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  • 1
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    Online Resource
    Targeted Metabolomics Identifies Elevated Serotonin Levels in Carriers of a TCF7L2 Diabetes Risk Allele
    American Diabetes Association ; 2018
    In:  Diabetes Vol. 67, No. Supplement_1 ( 2018-07-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 67, No. Supplement_1 ( 2018-07-01)
    Abstract: The transcription factor 7-like 2 (TCF7L2) is part of the Wnt signaling pathway. Its polymorphism rs7903146 is associated with risk for metabolic diseases, primarily diabetes, whereas the molecular mechanisms explaining how TCF7L2 impacts metabolism have remained unsolved. We evaluated the metabolic profile of a total of 394 angiographied patients with respect to their rs7903146 genotype (C/T) using targeted metabolomics in a discovery (n=154) and a validation (n=240) study. We identified serotonin as the top ranked metabolite to be increased in carriers of the diabetes risk allele (T) in both studies. For all 394 patients fold change was 44.6% (p=2.e-5), and in multivariate logistic regression analyses, serotonin concentration was significantly associated with the rs7903146 genotype even after full adjustment including diabetes (stand. adj. OR 2.69[1.23-5.87]; p=0.013). In a larger cohort of 1660 similar patients, we found that risky allele carriers had a significantly higher fasting glucose (116 vs. 109 mg/dl, p=0.007), post-challenge glucose (147 vs. 135 mg/dl, p=0.036), HbA1c (6.2 vs. 6.0 %, p & lt;0.001), and prevalence of T2DM (30.8 vs. 25.8 %, p=0.022) than patients without the risky allele. Apart from rs7903146, analyzing the whole gene, we found that 9 out of 19 unlinked SNPs in TCF7L2 were significantly associated with serotonin as well. In conclusion, this study identifies a significant association between elevated serotonin concentrations and the diabetes risk allele of the TCF7L2 rs7903146 polymorphism. Recently, Wnt-signalling has been suggested to be involved in serotonin expression and serotonin has been shown to regulate glucose homeostasis, to increase the risk of diabetes, and to be elevated in diabetic subjects. Together, these new findings suggest that serotonin may be, at least in part, involved in the impact of Wnt/TCF7L2-signalling on metabolic homeostasis and diabetes. Disclosure A. Leiherer: None. A. Muendlein: None. K. Geiger: None. C.H. Saely: None. E. Brandtner: None. J. Ebner: None. B. Larcher: None. A. Mader: None. P. Fraunberger: None. H. Drexel: None.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db18-1710-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
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  • 2
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    Betatrophin Predicts Cardiovascular Events Independently from the Presence of Type 2 Diabetes and Coronary Artery Disease
    American Diabetes Association ; 2018
    In:  Diabetes Vol. 67, No. Supplement_1 ( 2018-07-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 67, No. Supplement_1 ( 2018-07-01)
    Abstract: Betatrophin, also known as ANGPTL8 or lipasin is a nutritionally-regulated protein secreted by the liver and adipose tissue. It is associated with type 2 diabetes mellitus (T2DM) and lipid metabolism. Whether betatrophin is associated with the risk for cardiovascular events is unknown and is addressed in the present study. We measured betatrophin in 553 patients undergoing coronary angiography for the evaluation of established or suspected stable coronary artery disease (CAD) and prospectively recorded cardiovascular events in these patients during a follow-up period of up to 8 years. During follow-up, 301 cardiovascular events occurred. The incidence of cardiovascular events was significantly higher in patients with T2DM (n=161) than in those who did not have diabetes (47.2% vs. 34.4%; p=0.005). Betatrophin was significantly and inversely associated with cardiovascular events both univariately (HR 0.64 [95% CI 0.47-0.87], p=0.004) and after full adjustment including T2DM and baseline CAD (HR 0.55 [95% CI 0.40-0.76] , p & lt;0.001). The inclusion of betatrophin to a basic prediction model for the cardiovascular event risk significantly increased model performance (NRI=0.188, p & lt;0.01). In conclusion, this study for the first time shows that betatrophin predicts cardiovascular events independently from conventional risk factors including the presence of T2DM. Disclosure A. Leiherer: None. A. Muendlein: None. K. Geiger: None. C.H. Saely: None. E. Brandtner: None. J. Ebner: None. B. Larcher: None. A. Mader: None. P. Fraunberger: None. H. Drexel: None.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db18-160-OR
