Publications by authors named "Harald Staiger"

144 Publications

Elevated Circulating Glutamate Is Associated With Subclinical Atherosclerosis Independently of Established Risk Markers: A Cross-Sectional Study.

J Clin Endocrinol Metab 2021 Jan;106(2):e982-e989

Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Centre Munich, Tübingen, Germany.

Objective: Elevated plasma glutamate levels are associated with an increased risk of cardiovascular disease (CVD). Because plasma glutamate levels are also strongly associated with visceral adiposity, nonalcoholic fatty liver disease, insulin resistance, and high circulating levels of branched-chain amino acids (BCAAs), it is unknown to what extent elevated circulating glutamate is an independent marker of an increased risk of atherosclerosis.

Methods: Plasma levels of glutamate and BCAAs were measured in 102 individuals who were precisely phenotyped for body fat mass and distribution (magnetic resonance [MR] tomography), liver fat content (1H-MR spectroscopy), insulin sensitivity (oral glucose tolerance test and hyperinsulinemic, euglycemic clamp [N = 57]), and carotid intima media thickness (cIMT).

Results: Plasma glutamate levels, adjusted for age, sex, body fat mass, and visceral fat mass, correlated positively with liver fat content and cIMT (all std β ≥ .22, all P ≤ .023) and negatively with insulin sensitivity (std β ≤ -.31, P ≤ .002). Glutamate levels also were associated with cIMT, independently of additional adjustment for liver fat content, insulin sensitivity and BCAAs levels (std β ≥ .24, P ≤ .02). Furthermore, an independent positive association of glutamate and interleukin-6 (IL-6) levels was observed (N = 50; std β = .39, P = .03). Although glutamate, adjusted for age, sex, body fat mass, and visceral fat mass, also correlated positively with cIMT in this subgroup (std β = .31, P = .02), after additional adjustment for the parameters liver fat content, insulin sensitivity, BCAAs, or IL-6 levels, adjustment for IL-6 most strongly attenuated this relationship (std β = .28, P = .05).

Conclusions: Elevated plasma glutamate levels are associated with increased cIMT, independently of established CVD risk factors, and this relationship may in part be explained by IL-6-associated subclinical inflammation.
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http://dx.doi.org/10.1210/clinem/dgaa898DOI Listing
January 2021

Ectopic fat accumulation in human astrocytes impairs insulin action.

R Soc Open Sci 2020 Sep 16;7(9):200701. Epub 2020 Sep 16.

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

Astrocytes provide neurons with structural support and energy in form of lactate, modulate synaptic transmission, are insulin sensitive and act as gatekeeper for water, ions, glutamate and second messengers. Furthermore, astrocytes are important for glucose sensing, possess neuroendocrine functions and also play an important role in cerebral lipid metabolism. To answer the question, if there is a connection between lipid metabolism and insulin action in human astrocytes, we investigated if storage of ectopic lipids in human astrocytes has an impact on insulin signalling in those cells. Human astrocytes were cultured in the presence of a lipid emulsion, consisting of fatty acids and triglycerides, to induce ectopic lipid storage. After several days, cells were stimulated with insulin and gene expression profiling was performed. In addition, phosphorylation of Akt as well as glycogen synthesis and cell proliferation was assessed. Ectopic lipid storage was detected in human astrocytes after lipid exposure and lipid storage was persistent even when the fat emulsion was removed from the cell culture medium. Chronic exposure to lipids induced profound changes in the gene expression profile, whereby some genes showed a reversible gene expression profile upon removal of fat, and some did not. This included FOXO-dependent expression patterns. Furthermore, insulin-induced phosphorylation of Akt was diminished and also insulin-induced glycogen synthesis and proliferation was impaired in lipid-laden astrocytes. Chronic lipid exposure induces lipid storage in human astrocytes accompanied by insulin resistance. Analyses of the gene expression pattern indicated the potential of a partially reversible gene expression profile. Targeting astrocytic insulin resistance by reducing ectopic lipid load might represent a promising treatment target for insulin resistance of the brain in obesity, diabetes and neurodegeneration.
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http://dx.doi.org/10.1098/rsos.200701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540778PMC
September 2020

Increased mitochondrial respiration of adipocytes from metabolically unhealthy obese compared to healthy obese individuals.

Sci Rep 2020 07 24;10(1):12407. Epub 2020 Jul 24.

Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Nephrology, University Hospital Tübingen, Eberhard Karls University Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany.

Among obese subjects, metabolically healthy (MHO) and unhealthy obese (MUHO) subjects exist, the latter being characterized by whole-body insulin resistance, hepatic steatosis, and subclinical inflammation. Insulin resistance and obesity are known to associate with alterations in mitochondrial density, morphology, and function. Therefore, we assessed mitochondrial function in human subcutaneous preadipocytes as well as in differentiated adipocytes derived from well-matched donors. Primary subcutaneous preadipocytes from 4 insulin-resistant (MUHO) versus 4 insulin-sensitive (MHO), non-diabetic, morbidly obese Caucasians (BMI > 40 kg/m), matched for sex, age, BMI, and percentage of body fat, were differentiated in vitro to adipocytes. Real-time cellular respiration was measured using an XF24 Extracellular Flux Analyzer (Seahorse). Lipolysis was stimulated by forskolin (FSK) treatment. Mitochondrial respiration was fourfold higher in adipocytes versus preadipocytes (p = 1.6*10). In adipocytes, a negative correlation of mitochondrial respiration with donors' insulin sensitivity was shown (p = 0.0008). Correspondingly, in adipocytes of MUHO subjects, an increased basal respiration (p = 0.002), higher proton leak (p = 0.04), elevated ATP production (p = 0.01), increased maximal respiration (p = 0.02), and higher spare respiratory capacity (p = 0.03) were found, compared to MHO. After stimulation with FSK, the differences in ATP production, maximal respiration and spare respiratory capacity were blunted. The differences in mitochondrial respiration between MUHO/MHO were not due to altered mitochondrial content, fuel switch, or lipid metabolism. Thus, despite the insulin resistance of MUHO, we could clearly show an elevated mitochondrial respiration of MUHO adipocytes. We suggest that the higher mitochondrial respiration reflects a compensatory mechanism to cope with insulin resistance and its consequences. Preserving this state of compensation might be an attractive goal for preventing or delaying the transition from insulin resistance to overt diabetes.
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http://dx.doi.org/10.1038/s41598-020-69016-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382448PMC
July 2020

AMPK Subunits Harbor Largely Nonoverlapping Genetic Determinants for Body Fat Mass, Glucose Metabolism, and Cholesterol Metabolism.

