scholarly journals Diffusion Mechanism Modeling of Metformin in Human Organic Cationic Amino Acid Transporter one and Functional Impact of S189L, R206C, and G401S Mutation

2021 ◽  
Vol 11 ◽  
Author(s):  
Leydy Cano ◽  
Alejandro Soto-Ospina ◽  
Pedronel Araque ◽  
Maria Antonieta Caro-Gomez ◽  
Maria Victoria Parra-Marin ◽  
...  

Metformin used as a first-line drug to treat Type 2 Diabetes Mellitus is transported via organic cation channels to soft tissues. Mutations in the SLC22A1 gene, such as Gly401Ser, Ser189Leu, and Arg206Cys, may affect the drug’s therapeutic effect on these patients. This study aims at proposing a potential structural model for drug interactions with the hOCT1 transporter, as well as the impact of these mutations at both topological and electronic structure levels on the channel’s surface, from a chemical point of view with, in addition to exploring the frequency distribution. To chemically understand metformin diffusion, we used an open model from the protein model database, with ID PM0080367, viewed through UCSF Chimera. The effect of the mutations was assessed using computational hybrid Quantum Mechanics/Molecular Mechanics, based on the Austin Model 1 semi-empirical method using Spartan 18’ software. The results demonstrate coupling energy for metformin with amino acids F, W, H and Y, because of the interaction between the metformin dication and the electron cloud of π orbitals. The mutations analyzed showed changes in the chemical polarity and topology of the structure. The proposed diffusion model is a possible approach to the interaction mechanism between metformin and its transporter, as well as the impacts of variants, suggesting structural changes in the action of the drug. Metformin efficacy considerably varies from one patient to another; this may be largely attributed to the presence of mutations on the SLC22A1 gene. This study aims at proposing a potential structural model for metformin-hOCT1 (SLC22A1) transporter interaction, as well as the identification of the effect of mutations G401S (rs34130495), S189L (rs34104736), and R206C (616C > T) of the SLC22A1 gene at the topological and electronic structure levels on the channel surfaces, from a chemical viewpoint. Our results demonstrated that the coupling energies for metformin with aromatic amino acids F, W, H and Y, because of the interaction between the metformin dication and the electron cloud of π orbitals. Changes in the chemical environment’s polarity and the structure’s topology were reported in the mutations assessed. The diffusion model proposed is a potential approach for the mechanism of interaction of metformin with its transporter and the effects of variants on the efficacy of the drug in the treatment of type 2 diabetes. The assessment of the frequency of these mutations in a sample of Colombian type 2 diabetes patients suggests that different SLC22A1 gene variants might be involved in reduced OCT1 activity in the Colombian population since none of these mutations were detected.

2021 ◽  
Author(s):  
Ranyao Yang ◽  
Yue Hu ◽  
Chi Ho Lee ◽  
Yan Liu ◽  
Candela Diaz-Canestro ◽  
...  

Objective: Peptidase M20 domain containing 1 (PM20D1), a secreted enzyme catalysing condensation of fatty acids and amino acids into the bioactive lipids N-acyl amino acids (NAAA), induces uncoupling protein 1 (UCP1)-independent adaptive thermogenesis in brown/beige adipocytes in mice. This study aimed to explore the associations of the circulating levels of PM20D1 and major NAAA with obesity-related metabolic complications in humans. Design and Methods: Serum concentrations of PM20D1 and NAAA (C18:1-Leu and C18:1-Phe) in 256 Chinese subjects, including 78 lean and 178 overweight/obese individuals with or without diabetes, were measured with immunoassays and liquid chromatography-mass spectrometry respectively. The impact of sulfonylurea and rosiglitazone on their circulating levels was examined in 62 patients with type 2 diabetes. Results: Serum PM20D1 level was significantly elevated in overweight/obese individuals, and was closely associated with circulating levels of C18:1-Leu and C18:1-Phe. Furthermore, serum PM20D1, C18:1-Leu and C18:1-Phe concentrations correlated positively with several parameters of adiposity as well as fasting and 2-h postprandial glucose, HbA1c, fasting insulin, and HOMA-IR independent of BMI and age. Moreover, a significant elevation in PM20D1, C18:1-Leu and C18:1-Phe concentrations corresponding with increases in the number of components of the metabolic syndrome (MetS) was observed. Treatment with sulfonylurea significantly decreased circulating PM20D1, C18:1-Leu and C18:1-Phe in patients with type 2 diabetes. Conclusions: Increased serum levels of PM20D1 and its catalytic products NAAA are closely associated with obesity-related glucose dysregulation, insulin resistance and MetS, and can be potentially used as clinical biomarkers for diagnosing and monitoring these disorders.


Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 1612-P
Author(s):  
NADIRA SULTANA KAKOLY ◽  
ARUL EARNEST ◽  
HELENA TEEDE ◽  
LISA MORAN ◽  
DEBORAH LOXTON ◽  
...  

Author(s):  
Larisa Dmitrievna Popovich ◽  
Svetlana Valentinovna Svetlichnaya ◽  
Aleksandr Alekseevich Moiseev

Diabetes – a disease in which the effect of the treatment substantially depends on the patient. Known a study showed that the use of glucometers with the technology of three-color display of test results facilitates self-monitoring of blood sugar and leads to a decrease in glycated hemoglobin (HbAlc). Purpose of the study: to modeling the impact of using of a glucometer with a color-coded display on the clinical outcomes of diabetes mellitus and calculating, the potential economic benefits of reducing the hospitalization rate of patients with diabetes. Material and methods. Based on data from two studies (O. Schnell et al. and M. Baxter et al.) simulation of the reduction in the number of complications with the use of a glucometer with a color indication. In a study by O. Schnell et al. a decrease of HbA1c by 0.69 percent is shown when using the considered type of glucometers, which was the basis of the model. Results. In the model, the use of a glucometer with a color-coded display for type 1 diabetes led to a decrease in the total number of complications by 9.2 thousand over 5 years per a cohort of 40 thousand patients with different initial levels of HbA1c. In a cohort of 40 thousand patients with type 2 diabetes, the simulated number of prevented complications was 1.7 thousand over 5 years. When extrapolating these data to all patients with diabetes included in the federal register of diabetes mellitus (FRD), the number of prevented complications was 55.4 thousand cases for type 1 diabetes and 67.1 thousand cases for type 2 diabetes. The possible economic effect from the use of the device by all patients with a diagnosis of diabetes, which are included in the FRD, estimated at 1.5 billion rubles for a cohort of patients with type 1 diabetes and 5.3 billion rubles for patients with type 2 diabetes. Conclusion. Improving the effectiveness of self-monitoring, which is the result of the use of glucometers with color indicators, can potentially significantly reduce the incidence of complications in diabetes and thereby provide significant economic benefits to society.


2011 ◽  
Vol 7 (3) ◽  
pp. 185-189 ◽  
Author(s):  
Richdeep S. Gill ◽  
Arya M. Sharma ◽  
David P. Al-Adra ◽  
Daniel W. Birch ◽  
Shahzeer Karmali

2021 ◽  
Vol 9 (1) ◽  
pp. e001413
Author(s):  
Jonathan Yap ◽  
Kamalesh Anbalakan ◽  
Wan Ting Tay ◽  
Daniel Ting ◽  
Carol Yim Cheung ◽  
...  

IntroductionDiabetes mellitus is a growing public health epidemic in Asia. We examined the impact of type 2 diabetes, glycemic control and microvascular complications on mortality and cardiovascular outcomes in a multiethnic population-based cohort of Asians without prior cardiovascular disease.Research design and methodsThis was a prospective population-based cohort study in Singapore comprising participants from the three major Asian ethnic groups: Chinese, Malays and Indians, with baseline examination in 2004–2011. Participants with type 1 diabetes and those with cardiovascular disease at baseline were excluded. Type 2 diabetes, Hemoglobin A1c (HbA1c) levels and presence of microvascular complications (diabetic retinopathy and nephropathy) were defined at baseline. The primary outcome was all-cause mortality and major adverse cardiovascular events (MACEs), defined as a composite of cardiovascular mortality, myocardial infarction, stroke and revascularization, collected using a national registry.ResultsA total of 8541 subjects were included, of which 1890 had type 2 diabetes at baseline. Subjects were followed for a median of 6.4 (IQR 4.8–8.8) years. Diabetes was a significant predictor of mortality (adjusted HR 1.74, 95% CI 1.45 to 2.08, p<0.001) and MACE (adjusted HR 1.64, 95% CI 1.39 to 1.93, p<0.001). In those with diabetes, higher HbA1c levels were associated with increased MACE rates (adjusted HR (per 1% increase) 1.18, 95% CI 1.11 to 1.26, p<0.001) but not mortality (p=0.115). Subjects with two microvascular complications had significantly higher mortality and MACE compared with those with only either microvascular complication (adjusted p<0.05) and no microvascular complication (adjusted p<0.05).ConclusionDiabetes is a significant predictor of mortality and cardiovascular morbidity in Asian patients without prior cardiovascular disease. Among patients with type 2 diabetes, poorer glycemic control was associated with increased MACE but not mortality rates. Greater burden of microvascular complications identified a subset of patients with poorer outcomes.


2020 ◽  
Author(s):  
Björg Ásbjörnsdóttir ◽  
Marianne Vestgaard ◽  
Nicoline C. Do ◽  
Lene Ringholm ◽  
Lise L.T. Andersen ◽  
...  

