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Biomedical subjects

M Tschöp

Publications and source records attributed to M Tschöp.

At least 19 recordsLinked to original sources
PubMed2001

Weight loss at high altitude.

Loss of appetite and weight are frequently observed at altitudes above 5000 m. However, the pathophysiology behind changes in body composition at extreme altitude is still not fully understood. Proper acclimatization to altitude and high caloric intake minimizes, but can not completely prevent significant weight loss under the influence of hypobaric hypoxia. The discovery of leptin in 1994 has initiated a new research area investigating molecular networks that connect peripheral organs with the central nervous system to sense and regulate energy intake as well as energy expenditure. Since then, a whole microcosm of new hormones, neurotransmitters and receptors has been discovered and studied with respect to body weight control. Those agents include neuropeptide Y (NPY), agouti-related protein (AGRP), melanocortin receptors (MC-R), cocaine-amphetamine regulated transcript (CART), pro-opiomelanocortin (POMC), orexin A and B (hypocretins), melanin-concentrating hormone (MCH) and ghrelin (endogenous ligand of the growth hormone secretagogue receptor). This overview will introduce the current concepts of the molecular control of energy homeostasis and attempt to reexamine the effects of altitude on appetite and body composition in light of these concepts. An overview of studies on changes of appetite and body composition at high altitude will be followed by the presentation of recent data on changes of endocrine parameters at hypobaric hypoxia that could be involved in the pathophysiology of weight loss.

Altitude↗
PubMed2001

Post-prandial decrease of circulating human ghrelin levels.

Ghrelin, an endogenous ligand of the GH secretagogue-receptor, has recently been shown to stimulate GH secretion and to have orexigenic and adipogenic effects in rodents, but little is known about its regulation and biological function in humans. Gastric motor function is under control of the central nervous system; however, the afferent and efferent loops of this feedback control mechanism remain to be elucidated. In the study presented here we investigated the effect of nutrient intake on circulating human ghrelin levels, and a possible association between ghrelin levels and gastric emptying. Ten healthy volunteers received a standard meal after an overnight fast. Food intake significantly decreased plasma ghrelin levels from 248.5 +/- 15.0 to 179.5 +/- 17.9 fmol/ml (120 min after meal, p=0.047). Gastric emptying half-time (non-invasive 13C-octanoic acid breath test) was correlated with fasting plasma ghrelin levels (r=0.74, p=0.0013). Ghrelin appears to be one possible candidate to provide feedback signaling between nutrient intake, gastric motor function and the central nervous system.

Adult↗
PubMed2001

Rodent obesity models: an overview.

Animal obesity models differ widely in type and extent of obesity. They are either based on environmental factors (eg. high fat diet induced obesity), spontaneous mutants (i.e. ob/ob mice), genetically engineered animals (eg. mice with melanocortin receptor subtype-4 gene disruption (knock-out)) or mechanical intervention (eg. chemical lesion of the ventromedial hypothalamus). This article reviews available rodent models to study obesity and attempts to highlight the greatest utility for each model.

Animals↗
PubMed2001

Minireview: ghrelin and the regulation of energy balance--a hypothalamic perspective.

The recently discovered hormone, ghrelin, has been recognized as an important regulator of GH secretion and energy homeostasis. Orexigenic and adipogenic ghrelin is produced by the stomach, intestine, placenta, pituitary, and possibly in the hypothalamus. The concentration of circulating ghrelin, principally derived from the stomach, is influenced by acute and chronic changes in nutritional state. To date, most studies focused on the role of ghrelin in GH secretion or its function in complementing leptin action to prevent energy deficits. The potential significance of ghrelin in the etiology of obesity and cachexia as well as in the regulation of growth processes is the subject of ongoing discussions. A large quantity of information based on clinical trials and experimental studies with ghrelin and previously available synthetic ghrelin receptor agonists (GH secretagogues) must now be integrated with a rapidly increasing amount of data on the central regulation of metabolism and appetite. In this overview, we summarize recent findings and strategies on the integration of ghrelin into neuroendocrine networks that regulate energy homeostasis.