J Clin Endocrinol Metab 2020 01;105(1)

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

Context: Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a heterotrimeric enzyme and central regulator of cellular energy metabolism. The impact of single nucleotide polymorphisms (SNPs) in all 7 AMPK subunit genes on adiposity, glucose metabolism, and lipid metabolism has not yet been systematically studied.

Objective: To analyze the associations of common SNPs in all AMPK genes, and of different scores thereof, with adiposity, insulin sensitivity, insulin secretion, blood glucose, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, total cholesterol, and triglycerides.

Study Design And Methods: A cohort of 2789 nondiabetic participants from the Tübingen Family study of type 2 diabetes, metabolically characterized by oral glucose tolerance test and genotyped by genome-wide SNP array, was analyzed.

Results: We identified 6 largely nonoverlapping SNP sets across 4 AMPK genes (PRKAA1, PRKAA2, PRKAG2, PRKAG3) associated with adiposity, insulin sensitivity, insulin secretion, blood glucose, total/LDL cholesterol, or HDL cholesterol, respectively. A genetic score of body-fat-increasing alleles revealed per-allele effect sizes on body mass index (BMI) of +0.22 kg/m2 (P = 2.3 × 10-7), insulin sensitivity of -0.12 × 1019 L2/mol2 (P = 9.9 × 10-6) and 2-hour blood glucose of +0.02 mmol/L (P = 0.0048). Similar effects on blood glucose were observed with scores of insulin-sensitivity-reducing, insulin-secretion-reducing and glucose-raising alleles, respectively. A genetic cholesterol score increased total and LDL cholesterol by 1.17 mg/dL per allele (P = 0.0002 and P = 3.2 × 10-5, respectively), and a genetic HDL score decreased HDL cholesterol by 0.32 mg/dL per allele (P = 9.1 × 10-6).

Conclusions: We describe largely nonoverlapping genetic determinants in AMPK genes for diabetes-/atherosclerosis-related traits, which reflect the metabolic pathways controlled by the enzyme. Formation of trait-specific genetic scores revealed additivity of allele effects, with body-fat-raising alleles reaching a marked effect size. (J Clin Endocrinol Metab XX: 0-0, 2019).
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http://dx.doi.org/10.1210/clinem/dgz020DOI Listing
January 2020

Generation of a human induced pluripotent stem cell line (HMGUi002-A) from a healthy male individual.

Stem Cell Res 2019 08 7;39:101531. Epub 2019 Aug 7.

Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Stem Cell Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Technische Universität München, Ismaningerstraße 22, 81675 München, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany. Electronic address:

Induced pluripotent stem cells (iPSCs) can be used to generate different somatic cell types in vitro, including insulin-producing pancreatic β-cells. Here, we have generated iPSCs from a healthy male individual using an episomal reprogramming method. The resulting iPSCs are integration-free, have a normal karyotype and are pluripotent in vitro and in vivo. Furthermore, we show that this iPSC line can be differentiated into pancreatic lineage cells. Taken together, this iPSC line will be useful to test differentiation protocols towards β-cell as well as other cell types and will also serve as a control for drug development and disease modelling studies.
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http://dx.doi.org/10.1016/j.scr.2019.101531DOI Listing
August 2019

DEUS: an R package for accurate small RNA profiling based on differential expression of unique sequences.

Bioinformatics 2019 11;35(22):4834-4836

Institute of Computational Biology, Helmholtz Zentrum München GmbH, Neuherberg 85764, Germany.

Summary: Despite their fundamental role in various biological processes, the analysis of small RNA sequencing data remains a challenging task. Major obstacles arise when short RNA sequences map to multiple locations in the genome, align to regions that are not annotated or underwent post-transcriptional changes which hamper accurate mapping. In order to tackle these issues, we present a novel profiling strategy that circumvents the need for read mapping to a reference genome by utilizing the actual read sequences to determine expression intensities. After differential expression analysis of individual sequence counts, significant sequences are annotated against user defined feature databases and clustered by sequence similarity. This strategy enables a more comprehensive and concise representation of small RNA populations without any data loss or data distortion.

Availability And Implementation: Code and documentation of our R package at http://ibis.helmholtz-muenchen.de/deus/.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btz495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853685PMC
November 2019

What role do fat cells play in pancreatic tissue?

Mol Metab 2019 07 7;25:1-10. Epub 2019 May 7.

German Center for Diabetes Research (DZD), Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard Karls University of Tübingen, Tübingen, Germany. Electronic address:

Background: It is now generally accepted that obesity is a major risk factor for type 2 diabetes mellitus (T2DM). Hepatic steatosis in particular, as well as visceral and ectopic fat accumulation within tissues, is associated with the development of the disease. We recently presented the first study on isolated human pancreatic adipocytes and their interaction with islets [Gerst, F., Wagner, R., Kaiser, G., Panse, M., Heni, M., Machann, J., et al., 2017. Metabolic crosstalk between fatty pancreas and fatty liver: effects on local inflammation and insulin secretion. Diabetologia 60(11):2240-2251.]. The results indicate that the function of adipocytes depends on the overall metabolic status in humans which, in turn, differentially affects islet hormone release.

Scope Of Review: This review summarizes former and recent studies on factors derived from adipocytes and their effects on insulin-secreting β-cells, with particular emphasis on the human pancreas. The adipocyte secretome is discussed with a special focus on its influence on insulin secretion, β-cell survival and apoptotic β-cell death.

Major Conclusions: Human pancreatic adipocytes store lipids and release adipokines, metabolites, and pro-inflammatory molecules in response to the overall metabolic, humoral, and neuronal status. The differentially regulated adipocyte secretome impacts on endocrine function, i.e., insulin secretion, β-cell survival and death which interferes with glycemic control. This review attempts to explain why the extent of pancreatic steatosis is associated with reduced insulin secretion in some studies but not in others.
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http://dx.doi.org/10.1016/j.molmet.2019.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600604PMC
July 2019

Circulating FGF21 Levels in Human Health and Metabolic Disease.

Exp Clin Endocrinol Diabetes 2020 Nov 20;128(11):752-770. Epub 2019 May 20.

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

Human fibroblast growth factor 21 (FGF21) is primarily produced and secreted by the liver as a hepatokine. This hormone circulates to its target tissues (e. g., brain, adipose tissue), which requires two components, one of the preferred FGF receptor isoforms (FGFR1c and FGFR3c) and the co-factor beta-Klotho (KLB) to trigger downstream signaling pathways. Although targeting FGF21 signaling in humans by analogues and receptor agonists results in beneficial effects, e. g., improvements in plasma lipids and decreased body weight, it failed to recapitulate the improvements in glucose handling shown for many mouse models. FGF21's role and metabolic effects in mice and its therapeutic potential have extensively been reviewed elsewhere. In this review we focus on circulating FGF21 levels in humans and their associations with disease and clinical parameters, focusing primarily on obesity and obesity-associated diseases such as type-2 diabetes. We provide a comprehensive overview on human circulating FGF21 levels under normal physiology and metabolic disease. We discuss the emerging field of inactivating FGF21 in human blood by fibroblast activation protein (FAP) and its potential clinical implications.
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http://dx.doi.org/10.1055/a-0879-2968DOI Listing
November 2020

Point mutations in the PDX1 transactivation domain impair human β-cell development and function.

