Publications by authors named "Katarzyna Linder"

18 Publications

  • Page 1 of 1

No Effect of Lifestyle Intervention during Third Trimester on Brain Programming in Fetuses of Mothers with Gestational Diabetes.

Nutrients 2021 Feb 8;13(2). Epub 2021 Feb 8.

Helmholtz Center Munich at the University of Tübingen/fMEG Center, Institute for Diabetes Research and Metabolic Diseases, 72076 Tübingen, Germany.

Maternal metabolism and intrauterine conditions influence development of health and disease in offspring, leading to metabolic, physiologic, and/or epigenetic adaptation of the fetus. Maternal gestational diabetes (GDM) leads to higher incidence of obesity and type 2 diabetes in offspring. We have previously shown that fetuses of insulin-resistant mothers with GDM have a delayed reaction to auditory stimuli in the postprandial state, indicating a fetal central insulin resistance. We tested whether this effect could be influenced by a lifestyle intervention in mothers with GDM, including diet counselling and regular blood glucose measurements. We measured fetal brain activity over the course of a maternal glucose challenge, at two measurement time points (baseline at an average of 29 weeks of gestation and follow-up after 4 weeks) in mothers with GDM and mothers with normal glucose tolerance (NGT). Data from eight mothers were able to be included. Fetuses of GDM mothers showed longer latencies than those of NGT mothers postprandially at both measurement time points during the third trimester and did not show a difference in response patterns between baseline and after 4 weeks. Maternal postprandial blood glucose and insulin values did not change from baseline to follow-up either. While the overall intervention seems to have been effective, it does not appear to have influenced the fetal postprandial brain responses. This might have been because interventions for GDM take place relatively late in pregnancy. Future research should focus on maternal lifestyle interventions as early as possible during gestation, or even prenatally.
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http://dx.doi.org/10.3390/nu13020556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915982PMC
February 2021

Implementation of Urgent Start Peritoneal Dialysis Reduces Hemodialysis Catheter Use and Hospital Stay in Patients with Unplanned Dialysis Start.

Kidney Blood Press Res 2019 16;44(6):1383-1391. Epub 2019 Oct 16.

Department of Internal Medicine, Division of Diabetology, Endocrinology and Nephrology, University Hospital Tübingen, Tübingen, Germany.

Background: Unplanned start of renal replacement therapy is common in patients with end-stage renal disease and often accomplished by hemodialysis (HD) using a central venous catheter (CVC). Urgent start using peritoneal dialysis (PD) could be an alternative for some of the patients; however, this requires a hospital-based PD center that offers a structured urgent start PD (usPD) program.

Methods: In this prospective study, we describe the implementation of an usPD program at our university hospital by structuring the process from presentation to PD catheter implantation and start of PD within a few days. For clinical validation, we compared the patient flow before (2013-2015) and after (2016-2018) availability of usPD.

Results: In the 3 years before the availability of usPD, 14% (n = 12) of incident PD patients (n = 87) presented in an unplanned situation and were initially treated with HD using a CVC. In the 3 years after implementation of the usPD program, 18% (n = 18) of all incident PD patients (n = 103) presented in an unplanned situation of whom n = 12 (12%) were treated with usPD and n = 6 (6%) with initial HD. usPD significantly reduced the use of HD by 57% (p = 0.0005). Hospital stay was similar in patients treated with usPD (median 9 days) compared to those with elective PD (8 days), and significantly lower than in patients with initial HD (26 days, p = 0.0056).

Conclusions: Implementation of an usPD program reduces HD catheter use and hospital stay in the unplanned situation.
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http://dx.doi.org/10.1159/000503288DOI Listing
June 2020

Potential effects of reduced red meat compared with increased fiber intake on glucose metabolism and liver fat content: a randomized and controlled dietary intervention study.

Am J Clin Nutr 2019 02;109(2):288-296

Department of Internal Medicine IV, University Hospital of Tübingen, Tübingen, Germany.

Background: Epidemiological studies suggest that an increased red meat intake is associated with a higher risk of type 2 diabetes, whereas an increased fiber intake is associated with a lower risk.

Objectives: We conducted an intervention study to investigate the effects of these nutritional factors on glucose and lipid metabolism, body-fat distribution, and liver fat content in subjects at increased risk of type 2 diabetes.

