Phase I studies of the safety, tolerability, pharmacokinetics and pharmacodynamics of the dual glucagon receptor/glucagon-like peptide-1 receptor agonist BI 456906.

AIM: To report two phase I studies of the novel subcutaneous glucagon-like peptide-1 receptor/glucagon receptor (GLP-1R/GCGR) dual agonist BI 456906 versus placebo in healthy volunteers and people with overweight/obesity. MATERIALS AND METHODS: A phase Ia study (NCT03175211) investigated single rising doses (SRDs) of BI 456906 in 24 males with a body mass index (BMI) of 20-<30 kg/m2 . A phase Ib study (NCT03591718) investigated multiple rising doses (MRDs) of BI 456906 (escalated over 6 [Part A] or 16 [Part B] weeks) in 125 adults with a BMI of 27-40 kg/m2 . RESULTS: In the SRD study (N = 24), mean body weight decreased with increasing BI 456906 dose. In the MRD study, the maximum decreases in placebo-corrected mean body weight were at week 6 (-5.79%, dosage schedule [DS] 1; Part A) and week 16 (-13.8%, DS7; Part B). BI 456906 reduced plasma amino acids and glucagon, indicating target engagement at GCGRs and GLP-1Rs. Drug-related adverse events (AEs) increased with BI 456906 dose. The most frequent drug-related AE with SRDs was decreased appetite (n = 9, 50.0%), and two subjects (8.3%) did not complete the trial because of AEs (nausea and vomiting). During MRD Part A (N = 80), 10 subjects (12.5%) discontinued BI 456906, most commonly because of a cardiac or vascular AE (n = 6, 7.5%); during Part B (N = 45), eight subjects (17.8%) discontinued BI 456906, mainly because of AEs (n = 6, 13.3%), most commonly gastrointestinal disorders. CONCLUSIONS: BI 456906 produced a placebo-corrected body weight loss of 13.8% (week 16), highlighting its potential to promote clinically meaningful body weight loss in people with overweight/obesity.

The effects of transient receptor potential cation channel inhibition by BI 1358894 on cortico-limbic brain reactivity to negative emotional stimuli in major depressive disorder.

Abnormal emotional processing in major depressive disorder (MDD) has been associated with increased activation to negative stimuli in cortico-limbic brain regions. The authors investigated whether treatment with BI 1358894, a small-molecule inhibitor of the transient receptor potential cation channel subfamily C leads to attenuated activity in these areas in MDD patients. 73 MDD patients were randomized to receive a single oral dose of BI 1358894 (100 mg), citalopram (20 mg), or matching placebo. Brain responses to emotional faces and scenes were investigated using functional magnetic resonance imaging. Primary endpoints were BOLD signal changes in response to negative faces in cortico-limbic brain regions, i.e. bilateral amygdala (AMY), dorsolateral prefrontal cortex, anterior insula (AI), and anterior cingulate cortex. Secondary endpoints were BOLD signal changes in response to negative scenes. For each region, separate ANOVA models were computed for the comparison of treatments (BI 1358894 or citalopram) vs. placebo. The adjusted treatment differences in the % BOLD signal changes in the faces task showed that BI 1358894 induced signal reduction in bilateral AMY and left AI. In the scenes task, BI 1358894 demonstrated significant signal reduction in bilateral AMY, AI, anterior cingulate cortex and left dorsolateral prefrontal cortex. Citalopram failed to induce any significant reductions in BOLD signal in both tasks. BI 1358894-mediated inhibition of the transient receptor potential cation channel subfamily resulted in strong signal reduction in cortico-limbic brain regions, thereby supporting development of this mechanism of action for MDD patients.

Evaluation of the efficacy, safety and tolerability of orally administered BI 409306, a novel phosphodiesterase type 9 inhibitor, in two randomised controlled phase II studies in patients with prodromal and mild Alzheimer's disease.

