Genetic and Pharmacologic Models for Type 1 Diabetes

Leiter, Edward H.; Schile, Andrew

doi:10.1002/9780470942390.mo120154

Cited by 31 publications

(19 citation statements)

References 72 publications

(60 reference statements)

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“…To further explore the ability of trimeprazine to protect β cells, we investigated its effects in NOD mice, a well-known model of autoimmune T cell–mediated T1DM (54). T1DM is a common, severe, chronic autoimmune disease characterized by the progressive loss of self-tolerance to β cells that leads to the destruction of these cells and to hyperglycemia (55).…”

Section: Discussionmentioning

confidence: 99%

Trimeprazine increases IRS2 in human islets and promotes pancreatic β cell growth and function in mice

Kuznetsova

Hollister-Lock

et al. 2016

JCI Insight

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The capacity of pancreatic β cells to maintain glucose homeostasis during chronic physiologic and immunologic stress is important for cellular and metabolic homeostasis. Insulin receptor substrate 2 (IRS2) is a regulated adapter protein that links the insulin and IGF1 receptors to downstream signaling cascades. Since strategies to maintain or increase IRS2 expression can promote β cell growth, function, and survival, we conducted a screen to find small molecules that can increase IRS2 mRNA in isolated human pancreatic islets. We identified 77 compounds, including 15 that contained a tricyclic core. To establish the efficacy of our approach, one of the tricyclic compounds, trimeprazine tartrate, was investigated in isolated human islets and in mouse models. Trimeprazine is a first-generation antihistamine that acts as a partial agonist against the histamine H1 receptor (H1R) and other GPCRs, some of which are expressed on human islets. Trimeprazine promoted CREB phosphorylation and increased the concentration of IRS2 in islets. IRS2 was required for trimeprazine to increase nuclear Pdx1, islet mass, β cell replication and function, and glucose tolerance in mice. Moreover, trimeprazine synergized with anti-CD3 Abs to reduce the progression of diabetes in NOD mice. Finally, it increased the function of human islet transplants in streptozotocin-induced (STZ-induced) diabetic mice. Thus, trimeprazine, its analogs, or possibly other compounds that increase IRS2 in islets and β cells without adverse systemic effects might provide mechanism-based strategies to prevent the progression of diabetes.

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Section: Discussionmentioning

confidence: 99%

Trimeprazine increases IRS2 in human islets and promotes pancreatic β cell growth and function in mice

Kuznetsova

Hollister-Lock

et al. 2016

JCI Insight

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“…These mice are commercially available and described in detail elsewhere in the Current Protocols in Mouse Biology series (Leiter and Schile, 2013). They have not been widely used in neuropathy studies to date, presumably due to limited availability and relatively high cost.…”

Section: Strategic Planning: Choosing a Model Systemmentioning

confidence: 99%

Peripheral Neuropathy in Mouse Models of Diabetes

et al. 2016

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Peripheral neuropathy is a frequent complication of chronic diabetes that most commonly presents as a distal degenerative polyneuropathy with sensory loss. Around 20–30% of such patients may also experience neuropathic pain. The underlying pathogenic mechanisms are uncertain and therapeutic options are limited. Rodent models of diabetes have been used for more than 40 years to study neuropathy and evaluate potential therapies. For much of this period, streptozotocin-diabetic rats were the model of choice. The emergence of new technologies that allow relatively cheap and routine manipulations of the mouse genome has prompted increased use of mouse models of diabetes to study neuropathy. In this article, we describe the commonly used mouse models of type 1 and type 2 diabetes and provide protocols to phenotype the structural, functional and behavioral indices of peripheral neuropathy with a particular emphasis on assays pertinent to the human condition.

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“…T1D develops spontaneously in autoimmune prone nonobese diabetic (NOD) mice or can be elicited after serial injection of low dose streptozotocin (STZ, an islet β-cell toxin) in other strains (71). Infection with S. mansoni , T. spiralis, Hpb , or L. sigmodontis protects NOD mice from insulitis (72–75).…”

Section: Helminths and Other Immune Mediated Diseasesmentioning

confidence: 99%

Helminth Infections Decrease Host Susceptibility to Immune-Mediated Diseases

Weinstock

Elliott

2014

The Journal of Immunology

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Helminthic infection has become rare in highly industrialized nations. Concurrent with the decline in helminthic infection is an increase in prevalence of inflammatory disease. Removal of helminths from our environment and their powerful effects on host immunity may have contributed to this increase. Several different helminth species can abrogate disease in murine models of inflammatory bowel disease, type 1 diabetes, multiple sclerosis and other conditions. Helminths evoke immune regulatory pathways often involving dendritic cells, Tregs and macrophages that help control disease. Cytokines such as IL4, IL10 and TGFβ have a role. Notable is helminthic modulatory effect on innate immunity, which impedes development of aberrant adaptive immunity. Investigators are identifying key helminth-derived immune modulatory molecules that may have therapeutic utility in the control of inflammatory disease.

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Genetic and Pharmacologic Models for Type 1 Diabetes

Cited by 31 publications

References 72 publications

Trimeprazine increases IRS2 in human islets and promotes pancreatic β cell growth and function in mice

Trimeprazine increases IRS2 in human islets and promotes pancreatic β cell growth and function in mice

Peripheral Neuropathy in Mouse Models of Diabetes

Helminth Infections Decrease Host Susceptibility to Immune-Mediated Diseases

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