Beta Cell Therapies for Preventing Type 1 Diabetes: From Bench to Bedside

Abstract

Type 1 diabetes (T1D) is a chronic metabolic disease characterized by insulin deficiency, generally resulting from progressive autoimmune-mediated destruction of pancreatic beta cells. While the phenomenon of beta cell autoimmunity continues to be an active area of investigation, recent evidence suggests that beta cell stress responses are also important contributors to disease onset. Here we review the pathways driving different kinds of beta cell dysfunction and their respective therapeutic targets in the prevention of T1D. We discuss opportunities and important open questions around the effectiveness of beta cell therapies and challenges for clinical utility. We further evaluate ways in which beta cell drug therapy could be combined with immunotherapy for preventing T1D in light of our growing appreciation of disease heterogeneity and patient endotypes. Ultimately, the emergence of pharmacologic beta cell therapies for T1D have armed us with new tools and closing the knowledge gaps in T1D etiology will be essential for maximizing the potential of these approaches.

DNA damage to β cells in culture recapitulates features of senescent β cells that accumulate in type 1 diabetes

“…Senescent β cells in NOD mice are characterized by upregulation of p21 and p16 Ink4a , DDR activation, a Bcl-2-mediated prosurvival phenotype, elevated SA-βgal activity and a SASP involving IL-6, Igfbp3, Serpine1, Mmp2, and Flnb [ 7 ]. The presence of persistent DDR, selective Bcl-2 upregulation and contents of SASP generally differentiates stress-induced senescence in β cells that occurs in NOD mice from natural aging and β cell senescence as reported in mouse models of Type 2 Diabetes and maturity onset diabetes of the young (MODY) [ [10] , [11] , [12] , [13] ]. Notably, in NOD mice, elimination of senescent β cells with Bcl-2 family inhibitors (senolytic compounds), or suppression of SASP with Bromodomain ExtraTerminal domain inhibitors, halts disease progression [ 7 , 14 ].…”

Islet Dysfunction in a Novel Transgenic Model of T Cell Insulitis

“…Increased islet size is also observed in human TID, where T1D organ donors that had insulitis had a significantly higher insulin-positive beta cell area compared to T1D organ donors without insulitis [ 19 ]. The increase in beta-cell area is thought to be due to inflammatory or metabolic stress [ 43 , 44 , 45 ]. The BL/6-CD3FLAGmIR transgenic mice had an increased islet size and higher number of beta-cell nuclei as compared to BL/6 mice from 15 to 35 weeks of age.…”

Heterogeneity of Diabetes: β-Cells, Phenotypes, and Precision Medicine: Proceedings of an International Symposium of the Canadian Institutes of Health Research’s Institute of Nutrition, Metabolism and Diabetes and the U.S. National Institutes of Health’s National Institute of Diabetes and Digestive and Kidney Diseases

“…The development of senescent b-cells is progressive, accumulating as the disease progresses, and heterogeneous, with differences in the proportion of senescent b-cells among islets and individuals. Importantly, senescent b-cells are potentially targetable (73), and indeed antisenescence drugs were found to reduce the incidence of diabetes in NOD mice (61). Much more work needs to be done to understand senescence in both type 1 and type 2 diabetes, including an understanding of the specific triggers, how senescence relates to other states of b-cell dysfunction in diabetes, and how senescent b-cells may be best targeted in disease.…”