RESUMEN
AIM: To determine the influence of polymorphisms on the effects of metformin on HbA1c, daily dose of insulin and metformin plasma concentration. Methods: In a post hoc analysis of a 4.3 year placebo-controlled randomized trial with 390 patients with Type 2 diabetes already on insulin, we analyzed the influence of polymorphisms in genes coding for ATM and the transporters OCT1 and MATE1. Outcome measures were a combined HbA1c + daily dose of insulin Z score and metformin plasma concentrations. RESULTS: rs11212617 (ATM) was associated with an improved Z score and a lower metformin plasma concentration. In addition, the major allele of rs2289669 (MATE1) was also associated with an improved Z score. CONCLUSION: The ATM SNP rs11212617 significantly affected the effect of metformin and metformin plasma concentration. Further research is needed to determine the clinical importance of these findings, in particular the effects on metformin plasma concentration.
Asunto(s)
Proteínas de la Ataxia Telangiectasia Mutada/genética , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/genética , Metformina/sangre , Metformina/uso terapéutico , Polimorfismo de Nucleótido Simple/genética , Adulto , Anciano , Anciano de 80 o más Años , Diabetes Mellitus Tipo 2/sangre , Femenino , Genotipo , Humanos , Hipoglucemiantes/sangre , Hipoglucemiantes/uso terapéutico , Insulina/genética , Masculino , Persona de Mediana Edad , Proteínas de Transporte de Catión Orgánico/genética , Transportador 1 de Catión Orgánico/genéticaRESUMEN
AIMS: To study the effects of metformin, as compared to placebo, on serum levels of vitamin D (25-hydroxyvitamin D [25(OH)D]) in patients with advanced type 2 diabetes. MATERIALS AND METHODS: In the HOME trial, a randomized placebo-controlled trial, 390 insulin-treated patients with type 2 diabetes were treated with 850 mg metformin or placebo thrice daily for 52 months. In a post-hoc analysis, we examined changes in the combined levels of 25(OH)D2 and 25(OH)D3 at 4 and 16 months during the study. RESULTS: Mean combined 25(OH)D at baseline was 68.2 nmoL/L (95% confidence interval [CI]: 65.5-71.1). In mixed model analysis, metformin, as compared to placebo, had no effect on 25(OH)D levels during 16 months (coefficient: 1.002 per month, multiplicative model; 95% CI: 0.998-1.006, P = .30). Metformin was associated with a small increase of 25(OH)D2 (coefficient: 1.012 per month; 95% CI: 1.003-1.021, P = .008). However, 25(OH)D2 is only a very small fraction (3%) of 25(OH)D. Seasonal variation had the biggest impact on 25(OH)D levels. Vitamin B12 levels were not associated with the levels of 25(OH)D. CONCLUSION: Metformin had no effect on serum 25(OH)D during 16 months in the setting of a clinical randomized controlled trial in patients with type 2 diabetes. Our results show that metformin doesn't lead to vitamin D deficiency.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/efectos adversos , Metformina/efectos adversos , Estado Nutricional/efectos de los fármacos , Deficiencia de Vitamina D/inducido químicamente , 25-Hidroxivitamina D 2/sangre , Factores de Edad , Anciano , Índice de Masa Corporal , Calcifediol/sangre , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Hipoglucemiantes/uso terapéutico , Masculino , Metformina/uso terapéutico , Persona de Mediana Edad , Países Bajos/epidemiología , Servicio Ambulatorio en Hospital , Sobrepeso/complicaciones , Prevalencia , Estaciones del Año , Factores Sexuales , Deficiencia de Vitamina D/complicaciones , Deficiencia de Vitamina D/epidemiologíaRESUMEN
AIMS: Metformin treatment is associated with a decrease of serum vitamin B12, but whether this reflects tissue B12 deficiency is controversial. We studied the effects of metformin on serum levels of methylmalonic acid (MMA), a biomarker for tissue B12 deficiency, and on onset or progression of neuropathy. METHODS: In the HOME trial, 390 insulin-treated patients with type 2 diabetes were treated with metformin or placebo for 52months. In a post hoc analysis, we analyzed the association between metformin, MMA and a validated Neuropathy Score (NPS). RESULTS: Metformin vs placebo increased MMA at the end of the study (95%CI: 0.019 to 