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
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  • 3
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    Online Resource
    The Association between the Adipokine C1QTNF1 and Type 2 Diabetes Is Significantly Modulated by Obesity
    American Diabetes Association ; 2018
    In:  Diabetes Vol. 67, No. Supplement_1 ( 2018-07-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 67, No. Supplement_1 ( 2018-07-01)
    Abstract: C1q and tumor necrosis factor related protein 1 (C1QTNF1) is an adipokine which has recently captured attention as a modulator of various metabolic pathways. As shown in animal and in vitro studies C1QTNF1 enhances glucose and fatty acid oxidation and improves insulin sensitivity. Paradoxically, C1QTNF1 serum levels were found to be elevated in patients with type 2 diabetes (T2DM). To further elucidate the role of serum C1QTNF1 in T2DM, we investigated its association with metabolic parameters linked to T2DM in 542 patients undergoing coronary angiography for the evaluation for established or suspected stable coronary artery disease. In the total study cohort, C1QTNF1 was significantly (p-values & lt;0.001 for all comparisons) increased in patients with T2DM, the metabolic syndrome (MetS), as well as in obese patients (defined as BMI ≥30 kg/m2). Further, C1QTNF1 was positively correlated with BMI, fasting glucose, HbA1c, CRP, and the homeostatic model assessment (HOMA) index of insulin resistance (all p-values & lt;0.001), but not with the HOMA index of beta-cell function (p & gt;0.05). Subgroup analyses with respect to obesity revealed that the association between C1QTNF1 and T2DM was highly significant in obese patients (p & lt;0.001), but not in non-obese subjects (p=0.076). An interaction term obesity x C1QTNF1 was significant (p = 0.018), indicating a significantly stronger association between C1QTNF1 and T2DM in obese patients than in non-obese subjects. Similarly, the association between C1QTNF1 and the MetS was significant only in obese patients (p=0.009), but not in non-obese subjects (p=0.074), We conclude that obesity significantly influences the association between C1QTNF1 serum levels and T2DM and should be considered in further studies evaluating the relationship of C1QTNF1 with metabolic traits. Disclosure K. Geiger: None. A. Muendlein: None. A. Leiherer: None. C.H. Saely: None. J. Ebner: None. E. Brandtner: None. B. Larcher: None. A. Mader: None. P. Fraunberger: None. H. Drexel: None.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db18-1943-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
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  • 4
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    209-OR: Ceramide-Based Lipid Profiles and the Prevalence of Type 2 Diabetes Differ between Patients with Coronary Artery Disease and Those with Peripheral Artery Disease
    American Diabetes Association ; 2022
    In:  Diabetes Vol. 71, No. Supplement_1 ( 2022-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 71, No. Supplement_1 ( 2022-06-01)
    Abstract: Serum lipids and metabolic diseases, in particular type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD) , predict the atherosclerotic diseases coronary artery disease (CAD) and peripheral arterial disease (PAD) . However, it is not known in how far a more detailed characterization including serum lipids improves discrimination of PAD from CAD. A cohort of 274 statin-naïve patients with either PAD (n = 89) or stable CAD (n = 185) were referred to metabolic screening and were characterized using nuclear magnetic resonance- and liquid chromatography-tandem mass spectrometry based advanced lipid and lipoprotein analysis. Results were validated in an independent cohort of 1239 patients with PAD or CAD. We found a significant difference in T2D prevalence and in the ceramide-based lipid profile between PAD and CAD patients. However, neither cholesterol-based markers (including LDL-C, HDL-C) and detailed lipoprotein profiles nor the NAFLD status differed significantly between PAD and CAD patients (figure) . The difference between ceramide-based lipid profiles of CAD and PAD remained significant also after adjusting for body composition, smoking, inflammatory parameters, and T2D. We conclude that PAD and CAD differ in ceramide-based lipid profiles and T2D status, but not in other lipid characteristics or metabolic diseases. Disclosure A.Leiherer: None. A.Jylha: None. M.Laaperi: None. R.Laaksonen: None. W.Maerz: None. P.Fraunberger: None. M.Kleber: None. H.Drexel: None. A.Muendlein: None. E.Brandtner: None. C.H.Saely: None. A.Vonbank: None. A.Mader: None. L.Sprenger: None. M.Maechler: None. B.Larcher: None.