Methods: This prospective, randomized, and controlled dietary intervention study was performed over 6 mo. All groups decreased their daily caloric intake by 400 kcal. The "control" group (N = 40) only had this requirement. The "no red meat" group (N = 48) in addition aimed to avoid the intake of red meat, and the "fiber" group (N = 44) increased intake of fibers to 40 g/d. Anthropometric parameters and frequently sampled oral glucose tolerance tests were performed before and after intervention. Body-fat mass and distribution, liver fat, and liver iron content were assessed by MRI and single voxel proton magnetic resonance spectroscopy.

Results: Participants in all groups lost weight (mean 3.3 ± 0.5 kg, P < 0.0001). Glucose tolerance and insulin sensitivity improved (P < 0.001), and body and visceral fat mass decreased in all groups (P < 0.001). These changes did not differ between groups. Liver fat content decreased significantly (P < 0.001) with no differences between the groups. The decrease in liver fat correlated with the decrease in ferritin during intervention (r2 = 0.08, P = 0.0021). This association was confirmed in an independent lifestyle intervention study (Tuebingen Lifestyle Intervention Program, N = 229, P = 0.0084).

Conclusions: Our data indicate that caloric restriction leads to a marked improvement in glucose metabolism and body-fat composition, including liver-fat content. The marked reduction in liver fat might be mediated via changes in ferritin levels. In the context of caloric restriction, there seems to be no additional beneficial impact of reduced red meat intake and increased fiber intake on the improvement in cardiometabolic risk parameters. This trial was registered at clinicaltrials.gov as NCT03231839.
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http://dx.doi.org/10.1093/ajcn/nqy307DOI Listing
February 2019

Dietary Niacin Intake Predicts the Decrease of Liver Fat Content During a Lifestyle Intervention.

Sci Rep 2019 02 4;9(1):1303. Epub 2019 Feb 4.

Department of Internal Medicine IV, University Hospital of Tübingen, Tübingen, Germany.

Niacin inhibits fatty acid flux from adipose tissue to liver, reduces hepatic triglyceride synthesis and increases hepatic lipid oxidation. Thus, niacin may have a role in the regulation of liver fat content in humans. We tested if dietary intake of niacin predicts change of liver fat content during a lifestyle intervention. To this end, we estimated the composition of diet from diaries of 202 healthy subjects at risk of type 2 diabetes undergoing lifestyle intervention comprising physical activity and diet counselling. Total-, subcutaneous- and visceral adipose tissue mass were measured by magnetic resonance (MR) tomography and liver fat content by H-MR spectroscopy at baseline and after 9 months of follow-up. Among fat compartments, liver fat content showed the largest decrease (-32%, p < 0.0001). High baseline niacin intake predicted a larger decrease of liver fat (p = 0.004). Subjects in the highest quartile of niacin intake at baseline also had the largest decrease of liver fat (1:-10%; 2:-27%; 3:-35%; 4:-37%). Among 58 subjects with nonalcoholic fatty liver disease (NAFLD) at baseline, NAFLD resolved in 23 subjects during the lifestyle intervention. For one standard deviation increase in niacin intake, the odds ratio for resolution of NAFLD was 1.77 (95% CI, 1.00-3.43). High dietary niacin intake may have a favorable effect on the reduction of liver fat during lifestyle intervention.
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http://dx.doi.org/10.1038/s41598-018-38002-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6362104PMC
February 2019

Family History of Diabetes Is Associated With Delayed Fetal Postprandial Brain Activity.

Front Endocrinol (Lausanne) 2018 20;9:673. Epub 2018 Nov 20.

Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.

We have previously shown that fetuses of mothers with gestational diabetes mellitus (GDM) and insulin resistance exhibit a prolongation of fetal auditory event-related brain responses (fAER) compared to fetuses of normal glucose tolerant women during an oral glucose tolerance test (oGTT). This implies that maternal metabolism may program the developing fetal brain. We now asked whether a family history of type 2 diabetes without metabolic programing also impacts fetal brain activity. We therefore investigated brain activity in fetuses of normal glucose tolerant mothers with and without family history of type 2 diabetes (FHD+ and FHD-). A 75 g oGTT was performed in healthy pregnant women. Plasma glucose and insulin levels were measured after 0, 60, and 120 min. Each blood draw was preceded by fetal magnetoencephalographic (fMEG) recordings of fAER. From a group of 167 participants, a subsample of 52 metabolically healthy women, 37 with a negative, and 15 with a positive FHD (at least one first- or second-degree relative) was carefully selected based on the following inclusion criteria: inconspicuous pregnancy, no GDM, BMI 18.5-30 kg/m, no preterm birth and at least two fMEG with detectable fetal responses during oGTT. An ANOVA showed a significant interaction between fMEG measurement time during the oGTT and FHD on fAER latency [ = 4.163, = 0.018]. Fetuses of mothers with FHD+ had a prolonged fAER (273 ± 113 ms) compared to fetuses of mothers with FHD- (219 ± 69 ms) at 60 min during the oGTT [ = 4.902, = 0.032]. There were no significant differences in age, BMI before pregnancy, weight gain during pregnancy and gestational age between the groups. Maternal glucose levels and insulin sensitivity were also not significantly different. In addition to the previously shown influence of maternal metabolism on fetal brain activity, maternal family history of diabetes (FHD) is also linked to fetal postprandial brain activity. This indicates that genetic and/or epigenetic factors modulate the postprandial brain response of the developing fetus.
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http://dx.doi.org/10.3389/fendo.2018.00673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6256935PMC
November 2018