0.055, p=0.001). Mediation analysis showed that the effect of metformin on the NPS consisted of a beneficial effect through lowering HbA1c (-0.020 per gram year) and an adverse effect through increasing MMA (0.042 per gram year), resulting in a non-significant net effect (0.032 per gram year, 95% CI: -0.121 to 0.182, p=0.34). CONCLUSION: Metformin not only reduces serum levels of B12, but also progressively increases serum MMA. The increase of MMA in metformin users was associated with significant worsening of the NPS. These results provide further support that metformin-related B12 deficiency is clinically relevant. Monitoring of B12 in users of metformin should be considered.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Metformina/uso terapéutico , Ácido Metilmalónico/sangre , Deficiencia de Vitamina B 12/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Retrospectivos , Factores de Tiempo , Vitamina B 12/sangre , Deficiencia de Vitamina B 12/sangre , Deficiencia de Vitamina B 12/complicacionesRESUMEN
Metformin prevents weight gain in patients with type 2 diabetes (T2D). However, the mechanisms involved are still unknown. In this post hoc analysis of the HOME trial, we aimed to determine whether metformin affects energy intake. Patients with T2D were treated with 850 mg metformin or received placebo added to insulin (1-3 times daily) for 4.3 years. Dietary intake was assessed at baseline, after 1 year and after 4.3 years, according to the dietary history method. Among the 310 included participants, 179 (93 placebo, 86 metformin) completed all 3 dietary assessments. We found no significant difference in energy intake after 4.3 years between the groups (metformin vs placebo: -31.0 kcal/d; 95% CI, -107.4 to 45.4; F-value, 1.3; df = 415; P = .27). Body weight in placebo users increased significantly more than in metformin-users during 4.3 years (4.9 ± 4.9 vs 1.1 ± 5.2 kg; t test: P ≤ .001). Linear mixed models did not show a significant effect of energy intake as explanation for the difference in weight gain between the groups (F-value, 0.1; df = 1; P = .82). In conclusion, the prevention of weight gain by metformin cannot be explained by reduced energy intake.
Asunto(s)
Fármacos Antiobesidad/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Insulina/efectos adversos , Metformina/uso terapéutico , Obesidad/prevención & control , Sobrepeso/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Depresores del Apetito/uso terapéutico , Índice de Masa Corporal , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Método Doble Ciego , Quimioterapia Combinada/efectos adversos , Ingestión de Energía/efectos de los fármacos , Femenino , Estudios de Seguimiento , Humanos , Hiperglucemia/prevención & control , Hipoglucemia/inducido químicamente , Hipoglucemia/prevención & control , Hipoglucemiantes/efectos adversos , Insulina/uso terapéutico , Masculino , Persona de Mediana Edad , Obesidad/inducido químicamente , Obesidad/complicaciones , Obesidad/fisiopatología , Sobrepeso/complicaciones , Sobrepeso/etiología , Aumento de Peso/efectos de los fármacosRESUMEN
Metformin is the first-line antidiabetic drug with over 100 million users worldwide, yet its mechanism of action remains unclear. Here the Metformin Genetics (MetGen) Consortium reports a three-stage genome-wide association study (GWAS), consisting of 13,123 participants of different ancestries. The C allele of rs8192675 in the intron of SLC2A2, which encodes the facilitated glucose transporter GLUT2, was associated with a 0.17% (P = 6.6 × 10(-14)) greater metformin-induced reduction in hemoglobin A1c (HbA1c) in 10,577 participants of European ancestry. rs8192675 was the top cis expression quantitative trait locus (cis-eQTL) for SLC2A2 in 1,226 human liver samples, suggesting a key role for hepatic GLUT2 in regulation of metformin action. Among obese individuals, C-allele homozygotes at rs8192675 had a 0.33% (3.6 mmol/mol) greater absolute HbA1c reduction than T-allele homozygotes. This was about half the effect seen with the addition of a DPP-4 inhibitor, and equated to a dose difference of 550 mg of metformin, suggesting rs8192675 as a potential biomarker for stratified medicine.
