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Research

Human Autopsy Tissue is important for our Research Photo: KM
Isolated RNA from tissue Photo: KM

Future therapy for diabetes: Save the beta-cell!

The Islet Biology Laboratory within the Centre for Biomolecular Interactions Bremen, University of Bremen is a purpose built islet research center, especially for diabetes research and includes research facilities for fundamental molecular and cellular biology and metabolism and for translational, human disease relevant research.

Concurrent with obesity, the global incidence of diabetes is increasing at an alarming rate, currently more than 420 Million people have diabetes. Our Lab seeks for a better mechanistic understanding of how the disease develops and for successful strategies to stop this epidemic.

Pancreatic β-cell death is the fundamental cause of type 1 diabetes (T1D) and a contributing factor to the reduced β-cell mass in type 2 diabetes (T2D). In both cases the mechanisms of beta-cell death are complex and as yet not fully defined. Modulation of apoptosis and identification of its stimuli is our approach towards the treatment of this metabolic disorder. Novel agents that can selectively block beta-cell apoptosis are urgently needed, since current therapies are directed towards alleviating only the symptoms and not the cause of the disease.

We work interdisciplinary and with multiple cellular in vitro and in vivo experimental models up to human autopsy and biopsy tissue. The identification of environmental factors, which lead to the disease is the 1st step towards its intervention. We look at viral and inflammatory pathways and the beta-cells’ response to stress, hyperactivation and hypernutrition.

The beta-cell has a very limited capacity to compensate for such environmental stress factors. With the identification of disturbances in the Hippo developmental pathway, we hope to induce beta-cell restoration and regeneration and thus, reversal of the disease in future.

portrait of Kathrin Maedler in the lab
Our aim is to restore functional beta-cells in patients with diabetes.
picture of complex inflammation in human pancreatic islets
Wei He et al., TLR4 triggered complex inflammation in human pancreatic islets. BBA Molecular Basis of Disease 2018

Secreted pro-inflammatory cytokines and chemokines into the proximity of the β-cell induce their destruction and impair insulin secretion. Several studies show that through several stimuli, intra-islet inflammation is causative for β-cell failure in both Type 1 and Type 2 Diabetes. A pro-inflammatory network then leads to potentiation of cytokine secretion and b-cell death

Only a combination of blocking immune-mediated beta-cell destruction together with restoration of beta-cell survival may therefore be successful strategy for future diabetes therapy.

Wei He et al., TLR4 triggered complex inflammation in human pancreatic islets. BBA Molecular Basis of Disease 2018

For a successful therapy both, beta cell death as well as their loss of function needs to be targeted, and it is of little interest, what comes earlier.

Clearly, beta cell loss is causative for both types of diabetes and thus, the elucidation of the molecular processes associated with beta cell apoptosis and maintenance of beta cell mass is critical to develop new therapeutic strategies to prevent and/or delay these pathological events, since current treatment strategies do not -yet- include the preservation of the endogenous beta cell mass. Inhibiting pro-apoptotic or potentiating anti-apoptotic signaling can serve as potential strategy for restoring beta cell survival in diabetes.

We identified the serine/threonine kinase Mammalian Sterile 20-like kinase 1 (MST1) as a critical regulator of apoptotic beta cell death and dysfunction. MST1 activates several apoptotic signaling pathways, leading to a vicious cycle of cell death.

We found that MST1 is strongly activated in a diabetic beta cell and induces not only its death but also impairs insulin secretion through promoting proteasomal degradation of key beta cell transcription factor PDX1 which is critical for insulin gene expression.

Pre-clinical studies in various diabetic animal models show that MST1 deficiency remarkably restores normoglycemia and beta cell function and prevents the development of diabetes. Importantly, MST1 deficiency can also restore survival in already fully diabetic beta cells.

Modulation of apoptosis through MST1 inhibition may serve as target for the development of novel therapies for diabetes, which trigger the cause of the disease, namely the destruction of the beta cells.

The major current focus of our investigation is to identify and test the efficacy of potent inhibitors of this death signaling pathway to protect beta cells against the effects of autoimmune attack in type 1 diabetes and preserve beta cell mass and function in type 2 diabetes.

 

Amin Ardestani & Kathrin Maedler. MST1: a promising therapeutic target to restore functional beta cell mass in diabetes. Diabetologia 59, 1843-9 (2016).

