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Roman Muff, Walter Born and Jan A Fischer

Muff R, Born W, Fischer JA. Calcitonin, calcitonin gene-related peptide, adrenomedullin and amylin: homologous peptides, separate receptors and overlapping biological actions. Eur J Endocrinol 1995;133:17–20. ISSN 0804–4643

Calcitonin, calcitonin gene-related peptide, adrenomedullin and amylin are structurally related peptides with N-terminal 6–7 amino acid ring structures linked by a disulfide bridge and with amidated C-termini. Among the related bioactive peptides, the structures of the calcitonin receptor and subtypes thereof have been identified so far through molecular cloning. Cross-reaction between receptors of calcitonin, calcitonin gene-related peptide, adrenomedullin and amylin, as well as overlapping biological actions, anticipate that the respective receptors belong to a family of G-protein-coupled receptors that include those of parathyroid hormone, secretin and vasointestinal peptide.

Jan A Fischer, Klinik Balgrist, Forchstrasse 340, CH-8008 Zurich, Switzerland

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Christoph Dodt, Karl-Josef Theine, Dirk Uthgenannt, Jan Born and Horst Lorenz Fehm

Dodt C, Theine K-J, Uthgenannt D, Born J, Fehm HL. Basal secretory activity of the hypothalamo–pituitary–adrenocortical axis is enhanced in healthy elderly. An assessment during undisturbed nighttime sleep. Eur J Endocrinol 1994;131:443–50. ISSN 0804–4643

The process of aging is characterized by a disturbed neuroendocrine regulation, including a changed secretory activity of the hypothalamo–pituitary–adrenocortical (HPA) axis. In the present study adrenocorticotropin (ACTH) and cortisol secretion was monitored during nocturnal sleep (controlled by somnopolygraphy) in healthy aged men (N = 10, age range 70–92 years, mean 78.2 years) and women (N = 10, age range 70–88 years, mean 78.6 years), and in young male controls (N = 16, age range 20–34 years, mean 24.9 years). Blood was drawn every 15 min. Most important, basal HPA secretory activity was enhanced distinctly in the elderly, as indicated by significantly elevated nadirs of plasma cortisol and ACTH concentrations occurring during early nocturnal sleep (p < 0.001, compared to young controls) and by elevated average levels of cortisol and ACTH between 23.00 and 03.00 h (p < 0.001). The first rise in nocturnal plasma cortisol began, on average, 67 min earlier than in young controls (p < 0.005). Changes of endocrine activity were associated with marked reductions of slow-wave sleep (SWS, p < 0.05) and rapid eye movement (REM) sleep in the elderly (p < 0.01), while time awake and in stage 1 sleep was increased. The REM sleep coincided with decreased HPA secretory activity, irrespective of age, indicating that the link between the ultradian sleep structure and the secretory HPA activity is maintained in the elderly. It is concluded that the agerelated elevation of basal HPA secretory activity is of central nervous origin, leading to a phase advance of the circadian pacemaker and an elevation of the basal secretory rate of the HPA axis. Considering complementary results from animal studies, it is suggested that basal HPA hypersecretion associated with SWS deficits in the elderly are markers for an altered function of hippocampal corticosteroid receptors which are involved in the tonic inhibition of HPA secretory activity.

C Dodt, Klinische Forschergruppe "Klinische Neuroendokrinologie", Zentrum Innere Medizin, Medizinische Universität zu Lübeck. Ratzeburger Allee 160, D-23538 Lübeck, Germany

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Jan Born, Ina Ditschuneit, Martin Schreiber, Christoph Dodt and Horst L Fehm

Born J, Ditschuneit I, Schreiber M, Dodt C, Fehm HL. Effects of age and gender on pituitary-adrenocortical responsiveness in humans. Eur J Endocrinol 1995;132:705–11. ISSN 0804–4643

