Artificial-Intelligence-Assisted Discovery of Genetic Factors for Precision Medicine of Antiplatelet Therapy in Diabetic Peripheral Artery Disease.

An increased risk of cardiovascular events was identified in patients with peripheral artery disease (PAD). Clopidogrel is one of the most widely used antiplatelet medications. However, there are heterogeneous outcomes when clopidogrel is used to prevent cardiovascular events in PAD patients. Here, we use an artificial intelligence (AI)-assisted methodology to identify genetic factors potentially involved in the clopidogrel-resistant mechanism, which is currently unclear. Several discoveries can be pinpointed. Firstly, a high proportion (>50%) of clopidogrel resistance was found among diabetic PAD patients in Taiwan. Interestingly, our result suggests that platelet function test-guided antiplatelet therapy appears to reduce the post-interventional occurrence of major adverse cerebrovascular and cardiac events in diabetic PAD patients. Secondly, AI-assisted genome-wide association study of a single-nucleotide polymorphism (SNP) database identified a SNP signature composed of 20 SNPs, which are mapped into 9 protein-coding genes (SLC37A2, IQSEC1, WASHC3, PSD3, BTBD7, GLIS3, PRDM11, LRBA1, and CNR1). Finally, analysis of the protein connectivity map revealed that LRBA, GLIS3, BTBD7, IQSEC1, and PSD3 appear to form a protein interaction network. Intriguingly, the genetic factors seem to pinpoint a pathway related to endocytosis and recycling of P2Y12 receptor, which is the drug target of clopidogrel. Our findings reveal that a combination of AI-assisted discovery of SNP signatures and clinical parameters has the potential to develop an ethnic-specific precision medicine for antiplatelet therapy in diabetic PAD patients.

Thermal Perception Abnormalities Can Predict Diabetic Kidney Disease in Type 2 Diabetes Mellitus Patients.

BACKGROUND: Previous studies have illustrated clinical associations between diabetic peripheral neuropathy (DPN) and diabetic kidney disease (DKD). Quantitative sensory testing (QST) can accurately detect thermal perception abnormalities and aid in the early diagnosis of asymptomatic small-fiber DPN in patients with type 2 diabetes. The aim of this study was to determine the predictive value of thermal perception abnormalities by QST to detect DKD. METHODS: We prospectively enrolled 432 patients with type 2 diabetes (50.2% male, mean age 57.2 years, and average duration of diabetes 9.9 years) at our hospital between 2016 and 2017. Demographic and clinical data of the patients were recorded and analyzed. Diagnosis and staging of DKD were determined by urinary albumin excretion rate and estimated glomerular filtration rate. The presence of thermal perception abnormalities was determined by QST. Multiple logistic regression and receiver operating characteristic (ROC) analyses were performed to investigate the relationships between thermal perception abnormalities and DKD in these patients. RESULTS: In multiple regression analysis, abnormal cold perception in the lower limbs was associated with an increased risk of advanced DKD. Area under the ROC curve analysis revealed that four-limb cold perception abnormalities had the best discriminatory power (0.741 ± 0.053) to predict advanced DKD. CONCLUSIONS: Our results demonstrate the value of using thermal perception abnormalities to identify patients with type 2 diabetes also at risk of DKD.

Circulating Klotho levels can predict long-term macrovascular outcomes in type 2 diabetic patients.

BACKGROUND AND AIMS: Type 2 diabetes is a global health problem that is associated with a wide variety of vascular complications and associated morbidity and mortality. Klotho is an enzyme and transmembrane protein, and increasing evidence suggests that Klotho may contribute to reduced oxidative stress, improved endothelial function, and vasoprotection. To date, the physiological role of Klotho in vascular complications associated with diabetes is unclear. METHODS: We prospectively recruited 252 patients with type 2 diabetes, who visited an outpatient clinic at our hospital between 2009 and 2011. Patients in the top and bottom tertiles of circulating Klotho levels were enrolled for analysis. RESULTS: Of the 168 patients enrolled, 45.8% were male, the mean age was 57.2 years, and the average duration of diabetes was 7.58 years. In multiple regression analysis, a high Klotho level was associated with a reduced risk of developing coronary artery disease and cerebrovascular accidents. Klotho level was also an independent predictor for the development of macroangiopathies within the 7-year study period. CONCLUSIONS: Our results suggest that circulating Klotho level is a predictor of long-term macrovascular outcomes in patients with type 2 diabetes.

Serum levels of uncoupling proteins in patients with differential insulin resistance: A community-based cohort study.