BACKGROUND: There are currently no approved treatments for the prodromal stage of Alzheimer's disease (AD). Approved symptomatic treatments for mild-to-moderate AD include acetylcholinesterase inhibitors and memantine, but more efficacious treatments are needed. BI 409306 is a potent and selective phosphodiesterase 9 inhibitor assessed for the symptomatic treatment of AD. Efficacy and safety of BI 409306 was analysed in two phase II proof-of-concept clinical trials in cognitive impairment associated with prodromal AD (study 1) and mild AD (study 2). METHODS: Two multicentre, double-blind, parallel-group, randomised controlled phase II studies were conducted (North America/Europe). Following study run-in, eligible subjects were randomised to one of four oral doses of BI 409306 (10-50 mg daily) or placebo (1:1:1:1:2 ratio) for 12 weeks. The primary efficacy endpoint was the change from baseline in Neuropsychological Test Battery (NTB) total z-score after 12 weeks' treatment. Secondary efficacy assessments included change from baseline in Clinical Dementia Rating scale-Sum of Boxes (CDR-SB), Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog11) and Alzheimer's Disease Cooperative Study-Activities of Daily Living scale (ADCS-ADL; mild cognitive impairment [MCI] version for prodromal patients) after 12 weeks' treatment. Safety and tolerability assessments included adverse event reporting and vital sign monitoring. Change from baseline in NTB total z-score (primary endpoint) and CDR-SB were analysed using the restricted maximum likelihood-based mixed-effects model with repeated measurement. An analysis of covariance model was used to assess other secondary endpoints. RESULTS: Four hundred fifty-seven patients were randomised (study 1 for prodromal AD, N = 128; study 2 for mild AD, N = 329); 427 (93.4%) completed. A prespecified pooled analysis of the primary endpoint revealed no significant changes in NTB total composite z-score at week 12 in the BI 409306 treatment groups compared with placebo, with similar findings observed in the individual studies. The analysis of all secondary endpoints, including pooled analysis of CDR-SB and ADAS-Cog11, ADCS-MCI-ADL (study 1), ADCS-ADL (study 2), also gave no indication of a treatment benefit for BI 409306, compared with placebo. BI 409306 was well tolerated. CONCLUSIONS: Overall, the data do not demonstrate efficacy of BI 409306 in improving cognition in patients with prodromal and mild AD. BI 409306 is well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02240693 and NCT02337907 . Registered 15 September 2014 and 09 January 2015, respectively.

Sensitive troponins--which suits better for hemodialysis patients? Associated factors and prediction of mortality.

BACKGROUND: In hemodialysis patients, elevated plasma troponin concentrations are a common finding that has even increased with the advent of newly developed sensitive assays. However, the interpretation and relevance of this is still under debate. METHODS: In this cross-sectional study, we analyzed plasma concentrations of sensitive troponin I (TnI) and troponin T (TnT) in stable ambulatory hemodialysis patients (n = 239) and investigated their associations with clinical factors and mortality. RESULTS: In all of the enrolled patients, plasma TnI or TnT was detectable at a median concentration of 14 pg/ml (interquartile range: 7-29) using the Siemens TnI ultra assay and 49 pg/ml (31-74) using the Roche Elecsys high sensitive TnT assay. Markedly more patients exceeded the 99th percentile for TnT than for TnI (95% vs. 14%, p<0.0001). In a multivariate linear regression model, TnT was independently associated with age, gender, systolic dysfunction, time on dialysis, residual diuresis and systolic blood pressure, whereas TnI was independently associated with age, systolic dysfunction, pulse pressure, time on dialysis and duration of a HD session. During a follow-up period of nearly two years, TnT concentration above 38 pg/mL was associated with a 5-fold risk of death, whereas elevation of TnI had a gradual association to mortality. CONCLUSION: In hemodialysis patients, elevations of plasma troponin concentrations are explained by cardiac function and dialysis-related parameters, which contribute to cardiac strain. Both are highly predictive of increased risk of death.

Active depression is associated with regional adiposity in the upper abdomen and the neck.

OBJECTIVE: In major depression, the incidence of overweight, the risk of type 2 diabetes, as well as cardiovascular disease is increased. Aim was to determine body fat distribution in depressive and healthy females using whole body Magnetic Resonance Imaging (MRI). Measurements of total adipose tissue (TAT), visceral (VAT), and subcutaneous adipose tissue (SCAT) at the trunk and the whole body fat distribution along the body axis were performed and compared. Differences in body fat distribution between depressive and healthy females and their location were evaluated. METHODS: In total, 11 women with a depressive syndrome (major depression, MD) and 45 healthy female volunteers (HC) matched for age and body mass index were compared. Total tissue (TT), TAT, VAT, and SCAT were quantified using T1-weighted whole body MRI. Adipose tissue distribution was compared along the body axis. RESULTS: MD patients showed higher adipose tissue volumes than the HC group. Especially in the upper abdomen, at the upper extremities and the neck, MD patients are characterized by a significantly higher adipose tissue mass compared to the HC group. CONCLUSIONS: The results of this study confirm the hypothesis of a high stress level with a disturbed hypothalamic-pituitary-adrenal (HPA) axis leading to a Cushing-like habitus and high visceral fat levels. The increased fat levels at the arms, as well as the whole body fat may be well-founded by a lack of activity in depression. These effects should be evaluated in further longitudinal studies investigating patients with a depressive syndrome and after remission.