Animals↗
PubMed2001

Plasma ghrelin concentration and energy balance: overfeeding and negative energy balance studies in twins.

Central (intracerebral ventral) and peripheral (subcutaneous and intraperitoneal) administration of ghrelin causes obesity in rodents by increasing food intake and decreasing fat oxidation. Recent studies in humans have shown that plasma ghrelin concentration was inversely related to body fat and was lower in Pima Indians, a population susceptible to obesity. Whether ghrelin plays a role in the etiology of obesity in humans is unknown. We, therefore, measured plasma ghrelin concentration before and after two interventions in monozygotic twins previously studied at Laval University, Quebec City. Twelve pairs of monozygotic twins were overfed by 84,000 kcal over a 100-day period, whereas another seven pairs of monozygotic twins were submitted to a 53,000 kcal negative energy balance induced by exercise over a 93-day period. At baseline, for all the subjects, plasma ghrelin concentration was negatively correlated with body mass and body fatness (r varying from 0.36 to 0.45). The intraclass coefficient for the twin resemblance (r(I) = 0.75; p = 0.006) indicated that plasma ghrelin concentration is a familial trait. In response to the 100-day intervention, plasma ghrelin exhibited a non-significant decrease of 61 +/- 30 fmol/l (p = 0.18) with overfeeding and a non-significant increase of 58 +/- 34 fmol/l (p = 0.17) with negative energy balance. However, there was no relationship between baseline plasma ghrelin concentration and the magnitude of body weight change in both interventions. These first experimental data under "clamped energy balance conditions" do not provide evidence that plasma ghrelin is involved in the etiology of human obesity. However, studies in free-living individuals are needed to clarify this question.

Adipocytes↗
PubMed2001

Circulating ghrelin levels are decreased in human obesity.

Ghrelin is a novel endogenous natural ligand for the growth hormone (GH) secretagogue receptor that has recently been isolated from the rat stomach. Ghrelin administration stimulates GH secretion but also causes weight gain by increasing food intake and reducing fat utilization in rodents. To investigate the possible involvement of ghrelin in the pathogenesis of human obesity, we measured body composition (by dual X-ray absorption) as well as fasting plasma ghrelin concentrations (radioimmunoassay) in 15 Caucasians (8 men and 7 women, 31+/-9 years of age, 92+/-24 kg body wt, and 29+/-10% body fat, mean +/- SD) and 15 Pima Indians (8 men and 7 women, 33+/-5 years of age, 97+/-29 kg body wt, and 30+/-8% body fat). Fasting plasma ghrelin was negatively correlated with percent body fat (r = -0.45; P = 0.01), fasting insulin (r = -0.45; P = 0.01) and leptin (r = -0.38; P = 0.03) concentrations. Plasma ghrelin concentration was decreased in obese Caucasians as compared with lean Caucasians (P < 0.01). Also, fasting plasma ghrelin was lower in Pima Indians, a population with a very high prevalence of obesity, compared with Caucasians (87+/-28 vs. 129+/-34 fmol/ml; P < 0.01). This result did not change after adjustment for fasting plasma insulin concentration. There was no correlation between fasting plasma ghrelin and height. Prospective clinical studies are now needed to establish the role of ghrelin in the pathogenesis of human obesity.

Adult↗
PubMed2001

Weight gain decreases elevated plasma ghrelin concentrations of patients with anorexia nervosa.

