Metformin-treated Diabetic Patients Research Articles

Association between metformin and vitamin B12 deficiency in patients with type 2 diabetes

Diabetes mellitus (DM) is still one of the most common diseases worldwide, and its prevalence is still increasing globally. According to the American and European recommendations, metformin is considered a first-line oral hypo-glycemic drug for controlling type 2 DM (T2DM) patients. Metformin is the ninth most often prescribed drug in the world, and at least 120 million diabetic people are estimated to receive the drug. In the last 20 years, there has been increasing evidence of vitamin B12 deficiency among metformin-treated diabetic patients. Many studies have reported that vitamin B12 deficiency is related to the ma-labsorption of vitamin B12 among metformin-treated T2DM patients. Vitamin B12 deficiency may have a very bad complication for the T2DM patient. In this review, we will focus on the effect of metformin on the absorption of vitamin B12 and on its proposed mechanisms in hindering vitamin B12 absorption. In addition, the review will describe the clinical outcomes of vitamin B12 deficiency in metformin-treated T2DM.

Metal Complex Formation and Anticancer Activity of Cu(I) and Cu(II) Complexes with Metformin.

Metformin has been used for decades in millions of type 2 diabetes mellitus patients. In this time, correlations between metformin use and the occurrence of other disorders have been noted, as well as unpredictable metformin side effects. Diabetes is a significant cancer risk factor, but unexpectedly, metformin-treated diabetic patients have lower cancer incidence. Here, we show that metformin forms stable complexes with copper (II) ions. Both copper(I)/metformin and copper(II)/metformin complexes form adducts with glutathione, the main intracellular antioxidative peptide, found at high levels in cancer cells. Metformin reduces cell number and viability in SW1222 and K562 cells, as well as in K562-200 multidrug-resistant cells. Notably, the antiproliferative effect of metformin is enhanced in the presence of copper ions.

A Study of Associations Between Plasma Metformin Concentration, Lactic Acidosis, and Mortality in an Emergency Hospitalization Context.

To determine the plasma metformin concentration threshold associated with lactic acidosis and analyze the outcome in metformin-treated patients with lactic acidosis hospitalized in an emergency context. A retrospective, observational, single-center study. Emergency department and ICUs at Amiens University Hospital (Amiens, France). All consecutive patients with data on arterial lactate and pH up to 12 hours before or after a plasma metformin assay within 24 hours of admission, over a 9.7-year period. None. The study population consisted of 194 metformin-treated diabetic patients (median age: 68.6; males: 113 [58.2%]); 163 (84%) had acute kidney injury, which was associated variously with dehydration (45.4%), sepsis (41.1%), cardiogenic shock (20.9%), and diabetic ketoacidosis (16%). Eighty-seven patients (44.8%) had lactic acidosis defined as an arterial blood pH less than 7.35 and a lactate concentration greater than or equal to 4 mM, and 38 of them (43.7%) died in the ICU. A receiver operating characteristic curve analysis showed that a metformin concentration threshold of 9.9 mg/L was significantly associated with the occurrence of lactic acidosis (specificity: 92.9%; sensitivity: 67.1%; area under the receiver operating characteristic curve: 0.83; p < 0.0001). Among lactic acidosis-positive patients, however, in-ICU death was less frequent when the metformin concentration was greater than or equal to 9.9 mg/L (33.9% vs 61.3% for < 9.9 mg/L; p = 0.0252). After adjustment for the Simplified Acute Physiology Score II, in-ICU death was positively associated with prothrombin activity less than 70% and negatively associated with the initiation of renal replacement therapy at admission. In metformin-treated patients admitted in an emergency context, a plasma metformin concentration greater than or equal to 9.9 mg/L was strongly associated with the presence of lactic acidosis. This threshold may assist with the delicate decision of whether or not to initiate renal replacement therapy. Indeed, the outcome of lactic acidosis might depend on the prompt initiation of renal replacement therapy-especially when liver failure reduces lactate elimination.