Neuronal Food Reward Activity in Patients With Type 2 Diabetes With Improved Glycemic Control After Bariatric Surgery.

Diabetes Care 2016 Aug 12;39(8):1311-7. Epub 2016 Jun 12.

Department of Internal Medicine IV, University Hospital, Tübingen, Germany German Center for Diabetes Research, München-Neuherberg, Germany Department of Pharmacy and Biochemistry, Faculty of Science, University of Tübingen, Tübingen, Germany.

Objective: Obesity and type 2 diabetes mellitus (T2DM) are associated with altered food-related neuronal functions. Besides weight loss, substantial improvement of glucose metabolism in patients with T2DM can be achieved by bariatric surgery. We aimed to target the neuronal and behavioral correlates of improved glycemic control after bariatric surgery.

Research Design And Methods: Two patient groups with T2DM were recruited. The treatment group (n = 12) consisted of patients who had undergone Roux-en-Y gastric bypass (RYGB) surgery, and a control group consisted of patients who did not undergo surgery (n = 12). The groups were matched for age and current BMI. HbA1c was matched by using the presurgical HbA1c of the RYGB group and the current HbA1c of the nonsurgical group. Neuronal activation during a food reward task was measured using functional MRI (fMRI). Behavioral data were assessed through questionnaires.

Results: RYGB improved HbA1c from 7.07 ± 0.50 to 5.70 ± 0.16% (P < 0.05) and BMI from 52.21 ± 1.90 to 35.71 ± 0.84 kg/m(2) (P < 0.001). Behavioral results showed lower wanting and liking scores as well as lower eating behavior-related pathologies for the patients after RYGB than for similar obese subjects without surgery but with impaired glycemic control. The fMRI analysis showed higher activation for the nonsurgical group in areas associated with inhibition and reward as well as in the precuneus, a major connectivity hub in the brain. By contrast, patients after RYGB showed higher activation in the visual, motor, cognitive control, memory, and gustatory regions.

Conclusions: In obese patients with diabetes, RYGB normalizes glycemic control and leads to food reward-related brain activation patterns that are different from those of obese patients with less-well-controlled T2DM and without bariatric surgery. The differences in food reward processing might be one factor in determining the outcome of bariatric surgery in patients with T2DM.
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http://dx.doi.org/10.2337/dc16-0094DOI Listing
August 2016

Gestational Diabetes Impairs Human Fetal Postprandial Brain Activity.

J Clin Endocrinol Metab 2015 11 14;100(11):4029-36. Epub 2015 Oct 14.

Department of Internal Medicine (K.L., M.H., H.-U.H., A.F.), Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany; fMEG Center, University of Tübingen (F.S., I.K.-S., S.K., M.W., H.P.), Tübingen, Germany; German Center for Diabetes Research, Neuherberg, Germany (K.L., F.S., L.F., M.H., H.-U.H., H.P., A.F.); Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen (K.L., F.S., L.F., M.H., H.-U.H., H.P., A.F.), Tübingen, Germany; Department of Obstetrics and Gynecology (I.K.-S.), University Hospital Tübingen, Tübingen, Germany; Department of Pharmacy and Biochemistry (H.P.), Faculty of Science, University of Tübingen, Tübingen, Germany.

Context: Gestational diabetes (GDM) influences the fetal phenotype.

Objective: In the present study, our aim was to determine the effect of GDM specifically on fetal brain activity.