    Type of Medium: Online Resource
    ISSN: 0012-1797
    URL: Article
    DOI: 10.2337/db22-209-OR
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2022
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  • 5
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    Metabolomics Shows an Association of Betatrophin with Bile Acids, Suggesting an Involvement of Betatrophin in Bile Acid–Mediated Metabolic Control
    American Diabetes Association ; 2018
    In:  Diabetes Vol. 67, No. Supplement_1 ( 2018-07-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 67, No. Supplement_1 ( 2018-07-01)
    Abstract: Betatrophin, also known as ANGPTL8, is secreted by liver and adipose tissue and plays an important role in glucose and lipid metabolism, but the mechanisms behind this remain unclear. Betatrophin is highly activated by active triiodothyronine (T3), a key player in metabolic control, which in turn is activated by bile acids (BA) via the BA-G-protein-coupled receptor TGR5-cAMP-deiodinase (D2), mediating the conversion of prohormone thyroxine to T3. We here measured betatrophin by ELISA and also applied GWAS and targeted metabolomic profiling in 233 serum samples of coronary angiographied patients. We found a correlation between betatrophin and BMI (r=0.142, p & lt;0.001), fasting glucose (r=0.133, p=0.002), insulin (r=0.221, p & lt;0.001), triglycerides (r=0.233, p & lt;0.001), HDL (-0.122, p=0.004), and oxLDL (r=0.247, p & lt;0.001). GWAs also found a genome wide-association between betatrophin and genomic variants in sterol transporter genes ABCG5/G8 and ABCA1. In the metabolomic assay we identified BA as the top metabolites to be associated with betatrophin concentration in serum (CDCA, r=0.234, p & lt;0.001; GDCA, r=0.247, p & lt;0.001; GCA, r=0.269, p & lt;0.001; GCDCA, r=0.268, p & lt;0.001; GLCA, r=0.211, p=0.002; TDCA, r=0.184, p=0.006). In conclusion, this study for the first time describes the association between betatrophin and BA. As (i) T3 is activated by BA via the BA-TGR5-cAMP-D2 signalling pathway and (ii) T3 is a strong activator of betatrophin, the link between betatrophin concentration and BA suggests that, at least in part, the impact of BA on energy homeostasis and metabolic control may be mediated via betatrophin. Moreover, TGR5 receptors have also been identified on pancreatic islet α- and β-cells and are stimulating insulin secretion in β-cells and able to restore β-cell mass and function under hyperglycemic conditions. Altogether, this may elucidate the impact of betatrophin on lipid and glucose metabolism. Disclosure A. Leiherer: None. A. Muendlein: None. K. Geiger: None. C.H. Saely: None. E. Brandtner: None. J. Ebner: None. B. Larcher: None. A. Mader: None. P. Fraunberger: None. H. Drexel: None.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db18-1947-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
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  • 6
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    Online Resource
    The Novel Adipokine C1QTNF1 Significantly Predicts the Incidence of Future Major Cardiovascular Events in Patients with Type 2 Diabetes
    American Diabetes Association ; 2018
    In:  Diabetes Vol. 67, No. Supplement_1 ( 2018-07-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 67, No. Supplement_1 ( 2018-07-01)
    Abstract: Increased serum levels of the novel adipokine C1q and tumor necrosis factor related protein 1 (C1QTNF1) have been linked with type 2 diabetes (T2DM) and ischemic heart disease. The impact of circulating C1QTNF1 on the incidence of future major cardiovascular events (MACE) is unclear and is addressed in the present study. We measured C1QTNF1 serum levels in 542 patients undergoing coronary angiography for the evaluation of established or suspected coronary artery disease (CAD) using an enzyme-linked immunosorbent assay. Prospectively, MACE were recorded over a mean follow-up period of 6.3 years. C1QTNF1 serum levels at baseline were significantly increased in patients with T2DM (n=160) compared to those without diabetes (521.4 ± 224.8 vs. 429.5 ± 130.3 ng/ml; p & lt;0.001). Prospectively, the incidence of MACE increased significantly through tertiles of C1QTNF1 (17.8%, 24.7%, and 29.7% in the 1st, 2nd and 3rd tertiles, respectively; ptrend=0.010). Also after adjustment for age, sex, and T2DM as well as after additional adjustment for body mass index, hypertension, LDL cholesterol, HDL cholesterol, triglycerides, and angiographically determined baseline CAD, C1QTNF1 significantly predicted MACE, with adjusted HRs of 1.30 [1.04-1.61]; p=0.019 and 1.36 [1.09-1.70] ; p=0.007, respectively. Patients with T2DM were at a significantly higher risk of MACE than those who did not have diabetes (48% vs. 26%; p=0.003). C1QTNF1 in subgroup analyses also in T2DM patients proved to be a strong predictor of MACE (adjusted HR 1.57 [1.10-2.24]; p=0.013). We conclude that high serum levels of C1QTNF1 significantly predict MACE, in particular in patients with T2DM. Disclosure A. Muendlein: None. A. Leiherer: None. C.H. Saely: None. K. Geiger: None. J. Ebner: None. E. Brandtner: None. B. Larcher: None. A. Mader: None. P. Fraunberger: None. H. Drexel: None.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db18-285-OR
