Influence of TCF7L2 gene variants on the therapeutic response to the dipeptidylpeptidase-4 inhibitor linagliptin

Aims/hypothesis Individuals carrying variants of the transcription factor 7-like 2 gene (TCF7L2) are at increased risk for type 2 diabetes. These metabolic genetic risk factors have been linked to diminished pancreatic islet-cell responsiveness to incretins, thus pharmacological interventions aimed at amplifying endogenous incretin biology may be affected. However, clinical evidence from randomised controlled trials so far is lacking. We investigated the influence of TCF7L2 risk alleles on the response to treatment with the dipeptidylpeptidase-4 (DPP-4) inhibitor linagliptin from four 24 week, phase III, placebo-controlled trials. Methods Pharmacogenomic samples and clinical data were available from 961 patients with type 2 diabetes. Whole-blood DNA samples were genotyped for TCF7L2 single-nucleotide polymorphisms in conjunction with assessments of 24 week changes in HbA1c. Results Linagliptin lowered HbA1c meaningfully in all three genotypes of rs7903146 (non-risk variant carriers CC [n = 356]: −0.82% [−9.0 mmol/mol], p < 0.0001; heterozygous CT [n = 264]: −0.77% [−8.4 mmol/mol], p < 0.0001; homozygous risk variant carriers TT [n = 73]: −0.57% [−6.2 mmol/mol], p < 0.0006). No significant treatment differences were seen between CC and CT patients, although HbA1c response was reduced in TT compared with CC patients (~0.26% [~2.8 mmol/mol], p = 0.0182). Conclusions/interpretation Linagliptin significantly improved hyperglycaemia in patients with type 2 diabetes both with and without the TCF7L2 gene diabetes risk alleles. However, differences in treatment response were observed, indicating that diabetes susceptibility genes may be an important contributor to the inter-individual variability of treatment response.Accepted versio

Urinary Exosomal miRNA Signature in Type II Diabetic Nephropathy Patients.

MicroRNAs (miRNAs) are short non-coding RNA species which are important post-transcriptional regulators of gene expression and play an important role in the pathogenesis of diabetic nephropathy. miRNAs are present in urine in a remarkably stable form packaged in extracellular vesicles, predominantly exosomes. In the present study, urinary exosomal miRNA profiling was conducted in urinary exosomes obtained from 8 healthy controls (C), 8 patients with type II diabetes (T2D) and 8 patients with type II diabetic nephropathy (DN) using Agilent´s miRNA microarrays. In total, the expression of 16 miRNA species was deregulated (>2-fold) in DN patients compared to healthy donors and T2D patients: the expression of 14 miRNAs (miR-320c, miR-6068, miR-1234-5p, miR-6133, miR-4270, miR-4739, miR-371b-5p, miR-638, miR-572, miR-1227-5p, miR-6126, miR-1915-5p, miR-4778-5p and miR-2861) was up-regulated whereas the expression of 2 miRNAs (miR-30d-5p and miR-30e-5p) was down-regulated. Most of the deregulated miRNAs are involved in progression of renal diseases. Deregulation of urinary exosomal miRNAs occurred in micro-albuminuric DN patients but not in normo-albuminuric DN patients. We used qRT-PCR based analysis of the most strongly up-regulated miRNAs in urinary exosomes from DN patients, miRNAs miR-320c and miR-6068. The correlation of miRNA expression and micro-albuminuria levels could be replicated in a confirmation cohort. In conclusion, urinary exosomal miRNA content is altered in type II diabetic patients with DN. Deregulated miR-320c, which might have an impact on the TGF-β-signaling pathway via targeting thrombospondin 1 (TSP-1) shows promise as a novel candidate marker for disease progression in type II DN that should be evaluated in future studies

Challenges in tackling energy expenditure as obesity therapy: From preclinical models to clinical application

Background: A chronic imbalance of energy intake and energy expenditure results in excess fat storage. The obesity often caused by this overweight is detrimental to the health of millions of people. Understanding both sides of the energy balance equation and their counter-regulatory mechanisms is critical to the development of effective therapies to treat this epidemic. Scope of review: Behaviors surrounding ingestion have been reviewed extensively. This review focuses more specifically on energy expenditure regarding bodyweight control, with a particular emphasis on the organs and attractive metabolic processes known to reduce bodyweight. Moreover, previous and current attempts at anti-obesity strategies focusing on energy expenditure are highlighted. Precise measurements of energy expenditure, which consist of cellular, animal, and human models, as well as measurements of their translatability, are required to provide the most effective therapies. Major conclusions: A precise understanding of the components surrounding energy expenditure, including tailored approaches based on genetic, biomarker, or physical characteristics, must be integrated into future anti-obesity treatments. Further comprehensive investigations are required to define suitable treatments, especially because the complex nature of the human perspective remains poorly understood

Principal component analysis.

<p>Displayed are the first three major components from the principal component analysis. (green = C; yellow = T2D; red = DN).</p

Expression of differentially expressed miRNAs in DN patients analyzed by microarray and qRT-PCR.

<p>Gene expression profiles of up-regulated miR-320c and miR-6068 and unresponsive miR-6076 were verified by qRT-PCR. Relative miRNA expression was normalized to the mean expression of healthy controls. Significant differences to controls are indicated by * (<i>P</i><0.05).</p

Differentially regulated miRNAs in DN patients.

<p>Differentially regulated miRNAs in DN patients.</p

miR-320c expression correlation with eGFR and UACR.

<p>Correlation between miR-320c expression in T2D and DN patients and historical eGFR in the screening cohort (A) and the confirmation cohort (D). Correlation between miR-320c expression only in DN patients and historical eGFR in the screening cohort (B) and the confirmation cohort (E). Correlation between miR-320c expression in DN patients and UACR in the screening cohort (C) and the confirmation cohort (F). Data were compared by Pearson´s correlation coefficient.</p

Heat map of expression levels of differentially expressed miRNAs in DN patients.

<p>Fold change of expression levels were normalized to the mean signal intensities of healthy controls. Red and green colors represent fold change up- and down-regulation, respectively, as indicated by the linear scale bar (C = healthy controls; D = T2D patients; DN = type II diabetic nephropathy patients).</p

Expression of differentially expressed miRNAs in the confirmation cohort.

<p>Expression of differentially expressed miRNAs miR-320c and miR-6068 and unresponsive miR-6076 in a second cohort were verified by qRT-PCR. Relative miRNA expression was normalized to the mean expression of healthy controls. Significant differences to controls are indicated by * (<i>P</i><0.05).</p