In vitro responsiveness of human muscle cell peroxisome proliferator-activated receptor δ reflects donors' insulin sensitivity in vivo.

BACKGROUND: Peroxisome proliferator-activated receptor δ (PPARδ) activation enhances muscular fatty acid oxidation and oxidative phosphorylation, and muscle's oxidative capacity positively associates with whole-body insulin sensitivity. Therefore, we asked here whether human muscle cell PPARD expression is a determinant of donors' insulin sensitivity. MATERIALS AND METHODS: Skeletal muscle cells derived from 38 nondiabetic donors were differentiated in vitro to myotubes, and gene (mRNA) expression was quantified by real-time RT-PCR. Donors' insulin sensitivity was calculated from plasma insulin and glucose levels during oral glucose tolerance test (OGTT) and hyperinsulinemic-euglycemic clamp. RESULTS: Basal myotube PPARD expression was closely related to the expression of its target genes PDK4 and ANGPTL4 (P = 0·0312 and P = 0·0003, respectively). Basal PPARD, PDK4 and ANGPTL4 expression levels were not associated with donors' insulin sensitivity (P > 0·2, all). Treatment of myotubes with a selective high-affinity PPARδ agonist (GW501516) did not change mean PPARD, but enhanced mean PDK4 and ANGPTL4 expression 13- and 16-fold, respectively (P < 0·0001, both). The individual PDK4 and ANGPTL4 expression levels reached upon GW501516 treatment were associated with donors' insulin sensitivity neither (P > 0·2, both). However, GW501516-mediated fold increments in PDK4 and ANGPTL4 expression, reflecting PPARδ responsiveness, were positively associated with donors' insulin sensitivity derived from OGTT (P = 0·0182 and P = 0·0231, respectively) and hyperinsulinemic-euglycemic clamp (P = 0·0046 and P = 0·0258, respectively). CONCLUSIONS: Using a highly selective pharmacological tool, we show here that the individual responsiveness of human muscle cell PPARδ, rather than the absolute PPARD expression level, represents a major determinant of insulin sensitivity.

Cardiorespiratory fitness determines the reduction in blood pressure and insulin resistance during lifestyle intervention.

OBJECTIVE: Lifestyle intervention is not always effective for improving arterial hypertension and other cardiovascular risk factors, and the parameters determining the outcome are not known. Because high cardiorespiratory fitness (CRF) protects from cardiovascular disease and mortality, we determined whether CRF at baseline predicts the improvement of blood pressure and other cardiovascular risk factors during a lifestyle intervention. METHODS: A total of 219 patients at risk for type 2 diabetes, who underwent a 9-month lifestyle intervention with diet modification and increase in physical activity, and had measurement of CRF, were studied. Insulin sensitivity was estimated during a 75-g oral glucose tolerance test. Total body, visceral and liver fat were measured by magnetic resonance (MR) tomography and H-MR spectroscopy. CRF was estimated using two different methods, an incremental cycle exercise (maximal aerobic capacity-VO2max) test and a motorized treadmill (individual anaerobic threshold) test. RESULTS: After 9 months of intervention adiposity, glycemia, CRF, insulin sensitivity, SBP and serum lipids (except high-density lipoprotein cholesterol, P = 0.65) improved (all other P ≤ 0.006). DBP did not change significantly (P = 0.06). High CRF at baseline predicted decreases in SBP (P ≤ 0.0002) and DBP (P ≤ 0.004), and increase in insulin sensitivity (P ≤ 0.04), but not change in serum lipids (all P ≥ 0.06). For 1 SD increase in baseline CRF the odds ratio for resolution of hypertension or prehypertension was 2.26 (individual anaerobic threshold; 95% CI 1.40-3.80) and 1.75 (VO2max; 95% CI 1.08-2.89). CONCLUSION: CRF at baseline predicts the effectiveness of a lifestyle intervention in improving insulin sensitivity, and particularly blood pressure.

