The Role of Phosphatidylethanolamine N-Methyltransferase (PEMT) and Its Waist-Hip-Ratio-Associated Locus rs4646404 in Obesity-Related Metabolic Traits and Liver Disease.

In previous genome-wide association studies (GWAS), genetic loci associated with obesity and impaired fat distribution (FD) have been identified. In the present study, we elucidated the role of the PEMT gene, including the waist-hip-ratio-associated single nucleotide polymorphism rs4646404, and its influence on obesity-related metabolic traits. DNA from 2926 metabolically well-characterized subjects was used for genotyping. PEMT expression was analyzed in paired visceral (vis) and subcutaneous (sc) adipose tissue (AT) from a subset of 574 individuals. Additionally, PEMT expression was examined in vis, sc AT and liver tissue in a separate cohort of 64 patients with morbid obesity and liver disease. An in vitro Pemt knockdown was conducted in murine epididymal and inguinal adipocytes. Our findings highlight tissue-specific variations in PEMT mRNA expression across the three studied tissues. Specifically, vis PEMT mRNA levels correlated significantly with T2D and were implicated in the progression of non-alcoholic steatohepatitis (NASH), in contrast to liver tissue, where no significant associations were found. Moreover, sc PEMT expression showed significant correlations with several anthropometric- and metabolic-related parameters. The rs4646404 was associated with vis AT PEMT expression and also with diabetes-related traits. Our in vitro experiments supported the influence of PEMT on adipogenesis, emphasizing its role in AT biology. In summary, our data suggest that PEMT plays a role in regulating FD and has implications in metabolic diseases.

Effects of Weight Loss on Glutathione Peroxidase 3 Serum Concentrations and Adipose Tissue Expression in Human Obesity.

BACKGROUND/AIMS: Altered expression and circulating levels of glutathione peroxidase 3 (GPX3) have been observed in obesity and type 2 diabetes (T2D) across species. Here, we investigate whether GPX3 serum concentrations and adipose tissue (AT) GPX3 mRNA expression are related to obesity and weight loss. METHODS: GPX3 serum concentration was measured in 630 individuals, including a subgroup (n = 293) for which omental and subcutaneous (SC) GPX3 mRNA expression has been analyzed. GPX3 analyses include three interventions: 6 months after bariatric surgery (n = 80) or combined exercise/hypocaloric diet (n = 20) or two-step bariatric surgery (n = 24) studies. RESULTS: Bariatric surgery-induced weight loss (-25.8 ± 8.4%), but not a moderate weight reduction of -8.8 ± 6.5% was associated with significantly reduced GPX3 serum concentrations. GPX3 mRNA is significantly higher expressed in AT from individuals with normal glucose metabolism compared to T2D patients. SC AT GPX3 expression is significantly higher in lean compared to obese as well as in insulin-sensitive compared insulin-resistant individuals with obesity. Weight loss after bariatric surgery causes a significant increase in SC AT GPX3 expression. AT GPX3 expression significantly correlates with age, BMI, fat distribution, insulin sensitivity (only SC AT), but not with circulating GPX3. CONCLUSION: Our data support the notion that SC AT GPX3 expression is associated with obesity, fat distribution and related to whole body insulin resistance.

Measuring Biological Age via Metabonomics: The Metabolic Age Score.

Chronological age is one of the most important risk factors for adverse clinical outcome. Still, two individuals at the same chronological age could have different biological aging states, leading to different individual risk profiles. Capturing this individual variance could constitute an even more powerful predictor enhancing prediction in age-related morbidity. Applying a nonlinear regression technique, we constructed a metabonomic measurement for biological age, the metabolic age score, based on urine data measured via (1)H NMR spectroscopy. We validated the score in two large independent population-based samples by revealing its significant associations with chronological age and age-related clinical phenotypes as well as its independent predictive value for survival over approximately 13 years of follow-up. Furthermore, the metabolic age score was prognostic for weight loss in a sample of individuals who underwent bariatric surgery. We conclude that the metabolic age score is an informative measurement of biological age with possible applications in personalized medicine.

Effects of weight loss and exercise on apelin serum concentrations and adipose tissue expression in human obesity.

