Abhängig ob ein Patient/eine Patientin das Krankheitsbild des Typ-1- oder Typ-2-Diabetes aufweist, wird die Therapieform gewählt. So benötigen Patienten und Patientinnen mit Typ-1-Diabetes aufgrund des Insulinmangels, eine Insulintherapie. In diesem Symposium werden neue Forschungsansätze für Typ-1-Diabetes diskutiert mit einem Fokus auf die Betazelle als Zielstruktur der Diabetestherapie.
Die Therapie des Typ-2-Diabetes umfasst eine größere Auswahl an Medikamenten mit dem Ziel die Insulinproduktion und Funktion der Betazelle zu verbessern oder/und den Zuckerstoffwechsel positiv zu beeinflussen. Beispiele hierfür sind GLP-1 Analoga, Sulfonylharnstoffe, Metformin oder alpha-Glucosidase Hemmer. Eine Kombinationstherapie kann Vorteile für Patienten und Patientinnen mit sich bringen, kann aber auch aufgrund der Kombination von unterschiedlichen Präparaten erweiterte Nebenwirkungen aufweisen. In diesem Teil werden neue Therapiemöglichkeiten aus der präklinischen Forschung beschrieben, u.a. Duale- oder Triple-Agonisten welche einen Mehrwert für die Behandlung des Diabetes aufzeigen können.
15:02 Uhr
Preisverleihung Hans-Christian-Hagedorn-Projektförderung
15:07 Uhr
Multiple Agonisten
15:27 Uhr
Betazellen als Ziel der Diabetestherapie: Masse oder Funktion?
15:47 Uhr
Glucagonotropic effect of KCl but not sulfonylureas on alpha cells from SUR1-KO mice
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Autor:innen:
E. Früh (Braunschweig, DE)
D. Brüning (Braunschweig, DE)
I. Rustenbeck (Braunschweig, DE)
Background and aims: Like pancreatic beta-cells, pancreatic alpha-cells release their hormone by depolarization-induced exocytosis. However the preceding stimulus secretion coupling has remained a matter of debate.
Methods: Insulin and glucagon were determined by ELISA from the same efflux fraction of batch-perifused NMRI and SUR1-KO mouse islets. Alpha-cells were isolated from these islets by incubation with alloxan and culturing for 24h. In such cells the membrane potential was determined by patch-clamping and cytosolic Ca2+ concentration ([Ca2+]i) by microfluorometry. Identity was confirmed by immunofluorescence.
Results: Alloxan-surviving islet cells were considered as bona fide alpha-cells when they reacted to both, arginine and glutamate. Immunofluorescence confirmed this to be the case in ca. 85%. Whereas KCl reproducibly depolarized the plasma membrane potential of alpha-cells by 11 mV (15 mM) and by 29 mV (40 mM), 500 µM tolbutamide had a much more variable effect on membrane potential and [Ca2+]i, but was entirely ineffective on SUR1-KO alpha-cells. In the presence of 1 mM glucose and 1 µM clonidine (to block insulin secretion), 500 µM tolbutamide had a modest glucagonotropic effect on NMRI islets, but was ineffective on SUR1-KO islets. In both cases 40 mM KCl led to marked and lasting increase of glucagon secretion.
Conclusion: When paracrine inhibition by beta-cells is prevented, strong depolarization by KCl results in a marked and lasting glucagonotropic effect. The modest effect of sulfonylureas in normal alpha-cells is absent in SUR1-KO islets, emphasizing the limited role of KATP-dependent signaling in glucagon release.