Insulin sensitivity and liver fat: role of iron load.

CONTEXT: Increased liver fat (LF) is associated with insulin resistance. However, a considerable individual variability between LF and insulin sensitivity (IS) is observed, and at equal levels of LF, insulin-resistant as well as insulin-sensitive individuals are found. OBJECTIVE: Our objective was to study whether hepatic iron load (HIL) explains some of the variation between IS and LF. DESIGN: HIL was measured using a quantitative T2* magnetic resonance gradient echo imaging technique, and LF was measured by (1)H-magnetic resonance spectroscopy. Low T2* values indicate high HIL. We studied the association of LF and HIL with anthropometric data and IS. A total of 113 healthy nondiabetic subjects [69 females, 44 males; age 47 ± 1 yr; body mass index (BMI) = 28.9 ± 0.5 kg/m(2)] at increased risk for type 2 diabetes were included in the study. RESULTS: T2* values adjusted for age negatively associated with serum ferritin levels (P < 0.0001) and positively associated with IS (P = 0.009). In addition, T2* values associated with LF (P = 0.008) but not with BMI (P = 0.6). In a multivariate model, IS adjusted for gender, age, and BMI was associated with T2* values (P = 0.015). IS adjusted for gender and age was independently associated with LF (P = 0.033) and T2* values (P = 0.004). In a stepwise regression analysis, LF explained 13.5% (P < 0.01) of the variation in IS, and HIL explained an additional 4.1% (P = 0.03). CONCLUSIONS: HIL explains part of the variation between LF and IS. The mechanism by which iron load induces insulin resistance is possibly independent of the pathways involved in insulin resistance induced by fatty liver disease.

Morning to evening changes of intramyocellular lipid content in dependence on nutrition and physical activity during one single day: a volume selective 1H-MRS study.

OBJECT: Intramyocellular lipids (IMCL) were shown to be metabolically highly active. In order to get insight into short-term regulation of IMCL and to reveal related problems with standardization in metabolic studies using the common signal ratio IMCL/Cr3, relative concentration changes from morning to evening in the same day were examined under four different nutritional and exercise conditions. MATERIAL AND METHODS: Twelve healthy male volunteers participated in an interventional program, comprising single days of fasting (F), low-caloric/low-fat diet (LC), or high-caloric/high-fat diet (HC), combined with low physical activity. A forth day course consisted of unchanged nutrition and extensive exercise (EX). (1)H-MRS of tibialis anterior (TA) and soleus muscle (SOL) was performed on a 3 T whole-body imager in the early morning and 12 h later after the intervention applying a single voxel STEAM technique. RESULTS: Interventions resulted in a clear reduction of IMCL/ Cr3 after F (IMCL/Cr3(TA): -28.1 ± 4.9%, IMCL/Cr3(SOL): -21.0 ± 3.7%) and EX (IMCL/Cr3(TA): -33.9 ± 4.9%, IMCL/Cr3(SOL): -18.3 ± 3.9%). LC led to slightly decreased IMCL/Cr3 ratio in the evening (IMCL/Cr3(TA): -8.7 ± 4.4%, IMCL/Cr3(SOL): -7.3 ± 2.7%), whereas negligible changes were detectable after HC (IMCL/Cr3(TA): + 0.6 ± 2.3%, IMCL/Cr3L(SOL): -0.2 ± 1.3%). CONCLUSION: Only high-caloric/high-fat diet combined with low physical activity led to nearly unchanged IMCL/Cr3 ratios in the evening when compared to corresponding measurements in the morning. In contrast, low-caloric/low-fat diet and especially fasting led to increasingly depleted IMCL stores in the evening. This depletion seems to be further emphasized by increased physical activity. An interesting aspect is the marked reduction of IMCL/Cr3 after 12 h of fasting, since a dramatic increase in IMCL has been reported after starvation over several days. Results of this study imply that highly standardized conditions regarding diet and physical activity are necessary for a proper assessment of IMCL data in metabolic studies.

The impact of genetic variation in the G6PC2 gene on insulin secretion depends on glycemia.

