Dennis Heutling

Insulin and Metformin Regulate Circulating and Adipose Tissue Chemerin

OBJECTIVE To assess chemerin levels and regulation in sera and adipose tissue from women with polycystic ovary syndrome (PCOS) and matched control subjects. RESEARCH DESIGN AND METHODS Real-time RT-PCR and Western blotting were used to assess mRNA and protein expression of chemerin. Serum chemerin was measured by enzyme-linked immunosorbent assay. We investigated the in vivo effects of insulin on serum chemerin levels via a prolonged insulin-glucose infusion. Ex vivo effects of insulin, metformin, and steroid hormones on adipose tissue chemerin protein production and secretion into conditioned media were assessed by Western blotting and enzyme-linked immunosorbent assay, respectively. RESULTS Serum chemerin, subcutaneous, and omental adipose tissue chemerin were significantly higher in women with PCOS (n = 14; P < 0.05, P < 0.01). Hyperinsulinemic induction in human subjects significantly increased serum chemerin levels (n = 6; P < 0.05, P < 0.01). In adipose tissue explants, insulin significantly increased (n = 6; P < 0.05, P < 0.01) whereas metformin significantly decreased (n = 6; P < 0.05, P < 0.01) chemerin protein production and secretion into conditioned media, respectively. After 6 months of metformin treatment, there was a significant decrease in serum chemerin (n = 21; P < 0.01). Importantly, changes in homeostasis model assessment–insulin resistance were predictive of changes in serum chemerin (P = 0.046). CONCLUSIONS Serum and adipose tissue chemerin levels are increased in women with PCOS and are upregulated by insulin. Metformin treatment decreases serum chemerin in these women.

Metformin Decreases the Adipokine Vaspin in Overweight Women With Polycystic Ovary Syndrome Concomitant With Improvement in Insulin Sensitivity and a Decrease in Insulin Resistance

OBJECTIVE—Polycystic ovary syndrome (PCOS) is associated with insulin resistance and obesity. Vaspin (visceral adipose tissue–derived serine protease inhibitor) levels increase with hyperinsulinemia and obesity. Currently, no data exists on vaspin in PCOS women. We therefore assessed mRNA and protein levels of vaspin, including circulating vaspin, from subcutaneous and omental adipose tissue of PCOS women and matched control subjects. Ex vivo regulation of adipose tissue vaspin and the effects of metformin treatment on circulating vaspin levels in PCOS subjects were also studied. RESEARCH DESIGN AND METHODS—Real-time RT-PCR and Western blotting were used to assess mRNA and protein expression of vaspin. Serum vaspin was quantified by enzyme-linked immunosorbent assay. The effects of d-glucose, insulin, and gonadal and adrenal steroids on adipose tissue vaspin were analyzed ex vivo. RESULTS—There were significantly higher levels of circulating vaspin (P < 0.05), vaspin mRNA (P < 0.05), and protein (P < 0.05) in omental adipose tissue of PCOS women. Interestingly, in omental adipose tissue explants, glucose significantly increased vaspin protein levels and secretion into conditioned media (P < 0.001). Also, after 6 months of metformin treatment, there was a significant decrease in serum vaspin levels in PCOS women (P < 0.001). Furthermore, multivariate regression analysis revealed that following metformin therapy, changes in circulating glucose levels were predictive of changes in serum vaspin levels (P = 0.014). CONCLUSIONS—We report, for the first time, elevated serum and omental adipose tissue levels of vaspin in overweight PCOS women and ex vivo regulation of vaspin, predominantly by glucose. More importantly, metformin treatment decreases serum vaspin levels, a novel observation.

Sympathetic Function in Human Carriers of Melanocortin-4 Receptor Gene Mutations

CONTEXT Melanocortinergic pathways clearly appear to be involved in obesity-associated sympathetic overactivity and its hemodynamic and thermoregulatory consequences. Individuals with dysfunctional mutations in the melanocortin-4 receptor gene (MC4R) are subject to obesity without developing hypertension. OBJECTIVE This study aimed at characterizing the impact of the MC4R on sympathetic nerve traffic relevant to the cardiovascular system in humans. PARTICIPANTS Participants included eight heterozygous carriers of MC4R mutations leading to a reduced function and control subjects matched for gender, age, and body mass index. MEASUREMENTS We investigated vasoconstrictive muscle sympathetic nerve activity (MSNA), a direct measure of central sympathetic nervous outflow. MSNA was recorded microneurographically from the peroneal nerve at supine rest and during apnea-induced sympathoexcitation. Sympathetic activity was correlated with serum leptin levels and hemodynamic and anthropometric data. RESULTS Individuals with MC4R impairment due to functional MC4R mutations were characterized by an inverse correlation between MSNA with body mass index and leptin levels, with the most obese subjects having the lowest MSNA. Resting MSNA, diastolic blood pressure, and heart rate tended to be lower in MC4R mutation carriers, and stimulated MSNA during apnea was significantly lower as compared with control subjects. CONCLUSION The fact that obese subjects with MC4R mutations show an inverse relationship between obesity and MSNA suggests that central sympathetic outflow to the vasculature might depend on functional melanocortinergic pathways. Their dysfunction could explain reduced sympathoexcitability, lower sympathetic nerve-induced lipolysis, and the fact that blood pressure is rarely elevated in this type of obesity.