OBJECTIVE: Apelin is an adipokine which plays a role in the regulation of glucose homeostasis and may contribute to the link between increased adipose tissue mass and obesity related metabolic diseases. Here we investigate the role of omental and subcutaneous (SC) adipose tissue apelin and its receptor APJ mRNA expression in human obesity and test the hypothesis that changes in circulating apelin are associated with reduced fat mass in three weight loss intervention studies. METHODS: Apelin serum concentration was measured in 740 individuals in a cross-sectional (n = 629) study including a subgroup (n = 161) for which omental and SC apelin mRNA expression has been analyzed and in three interventions: 12 weeks exercise (n = 60), 6 months calorie-restricted diet (n = 19), 12 months after bariatric surgery (n = 32). RESULTS: Apelin mRNA is significantly higher expressed in adipose tissue of patients with type 2 diabetes and correlates with circulating apelin, BMI, body fat, C-reactive protein, and insulin sensitivity. Obesity surgery-induced weight loss causes a significant reduction in omental and SC apelin expression. All interventions led to significantly reduced apelin serum concentrations which significantly correlate with improved insulin sensitivity, independently of changes in BMI. CONCLUSIONS: Reduced apelin expression and serum concentration may contribute to improved insulin sensitivity beyond significant weight loss.

Short-term changes of the urine metabolome after bariatric surgery.

Bariatric surgery leads to a loss of excess weight and to a remission of diabetes in a majority of patients. In an attempt to explain these underlying mechanisms, a broad range of metabolic alterations have been suggested. We aimed to investigate short-term changes in the urinary metabolome after bariatric surgery. Data for 50 patients who underwent bariatric surgery at the Municipal Hospital of Dresden-Neustadt, Germany, were used. Healthy controls were selected from the Study of Health in Pomerania. Non-fasting, spontaneous urine samples were collected, (1)H NMR spectroscopic analysis was performed, and metabolites were quantified (Chenomx NMR suite). Orthogonal projections to latent structures discriminant analysis (OPLS-DA) models were carried out (pre-operative versus controls, and post-operative versus controls). On the basis of the urine metabolome separations between pre-operative (predictive ability Q2Y=85.6%; total explained variance R2X=58.3%), or post-operative (Q2Y=82.1%; R2X=44.4%) and controls were possible. Metabolites including hippuric acid, 3-hydroxybutyrate, 2-hydroxyisobutyrate, and trigonelline, were altered among patients. In obese patients, 2-hydroxyisobutyrate levels were higher, whereas trigonelline and hippuric acid levels were lower than in controls. The highest levels of 3-hydroxybutyrate were found in post-operative samples, whereas the metabolite was not present in controls, and only at low levels in pre-operative samples. In conclusion, we demonstrated that the urinary metabotype differs between obese patients and healthy controls. The metabolic alterations identified after bariatric procedures increase our knowledge about the metabolic traits associated with weight reduction. Whether urinary metabotypes might be used for early prediction of a successful bariatric procedure should be evaluated in long-term observations.

Effects of weight loss and exercise on chemerin serum concentrations and adipose tissue expression in human obesity.

Chemerin is a chemoattractant adipokine that regulates adipogenesis and may induce insulin resistance. Chemerin serum concentrations are elevated in obese, insulin-resistant, and inflammatory states in vivo. Here we investigate the role of omental (OM) and subcutaneous (SC) adipose tissue chemerin and CMKLR1 messenger RNA (mRNA) expression in human obesity. In addition, we test the hypothesis that changes in chemerin serum concentrations are primarily associated with reduced body fat mass in the context of 3 weight loss intervention studies. Chemerin serum concentration was measured in 740 individuals in a cross-sectional (n = 629) study including a subgroup (n = 161) for which OM and SC chemerin mRNA expression has been analyzed as well as in 3 interventions including 12 weeks of exercise (n = 60), 6 months of calorie-restricted diet (n = 19) studies, and 12 months after bariatric surgery (n = 32). Chemerin mRNA is significantly higher expressed in adipose tissue of patients with type 2 diabetes mellitus and correlates with circulating chemerin, body mass index (BMI), percentage body fat, C-reactive protein, homeostasis model assessment of insulin resistance, and glucose infusion rate in euglycemic-hyperinsulinemic clamps. CMKLR1 mRNA expression was not significantly different between the 2 fat depots. Obesity surgery-induced weight loss causes a significant reduction on both OM and SC chemerin expression. All interventions led to significantly reduced chemerin serum concentrations. Decreased chemerin serum concentrations significantly correlate with improved glucose infusion rate and reduced C-reactive protein levels independently of changes in BMI. Insulin resistance and inflammation are BMI-independent predictors of elevated chemerin serum concentrations. Reduced chemerin expression and serum concentration may contribute to improved insulin sensitivity and subclinical inflammation beyond significant weight loss.

