Background
Diabetes is a growing epidemic with major impact on life style, health and life expectancy of the affected patients. Diabetes develops when systemic insulin concentrations are insufficient to control blood glucose homeostasis. Recent research of our lab and other groups has demonstrated that simultaneous deteriorations of both, number and function of insulin secreting beta cells are the cause of this shortage in insulin. Thereby, the different phases of diabetes pathogenesis are characterized by distinct alterations of beta cell mass and/or function. Based on these findings we believe that parallel targeting of beta cell function and mass is necessary to successfully treat diabetes. Thus, our group aims to discover novel therapeutic targets for type 1, type 2 and gestational diabetes by investigating the role of beta cell mass and function at distinct stages of diabetes pathogenesis and therapy.

Targeting beta cell function
Beta cell function exhibits enormous plasticity in response to various physiological and pathophysiological situations. Under normal conditions functional compensation of insulin secretion significantly contributes to preventing the development of type 2 diabetes and gestational diabetes. However, in diabetes pathogenesis beta cell dysfunction hinders functional compensation resulting in hyperglycemia. Thus, our projects addressing beta cell function aim to reveal the underlying mechanisms of functional compensation and beta cell dysfunction to protect and recover beta cell function in diabetes therapy.

Targeting beta cell mass
Also the number of beta cells can increase during obesity and pregnancy in an attempt to balance the greater insulin demand under these conditions. However, the regenerative mechanisms underlying this enlargement of beta cell mass as well as the reasons for its failure during the development of type 2 diabetes and gestational diabetes are unclear. We aim to understand the bases of beta cell regeneration to enable their induction in the prevention of type 2 diabetes and gestational diabetes. In addition, we use our expertise to facilitate the development of functionally mature beta cells from embryonic stem cells for cell replacement therapies of type 1 diabetes.

Approach
The unique approach of our lab in tackling these tasks is the study of islet of Langerhans mass and function under most physiological conditions. Thereby, we aim to account for the numerous local and systemic signals which regulate the complex physiology of islet pathology and regeneration inside the living organism. For that purpose we have established novel in situ and in vivo technical platforms to complement standard methods of islet research.

A key aspect of our work is the translation of our research to the human situation. Over the last years we have built up national and international collaborations to obtain acute human tissue, giving us the unique opportunity to employ our techniques for the investigation of human diabetes therapies.

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Figure 1: Longitudinal in vivo observation of autoimmune beta cell destruction during type 1 diabetes progression. Green: beta cells; Magenta: blood vessels; Grey: cell lightscatter. (Chmelova et al, Diabetes, 2015)

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Figure 2: Longitudinal in vivo observation of beta cell regeneration in the attempt to prevent type 2 diabetes development during high fat diet feeding (HFD). Green: beta cells; Magenta: blood vessels. (Chen et al, Diabetes, 2016)