Asunto(s)
Diabetes Mellitus Tipo 2/genética , Transportador de Glucosa de Tipo 2/genética , Hipoglucemiantes/uso terapéutico , Metformina/uso terapéutico , Polimorfismo de Nucleótido Simple/genética , Carácter Cuantitativo Heredable , Glucemia/análisis , Índice de Masa Corporal , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Estudio de Asociación del Genoma Completo , Hemoglobina Glucada/análisis , Humanos , Población BlancaRESUMEN
AIMS: Distorted wall shear stress (WSS) in patients with type 2 diabetes mellitus (T2DM) may be partly explained by an altered red blood cell aggregation tendency (RAT) on viscosity at low shear rate (SR). The present study evaluates viscosity modeling by implementation of hematocrit and RAT in patients with and without T2DM (non-T2DM). METHODS: A Couette viscometer and LORCA aggregometer provided viscosity and RAT on 6 shear rates in 55 patients (46-78 yrs, 66% male, T2DM: n = 28), following informed consent. Using a K-fold cross-validation, two linear mixed models predicted by SR and Hct and by SR, Hct and RAT were compared. RESULTS: In non-T2DM modeling was improved in relatively low RATs (48%, p = 1.0 x 10-11) and became worse in relatively high RATs (-18%, p = 0.019). In T2DM the opposite was observed, as modeling became worse in relatively low RATs (-16%, p = 0.001) but was improved in relatively high RATs (22%, p = 0.022). CONCLUSIONS: In addition to confirming previous research, major differences in modeling improvement between T2DM and non-T2DM were found. Especially patients with T2DM, a high RAT and often high viscosity at low SR benefit from a more accurate viscosity modeling. Further studies should evaluate how these findings affect WSS in these patients.
Asunto(s)
Viscosidad Sanguínea , Diabetes Mellitus Tipo 2/sangre , Agregación Eritrocitaria , Estrés Mecánico , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos BiológicosRESUMEN
Our study in rat hearts examined whether activation of adenosine A(1) or A(3) receptors improved functional recovery and reduced apoptosis resulting from low-flow ischemia. Prior to 30 min low-flow ischemia (0.6 ml/min; 6% of baseline flow), Langendorff rat hearts were preconditioned with two 5-min cycles of (a) ischemia (PC; n=7), (b) infusion of 250 nM adenosine A(1) receptor agonist 2-chloro-N(6)-cyclopentyladenosine (CCPA; n=6), or (c) infusion of 50 nM adenosine A(3) receptor agonist N(6)-(3-iodobenzyl)-adenosine-5'-N-methyl-uronamide (IB-MECA; n=8). Recovery of function was improved in PC (71+/-3%), CCPA (68+/-6%) and IB-MECA (68+/-4%) groups compared to control hearts (46+/-5%; P<0.05). Cumulative release of total purines during ischemia-reperfusion was approx. 50% lower in PC, CCPA and IB-MECA groups compared to controls (P<0.05) and was significantly correlated to the percentage functional recovery (R(2)=0.55; P<0.05). The number of cytosolic histone-associated-DNA fragments, a hallmark of apoptosis and measured by Enzyme Linked ImmunoSorbent Assay (ELISA), was small and not different between groups after 30 min reperfusion. However, CCPA (0.6+/-0.1 absorbance units) and MECA (0.7+/-0.1 units; P<0.05 vs. PC) decreased apoptosis after 150 min reperfusion compared to PC (1.4+/-0.3 units) and control (1.2+/-0.1 units) hearts. This study shows that adenosine triggers protection of function in preconditioned rat hearts via both the adenosine A(1) and A(3) receptor. In clinical practice, pharmacological stimulation of adenosine A(3) receptors may be advantageous over adenosine A(1) receptor activation due to a lack of contractile side-effects. In contrast to ischemic preconditioning, pharmacological stimulation of adenosine A(1) or A(3) receptors reduced apoptosis. Furthermore, total purine release may serve as a marker of the degree of functional protection.