Fasting-sensitive SUMO-switch on Prox1 controls hepatic cholesterol metabolism.

Accumulation of excess nutrients hampers proper liver function and is linked to nonalcoholic fatty liver disease (NAFLD) in obesity. However, the signals responsible for an impaired adaptation of hepatocytes to obesogenic dietary cues remain still largely unknown. Post-translational modification by the small ubiquitin-like modifier (SUMO) allows for a dynamic regulation of numerous processes including transcriptional reprogramming. We demonstrate that specific SUMOylation of transcription factor Prox1 represents a nutrient-sensitive determinant of hepatic fasting metabolism. Prox1 is highly SUMOylated on lysine 556 in the liver of ad libitum and refed mice, while this modification is abolished upon fasting. In the context of diet-induced obesity, Prox1 SUMOylation becomes less sensitive to fasting cues. The hepatocyte-selective knock-in of a SUMOylation-deficient Prox1 mutant into mice fed a high-fat/high-fructose diet leads to a reduction of systemic cholesterol levels, associated with the induction of liver bile acid detoxifying pathways during fasting. The generation of tools to maintain the nutrient-sensitive SUMO-switch on Prox1 may thus contribute to the development of "fasting-based" approaches for the preservation of metabolic health.

Development of a peptide drug restoring AMPK and adipose tissue functionality in cancer cachexia.

Cancer cachexia is a severe systemic wasting disease that negatively affects quality of life and survival in patients with cancer. To date, treating cancer cachexia is still a major unmet clinical need. We recently discovered the destabilization of the AMP-activated protein kinase (AMPK) complex in adipose tissue as a key event in cachexia-related adipose tissue dysfunction and developed an adeno-associated virus (AAV)-based approach to prevent AMPK degradation and prolong cachexia-free survival. Here, we show the development and optimization of a prototypic peptide, Pen-X-ACIP, where the AMPK-stabilizing peptide ACIP is fused to the cell-penetrating peptide moiety penetratin via a propargylic glycine linker to enable late-stage functionalization using click chemistry. Pen-X-ACIP was efficiently taken up by adipocytes, inhibited lipolysis, and restored AMPK signaling. Tissue uptake assays showed a favorable uptake profile into adipose tissue upon intraperitoneal injection. Systemic delivery of Pen-X-ACIP into tumor-bearing animals prevented the progression of cancer cachexia without affecting tumor growth and preserved body weight and adipose tissue mass with no discernable side effects in other peripheral organs, thereby achieving proof of concept. As Pen-X-ACIP also exerted its anti-lipolytic activity in human adipocytes, it now provides a promising platform for further (pre)clinical development toward a novel, first-in-class approach against cancer cachexia.

Walking 200 min per day keeps the bariatric surgeon away.

Exercise and increased physical activity are vital components of the standard treatment guidelines for many chronic diseases such as diabetes, obesity and cardiovascular disease. Although strenuous exercise cannot be recommended to people with numerous chronic conditions, walking is something most people can perform. In comparison to high-intensity training, the metabolic consequences of low-intensity walking have been less well studied. We present here a feasibility study of a subject who performed an exercise intervention of low-intensity, non-fatiguing walking on a deskmill/treadmill for 200 min daily, approximately the average time a German spends watching television per day. This low-impact physical activity has the advantages that it can be done while performing other tasks such as reading or watching TV, and it can be recommended to obese patients or patients with heart disease. We find that this intervention led to substantial weight loss, comparable to that of bariatric surgery. To study the metabolic changes caused by this intervention, we performed an in-depth metabolomic profiling of the blood both directly after walking to assess the acute changes, as well as 1.5 days after physical activity to identify the long-term effects that persist. We find changes in acylcarnitine levels suggesting that walking activates fatty acid beta oxidation, and that this mitochondrial reprogramming is still visible 1.5 days post-walking. We also find that walking mildly increases gut permeability, leading to increased exposure of the blood to metabolites from the gut microbiome. Overall, these data provide a starting point for designing future intervention studies with larger cohorts.

Interaction of mental comorbidity and physical multimorbidity predicts length-of-stay in medical inpatients.