Mol Metab 2019 06 20;24:80-97. Epub 2019 Mar 20.

Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Stem Cell Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Technische Universität München, Ismaningerstraße 22, 81675 München, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany. Electronic address:

Objective: Hundreds of missense mutations in the coding region of PDX1 exist; however, if these mutations predispose to diabetes mellitus is unknown.

Methods: In this study, we screened a large cohort of subjects with increased risk for diabetes and identified two subjects with impaired glucose tolerance carrying common, heterozygous, missense mutations in the PDX1 coding region leading to single amino acid exchanges (P33T, C18R) in its transactivation domain. We generated iPSCs from patients with heterozygous PDX1, PDX1 mutations and engineered isogenic cell lines carrying homozygous PDX1, PDX1 mutations and a heterozygous PDX1 loss-of-function mutation (PDX1).

Results: Using an in vitro β-cell differentiation protocol, we demonstrated that both, heterozygous PDX1, PDX1 and homozygous PDX1, PDX1 mutations impair β-cell differentiation and function. Furthermore, PDX1 and PDX1 mutations reduced differentiation efficiency of pancreatic progenitors (PPs), due to downregulation of PDX1-bound genes, including transcription factors MNX1 and PDX1 as well as insulin resistance gene CES1. Additionally, both PDX1 and PDX1 mutations in PPs reduced the expression of PDX1-bound genes including the long-noncoding RNA, MEG3 and the imprinted gene NNAT, both involved in insulin synthesis and secretion.

Conclusions: Our results reveal mechanistic details of how common coding mutations in PDX1 impair human pancreatic endocrine lineage formation and β-cell function and contribute to the predisposition for diabetes.
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http://dx.doi.org/10.1016/j.molmet.2019.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531841PMC
June 2019

Gene x Gene Interactions Highlight the Role of Incretin Resistance for Insulin Secretion.

Front Endocrinol (Lausanne) 2019 21;10:72. Epub 2019 Feb 21.

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

Genetic polymorphisms in are the strongest common risk variants for type 2 diabetes mellitus (T2D). We and others have shown that genetic variation in and affect incretin-stimulated insulin secretion. A recent genome-wide association study discovered genetic variants associated with incretin levels. We hypothesized that these SNPs (single nucleotide polymorphisms) interact with the well-known variant rs7903146 on insulin secretion due to their incretin altering effect. In this retrospective analysis, we used data from the cross-sectional TUEF-cohort ( = 2929) and a hyperglycemic clamp study using additional GLP-1 infusion at the end of the clamp ( = 76). Insulin secretion was measured by evaluating OGTT-derived indexes of insulin secretion and insulin/C-peptide levels during clamp. We genotyped rs7903146 in , rs10010131 in , and six SNPs associated with GLP-1 and GIP levels. One of the six incretin-associated SNPs, rs17681684 in , exhibited significant SNP x SNP interactions with rs7903146 in on insulin secretion ( = 0.0024) after correction for multiple testing. Three further SNP's showed nominally significant interactions ( < 0.05). In the hyperglycemic clamp study, rs7903146 in also interacted with rs17681684 on AUC C-peptide during the GLP-1 stimulation phase, thereby replicating the above finding. The findings exemplify the role of SNP x SNP interactions in the genetics of type 2 diabetes mellitus and corroborate the existence of clinically relevant differences in incretin sensitivity.
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http://dx.doi.org/10.3389/fendo.2019.00072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393347PMC
February 2019

A Polygenic Risk Score of Lipolysis-Increasing Alleles Determines Visceral Fat Mass and Proinsulin Conversion.

J Clin Endocrinol Metab 2019 04;104(4):1090-1098

German Center for Diabetes Research (DZD), Neuherberg, Germany.

Context: Primary dysregulation of adipose tissue lipolysis caused by genetic variation and independent of insulin resistance could explain unhealthy body fat distribution and its metabolic consequences.

Objective: To analyze common single nucleotide polymorphisms (SNPs) in 48 lipolysis-, but not insulin-signaling-related genes, to form polygenic risk scores of lipolysis-associated SNPs, and to investigate their effects on body fat distribution, glycemia, insulin sensitivity, insulin secretion, and proinsulin conversion.

Study Design, Participants, And Methods: SNP array, anthropometric, and metabolic data were available from up to 2789 participants without diabetes of the Tübingen Family study of type 2 diabetes characterized by oral glucose tolerance tests. In a subgroup (n = 942), magnetic resonance measurements of body fat stores were available.

Results: We identified insulin-sensitivity-independent nominal associations (P < 0.05) of SNPs in 10 genes with plasma free fatty acids (FFAs), in 7 genes with plasma glycerol and in 6 genes with both, plasma FFAs and glycerol. A score formed of the latter SNPs (in ADCY4, CIDEA, GNAS, PDE8B, PRKAA1, PRKAG2) was associated with plasma FFA and glycerol measurements (1.4*10-9 ≤ P ≤ 1.2*10-5), visceral adipose tissue mass (P = 0.0326), and proinsulin conversion (P ≤ 0.0272). The more lipolysis-increasing alleles a subject had, the lower was the visceral fat mass and the lower the proinsulin conversion.

Conclusions: We found evidence for a genetic basis of adipose tissue lipolysis resulting from common SNPs in CIDEA, AMP-activated protein kinase subunits, and cAMP signaling components. A genetic score of lipolysis-increasing alleles determined lower visceral fat mass and lower proinsulin conversion.
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http://dx.doi.org/10.1210/jc.2018-02042DOI Listing
April 2019

ADAMTS9 Regulates Skeletal Muscle Insulin Sensitivity Through Extracellular Matrix Alterations.

Diabetes 2019 03 9;68(3):502-514. Epub 2019 Jan 9.