Efficacy and tolerability of pegylated IFN-alpha in patients with neuroendocrine gastroenteropancreatic carcinomas.

Interferon-alpha (IFN-alpha) is well established in the treatment of neuroendocrine carcinomas (NEC). Treatment is accompanied by fatigue and flu-like symptoms. In patients with chronic hepatitis C, pegylated IFN (PEGIFN) leads to improved antiviral efficacy and good tolerability. Our aim was to assess the efficacy and tolerability of PEG-IFN on the management of patients with well-differentiated NEC of the gastroenteropancreatic system. In 17 patients, the effect of PEG-IFN-alpha2b was studied. After first-line octreotide treatment, IFN-alpha was added at the time of tumor progression. Six patients were switched from conventional IFN-alpha, and 11 patients were IFN naive. Inhibition of tumor growth, including stabilization of disease, occurred in 13 of 17 patients, and biochemical and symptomatic responses were seen in 7 of 10 patients with functionally active tumors. Tolerability of PEG-IFN-alpha2b was much better than that of IFN-alpha. Fatigue occurred in 59% of all patients but was mild in severity. Eleven of thirteen patients who had a benefit remained on therapy for a median time of 20 months (range 6-30 months). PEG-IFN-alpha2b provides symptomatic and antiproliferative efficacy in patients with NEC. Better tolerability of PEG-IFN-alpha2b improved patients' compliance, justifying its use in patients who do not tolerate conventional IFN-alpha treatment.

Circulating levels of angiogenic cytokines can predict tumour progression and prognosis in neuroendocrine carcinomas.

OBJECTIVE: The growth behaviour of well-differentiated neuroendocrine carcinomas of the gastro-entero-pancreatic system varies greatly and parameters predicting their prognosis are lacking. The aim of our study was to investigate whether tumour growth could be correlated with the release of proangiogenic factors into the circulation. PATIENTS AND METHODS: Circulating vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), basic fibroblast growth factor (bFGF) and angiogenin were measured in 38 patients with advanced neuroendocrine carcinomas and compared to healthy age-matched controls. In 20 patients, angiogenic cytokine levels were measured at consecutive time points and correlated to tumour progression as assessed by abdominal CT scan, MRI and chromogranin A levels. RESULTS: VEGF levels were elevated in patients compared to controls (P < 0.002) and clearly associated with tumour progression (P < 0.005). Angiogenin levels were significantly higher in patients than in controls (P < 0.003), while high IL-8 levels were predictive of shorter survival. Angiogenin and bFGF levels were correlated neither with tumour growth nor with patient survival. CONCLUSIONS: VEGF and IL-8 are associated with tumour progression and might qualify as markers of prognosis and therapy control in patients with neuroendocrine carcinomas. Our results support the notion that specific anti-angiogenic therapies should be evaluated in neuroendocrine carcinoma patients.

Resistin levels in patients with obstructive sleep apnoea syndrome--the link to subclinical inflammation?

BACKGROUND: The role of resistin, a "new" white adipose tissue hormone, still needs to be established. Its linkage to insulin sensitivity and body mass was controversial in previous studies. MATERIAL/METHODS: Twenty obese patients (BMI: 32.1+/-6.9 kg/m2 ) with obstructive sleep apnoea syndrome (OSAS) (Apnoea-Hypopnoea Index: 48.6+/-19.1, underwent measurements of resistin, interleukin-6 (IL-6), intracellular adhesion molecule-1 (ICAM-1), CRP and the insulin sensitivity index (ISI) by hyperinsulinaemic euglycaemic clamp before, 2 days and 2 months after onset of CPAP treatment. RESULTS: Resistin remained unchanged during CPAP-therapy and was negatively correlated to ISI (r=-0.359; p=0.006), the latter was significantly improved by CPAP (p<0.001). In a correlation matrix, IL-6 and ICAM-1 were significantly (p=0.001) correlated to resistin (p=0.614 and 0.427). Changes of inflammatory markers under CPAP treatment were related to AHI, as well as resistin changes. CONCLUSIONS: In agreement with previous investigations, we could only demonstrate a weak linkage between ISI and resistin. However, at least in obese patients with OSAS, there is a close relation to subclinical inflammation (IL-6) and endothelial activation (ICAM-1).