Design: Pregnant participants underwent an oral glucose tolerance test (OGTT, 75 g). At 0, 60, and 120 minutes, maternal metabolism was determined, and fetal auditory evoked fields were recorded with a fetal magnetoencephalographic device.

Setting: All measurements were performed at the fMEG Center in Tübingen.

Participants: Twelve women with GDM and 28 normal glucose-tolerant (NGT) pregnant women participated on a voluntary basis.

Interventions: OGTT (75 g, 120 minutes) was used in this study.

Main Outcomes And Measures: Fetal auditory evoked response latencies were determined for this study.

Results: In the fetuses of NGT women, latencies decreased between 0 and 60 minutes from 260 ± 90 to 206 ± 74 ms (P = .008) and remained stable until 120 minutes (206 ± 74 vs 230 ± 79, P =.129). In fetuses of women with GDM, there was no change in response latencies during OGTT (P = .11). Sixty minutes after glucose ingestion, fetal latencies in the GDM group were longer than in the NGT group (296 ± 82 vs 206 ± 74 ms, P = .001). Linear regression revealed a significant effect of maternal glucose, insulin levels, and insulin sensitivity on response latencies after 60 minutes.

Conclusions: Fetal postprandial brain responses were slower in the offspring of women with GDM. This might indicate that gestational diabetes directly affects fetal brain development and may lead to central nervous insulin resistance in the fetus.
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http://dx.doi.org/10.1210/jc.2015-2692DOI Listing
November 2015

Dopamine Depletion Reduces Food-Related Reward Activity Independent of BMI.

Neuropsychopharmacology 2016 May 9;41(6):1551-9. Epub 2015 Oct 9.

Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.

Reward sensitivity and possible alterations in the dopaminergic-reward system are associated with obesity. We therefore aimed to investigate the influence of dopamine depletion on food-reward processing. We investigated 34 female subjects in a randomized placebo-controlled, within-subject design (body mass index (BMI)=27.0 kg/m(2) ±4.79 SD; age=28 years ±4.97 SD) using an acute phenylalanine/tyrosine depletion drink representing dopamine depletion and a balanced amino acid drink as the control condition. Brain activity was measured with functional magnetic resonance imaging during a 'wanting' and 'liking' rating of food items. Eating behavior-related traits and states were assessed on the basis of questionnaires. Dopamine depletion resulted in reduced activation in the striatum and higher activation in the superior frontal gyrus independent of BMI. Brain activity during the wanting task activated a more distributed network than during the liking task. This network included gustatory, memory, visual, reward, and frontal regions. An interaction effect of dopamine depletion and the wanting/liking task was observed in the hippocampus. The interaction with the covariate BMI was significant in motor and control regions but not in the striatum. Our results support the notion of altered brain activity in the reward and prefrontal network with blunted dopaminergic action during food-reward processing. This effect is, however, independent of BMI, which contradicts the reward-deficiency hypothesis. This hints to the hypothesis suggesting a different or more complex mechanism underlying the dopaminergic reward function in obesity.
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http://dx.doi.org/10.1038/npp.2015.313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4832016PMC
May 2016

Resting-state functional connectivity of the human hypothalamus.

Hum Brain Mapp 2014 Dec 14;35(12):6088-96. Epub 2014 Aug 14.

Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, 72076, Tübingen, Germany; German Center for Diabetes Research, 85764, Neuherberg, Germany; Institute of Medical Psychology and Behavioral Neurobiology, Eberhard Karls University Tübingen, 72076, Tübingen, Germany; fMEG Center, Eberhard Karls University Tübingen, 72076, Tübingen, Germany.

The hypothalamus is of enormous importance for multiple bodily functions such as energy homeostasis. Especially, rodent studies have greatly contributed to our understanding how specific hypothalamic subregions integrate peripheral and central signals into the brain to control food intake. In humans, however, the neural circuitry of the hypothalamus, with its different subregions, has not been delineated. Hence, the aim of this study was to map the hypothalamus network using resting-state functional connectivity (FC) analyses from the medial hypothalamus (MH) and lateral hypothalamus (LH) in healthy normal-weight adults (n = 49). Furthermore, in a separate sample, we examined differences within the LH and MH networks between healthy normal-weight (n = 25) versus overweight/obese adults (n = 23). FC patterns from the LH and MH revealed significant connections to the striatum, thalamus, brainstem, orbitofrontal cortex, middle and posterior cingulum and temporal brain regions. However, our analysis revealed subtler distinctions within hypothalamic subregions. The LH was functionally stronger connected to the dorsal striatum, anterior cingulum, and frontal operculum, while the MH showed stronger functional connections to the nucleus accumbens and medial orbitofrontal cortex. Furthermore, overweight/obese participants revealed heightened FC in the orbitofrontal cortex and nucleus accumbens within the MH network. Our results indicate that the MH and LH network are tapped into different parts of the dopaminergic circuitry of the brain, potentially modulating food reward based on the functional connections to the ventral and dorsal striatum, respectively. In obese adults, FC changes were observed in the MH network.
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http://dx.doi.org/10.1002/hbm.22607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6869436PMC
December 2014