BACKGROUND: Mental comorbidities of physically ill patients lead to higher morbidity, mortality, health-care utilization and costs. OBJECTIVE: The aim of the study was to investigate the impact of mental comorbidity and physical multimorbidity on the length-of-stay in medical inpatients at a maximum-care university hospital. DESIGN: The study follows a retrospective, quantitative cross-sectional analysis approach to investigate mental comorbidity and physical multimorbidity in internal medicine patients. PATIENTS: The study comprised a total of n = 28.553 inpatients treated in 2017, 2018 and 2019 at a German Medical University Hospital. MAIN MEASURES: Inpatients with a mental comorbidity showed a median length-of-stay of eight days that was two days longer compared to inpatients without a mental comorbidity. Neurotic and somatoform disorders (ICD-10 F4), behavioral syndromes (F5) and organic disorders (F0) were leading with respect to length-of-stay, followed by affective disorders (F3), schizophrenia and delusional disorders (F2), and substance use (F1), all above the sample mean length-of-stay. The impact of mental comorbidity on length-of-stay was greatest for middle-aged patients. Mental comorbidity and Elixhauser score as a measure for physical multimorbidity showed a significant interaction effect indicating that the impact of mental comorbidity on length-of-stay was greater in patients with higher Elixhauser scores. CONCLUSIONS: The findings provide new insights in medical inpatients how mental comorbidity and physical multimorbidity interact with respect to length-of-stay. Mental comorbidity had a large effect on length-of-stay, especially in patients with high levels of physical multimorbidity. Thus, there is an urgent need for new service models to especially care for multimorbid inpatients with mental comorbidity.

Receptor autoantibodies: Associations with cardiac markers, histology, and function in human non-ischaemic heart failure.

AIMS: A causal link between non-ischaemic heart failure (HF) and humoral autoimmunity against G-protein-coupled receptors (GPCR) remains unclear except for Chagas' cardiomyopathy. Uncertainty arises from ambiguous reports on incidences of GPCR autoantibodies, spurious correlations of autoantibody levels with disease activity, and lack of standardization and validation of measuring procedures for putatively cardio-pathogenic GPCR autoantibodies. Here, we use validated and certified immune assays presenting native receptors as binding targets. We compared candidate GPCR autoantibody species between HF patients and healthy controls and tested associations of serum autoantibody levels with serological, haemodynamic, metabolic, and functional parameters in HF. METHODS: Ninety-five non-ischaemic HF patients undergoing transcatheter endomyocardial biopsy and 60 healthy controls were included. GPCR autoantibodies were determined in serum by IgG binding to native receptors or a cyclic peptide (for ß1AR autoantibodies). In patients, cardiac function, volumes, and myocardial structural properties were assessed by cardiac magnetic resonance imaging; right heart catheterization served for determination of cardiac haemodynamics; endomyocardial biopsies were used for histological assessment of cardiomyopathy and determination of cardiac mitochondrial oxidative function by high-resolution respirometry. RESULTS: Autoantibodies against ß1 adrenergic (ß1 AR) , M5-muscarinic (M5AR), and angiotensin II type 2 receptors (AT2R) were increased in HF (all P < 0.001). Autoantibodies against α1 -adrenergic (α1 AR) and angiotensin II type 1 receptors (AT1R) were decreased in HF (all P < 0.001). Correlation of alterations of GPCR autoantibodies with markers of cardiac or systemic inflammation or cardiac damage, haemodynamics, myocardial histology, or left ventricular inflammation (judged by T2 mapping) were weak, even when corrected for total IgG. ß1 AR autoantibodies were related inversely to markers of left ventricular fibrosis indicated by T1 mapping (r = -0.362, P < 0.05) and global longitudinal strain (r = -0.323, P < 0.05). AT2R autoantibodies were associated with improved myocardial mitochondrial coupling as measured by high-resolution respirometry in myocardial biopsies (r = -0.352, P < 0.05). In insulin-resistant HF patients, AT2R autoantibodies were decreased (r = -.240, P < 0.05), and AT1R autoantibodies were increased (r = 0.212, P < 0.05). CONCLUSIONS: GPCR autoantibodies are markedly altered in HF. However, they are correlated poorly or even inversely to haemodynamic, metabolic, and functional markers of disease severity, myocardial histology, and myocardial mitochondrial efficiency. These observations do not hint towards a specific cardio-pathogenic role of GPCR autoantibodies and suggest that further investigations are required before specific therapies directed at GPCR autoantibodies can be clinically tested in non-ischaemic HF.