The uncoupling protein (UCP) belongs to a family of energy-dissipating proteins in mitochondria. Increasing evidences have indicated that UCPs have immense impact on glucose homeostasis and are key proteins in metabolic syndrome. For applying the findings to clinical practice, we designed a study to explore the association between serum UCPs 1-3 and insulin resistance. This investigation prospectively recorded demographical parameter and collected blood samples of 1071 participants from 4 districts in Northeastern Taiwan during the period from August 2013 to July 2014. Propensity score matching by age and sex in patients with top and bottom third homeostasis model assessment of insulin resistance (HOMA-IR) levels was performed, and 326 subjects were enrolled for further studies. The mean age of the patients was 59.4 years and the majority of them (65.5%) were females. The prevalence of metabolic syndrome was 35.5%. Our results demonstrated that serum UCPs 1-3 were significantly associated with differences in HOMA-IR levels. Multiple logistic regression analysis indicated that low UCP 1 and features of metabolic syndrome, namely hypertension, diabetes, body mass index, and high-density lipoprotein, were independent determinants for high HOMA-IR levels. We thus determined that low serum UCP 1 is a predictor for high resistance to insulin.

Correlation and presentation of thyroid functional status with thyroid autoantibodies in long-term follow-up of autoimmune thyroiditis: A study of 116 cases.

BACKGROUND/PURPOSE: The most common diagnostic finding of autoimmune thyroid disease (AITD) is the presence of antithyroid antibodies. While autoimmune thyroiditis (AT) is a common AITD, aspiration cytology is one of the important diagnostic tools of AT. METHODS: We evaluated 116 AT patients with ultrasound-guided aspiration cytology and then analyzed the correlation between thyroid hormone status and thyroid autoantibodies. This was a retrospective analysis with prospective collection of data with a mean follow-up period of 68.8 ± 37.8 months. The patients were classified as either euthyroid, hypothyroid, or hyperthyroid (HT). Of the 116 patients, 22 were hypothyroid, 37 were euthyroid, and 57 were HT. RESULTS: During the follow-up period, 95.5% of the hypothyroid group remained hypothyroid and only one patient improved to euthyroid. In the euthyroid group, 16.2% progressed to hypothyroid and 83.8% remained euthyroid. In the HT group, 8.7% progressed to hypothyroid, 70.2% progressed to euthyroid, and 21.1% remained HT. Most patients with a high titer of thyroglobulin antibody (TgAb) will progress to hypothyroid, and patients with a high titer of thyroid stimulating hormone (TSH) receptor antibody (TRAb) will remain HT. Strong correlations between thyroid functional status and positive number of thyroid autoantibodies were seen in this study. Patients with all the three antibodies positive had a high prevalence of hyperthyroidism. CONCLUSION: In our study, most patients were HT; this may be because of the early diagnosis and treatment of AT in our clinic. Although antithyroperoxidase antibody (TPOAb) is a hallmark antibody of HT, it cannot predict the initial presentation and clinical outcome.

Clinical value of NGAL, L-FABP and albuminuria in predicting GFR decline in type 2 diabetes mellitus patients.

OBJECTIVES: Neutrophil gelatinase-associated lipocalin (NGAL) and liver-type fatty acid binding protein (L-FABP) are emerging as excellent biomarkers in the urine and plasma for the early prediction of acute and chronic kidney injury. The aims of this prospective study were to determine the role of albuminuria, and that of serum and urine levels of NGAL and L-FABP as predictors of a decline in the glomerular filtration rate (GFR) in patients with type 2 diabetes. METHODS: A longitudinal cohort study with one hundred forty type 2 diabetic patients was conducted. Serum and urine levels of NGAL and L-FABP, and the urine albumin excretion rate were determined. The correlation between the kidney injury biomarkers and rate of GFR decline was analyzed. RESULTS: The eGFR of study subjects decreased significantly as the study progressed (86.4±31.1 vs. 74.4±27.3 ml/min/1.73 m(2), P<0.001), and the urine albumin excretion rate increased significantly (264.9±1060.3 vs. 557.7±2092.5 mg/day, P = 0.009). The baseline urine albumin excretion rate and serum L-FABP level were significantly correlated with baseline eGFR (P<0.05). The results of regression analysis for the correlations between the rate of eGFR change and the baseline levels of NGAL and L-FABP, and the urine albumin excretion rate showed that only the urine albumin excretion rate was significantly correlated with the rate of eGFR change (standardized coefficients: -0.378; t: -4.298; P<0.001). CONCLUSIONS: Tubular markers, such as NGAL and L-FABP, may not be predictive factors associated with GFR decline in type 2 diabetic patients.

Axial length and proliferative diabetic retinopathy.