Section for Metabolic Receptology, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

The rs4607103 C allele is one of the few gene variants proposed to increase the risk of type 2 diabetes through an impairment of insulin sensitivity. We show that the variant is associated with increased expression of the secreted ADAMTS9 and decreased insulin sensitivity and signaling in human skeletal muscle. In line with this, mice lacking selectively in skeletal muscle have improved insulin sensitivity. The molecular link between ADAMTS9 and insulin signaling was characterized further in a model where ADAMTS9 was overexpressed in skeletal muscle. This selective overexpression resulted in decreased insulin signaling presumably mediated through alterations of the integrin β1 signaling pathway and disruption of the intracellular cytoskeletal organization. Furthermore, this led to impaired mitochondrial function in mouse muscle-an observation found to be of translational character because humans carrying the risk allele have decreased expression of mitochondrial markers. Finally, we found that the link between ADAMTS9 overexpression and impaired insulin signaling could be due to accumulation of harmful lipid intermediates. Our findings contribute to the understanding of the molecular mechanisms underlying insulin resistance and type 2 diabetes and point to inhibition of ADAMTS9 as a potential novel mode of treating insulin resistance.
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http://dx.doi.org/10.2337/db18-0418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6385758PMC
March 2019

Preadipocytes of obese humans display gender-specific bioenergetic responses to glucose and insulin.

Mol Metab 2019 02 26;20:28-37. Epub 2018 Nov 26.

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), Neuherberg, Germany; Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry, Eberhard Karls University Tübingen, Tübingen, Germany.

Background/objectives: Although the prevalence of obesity and its associated metabolic disorders is increasing in both sexes, the clinical phenotype differs between men and women, highlighting the need for individual treatment options. Mitochondrial dysfunction in various tissues, including white adipose tissue (WAT), has been accepted as a key factor for obesity-associated comorbidities such as diabetes. Given higher expression of mitochondria-related genes in the WAT of women, we hypothesized that gender differences in the bioenergetic profile of white (pre-) adipocytes from obese (age- and BMI-matched) donors must exist.

Subjects/methods: Using Seahorse technology, we measured oxygen consumption rates (OCR) and extracellular acidification rates (ECAR) of (pre-)adipocytes from male (n = 10) and female (n = 10) deeply-phenotyped obese donors under hypo-, normo- and hyperglycemic (0, 5 and 25 mM glucose) and insulin-stimulated conditions. Additionally, expression levels (mRNA/protein) of mitochondria-related genes (e.g. UQCRC2) and glycolytic enzymes (e.g. PKM2) were determined.

Results: Dissecting cellular OCR and ECAR into different functional modules revealed that preadipocytes from female donors show significantly higher mitochondrial to glycolytic activity (higher OCR/ECAR ratio, p = 0.036), which is supported by a higher ratio of UQCRC2 to PKM2 mRNA levels (p = 0.021). However, no major gender differences are detectable in in vitro differentiated adipocytes (e.g. OCR/ECAR, p = 0.248). Importantly, glucose and insulin suppress mitochondrial activity (i.e. ATP-linked respiration) significantly only in preadipocytes of female donors, reflecting their trends towards higher insulin sensitivity.

Conclusions: Collectively, we show that preadipocytes, but not in vitro differentiated adipocytes, represent a model system to reveal gender differences with clinical importance for metabolic disease status. In particular preadipocytes of females maintain enhanced mitochondrial flexibility, as demonstrated by pronounced responses of ATP-linked respiration to glucose.
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http://dx.doi.org/10.1016/j.molmet.2018.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358537PMC
February 2019

Genome-Wide and Abdominal MRI Data Provide Evidence That a Genetically Determined Favorable Adiposity Phenotype Is Characterized by Lower Ectopic Liver Fat and Lower Risk of Type 2 Diabetes, Heart Disease, and Hypertension.

Diabetes 2019 01 23;68(1):207-219. Epub 2018 Oct 23.

Section of Investigative Medicine, Imperial College London, London, U.K.

Recent genetic studies have identified alleles associated with opposite effects on adiposity and risk of type 2 diabetes. We aimed to identify more of these variants and test the hypothesis that such favorable adiposity alleles are associated with higher subcutaneous fat and lower ectopic fat. We combined MRI data with genome-wide association studies of body fat percentage (%) and metabolic traits. We report 14 alleles, including 7 newly characterized alleles, associated with higher adiposity but a favorable metabolic profile. Consistent with previous studies, individuals carrying more favorable adiposity alleles had higher body fat % and higher BMI but lower risk of type 2 diabetes, heart disease, and hypertension. These individuals also had higher subcutaneous fat but lower liver fat and a lower visceral-to-subcutaneous adipose tissue ratio. Individual alleles associated with higher body fat % but lower liver fat and lower risk of type 2 diabetes included those in , , and , whereas the allele in was paradoxically associated with higher visceral fat but lower risk of type 2 diabetes. Most identified favorable adiposity alleles are associated with higher subcutaneous and lower liver fat, a mechanism consistent with the beneficial effects of storing excess triglycerides in metabolically low-risk depots.
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http://dx.doi.org/10.2337/db18-0708DOI Listing
January 2019

The Expression of Aldolase B in Islets Is Negatively Associated With Insulin Secretion in Humans.

J Clin Endocrinol Metab 2018 12;103(12):4373-4383

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

Context: Reduced β-cell mass, impaired islet function, and dedifferentiation are considered causal to development of hyperglycemia and type 2 diabetes. In human cohort studies, changes of islet cell-specific expression patterns have been associated with diabetes but not directly with in vivo insulin secretion.

Objective: This study investigates alterations of islet gene expression and corresponding gene variants in the context of in vivo glycemic traits from the same patients.

Methods: Fasting blood was collected before surgery, and pancreatic tissue was frozen after resection from 18 patients undergoing pancreatectomy. Islet tissue was isolated by laser capture microdissection. Islet transcriptome was analyzed using microarray and quantitative RT-PCR. Proteins were examined by immunohistochemistry and western blotting. The association of gene variants with insulin secretion was investigated with oral glucose tolerance test (OGTT)-derived insulin secretion measured in a large cohort of subjects at increased risk of type 2 diabetes and with hyperglycemic clamp in a subset.

Results: Differential gene expression between islets from normoglycemic and hyperglycemic patients was prominent for the glycolytic enzyme ALDOB and the obesity-associated gene FAIM2. The mRNA levels of both genes correlated negatively with insulin secretion and positively with HbA1c. Islets of hyperglycemic patients displayed increased ALDOB immunoreactivity in insulin-positive cells, whereas α- and δ-cells were negative. Exposure of isolated islets to hyperglycemia augmented ALDOB expression. The minor allele of the ALDOB variant rs550915 associated with significantly higher levels of C-peptide and insulin during OGTT and hyperglycemic clamp, respectively.

Conclusion: Our analyses suggest that increased ALDOB expression in human islets is associated with lower insulin secretion.
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http://dx.doi.org/10.1210/jc.2018-00791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6915830PMC
December 2018

Chronic d-serine supplementation impairs insulin secretion.

