Genes, Reporter; Glyceraldehyde-3-Phosphate Dehydrogenases; Humans; Hypoglycemic Agents; Metformin; Mutagenesis, Site-Directed; Reverse Transcriptase Polymerase Chain Reaction; Transcription, Genetic
PubMed: 19571378
DOI: 10.1248/bpb.32.1160 -
PloS One 2014Some cancer cells can survive under glucose deprivation within the microenvironment of a tumor. Recently, we reported that N-linked (β-N-acetylglucosamine)2...
Some cancer cells can survive under glucose deprivation within the microenvironment of a tumor. Recently, we reported that N-linked (β-N-acetylglucosamine)2 [N-GlcNAc2]-modified proteins induce G2/M arrest and cell death under glucose deprivation. Here, we investigated whether such a response to glucose deprivation contributes to the survival of renal cell carcinomas, which are sensitive to nutritional stress. Specifically, we analyzed seven renal carcinoma cell lines. Four of these cell lines produced N-GlcNAc2-modified proteins and led G2/M-phase arrest under glucose deprivation, leading to cell death. The remaining three cell lines did not produce N-GlcNAc2-modified proteins and undergo G1/S-phase arrest under glucose deprivation, leading to survival. The four dead cell lines displayed significant up-regulation in the UDP-GlcNAc biosynthesis pathway as well as increased phosphorylation of p53, which was not observed in the surviving three cell lines. In addition, the four dead cell lines showed prolonged up-regulated expression of ATF3, which is related to unfolded protein response (UPR), while the surviving three cell lines showed only transient up-regulation of ATF3. In this study, we demonstrated that the renal carcinoma cells which accumulate N-GlcNAc2-modified proteins under glucose deprivation do not survive with abnormaly prolonged UPR pathway. By contrast, renal carcinoma cells that do not accumulate N-GlcNAc2-modified proteins under these conditions survive. Morover, we demonstrated that buformin, a UPR inhibitor, efficiently reduced cell survival under conditions of glucose deprivation for both sensitive and resistant phenotypes. Further studies to clarify these findings will lead to the development of novel chemotherapeutic treatments for renal cancer.
Topics: Acetylglucosamine; Activating Transcription Factor 3; Buformin; Cell Death; Cell Line, Tumor; G2 Phase Cell Cycle Checkpoints; Gene Expression Regulation; Glucose; Glycoproteins; Glycosylation; Humans; Hypoglycemic Agents; Kidney Neoplasms; M Phase Cell Cycle Checkpoints; Tumor Microenvironment; Tumor Suppressor Protein p53
PubMed: 24796485
DOI: 10.1371/journal.pone.0096168 -
Endocrinologia Japonica Apr 1975This report deals with a detailed course of one patient with acromegaly who had a pituitary apoplexy. The pituitary apoplexy occurred suddenly 5 days after...
This report deals with a detailed course of one patient with acromegaly who had a pituitary apoplexy. The pituitary apoplexy occurred suddenly 5 days after administration of a oral hypoglycemic agent, buformin, during hospitalization. Immediately after the attack changes of the concentrations of several hormones such as serum growth-hormone, serum thyroid hormone and urinary 17-hydroxycorticosteroids were followed until the development to hypopituitary state. Simultaneously with the decrease of the concentrations of the above-mentioned hormones, a regression of the physical manifestations of acromegaly and a complete amelioration of diabetes mellitus were observed.
Topics: 17-Hydroxycorticosteroids; Acromegaly; Adrenocorticotropic Hormone; Blood Glucose; Growth Hormone; Humans; Insulin; Male; Middle Aged; Pituitary Diseases; Remission, Spontaneous; Thyroid Hormones; Thyrotropin; Thyrotropin-Releasing Hormone
PubMed: 168061
DOI: 10.1507/endocrj1954.22.181