Matthias Banasch

Glucagon-like peptide 1 (GLP-1) suppresses ghrelin levels in humans via increased insulin secretion.

INTRODUCTION Ghrelin is an orexigenic peptide predominantly secreted by the stomach. Ghrelin plasma levels rise before meal ingestion and sharply decline afterwards, but the mechanisms controlling ghrelin secretion are largely unknown. Since meal ingestion also elicits the secretion of the incretin hormone glucagon-like peptide 1 (GLP-1), we examined whether exogenous GLP-1 administration reduces ghrelin secretion in humans. PATIENTS AND METHODS 14 healthy male volunteers were given intravenous infusions of GLP-1(1.2 pmol x kg(-1) min(-1)) or placebo over 390 min. After 30 min, a solid test meal was served. Venous blood was drawn frequently for the determination of glucose, insulin, C-peptide, GLP-1 and ghrelin. RESULTS During the infusion of exogenous GLP-1 and placebo, GLP-1 plasma concentrations reached steady-state levels of 139+/-15 pmol/l and 12+/-2 pmol/l, respectively (p<0.0001). During placebo infusion, ghrelin levels were significantly reduced in the immediate postprandial period (p<0.001), and rose again afterwards. GLP-1 administration prevented the initial postprandial decline in ghrelin levels, possibly as a result of delayed gastric emptying, and significantly reduced ghrelin levels 150 and 360 min after meal ingestion (p<0.05). The patterns of ghrelin concentrations in the experiments with GLP-1 and placebo administration were inversely related to the respective plasma levels of insulin and C-peptide. CONCLUSIONS GLP-1 reduces the rise in ghrelin levels in the late postprandial period at supraphysiological plasma levels. Most likely, these effects are indirectly mediated through its insulinotropic action. The GLP-1-induced suppression of ghrelin secretion might be involved in its anorexic effects.

Human PACAP response gene 1 (p22/PRG1): proliferation-associated expression in pancreatic carcinoma cells.

p22/PACAP response gene-1 (PRG1) is a novel rat early response gene expressed during induction of proliferation and stress response. In humans, a homolog of p22/PRG1, designated IEX-1/DIF-2, exists, yet the exact function of this gene remains elusive. To characterize the expression of p22/PRG1 in human cancers, we analyzed the expression of p22/PRG1 in the human pancreatic carcinoma cell lines 818-4, PT45, and PancTu1. Serum or growth factors, like epidermal growth factor (EGF) and hepatocyte growth factor (HGF), rapidly and transiently induced transcription of p22/PRG1 in these cells, correlating with the mitogenic response. Treatment with TNF-alpha was followed by a rapid increase of p22/PRG1 messenger RNA (mRNA) levels in PT45 and Panc-Tul cells, which proliferate in the presence of TNF-alpha, but not in 818-4 cells, which are growth-inhibited when treated with TNF-alpha. Our findings suggest that human p22/PRG1 is expressed in various pancreatic carcinoma cells as a growth-associated early response gene.

Uridine supplementation enhances hepatic mitochondrial function in thymidine-analogue treated HIV-infected patients.

Supplementation with uridine offers the possibility of a new and promising approach to nucleoside analogue reverse transcriptase inhibitor-associated mitochondrial toxicity. We investigated the metabolic effects of short-course treatment with the uridine-enriched food supplement NucleomaxX on hepatic mitochondrial function in thymidine-analogue treated HIV-infected patients. Mitochondrial function was assessed by a recently introduced non-invasive 13C-methionine breath test. NucleomaxX supplementation enhanced mitochondrial decarboxylation function reversibly but reproducibly in all patients. Repeated administration in shorter treatment intervals may maintain this effect.

Rimonabant as a novel therapeutic option for nonalcoholic steatohepatitis.

