Aa van der Heijden

Variants in Pharmacokinetic Transporters and Glycemic Response to Metformin: A Metgen Meta‐Analysis

Therapeutic response to metformin, a first‐line drug for type 2 diabetes (T2D), is highly variable, in part likely due to genetic factors. To date, metformin pharmacogenetic studies have mainly focused on the impact of variants in metformin transporter genes, with inconsistent results. To clarify the significance of these variants in glycemic response to metformin in T2D, we performed a large‐scale meta‐analysis across the cohorts of the Metformin Genetics Consortium (MetGen). Nine candidate polymorphisms in five transporter genes (organic cation transporter [OCT]1, OCT2, multidrug and toxin extrusion transporter [MATE]1, MATE2‐K, and OCTN1) were analyzed in up to 7,968 individuals. None of the variants showed a significant effect on metformin response in the primary analysis, or in the exploratory secondary analyses, when patients were stratified according to possible confounding genotypes or prescribed a daily dose of metformin. Our results suggest that candidate transporter gene variants have little contribution to variability in glycemic response to metformin in T2D.

Real-world evidence of suboptimal blood pressure control in patients with type 2 diabetes

Aims: In order to eventually improve blood pressure (BP) management, the aim of this study was to identify subgroups of type 2 diabetes mellitus (T2DM) patients with distinct trajectories of SBP levels. Identifying subgroups with distinct SBP trajectories helps to better understand the course of SBP levels in T2DM patients and its associated consequences. Subgroup characteristics were determined and the prevalence of complications and mortality rates over time in the different subgroups was investigated. Methods: Five thousand, seven hundred and eleven T2DM patients with at least two SBP follow-up measurements were selected from a prospective T2DM cohort of 9849 T2DM patients. The mean follow-up period was 5.7 years (range 2–9 years). Latent Class Growth Modeling, as currently the most flexible cluster analysis available, was performed to identify subgroups of patients with distinct SBP trajectories. Subgroup characteristics were determined by multinomial logistic regression analyses. Results: Four subgroups with distinct SBP trajectories were identified. The largest subgroup (85.6%) showed adequate SBP control (at or around 140 mmHg) over time. The second subgroup (5.6%) were hypertensive in the first years, responded slowly to BP management and eventually reached SBP control. The third subgroup (3.4%) showed deteriorating hypertension during the first 4 years, then showed insufficient response to BP management. The fourth subgroup (5.4%) showed deteriorating hypertension over time. Patients within subgroups 2–4 were significantly older, comprised more women, used more antihypertensive medication and had a higher prevalence of retinopathy, microalbuminuria and cardiovascular disease (CVD) mortality. Conclusion: More than 85% reached and maintained adequate SBP control. Subgroups with a more unfavourable course of SBP control also showed higher rates of microvascular complications and CVD mortality over time. This study identified important subgroups to target in order to improve BP management in T2DM patients.

Effectiveness of insulin therapy in people with Type 2 diabetes in the Hoorn Diabetes Care System

To identify HbA1c trajectories after the start of insulin treatment and to identify clinically applicable predictors of the response to insulin therapy.

Policy evaluation in diabetes prevention and treatment using a population-based macro simulation model: the MICADO model

To test a simulation model, the MICADO model, for estimating the long‐term effects of interventions in people with and without diabetes.

Modelling integrated care for diabetes based on observational data: the MICADO model

Background and aims: TCF7L2 is both an activator and an inhibitor of transcription and the most highly associated type 2 diabetes gene known to date. It influences beta cell survival and function, i.e. incretin hormonal effects, insulin processing and secretion. However, its target genes in pancreatic islets are not fully described and the molecular mechanism whereby it propagates its effects on islet function is not known. The aim of this study is to identify the molecular mechanisms through which TCF7L2 influence beta cell survival and function. Materials and methods: Wister rat primary islets and INS-1 (832/13) cells were incubated with siRNA against Tcf7l2, both Tcf7l2 and TP53INP1 or both TCF7L2 and TP53 in 5.5 mM and 14.3 mM glucose. TCF7L2 activity, p53 activity and target gene expression (using qPCR) were measured after siRNA treatment. INS-1 cell apoptosis was measured by DNA degradation levels, caspase-3/7 levels and by using antibodies against Annexin V, and 7-AAD, visualized using confocal microscopy. Rat islet viability was estimated measuring metabolic rate. Rat islet apoptosis was estimated by measuring Caspase-3/7 level. Results: The type 2 diabetes associated genes TP53INP1, FTO, GIPR and ADAMTS9 were identified as TCF7L2 potential target gene using chromatin immunoprecipitation on microarrays. In INS-1 cells, siRNA mediated Tcf7l2 knock down (69.5 %) resulted in decreased TCF7L2 activity (91%) and differential expression of the target genes: Tp53 (14.5% increase), TP53INP1 (65.9% increase) and ADAMTS9 (82.8% decrease). TCF7L2 knockdown also lead to reduced cell viability (65%) and increased apoptosis (113%). The TCF7L2 induced cell death was replicated in rat primary islets. When restoring (decreasing) the Tp53inp1 expression level in TCF7L2 depleted islets, the decrease in cell viability and increase in apoptosis were prevented, suggesting that the Tcf7l2 effect is mediated via Tp53inp1. Furthermore, p53 depletion prohibited TCF7L2 down regulation induced cell death and elevation of Tp53inp1 expression in both INS-1 cells and rat primary islets. Conclusion: The type 2 diabetes associated genes TP53INP1 and ADAMTS9 are target genes of TCF7L2 in pancreatic islets. TCF7L2 induced apoptosis and decreased cell viability are mediated through activation of p53 and increased p53INP1 expression.