Mol Metab 2018 10 25;16:191-202. Epub 2018 Jul 25.

RG Adipocytes & Metabolism, Institute for Diabetes & Obesity, Helmholtz Center Munich, 85748 Garching, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany. Electronic address:

Objective: The metabolic role of d-serine, a non-proteinogenic NMDA receptor co-agonist, is poorly understood. Conversely, inhibition of pancreatic NMDA receptors as well as loss of the d-serine producing enzyme serine racemase have been shown to modulate insulin secretion. Thus, we aim to study the impact of chronic and acute d-serine supplementation on insulin secretion and other parameters of glucose homeostasis.

Methods: We apply MALDI FT-ICR mass spectrometry imaging, NMR based metabolomics, 16s rRNA gene sequencing of gut microbiota in combination with a detailed physiological characterization to unravel the metabolic action of d-serine in mice acutely and chronically treated with 1% d-serine in drinking water in combination with either chow or high fat diet feeding. Moreover, we identify SNPs in SRR, the enzyme converting L-to d-serine and two subunits of the NMDA receptor to associate with insulin secretion in humans, based on the analysis of 2760 non-diabetic Caucasian individuals.

Results: We show that chronic elevation of d-serine results in reduced high fat diet intake. In addition, d-serine leads to diet-independent hyperglycemia due to blunted insulin secretion from pancreatic beta cells. Inhibition of alpha 2-adrenergic receptors rapidly restores glycemia and glucose tolerance in d-serine supplemented mice. Moreover, we show that single nucleotide polymorphisms (SNPs) in SRR as well as in individual NMDAR subunits are associated with insulin secretion in humans.

Conclusion: Thus, we identify a novel role of d-serine in regulating systemic glucose metabolism through modulating insulin secretion.
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http://dx.doi.org/10.1016/j.molmet.2018.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6157639PMC
October 2018

BMI-Independent Effects of Gestational Diabetes on Human Placenta.

J Clin Endocrinol Metab 2018 09;103(9):3299-3309

Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at Eberhard Karls University Tübingen, Tübingen, Germany.

Purpose: Recently, alterations in maternal lipid metabolism were associated with gestational diabetes mellitus (GDM). However, detailed plasma lipid profiles and their relevance for placental and fetal metabolism are currently not understood.

Methods: Maternal and placental lipid profiles were characterized in women with GDM and women with normal glucose tolerance (NGT). Inflammatory gene expression was compared in placentas and primary term trophoblasts between the groups. In addition, trophoblasts were stimulated with nonesterified fatty acids (NEFAs), and effects on gene expression were quantified. Finally, placental macrophage content and cord blood concentrations of inflammatory parameters and NEFAs were compared between women with GDM and women with NGT with similar body mass index (BMI).

Results: Palmitate and stearate levels were elevated in both maternal plasma and placental tissue of women with GDM. Placental GDM-associated elevations of IL6, IL8, and TLR2 expression were reflected in trophoblasts derived from women with GDM. Stimulation of primary trophoblasts with palmitate led to increased mRNA expression and protein release of the cytokine IL6 and the chemokine IL8. In line with this, elevated amounts of CD68-positive cells were quantified in the placental tissue of women with GDM. No GDM-associated elevations in a range of inflammatory parameters and NEFAs in cord blood of NGT vs GDM neonates was found.

Conclusions: GDM, independently of BMI, altered maternal plasma NEFAs and the placental lipid profile. GDM was associated with trophoblast and whole-placenta lipoinflammation; however, this was not accompanied by elevated concentrations of inflammatory cytokines or NEFAs in neonatal cord blood.
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http://dx.doi.org/10.1210/jc.2018-00397DOI Listing
September 2018

Single Nucleotide Polymorphisms in the G-Protein Coupled Receptor Kinase 5 (GRK5) Gene are associated with Plasma LDL-Cholesterol Levels in Humans.

Sci Rep 2018 05 17;8(1):7745. Epub 2018 May 17.

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

Genetically modified mice models suggest an important role for G-protein-coupled receptor kinase 5 (GRK5) in the pathophysiology of obesity and related disorders. We investigated whether single nucleotide polymorphisms (SNPs) in the gene encoding GRK5 affect cardiometabolic traits in humans. We genotyped 3 common SNPs in intron 1 (rs1980030, rs10466210, rs9325562) and one SNP in intron 3 (rs10886471) of GRK5 in 2332 subjects at risk for type 2 diabetes. Total- and visceral fat mass were measured by magnetic resonance (MR) tomography and liver fat content by H-MR spectroscopy. Insulin secretion and sensitivity were estimated during an OGTT and measured during the euglycemic, hyperinsulinemic clamp (n = 498). Carriers of the minor allele of rs10466210 and rs1980030 had higher total- and LDL-cholesterol levels (p = 0.0018 and p = 0.0031, respectively, for rs10466210; p = 0.0035 and p = 0.0081, respectively, for rs1980030), independently of gender, age, BMI and lipid-lowering drugs. The effects of rs10466210 withstood Bonferroni correction. Similar associations were observed with apolipoprotein B levels (p = 0.0034 and p = 0.0122, respectively). Carriers of the minor allele of rs10466210 additionally displayed a trend for higher intima-media thickness of the carotid artery (p = 0.075). GRK5 may represent a novel target for strategies aiming at lowering LDL-cholesterol levels and at modifying cardiovascular risk.
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http://dx.doi.org/10.1038/s41598-018-26055-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5958094PMC
May 2018

A computational biology approach of a genome-wide screen connected miRNAs to obesity and type 2 diabetes.

Mol Metab 2018 05 15;11:145-159. Epub 2018 Mar 15.

German Institute of Human Nutrition Potsdam-Rehbruecke, Department of Experimental Diabetology, 14558, Nuthetal, Germany; German Center for Diabetes Research (DZD), 85764, München-Neuherberg, Germany. Electronic address:

Objective: Obesity and type 2 diabetes (T2D) arise from the interplay between genetic, epigenetic, and environmental factors. The aim of this study was to combine bioinformatics and functional studies to identify miRNAs that contribute to obesity and T2D.

Methods: A computational framework (miR-QTL-Scan) was applied by combining QTL, miRNA prediction, and transcriptomics in order to enhance the power for the discovery of miRNAs as regulative elements. Expression of several miRNAs was analyzed in human adipose tissue and blood cells and miR-31 was manipulated in a human fat cell line.