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
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  • 7
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    Elevated Parathyroid Hormone Is Associated with an Increased Mortality Risk in Type 2 Diabetes
    American Diabetes Association ; 2018
    In:  Diabetes Vol. 67, No. Supplement_1 ( 2018-07-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 67, No. Supplement_1 ( 2018-07-01)
    Abstract: Parathyroid hormone (PTH) is one of the main regulators of calcium homeostasis. PTH levels are elevated in primary hyperparathyroidism as well as with vitamin D deficiency or chronic kidney disease. The association of increased PTH levels with all-cause mortality in high-risk patients is unclear. We therefore investigated the impact of serum PTH on mortality risk in a large series of 939 patients undergoing coronary angiography for the evaluation of established or suspected coronary artery disease (CAD), including 244 patients with type 2 diabetes (T2DM). Prospectively, deaths were recorded over a mean follow-up period of 6.2 years. PTH at baseline was inversely associated with eGFR (rho=-0.228; p & lt;0.001) and 25-hydroxy-vitamin D (rho=-0.243; p & lt;0.001) and was positively associated with age (rho=0.122; p & lt;0.001) and BMI (rho=0.099, p=0.002). Prospectively, elevated PTH was not significantly associated with an increased mortality risk in the total study cohort (standardized HR 1.30 [0.96-1.76]; p=0.092). However, subgroup analysis with respect to T2DM showed a highly significant association of PTH with mortality in patients with T2DM (HR 2.32 [1.37-3.95] ; p=0.002), but no association of PTH with mortality in nondiabetic subjects (HR 1.04 [0.82-1.32]; p=0.766). An interaction term T2DM x PTH was significant (p=0.006), indicating a significantly stronger influence of PTH on mortality risk in patients with diabetes than in individuals without T2DM. The impact of PTH on mortality risk in patients with T2DM remained significant after adjustment for age, gender, and BMI (HR 2.30 [1.34-3.93] ; p=0.002) as well as after additional adjustment for, smoking, kidney function, baseline vitamin D and angiographically determined baseline CAD (HR 1.91 [1.07-3.40]; p=0.029). We conclude that elevated PTH levels are a strong and independent predictor of all-cause mortality in patients with T2DM. Disclosure A. Muendlein: None. A. Leiherer: None. C.H. Saely: None. K. Geiger: None. E. Brandtner: None. B. Larcher: None. A. Mader: None. P. Fraunberger: None. M. Kleber: None. A. Dressel: None. W. Maerz: None. H. Drexel: None.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db18-1484-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
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  • 8
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    Online Resource
    Betatrophin Is Associated with Type 2 Diabetes and Markers of Insulin Resistance
    American Diabetes Association ; 2018
    In:  Diabetes Vol. 67, No. Supplement_1 ( 2018-07-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 67, No. Supplement_1 ( 2018-07-01)
    Abstract: Betatrophin, also known as ANGPTL8, is secreted by the liver, and its expression is upregulated by nutrition. However, conflicting reports exist on the association of betatrophin with insulin resistance, type 2 diabetes (T2DM) and coronary artery disease (CAD). We therefore measured betatrophin in 553 patients undergoing coronary angiography for the evaluation of established or suspected CAD. T2DM patients (n=161) had higher betatrophin than those without T2DM (12.9±19.0 vs. 9.3±9.0 ng/ml; p=0.005). Betatrophin however did not differ significantly between patients with significant CAD (n=347) and those who did not have significant CAD (10.5±13.5 ng/ml vs. 10.2±11.8 ng/ml; p=0.654). Betatrophin was positively correlated with waist circumference (r=0.150, p=0.001), BMI (r=0.142, p=0.001), fasting glucose (r=0.133, p=0.002), HbA1c (r=0.125, p=0.003), serum insulin (r=0.221, p & lt;0.001), the HOMA index of insulin resistance (r=0.226, p & lt;0.001) and the fatty liver index (r=0.231, p & lt;0.001). In multivariate analysis betatrophin proved to be an independent predictor of diabetes, with a standardized adjusted odds ratio of 1.23 [95% CI 1.01-1.51], p=0.043. We conclude that betatrophin is associated with T2DM and markers of insulin resistance. Disclosure A. Leiherer: None. A. Muendlein: None. K. Geiger: None. C.H. Saely: None. E. Brandtner: None. J. Ebner: None. B. Larcher: None. A. Mader: None. P. Fraunberger: None. H. Drexel: None.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db18-2445-PUB
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
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