Central insulin administration improves whole-body insulin sensitivity via hypothalamus and parasympathetic outputs in men.

Diabetes 2014 Dec 15;63(12):4083-8. Epub 2014 Jul 15.

Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.

Animal studies suggest that insulin action in the brain is involved in the regulation of peripheral insulin sensitivity. Whether this holds true in humans is unknown. Using intranasal application of insulin to the human brain, we studied the impacts of brain insulin action on whole-body insulin sensitivity and the mechanisms involved in this process. Insulin sensitivity was assessed by hyperinsulinemic-euglycemic glucose clamp before and after intranasal application of insulin and placebo in randomized order in lean and obese men. After insulin spray application in lean subjects, a higher glucose infusion rate was necessary to maintain euglycemia compared with placebo. Accordingly, clamp-derived insulin sensitivity index improved after insulin spray. In obese subjects, this insulin-sensitizing effect could not be detected. Change in the high-frequency band of heart rate variability, an estimate of parasympathetic output, correlated positively with change in whole-body insulin sensitivity after intranasal insulin. Improvement in whole-body insulin sensitivity correlated with the change in hypothalamic activity as assessed by functional magnetic resonance imaging. Intranasal insulin improves peripheral insulin sensitivity in lean but not in obese men. Furthermore, brain-derived peripheral insulin sensitization is associated with hypothalamic activity and parasympathetic outputs. Thus, the findings provide novel insights into the regulation of insulin sensitivity and the pathogenesis of insulin resistance in humans.
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http://dx.doi.org/10.2337/db14-0477DOI Listing
December 2014

Maternal insulin sensitivity is associated with oral glucose-induced changes in fetal brain activity.

Diabetologia 2014 Jun 28;57(6):1192-8. Epub 2014 Mar 28.

Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany.

Aims/hypothesis: Fetal programming plays an important role in the pathogenesis of type 2 diabetes. The aim of the present study was to investigate whether maternal metabolic changes during OGTT influence fetal brain activity.

Methods: Thirteen healthy pregnant women underwent an OGTT (75 g). Insulin sensitivity was determined by glucose and insulin measurements at 0, 60 and 120 min. At each time point, fetal auditory evoked fields were recorded with a fetal magnetoencephalographic device and response latencies were determined.

Results: Maternal insulin increased from a fasting level of 67 ± 25 pmol/l (mean ± SD) to 918 ± 492 pmol/l 60 min after glucose ingestion and glucose levels increased from 4.4 ± 0.3 to 7.4 ± 1.1 mmol/l. Over the same time period, fetal response latencies decreased from 297 ± 99 to 235 ± 84 ms (p = 0.01) and then remained stable until 120 min (235 ± 84 vs 251 ± 91 ms, p = 0.39). There was a negative correlation between maternal insulin sensitivity and fetal response latencies 60 min after glucose ingestion (r = 0.68, p = 0.02). After a median split of the group based on maternal insulin sensitivity, fetuses of insulin-resistant mothers showed a slower response to auditory stimuli (283 ± 79 ms) than those of insulin-sensitive mothers (178 ± 46 ms, p = 0.03).

Conclusions/interpretation: Lower maternal insulin sensitivity is associated with slower fetal brain responses. These findings provide the first evidence of a direct effect of maternal metabolism on fetal brain activity and suggest that central insulin resistance may be programmed during fetal development.
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http://dx.doi.org/10.1007/s00125-014-3217-9DOI Listing
June 2014

Relationships of body composition and liver fat content with insulin resistance in obesity-matched adolescents and adults.

Obesity (Silver Spring) 2014 May 19;22(5):1325-31. Epub 2014 Mar 19.

Department of Internal Medicine Division of Endocrinology and Diabetology Vascular Medicine Nephrology and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen (IDM), Tübingen, Germany.

