Lipids and immunoinflammatory pathways of beta cell destruction

Abstract

Islet inflammation contributes to beta cell demise in both type 1 and type 2 diabetes. 12-Lipoxygenase (12-LO, gene expressed as ALOX12 in human and 12-Lo in rodents in this manuscript) produces proinflammatory metabolites such as 12(S)-hydroxyeicosatetraenoic acids through dioxygenation of polyunsaturated fatty acids. 12-LO was first implicated in diabetes when the increase in 12-Lo expression and 12(S)-hydroxyeicosatetraenoic acid was noted in rodent models of diabetes. Subsequently, germline 12-Lo−/− was shown to prevent the development of hyperglycemia in mouse models of type 1 diabetes and in high-fat fed mice. More recently, beta cell-specific 12-Lo−/− was shown to protect mice against hyperglycaemia after streptozotocin and a high-fat diet. In humans, 12-LO expression is increased in pancreatic islets of autoantibody-positive, type 1 diabetic and type 2 diabetic organ donors. Interestingly, the high expression of ALOX12 is associated with the alteration in first-phase glucose-stimulated insulin secretion in human type 2 diabetic islets. To further clarify the role of islet 12-LO in diabetes and to validate 12-LO as a therapeutic target of diabetes, we have studied selective pharmacologic inhibitors for 12-LO. The compounds we have identified show promise: they protect beta cell lines and human islets from apoptosis and preserve insulin secretion when challenged by proinflammatory cytokine mixture. Currently studies are underway to test the compounds in mouse models of diabetes. This review summarizes a presentation given at the ‘Islet inflammation in type 2 diabetes’ symposium at the 2015 annual meeting of the EASD. It is accompanied two other mini-reviews on topics from this symposium (by Simone Baltrusch, DOI: XXX and Marc Donath, DOI: XXX) and a commentary by the Session Chair, Piero Marchetti (DOI: XXX).

Insulitis in the pathogenesis of type 1 diabetes

“…This limited pathology has also been noted in recipients of pancreas transplants who had developed T1D recurrence in their grafts . There is increasing evidence that inflammation and beta cell dysfunction may be important pathogenic mechanisms at the time of initial disease manifestation and contribute to cause the symptoms of severe hyperglycemia . Moreover, islet function may be recoverable , as shown by the DiViD study: islets isolated from the pancreas obtained via biopsy in newly diagnosed T1D recovered function in culture.…”

ABCA12 regulates insulin secretion from β‐cells

“…Although the improvement in insulin secretion by cholesterol-rich diet may seem counterintuitive, it is important to recognise that the impact of this diet on insulin secretion in control mice was negative, suggesting that maintaining an appropriate balance in cholesterol levels and distribution is critical to normal insulin secretion. Most of the studies on the effect of dietary lipids on insulin secretion have been undertaken using high-fat (rather than high cholesterol) dietary regimens [32,33]. The failure of heterologous ABCA1 to rescue these changes argues strongly that this is a direct effect of ABCA12, and while similar cholesterol driven rescue of GSIS has been reported in b-cells lacking ABCG1 [20], the failure of restoration of ABCG1 levels to correct GSIS indicates that this is likely to be a parallel mechanism specific to ABCA12.…”

Nano‐curcumin safely prevents streptozotocin‐induced inflammation and apoptosis in pancreatic beta cells for effective management of Type 1 diabetes mellitus

“…T1DM prevention in high‐risk individuals remains the highest priority where the goal is to maintain endogenous beta cell function (Creusot et al, ; Li et al, ). Therefore, protection of beta cells from cell death is considered as a new therapeutic target (Srimal and Dhawan, ; Ardestani and Maedler, ; Imai et al, ; Roy et al, ), where natural and safe anti‐inflammatory agents, such as curcumin (CUR)(Srimal and Dhawan, ; Castro et al, ), can perform better than some of the biological agents, such as canakinumab, a fully human anti‐IL‐1β monoclonal antibody (IgG‐1κ class), tested in trials with limited success (Cabrera et al, ). A critical barrier to the clinical translation of the anti‐inflammatory effects of CUR is its limited oral bioavailability (Shaikh et al, ).…”