Hormontherapie und Anti-Aging

ZusammenfassungDer Wunsch nach einem langen Leben ist tief in den meisten Menschen verwurzelt. Erfreulicherweise hat die Lebenserwartung in den letzten Jahrzehnten deutlich zugenommen. Auf der anderen Seite aber ist ein fortgeschrittenes Alter mit einer Zunahme der Morbidität verbunden. Daher ist es notwendig, Strategien zu entwickeln, die über eine alleinige Lebensverlängerung hinausgehend zu einer Anhebung der Lebensqualität im Alter führen. Verschiedene Substanzen, welche Alterungsprozesse bremsen sowie Krebs- und degenerativen Erkrankungen vorbeugen sollen, sind Gegenstand wissenschaftlicher Untersuchungen. Insbesondere Hormonen wird eine Anti-Aging-Wirkung zugeschrieben. Diese Übersicht stellt die hierzu vorliegenden Studiendaten vor.AbstractThe desire for a long life is deeply embedded in nearly all men. Fortunately life expectancy has remarkably increased over the past decades, on the other hand advancing age is frequently associated with a rise in morbidity. Above simply prolonging life there is a need to search for strategies to improve the quality of life in the elderly. Different substances to prevent premature aging, cancer and degenerative disorders appear to be promising candidates. Since it has been suggested that the decline of different hormones over the lifespan is closely related to the aging process replacement of these hormones may be a strategy against aging. Especially hormones like growth hormone, DHEA, testosterone and melatonin were considered as anti-aging agents.This review is focusing on the theoretical background and the previously known effects of different hormones to slow aging processes. Despite some promising results in a variety of studies conducted over the past years presently available data do not justify the broad use of hormones for anti-aging purposes. However, although no single hormone can be recognized as a ‘rejuvenating’ and life extending agent, some of their actions may be beneficial for the aging process.

Das polyzystische Ovarsyndrom

ZusammenfassungDas polyzystische Ovarsyndrom (PCOS) ist eine häufige endokrine Erkrankung und betrifft Frauen im gebärfähigen Alter. Das klinische Bild ist von Zyklusstörungen, Infertilität und Hyperandrogenismus geprägt. Es besteht ein erhöhtes Risiko für die Entwicklung eines Typ-2-Diabetes. Die Mehrzahl der Frauen mit einem PCOS ist übergewichtig und weist eine Insulinresistenz auf, welche die wesentliche Ursache für das ungünstige kardiovaskuläre Risikoprofil und das gehäufte Auftreten eines metabolischen Syndroms ist.AbstractPolycystic ovary syndrome (PCOS) is a common endocrine disorder affecting women in the reproductive age and is a major cause of anovulation, hyperandrogenism and infertility. Since obesity and insulin resistance are predominant features of women with PCOS, a variety of metabolic disturbances are associated. There is a marked increase in the risk of developing type-2 diabetes in these patients and a majority of women with PCOS will subsequently harbour an enhanced cardiovascular risk.

[Polycystic ovary syndrome. Prototype of a cardio-metabolic syndrome].

ZusammenfassungDas polyzystische Ovarsyndrom (PCOS) ist eine häufige endokrine Erkrankung und betrifft Frauen im gebärfähigen Alter. Das klinische Bild ist von Zyklusstörungen, Infertilität und Hyperandrogenismus geprägt. Es besteht ein erhöhtes Risiko für die Entwicklung eines Typ-2-Diabetes. Die Mehrzahl der Frauen mit einem PCOS ist übergewichtig und weist eine Insulinresistenz auf, welche die wesentliche Ursache für das ungünstige kardiovaskuläre Risikoprofil und das gehäufte Auftreten eines metabolischen Syndroms ist.AbstractPolycystic ovary syndrome (PCOS) is a common endocrine disorder affecting women in the reproductive age and is a major cause of anovulation, hyperandrogenism and infertility. Since obesity and insulin resistance are predominant features of women with PCOS, a variety of metabolic disturbances are associated. There is a marked increase in the risk of developing type-2 diabetes in these patients and a majority of women with PCOS will subsequently harbour an enhanced cardiovascular risk.

Molekulare Pathogenese endokriner Tumoren

Zum ThemaObgleich wesentliche Aspekte der Pathogenese endokriner Tumoren noch ungeklärt sind, lassen sich doch generelle Prinzipien der Tumorentstehung (Klonalität, Bedeutung von Onkogenen und Tumorsuppressorgenen sowie auch der Nachweis spontaner somatischer und der von Keimbahnmutationen) auf endokrine Tumore anwenden. Gerade familiäre endokrine Tumorsyndrome mit hoher Penetranz und variabler Expression beeinflussen unser Verständnis von der Pathogenese, aber auch von der Anwendbarkeit dieser genetischen Veränderungen auf klinisch relevante Fragestellungen in hohem Maße. Spezielle Aspekte der Pathogenese eines endokrinen Tumors bestehen v. a. auch darin, dass nicht nur Zellwachstum und -vermehrung, sondern auch die Funktion endokriner Zellen (i. e. Hormonsekretion) und damit klinischer Phänotyp der Erkrankung beeinflusst werden. Aus der unterschiedlichen Hormonsekretion oder auch der Rezeptorexpression lassen sich unmittelbar diagnostische und therapeutische Prinzipien ableiten. Einige Aspekte der molekularen Grundlagen endokriner Tumorentstehung werden exemplarisch an den Tumoren der Hypophyse, Schilddrüse und Nebenniere dargestellt.