Lower Hepatic Fat Is Associated With Improved Insulin Secretion in a High-Risk Prediabetes Subphenotype During Lifestyle Intervention.

The objective of this work was to investigate whether impaired insulin secretion can be restored by lifestyle intervention in specific subphenotypes of prediabetes. We assigned 1,045 participants from the Prediabetes Lifestyle Intervention Study (PLIS) to six recently established prediabetes clusters. Insulin secretion was assessed by a C-peptide-based index derived from oral glucose tolerance tests and modeled from three time points during a 1-year intervention. We also analyzed the change of glycemia, insulin sensitivity, and liver fat. All prediabetes high-risk clusters (cluster 3, 5, and 6) had improved glycemic traits during the lifestyle intervention, whereas insulin secretion only increased in clusters 3 and 5 (P < 0.001); however, high liver fat in cluster 5 was associated with a failure to improve insulin secretion (Pinteraction < 0.001). Thus, interventions to reduce liver fat have the potential to improve insulin secretion in a defined subgroup of prediabetes.

Hepatocyte-specific activity of TSC22D4 triggers progressive NAFLD by impairing mitochondrial function.

OBJECTIVE: Fibrotic organ responses have recently been identified as long-term complications in diabetes. Indeed, insulin resistance and aberrant hepatic lipid accumulation represent driving features of progressive non-alcoholic fatty liver disease (NAFLD), ranging from simple steatosis and non-alcoholic steatohepatitis (NASH) to fibrosis. Effective pharmacological regimens to stop progressive liver disease are still lacking to-date. METHODS: Based on our previous discovery of transforming growth factor beta-like stimulated clone (TSC)22D4 as a key driver of insulin resistance and glucose intolerance in obesity and type 2 diabetes, we generated a TSC22D4-hepatocyte specific knockout line (TSC22D4-HepaKO) and exposed mice to control or NASH diet models. Mechanistic insights were generated by metabolic phenotyping and single-nuclei RNA sequencing. RESULTS: Hepatic TSC22D4 expression was significantly correlated with markers of liver disease progression and fibrosis in both murine and human livers. Indeed, hepatic TSC22D4 levels were elevated in human NASH patients as well as in several murine NASH models. Specific genetic deletion of TSC22D4 in hepatocytes led to reduced liver lipid accumulation, improvements in steatosis and inflammation scores and decreased apoptosis in mice fed a lipogenic MCD diet. Single-nuclei RNA sequencing revealed a distinct TSC22D4-dependent gene signature identifying an upregulation of mitochondrial-related processes in hepatocytes upon loss of TSC22D4. An enrichment of genes involved in the TCA cycle, mitochondrial organization, and triglyceride metabolism underscored the hepatocyte-protective phenotype and overall decreased liver damage as seen in mouse models of hepatocyte-selective TSC22D4 loss-of-function. CONCLUSIONS: Together, our data uncover a new connection between targeted depletion of TSC22D4 and intrinsic metabolic processes in progressive liver disease. Hepatocyte-specific reduction of TSC22D4 improves hepatic steatosis and promotes hepatocyte survival via mitochondrial-related mechanisms thus paving the way for targeted therapies.

Accumulation of acetaldehyde in aldh2.1-/- zebrafish causes increased retinal angiogenesis and impaired glucose metabolism.