An Investigation on Vitamin B12 Serum Levels among Type 2 Diabetic Patients Treated with Metformin Compared to Normal Levels

Background: Given the increasing prevalence of type 2 diabetes in the community and the use of metformin as one of its most common therapies as well as presence of some evidences on a link between the use of this medicine and vitamin B12 levels, we decided to measure and compare serum level of vitamin B12 among the diabetic patients under treatment by metformin and compare with its natural content. Decreased Vitamin B12 levels leads to some clinical problems including anemia, gastrointestinal disorders (diarrhea, constipation, decreased appetite, etc.,), neurological disorders (tingle, numbness, muscle weakness, etc.,) and mental disorders (memory impairment, depression, behavioral problems, etc.,). Therefore, we would determine if the duration of metformin use and dosage may be effective on serum levels of vitamin B12 among metformin-treated diabetic patients.&#x0D; Methods: Serum vitamin B12 level in metformin-treated type 2 diabetic patients referred to Rasoul-e-Akram Hospital and Specialist Clinic of Taban in Tehran in 2016 (306 subjects selected by convenience sampling) was determined and then compared to its normal level.&#x0D; Results: Of the 306 participants in the study, 120 ones were females (39.2%) and 186 ones were males (60.8%). Also, 150 ones (49%) were healthy and 156 ones (51%) were suffering from diabetes Miletus. There was a significant difference between the type 2 diabetes mellitus and healthy individuals with quantitative variables such as age, height, weight, BMI, serum cholesterol (Chol) level, LDL serum level, HDL serum level, triglyceride (TG) level. The mean blood level of Vitamin B12 level was 448.92±156.75pg/mL among all participants. A Vitamin B12 deficiency frequency of above 6% was seen among diabetic patients. In regression analysis, a model was defined based on which age, gender, diabetes and Metformin used had a significant effect on serum levels of vitamin B-12. Also, none of the variables gender, age, duration of treatment, metformin quantity, weight and BMI was associated with a deficiency of vitamin B12.&#x0D; Conclusion: In the diabetic group, the prevalence of Vitamin B12 deficiency was more than6%. It was also seen that age, gender, diabetes mellitus, metformin intake and metformin content had a significant effect on serum B12 levels. Therefore, measurement of serum levels of vitamin B12 in metformin-treated subjects is recommended.

Is it necessary to discontinue metformin in diabetic patients with GFR > 60 ml/min per 1.73 m2 undergoing coronary angiography: A controversy still exists?

Background: Although metformin is not directly nephrotoxic, it has been postulated that it can impair gluconeogenesis from lactate, which may lead lactate to be accumulated under circumstances such as contrast-induced nephropathy. The present study aims to assess the role of metformin in lactate production in a group of diabetic patients with GFR > 60 ml/min per 1.73 m2undergoing coronary angiography. Methods: In the present randomized clinical trial, 162 metformin-treated diabetic patients were enrolled. The enlisted patients were scheduled to undergo coronary angiography at Modarres Hospital from Feb 2012 to Nov 2012. Patients were randomly allocated to continue metformin during peri-angiography period (M (+) group) or to stop the medication 24 hours prior the procedure (M (-) group). All the patients had glomerular filtration rate of >60 mL/min per 1.73 m2. Iodixanol was the only contrast media which in all patients. Metformin-associated lactic acidosis (MALA) was defined as an arterial pH <7.35 and plasma lactate concentration >5 mmol/L. Results:162 patients, including79 (48.7%) male and 83 (51.3%) female patients were enrolled in the study. The average of GFR was comparable in both groups (76 ml/min per 1.73 m2in the M (+) group versus 79 ml/min per 1.73 m2in the M (-) group, p=0.53). No significant difference was observed in the mean dose of metformin before the study between the 2 groups (2.18 tablets per day in M (+) group vs. 2.21 tablets per day in M(-) group, p=0.62).No lactic acidosis was observed in the studied groups. Conclusion: In conclusion, the results of the present study indicate that metformin continuation in diabetic patients with a GFR of more than 60 ml/min per 1.73 m2 undergoing coronary angiography does not enhance the risk of MALA development. (www.actabiomedica.it)

The cell-autonomous mechanisms underlying the activity of metformin as an anticancer drug.