Amin Ardestani et al. MST1 is a key regulator of beta cell apoptosis and dysfunction in diabetes. Nature Medicine, 2014 VOLUME 20 , NUMBER 4 , APRIL 2014

Amin Ardestani & Kathrin Maedler. The Hipposignalingpathway in pancreatic β-cells: functionsandregulations, EndocrRev. 2017 Oct 18. doi: 10.1210/er.2017-00167.

Amin Ardestani, BlazLupse& Kathrin Maedler. Hippo Signaling: Key Emerging Pathway in Cellular and Whole-Body Metabolism. Trends EndocrinolMetab. 2018 May 5. pii: S1043-2760(18)30089-4

microscopic images of MST1 is a key regulator of beta cell apoptosis and dysfunction in diabetes
Amin Ardestani et al. MST1 is a key regulator of beta cell apoptosis and dysfunction in diabetes. Nature Medicine, 2014 VOLUME 20 , NUMBER 4 , APRIL 2014
microscopic image
Amin Ardestani et al. MST1 is a key regulator of beta cell apoptosis and dysfunction in diabetes. Nature Medicine, 2014 VOLUME 20 , NUMBER 4 , APRIL 2014
image of the Hippo signaling pathway in pancreatic ß-cells
Amin Ardestani & Kathrin Maedler. The Hippo signaling pathway in pancreatic β-cells: functions and regulations, Endocr Rev. 2017 Oct 18. doi: 10.1210/er.2017-00167.
microscopic image of Pro-proliferative and anti-apoptotic action of exogenously introduced YAP in pancreatic β-cells
Ting Yuan, Sahar Rafizadeh, Zahra Azizi, Blaz Lupse, Kanaka Durga Devi Gorrepati, Sushil Awal, Jose Oberholzer, Kathrin Maedler & Amin Ardestani: Pro-proliferative and anti-apoptotic action of exogenously introduced YAP in pancreatic β-cells. JCI Insight. 2016 Nov3;1(18):e86326.

The essential points toward the investigations of Hippo functions in the beta-cell (Endocr Rev. 2017):

• The Hippo pathway regulates pancreas development including pancreatic progenitor cell proliferation, cell specification and differentiation as well as growth and cellular plasticity of the pancreas.

• Hippo signaling is very complex and dynamic and interacts and crosstalks with many other signaling pathways, which regulate b-cell survival, such as the intrinsic apoptotic pathway, mTOR, PI3K-AKT and MAPK-JNK to respond to exogenous and endogenous stimuli.

• Hippo pathway components control various aspects of β-cell homeostasis including b-cell function, survival and proliferation.

• The Hippo terminal effector YAP is not expressed in mature endocrine islet cells and its reconstitution promotes β-cell proliferation and survival.

• Targeting Hippo pathway could be an essential therapeutic approach for β-cell regenerative therapy.

 

Amin Ardestani & Kathrin Maedler. The Hipposignalingpathway in pancreatic β-cells: functionsandregulations, EndocrRev. 2017 Oct 18. doi: 10.1210/er.2017-00167.

Amin Ardestani, BlazLupse& Kathrin Maedler. Hippo Signaling: Key Emerging Pathway in Cellular and Whole-Body Metabolism. Trends EndocrinolMetab. 2018 May 5. pii: S1043-2760(18)30089-4

microscopic image of viral infection in the pancreas
Niels Busse et al., Detection and localization of viral infection in the pancreas of patients with type 1 diabetes using short fluorescently-labelled oligonucleotide probes. Oncotarget. 2017

Enteroviruses, specifically of the Coxsackie B virus family, may directly trigger islet autoimmunity and type 1 diabetes, but their detection in the pancreas has been difficult.
Here we designed a panel of fluorescently labeled oligonucleotide probes, which specifically bind to the enteroviral genome of the picornaviridae family. They allow detection of very low copies of the virus genome in tissue samples from T1D patients. With these probes enteroviral RNA was detected with high sensitivity and specificity in infected cells and tissues.
Further recent in depth analysis of mechanisms of EV-mediated beta-cell destruction identified strong association of islet cell infection and beta-cell death and dysfunction.
Our current work will identify specific virus sequences as well as pancreatic localization of the viruses in diabetes.