Reactive carbonyl species (RCS) are spontaneously formed in the metabolism and modify and impair the function of DNA, proteins and lipids leading to several organ complications. In zebrafish, knockout of the RCS detoxifying enzymes glyoxalase 1 (Glo 1), aldehyde dehydrogenase 3a1 (Aldh3a1) and aldo-ketoreductase 1a1a (Akr1a1a) showed a signature of elevated RCS which specifically regulated glucose metabolism, hyperglycemia and diabetic organ damage. aldh2.1 was compensatory upregulated in glo1-/- animals and therefore this study aimed to investigate the detoxification ability for RCS by Aldh2.1 in zebrafish independent of ethanol exposure. aldh2.1 knockout zebrafish were generated using CRISPR/Cas9 and subsequently analyzed on a histological, metabolomic and transcriptomic level. aldh2.1-/- zebrafish displayed increased endogenous acetaldehyde (AA) inducing an increased angiogenesis in retinal vasculature. Expression and pharmacological interventional studies identified an imbalance of c-Jun N-terminal kinase (JNK) and p38 MAPK induced by AA, which mediate an activation of angiogenesis. Moreover, increased AA in aldh2.1-/- zebrafish did not induce hyperglycemia, instead AA inhibited the expression of glucokinase (gck) and glucose-6-phosphatase (g6pc), which led to an impaired glucose metabolism. In conclusion, the data have identified AA as the preferred substrate for Aldh2.1's detoxification ability, which subsequently causes microvascular organ damage and impaired glucose metabolism.

A macrophage-hepatocyte glucocorticoid receptor axis coordinates fasting ketogenesis.

Fasting metabolism and immunity are tightly linked; however, it is largely unknown how immune cells contribute to metabolic homeostasis during fasting in healthy subjects. Here, we combined cell-type-resolved genomics and computational approaches to map crosstalk between hepatocytes and liver macrophages during fasting. We identified the glucocorticoid receptor (GR) as a key driver of fasting-induced reprogramming of the macrophage secretome including fasting-suppressed cytokines and showed that lack of macrophage GR impaired induction of ketogenesis during fasting as well as endotoxemia. Mechanistically, macrophage GR suppressed the expression of tumor necrosis factor (TNF) and promoted nuclear translocation of hepatocyte GR to activate a fat oxidation/ketogenesis-related gene program, cooperatively induced by GR and peroxisome proliferator-activated receptor alpha (PPARα) in hepatocytes. Together, our results demonstrate how resident liver macrophages directly influence ketogenesis in hepatocytes, thereby also outlining a strategy by which the immune system can set the metabolic tone during inflammatory disease and infection.

Effectiveness of real-time continuous glucose monitoring to improve glycaemic control and pregnancy outcome in patients with gestational diabetes mellitus: a study protocol for a randomised controlled trial.

INTRODUCTION: Real-time continuous glucose monitoring (rt-CGM) informs users about current interstitial glucose levels and allows early detection of glycaemic excursions and timely adaptation by behavioural change or pharmacological intervention. Randomised controlled studies adequately powered to evaluate the impact of long-term application of rt-CGM systems on the reduction of adverse obstetric outcomes in women with gestational diabetes (GDM) are missing. We aim to assess differences in the proportion of large for gestational age newborns in women using rt-CGM as compared with women with self-monitored blood glucose (primary outcome). Rates of neonatal hypoglycaemia, caesarean section and shoulder dystocia are secondary outcomes. A comparison of glucose metabolism and quality of life during and after pregnancy completes the scope of this study. METHODS AND ANALYSIS: Open-label multicentre randomised controlled trial with two parallel groups including 372 female patients with a recent diagnosis of GDM (between 24+0 until 31+6 weeks of gestation): 186 with rt-CGM (Dexcom G6) and 186 with self-monitored blood glucose (SMBG). Women with GDM will be consecutively recruited and randomised to rt-CGM or control (SMBG) group after a run-in period of 6-8 days. The third visit will be scheduled 8-10 days later and then every 2 weeks. At every visit, glucose measurements will be evaluated and all patients will be treated according to the standard care. The control group will receive a blinded CGM for 10 days between the second and third visit and between week 36+0 and 38+6. Cord blood will be sampled immediately after delivery. 48 hours after delivery neonatal biometry and maternal glycosylated haemoglobin A1c (HbA1c) will be assessed, and between weeks 8 and 16 after delivery all patients receive a re-examination of glucose metabolism including blinded CGM for 8-10 days. ETHICS AND DISSEMINATION: This study received ethical approval from the main ethic committee in Vienna. Data will be presented at international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03981328; Pre-results.