The biguanide drug metformin profoundly affects cell metabolism, causing an impairment of the cell energy balance and triggering a plethora of pleiotropic effects that vary depending on the cellular or environmental context. Interestingly, a decade ago, it was observed that metformin-treated diabetic patients have a significantly lower cancer risk. Although a variety of in vivo and in vitro observations emphasising the role of metformin as anticancer drug have been reported, the underlying mechanisms are still poorly understood. Here, we discuss our current understanding of the molecular mechanisms that are perturbed by metformin treatment and that might be relevant to understand its antitumour activities. We focus on the cell-autonomous mechanisms modulating growth and death of cancer cells.

Metformin stimulates IGFBP-2 gene expression through PPARalpha in diabetic states.

The anti-diabetic drug, metformin, exerts its action through AMP-activated protein kinase (AMPK), and Sirtuin (Sirt1) signaling. Insulin-like growth factor (IGF)-binding protein 2 (IGFBP-2) prevents IGF-1 binding to its receptors, thereby contributing to modulate insulin sensitivity. In this study, we demonstrate that metformin upregulates Igfbp-2 expression through the AMPK-Sirt1-PPARα cascade pathway. In the liver of high fat diet, ob/ob, and db/db mice, Igfbp-2 expression was significantly decreased compared to the expression levels in the wild-type mice (p < 0.05). Upregulation of Igfbp-2 expression by metformin administration was disrupted by gene silencing of Ampk and Sirt1, and this phenomenon was not observed in Pparα-null mice. Notably, activation of IGF-1 receptor (IGF-1R)-dependent signaling by IGF-1 was inhibited by metformin. Finally, when compared to untreated type 2 diabetes patients, the metformin-treated diabetic patients showed increased IGFBP-2 levels with diminished serum IGF-1 levels. Taken together, these findings indicate that IGFBP-2 might be a new target of metformin action in diabetes and the metformin-AMPK-Sirt1-PPARα-IGFBP-2 network may provide a novel pathway that could be applied to ameliorate metabolic syndromes by controlling IGF-1 bioavailability.

SUN-PP004: Combined Intervention with Pioglitazone and N-3 Fatty Acids in Metformin-Treated Diabetic Patients on Postprandial Lipid Clearance and Selected Cytokines

SUN-PP004: Combined Intervention with Pioglitazone and N-3 Fatty Acids in Metformin-Treated Diabetic Patients on Postprandial Lipid Clearance and Selected Cytokines

Vitamin B12 in metformin-treated diabetic patients: a cross-sectional study in Brazil

The objective of this study was to evaluate the presence of vitamin B12 deficiency and the factors associated with serum vitamin B12 levels in a sample of metformin-treated Brazilian diabetic patients. Cross-sectional study. 144 patients were included. Serum vitamin B12 levels were low (< 125 pmol/L) in 10 patients (6.9%) and possibly low (125 - 250 pmol/L) in 53 patients (36.8%). Serum vitamin B12 levels were negatively associated with age (B = -3.17; β= -0.171; p = 0.037) and duration of metformin use (B= -33.36; β= -0.161; p = 0.048), and positively associated with the estimated intake of vitamin B12 (B= 67.96; β= 0.249; p = 0.002). The present findings suggest a high prevalence of vitamin B12 deficiency in metformin-treated diabetic patients. Older patients, patients in long term treatment with metformin and low vitamin B12 intake are probably more prone to this deficiency.

