Thinking bedside at the bench: the NOD mouse model of T1DM

Abstract

Studies over the past 35 years in the nonobese diabetic (NOD) mouse have shown that a number of agents can prevent or even reverse type 1 diabetes mellitus (T1DM); however, these successes have not been replicated in human clinical trials. Although some of these interventions have delayed disease onset or progression in subsets of participants, none have resulted in a complete cure. Even in the most robust responders, the treatments do not permanently preserve insulin secretion or stimulate the proliferation of β cells, as has been observed in mice. The shortfalls of translating NOD mouse studies into the clinic questions the value of using this model in preclinical studies. In this Perspectives, we suggest how immunological and genetic differences between NOD mice and humans might contribute to the differential outcomes and suggest ways in which the mouse model might be modified or applied as a tool to develop treatments and improve understanding of clinical trial outcomes.

Animal models for diabetes: Understanding the pathogenesis and finding new treatments

“…There are numerous examples of successful interventions in NOD mice that have failed in humans including anti-CD3 therapy and oral insulin. These are eloquently reviewed by Reed and Herold [23]. There are a variety of reasons of why the pre-clinical studies in NOD mice may not lead to success in clinical trials.…”

“…Indeed intervention in NOD mice is usually made early and it has been shown that early intervention is most likely to successfully prevent Type 1 diabetes development in this model. Other problems include immunological differences between mice and humans and dosing issues [23]. It should also be noted that incidence of diabetes in NOD mice increases in a clean (specific pathogen free) environment [24] whereas in humans environmental factors such as viruses may play an important aspect of disease development [25].…”

“…The NOD mouse has been used extensively in prevention studies, with varying success in predicting clinical outcome [16,23]. Indeed it has been suggested that this model overestimates the clinical success of an interventional experimental drug.…”

New insights into the architecture of the islet of Langerhans: a focused cross-species assessment

“…But this approach may fall short in terms of reflecting critical aspects of human islet pathophysiology [15,16]. Because islets of non-human primate (NHP) or human origin are increasingly becoming available (albeit in limited numbers), there is an important and creeping increase in the number of studies on primate islets.…”

A 1D model of the arterial circulation in mice

“…Mice in particular are a common model in hypothesis-driven cardiovascular research (Treuting et al, 2012) due to their short lifespan, their small size, the similarity of their well-decrypted genome with the human one and, most importantly, the possibility to induce genetic modifications (Pennacchio, 2003). Genetically or pharmacologically altered mouse models have provided insight into (amongst many other cardiovascular applications) abdominal aortic aneurysm (Trachet et al, 2014a,b), stable and unstable atherosclerotic plaque (Van der Donckt et al, 2014;De Wilde et al, 2015), diabetes (Reed and Herold, 2015), hypertrophy (Yamaguchi et al, 2007) and Marfan syndrome (Campens et al, 2015). However, since mice have a much smaller (aortic dimensions are 10x smaller, Tab.…”