Results: In 17 partially overlapping QTL for obesity and T2D 170 miRNAs were identified. Four miRNAs (miR-15b, miR-30b, miR-31, miR-744) were recognized in gWAT (gonadal white adipose tissue) and six (miR-491, miR-455, miR-423-5p, miR-132-3p, miR-365-3p, miR-30b) in BAT (brown adipose tissue). To provide direct functional evidence for the achievement of the miR-QTL-Scan, miR-31 located in the obesity QTL Nob6 was experimentally analyzed. Its expression was higher in gWAT of obese and diabetic mice and humans than of lean controls. Accordingly, 10 potential target genes involved in insulin signaling and adipogenesis were suppressed. Manipulation of miR-31 in human SGBS adipocytes affected the expression of GLUT4, PPARγ, IRS1, and ACACA. In human peripheral blood mononuclear cells (PBMC) miR-15b levels were correlated to baseline blood glucose concentrations and might be an indicator for diabetes.

Conclusion: Thus, miR-QTL-Scan allowed the identification of novel miRNAs relevant for obesity and T2D.
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http://dx.doi.org/10.1016/j.molmet.2018.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6001404PMC
May 2018

Pharmacogenetics of oral antidiabetic therapy.

Pharmacogenomics 2018 04 27;19(6):577-587. Epub 2018 Mar 27.

Institute for Diabetes Research & Metabolic Diseases of the Helmholtz Centre Munich at the Eberhard Karls University Tübingen, Germany.

Type 2 diabetes prevalence is still on the rise worldwide. Antidiabetic drugs are widely prescribed to patients with Type 2 diabetes. Most patients start with metformin which is mostly well tolerated. However, a high percentage of patients fail to achieve glycemic control. The effectiveness of metformin as well as most other antidiabetic drugs depends among other factors on interindividual genetic differences that are up to now ignored in the treatment of Type 2 diabetes. Interestingly, many genes influencing the effectiveness of antidiabetic drugs are Type 2 diabetes risk genes making matters worse. Here, we shed light on these interindividual genetic differences.
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http://dx.doi.org/10.2217/pgs-2017-0195DOI Listing
April 2018

Effects of resveratrol supplementation on liver fat content in overweight and insulin-resistant subjects: A randomized, double-blind, placebo-controlled clinical trial.

Diabetes Obes Metab 2018 07 22;20(7):1793-1797. Epub 2018 Mar 22.

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

We performed the largest randomized, placebo-controlled clinical trial to date (N = 112, 12-week intervention) to investigate the effects and safety of resveratrol supplementation on liver fat content and cardiometabolic risk parameters in overweight and obese and insulin-resistant subjects. At baseline the variability in liver fat content was very large, ranging from 0.09% to 37.55% (median, 7.12%; interquartile range, 3.85%-12.94%). Mean (SD) liver fat content was 9.22 (6.85) % in the placebo group and 9.91 (7.76) % in the resveratrol group. During the study liver fat content decreased in the placebo group (-0.7%) but not in the resveratrol group (-0.03%) (differences between groups: P = .018 for the intention-to-treat [ITT] population; N = 54, resveratrol, N = 54, placebo and P = .0077 for the per protocol [PP] population). No effects of resveratrol supplementation on cardiometabolic risk parameters were observed. Resveratrol supplementation was well tolerated and safe. In conclusion, these data suggest that resveratrol supplementation is safe and that it does not considerably impact liver fat content or cardiometabolic risk parameters in humans.
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http://dx.doi.org/10.1111/dom.13268DOI Listing
July 2018

Increased Ifi202b/IFI16 expression stimulates adipogenesis in mice and humans.

Diabetologia 2018 05 24;61(5):1167-1179. Epub 2018 Feb 24.

Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Arthur-Scheunert-Allee 114-116, D-14558, Nuthetal, Germany.

Aims/hypothesis: Obesity results from a constant and complex interplay between environmental stimuli and predisposing genes. Recently, we identified the IFN-activated gene Ifi202b as the most likely gene responsible for the obesity quantitative trait locus Nob3 (New Zealand Obese [NZO] obesity 3). The aim of this study was to evaluate the effects of Ifi202b on body weight and adipose tissue biology, and to clarify the functional role of its human orthologue IFI16.

Methods: The impact of Ifi202b and its human orthologue IFI16 on adipogenesis was investigated by modulating their respective expression in murine 3T3-L1 and human Simpson-Golabi-Behmel syndrome (SGBS) pre-adipocytes. Furthermore, transgenic mice overexpressing IFI202b were generated and characterised with respect to metabolic traits. In humans, expression levels of IFI16 in adipose tissue were correlated with several variables of adipocyte function.

Results: In mice, IFI202b overexpression caused obesity (Δ body weight at the age of 30 weeks: 10.2 ± 1.9 g vs wild-type mice) marked by hypertrophic fat mass expansion, increased expression of Zfp423 (encoding the transcription factor zinc finger protein [ZFP] 423) and white-selective genes (Tcf21, Tle3), and decreased expression of thermogenic genes (e.g. Cidea, Ucp1). Compared with their wild-type littermates, Ifi202b transgenic mice displayed lower body temperature, hepatosteatosis and systemic insulin resistance. Suppression of IFI202b/IFI16 in pre-adipocytes impaired adipocyte differentiation and triacylglycerol storage. Humans with high levels of IFI16 exhibited larger adipocytes, an enhanced inflammatory state and impaired insulin-stimulated glucose uptake in white adipose tissue.

Conclusions/interpretation: Our findings reveal novel functions of Ifi202b and IFI16, demonstrating their role as obesity genes. These genes promote white adipogenesis and fat storage, thereby facilitating the development of obesity-associated insulin resistance.
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http://dx.doi.org/10.1007/s00125-018-4571-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6448999PMC
May 2018

Serine/threonine protein kinase 25 antisense oligonucleotide treatment reverses glucose intolerance, insulin resistance, and nonalcoholic fatty liver disease in mice.

Hepatol Commun 2018 01 20;2(1):69-83. Epub 2017 Nov 20.

Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Institute of Medicine University of Gothenburg, Sahlgrenska University Hospital Gothenburg Sweden.