To the Editor: Nonalcoholic steatohepatitis (NASH), a chronic liver disease characterized by insulin resistance, accumulation of hepatic fat and hepatocellular necroinflammation, has been recognized as a leading cause of (cryptogenic) liver cirrhosis in developed countries. The pathogenesis of NASH has been tightly linked to the presence of obesity and type 2 diabetes (T2DM), both of which have become increasingly prevalent over the recent decades (1, 2). Current treatment regiments for NASH include lifestyle modification (diet, increased physical activity) as well as pharmacological interventions aiming to improve insulin sensitivity, such as metformin of thiazolidinediones. However, given the rising incidence of NASH and the limitations associated with current treatment strategies (lack of adherence to dietary regimens, side effects of metformin or glitazone treatment), novel therapeutic approaches are warranted. The endocannabinoid (EC) system is a physiological network implicated in appetite control and energy homeostasis. Thus, an over-activity of the EC system leads to excessive caloric intake and obesity, whereas antagonizing cannabinoid type 1 (CB1) receptors using the selective CB1 blocker rimonabant reduces food consumption and body weight over longer treatment periods (3, 4). In addition to these central nervous effects, rimonabant treatment has led to significant improvements in lipid profiles, insulin sensitivity and glucose homeostasis (5–7). Owing to these pleiotropic metabolic effects, the drug has been widely used for the treatment of obesity, dyslipidaemia and type 2 diabetes. Because the CB1 receptor is also present in the liver, where it enhances the expression of the lipogenic transcription factors (8, 9), antagonizing the EC system might also attenuate the phenotype of nonalcoholic fatty liver disease (NAFLD). Based on these considerations, we examined the effects of rimonabant of hepatic and metabolic functions in a patient with NASH.

Diagnosis and treatment of gastrinoma in the era of proton pump inhibitors.

ZusammenfassungDas Zollinger-Ellison-Syndrom (ZES) ist pathophysiologisch durch eine Hypergastrinämie charakterisiert, die von einem Gastrin-sezernierenden neuroendokrinen Tumor mit Primärlokalisation im Duodenum oder Pankreas stammt resultiert. Die chronische Hypergastrinämie führt zu einer Säurehypersekretion und konsekutiv zu rezidivierenden oder refraktären Ulcera im oberen Gastrointestinaltrakt oder zu einer chronischen Diarrhoe. Die Hälfte aller Patienten mit ZES hat Fernmetastasen in der Leber zum Zeitpunkt der Diagnose und ebenfalls die Hälfte aller Patienten mit ZES hat als Leitsymptom der Erkrankung eine chronische Durchfallerkrankung und kein peptisches Ulkusleiden. Gastrinome manifestieren sich sporadisch oder vor dem genetischen Hintergrund des MEN-I-Syndroms. Die Diagnose basiert im wesentlichen auf der Anamnese, die Aufschluss gibt über rezidivierenden Ulkusepisoden oder schwere Refluxösophagitiden, die auf Standardtherapieregime keine Besserung erfahren, und/oder über eine chronische Diarrhoe. Die Endoskopie des oberen Gastrointestinaltraktes sichert die Diagnose des peptischen Ulkusleidens unter anderem auch in anatomischen Regionen weit distal des Bulbus duodeni oder gar im Jejunum. Ulcerationen, die gruppiert auftreten, sind häufig zu beobachten und somit verdächtig auf eine substantielle Hypersekretion von Säure. Ein pH-Wert des Magensekretes von > 2 schließt ein ZES mit sehr großer Wahrscheinlichkeit aus. Der biochemische Tumornachweis gelingt über erhöhte Serumgastrinspiegel. Der Serumgastrinspiegel kann im Nüchternzustand oder nach Stimulation mit Calcium oder Sekretin bestimmt werden. Eine sehr hohe Sensitivität für die Diagnose hat die Bestimmung des Verhältnisses der basalen (basal acid output, BAO) zur maximal stimulierten (maximal acid otuput, MAO) Säuresekretion des Magens. Ein Verhältnis von BAO / MAO von > 0,6 ist hochgradig spezifisch für ein Gastrinom. Für die Lokalisationsdiagnostik stehen neben der Computertomographie die Somatostatin-Rezeptor-Szintigraphie, der transabdominelle und der endoskopische Ultraschall zur Verfügung. Falls diese Techniken keine exakte präoperative Lokalisationsdiagnostik gestehen, besteht die Möglichkeit zum intraoperativen Ultraschall und zur Diaphanoskopie der Duodenalwand. Die Wahl der Therapie ist individuell und abhängig von der klinischen Beschwerdesymptomatik und der Tumorlokalisation. Die vollständige chirurgische Resektion bietet die einzige Chance auf eine dauerhafte Heilung des Patienten. Ist dies jedoch nicht möglich, steht das effektive pharmakologische Management des Säurehypersekretionssyndroms im Vordergrund.SummaryThe Zollinger-Ellison syndrome is characterized pathophysiologically by a significant hypergastrinemia derived from a gastrin-secreting neuroendocrine tumor with a primary location in the pancreas or duodenum. Chronic hypergastrinemia in turn triggers gastric acid hypersecretion yielding in chronic or recurrent or refractory peptic ulcer disease and/or chronic diarrhea. One half of patients with ZES will have distant metastases in the liver by the time the diagnosis is established and one half of all patients with ZES will experience chronic diarrhea as chief complaint rather than peptic ulcer-related symptoms and signs. Gastrinomas have been reported to either manifest sporadically or to occur in conjunction with the genetic backgroung of the MEN-I syndrome. Diagnosis is based on the patients history which is typically characterized by recurrent episodes of peptic ulcer disease or by severe reflux esophagitis and/or diarrhea or by acid-related symptoms which fail to respond to standard treatment regimens. Upper gastrointestinal tract endoscopy will provide evidence for peptic ulcer disease in anatomical regions located aborally the duodenal bulb within the descending part of the duodenum or even farther distally within the jejunum. Peptic ulcers frequently occur in groups indicating some substantial acid hypersecretion. A gastric pH > 2 is mutually exclusive for ZES. Increased serum gastrin levels confirm the diagnosis biochemically. Gastrin secretion can be determined in the basal state or following stimulation with secretin or calcium. High sensitivity and specifity for the diagnosis of ZES is provided by determining the ratio of basal versus pentagastrin-stimulated gastric acid secretion: The ratio of BAO / MAO > 0.6 is highly specific for gastrinoma. To localize the gastrinsecreting tumor computer-assisted tomography, endoscopic ultrasound, and somatostatin receptor scintigraphy provide useful help but most recently, endoscopic ultrasound with high resolution transducers appear to improve preoperative site localization. If modern imaging techniques fail to elucidate the site of the tumor, intraoperative diaphany may help to detect gastrinomas within the duodenal wall. Definitive treatment will only be achieved by total surgical resection of the gastrin-producing tumor in the pancreas or duodenum including dissection of the regional lymph nodes. Control of symptoms will have to be achieved by administration of highly potent proton pump inhibitors in up to 2-3-fold increased standard doses to inhibit gastric acid hypersecretion. Elevation of gastric pH > 4 will be the therapeutic target to protect the mucosa of the upper gastrointestinal tract. Basal acid output should be reduced to less than 10 mEq H+ per hour which requires administration of highly potent proton pump inhibitors with a recommended starting dose of 60 mg omeprazole equivalents per day.