OBJECTIVE: Ghrelin is a new gastric hormone that has been identified as an endogenous ligand for the growth hormone (GH) secretagogue receptor subtype 1a (GHS-R1a). Ghrelin administration however not only stimulates GH secretion but also induces adiposity in rodents by increasing food intake and decreasing fat utilization. We hypothesized that impaired ghrelin secretion in anorexia nervosa may be involved in the pathogenesis of this eating disorder. To examine this hypothesis and to further investigate the role for ghrelin in regulating energy homeostasis, we analyzed circulating ghrelin levels in patients with anorexia nervosa and examined possible correlations with clinical parameters before and after weight gain. METHODS: Plasma ghrelin levels were measured in overnight fasting plasma samples from 36 female patients with anorexia nervosa (age: 25.0+/-1.2 years, BMI: 15.2+/-0.2 kg/m(2)) before and after weight gain following psychotherapeutic treatment intervention in a psychosomatic institution. Plasma ghrelin levels were also measured in fasting plasma samples from 24 age-matched female controls (31+/-1.4 years, BMI: 22.9+/-0.45 kg/m(2)). For quantification of ghrelin levels a commercially available radioimmunoassay (Phoenix Pharmaceuticals, USA) was used. RESULTS: Fasting plasma ghrelin levels in anorectic patients were significantly higher (1057+/-95 pg/ml) than in normal age-matched female controls (514+/-63 pg/ml n=24, P=0.02). Therapeutic intervention in a psychosomatic institution caused an BMI increase of 14% (P<0.001) leading to a significant decrease in circulating ghrelin levels of 25%, (P=0.001). A significant negative correlation between Deltaghrelin and DeltaBMI was observed (correlation coefficient: -0.47, P=0.005, n=36). CONCLUSION: We show for the first time that fasting plasma levels of the novel appetite-modulating hormone ghrelin are elevated in anorexia nervosa and return to normal levels after partial weight recovery. These observations suggest the possible existence of ghrelin resistance in cachectic states such as caused by eating disorders. Future studies are necessary to investigate putative mechanisms of ghrelin resistance such as a possible impairment of intracellular ghrelin receptor signaling in pathophysiological states presenting with cachexia.

Adolescent↗
PubMed2000

Ghrelin induces adiposity in rodents.

The discovery of the peptide hormone ghrelin, an endogenous ligand for the growth hormone secretagogue (GHS) receptor, yielded the surprising result that the principal site of ghrelin synthesis is the stomach and not the hypothalamus. Although ghrelin is likely to regulate pituitary growth hormone (GH) secretion along with GH-releasing hormone and somatostatin, GHS receptors have also been identified on hypothalamic neurons and in the brainstem. Apart from potential paracrine effects, ghrelin may thus offer an endocrine link between stomach, hypothalamus and pituitary, suggesting an involvement in regulation of energy balance. Here we show that peripheral daily administration of ghrelin caused weight gain by reducing fat utilization in mice and rats. Intracerebroventricular administration of ghrelin generated a dose-dependent increase in food intake and body weight. Rat serum ghrelin concentrations were increased by fasting and were reduced by re-feeding or oral glucose administration, but not by water ingestion. We propose that ghrelin, in addition to its role in regulating GH secretion, signals the hypothalamus when an increase in metabolic efficiency is necessary.

Adipose Tissue↗
PubMed2000

High altitude increases circulating interleukin-6, interleukin-1 receptor antagonist and C-reactive protein.