CONTEXT: Single-nucleotide polymorphisms (SNPs) within the G6PC2 locus are associated with fasting glucose and insulin secretion. These SNPs are not associated with type 2 diabetes risk. OBJECTIVE: Our objective was to investigate whether the impact of the SNP on variables of glucose-stimulated insulin secretion is influenced by glucose tolerance status. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTION: In this cross-sectional study, we genotyped 1505 healthy Caucasian subjects [normal glucose tolerance (NGT), 1098; impaired glucose tolerance (IGT)/impaired fasting glucose (IFG), 407] for SNP rs560887 within the G6PC2 locus. A subgroup of 326 subjects underwent an iv glucose tolerance test, and 512 participants took part in a hyperinsulinemic-euglycemic clamp. For replication, SNP rs560887 was genotyped in 457 subjects (NGT, 265; IGT, 192) from four independent German and Dutch studies who underwent a hyperglycemic clamp. MAIN OUTCOME MEASURE: Insulin secretion was evaluated. RESULTS: Carriers of the major G-allele exhibited increased fasting glycemia (P<0.0001). Insulin sensitivity and secretion were not associated with the SNP (P≥0.06). Glucose tolerance status and genotype interacted on insulin secretion (P=0.036), such that in NGT subjects, the minor A-allele of rs560887 was associated with decreased insulinogenic index (P=0.044), which was not the case in subjects with IFG/IGT (P=1.0). During the iv glucose tolerance test, an association of A-allele carriers with decreased first-phase insulin secretion was also observed only in NGT subjects (P=0.0053). Likewise, in the hyperglycemic clamp group, the A-allele was associated with decreased first-phase insulin secretion only in the NGT group (P=0.022) but not in the IGT group. CONCLUSIONS: The effects of hyperglycemia on insulin secretion override the more subtle effects of genetic variation in the G6PC2 locus on insulin secretion.

Follow-up whole-body assessment of adipose tissue compartments during a lifestyle intervention in a large cohort at increased risk for type 2 diabetes.

PURPOSE: To assess adipose body compartments with magnetic resonance (MR) imaging and MR spectroscopy during a lifestyle intervention program that included optimized nutrition and controlled physical activity in subjects at increased risk for type 2 diabetes to determine factors that may help predict an increase in insulin sensitivity following the intervention. MATERIALS AND METHODS: This prospective study was approved by the local review board. All participants gave written informed consent. MR imaging and MR spectroscopy were performed in 243 subjects (99 men and 144 women) before and 9 months after enrollment in a lifestyle intervention program. The results of whole-body MR imaging were used to calculate tissue profiles, differentiating between adipose tissue--especially visceral adipose tissue--and lean tissue. The concentration of hepatic lipids and intramyocellular lipids in the anterior tibial and soleus muscles was determined with MR spectroscopy, and insulin sensitivity was estimated by using an oral glucose tolerance test. The Student t test was used to assess differences between groups, and multivariate regression models were used to assess the value of adipose tissue compartments in the prediction of insulin sensitivity. RESULTS: Compared with women, men had almost twice the amount of visceral adipose tissue and a smaller amount of total adipose tissue (25.9% for men and 36.9% for women) at baseline. In addition, their insulin sensitivity was significantly lower than that of women. The most pronounced changes in adipose tissue were detected for visceral adipose tissue (from 4.9 L to 4.1 L [ie, -15.1%] in men and from 2.3 L to 1.9 L [ie, -15.8%] in women) and hepatic lipids (from 8.6% to 5.4% [ie, -36.8%] in men and from 5.1% to 4.3% [ie, -16.5%] in women). The mean insulin sensitivity improved significantly (from 11.3 arbitrary units [au] to 14.6 au [ie, +29.9%] in men and from 13.6 au to 14.6 au [ie, +7.5%] in women), with 70 of the 99 men (71%) and 84 of 144 women (58%) showing an increase in insulin sensitivity. In men, low concentrations of visceral adipose tissue, hepatic lipids, and abdominal subcutaneous fat at baseline were predictive of successful intervention in terms of changes in insulin sensitivity; in women, only low hepatic lipid levels were significantly predictive of successful intervention. CONCLUSION: Visceral adipose tissue and hepatic lipids, as assessed with MR imaging and MR spectroscopy, can be significantly reduced during lifestyle intervention. Their baseline values emerged as predictive factors for an improvement of insulin sensitivity.