13C-methionine breath test detects distinct hepatic mitochondrial dysfunction in HIV-infected patients with normal serum lactate.

Objective:To assess mitochondrial respiratory chain dysfunction in different treatment groups of HIV-infected patients with normal serum lactate by measuring hepatic mitochondrial decarboxylation capacity by the 13C-methionine breath test (MeBT) and to correlate MeBT results with mitochondrial DNA (mtDNA) content in peripheral blood mononuclear cells (PBMCs). Methods:Four groups were studied: HIV-negative controls (n = 10), treatment-naive patients (n = 15), antiretroviral therapy (ART)-treated patients with asymptomatic disease (n = 15), and patients with long-term treatment and clinical evidence of lipoatrophy (n = 15). After oral administration of 13C-methionine, 13CO2 exhalation was determined by infrared spectroscopy. MtDNA content in PBMCs was assessed by real-time polymerase chain reaction quantification. Results:13CO2 exhalation in lipoatrophic patients and therapy-naive patients was distinctly decreased when compared with that in healthy controls and asymptomatic patients (P < 0.001). The functional mitochondrial impairment in lipoatrophic patients was associated with a 47% decline in mtDNA content. MeBT results and mtDNA were significantly correlated in ART-treated patients (r = 0.77, P < 0.0001). Conclusions:MeBT is a simple noninvasive method to detect mitochondrial dysfunction in HIV-infected patients that correlates with mtDNA depletion in PBMCs of ART-treated individuals. Decreased hepatic methionine metabolism in therapy-naive patients may reflect the functional relevance of viral-mediated mitochondrial toxicity.

The non-invasive 13C-methionine breath test detects hepatic mitochondrial dysfunction as a marker of disease activity in non-alcoholic steatohepatitis