RET germline mutation in codon 791 in a family representing 3 generations from age 5 to age 70 years: should thyroidectomy be performed?

OBJECTIVE: To describe a kindred with a rare RET germline mutation in codon 791 and discuss potential management strategies. METHODS: We present clinical and biochemical data as well as results of mutation analysis in our study subjects and provide an overview of related published reports. RESULTS: Multiple endocrine neoplasia type 2 (MEN 2) is a familial cancer syndrome characterized by the development of medullary thyroid carcinoma (MTC), pheochromocytoma, and parathyroid hyperplasia or adenoma. Germline mutations in RET are responsible for this autosomal dominant syndrome. Familial MTC is a variant of MEN 2A and can be caused by RET mutations in codon 791. Deaths from gene carriers with mutations in these codons have not yet been reported. In general, gene carriers with these RET mutations have late-onset MTC. Because only a few kindreds with this specific mutation have been identified and no long-term follow-up data are available, management of these patients can be a challenge. We illustrate the difficulties with decisions about not only when to perform thyroidectomy in these patients but also whether thyroidectomy should even be considered in such gene carriers with a benign course. Our reported kindred included four carriers with a codon 791 RET germline mutation, one of whom had the rare concomitant occurrence of acromegaly and MEN 2A. The 70-year-old mother had acromegaly and hyperparathyroidism but normal serum calcitonin levels and normal findings on thyroid ultrasound examination. She refused pentagastrin testing and any surgical intervention. The 37-year-old daughter had hypothyroidism, a small thyroid gland, and negative results of pentagastrin stimulation testing of calcitonin. The 18-year-old grandson also had a negative pentagastrin test result and normal thyroid ultrasound findings. The 5-year-old granddaughter had normal results of thyroid ultrasonography. In all patients, we recommended thyroidectomy. CONCLUSION: Prospective studies are needed to clarify which patients with codon 791 RET germline mutation should undergo thyroidectomy.

Defective suppressor function of human CD4+ CD25+ regulatory T cells in autoimmune polyglandular syndrome type II.

In autoimmune polyglandular syndromes (APS), several organ-specific autoimmune diseases are clustered. Although APS type I is caused by loss of central tolerance, the etiology of APS type II (APS-II) is currently unknown. However, in several murine models, depletion of CD4(+) CD25(+) regulatory T cells (T(regs)) causes a syndrome resembling human APS-II with multiple endocrinopathies. Therefore, we hypothesized that loss of active suppression in the periphery could be a hallmark of this syndrome. T(regs) from peripheral blood of APS-II, control patients with single autoimmune endocrinopathies, and normal healthy donors showed no differences in quantity (except for patients with isolated autoimmune diseases), in functionally important surface markers, or in apoptosis induced by growth factor withdrawal. Strikingly, APS-II T(regs) were defective in their suppressive capacity. The defect was persistent and not due to responder cell resistance. These data provide novel insights into the pathogenesis of APS-II and possibly human autoimmunity in general.

Outcome after duodenum-preserving pancreatic head resection is improved compared with classic Whipple procedure in the treatment of chronic pancreatitis.