Objective: While in adults not total body- or visceral fat mass, but liver fat content was found to independently determine insulin resistance, it is unclear whether these relationships are already present in obese adolescents.

Methods: Thirty-nine overweight/obese adolescents were matched for sex and BMI with 39 adults. To compare the age- and sex-specific BMI values of adolescents and adults, the percentile value of each adolescent was projected to the age of 18. Body fat depots were quantified by whole-body magnetic resonance (MR) imaging. Liver fat content was measured with (1)H-MR spectroscopy. Insulin resistance was estimated from the homeostasis model assessment of insulin resistance (HOMA-IR).

Results: Compared to overweight and obese adults, adolescents had higher HOMA-IR (P < 0.001) and lower lean body mass (P = 0.002). Furthermore, they had higher total body- (P = 0.02), but lower visceral- (P < 0.001) fat mass, while liver fat content was not significantly different between the groups (P = 0.16). In both groups liver fat content (both P ≤ 0.007), but not total body- or visceral fat mass (all P ≥ 0.64) was an independent predictor of insulin resistance.

Conclusions: Having lower visceral fat mass, overweight and obese adolescents are more insulin resistant than sex- and BMI-matched adults. Liver fat content, but not total body- or visceral fat mass, is an independent determinant of insulin resistance in adolescents.
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http://dx.doi.org/10.1002/oby.20685DOI Listing
May 2014

Olive oil aroma extract modulates cerebral blood flow in gustatory brain areas in humans.

Am J Clin Nutr 2013 Nov 11;98(5):1360-6. Epub 2013 Sep 11.

Institute of Medical Psychology and Behavioral Neurobiology, University of Tübingen, Tübingen, Germany (HP, MAH, RV, SF, and SK); the fMEG Center, University of Tübingen, Tübingen, Germany (HP, MAH, RV, SF, and SK); the Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany (AF, KL, and LF); the Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany (AF, HP, and SK); the German Center for Diabetes Research, Neuherberg, Germany (AF, HP, and SK); the Institute of Food Science and Biotechnology, University of Hohenheim, Stuttgart, Germany (AK and JH); the German Research Center for Food Chemistry, Freising, Germany (PS); and the Department of Nutritional and Physiological Chemistry, University of Vienna, Vienna, Austria (VS).

Background: Low- and high-fat meals affect homeostatic and gustatory brain areas differentially. In a previous study, we showed that a high-fat meal decreased cerebral blood flow (CBF) in homeostatic brain areas (hypothalamus), whereas a low-fat meal increased CBF in gustatory regions (anterior insula).

Objective: The aim of this study was to investigate the long-lasting effect of fat-free flavor-active compounds of olive oil on the brain and whether those aroma components can trigger fat-associated brain responses in homeostatic and gustatory regions.

Design: Eleven healthy male subjects participated in a functional magnetic resonance imaging study. On 2 measurement days, subjects consumed single-blinded a plain low-fat yogurt or low-fat yogurt mixed with a fat-free aroma extract of olive oil. Resting CBF was measured before and 30 and 120 min after yogurt intake. Hunger was rated before each measurement. Blood samples were collected at 6 time points.

Results: The extract-containing yogurt elicited higher CBF in the frontal operculum 30 and 120 min after a meal. Furthermore, the activity change in the anterior insula after 30 min correlated positively with the glucose change in the extract condition only. No effects were observed in the hypothalamus.

Conclusions: The anterior insula and the frontal operculum are regarded as the primary taste cortex. Modulation of the frontal operculum by the yogurt containing the olive oil extract suggests that it might be possible to simulate fat-triggered sensations in the brain on the gustatory level, possibly by ingredients the body implicitly associates with fat. This trial was registered at clinicaltrials.gov as NCT01716286.
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http://dx.doi.org/10.3945/ajcn.113.062679DOI Listing
November 2013

Polymorphism rs3123554 in CNR2 reveals gender-specific effects on body weight and affects loss of body weight and cerebral insulin action.

Obesity (Silver Spring) 2014 Mar 25;22(3):925-31. Epub 2014 Jan 25.

Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, Eberhard Karls University, Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen (Paul Langerhans Institute Tübingen), Tübingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany.

Objective: The cannabinoid-receptor system is involved in the regulation of food intake. Here, we test whether single nucleotide polymorphisms (SNPs) in CNR2, encoding the cannabinoid-receptor 2, are associated with weight in a cross-sectional cohort. Furthermore, we wanted to investigate if the identified hits influence weight loss during lifestyle intervention; and study a potential involvement of cerebral insulin action.

