Presence of residual beta cells and co-existing islet autoimmunity in the NOD mouse during longstanding diabetes: a combined histochemical and immunohistochemical study

Reddy, Shiva; Chai, Ryan C.; Rodrigues, Jessica A.; Hsu, Tzu-Hsuan; Robinson, Elizabeth

doi:10.1007/s10735-007-9122-5

Cited by 11 publications

(14 citation statements)

References 31 publications

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“…Glucagon staining was present throughout the islet at all time points (Fig. 2f,i,l), consistent with the phenomenon of a 'collapsed' islet that is largely devoid of beta cells [26]. These findings correlated with elevated fasting blood glucose levels in Ins2 Akita mice taken immediately before killing for immunohistological analysis.…”

Section: Resultssupporting

confidence: 79%

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A new immunodeficient hyperglycaemic mouse model based on the Ins2 Akita mutation for analyses of human islet and beta stem and progenitor cell function

et al. 2008

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Aims/hypothesis To develop and validate a new immunodeficient mouse strain that spontaneously develops a nonautoimmune hyperglycaemia to serve as a diabetic host for human islets and human beta stem and progenitor cells without the need for induction of hyperglycaemia by toxic chemicals with their associated side effects. Methods We generated and characterised a new strain of immunodeficient spontaneously hyperglycaemic mice, the NOD-Rag1 null Prf1 null Ins2 Akita strain and compared this strain with the NOD-scid Il2rγ null (also known as Il2rg) immunodeficient strain rendered hyperglycaemic by administration of a single dose of streptozotocin. Hyperglycaemic mice were transplanted with human islets ranging from 1,000 to 4,000 islet equivalents (IEQ) and were monitored for normalisation of blood glucose levels. Results NOD-Rag1 null Prf1 null Ins2 Akita mice developed spontaneous hyperglycaemia, similar to Ins2 Akita -harbouring strains of immunocompetent mice. Histological examination of islets in the host pancreas validated the spontaneous loss of beta cell mass in the absence of mononuclear cell infiltration. Human islets transplanted into spontaneously diabetic NOD-Rag1 null Prf1 null Ins2 Akita and chemically diabetic NOD-scid Il2rγ null mice resulted in a return to euglycaemia that occurred with transplantation of similar beta cell masses. Conclusions/interpretation The NOD-Rag1 null Prf1 null Ins2 Akita mouse is the first immunodeficient, spontaneously hyperglycaemic mouse strain described that is based on the Ins2 Akita mutation. This strain is suitable as hosts for human islet and human beta stem and progenitor cell transplantation in the absence of the need for pharmacological induction of diabetes. This strain of mice also has low levels of innate immunity and can be engrafted with a human immune system for the study of human islet allograft rejection.

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Section: Resultssupporting

confidence: 79%

“…2b) with glucagon staining localising to the periphery of the islet (Fig. 2c) [26]. Islets were still present in the pancreases of NOD-Rag1 null Prf1 null Ins2 Akita mice.…”

Section: Resultsmentioning

confidence: 87%

A new immunodeficient hyperglycaemic mouse model based on the Ins2 Akita mutation for analyses of human islet and beta stem and progenitor cell function

et al. 2008

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“…The δ -cell excess in murine 32 and human T1D, with precisely the same intermediates as found in the alloxan plus caerulein model, demonstrates the relevance of endocrine cell transdifferentiation to autoimmune diabetes. However, endocrine cell transdifferentiation following alloxan plus caerulein occurred only in islets where there were few β -cells, whereas in T1D, transdifferentiation occurred in islets with a substantial number of residual β -cells, most likely reflecting a difference in the stimulus for transdifferentiation in autoimmunity versus that induced by caerulein.…”

Section: Discussionmentioning

confidence: 55%

Pharmacological induction of pancreatic islet cell transdifferentiation: relevance to type I diabetes

Piran

et al. 2014

Cell Death Dis

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Type I diabetes (T1D) is an autoimmune disease in which an immune response to pancreatic β-cells results in their loss over time. Although the conventional view is that this loss is due to autoimmune destruction, we present evidence of an additional phenomenon in which autoimmunity promotes islet endocrine cell transdifferentiation. The end result is a large excess of δ-cells, resulting from α- to β- to δ-cell transdifferentiation. Intermediates in the process of transdifferentiation were present in murine and human T1D. Here, we report that the peptide caerulein was sufficient in the context of severe β-cell deficiency to induce efficient induction of α- to β- to δ-cell transdifferentiation in a manner very similar to what occurred in T1D. This was demonstrated by genetic lineage tracing and time course analysis. Islet transdifferentiation proceeded in an islet autonomous manner, indicating the existence of a sensing mechanism that controls the transdifferentiation process within each islet. The finding of evidence for islet cell transdifferentiation in rodent and human T1D and its induction by a single peptide in a model of T1D has important implications for the development of β-cell regeneration therapies for diabetes.

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“…With regard to diabetes severity, islet beta cell loss is nearly complete at diabetes onset in BB rats [16], in contrast to that of NOD mice [21,22] and humans, [23,24] in both of which there is evidence for residual beta cell function early in diabetes. With regard to diabetes progression, both NOD mice [25] and humans [24] have a progressive loss of residual beta cell mass and function with increasing duration of type 1 diabetes.…”

Section: Introductionmentioning

confidence: 99%

Loss of islet sympathetic nerves and impairment of glucagon secretion in the NOD mouse: relationship to invasive insulitis

et al. 2009

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Aims/hypothesis We hypothesised that non-obese diabetic mice (NOD) mice have an autoimmune-mediated loss of islet sympathetic nerves and an impairment of sympathetically mediated glucagon responses. We aimed: (1) to determine whether diabetic NOD mice have an early impairment of the glucagon response to insulin-induced hypoglycaemia (IIH) and a coincident loss of islet sympathetic nerves; (2) to determine whether invasive insulitis is required for this nerve loss; and (3) to determine whether sympathetically mediated glucagon responses are also impaired. Methods We measured glucagon responses to both IIH and tyramine in anaesthetised mice. We used immunohistochemistry to quantify islet sympathetic nerves and invasive insulitis. Results The glucagon response to IIH was markedly impaired in NOD mice after only 3 weeks of diabetes (change, −70%). Sympathetic nerve area within the islet was also markedly reduced at this time (change, −66%). This islet nerve loss was proportional to the degree of invasive insulitis. More importantly, blocking the infiltration prevented the nerve loss. Mice with autoimmune diabetes had an impaired glucagon response to sympathetic nerve activation, whereas those with non-autoimmune diabetes did not. Conclusions/interpretation The invasive insulitis seen in diabetic NOD mice causes early sympathetic islet neuropathy. Further studies are needed to confirm that early sympathetic islet neuropathy is responsible for the impaired glucagon response to tyramine.

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Presence of residual beta cells and co-existing islet autoimmunity in the NOD mouse during longstanding diabetes: a combined histochemical and immunohistochemical study

Cited by 11 publications

References 31 publications

A new immunodeficient hyperglycaemic mouse model based on the Ins2 Akita mutation for analyses of human islet and beta stem and progenitor cell function

A new immunodeficient hyperglycaemic mouse model based on the Ins2 Akita mutation for analyses of human islet and beta stem and progenitor cell function

Pharmacological induction of pancreatic islet cell transdifferentiation: relevance to type I diabetes

Loss of islet sympathetic nerves and impairment of glucagon secretion in the NOD mouse: relationship to invasive insulitis

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