[The Diabetic Heart and Heart Failure - Update on Mechanisms and Therapy]. / Das diabetische Herz und Herzinsuffizienz ­ Aktuelles zu Entstehung und Therapie.

Type 2 Diabetes mellitus (T2 D) is an independent risk factor for cardiovascular diseases and non-ischemic heart failure, an underestimated complication of T2 D. Diastolic dysfunction is an early sign of diabetes-related heart failure preceding its progression to systolic damage. The etiology of heart failure in these patients has recently been partially unveiled. Along with other mechanisms, hyperinsulinemia and hyperlipidemia cause increased myocardial lipid accumulation and oxidation, which leads to lipotoxicity, oxidative stress, inflammatory response and eventually impaired mitochondrial efficiency, fibrosis, apoptosis and contractile dysfunction. These myocardial alterations resemble the cellular mechanisms underlying the development of non-alcoholic fatty liver disease (NAFLD), a frequent comorbidity of T2 D and another risk factor for cardiovascular diseases and heart failure. Control of risk factors, lifestyle intervention and antihyperglycemic treatment are the recommended treatment for patients with T2 D and heart failure. While thiazolidindiones and some dipeptidyl peptidase 4 (DPP4) inhibitors may be detrimental for patients with heart failure, recent studies provided evidence for safe use of glucagon-like peptide 1 (GLP1) receptor agonists and for possible beneficial effects of sodium glucose co-transporter 2 (SGLT2) inhibitors on mortality and hospitalization of T2 D patients with heart failure. Treatment of NAFLD could also be beneficial for the cardiovascular outcome of patients with T2D-related heart failure. This article provides a brief summary of the current research on underlying mechanisms, clinical features and recently recommended therapeutic approaches for T2D-related heart failure.

Breathlessness and Restrictive Lung Disease: An Important Diabetes-Related Feature in Patients with Type 2 Diabetes.

BACKGROUND: Diabetes mellitus is a significant comorbidity of interstitial lung disease (ILD). OBJECTIVES: The aim of this study was to investigate the incidence of restrictive lung disease (RLD) and ILD in patients with prediabetes and type 2 diabetes (T2D). METHODS: Forty-eight nondiabetics, 68 patients with prediabetes, 29 newly diagnosed T2D, and 110 patients with long-term T2D were examined for metabolic control, diabetes-related complications, breathlessness, and lung function. Five participants with T2D, breathlessness, and RLD underwent multidetector computed tomography (MDCT) and a Six-Minute Walk Test (6MWT). Lung tissue from 4 patients without diabetes and from 3 patients with T2D was histologically examined for presence of pulmonary fibrosis. RESULTS: Breathlessness in combination with RLD was significantly increased in patients with prediabetes and T2D (p < 0.01). RLD was found in 9% of patients with prediabetes, in 20% of patients with newly diagnosed T2D, and in 27% of patients with long-term T2D. Thus, patients with long-term T2D had an increased risk of RLD (OR 5.82 [95% CI 1.71-20.5], p < 0.01). RLD was significantly associated with glucose metabolism and albuminuria (p < 0.01); furthermore, presence of nephropathy increased the risk of RLD (OR 8.57 [95% CI 3.4-21.9], p < 0.01) compared to nondiabetics. MDCT revealed ILD in 4 patients, the 6MWT correlated with the extent of ILD, and histological analysis showed fibrosing ILD in patients with T2D. CONCLUSIONS: This study demonstrates increased breathlessness and a high prevalence of RLD in patients with T2D, indicating an association between diabetes and fibrosing ILD.

Association of transketolase polymorphisms with measures of polyneuropathy in patients with recently diagnosed diabetes.