Diabetologia ◽  
2021 ◽  
Author(s):  
David Z. I. Cherney ◽  
◽  
Bernard Charbonnel ◽  
Francesco Cosentino ◽  
Samuel Dagogo-Jack ◽  
...  

Abstract Aims/hypothesis In previous work, we reported the HR for the risk (95% CI) of the secondary kidney composite endpoint (time to first event of doubling of serum creatinine from baseline, renal dialysis/transplant or renal death) with ertugliflozin compared with placebo as 0.81 (0.63, 1.04). The effect of ertugliflozin on exploratory kidney-related outcomes was evaluated using data from the eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes (VERTIS CV) trial (NCT01986881). Methods Individuals with type 2 diabetes mellitus and established atherosclerotic CVD were randomised to receive ertugliflozin 5 mg or 15 mg (observations from both doses were pooled), or matching placebo, added on to existing treatment. The kidney composite outcome in VERTIS CV (reported previously) was time to first event of doubling of serum creatinine from baseline, renal dialysis/transplant or renal death. The pre-specified exploratory composite outcome replaced doubling of serum creatinine with sustained 40% decrease from baseline in eGFR. In addition, the impact of ertugliflozin on urinary albumin/creatinine ratio (UACR) and eGFR over time was assessed. Results A total of 8246 individuals were randomised and followed for a mean of 3.5 years. The exploratory kidney composite outcome of sustained 40% reduction from baseline in eGFR, chronic kidney dialysis/transplant or renal death occurred at a lower event rate (events per 1000 person-years) in the ertugliflozin group than with the placebo group (6.0 vs 9.0); the HR (95% CI) was 0.66 (0.50, 0.88). At 60 months, in the ertugliflozin group, placebo-corrected changes from baseline (95% CIs) in UACR and eGFR were −16.2% (−23.9, −7.6) and 2.6 ml min−1 [1.73 m]−2 (1.5, 3.6), respectively. Ertugliflozin was associated with a consistent decrease in UACR and attenuation of eGFR decline across subgroups, with a suggested larger effect observed in the macroalbuminuria and Kidney Disease: Improving Global Outcomes in Chronic Kidney Disease (KDIGO CKD) high/very high-risk subgroups. Conclusions/interpretation Among individuals with type 2 diabetes and atherosclerotic CVD, ertugliflozin reduced the risk for the pre-specified exploratory composite renal endpoint and was associated with preservation of eGFR and reduced UACR. Trial registration ClinicalTrials.gov NCT01986881 Graphical abstract


2020 ◽  
Vol 30 (Supplement_5) ◽  
Author(s):  
I Guerrero Fernández de Alba ◽  
A Gimeno-Miguel ◽  
B Poblador Plou ◽  
K Bliek Bueno ◽  
J Carmona Pirez ◽  
...  

Abstract Background Type 2 diabetes mellitus (T2D) is often accompanied by other chronic diseases, including mental diseases (MD). This work aimed at studying MD prevalence in T2D patients and analyse its impact on T2D health outcomes. Methods Retrospective, observational study of individuals of the EpiChron Cohort aged 18 and over with prevalent T2D at baseline (2011) in Aragón, Spain (n = 63,365). Participants were categorized by the existence or absence of MD, defined as the presence of depression, anxiety, schizophrenia or substance abuse. MD prevalence was calculated, and a logistic regression model was performed to analyse the likelihood of the four studied health outcomes (4-year all-cause mortality, all-cause hospitalization, T2D-hospitalization, and emergency room visits) based on the presence of each type of MD, after adjusting by age, sex and number of comorbidities. Results Mental diseases were observed in 19% of T2D patients, with depression being the most frequent condition, especially in women (20.7% vs. 7.57%). Mortality risk was significantly higher in patients with MD (odds ratio -OR- 1.24; 95% confidence interval -CI- 1.16-1.31), especially in those with substance abuse (OR 2.18; 95% CI 1.84-2.57) and schizophrenia (OR 1.82; 95% CI 1.50-2.21). The presence of MD also increased the risk of T2D-hospitalization (OR 1.51; 95% CI 1.18-1.93), emergency room visits (OR 1.26; 95% CI 1.21-1.32) and all-cause hospitalization (OR 1.16; 95% CI 1.10-1.23). Conclusions The high prevalence of MD among T2D patients, and its association with health outcomes, underscores the importance of providing integrated, person-centred care and early detection of comorbid mental diseases in T2D patients to improve disease management and health outcomes. Key messages Comprehensive care of T2D should include specific strategies for prevention, early detection, and management of comorbidities, especially mental disorders, in order to reduce their impact on health. Substance abuse was the mental disease with the highest risk of T2D-hospitalization, emergency room visits and all-cause hospitalization.


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