Characterization of cellular plasticity in the pancreatic islet of Na+-D-glucose cotransporter 1 (SGLT1) knockout mice

• Applicant: Dr. Daniela Zdzieblo, Ph.D.
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 458690406

The sodium-glucose cotransporter 1 (SGLT1) is predominantly expressed in the small intestine regulating dietary glucose absorption, thereby directly affecting blood glucose homeostasis. Furthermore, SGLT1 is located in the kidney contributing to the reabsorption of filtered hepatic glucose. In view of these classical physiological roles, inhibition of SGLT1 is currently a promising therapeutic strategy in diabetic patients to prevent the increase in blood glucose levels after meal and to increase urinary glucose excretion. Recent data demonstrate that SGLT1 is expressed in a variety of organs comprising the heart, brain, lung, liver and the pancreas; however, organ-specific functions are only at the beginning to be understood. Own previously published data provide evidence that SGLT1 is important to maintain pancreatic islet integrity. Pancreatic islets of SGLT1 knockout mice display altered structural and functional characteristics. In addition, the cellular cytomorphology is disturbed with a decrease in insulin-secreting β- and increase in glucagon-secreting α-cells. Preliminary data suggest de- and/or transdifferentiation events, especially of β-cells, as underlying reasons that may account for these findings possibly to counteract the loss of α-cell-specific SGLT1 activity in the islet microenvironment. The aim of the proposed project is to characterize and trace de- and/or transdifferentiation processes in the SGLT1 knockout islet. Further, alterations in developmental programs during pancreatic lineage specification are studied. Transcriptome analyses should reveal underlying molecular programs. In view of its importance for blood glucose homeostasis, its interesting role as target for anti-hyperglycemic strategies and its relation to the loss of β-cell identity, the proposed project will significantly substantiate the understanding of pancreatic SGLT1 biology. Furthermore, the project will allow the identification of underlying molecular mechanisms, regulatory proteins and/or signaling pathways. In addition, the obtained findings will contribute to a more detailed understanding of β-cell identity changes, which is of high relevance, as the pancreatic islet is at the center of blood glucose homeostasis. In this context, preservation of cellular identities is fundamental to fine-tune the physiological level of circulating sugar in the body. Interestingly, there is increasing evidence that diabetes-associated alterations can inducevariations in islet cell compositions similar to those suggested for SGLT1 knockout islets. In this context, de- and/or transdifferentiation of mature β-cells were recently proposed to contribute to the loss of functional β-cell mass in the diabetic islet. Therefore, identifying key triggers and regulatory processes of β-cell plasticity is of great interest for new concepts addressing β-cell regeneration by reversing or pharmacologically blocking de- and/or transdifferentiation in the diseased islet.

• DFG Programme: Research Grants