Vitamin B12 in metformin-treated diabetic patients: a cross-sectional study in Brazil

Vitamin B12 in metformin-treated diabetic patients: a cross-sectional study in Brazil

Vitamin B12 in metformin-treated diabetic patients: a cross-sectional study in Brazil

Vitamin B12 in metformin-treated diabetic patients: a cross-sectional study in Brazil

Effect of homocysteine-lowering therapy on arterial elasticity and metabolic parameters in metformin-treated diabetic patients

Metformin may affect the risk of atherothrombotic disease. However, metformin increases levels of homocysteine (Hcy), considered an independent risk factor for atherosclerosis. We evaluate whether homocysteine-lowering has a beneficial effect on arterial elasticity and metabolic parameters in metformin-treated diabetic patients. In double-blind, placebo-controlled study, 60 diabetic patients treated with high dose of metformin were randomly assigned to receive daily oral supplementation with folate (1000 mcg), vitamins B12 (400 mcg) and B6 (10 mg) (group 1) or placebo (group 2). Lipid profile, HbA1C, insulin, C-peptide, hs-CRP, vitamin B12, folic acid, homocysteine, endothelin, homeostasis model assessment-insulin resistance (HOMA-IR) were measured. Arterial elasticity was evaluated using pulse wave contour analysis (HDI CR 2000, Eagan, MN). The two groups were similar at baseline in terms of hemodynamic and arterial elasticity parameters. After a 4-month small artery elasticity index (SAEI) was significantly greater in patients who received Hcy-lowering agents than in the placebo group: 4.3 ± 2.04 ml/mm Hg × 100 versus 3.2 ± 1.1 ml/mm Hg × 100, p = 0.01. Post-treatment vitamin B12 and folic acid levels were greater in group 1 versus group 2: 738.1 ± 279.9 pg/ml versus 566.1 ± 167.4 pg/ml, p = 0.007 and 14.9 ± 4.8 ng/ml versus 8.3 ± 2.9 ng/ml, p < 0.0001, respectively. Hcy level decreased significantly in the treatment group from 10.0 ± 4.4 to 7.6 ± 2.5 μmol/l, p = 0.002 and did not change in placebo group ( p = 0.9). Hcy-lowering therapy improved small arterial elasticity in diabetic patients treated with high dose of metformin. The improvement was associated with a decrease in Hcy as well as an increase in folic acid and vitamin B12. These findings suggest that Hcy-lowering may have beneficial vascular effect in metformin-treated diabetic patients.

Metformin-induced lactic acidosis in the presence of acute renal failure

Lactic acidosis occourred in 6 metformin-treated diabetic patients. Five of them had received 1.6 to 2.4 g metformin per day over a period of weeks or years. Acute renal failure, induced by i. v. pyelography, arteriography, or severe dehydration, preceded lactic acidosis by a few days and apparently precipitated it. The sixth patient had normal renal function prior to taking a massive overdose of metformin in an attempt at suicide. The metabolic pattern was very similar to that observed in phenformin-induced lactic acidosis: severe metabolic acidosis (pH: 7.02±0.95; HCO 3 − : 6.3±0.9 mmol/l; PaCO2: 25±4 mmHg; PaO2: 110±19 mmHg); hyperlactataemia (18.4±3.3 mmol/l) and high lactate/pyruvate ratio (51±5); high blood alanine (2.82±1.10 mmol/l); high 3-hydroxybutyrate (15.8±3.3 mmol/l) and high 3-hydroxybutyrate/ acetoacetate ratio (26±10). Hypoglycaemia (25 to 60 mg per 100 ml) was observed in 4 patients, in spite of high glucagon (760±148 pg/ml) and low insulin (13±5μU/ml) levels. A guanidine substance was characterized in the plasma at concentrations 45 to 110 μg/ml; it was similar to metformin and distinct from creatinine, according to chromatographic and other criteria; its concentration in the plasma decreased during dialysis, and the same substance appeared in the dialysis effluent. The treatment included massive alkalinization (710 ±130 mmol/l i. v. for 48 h), plasma volume expanders (5630±1000 ml/48 h), forced-diuresis and/or dialysis, insulin (30±10 U/48 h) and glucose (300 ±50 g/48 h). — It is concluded that: 1. metformin, like other biguanides, can induce lactic acidosis; 2. acute renal failure is a prominent causal factor; 3. pharmacokinetics of metformin account for this fact since metformin cannot be inactivated by the liver (as distinct from phenformin) and is normally excreted by the kidney; 4. accumulation of biguanide is suggested by guanidine assay in the plasma; 5. metformin should not be prescribed in the presence of renal failure.