IntroductionMitochondrial dysfunction plays a central role in the general pathogenesis of non-alcoholic fatty liver disease (NAFLD), increasing the risk of developing steatosis and subsequent hepatocellular inflammation. We aimed to assess hepatic mitochondrial function by a non-invasive 13C-methionine breath test (MeBT) in patients with histologically proven NAFLD.Methods118 NAFLD-patients and 18 healthy controls were examined by MeBT. Liver biopsy specimens were evaluated according to the NASH scoring system.ResultsHigher grades of NASH activity and fibrosis were independently associated with a significant decrease in cumulative 13C-exhalation (expressed as cPDR(%)). cPDR1.5h was markedly declined in patients with NASH and NASH cirrhosis compared to patients with simple steatosis or borderline diagnosis (cPDR1.5h: 3.24 ± 1.12% and 1.32 ± 0.94% vs. 6.36 ± 0.56% and 4.80 ± 0.88% respectively; p < 0.001). 13C-exhalation further declined in the presence of advanced fibrosis which was correlated with NASH activity (r = 0.36). The area under the ROC curve (AUROC) for NASH diagnosis was estimated to be 0.87 in the total cohort and 0.83 in patients with no or mild fibrosis (F0-1).ConclusionThe 13C-methionine breath test indicates mitochondrial dysfunction in non-alcoholic fatty liver disease and predicts higher stages of disease activity. It may, therefore, be a valuable diagnostic addition for longitudinal monitoring of hepatic (mitochondrial) function in non-alcoholic fatty liver disease.

Hepatic mitochondrial dysfunction in manifest and premanifest Huntington disease

Objective: In this cross-sectional study, we investigated whether there is evidence for hepatic mitochondrial dysfunction in manifest and/or premanifest Huntington disease (HD) by using the 13C-methionine breath test. Methods: The 13C-methionine breath test was performed within a group of 21 patients with early manifest HD without medication, 30 premanifest mutation carriers, as well as 36 healthy controls. Premanifest mutation carriers were stratified into the 2 groups preHD-A (further from predicted onset) and preHD-B (nearer) based on a calculation of the probability of estimated disease onset within 5 years. The 13C-methionine breath test was performed after an overnight fasting, breath samples were analyzed by nondispersive isotope-selective infrared spectroscopy, and results expressed as percentage dose recovered after 90 minutes of testing time. Statistical analyses comprised analysis of covariance and post hoc t tests. Results: Patients with manifest HD and mutation carriers from our preHD-B group revealed a lower amount of exhaled 13CO2 compared with healthy controls (p < 0.001 and p = 0.017, respectively). In a stepwise linear regression model, breath test results correlate to functional and cognitive scores of the Unified Huntingtons Disease Rating Scale in manifest and also in premanifest HD. For all mutation carriers together, there was a weak but significant correlation of breath test results to ratio caudate volume/total intracranial volume. Conclusion: This study demonstrates for the first time in vivo a subclinical, hepatic involvement in manifest and premanifest HD.

Longitudinal effects of hepatitis C virus treatment on hepatic mitochondrial dysfunction assessed by 13C‐methionine breath test

Background  Hepatitis C virus (HCV) infection is characterized by remarkable levels of oxidative stress induced by virus interactions with hepatic mitochondria.

Glucagon-like peptide 2 inhibits ghrelin secretion in humans

INTRODUCTION The growth hormone secretagogue receptor ligand ghrelin is known to play a pivotal role in the central nervous control of energy homeostasis. Circulating ghrelin levels are high under fasting conditions and decline after meal ingestion, but the mechanisms underlying the postprandial drop in ghrelin levels are poorly understood. In the present study we addressed, whether (1) exogenous GLP-2 administration decreases ghrelin levels and (2) what other endogenous factors are related to ghrelin secretion under fasting conditions. PATIENTS AND METHODS Fifteen healthy male volunteers were studied with the intravenous infusion of GLP-2 (2 pmol l(-1) min(-1)) or placebo over 120 min in the fasting state. Plasma concentrations of glucose, insulin, C-peptide, glucagon, intact GLP-2 and ghrelin were determined. RESULTS During the infusion of GLP-2, plasma concentrations of intact GLP-2 increased from 10.0+/-1.5 pmol/l to steady-state levels of 207.7+/-8.3 pmol/l (p < 0.0001). Administration of GLP-2 led to an approximately 10% reduction in ghrelin concentrations, whereas placebo administration was without an effect (p < 0.001). After cessation of the GLP-2 infusion, ghrelin levels returned to baseline values, and were no longer different from those in the placebo experiments. There was a strong inverse linear relationship between the fasting concentrations of ghrelin and the respective levels of glucose, insulin and C-peptide (r = 0.49, p < 0.01; r = 0.55, p < 0.01 and r = 0.59, p < 0.001, respectively). In contrast, there was no detectable association between fasting ghrelin levels and the ambient concentrations of glucagon or intact GLP-2. CONCLUSIONS GLP-2 inhibits ghrelin secretion in humans at plasma levels of approximately 200 pmol/l. However, the physiological importance of this effect appears to be minor compared to the actions of insulin and glucose.