Diabetes is a leading cause of morbidity and mortality worldwide, and predicted to affect over 500 million people by 2030. However, this growing burden of disease has not been met with a comparable expansion in therapeutic options. The appreciation of the pancreatic β-cell as a central player in the pathogenesis of both type 1 and type 2 diabetes has renewed focus on ways to improve glucose homeostasis by preserving, expanding and improving the function of this key cell type. Here, we provide an overview of the latest developments in this field, with an emphasis on the most promising strategies identified to date for treating diabetes by targeting the β-cell.

Targeting the pancreatic β-cell to treat diabetes

Type 1 and type 2 diabetes are characterized by chronic inflammation; both diseases involve pancreatic islet inflammation, while systemic low-grade inflammation is a feature of obesity and type 2 diabetes. Long-term activation of the innate immune system impairs insulin secretion and action, and inflammation also contributes to macrovascular and microvascular complications of diabetes. However, despite strong preclinical evidence and proof-of-principle clinical trials demonstrating that targeting inflammatory pathways can prevent cardiovascular disease and other complications in patients with diabetes, there are still no approved treatments for diabetes that target innate immune mediators. Here, we review recent advances in our understanding of the inflammatory pathogenesis of type 1 and type 2 diabetes from a translational angle and point out the critical gaps in knowledge that need to be addressed to guide drug development. The authors consider the inflammatory basis of type 1 and type 2 diabetes. In particular, they focus on the role of IL-1β in both diseases and discuss the feasibility of targeting innate immune mechanisms in the clinic.

Targeting innate immune mediators in type 1 and type 2 diabetes.

Protective role of sodium butyrate, a HDAC inhibitor on beta-cell proliferation, function and glucose homeostasis through modulation of p38/ERK MAPK and apoptotic pathways: study in juvenile diabetic rat.

Divalent Metal Transporter 1 Regulates Iron-Mediated ROS and Pancreatic β Cell Fate in Response to Cytokines

Cell-type-specific gene expression is physiologically modulated by the binding of transcription factors to genomic enhancer sequences, to which chromatin modifiers such as histone deacetylases (HDACs) are recruited. Drugs that inhibit HDACs are in clinical use but lack specificity. HDAC3 is a stoichiometric component of nuclear receptor co-repressor complexes whose enzymatic activity depends on this interaction. HDAC3 is required for many aspects of mammalian development and physiology, for example, for controlling metabolism and circadian rhythms. In this Review, we discuss the mechanisms by which HDAC3 regulates cell type-specific enhancers, the structure of HDAC3 and its function as part of nuclear receptor co-repressors, its enzymatic activity and its post-translational modifications. We then discuss the plethora of tissue-specific physiological functions of HDAC3.

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Integrative regulation of physiology by histone deacetylase 3

Histone deacetylases (HDACs) are promising pharmacological targets in cancer and autoimmune diseases. All 11 classical HDACs (HDAC1–11) are found in the pancreatic beta cell, and HDAC inhibitors (HDACi) protect beta cells from inflammatory insults. We investigated which HDACs mediate inflammatory beta cell damage and how the islet content of these HDACs is regulated in recent-onset type 1 diabetes. The rat beta cell line INS-1 and dispersed primary islets from rats, either wild type or HDAC1–3 deficient, were exposed to cytokines and HDACi. Molecular mechanisms were investigated using real-time PCR, chromatin immunoprecipitation and ELISA assays. Pancreases from healthy children and children with type 1 diabetes were assessed using immunohistochemistry and immunofluorescence. Screening of 19 compounds with different HDAC selectivity revealed that inhibitors of HDAC1, -2 and -3 rescued INS-1 cells from inflammatory damage. Small hairpin RNAs against HDAC1 and -3, but not HDAC2, reduced pro-inflammatory cytokine-induced beta cell apoptosis in INS-1 and primary rat islets. The protective properties of specific HDAC knock-down correlated with attenuated cytokine-induced iNos expression but not with altered expression of the pro-inflammatory mediators Il1α, Il1β, Tnfα or Cxcl2. HDAC3 knock-down reduced nuclear factor κB binding to the iNos promoter and HDAC1 knock-down restored insulin secretion. In pancreatic sections from children with type 1 diabetes of recent onset, HDAC1 was upregulated in beta cells whereas HDAC2 and -3 were downregulated in comparison with five paediatric controls. These data demonstrate non-redundant functions of islet class I HDACs and suggest that targeting HDAC1 and HDAC3 would provide optimal protection of beta cell mass and function in clinical islet transplantation and recent-onset type 1 diabetic patients.

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Histone deacetylases 1 and 3 but not 2 mediate cytokine-induced beta cell apoptosis in INS-1 cells and dispersed primary islets from rats and are differentially regulated in the islets of type 1 diabetic children

M. Damgaard Nielsen

Papers

Histone deacetylases 1 and 3 but not 2 mediate cytokine-induced beta cell apoptosis in INS-1 cells and dispersed primary islets from rats and are differentially regulated in the islets of type 1 diabetic children