We investigate a model in which strong noise in a subpopulation creates a metastable state in an otherwise unstable two-population system. The induced metastable state is vortexlike, and its persistence time grows exponentially with the noise strength. A variety of distinct scaling relations are observed depending on the relative strength of the subpopulation noises.

OBJECTIVE A progressive decline in insulin responses to glucose was noted in individuals before the onset of type 1 diabetes. We determined whether such abnormalities occurred in prediabetic NOD mice—the prototypic model for human type 1 diabetes. RESEARCH DESIGN AND METHODS Morning blood glucose was measured every other day in a cohort of NOD females. Glucose tolerance and insulin secretion were measured longitudinally by intraperitoneal glucose tolerance tests in NOD/ShiLtJ and BALB/cJ mice 6 to 14 weeks of age. Arginine-stimulated insulin secretion and insulin sensitivity were assessed during intraperitoneal arginine or intraperitoneal insulin tolerance tests. RESULTS During prediabetes, NOD females displayed a progressive increase in glucose levels followed by an acute onset of hyperglycemia. First-phase insulin responses (FPIRs) during the intraperitoneal glucose tolerance test (IPGTT) declined before loss of glucose tolerance in NOD. The failure of FPIR could be detected, with a decline in peak insulin secretion during IPGTT. Arginine-stimulated insulin secretion remained unchanged during the study period. The decline in insulin secretion in NOD mice could not be explained by changes in insulin sensitivity. CONCLUSIONS There was an impressive decline in FPIR before changes in glucose tolerance, suggesting that impairment of FPIR is an early in vivo marker of progressive β-cell failure in NOD mice and human type 1 diabetes. We portend that these phenotypes in NOD mice follow a similar pattern to those seen in humans with type 1 diabetes and validate, in a novel way, the importance of this animal model for studies of this disease.

Objective: The notion of combining immunomodulatory agents with the incretin exendin-4 (Ex-4) has seen considerable favor as a potential therapy for the reversal of type I diabetes in man. While the addition of Ex-4 provides modest improvement to the effectiveness of immunological-based monotherapies in reversing hyperglycemia in the nonobese diabetic (NOD) mouse, the mechanism of action underlying this effect remains controversial and formed the basis for this investigation. Research Design and Methods: Female NOD mice with new onset diabetes received either Ex-4 (0.2 mu g) or saline via daily intraperitoneal injection for 30 days. To maintain viability after diagnosis of diabetes, animals also received subcutaneous insulin pellets. When persistent hyperglycemia returned, animals were sacrificed and histological studies performed to assess beta-cell proliferation (BrdU+/insulin+; Ki67+/insulin+) and fractional insulin reactive area. Results: Ex-4-treated animals experienced diabetes reversal rates no better than controls. Despite this, Ex-4-treated mice demonstrated increased fractional insulin area (P=.035) and beta-cell proliferation as evidenced by elevated BrdU (P=.0001) and Ki67 staining (P=.04) with insulin co-localization. Also noteworthy, Ex-4-treated mice had poor weight gain following diagnosis in comparison to saline-treated animals (P=.003). Conclusions: Ex-4 monotherapy (0.2 mu g daily-10 mu g/kg per day) in NOD mice with new onset diabetes increases beta-cell proliferation and fractional insulin area. Ex-4 remains a promising component of combination therapies for type I diabetes. Additional studies are needed to identify a dose that maximizes beta-cell proliferation and minimizes potential side effects. (C) 2010 Elsevier Inc. All rights reserved.

Birth-death processes often exhibit an oscillatory behavior. We investigate a particular case where the oscillation cycles are marginally stable on the mean-field level. An iconic example of such a system is the Lotka-Volterra model of predator-prey interaction. Fluctuation effects due to discreteness of the populations destroy the mean-field stability and eventually drive the system toward extinction of one or both species. We show that the corresponding extinction time scales as a certain power-law of the population sizes. This behavior should be contrasted with the extinction of models stable in the mean-field approximation. In the latter case the extinction time scales exponentially with size.

Mouse antithymocyte globulin (mATG) prevents, as well as reverses, type 1 diabetes in NOD mice, through mechanisms involving modulation of the immunoregulatory activities of T lymphocytes. Dendritic cells (DC) play a pivotal role in the generation of T cell responses, including those relevant to the autoreactive T cells enabling type 1 diabetes. As Abs against DC are likely generated during production of mATG, we examined the impact of this preparation on the phenotype and function of DC to elucidate novel mechanisms underlying its beneficial activities. In vivo, mATG treatment transiently induced the trafficking of mature CD8(-) predominant DC into the pancreatic lymph node of NOD mice. Splenic DC from mATG-treated mice also exhibited a more mature phenotype characterized by reduced CD8 expression and increased IL-10 production. The resultant DC possessed a potent capacity to induce Th2 responses when cultured ex vivo with diabetogenic CD4(+) T cells obtained from BDC2.5 TCR transgenic mice. Cotransfer of these Th2-deviated CD4(+) T cells with splenic cells from newly diabetic NOD mice into NOD.RAG(-/-) mice significantly delayed the onset of diabetes. These studies suggest the alteration of DC profile and function by mATG may skew the Th1/Th2 balance in vivo and through such actions, represent an additional novel mechanism by which this agent provides its beneficial activities.