BACKGROUND: There is no consensus in the surgical management of chronic pancreatitis (cP) as to whether techniques preserving the duodenum are superior to pancreatoduodenectomy. This prospective study compared the outcome of standard pancreatoduodenectomy (PD) and duodenum-preserving pancreatic head resection (DPPHR) in treatment of selected patients with cP. METHODS: Inclusion criteria for this prospective controlled, nonrandomized study were patients suffering from cP centered in the head and with severe pain. Seventy consecutive patients underwent DPPHR (n = 38) or, if there was suspicion of malignancy, classic PD (n = 32). A multidimensional, psychometric questionnaire was used to measure the quality of life (QoL). QoL was compared with that of the general German population. Pain intensity was evaluated on the basis of the frequency of pain attacks, analgesic medication, and self-assessed pain score. Assessment of endocrine and exocrine function as well as nutritional status included oral glucose tolerance test, fecal elastase, stool frequency, and body mass index. The median follow-up was 34 months. RESULTS: Multiple clinical characteristics did not differ between the two groups except for age (P =.04), the tumor marker carbohydrate antigen 19-9 (P =.02), and the parameter suspicion of malignancy. There was no hospital mortality. Surgical morbidity was 19% in the PD group and 8% in the DPPHR group (P =.60). PD resulted in a longer median hospital stay than DPPHR (19 vs 15 days, P =.04). Complications of adjacent organs were definitively treated in 100% after PD and in 97% after DPPHR. Postoperative pain intensity as self-assessed by the patients was significantly less in the DPPHR group (P <.001), whereas the frequency of acute episodes (P =.27) and analgesic medication (P =.43) did not differ between the two groups. After surgery, symptom and functional scales of the DPPHR group were significantly better than those in the PD group and were similar to those of the overall German population. No significant difference was found between the two groups with regard to endocrine and exocrine function. Postoperative increase of body mass index was significantly higher in the DPPHR group (P <.001). CONCLUSIONS: DPPHR provides better results in the treatment of cP than PD in terms of QoL, pain intensity as self-assessed by the patients, nutritional status, and length of hospital stay.

Insulin resistance, hyperleptinemia, and obstructive sleep apnea in Launois-Bensaude syndrome.

OBJECTIVE: Launois-Bensaude Syndrome (LBS) is a very rare cause of obesity, characterized by a symmetrical accumulation of a very large number of lipomata in different regions of the body, excluding the face, the forearms, and the shanks. Obesity is known to be closely associated with insulin resistance, hyperleptinemia, and obstructive sleep apnea (OSA). We were interested in studying whether these conditions are also present in patients with obesity due to LBS with a similar frequency as in patients with "simple" truncal obesity. RESEARCH METHODS AND PROCEDURES: We performed polysomnography and hyperinsulinemic euglycemic clamp studies and measured serum leptin in three patients with LBS and in six patients with "simple" truncal obesity, matched for sex and body mass index (LBS group, 36.39 kg/m(2); controls, 35.82 kg/m(2)). RESULTS: Polysomnography revealed severe OSA in one LBS patient with marked "horsecollar lipomata." In the other LBS patients, no OSA could be demonstrated. The leptin levels of the two groups were comparable (LBS group, 36.39 microg/liter; controls, 37.18 microg/liter) and the insulin responsiveness index was also comparable in the two groups (LBS group, 3.47 micromol/kg. minute; controls, 3.79 micromol/kg. minute). DISCUSSION: Patients with LBS demonstrated similar metabolic features in terms of insulin sensitivity and hyperleptinemia as patients with "simple" truncal obesity. LBS is not strictly associated with OSA.

Quality of life in chronic pancreatitis: a prospective trial comparing classical whipple procedure and duodenum-preserving pancreatic head resection.

Few data are available with respect to quality of life after pancreatic head resection in patients with chronic pancreatitis. The aim of this study was to compare the classical Whipple pancreatoduodenectomy (PD) with the Beger duodenum-preserving pancreatic head resection (DPPHR), in terms of quality of life, using standardized, valid, and reliable questionnaires. Sixty-five consecutive patients were included in this study. The PD procedure was chosen when pancreatic cancer could not be ruled out (n = 30); otherwise DPPHR was performed (n = 35). Quality of life was measured prospectively three times with the European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire (QLQ-C30) and the Gastrointestinal Quality-of-Life Index (GIQLI). Both procedures led to a significant improvement in quality of life, especially with regard to pain status. However, at the second follow-up examination (18 to 24 months postoperatively), all functional scales and the most important symptom scales of the EORTC QLQ-C30 revealed a better quality of life in the DPPHR group compared to the PD group. After classical PD, more patients seem to develop diabetes mellitus. The EORTC QLQ-C30 was found to be a better tool for quality-of-life assessment than the GIQLI in patients with chronic pancreatitis.