15:57 Uhr
Effects of liraglutide plus PYY3-36 vs. Roux-en-Y gastric bypass on hypothalamic gene expression
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Autor:innen:
U. Dischinger (Würzburg, DE)
J. Hasinger (Würzburg, DE)
T. Heckel (Würzburg, DE)
T. Bischler (Würzburg, DE)
C. Otto (Würzburg, DE)
M. Hankir (Würzburg, DE)
F. Seyfried (Würzburg, DE)
M. Fassnacht (Würzburg, DE)
Background: Central effects of Roux-en-Y gastric bypass (RYGB) are highly suggestive, but still not entirely elucidated. Additionally, it is unclear, if they are cause or consequence of the pronounced weight loss. To further clarify this, we compared the effects of RYGB and a chronic systemic administration of glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine 3-36 (PYY3-36) on hypothalamic gene expression in a standardized experimental setting.
Methods: High-fat diet-induced obese male Wistar rats were randomized into six groups: RYGB, sham-operation, liraglutide, PYY3-36, PYY3-36+liraglutide, saline. Animals were kept on a free choice high- and low-fat diet. Food intake, preference and body weight were measured daily for 4 weeks. Open field (OF) and elevated plus maze (EPM) tests were performed. RNA sequencing and qPCR were performed with hypothalamic mRNA.
Results: RYGB and combined PYY3-36+liraglutide treatment led to a similar and plateaued weight loss and also reduced overall food intake and (less pronounced) high-fat preference compared to controls. The animals showed no signs of abnormal behavior in OF or EPM. RYGB led to a vast amount of upregulated genes and pathways in the hypothalamus, particularly the leptin receptor and its mediating pathways PI3K-Akt and JAK-STAT. By contrast, no relevant changes could be detected in PYY3-36+liraglutide, liraglutide and PYY treated animals.
Conclusions: While RYGB leads to pronounced hypothalamic changes, this is not the case for PYY3-36+liraglutide treated animals with a similar body weight course. This underlines the potential of RYGB as a “neurosurgical” intervention and might be the cause of the durability of its effectivity.
16:07 Uhr
Regulation of the activin-follistatin hormonal system in relation to glucometabolic status in mice, in healthy humans and in obese individuals undergoing bariatric surgery
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Autor:innen:
N. Perakakis (Boston, US)
A. Kokkinos (Athens, GR)
A. Joshi (Boston, US)
N. Peradze (Boston, US)
N. Tentolouris (Athens, GR)
W. Ghaly (Boston, US)
D. Tsilingiris (Athens, GR)
A. Alexandrou (Athens, GR)
C. Mantzoros (Boston, US)
Objective: Activins and their inhibitors, follistatins, control muscle growth and are being developed therapeutically against obesity and T2D. We aimed to investigate the tissue-expression profile of the activins-follistatins in diet-induced obesity(DIO)-prone C57BL/6J and DIO-resistant A/J mice and to assess whether activins, similarly to our recent report for follistatin, are regulated by glucose or lipids and predict the metabolic improvement after bariatric surgery (BS) in humans.
Methods: The expression of genes encoding activins, follistatins and their receptors were measured in white (WAT), brown (BAT) adipose tissue and skeletal muscle at 0, 3-4 and 8-10 weeks of high-fat diet (HFD) vs chow in C57BL/6J and A/J mice. Circulating activins were measured in a) healthy humans (n=32) during a 6h-oral and iv glucose and lipid intake, b) morbidly obese people undergoing gastric banding, Roux-en-Y bypass or sleeve gastrectomy in two clinical studies (n=14 and n=27).
Results: Follistatin mRNA levels in WAT, BAT and muscle are 80-90% lower in A/J compared to C57BL/6J mice. In C57BL/6J, HFD increases the mRNA expression of follistatin and follistatin-like 3 and decreases of INHBA (encoding activin A) in WAT, whereas it increases the expression of INHBB (encoding activin B) in WAT and BAT. In humans, glucose intake downregulates circulating activin A,B and AB. Three months after BS, activin AB (~25%) and its ratio to follistatin increases and predicts the weight loss and improvement in insulin sensitivity six months postoperatively.
Conclusion: The expression and circulation of activins-follistatins are related to glucometabolic status and predict metabolic outcomes prospectively after BS.
16:17 Uhr
Diskussion & Fragen