This study compared plasma concentrations of adrenocorticotropin (ACTH) and cortisol in young men (N = 10, mean age 24.4 years), young women (N = 10, mean age 25.4 years), old men (N = 8, mean age 81.6 years) and old women (N = 8. mean age 83.5 years) under basal resting conditions and after stimulation with either human corticotropin-releasing hormone (hCRH, 100 μg iv) or a combined injection of hCRH (100 μg and arginine vasopressin (VP, 0.5 IU iv). Basal secretion of cortisol did not differ among groups, but basal concentrations of ACTH were diminished in young women (p < 0.01), indicating an enhanced adrenal sensitivity to ACTH in these subjects. Pituitary responses to hCRH did not differ between young men and women. However, responses to hCRH/VP were stronger in the young females (p < 0.01), suggesting an enhanced pituitary responsiveness to the augmenting effect of VP on ACTH release in this group. Pituitary-adrenal secretory responses were greater in old than in young men after sole injection of hCRH (p < 0.05) and even more so after combined injection of hCRH/VP (p < 0.01). In old women, pituitary-adrenal secretory responses were also greater than in young women (p < 0.05). But, in particular for responses to hCRH/VP, these effects were less distinct than within the men. Results indicate an enhancing effect of age on pituitary responsiveness to the hypothalamic secretagogues hCRH and VP, modulated by the subject's gender.

Jan Born, Klinische Forschergruppe, Klinische Neuroendokrinologie, Medizinische Universität zu Lübeck, Haus 23 a, Ratzeburger Allee 160, 23538 Lübeck, Germany

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Kerstin M Oltmanns, Baerbel Dodt, Bernd Schultes, Hans H Raspe, Ulrich Schweiger, Jan Born, Horst L Fehm and Achim Peters

Objective: The prevalence of type 2 diabetes mellitus is increasing rapidly in industrialized countries, and adrenal glucocorticoids may intensify this disease. We sought to assess the relationship between diabetes-associated metabolic disturbances and cortisol concentrations in patients with type 2 diabetes.

Design: We investigated 190 type 2 diabetic patients who volunteered from a population study of 12 430 people in Luebeck and its suburbs. The target population comprised men and women born between 1939 and 1958 who initially received a postal questionnaire about their health status. We identified 346 subjects with confirmed diabetes mellitus and 216 patients participated in the study. Patients with type 1 diabetes were excluded.

Methods: Five salivary cortisol samples were collected before and after lunch, in the evening and then the next morning before and after standing. Clinical variables associated with diabetes were measured and correlated with cortisol concentrations.

Results: None of the cohort had salivary cortisol concentrations that exceeded the normally accepted range. Based on cortisol samples collected just prior to a standard lunch, the cohort was divided into tertiles. Cortisol was positively related to: fasting blood, urinary and postprandial glucose; glycosylated hemoglobin; and systolic and diastolic blood pressures (all P < 0.05). Cortisol concentrations also correlated with the relative abdominal mass (P < 0.05) when patients with marked glucosuria were excluded.

Conclusions: The degree of severity of several clinical measures of type 2 diabetes correlates with cortisol concentrations. Moreover, the results provide evidence for a positive relationship between metabolic disturbances and cortisol concentrations that are within the accepted normal range.

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Karen L van Hulst, Walter Born, Roman Muff, Cor Oosterwijk, Marinus A Blankenstein, Cornelis JM Lips, Jan A Fischer and Jo WM Höppener

Abstract

Objective: Human islet amyloid polypeptide (hIAPP), also named amylin, is a pancreatic β cell protein implicated in the pathogenesis of pancreatic islet amyloid formation and type 2 diabetes mellitus. To study the (patho)physiological roles of hIAPP, we have generated transgenic mice that overexpress hIAPP mRNA, in relation to endogenous mouse IAPP (mIAPP) mRNA, in pancreatic β cells. The biological activity of human and mouse IAPP derived from pancreatic extracts was determined.

Methods: Pancreatic and plasma extracts of transgenic and control mice were analyzed by reversedphase high-performance liquid chromatography (HPLC) and radioimmunoassay, yielding a separation of hIAPP from mIAPP. Biological activity of immunoreactive human and mouse IAPP components derived from pancreatic extracts was assessed by calcitonin receptor-mediated stimulation of cyclic AMP accumulation in T47D human breast carcinoma cells.

Results: The predominant immunoreactive human and mouse IAPP gene products had the retention times on HPLC analysis of the corresponding synthetic peptides. The ratio of bioactive over immunoreactive hIAPP and mIAPP was 0·93 ±0·18 and 1·19 ±0·56 respectively. In extracts of two plasma pools from 4 transgenic animals, hIAPP was 4·6- to 7-fold more abundant than mIAPP.

Conclusion; This study has shown that correctly processed hIAPP produced in transgenic mouse pancreatic β cells exhibits full biological activity. The results validate these transgenic mice for the study of (patho)physiological roles of hIAPP in vivo.

European Journal of Endocrinology 136 107–113