OBJECTIVEThe autoimmune destruction of β-cells in type 1 diabetes results in a loss of insulin production and glucose homeostasis. As such, an immense interest exists for the development of therapies capable of attenuating this destructive process through restoration of proper immune recognition. Therefore, we investigated the ability of the immune-depleting agent antithymocyte globulin (ATG), as well as the mobilization agent granulocyte colony–stimulating factor (GCSF), to reverse overt hyperglycemia in the nonobese diabetic (NOD) mouse model of type 1 diabetes.RESEARCH DESIGN AND METHODSEffects of each therapy were tested in pre-diabetic and diabetic female NOD mice using measurements of glycemia, regulatory T-cell (CD4+CD25+Foxp3+) frequency, insulitis, and/or β-cell area.RESULTSHere, we show that combination therapy of murine ATG and GCSF was remarkably effective at reversing new-onset diabetes in NOD mice and more efficacious than either agent alone. This combination also afforded durable reversal from disease (>180 days postonset) in animals having pronounced hyperglycemia (i.e., up to 500 mg/dl). Additionally, glucose control improved over time in mice subject to remission from type 1 diabetes. Mechanistically, this combination therapy resulted in both immunological (increases in CD4-to-CD8 ratios and splenic regulatory T-cell frequencies) and physiological (increase in the pancreatic β-cell area, attenuation of pancreatic inflammation) benefits.CONCLUSIONSIn addition to lending further credence to the notion that combination therapies can enhance efficacy in addressing autoimmune disease, these studies also support the concept for utilizing agents designed for other clinical applications as a means to expedite efforts involving therapeutic translation.

Recent studies, albeit controversial, have suggested that the incretin exendin-4 (Ex-4) is capable of inducing beta cell proliferation in vivo. Furthermore, this compound has been shown to enhance the ability of other agents (e.g., anti-CD3, antilymphocyte serum) to reverse type 1 diabetes (T1D) in NOD mice. However, the mechanisms underlying this beneficial action for disease reversal remain largely unclear. Herein, we tested the hypothesis that Ex-4 therapy may act as a stimulator of regulatory T cells (Tregs). We evaluated the effect of Ex-4 (Byetta; 0.2 microg/mouse/day for 30 days) treatment on the frequency and function of Tregs and changes in the cytokine profile of NOD mice with recently diagnosed T1D. In comparison to that of saline-treated control NOD mice, the frequency of Tregs was increased in Ex-4-treated mice. Suppression assays demonstrated a trend towards increased Treg suppression after administration of Ex-4, but were limited by small sample size. Lastly, Ex-4 treatment induced production of IL-10, indicating a possible shift towards a more Th2-like phenotype. Taken collectively, these data suggest that in addition to its potential effects on beta cell proliferation, Ex-4 may also act as a regulator of the immune response.

OBJECTIVE—Antilymphocyte serum can reverse overt type 1 diabetes in NOD mice; yet, the therapeutic parameters and immunological mechanisms underlying the ability for this agent to modulate autoimmune responses against β-cells are unclear, forming the rationale for this investigation. RESEARCH DESIGN AND METHODS—A form of antilymphocyte serum, rabbit anti-mouse thymocyte globulin (mATG), was utilized in a variety of in vivo and in vitro settings, each for the purpose of defining the physiological, immunological, and metabolic activities of this agent, with particular focus on actions influencing development of type 1 diabetes. RESULTS—We observed that mATG attenuates type 1 diabetes development in an age-dependent fashion, only proving efficacious at disease onset or in the late pre-diabetic phase (12 weeks of age). When provided at 12 weeks of age, mATG reversed pancreatic insulitis, improved metabolic responses to glucose challenge, and rapidly increased frequency of antigen-presenting cells in spleen and pancreatic lymph nodes. Surprisingly, mATG therapy dramatically increased, in an age-dependent fashion, the frequency and the functional activity of CD4+CD25+ regulatory T-cells. Adoptive transfer/cotransfer studies of type 1 diabetes also support the concept that mATG treatment induces a stable and transferable immunomodulatory repertoire in vivo. CONCLUSIONS—These findings indicate that an induction of immunoregulation, rather than simple lymphocyte depletion, contributes to the therapeutic efficacy of antithymocyte globulin and suggest that time-dependent windows for the ability to delay or reverse type 1 diabetes exist based on the capacity to enhance the functional activity of regulatory T-cells.

Environmental enrichment by increasing foraging behaviour and providing food item choice are widely practised and generally accepted as effective methods for reducing stereotypic behaviour in captive animals. In this study, the effectiveness of increasing foraging patch choice and food item choice on reducing motor stereotypy in two captive vicugna were examined. For the purposes of the study, first, browse was added to the vicugna's enclosure as an additional forage item and, second, the vicugna's normal feed was divided: half being provided in the indoor quarters and half in the outdoor yard. The results revealed that providing browse as an additional forage item increased the observed stereotypic behaviour; however, dividing the vicugna's feed, and therefore increasing forage patch choice, decreased stereotypy. This study was limited because of the small sample size and because the area in which the vicugna were performing stereotypic behaviour was partially visually obscured. However, this study has implications for animal welfare because it highlights the need to evaluate the suitability of foraging enrichment items, and suggests that more research into accommodating the adaptive foraging behaviour of this species in captivity may be necessary.