Hypoxic pulmonary vasoconstriction is associated with but may not be sufficient for the development of high-altitude pulmonary oedema (HAPO). Hypoxia is known to induce an inflammatory response in immune cells and endothelial cells. It has been speculated that hypoxia-induced inflammatory cytokines at high altitude may contribute to the development of HAPO by causing capillary leakage in the lung. We were interested if such an inflammatory response, possibly involved in a later development of HAPO, is detectable at high altitude in individuals without HAPO. We examined the plasma levels of interleukin 6 (IL-6), interleukin 1 receptor antagonist (IL-1ra) and C-reactive protein (CRP) in two independent studies: study A, Jungfraujoch, Switzerland, three overnight stays at 3458 m, n=12; study B: Capanna Regina Margherita, Italy, 3 overnight stays at 3647 m and one overnight stay at 4559 m, n=10. In both studies, probands showed symptoms of acute mountain sickness but no signs of HAPO. At the Jungfraujoch, IL-6 increased from 0.1+/-0.03 pg/ml to 2. 0+/-0.5 pg/ml (day 2, P=0.03), IL-1ra from 101+/-21 to 284+/-73 pg/ml (day 2, P=0.01), and CRP from 1.0+/-0.4 to 5.8+/-1.5 micrograms/ml (day 4, P=0.01). At the Capanna Margherita, IL-6 increased from 0. 5+/-0.2 pg/ml to 2.0+/-0.8 pg/ml (P=0.02), IL-1ra from 118+/-25 to 213+/-28 pg/ml (P=0.02), and CRP from 0.4+/-0.03 to 3.5+/-1.1 micrograms/ml (P=0.03). IL-8 was below the detection limit of the ELISA (<25 pg/ml) in both studies. The increase of IL-6 and IL-1ra in response to high altitude was delayed and preceded the increase of CRP. We conclude that: (1) circulating IL-6, IL-1ra and CRP are upregulated in response to hypobaric hypoxic conditions at high altitude, and (2) the moderate systemic increase of these inflammatory markers may reflect considerable local inflammation. The existence and the kinetics of high altitude-induced cytokines found in this study support the hypothesis that inflammation is involved in the development of HAPO.

Adult↗
PubMed2000

Effects of growth hormone replacement therapy on levels of cortisol and cortisol-binding globulin in hypopituitary adults.

OBJECTIVE: To determine if human growth hormone (hGH) replacement therapy alters pharmacokinetics of hydrocortisone (CS) substitution in hypopituitary adults. DESIGN: To this aim, we analysed serum and salivary CS profiles 270 min after oral CS administration at baseline and 6 and 12 months after initiation of hGH replacement therapy. METHODS: Serum IGF-I, cortisol-binding globulin (CBG), thyroxine-binding globulin (TBG) and sex hormone-binding hormone (SHBG) were measured using commercially available radioimmunoassays. In-house immunofluorometric assays were employed for measurements of CS and hGH. RESULTS: hGH replacement did not change total serum CS bioavailability (area under the serum cortisol profile curve). Interference of orally administered CS with salivary measurement of free CS (fCS) caused significant bias. Therefore, fCS levels were calculated from their total CS and cortisol-binding globulin (CBG) levels. CBG decreased by approximately 30% after both 6 and 12 months of hGH replacement therapy (n=20, P<0.01). A significant negative correlation between deltaCBG (CBG6months-CBGbaseline) and deltaIGF-I (IGF-I6months-IGF-Ibaseline) was observed (P=0.04). The calculated values of free CS tended to increase with physiological hGH replacement, but this effect was marginal and did not reach statistical significance. In contrast to the CBG concentrations, plasma levels of sex hormone-binding globulin and thyroxine-binding globulin were essentially stable. CONCLUSION: Given that no clinically relevant alterations in pharmacokinetics of CS were evoked by initiation of hGH replacement in hypopituitary adults, we conclude that CS substitution does not require dose adjustment after initiation of hGH replacement.

Adult↗
PubMed1999

Gastrointestinal involvement in patients with diabetes mellitus: Part I (first of two parts). Epidemiology, pathophysiology, clinical findings.

In patients with type 1 or type 2 diabetes mellitus disturbances of the gastrointestinal transit are well recognized. In decreasing order of frequency, transit disturbance through the colon, stomach, small intestine and esophagus as well as altered motility of the gallbladder occur. Acute changes of blood glucose concentrations have a major, however, reversible influence on motility in various parts of the intestinal tract. Long-term hyperglycemia may influence the incidence of gastrointestinal involvement via the occurrence of neuropathic changes of the autonomic nervous system. Early satiety, nausea, vomiting, weight loss, constipation, diarrhea and epigastric pain are often reported. These symptoms and recurrent episodes of hypoglycemia or prolonged hyperglycemia can result from intestinal transit disturbances.

Autonomic Nervous System↗
PubMed1999

Gastrointestinal involvement in patients with diabetes mellitus: Part II (second of two parts). Diagnostic procedures, pharmacological and nonpharmacological therapy.