Nonalcoholic fatty liver disease (NAFLD) contributes to the pathogenesis of type 2 diabetes and cardiovascular disease, and patients with nonalcoholic steatohepatitis (NASH) are also at risk of developing cirrhosis, liver failure, and hepatocellular carcinoma. To date, no specific therapy exists for NAFLD/NASH, which has been recognized as one of the major unmet medical needs of the twenty-first century. We recently identified serine/threonine protein kinase (STK)25 as a critical regulator of energy homeostasis and NAFLD progression. Here, we investigated the effect of antisense oligonucleotides (ASOs) targeting on the metabolic and molecular phenotype of mice after chronic exposure to dietary lipids. We found that ASOs efficiently reversed high-fat diet-induced systemic hyperglycemia and hyperinsulinemia, improved whole-body glucose tolerance and insulin sensitivity, and ameliorated liver steatosis, inflammatory infiltration, apoptosis, hepatic stellate cell activation, and nutritional fibrosis in obese mice. Moreover, ASOs suppressed the abundance of liver acetyl-coenzyme A carboxylase (ACC) protein, a key regulator of both lipid oxidation and synthesis, revealing the likely mechanism underlying repression of hepatic fat accumulation by ASO treatment. We also found that STK25 protein levels correlate significantly and positively with NASH development in human liver biopsies, and several common nonlinked single-nucleotide polymorphisms in the human gene are associated with altered liver fat, supporting a critical role of STK25 in the pathogenesis of NAFLD in humans. : Preclinical validation for the metabolic benefit of pharmacologically inhibiting STK25 in the context of obesity is provided. Therapeutic intervention aimed at reducing STK25 function may provide a new strategy for the treatment of patients with NAFLD, type 2 diabetes, and related complex metabolic diseases. ( 2018;2:69-83).
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http://dx.doi.org/10.1002/hep4.1128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5776874PMC
January 2018

Genome-wide analysis of PDX1 target genes in human pancreatic progenitors.

Mol Metab 2018 03 31;9:57-68. Epub 2018 Jan 31.

Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Parkring 11, 85748, Garching, Germany; Institute of Stem Cell Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Chair of ß-Cell Biology, Technische Universität München, Ismaningerstraße 22, 81675 München, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany. Electronic address:

Objective: Homozygous loss-of-function mutations in the gene coding for the homeobox transcription factor (TF) PDX1 leads to pancreatic agenesis, whereas heterozygous mutations can cause Maturity-Onset Diabetes of the Young 4 (MODY4). Although the function of Pdx1 is well studied in pre-clinical models during insulin-producing β-cell development and homeostasis, it remains elusive how this TF controls human pancreas development by regulating a downstream transcriptional program. Also, comparative studies of PDX1 binding patterns in pancreatic progenitors and adult β-cells have not been conducted so far. Furthermore, many studies reported the association between single nucleotide polymorphisms (SNPs) and T2DM, and it has been shown that islet enhancers are enriched in T2DM-associated SNPs. Whether regions, harboring T2DM-associated SNPs are PDX1 bound and active at the pancreatic progenitor stage has not been reported so far.

Methods: In this study, we have generated a novel induced pluripotent stem cell (iPSC) line that efficiently differentiates into human pancreatic progenitors (PPs). Furthermore, PDX1 and H3K27ac chromatin immunoprecipitation sequencing (ChIP-seq) was used to identify PDX1 transcriptional targets and active enhancer and promoter regions. To address potential differences in the function of PDX1 during development and adulthood, we compared PDX1 binding profiles from PPs and adult islets. Moreover, combining ChIP-seq and GWAS meta-analysis data we identified T2DM-associated SNPs in PDX1 binding sites and active chromatin regions.

Results: ChIP-seq for PDX1 revealed a total of 8088 PDX1-bound regions that map to 5664 genes in iPSC-derived PPs. The PDX1 target regions include important pancreatic TFs, such as PDX1 itself, RFX6, HNF1B, and MEIS1, which were activated during the differentiation process as revealed by the active chromatin mark H3K27ac and mRNA expression profiling, suggesting that auto-regulatory feedback regulation maintains PDX1 expression and initiates a pancreatic TF program. Remarkably, we identified several PDX1 target genes that have not been reported in the literature in human so far, including RFX3, required for ciliogenesis and endocrine differentiation in mouse, and the ligand of the Notch receptor DLL1, which is important for endocrine induction and tip-trunk patterning. The comparison of PDX1 profiles from PPs and adult human islets identified sets of stage-specific target genes, associated with early pancreas development and adult β-cell function, respectively. Furthermore, we found an enrichment of T2DM-associated SNPs in active chromatin regions from iPSC-derived PPs. Two of these SNPs fall into PDX1 occupied sites that are located in the intronic regions of TCF7L2 and HNF1B. Both of these genes are key transcriptional regulators of endocrine induction and mutations in cis-regulatory regions predispose to diabetes.

Conclusions: Our data provide stage-specific target genes of PDX1 during in vitro differentiation of stem cells into pancreatic progenitors that could be useful to identify pathways and molecular targets that predispose for diabetes. In addition, we show that T2DM-associated SNPs are enriched in active chromatin regions at the pancreatic progenitor stage, suggesting that the susceptibility to T2DM might originate from imperfect execution of a β-cell developmental program.
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http://dx.doi.org/10.1016/j.molmet.2018.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870105PMC
March 2018

Maternal whole blood cell miRNA-340 is elevated in gestational diabetes and inversely regulated by glucose and insulin.

Sci Rep 2018 01 22;8(1):1366. Epub 2018 Jan 22.

Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the Eberhard Karls University Tübingen, Tübingen, Germany.

The number of pregnancies complicated by gestational diabetes (GDM) is increasing worldwide. To identify novel characteristics of GDM, we studied miRNA profiles of maternal and fetal whole blood cells (WBCs) from GDM and normal glucose tolerant (NGT) pregnant women matched for body mass index and maternal age. After adjustment for maternal weight gain and pregnancy week, we identified 29 mature micro-RNAs (miRNAs) up-regulated in GDM, one of which, i.e., miRNA-340, was validated by qPCR. mRNA and protein expression of PAIP1, a miRNA-340 target gene, was found down-regulated in GDM women, accordingly. In lymphocytes derived from the mothers' blood and treated in vitro, insulin increased and glucose reduced miRNA-340 expression. In fetal cord blood samples, no associations of miRNA-340 with maternal GDM were observed. Our results provide evidence for insulin-induced epigenetic, i.e., miRNA-dependent, programming of maternal WBCs in GDM.
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http://dx.doi.org/10.1038/s41598-018-19200-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5778051PMC
January 2018

Identification of genetic elements in metabolism by high-throughput mouse phenotyping.

Nat Commun 2018 01 18;9(1):288. Epub 2018 Jan 18.

Monterotondo Mouse Clinic, Italian National Research Council (CNR), Institute of Cell Biology and Neurobiology, Adriano Buzzati-Traverso Campus, Via E. Ramarini 32, Monterotondo Scalo, RM, 00015, Italy.

