Pharmacogenetics of type 2 diabetes mellitus, the route toward tailored medicine

Type 2 diabetes mellitus (T2DM) is a chronic disease that has reached the levels of a global epidemic. In order to achieve optimal glucose control, it is often necessary to rely on combination therapy of multiple drugs or insulin because uncontrolled glucose levels result in T2DM progression and enhanced risk of complications and mortality. Several antihyperglycemic agents have been developed over time, and T2DM pharmacotherapy should be prescribed based on suitability for the individual patient's characteristics. Pharmacogenetics is the branch of genetics that investigates how our genome influences individual responses to drugs, therapeutic outcomes, and incidence of adverse effects. In this review, we evaluated the pharmacogenetic evidences currently available in the literature, and we identified the top informative genetic variants associated with response to the most common anti-diabetic drugs: metformin, DPP-4 inhibitors/GLP1R agonists, thiazolidinediones, and sulfonylureas/meglitinides. Overall, we found 40 polymorphisms for each drug class in a total of 71 loci, and we examined the possibility of encouraging genetic screening of these variants/loci in order to critically implement decision-making about the therapeutic approach through precision medicine strategies. It is possible then to anticipate that when the clinical practice will take advantage of the genetic information of the diabetic patients, this will provide a useful resource for the prevention of T2DM progression, enabling the identification of the precise drug that is most likely to be effective and safe for each patient and the reduction of the economic impact on a global scale

An importance sampling algorithm for generating exact eigenstates of the nuclear Hamiltonian

We endow a recently devised algorithm for generating exact eigensolutions of large matrices with an importance sampling, which is in control of the extent and accuracy of the truncation of their dimensions. We made several tests on typical nuclei using a correlated basis obtained from partitioning the shell model space. The sampling so implemented allows not only for a substantial reduction of the shell model space but also for an extrapolation to exact eigenvalues and E2 strengths.Comment: A compressed file composed of a text in latex of 19 pages and 9 figures in p

A polymorphism at IGF1 locus is associated with anemia

In vitro and in vivo studies suggest that IGF-1 has a role in erythropoiesis. There is evidence that the rs35767 C/T polymorphism near IGF1 is associated with plasma IGF-1 levels. We investigated the effect of this polymorphism on hemoglobin (Hb) concentration and anemia. The study group comprised 3286 adult Whites. The rs35767 polymorphism was screened using a TaqMan allelic discrimination assay. The rs35767 polymorphism was not associated with age, gender, BMI, waist circumference, smoking, blood pressure, plasma glucose, HbA1c, type 2 diabetes, HOMA-IR, hsCRP, eGFR, and lipid profile. Erythrocyte sedimentation rate (ESR), fibrinogen, and fasting insulin levels were significantly lower in TT genotype carriers compared with C allele carriers. Hb concentration was significantly higher in carriers of the TT genotype compared with C allele carriers, and a lower proportion of TT carriers had anemia. As compared with TT genotype carriers, those bearing the CC genotype had a 2.4-fold higher risk of anemia (OR 2.40, 95%CI 1.19-4.82), and those with the CT genotype had a 2.0-fold higher risk of anemia (OR 2.06, 95%CI 1.04-4.11). The association remained significant when fasting insulin, eGFR, smoking, diabetes, ACE inhibitors, sartans or diuretics treatments, use of metformin and pioglitazone were added to the model, but its independence was not retained after inclusion of fibrinogen and ESR values into the model. In conclusion, rs35767 TT allele carriers exhibited significantly higher concentrations of Hb, and lower risk of anemia compared with C allele carriers supporting the idea that IGF-1 plays a role in erythropoiesis homeostasis

Plasma kisspeptin levels are associated with insulin secretion in nondiabetic individuals

To evaluate if plasma kisspeptin concentrations are associated with insulin secretion, as suggested by recent in vitro studies, independently of confounders. 261 nondiabetic subjects were stratified into tertiles according to kisspeptin values. Insulin secretion was assessed using indexes derived from oral glucose tolerance test (OGTT). After adjusting for age, gender, and BMI, subjects in the highest (tertile 3) kisspeptin group exhibited significantly lower values of insulinogenic index, corrected insulin response (CIR30), and Stumvoll indexes for first-phase and second-phase insulin release as compared with low (tertile 1) or intermediate (tertile 2) kisspeptin groups. Univariate correlations between kisspeptin concentration and metabolic variables showed that kisspeptin concentration was significantly and positively correlated with age, blood pressure, and 2-h post-load glucose, and inversely correlated with BMI, and waist circumference. There was an inverse relationship between kisspeptin levels and OGTT-derived indexes of glucose-stimulated insulin secretion. A multivariable regression analysis in a model including all the variables significantly correlated with kisspeptin concentration showed thar age (β = -0.338, P<0.0001), BMI (β = 0.272, P<0.0001), 2-h post-load glucose (β = -0.229, P<0.0001), and kisspeptin (β = -0.105, P = 0.03) remained associated with insulinogenic index. These factors explained 34.6% of the variance of the insulinogenic index. In conclusion, kisspeptin concentrations are associated with insulin secretion independently of important determinants of glucose homeostasis such as gender, age, adiposity, 2-h post-load glucose, and insulin sensitivity

Elevated hemoglobin glycation index identify non-diabetic individuals at increased risk of kidney dysfunction

