Hans-Ewald Hohmeier, MD, PhD

Faculty Member, Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center

Position

Assistant Professor Department of Medicine, Division of Endocrinology, Metabolism, and Nutrition Duke University Medical Center

Contact

Carmichael Building

919 479 2342

hans.hohmeier@duke.edu

Summary

Hans Hohmeier is an Assistant Professor in the Department of Medicine (Division of Endocrinology, Metabolism, and Nutrition). His research interests focus on factors that control function and viability of mature islet beta-cells and how these factors can be exploited to prevent the loss of beta-cell mass and function in diabetes. Recently, he and his group have successfully identified transcription factors that increase proliferation and function of mature beta-cells. As they continue to investigate how these transcription factors and some of their target genes enhance beta-cell function, increase beta-cell proliferation and provide protection against beta-cell stressors, he and his group hope to discover target genes that can be further developed for the treatment of diabetes. 

PhD, Georg August Universität Göttingen, Germany. MD, Medizinische Hochschule Hannover, Universität Hannover, Germany

Both major forms of diabetes are characterized by a decrease in functional β-cell mass. Type 1 diabetes is caused by autoimmune destruction of pancreatic β-cells, whereas type 2 diabetes involves the combined loss of glucose-stimulated insulin secretion (GSIS) and a decrease of β-cell mass by nonautoimmune mechanisms.  Finding mechanisms that will increase functional islet β-cell mass by enhancing islet β-cell proliferation, survival, and function is the major goal of my research group.

In collaboration with Dr. Christopher Newgard, the Director of the Duke Molecular Physiology Institute, we have demonstrated that two homeodomain transcription factors involved in islet β-cell development, Pdx-1 and Nkx6.1, are able to induce robust increases in islet-cell proliferation when overexpressed in adult rodent islets. Overexpression of Nkx6.1 stimulates mainly β-cell proliferation, whereas Pdx-1 stimulates both α-cell and β-cell proliferation (1,2). Combined overexpression of Pdx-1 and Nkx6.1 led to an additive effect on islet-cell proliferation suggesting that Pdx-1 and Nkx6.1 have discrete activating mechanisms (2). Consistent with this observation, we demonstrated that overexpression of Pdx-1 and Nkx6.1 activate different cell cycle control genes (2,3). Overexpression of Pdx-1 upregulates expression of cyclins D1 and D2 and inhibition of cyclin D activation using a cdk4 inhibitor blocks Pdx-1-stimulated proliferation completely, but does not affect Nkx6.1 stimulated islet cell proliferation. Further investigation of the Nkx6.1 pathway revealed that the Nkx6.1 proliferative response is dependent on upregulation of the orphan nuclear receptors Nr4a1 and Nr4a3. The Nr4a factors in turn activate expression of key positive cell cycle regulators (cyclin E1 and E2F) while also causing degradation of the cell cycle repressor protein, p21, via activation of elements of the anaphase promoting complex (3).

We also investigated the functional impact overexpression of these transcription factors has. Overexpression of Pdx-1 maintains glucose-stimulated insulin secretion (GSIS), while overexpression of Nkx6.1 actually enhances GSIS. This distinguishes these two transcription factors among the reagents that are capable of increasing β-cell proliferation. In most cases induction of β-cell proliferation causes a loss of function such as insulin content or GSIS. The potentiation of GSIS by Nkx6.1 is mediated by a prohormone, VGF, and one of its processed peptides, TLQP-21 (4). TLQP-21 has a second positive effect on β-cell   function in that it protects β-cells from apoptotic cell death (4). 

We continue to explore the mechanisms by which Pdx-1, Nkx6.1, and their target genes increase β-cell proliferation, enhance β-cell function, and protect against β-cell stressors with the goal of discovering target genes that can be developed for the treatment of diabetes.

Staff

Lisa Poppe

Graduate/Medical Students

Jonathan Haldeman