Michele Solimena

Cell Biology of Pancreatic Beta Cells

Previous and current research

Our laboratory is interested in the cell biology of pancreatic beta cells, which produce and secrete insulin. A deficient output of insulin secretion relative to metabolic demands is the ultimate cause of all forms of diabetes mellitus. Beta cells store the insulin hormone within organelles termed secretory granules, which undergo fusion with the plasma membrane and release insulin in response to high levels of circulating glucose. Prolonged glucose stimulation depletes beta cells of insulin secretory granules, which must be quickly replenished.

The main question we are addressing is how beta cells regulate the turnover of insulin secretory granules, including their biogenesis, exocytosis and destruction. A mechanistic description of these processes may provide insight into the pathogenesis of type 1 and type 2 diabetes and contribute to the development of novel approaches for its treatment. These studies may also have general implications in the field of neuropeptide and peptide-hormone secretion from neurons and other endocrine cells.

Specifically, we are addressing the following key questions:

-       How is a beta cell counting its own insulin secretory granules?

-       Which are the molecular signatures associated with granule aging?

-       What accounts for the reduced mobility and propensity to undergo exocytosis of older versus younger insulin secretory granules?

-       Which posttranscriptional mechanisms allow glucose and other stimuli to prompt the rapid biogenesis of insulin secretory granules?

-       Which retrograde signaling pathways couple the exocytosis of insulin secretory granules with regulation of beta cell gene expression and replication?

Moreover, we are pursuing:

-       The isolation and characterization of islet precursor cells as a potential source to generate new pancreatic islets for the therapy of diabetes

-       siRNA and small compound high-throughput screenings for the identification of genes and drugs of potential interest for the therapy of diabetes

A) Electron microscopy of insulin granules in a rat pancreatic islets

B) Differential imaging of younger (in green) vs older (in red) insluin granules in insulinoma cells

C) Nucleocytoplasmic translocation of the mRNA binding protein PTBP1 (in yellow) in beta cells upon stimulation with IBMX. Nuclei of islet cells are labeled in blue.

Future prospects and goals

To this aim we employ a large array of quantitative imaging, molecular, and biochemical approaches using insulinoma cultured cells, isolated pancreatic islets and genetically modified mice as main model systems. We actively collaborate with structural biologists, biophysicists, bioinformatics and mathematicians to deepen our understanding at the level of single molecules and to elaborate in-silico predictive models of these processes. Through the collaboration with clinicians at our University we extend our investigations to human islets from non-diabetic as well as diabetic subjects.

About

1986: M.D, University of Milano School of Medicine, Italy 1993: Ph.D., University of Milano School of Medicine, Italy 1986-1988: Postdoctoral work at Dept. of Pharmacology and Toxicology, University of Milano 1988-1993: Postdoctoral fellow at Dept. of Cell Biology, Yale Univ. School of Medicine, New Haven, CT, USA 1994-1999: Assistant Professor, Dept. of Internal Medicine, Yale Univ. School of Medicine 1999-2001: Associate Professor, Dept. of Internal Medicine and Cell Biology, Yale Univ. School of Medicine 2001-2002: Group Leader at MPI-CBG since 2003: Professor of Experimental Diabetology, Medical School, TU Dresden since 2007: Fellow of the Max Planck Society since July 2009: Professor of Molecular Diabetology, Medical School TU Dresden

Selected publications

Knoch K-P, Meisterfeld R, Kersting S, Bergert H, Altkrüger A, Jäger M, Saeger H-D, Solimena M. (2006): cAMP-dependent Phosphorylation of PTB1 Promotes the Expression of Insulin Secretory Granule Proteins in β-Cells. Cell Metabol. 3: 123-134.

Mziaut H, Trajkovski M, Kersting S, Ehninger A, Altkruger A, Lemaitre RP, Schmidt D, Saeger HD, Lee MS, Drechsel DN, Muller S, Solimena M. (2006): Synergy of glucose and growth hormone signalling in islet cells through ICA512 and STAT5. Nat Cell Biol. 8: 435-445.

Borgonovo B, Ouwendijk J, Solimena M. (2006): Biogenesis of secretory granules. Curr Opin Cell Biol. 18: 365-370.

Mziaut H, Kersting S, Knoch KP, Fan WH, Trajkovski M, Erdmann K, Bergert H, Ehehalt F, Saeger HD, Solimena M. (2008): ICA512 signaling enhances pancreatic beta-cell proliferation by regulating cyclins D through STATs. Proc Natl Acad Sci U S A. 105: 674-679.

Trajkovski M, Mziaut H, Schubert S, Kalaidzidis Y, Altkrüger A, Solimena M. (2008): Regulation of insulin granule turnover in pancreatic beta-cells by cleaved ICA512. J Biol Chem. 283: 33719-33729.

Süss C, Czupalla C, Winter C, Pursche T, Knoch KP, Schroeder M, Hoflack B, Solimena M. (2009): Rapid changes of mRNA-binding protein levels following glucose and 3-isobutyl-1-methylxanthine stimulation of insulinoma INS-1 cells. Mol Cell Proteomics. 8: 393-408.

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