Hemoglobin glycation index (HGI), calculated as the difference between the observed value of HbA1 and the predicted HbA1c based on plasma glucose concentration, is a measure of the individual tendency toward non-enzymatic hemoglobin glycation which has been found to be positively associated with nephropathy in subjects with diabetes. In this cross-sectional study we aimed to evaluate whether higher HGI levels are associated with impaired kidney function also among nondiabetic individuals. The study group comprised 1505 White nondiabetic individuals stratified in quartiles according to HGI levels. Estimated glomerular filtration rate (eGFR) was calculated by using the MDRD equation. Individuals in the intermediate and high HGI groups exhibited a worse metabolic phenotype with increased levels of visceral obesity, total cholesterol, triglycerides, inflammatory biomarkers such as hsCRP and white blood cells count and lower values of HDL and insulin sensitivity assessed by Matsuda index in comparison to the lowest quartile of HGI. Subjects in the intermediate and high HGI groups displayed a graded decrease of eGFR levels in comparison with the lowest quartile of HGI. In a logistic regression analysis individuals in the highest quartile of HGI exhibited a significantly 3.6-fold increased risk of having chronic kidney disease (95% CI: 1.13-11.24, P = 0.03) and a significantly 1.6-fold increased risk of having a mildly reduced kidney function (95% CI: 1.19-2.28, P = 0.003) in comparison to individuals in the lowest HGI group. In conclusion HGI may be a useful tool to identify nondiabetic individuals with an increased risk of having kidney dysfunction

Insulin-like growth factor-1 is a negative modulator of glucagon secretion

Glucagon secretion involves a combination of paracrine, autocrine, hormonal, and autonomic neural mechanisms. Type 2 diabetes often presents impaired glucagon suppression by insulin and glucose. Insulin-like growth factor-I (IGF-1) has elevated homology with insulin, and regulates pancreatic β-cells insulin secretion. Insulin and IGF-1 receptors share considerable structure homology and function. We hypothesized the existence of a mechanism linking the inhibition of α-cells glucagon secretion to IGF-1. Herein, we evaluated the association between plasma IGF-1 and glucagon levels in 116 nondiabetic adults. After adjusting for age gender and BMI, fasting glucagon levels were positively correlated with 2-h post-load glycaemia, HOMA index and fasting insulin, and were negatively correlated with IGF-1 levels. In a multivariable regression, the variables independently associated to fasting glucagon were circulating IGF-1 levels, HOMA index and BMI, explaining 20.7% variation. To unravel the molecular mechanisms beneath IGF-1 and glucagon association, we investigated whether IGF-1 directly modulates glucagon expression and secretion in an in vitro model of α-cells. Our data showed that IGF-1 inhibits the ability of low glucose concentration to stimulate glucagon expression and secretion via activation of the phosphatidylinositol-3-kinase/Akt/FoxO1 pathway. Collectively, our results suggest a new regulatory role of IGF-1 on α-cells biological function

Reciprocal Association of Plasma IGF-1 and Interleukin-6 Levels With Cardiometabolic Risk Factors in Nondiabetic Subjects

OBJECTIVE—To examine the relationship between plasma IGF-1 and interleukin-6 (IL-6) levels in Caucasian nondiabetic subjects and evaluate the association of IGF-1 and IL-6 with the cardiometabolic risk factors characterizing metabolic syndrome (MetS)

Topic modeling and user network analysis on twitter during world lupus awareness day

Twitter is increasingly used by individuals and organizations to broadcast their feelings and practices, providing access to samples of spontaneously expressed opinions on all sorts of themes. Social media offers an additional source of data to unlock information supporting new insights disclosures, particularly for public health purposes. Systemic lupus erythematosus (SLE) is a complex, systemic autoimmune disease that remains a major challenge in therapeutic diagnostic and treatment management. When supporting patients with such a complex disease, sharing information through social media can play an important role in creating better healthcare services. This study explores the nature of topics posted by users and organizations on Twitter during world Lupus day to extract latent topics that occur in tweet texts and to identify what information is most commonly discussed among users. We identified online influencers and opinion leaders who discussed different topics. During this analysis, we found two different types of influencers that employed different narratives about the communities they belong to. Therefore, this study identifies hidden information for healthcare decision-makers and provides a detailed model of the implications for healthcare organizations to detect, understand, and define hidden content behind large collections of text

Drug-eluting Microspheres Compared to Conventional Transarterial Chemoembolization as First Line Treatment for Unresectable Hepatocellular Carcinoma: A Single-center Retrospective Cost-utility Analysis

Purpose: To assess the cost-utility of initial treatment with drug-eluting microspheres (DEM) transarterial chemoembolization (TACE) versus conventional (C)-TACE in patients with hepatocellular carcinoma considering the perspective of a Local Healthcare Authority in Italy. Materials and methods: The economic evaluation is based on a retrospective single-center study and individual patients' data whose details have been previously reported. The impact of initial treatment with DEM-TACE or C-TACE on disease progression, mortality, and direct health costs over a lifetime horizon were simulated and compared in terms of incremental cost-utility ratio expressed as costs per quality adjusted life years (QALY). Costs included direct health costs related to the first chemoembolization procedure and all subsequent follow-up costs associated with health care resources used for disease management. Probabilistic (PSA) sensitivity analysis was used to assess the robustness of the results. Results: A total of 101 patients in each treatment group were considered. All over the time-horizon median costs were €3,145.14 and €2,158.32 in the DEM-TACE and C-TACE group, respectively (p < 0.001); while mean costs were € 24,619 and € 17,001, respectively (p < 0.001). The ICUR was 6,461.86 €/QALY when using median costs derived from the study population as input for the health-economic evaluation and 49,932.15 €/QALY when the mean costs were considered. Results from PSA highlighted that using median costs DEM-TACE was always cost-effective, while using mean costs, it was preferable only 24.7% of times. Conclusions: The higher prices of DEMs are counterbalanced by the positive impact on QALY