Neonatal beta-cell apoptosis: a trigger for autoimmune diabetes?

Trudeau, Jacqueline D.; Dutz, Jan P.; Arany, Edith; Hill, David J.; Fieldus, Warren E.; Finegood, Diane T.

doi:10.2337/diabetes.49.1.1

Cited by 247 publications

(227 citation statements)

References 39 publications

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“…Genetic and environmental factors that affect their responses have been linked to the pathogenesis of DMT1, although the exact mechanisms remain unknown (Fan et al 2004;Shultz et al 1995). It has been suggested that deficient internalization and/or clearance of AC by Mfs may be linked to the development of autoimmunity (O'Brien et al 2006;Trudeau et al 2000;Marée et al 2008;Mohammad et al 2006). Both AC and pathogens are internalized by phagocytosis, although the cell surface receptors involved in these processes are different.…”

Section: Resultsmentioning

confidence: 99%

“…It is well accepted that the initiation and the progression of DMT1 is linked to intrinsic dysfunction in professional phagocytes (i.e., Mfs), which results in a compromised mounting of immune and inflammatory responses (Fan et al 2004;Shultz et al 1995;O'Brien et al 2006;Trudeau et al 2000;Marée et al 2008;Mohammad et al 2006). For example, it has been shown that deficient internalization of AC by Mfs derived from diabetic individuals is accompanied by decreased production of IL-10 and increased secretion of pro-inflammatory cytokines, generating an unusual pro-inflammatory environment in response to AC (O'Brien et al 2006;Trudeau et al 2000;Marée et al 2008;Mohammad et al 2006). On the contrary, incubation of DMT1-derived Mfs with pro-inflammatory stimuli has been shown to produce unusually high levels of PGE 2 , which leads to down-regulation of cellular immune activation and therefore a decrease in inflammation (Benhamou et al 1995).…”

Section: Introductionmentioning

confidence: 99%

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Rescuing of deficient killing and phagocytic activities of macrophages derived from non-obese diabetic mice by treatment with geldanamycin or heat shock: potential clinical implications

Vega

Charles

Alexander

2011

Cell Stress and Chaperones

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Diabetes mellitus type 1 (DMT1) is an autoimmune disease characterized by the destruction of insulinproducing cells in the pancreas. Diabetic patients are more susceptible to recurrent and uncontrolled infections, with worse prognoses than in healthy individuals. Macrophages (Mfs) derived from DMT1 individuals have compromised mounting of inflammatory and immune responses. The mechanisms responsible for these alterations remain unknown. It has been shown that the presence of extra-and intracellular heat shock proteins (hsp) positively modulates immune cell function. Using naive Mfs derived from nonobese diabetic (NOD) mice, a well-established mouse model for DMT1, we demonstrate that heat shock (HS) as well as treatment with geldanamycin (GA), significantly improves diabetic Mf activation, resulting in increased phagocytosis and killing of bacteria. Induction of HS did not affect the aberrant NOD-Mf cytokine profile, which is characterized by elevated IL-10 levels and normal tumor necrosis factor alpha. Our observations were consistent at pre-diabetic (normal random blood glucose) and diabetic (random blood glucose greater than 250 mg/dl) stages, suggesting that HS and GA treatment may compensate for intrinsic genetic alterations present in diabetic cells regardless of the stage of the disease. The mechanisms associated to this phenomenon are unknown, but they may likely be associated with the induction of hsp expression, a common factor between HS and GA treatment. Our results may open a new field for non-classical function of hsp and indicate that hsp expression may be used as a part of therapeutic approaches for the treatment of complications associated with DMT1 as well as other autoimmune diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Rescuing of deficient killing and phagocytic activities of macrophages derived from non-obese diabetic mice by treatment with geldanamycin or heat shock: potential clinical implications

Vega

Charles

Alexander

2011

Cell Stress and Chaperones

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“…Although the notion of early programming of Type 1 diabetes, which underlies this work, has not yet been clearly addressed in the literature, early events such as viral infection (in humans [26]), early induction of high levels of glucocorticoids [27] and a higher wave of apoptosis in islets of neonates (in the non-obese diabetic mouse [28,29]) have been associated with the later development of Type 1 diabetes.…”