Methods: 2006 subjects at increased risk for type 2 diabetes mellitus were genotyped for 5 tagging SNPs in the CNR2 locus. All subjects underwent a 75-g OGTT. 345 subjects participated in a lifestyle intervention (TUebingen Lifestyle Intervention Programme). Cerebrocortical insulin sensitivity was measured by magnetoencephalography after intranasal insulin application in 43 subjects.

Results: In the cross-sectional cohort, the minor allele of rs3123554 was associated with lower BMI (Padd = 0.01, Prec = 0.004), and this was attributable to its effect in women only. Interestingly, during lifestyle intervention, carriers of the same allele lost less body weight (Padd = 0.03, Prec = 0.008). Moreover, carriers of this minor allele showed lower cerebral insulin sensitivity (Prec = 0.0402).

Conclusions: The minor allele of rs3123554 is associated cross-sectionally with lower body weight, whereas during intervention the same allele led to less reduction of body weight. Reduced cerebral insulin sensitivity in carriers of this allele might contribute to these disadvantageous effects during lifestyle intervention.
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http://dx.doi.org/10.1002/oby.20573DOI Listing
March 2014

Genetic variation in NR1H4 encoding the bile acid receptor FXR determines fasting glucose and free fatty acid levels in humans.

J Clin Endocrinol Metab 2013 Jul 2;98(7):E1224-9. Epub 2013 May 2.

Department of Internal Medicine, Division of Endocrinology, University Hospital, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.

Context: Bile acid signaling via farnesoid X receptor (FXR) regulates glucose and lipid levels, fat mass, and hepatic steatosis in animal models.

Objective: To understand the role of FXR in human metabolism, we investigated associations of common single-nucleotide polymorphisms (SNPs) in the FXR-encoding gene NR1H4 with glucose and lipid metabolism, body fat mass, and liver fat content.

Design: We genotyped 2166 healthy German subjects for 7 tagging SNPs within NR1H4 (rs35735, rs1030454, rs11110415, rs11610264, rs17030285, rs4764980, and rs11110390) covering 100% of common genetic variation (minor allele frequency > 10%).

Outcome Measures: Subjects were metabolically characterized by an oral glucose tolerance test. In subgroups, hyperinsulinemic-euglycemic clamp and liver fat quantification by (1)H-magnetic resonance spectroscopy were performed.

Results: SNP rs4764980 was significantly associated with fasting glycemia (P = .0043) and nominally associated with fasting and postglucose load free fatty acid (FFA) levels (P = .01). Upon interrogation of publicly available Meta-Analyses of Glucose and Insulin-related traits Consortium data, the association of rs4764980 with fasting glycemia was replicated (Meta-Analyses of Glucose and Insulin-related traits Consortium, P = .005). Additionally, SNP rs11110390 showed significant associations with fasting (P = .0054) and postload (P = .0051) FFA levels. For none of the investigated SNPs, associations with insulin secretion or sensitivity, body fat mass, or liver fat content were detected.

Conclusions: We conclude that FXR contributes to fasting glucose and FFA levels in humans independent of unhealthy body fat accumulation. The receptor represents an interesting target to influence lipid and glucose metabolism.
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http://dx.doi.org/10.1210/jc.2013-1177DOI Listing
July 2013

Polymorphism rs11085226 in the gene encoding polypyrimidine tract-binding protein 1 negatively affects glucose-stimulated insulin secretion.

PLoS One 2012 15;7(10):e46154. Epub 2012 Oct 15.

Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Department of Internal Medicine, Eberhard Karls University Tübingen, Tübingen, Germany.

Objective: Polypyrimidine tract-binding protein 1 (PTBP1) promotes stability and translation of mRNAs coding for insulin secretion granule proteins and thereby plays a role in β-cells function. We studied whether common genetic variations within the PTBP1 locus influence insulin secretion, and/or proinsulin conversion.

Methods: We genotyped 1,502 healthy German subjects for four tagging single nucleotide polymorphisms (SNPs) within the PTBP1 locus (rs351974, rs11085226, rs736926, and rs123698) covering 100% of genetic variation with an r(2)≥0.8. The subjects were metabolically characterized by an oral glucose tolerance test with insulin, proinsulin, and C-peptide measurements. A subgroup of 320 subjects also underwent an IVGTT.