Glycemia determines the effect of type 2 diabetes risk genes on insulin secretion.

OBJECTIVE: Several single nucleotide polymorphisms (SNPs) in diabetes risk genes reduce glucose- and/or incretin-induced insulin secretion. Here, we investigated interactions between glycemia and such diabetes risk polymorphisms. RESEARCH DESIGN AND METHODS: Insulin secretion was assessed by insulinogenic index and areas under the curve of C-peptide/glucose in 1,576 subjects using an oral glucose tolerance test (OGTT). Participants were genotyped for 10 diabetes risk SNPs associated with ß-cell dysfunction: rs5215 (KCNJ11), rs13266634 (SLC30A8), rs7754840 (CDKAL1), rs10811661 (CDKN2A/2B), rs10830963 (MTNR1B), rs7903146 (TCF7L2), rs10010131 (WFS1), rs7923837 (HHEX), rs151290 (KCNQ1), and rs4402960 (IGF2BP2). Furthermore, the impact of the interaction between genetic variation in TCF7L2 and glycemia on changes in insulin secretion was tested in 315 individuals taking part in a lifestyle intervention study. RESULTS: For the SNPs in TCF7L2 and WFS1, we found a significant interaction between glucose control and insulin secretion (all P ≤ 0.0018 for glucose × genotype). When plotting insulin secretion against glucose at 120 min OGTT, the compromising SNP effects on insulin secretion are most apparent under high glucose. In the longitudinal study, rs7903146 in TCF7L2 showed a significant interaction with baseline glucose tolerance upon change in insulin secretion (P = 0.0027). Increased glucose levels at baseline predicted an increase in insulin secretion upon improvement of glycemia by lifestyle intervention only in carriers of the risk alleles. CONCLUSIONS: For the diabetes risk genes TCF7L2 and WFS1, which are associated with impaired incretin signaling, the level of glycemia determines SNP effects on insulin secretion. This indicates the increasing relevance of these SNPs during the progression of prediabetes stages toward clinically overt type 2 diabetes.

Interscapular fat is strongly associated with insulin resistance.

CONTEXT: Subcutaneous abdominal adipose tissue (SCAAT), visceral adipose tissue (VAT), fat in the neck area [interscapular fat (IF)], and liver fat (LF) are associated with metabolic traits related to insulin resistance. Whole-body magnetic resonance imaging and spectroscopy offer a unique approach to quantify fat depots in larger cohorts. OBJECTIVE: The objective was to study 1) the impact of the aforementioned fat depots on insulin sensitivity in a cross-sectional design and 2) changes in these fat depots and in insulin sensitivity during a lifestyle intervention (LI). DESIGN: One hundred eighty-seven subjects were included in the cross-sectional study. Follow-up data during LI were available in 172 subjects. Body fat depots were quantified by whole-body magnetic resonance imaging, and representative reference slices at the umbilical level (SCAAT, VAT) and at the level of the shoulder joint (IF) were analyzed. LF was measured by (1)H-magnetic resonance spectroscopy. Insulin sensitivity was estimated from an oral glucose tolerance test. RESULTS: Cross-sectionally, SCAAT, VAT, IF, and LF were negatively associated with IS (all P < 0.0001). The change in insulin sensitivity during LI was associated with the changes in these fat depots (all P < 0.001). In a multivariate model, the change in insulin sensitivity during LI adjusted for gender, age, LF, and IF at baseline was associated with change in IF (P < 0.01) and with change in LF (P < 0.0001). CONCLUSIONS: IF represents a subcutaneous fat depot determining whole-body IS, both cross-sectionally and during LI. The impact of LF and IF on insulin sensitivity appears to be independent from each other. Additional studies are needed to clarify the metabolic properties of IF.

Association of obesity risk SNPs in PCSK1 with insulin sensitivity and proinsulin conversion.

