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- Kanai, M, et al.
(författare)
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- 2023
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swepub:Mat__t
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- Dawed, Adem Y., et al.
(författare)
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Variation in the plasma membrane monoamine transporter (PMAT) (encoded by SLC29A4) and organic cation transporter 1 (OCT1) (encoded by SLC22A1) and gastrointestinal intolerance to metformin in type 2 diabetes : An IMI direct study
- 2019
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Ingår i: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 42:6, s. 1027-1033
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE Gastrointestinal adverse effects occur in 20–30% of patients with metformin-treated type 2 diabetes, leading to premature discontinuation in 5–10% of the cases. Gastrointestinal intolerance may reflect localized high concentrations of metformin in the gut. We hypothesized that reduced transport of metformin via the plasma membrane monoamine transporter (PMAT) and organic cation transporter 1 (OCT1) could increase the risk of severe gastrointestinal adverse effects. RESEARCH DESIGN AND METHODS The study included 286 severe metformin-intolerant and 1,128 metformin-tolerant individuals from the IMI DIRECT (Innovative Medicines Initiative: DIabetes REsearCh on patient straTification) consortium. We assessed the association of patient characteristics, concomitant medication, and the burden of mutations in the SLC29A4 and SLC22A1 genes on odds of intolerance. RESULTS Women (P < 0.001) and older people (P < 0.001) were more likely to develop metformin intolerance. Concomitant use of transporter-inhibiting drugs increased the odds of intolerance (odds ratio [OR] 1.72, P < 0.001). In an adjusted logistic regression model, the G allele at rs3889348 (SLC29A4) was associated with gastrointestinal intolerance (OR 1.34, P = 0.005). rs3889348 is the top cis-expression quantitative trait locus for SLC29A4 in gut tissue where carriers of the G allele had reduced expression. Homozygous carriers of the G allele treated with transporter-inhibiting drugs had more than three times higher odds of intolerance compared with carriers of no G allele and not treated with inhibiting drugs (OR 3.23, P < 0.001). Use of a genetic risk score derived from rs3889348 and SLC22A1 variants found that the odds of intolerance were more than twice as high in individuals who carry three or more risk alleles compared with those carrying none (OR 2.15, P = 0.01). CONCLUSIONS These results suggest that intestinal metformin transporters and concomitant medications play an important role in the gastrointestinal adverse effects of metformin.
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- Rauh, Simone P, et al.
(författare)
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Predicting glycated hemoglobin levels in the non-diabetic general population : development and validation of the DIRECT-DETECT prediction model - a DIRECT study
- 2017
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 12:2
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: To develop a prediction model that can predict HbA1c levels after six years in the non-diabetic general population, including previously used readily available predictors.METHODS: Data from 5,762 initially non-diabetic subjects from three population-based cohorts (Hoorn Study, Inter99, KORA S4/F4) were combined to predict HbA1c levels at six year follow-up. Using backward selection, age, BMI, waist circumference, use of anti-hypertensive medication, current smoking and parental history of diabetes remained in sex-specific linear regression models. To minimize overfitting of coefficients, we performed internal validation using bootstrapping techniques. Explained variance, discrimination and calibration were assessed using R2, classification tables (comparing highest/lowest 50% HbA1c levels) and calibration graphs. The model was externally validated in 2,765 non-diabetic subjects of the population-based cohort METSIM.RESULTS: At baseline, mean HbA1c level was 5.6% (38 mmol/mol). After a mean follow-up of six years, mean HbA1c level was 5.7% (39 mmol/mol). Calibration graphs showed that predicted HbA1c levels were somewhat underestimated in the Inter99 cohort and overestimated in the Hoorn and KORA cohorts, indicating that the model's intercept should be adjusted for each cohort to improve predictions. Sensitivity and specificity (95% CI) were 55.7% (53.9, 57.5) and 56.9% (55.1, 58.7) respectively, for women, and 54.6% (52.7, 56.5) and 54.3% (52.4, 56.2) for men. External validation showed similar performance in the METSIM cohort.CONCLUSIONS/INTERPRETATION: In the non-diabetic population, our DIRECT-DETECT prediction model, including readily available predictors, has a relatively low explained variance and moderate discriminative performance, but can help to distinguish between future highest and lowest HbA1c levels. Absolute HbA1c values are cohort-dependent.
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