PURPOSE: To determine the correlation between axial length and diabetic retinopathy (DR) in patients with diabetes mellitus for 10 years or more. METHODS: This study was a prospective, observational, cross-sectional study. Patients with diabetes for 10 years or more were included. We excluded eyes with any other significant ocular disease or any prior intraocular surgery, except uncomplicated cataract surgery. Only one eye of each patient was included as the study eye. The severity of DR was graded as no DR, non-proliferative DR (NPDR), or proliferative DR (PDR). Axial length was measured by A-scan ultrasound (10 MHz Transducer, AL-2000 Biometer/Pachymeter; Tomey, Phoenix, AZ). Univariate logistic regression models were used to evaluate the relationship between the dependent variables (any DR, PDR) and all potential risk factors. Axial length and other factors with p value <0.1 were included in multivariate logistic regression models. Backward selection based on the likelihood ratio statistic was used to select the final models. RESULTS: We included 166 eyes from 166 patients (93 female and 73 male; mean age, 68.8 years). The mean diabetes duration was 15.4 years. Fifty-four (32.5%) eyes had no DR, 72 (43.4%) eyes had NPDR, and 40 (24.1%) eyes had PDR. In univariate analysis, hypertension (p = 0.009), renal impairment (p = 0.079), and insulin use (p = 0.009) were associated with developing any DR. Hypertension (p = 0.042), renal impairment (p = 0.014), insulin use (p = 0.040), pseudophakia (p = 0.019), and axial length (p = 0.076) were associated with developing PDR. In multivariate analysis, hypertension (p = 0.005) and insulin use (p = 0.010) were associated with developing any DR. Hypertension (p = 0.020), renal impairment (p = 0.025), pseudophakia (p = 0.006), and axial length (p = 0.024) were associated with developing PDR. CONCLUSIONS: This observational study suggests an inverse relationship between axial length and the development of PDR in patients with diabetes for 10 years or more. No relationship was found between axial length and the development of any DR.

Correlation of clinical changes with regard to thyroxine replacement therapy in hypothyroid patients: focusing on the change of renal function.

Thyroid dysfunction has an important role in renal insufficiency. The aim of the study was to correlate the change of renal function with other clinical factors after thyroxine therapy in hypothyroid patients. A prospective study was designed and 30 hypothyroid patients were included. All study subjects received 0.15-0.2 mg/day thyroxine for 12 weeks. Diastolic blood pressure and serum levels of creatine phosphokinase (CPK) and myoglobulin decreased significantly after thyroxine therapy. Serum creatinine decreased (0.87 ± 0.22 vs. 0.70 ± 0.17 mg/dl, p < 0.001) and estimated glomerular filtration rate (eGFR) increased significantly (82.06 ± 31.08 vs. 100.31 ± 31.79 ml/min/1.73 m(2); p < 0.001) after thyroxine replacement. Left ventricular ejection fraction (LVEF) was significantly increased after thyroxine replacement (64.47 ± 11.94 vs. 72.40 ± 13.89%, p = 0.026). No significant vascular functional changes of peripheral (pulse wave velocity) and renal interlobar arteries (pulsatility index and resistance index) were noted. The change of eGFR significantly correlated with the changes of serum-free T(4) (fT(4)), CPK, myoglobulin and LVEF. The correlation between the change of eGFR and thyroid-stimulating hormone (TSH) level was not significant. In conclusion, the GFR of hypothyroid patients increased significantly after thyroxine replacement. The change of GFR was significantly correlated with the changes of fT(4), CPK, myoglobulin and LVEF, but not with TSH.

Comparison of the effects of sibutramine and orlistat on obese, poorly-controlled type 2 diabetic patients.

BACKGROUND: We assessed and directly compared weight loss effects of sibutramine and orlistat treatment in a group of obese, poorly-controlled type 2 diabetic patients. METHODS: This study recruited 34 diabetic subjects [glycohemoglobin (HbA1c) > 8%] with a body mass index of at least 27 kg/m2. A 36-week, three-phase, prospective, randomized, cross-over comparative study was conducted. In phase 1, 34 patients were randomly divided into two groups. One group received sibutramine for 3 months, then completed a 3 month wash-out period and, finally, shifted to orlistat for another 3 months. The second group followed the same procedure but received orlistat first and then sibutramine. The efficacy measures were rate of weight reduction, glycemic control, insulin sensitivity and cardiovascular risk factors, including waist circumference, lipid profiles and blood pressure. RESULTS: The sibutramine-treated group achieved 2.0 kg (2.5%) weight loss with observable but not statistically significant changes in insulin sensitivity, glycemic control, and cardiovascular risk factors. There were no significant changes in systolic or diastolic blood pressure. The weight reduction in the orlistat-treated group was only 0.8 kg (0.9%), which was significantly less than that of the sibutramine group. There were significant differences in total cholesterol, low density lipoprotein cholesterol and HbA1C. Direct comparative analysis revealed no significant differences between these two groups. CONCLUSION: This study indicates that sibutramine treatment produced greater reduction in weight than orlistat in obese, poorly-controlled type 2 diabetic patients. However, no significant differences in waist circumference, and lipid or glucose levels were found between the two groups.