Results: PTBP1 SNP rs11085226 was nominally associated with lower insulinogenic index and lower cleared insulin response in the OGTT (p≤0.04). The other tested SNPs did not show any association with the analyzed OGTT-derived secretion parameters. In the IVGTT subgroup, SNP rs11085226 was accordingly associated with lower insulin levels within the first ten minutes following glucose injection (p = 0.0103). Furthermore, SNP rs351974 was associated with insulin levels in the IVGTT (p = 0.0108). Upon interrogation of MAGIC HOMA-B data, our rs11085226 result was replicated (MAGIC p = 0.018), but the rs351974 was not.

Conclusions: We conclude that common genetic variation in PTBP1 influences glucose-stimulated insulin secretion. This underlines the importance of PTBP1 for beta cell function in vivo.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0046154PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3471934PMC
March 2013

Allele summation of diabetes risk genes predicts impaired glucose tolerance in female and obese individuals.

PLoS One 2012 29;7(6):e38224. Epub 2012 Jun 29.

Department of Internal Medicine, Division of Endocrinology, Diabetology, Nephrology, Vascular Disease and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany.

Introduction: Single nucleotide polymorphisms (SNPs) in approximately 40 genes have been associated with an increased risk for type 2 diabetes (T2D) in genome-wide association studies. It is not known whether a similar genetic impact on the risk of prediabetes (impaired glucose tolerance [IGT] or impaired fasting glycemia [IFG]) exists.

Methods: In our cohort of 1442 non-diabetic subjects of European origin (normal glucose tolerance [NGT] n = 1046, isolated IFG n = 142, isolated IGT n = 140, IFG+IGT n = 114), an impact on glucose homeostasis has been shown for 9 SNPs in previous studies in this specific cohort. We analyzed these SNPs (within or in the vicinity of the genes TCF7L2, KCNJ11, HHEX, SLC30A8, WFS1, KCNQ1, MTNR1B, FTO, PPARG) for association with prediabetes.

Results: The genetic risk load was significantly associated with the risk for IGT (p = 0.0006) in a model including gender, age, BMI and insulin sensitivity. To further evaluate potential confounding effects, we stratified the population on gender, BMI and insulin sensitivity. The association of the risk score with IGT was present in female participants (p = 0.008), but not in male participants. The risk score was significantly associated with IGT (p = 0.008) in subjects with a body mass index higher than 30 kg/m(2) but not in non-obese individuals. Furthermore, only in insulin resistant subjects a significant association between the genetic load and the risk for IGT (p = 0.01) was found.

Discussion: We found that T2D genetic risk alleles cause an increased risk for IGT. This effect was not present in male, lean and insulin sensitive subjects, suggesting a protective role of beneficial environmental factors on the genetic risk.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0038224PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3387191PMC
November 2012

Fat intake modulates cerebral blood flow in homeostatic and gustatory brain areas in humans.

Am J Clin Nutr 2012 Jun 9;95(6):1342-9. Epub 2012 May 9.

MEG Center, University of Tübingen, Tübingen, Germany.

Background: The hypothalamus is the central homeostatic control region of the brain and, therefore, highly influenced by nutrients such as glucose and fat. Immediate and prolonged homeostatic effects of glucose ingestion have been well characterized. However, studies that used stimulation with fat have mainly investigated immediate perceptional processes. Besides homeostatic processes, the gustatory cortex, including parts of the insular cortex, is crucial for the processing of food items.

Objective: The aim of this study was to investigate the effect of high- compared with low-fat meals on the hypothalamus and the insular cortex.

Design: Eleven healthy men participated in a single-blinded, functional MRI study of high- and low-fat meals on 2 measurement days. Cerebral blood flow (CBF) was measured before and 30 and 120 min after intake of high- and low-fat yogurts. Hunger was rated and blood samples were taken before each CBF measurement.

Results: High-fat yogurt induced a pronounced decrease in CBF in the hypothalamus, and the corresponding CBF change correlated positively with the insulin change. Furthermore, insular activity increased after 120 min in the low-fat condition only. The CBF change in both regions correlated positively in the high-fat condition.

Conclusions: The decrease in hypothalamic activity and the interaction with the insular cortex elicited by fat may contribute to an efficient energy homeostasis. Therefore, fat might be a modulator of homeostatic and gustatory brain regions and their interaction. This trial was registered at clinicaltrials.gov as NCT01516021.
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http://dx.doi.org/10.3945/ajcn.111.031492DOI Listing
June 2012
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