Diagnostic work-up in patients with diabetes mellitus, in whom gastrointestinal involvement is suspected comprises the assessment of gastrointestinal transit times, endoscopy, esophageal pH-metry or manometry, sonography and lactulose- or glucose-H2-breath tests. Prokinetic agents such as metoclopramide, cisapride or erythromycin and substances like loperamide, octreotide or clonidine are used to improve gastrointestinal dysfunction. Furthermore, in recent trials which aimed for the modulation of gastrointestinal transit times, cholecystokinin, proteinase inhibitors or amylin were administered in patients with diabetes mellitus. Nonpharmacological interventions include pancreas and kidney transplantation, gastric pacemakers and biofeedback training.

Diabetes Mellitus, Type 1↗
PubMed1998

[A 35-year old male patient with fever and painful swelling of the pectoral glands following a short visit to Sri Lanka].

HISTORY AND CLINICAL FINDINGS: One week after returning from a two-week holiday in Sri Lanka a 35-year-old man started to have recurrent bouts of fever, up to 39.2 degrees C, as well as pain over the left upper abdomen, the back of the right thorax and bilateral pain on pressure with swelling of both breasts. He went to the Tropical Institute in Munich to have malaria excluded. There signs of cholestasis were noted and sonography revealed multiple round foci in the liver. As he had lost 10 kg in 3 weeks he was admitted to a medical unit for further tests. Physical examination now showed bilateral gynaecomastia and marked pressure resistance in the upper abdomen. Proprioceptor reflexes were greatly increased but equal bilaterally. INVESTIGATIONS: Inflammatory parameters were raised (C-reactive protein 22.6 mg/dl, ferritin level 2674 micrograms/l, erythrocyte sedimentation rate 50/82 mm), there also were a leucocytosis (20,600 WBC/mm3) and a raised lactate dehydrogenase level of 613 U/l. In addition, thyroid stimulating hormone was reduced to < 0.03 microU/ml, while free thyroxine was raised to 2.7 ng/dl. The pregnancy test was positive. On quantitative analysis the human beta-chorionic gonadotropin (hCG) level was markedly raised to 193,200 mIU/ml. Abdominal and thoracic computed tomography revealed multiple round metastasis-like masses in the liver and in the lung, and a thickened cardia. Serology for malaria, amoebiasis and echinococciasis was negative, sonography of the testes and thyroid was unremarkable. Endoscopy revealed a polypoid tumour at the gastro-oesophageal junction which histologically was an undifferentiated hCG-positive choriocarcinoma. TREATMENT AND COURSE: The neoplasm at first responded with partial remission (hCG minimally 39 mIU/ml) to chemotherapy (PEI schema: cisplatin, etoposide, ifosfamide) but then progressed, also under treatment of recurrences with paclitaxel, ifosfamide and cisplatin. The patient has since received high-dosage chemotherapy with autologous stem-cell transplantation.

Adult↗
PubMed1998

Childhood onset of GH deficiency: reassessment of GH status and effects of substitution.

The final height of 77 patients with growth hormone (GH) insufficiency of childhood onset was analysed. Patients were treated between 1968 and 1996 for 1-15 years. The mean final height in patients with severe GH deficiency was 163.9 cm (males) or 151.1 cm (female patients). In patients with partial GH insufficiency, the mean final heights were 166.2 and 157.7 cm, respectively, and in patients with GH deficiency caused by intracerebral tumours, 175.9 or 160.2 cm, respectively. Late established diagnosis, lack of (pituitary) GH during the time prior to 1980 or low frequency of injections per week were related to the fact that final height was often below the target height range. In four of 51 retested patients with childhood onset GH deficiency, a normal response of the pituitary gland to pharmacological testing was found, whereas all other patients still suffered from GH insufficiency. An increased amount of fat and a decreased amount of lean body mass as well as low bone mineral density (12 out of 15 patients) could be demonstrated at re-evaluation.

Adolescent↗