BACKGROUND: Shunting of glycolytic intermediates into the pentose phosphate pathway has been suggested to protect from hyperglycaemia-induced microvascular damage. We hypothesized that genetic variability in the gene encoding transketolase, a key pentose phosphate pathway enzyme, contributes to early nerve dysfunction in recent-onset diabetes. METHODS: In this cross-sectional study, we assessed nine single nucleotide polymorphisms (SNPs) in the transketolase gene, plasma methylglyoxal concentrations, and clinical and quantitative measures of peripheral nerve function in 165 type 1 and 373 type 2 diabetic patients with a diabetes duration up to 1 year. RESULTS: The Total Symptom Score was associated with transketolase SNPs rs7648309, rs62255988, and rs7633966, while peroneal motor nerve conduction velocity (MNCV) correlated only with rs7648309 (P < 0.01). Cold thermal detection threshold (TDT) (foot) was associated with transketolase SNPs rs11130362 and rs7648309, while warm TDT (hand) correlated with rs62255988 and rs7648309 (P < 0.01). After Bonferroni correction, the correlations of transketolase SNP rs7648309 with Total Symptom Score and rs62255988 with warm TDT (hand) remained statistically significant. Among subgroups, men with type 2 diabetes showed the strongest associations. No associations were observed between each of the nine tagged transketolase SNPs and plasma methylglyoxal concentrations. CONCLUSIONS: The observed associations of genetic variation in transketolase enzyme with neuropathic symptoms and reduced thermal sensation in recent-onset diabetes suggest a role of pathways metabolizing glycolytic intermediates in early diabetic neuropathy. Copyright © 2016 John Wiley & Sons, Ltd.

Differential Patterns of Impaired Cardiorespiratory Fitness and Cardiac Autonomic Dysfunction in Recently Diagnosed Type 1 and Type 2 Diabetes.

OBJECTIVE: Both impaired cardiorespiratory fitness (CRF) and heart rate variability (HRV) are predictors of mortality, but their relative roles in recent-onset diabetes are unknown. We determined to which extent CRF and HRV are reduced and interrelated in recent-onset diabetes. RESEARCH DESIGN AND METHODS: Participants from the German Diabetes Study with type 1 (n = 163) or type 2 (n = 188) diabetes with known diabetes duration <1 year and two age-matched glucose-tolerant control groups (n = 40 each) underwent spiroergometry and HRV assessment during a hyperinsulinemic-euglycemic clamp. RESULTS: Compared with control subjects, patients with type 2 diabetes showed reduced VO2max (median [1st-3rd quartiles] 19.3 [16.5-22.9] vs. 25.6 [20.7-29.9] mL/kg body weight/min; P < 0.05), diminished VCO2max (23.0 [19.1-26.8] vs. 30.9 [24.5-34.4] mL/kg body weight/min; P < 0.05), blunted heart rate recovery after 2 min (-29.0 [-35.0 to -23.0] vs. -36.0 [-42.8 to -28.0] beats/min; P < 0.05), and reduced HRV in four of nine indices, whereas patients with type 1 diabetes had unaltered CRF but reduced HRV in three of nine indices (P < 0.05), indicating diminished vagal and sympathetic HRV modulation. HRV measures correlated with VO2max in patients with type 1 diabetes (r >0.34; P < 0.05) but not in those with type 2 diabetes. CONCLUSIONS: CRF is reduced in recently diagnosed type 2 diabetes but preserved in type 1 diabetes, whereas cardiac autonomic function is reduced in both diabetes types but is strongly associated with CRF only in type 1 diabetes. These results support the therapeutic concept of promoting physical fitness in the early course of diabetes.

Deep subcutaneous adipose tissue lipid unsaturation associates with intramyocellular lipid content.