Section: Discussionmentioning

confidence: 99%

Effect of maternal low-protein diet and taurine on the vulnerability of adult Wistar rat islets to cytokines

et al. 2004

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Aims/hypothesis. A maternal low-protein diet has been shown to induce an increased susceptibility of fetal islets to cytokines, but this effect can be avoided by maternal taurine supplementation. Here, we question whether these effects persist until adulthood in the offspring, despite the animal having a normal diet after weaning. Methods. Pregnant Wistar rats received a diet of either 20% or 8% protein (control [C group] and recuperated [R group] respectively), which was or was not supplemented with taurine (control treated with taurine [CT group] and recuperated treated with taurine [RT group] respectively) during gestation and lactation. When the female offspring reached adulthood, an OGTT was performed. In a second stage, islets were isolated from these offspring, then pretreated or not with taurine, and subsequently treated with cytokines. Results. Fasting glycaemia was higher (p<0.05) and insulinaemia was lower (p<0.01) in the R group than in the C group. Taurine supplementation decreased insulinaemia in the CT group and tended to increase it in the RT group. After the OGTT, glycaemia in R animals was not different from that in the C group, despite a blunted insulin response (p<0.05) which was restored by taurine. Supplementation in C-group mothers led to a weak glucose intolerance. In vitro, more apoptotic cells were observed in R islets after cytokines treatment (p<0.01). The addition of taurine to the culture medium in the R and C groups protected the islets from the cytokines (p<0.01). Maternal taurine supplementation decreased the sensitivity of islets in the RT group (p<0.01), but increased sensitivity in the CT group (p<0.01). Conclusions/interpretation. The increased vulnerability of islets to cytokines due to a restriction of protein during fetal development was still evident when the offspring reached adulthood. The low-protein diet also induced hyperglycaemia in the presence of lower insulinaemia. Taurine supplementation protected adult islets of the R group from cytokine toxicity and restored the insulinaemia. However, unnecessary supplementation of taurine could have detrimental effects.

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“…The second wave of expansion of endocrine cells is noted at day 15 (Han et al, 1986). There is evidence of considerable restructuring of the endocrine pancreas through islet cell apoptosis in neo-nates (Trudeau et al, 2000). The GLP-1R transcript has been detected in rat fetal islets taken at embryonic day 21 and in neonate suckling rats (Garcia-Flores et al, 2001).…”

Section: Effects Of Glp-1r Activation During Pancreatic Development Amentioning

confidence: 99%

Mechanisms of action of glucagon-like peptide 1 in the pancreas

Doyle

Egan

2007

Pharmacology & Therapeutics

578

465

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Glucagon-like peptide-1 is a hormone that is encoded in the proglucagon gene. It is mainly produced in enteroendocrine L cells of the gut and is secreted into the blood stream when food containing fat, protein hydrolysate and/or glucose enters the duodenum. Its particular effects on insulin and glucagon secretion have generated a flurry of research activity over the past twenty years culminating in a naturally occurring GLP-1 receptor agonist, exendin-4, now being used to treat type 2 diabetes. GLP-1 engages a specific G-protein coupled receptor that is present in tissues other than the pancreas (brain, kidney, lung, heart, major blood vessels). The most widely studied cell activated by GLP-1 is the insulin-secreting beta cell where its defining action is augmentation of glucose-induced insulin secretion. Upon GLP-1 receptor activation, adenylyl cyclase is activated and cAMP generated, leading, in turn, to cAMP-dependent activation of second messenger pathways, such as the PKA and Epac pathways. As well as short-term effects of enhancing glucose-induced insulin secretion, continuous GLP-1 receptor activation also increases insulin synthesis, and beta cell proliferation and neogenesis. Although these latter effects cannot be currently monitored in humans, there are substantial improvements in glucose tolerance and increases in both first phase and plateau phase insulin secretory responses in type 2 diabetic patients treated with exendin-4. This review we will focus on the effects resulting from GLP-1 receptor activation in islets of Langerhans

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Neonatal beta-cell apoptosis: a trigger for autoimmune diabetes?

Cited by 247 publications

References 39 publications

Rescuing of deficient killing and phagocytic activities of macrophages derived from non-obese diabetic mice by treatment with geldanamycin or heat shock: potential clinical implications

Rescuing of deficient killing and phagocytic activities of macrophages derived from non-obese diabetic mice by treatment with geldanamycin or heat shock: potential clinical implications

Effect of maternal low-protein diet and taurine on the vulnerability of adult Wistar rat islets to cytokines

Mechanisms of action of glucagon-like peptide 1 in the pancreas

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