BACKGROUND: Prohormone convertase 1 is involved in maturation of peptides. Rare mutations in gene PCSK1, encoding this enzyme, cause childhood obesity and abnormal glucose homeostasis with elevated proinsulin concentrations. Common single nucleotide polymorphisms (SNPs) within this gene, rs6232 and rs6235, are associated with obesity. We studied whether these SNPs influence the prediabetic traits insulin resistance, beta-cell dysfunction, or glucose intolerance. METHODS: We genotyped 1498 German subjects for SNPs rs6232 and rs6235 within PCSK1. The subjects were metabolically characterized by oral glucose tolerance test with glucose, insulin, proinsulin, and C-peptide measurements. A subgroup of 512 subjects underwent a hyperinsulinemic-euglycemic clamp. RESULTS: The minor allele frequencies were 25.8% for SNP rs6235 and 6.0% for rs6232. After adjustment for sex and age, we found no association of SNPs rs6235 and rs6232 with BMI or other weight-related traits (all p >or= 0.07). Both minor alleles, adjusted for sex, age, BMI and insulin sensitivity were associated with elevated AUCproinsulin and AUCproinsulin/AUCinsulin (rs6235: p(additive) model or= 0.08). The minor allele of SNP rs6232 was additionally associated with 15% higher OGTT-derived and 19% higher clamp-derived insulin sensitivity (pdom

Novel obesity risk loci do not determine distribution of body fat depots: a whole-body MRI/MRS study.

A recent meta-analysis of genome-wide association studies has identified six new risk-loci for common obesity. We studied whether these risk loci influence the distribution of body fat depots. We genotyped 1,469 nondiabetic subjects for the single-nucleotide polymorphisms (SNPs) TMEM18 rs6548238, KCTD15 rs11084753, GNPDA2 rs10938397, SH2B1 rs7498665, MTCH2 rs10838738, and NEGR1 rs2815752. We assessed BMI, waist circumference, total body fat, and lean body mass (bioimpedance). All subjects underwent an oral glucose tolerance test (OGTT) for estimation of insulin sensitivity. In 332 subjects, we measured total adipose tissue (TAT), visceral adipose tissue (VAT), nonvisceral adipose tissue (NVAT), liver fat content, and intramyocellular lipids (IMCLs) using whole-body magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). In the dominant inheritance model, the risk alleles of TMEM18 rs6548238 and MTCH2 rs10838738 were nominally associated with higher BMI (P = 0.04, both). The risk allele of TMEM18 rs6548238 was additionally associated with higher waist circumference and total body fat (P 0.009, dominant inheritance model). Therefore, our results suggest that these new obesity SNPs, despite their influence on BMI, are neither associated with a metabolically unfavorable nor with a favorable body composition.

Gene variants of TCF7L2 influence weight loss and body composition during lifestyle intervention in a population at risk for type 2 diabetes.

OBJECTIVE: The impact of the diabetes risk gene transcription factor 7-like 2 (TCF7L2) on body weight is unclear. As TCF7L2 is expressed in adipose tissue and involved in Wnt-dependent regulation of adipogenesis, we studied the impact of TCF7L2 variants on body composition and weight loss during lifestyle intervention. RESEARCH DESIGN AND METHODS: We genotyped 309 German subjects at increased risk for type 2 diabetes for single nucleotide polymorphisms (SNPs) rs7903146, rs12255372, rs11196205, and rs7895340 in TCF7L2 and performed oral glucose tolerance tests before and after a 9-month lifestyle intervention. Fat distribution was quantified using whole-body magnetic resonance imaging/spectroscopy in a subgroup of 210 subjects. RESULTS: After adjustment for confounding variables, we observed a negative impact of the type 2 diabetes allele of SNP rs7903146 on change in BMI (P = 0.0034) and on changes in nonvisceral (P = 0.0032) and visceral fat (P = 0.0165) during lifestyle intervention. An association of rs7903146 with lifestyle intervention-induced changes in insulin secretion, glucose concentrations, liver fat, or insulin sensitivity were not detected (all P > 0.2). Essentially the same results were obtained with SNP rs1255372. In contrast, we found no effects of SNPs rs11196205 and rs7895340 on change in BMI (all P > or = 0.5). CONCLUSIONS: Our data reveal that diabetes-associated alleles of TCF7L2 are associated with less weight loss in response to lifestyle intervention. Thus, diabetes-associated TCF7L2 gene variation predicts the success of lifestyle intervention in terms of weight loss and determines individual susceptibility toward environmental factors.

Correlation of fat distribution in whole body MRI with generally used anthropometric data.