BACKGROUND: Obese twins have lower saturated and higher long-chain polyunsaturated fatty acids (FA) in subcutaneous adipose tissue (SAT) compared to their lean monozygotic (MZ) co-twin. Whether this holds for metabolically distinct deep (DSAT) and superficial (SSAT) depots is unknown. Here we use non-invasive magnetic resonance spectroscopy (MRS) to measure the FA unsaturation in body mass index (BMI) discordant MZ twins in DSAT and SSAT and their relationship to ectopic fat content and body fat distribution. The main finding is further confirmed in an independent cohort using standardized measurement times. METHODS: MRS and magnetic resonance imaging were used to measure DSAT and SSAT unsaturation and their relationship to intramyocellular lipids (IMCL), hepatocellular lipids (HCL) and the amount of subcutaneous (SAT) and visceral adipose tissue (VAT) in 16 pairs of healthy monozygotic twins (MZ) discordant for BMI. A second independent cohort of 12 healthy volunteers was used to measure DSAT unsaturation and IMCL with standardized measurement time. One volunteer also underwent repeated random measurements of DSAT unsaturation and IMCL. RESULTS: In accordance with biopsy studies SSAT unsaturation was higher in the heavier twins (15.2±1.0% vs. 14.4±1.5%, P=0.024) and associated with SAT volume (R=0.672, P=0.001). DSAT unsaturation did not differ between twins (11.4±0.8 vs. 11.0±1.0, P=0.267) and associated inversely with IMCL content (R=-0.462, P=0.001). The inverse association between DSAT unsaturation and IMCL was also present in the participants of the second cohort (R=-0.641, P=0.025) and for the repeated sampling at random of one person (R=-0.765, P=0.027). CONCLUSIONS: DSAT and SSAT FA unsaturation shows distinct associations with obesity and IMCL in MZ twins, reflecting compartment-specific metabolic activities. The FA unsaturation in the DSAT depot associates inversely with IMCL content, which raises the possibility of cross talk between the DSAT depot and the rapid turnover IMCL depot.

Pancreatic adipose tissue infiltration, parenchymal steatosis and beta cell function in humans.

AIMS/HYPOTHESIS: This study aimed to perform a comprehensive analysis of interlobular, intralobular and parenchymal pancreatic fat in order to assess their respective effects on beta cell function. METHODS: Fifty-six participants (normal glucose tolerance [NGT] (n = 28), impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) (n = 14) and patients with type 2 diabetes (n = 14)) underwent a frequent-sampling OGTT and non-invasive magnetic resonance imaging (MRI; whole-body and pancreatic) and proton magnetic resonance spectroscopy ((1)H-MRS; liver and pancreatic fat). Total pancreatic fat was assessed by a standard 2 cm(3) (1)H-MRS method, intralobular fat by 1 cm(3) (1)H-MRS that avoided interlobular fat within modified DIXON (mDIXON) water images, and parenchymal fat by a validated mDIXON-MRI fat-fraction method. RESULTS: Comparison of (1)H-MRS techniques revealed an inhomogeneous distribution of interlobular and intralobular adipose tissue, which increased with decreasing glucose tolerance. mDIXON-MRI measurements provided evidence against uniform steatosis, revealing regions of parenchymal tissue void of lipid accumulation in all participants. Total (r = 0.385, p < 0.01) and intralobular pancreas adipose tissue infiltration (r = 0.310, p < 0.05) positively associated with age, but not with fasting or 2 h glucose levels, BMI or visceral fat content (all p > 0.5). Furthermore, no associations were found between total and intralobular pancreatic adipose tissue infiltration and insulin secretion or beta cell function within NGT, IFG/IGT or patients with type 2 diabetes (all p > 0.2). CONCLUSIONS/INTERPRETATION: The pancreas does not appear to be another target organ for abnormal endocrine function because of ectopic parenchymal fat storage. No relationship was found between pancreatic adipose tissue infiltration and beta cell function, regardless of glucose tolerance status.

[The adipose tissue as an endocrine organ]. / Das Fettgewebe als endokrines Organ.

The adipose tissue stores excess energy but also produces a series of substances including cytokines (adipocytokines) which participate in regulatory processes. The physiologic and pathophysiologic relevance of these factors has only recently been described in more detail. Defects in adiponectin as well as overproduction of free fatty acids play an important role in the development of insulin resistance typical for obesity. Rare forms of obesity or lipodystrophy can now be explained by defects in the leptin system. The contribution of adipose tissue and its cytokines to the relationship between inflammation and the metabolic syndrome is currently under investigation.