Abstract
A hallmark feature of type 1 and type 2 diabetes mellitus is the progressive dysfunction and loss of insulin-producing pancreatic beta cells, and inflammatory cytokines are known to trigger beta cell death. Here we asked whether the anti-oxidant protein DJ-1 encoded by the Parkinson’s disease gene PARK7 protects islet cells from cytokine- and streptozotocin-mediated cell death. Wild type and DJ-1 knockout mice (KO) were treated with multiple low doses of streptozotocin (MLDS) to induce inflammatory beta cell stress and cell death. Subsequently, glucose tolerance tests were performed, and plasma insulin as well as fasting and random blood glucose concentrations were monitored. Mitochondrial morphology and number of insulin granules were quantified in beta cells. Moreover, islet cell damage was determined in vitro after streptozotocin and cytokine treatment of isolated wild type and DJ-1 KO islets using calcein AM/ethidium homodimer-1 staining and TUNEL staining. Compared to wild type mice, DJ-1 KO mice became diabetic following MLDS treatment. Insulin concentrations were substantially reduced, and fasting blood glucose concentrations were significantly higher in MLDS-treated DJ-1 KO mice compared to equally treated wild type mice. Rates of beta cell apoptosis upon MLDS treatment were twofold higher in DJ-1 KO mice compared to wild type mice, and in vitro inflammatory cytokines led to twice as much beta cell death in pancreatic islets from DJ-1 KO mice versus those of wild type mice. In conclusion, this study identified the anti-oxidant protein DJ-1 as being capable of protecting pancreatic islet cells from cell death induced by an inflammatory and cytotoxic setting.
Highlights
Both, type 1 and type 2 diabetes mellitus (T1DM and T2DM) are associated with a progressive dysfunction and loss of beta cells in pancreatic islets [1,2,3]
Compared to multiple low doses of streptozotocin (MLDS)-treated wild type mice, DJ-1 knockout mice (KO) led to higher fasting blood glucose concentrations (Fig 1c and 1d), and glucose tolerance was impaired in DJ-1 KO mice (Fig 1e and 1f)
DJ1 KO mice lost weight in the weeks following the STZ injections, whereas the body weight of MLDS-treated wild type mice remained unchanged (S2 Fig). Since both the fasting and random plasma insulin concentrations were significantly lower in DJ-1 KO mice compared to MLDS-treated wild type mice (Fig 1g and 1h), the data suggest that DJ-1 helps to protect pancreatic islets from cell death induced by the MLDS treatment
Summary
Type 1 and type 2 diabetes mellitus (T1DM and T2DM) are associated with a progressive dysfunction and loss of beta cells in pancreatic islets (or islets of Langerhans) [1,2,3]. Humans with established T2DM show increased circulating pro-inflammatory cytokine levels and display low-grade islet inflammation suggesting that an inflammatory stress contributes to beta cell dysfunction and death in T2DM [4, 7,8,9]. We and others have recently analysed in beta cells the role of the anti-oxidant protein DJ-1 that is highly expressed in mouse and human pancreatic islets [10,11,12]. In analogy to the protective effect of DJ-1 in neurons [13, 14], DJ-1 is probably required in pancreatic islets to protect beta cells from oxidative stress, since beta cells express low amounts of other anti-oxidant proteins [10, 12, 15, 16]
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