Metabolic diseases are a worldwide problem but the underlying genetic factors and their relevance to metabolic disease remain incompletely understood. Genome-wide research is needed to characterize so-far unannotated mammalian metabolic genes. Here, we generate and analyze metabolic phenotypic data of 2016 knockout mouse strains under the aegis of the International Mouse Phenotyping Consortium (IMPC) and find 974 gene knockouts with strong metabolic phenotypes. 429 of those had no previous link to metabolism and 51 genes remain functionally completely unannotated. We compared human orthologues of these uncharacterized genes in five GWAS consortia and indeed 23 candidate genes are associated with metabolic disease. We further identify common regulatory elements in promoters of candidate genes. As each regulatory element is composed of several transcription factor binding sites, our data reveal an extensive metabolic phenotype-associated network of co-regulated genes. Our systematic mouse phenotype analysis thus paves the way for full functional annotation of the genome.
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http://dx.doi.org/10.1038/s41467-017-01995-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773596PMC
January 2018

Higher prevalence of lymph node metastasis in prostate cancer in patients with diabetes.

Endocr Relat Cancer 2018 03 12;25(3):L19-L22. Epub 2018 Jan 12.

Department of Internal MedicineDivision of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University of Tübingen, Tübingen, Germany.

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http://dx.doi.org/10.1530/ERC-17-0465DOI Listing
March 2018

Integrative network analysis highlights biological processes underlying GLP-1 stimulated insulin secretion: A DIRECT study.

PLoS One 2018 2;13(1):e0189886. Epub 2018 Jan 2.

Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.

Glucagon-like peptide 1 (GLP-1) stimulated insulin secretion has a considerable heritable component as estimated from twin studies, yet few genetic variants influencing this phenotype have been identified. We performed the first genome-wide association study (GWAS) of GLP-1 stimulated insulin secretion in non-diabetic individuals from the Netherlands Twin register (n = 126). This GWAS was enhanced using a tissue-specific protein-protein interaction network approach. We identified a beta-cell protein-protein interaction module that was significantly enriched for low gene scores based on the GWAS P-values and found support at the network level in an independent cohort from Tübingen, Germany (n = 100). Additionally, a polygenic risk score based on SNPs prioritized from the network was associated (P < 0.05) with glucose-stimulated insulin secretion phenotypes in up to 5,318 individuals in MAGIC cohorts. The network contains both known and novel genes in the context of insulin secretion and is enriched for members of the focal adhesion, extracellular-matrix receptor interaction, actin cytoskeleton regulation, Rap1 and PI3K-Akt signaling pathways. Adipose tissue is, like the beta-cell, one of the target tissues of GLP-1 and we thus hypothesized that similar networks might be functional in both tissues. In order to verify peripheral effects of GLP-1 stimulation, we compared the transcriptome profiling of ob/ob mice treated with liraglutide, a clinically used GLP-1 receptor agonist, versus baseline controls. Some of the upstream regulators of differentially expressed genes in the white adipose tissue of ob/ob mice were also detected in the human beta-cell network of genes associated with GLP-1 stimulated insulin secretion. The findings provide biological insight into the mechanisms through which the effects of GLP-1 may be modulated and highlight a potential role of the beta-cell expressed genes RYR2, GDI2, KIAA0232, COL4A1 and COL4A2 in GLP-1 stimulated insulin secretion.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0189886PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5749727PMC
January 2018

Androgen receptor overexpression in prostate cancer in type 2 diabetes.

Mol Metab 2018 02 5;8:158-166. Epub 2017 Dec 5.

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

Objective: While prostate cancer does not occur more often in men with diabetes, survival is markedly reduced in this patient group. Androgen signaling is a known and major driver for prostate cancer progression. Therefore, we analyzed major components of the androgen signaling chain and cell proliferation in relation to type 2 diabetes.

Methods: Tumor content of 70 prostate tissue samples of men with type 2 diabetes and 59 samples of patients without diabetes was quantified by an experienced pathologist, and a subset of 51 samples was immunohistochemically stained for androgen receptor (AR). mRNA expression of AR, insulin receptor isoform A (IR-A) and B (IR-B), IGF-1 receptor (IGF1R), Cyp27A1 and Cyp7B1, PSA gene KLK3, PSMA gene FOLH1, Ki-67 gene MKI67, and estrogen receptor beta (ESR2) were analyzed by RT-qPCR.

Results: AR mRNA and protein expression were associated with the tumor content only in men with diabetes. AR expression also correlated with downstream targets PSA (KLK3) and PSMA (FOLH1) and increased cell proliferation. Only in diabetes, AR expression was correlated to higher IR-A/IR-B ratio and lower IR-B/IGF1R ratio, thus, in favor of the mitogenic isoforms. Reduced Cyp27A1 and increased Cyp7B1 expressions in tumor suggest lower levels of protective estrogen receptor ligands in diabetes.

Conclusions: We report elevated androgen receptor signaling and activity presumably due to altered insulin/IGF-1 receptors and decreased levels of protective estrogen receptor ligands in prostate cancer in men with diabetes. Our results reveal new insights why these patients have a worse prognosis. These findings provide the basis for future clinical trials to investigate treatment response in patients with prostate cancer and diabetes.
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http://dx.doi.org/10.1016/j.molmet.2017.11.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985051PMC
February 2018

Excessive fuel availability amplifies the FTO-mediated obesity risk: results from the TUEF and Whitehall II studies.

Sci Rep 2017 11 14;7(1):15486. Epub 2017 Nov 14.

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

Variation in FTO is the most important common genetic determinant of body weight. Altered energy metabolism could underlie this association. We hypothesized that higher circulating glucose or triglycerides can amplify the FTO impact on BMI. In 2671 subjects of the TUEF study, we investigated the interaction effect of fasting glucose and triglyceride levels with rs9939609 in FTO on BMI. We analysed the same interaction effect by longitudinally utilizing mixed effect models in the prospective Whitehall II study. In TUEF, we detected an interaction effect between fasting glucose and fasting triglycerides with rs9939609 on BMI (p = 0.0005 and p = 5 × 10, respectively). The effect size of one risk allele was 1.4 ± 0.3 vs. 2.2 ± 0.44 kg/m² in persons with fasting glucose levels below and above the median, respectively. Fasting triglycerides above the median increased the per-allele effect from 1.4 ± 0.3 to 1.7 ± 0.4 kg/m. In the Whitehall II study, body weight increased by 2.96 ± 6.5 kg during a follow-up of 13.5 ± 4.6 yrs. Baseline fasting glucose and rs9939609 interacted on weight change (p = 0.009). Higher fasting glucose levels may amplify obesity-risk in FTO carriers and lead to an exaggerated weight gain over time. Since weight gain perpetuates metabolic alterations, this interplay may trigger a vicious circle that leads to obesity and diabetes.
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http://dx.doi.org/10.1038/s41598-017-15744-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5686126PMC
November 2017