Cost-effectiveness of centralised and partly centralised care compared to usual care for patients with type 2 diabetes

Background and aims: Metabolic disruptions characterized by high hepatic lipid content (HLC) are associated with impairments in whole body glucose homeostasis. To gain insight on the role of hepatic lipids in the metabolic performance in the absence artificial metabolic stresses we measured non- invasively and longitudinally the HLC and profile in mice during adult devel - opment by Magnetic Resonance (MR) Spectroscopy in vivo . In parallel, mice were challenged with insulin and glucose tolerance tests. Materials and methods: Male (N=10) and female (N=10) C57Bl/6J mice were studied at 3 (3Mo), 7 (7Mo) and 10 months (10Mo) of age. Mice were scanned in a 14.1 T magnet with a 1 H quadrature surface coil over the abdo - men. Localized 1 H spectra were acquired from a 8 μl volume with stimulated echo acquisition mode sequence and the HLC expressed as the percent of to - tal 1 H MR signal, with corrections for spin-spin relaxation effects. Additional spectra were acquired from the same volume with suppression of the water signal to enable the detection and quantification of all the lipid protons. The lipid profile was characterized by the following indices: saturated component (SC); unsaturated fatty acyl chains (UFA); mean number of double bonds per fatty acyl chain (ndb/FA), mean number of poly-unsaturated double bonds per fatty acyl chain (PUdb/FA) and per UFA (PUdb/UFA); mean chain length (MCL). OGTTs (1.5 g/Kg) and i.p. insulin tolerance tests (ITTs) were per - formed after a 6h-fast. Plasma insulin was determined by ELISA and insulin sensitivity estimated with the quantitative insulin check index (QUICKI) as the inverse of the log 10 sum of fasting insulin (μIU/ml) and fasting glucose (mg/dl). Data are expressed as mean ± SEM. Statistical significance was ac - cepted for a P < 0.05 (one-way ANOVA with Newman-Keuls post test) and correlations assessed by the Pearson r coefficient. Results: In males, the HLC at 3Mo was 1.35 ± 0.15%, increasing to 3.06 ± 0.38% at 7Mo, not different from 2.70 ± 0.31% at 10Mo. Females had higher HLC at 3Mo (2.63 ± 0.19%) but no further changes henceforward (2.31 ± 0.20% at 7Mo; 2.36 ± 0.20% at10 Mo). In males, the SC and MCL of hepatic lipids increased with age, with a trend for decreased PUdb/FA and PUdb/ UFA with no changes in ndb/FA or UFA content. Females showed the same trends. Glycemia 3h-post ITT and 2h-post OGTT was lower in females, while QUICKI was higer. These scores were preserved until 10Mo in females. In males, glycemia 2-h post OGTT increased with age and the area above the curve (AAC) for the ITT decreased. In males, but not females, higher body weight correlated with hepatic lipid accumulation ( r = 0.7); worse ITT scores correlated with higher body weight ( r = -0.6) and HLC ( r = -0.7) and lower Pudb/UFA ( r = 0.5); worse OGTT scores correlated with higher HLC ( r = 0.4). Conclusion: In male mice, loss of insulin sensitivity correlated with weight gain, HL accumulation and lower poly-unsaturation. Glucose intolerance was specifically associated with HLC, suggesting a deleterious effect of lipids on the adaptation of hepatic metabolism to the fed state. This behaviour was not observed in females even if they showed similar HLC. In fact, the poly- unsaturation of HL in females didn’t change with HLC, suggesting a positive effect of PUFA on preserving the hepatic metabolic performance.