OBJECTIVES: : Obesity is a commonly known risk for many diseases such as metabolic syndrome and cardiovascular disease. Especially important is the discrimination of the adipose tissue inside the abdomen and the subcutaneous adipose tissue. Aim of this study was to compare the whole body fat distribution, and the volume of different adipose tissue compartments respectively, with anthropometric data. MATERIALS AND METHODS: : Sixty-eight volunteers (20 males, 48 females, 42.3 +/- 15.4 years) were investigated in the context of 2 whole body magnetic resonance imaging (MRI) studies which compared the body fat distribution of depressive and bulimic patients with healthy controls. Unpublished data acquired in these studies were analyzed retrospectively.The sample consisted of 38 healthy volunteers, 17 patients with a depressive syndrome and 13 women suffering from bulimia nervosa. Individual body volume, total adipose tissue (TAT) volume, subcutaneous adipose tissue (SCAT) volume at the trunk, and visceral adipose tissue (VAT) volume were determined, using whole body MRI. Additionally, body fat profiles were standardized and a mean body distribution was calculated. Other modalities to acquire body fat content were: skin fold caliper, body impedance (3 different devices) and simple anthropometric data (Waist to Hip Ratio [WHR], Body Mass Index [BMI], distance of the aponeurosis of the rectus abdominis muscle to the ventral rim of the abdominal aorta (measured in MRI images on umbilical level) (AD) and subcutaneous adipose tissue thickness at the same level). The different modalities were correlated with the MRI data. RESULTS: : There were highly significant correlations between the skin fold data and TAT (Spearman coefficient 0.668, P >/= 0.0004) and SCAT (0.662, P >/= 0.0004). But there was no correlation with VAT. Impedance data revealed significant correlations of TAT and SCAT (Spearman 0.7, P >/= 0.0004).Simple anthropometric data like waist and hip circumference, WHR, and BMI revealed significant correlations (Spearman coefficient around 0.7-0.4, P < 0.05) with the fat compartments TAT, VAT, and SCAT.The standardized body fat slices and the VAT slices were correlated with the anthropometric data and impedance data to explore specific areas along the body axis where the correlations were higher or weaker. Skinfold data, BMI, and body impedance data yielded significant correlations with TAT along the whole body axis, as well as with VAT in almost the whole analyzed area. However, there was no special body region with locally higher correlations. WHR depicted high correlations with whole VAT, and regional TAT at the abdomen (and not with the other body regions) especially in women. Therefore, it seems to be the best marker for abdominal fat and VAT in this study. CONCLUSIONS: : We compared different body measures and body fat devices with the whole body fat distribution acquired by MRI. Generally, there were significant correlations of all modalities with body fat content (TAT) and mainly with SCAT. Correlations with VAT compartment were much weaker and an adequate estimation of VAT is, therefore, not possible. Only WHR revealed significant correlations with the fat in the body center, but only in women. If it is important to investigate especially the VAT which is responsible for a higher cardiovascular risk, risk for a metabolic syndrome and that is correlated with the course of different psychiatric diseases, cross sectional techniques such as MRI can not be substituted by simpler methods.

Impact of variation near MC4R on whole-body fat distribution, liver fat, and weight loss.

Polymorphisms near the melanocortin-4 receptor (MC4R) gene locus are associated with body weight. Recent studies have shown that they influence insulin sensitivity and incidence of the metabolic syndrome. Thus, we hypothesized that the candidate single-nucleotide polymorphism (SNP) rs17782313 near MC4R additionally influences body fat distribution and its change during lifestyle intervention. To test this, 343 German subjects were genotyped for SNP rs17782313. Body composition was assessed using magnetic resonance technique. Subjects were characterized by an oral glucose tolerance test (OGTT). A subgroup of 242 subjects participated in a 9-month lifestyle intervention. In the overall cohort, the C allele was associated with a higher BMI (P=0.0013), but had no impact on glucose tolerance or insulin sensitivity (all P>or=0.10). There was an effect of the SNP on total body fat (P=0.022) and nonvisceral fat (P=0.017), but not on liver fat and visceral fat (all P>or=0.33). In the subgroup undergoing lifestyle intervention, SNP rs17782313 had no impact on changes in body weight or fat distribution. Despite an association with BMI and nonvisceral adipose tissue, the SNP rs17782313 did not influence visceral adipose tissue. Thus, this candidate SNP for human obesity may preferentially affect the accumulation of subcutaneous adipose tissue. Furthermore, the variation near MC4R has no effect on success of weight loss during lifestyle intervention.