Type 1 Diabetes Mellitus
ICD-10 Code E10
What is the clinical spectrum of type 1 diabetes mellitus?
Type 1 diabetes mellitus (T1DM) is an autoimmune metabolic disease characterized by chronically elevated plasma glucose concentrations and intracellular energy deprivation. T1DM is caused by T-cell-mediated destruction of pancreatic insulin-producing beta-cells.
The resulting insulin deficiency disrupts glucose transport into insulin-dependent cells, producing fatigue, dehydration and excessive thirst. Metabolic pathways such as lipolysis and ketogenesis, that are subsequently triggered to compensate for the lack of entry of glucose into cells, contribute heavily to the clinical features of weight loss and muscle wasting. T1DM-associated diabetic complications commonly include cardiovascular disease, nephropathy, retinopathy, diabetic wounds, psychiatric disorders, dental issues, and peripheral neuropathy.
T1DM exhibits heterogeneous phenotypes, with inter-individual variability in age of onset which can range from childhood to adulthood, in the rate of beta-cells destruction which can be rapid in some individuals and slowly progressive in others, and in the type of immune cells involved in the autoimmune attack.
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What do we know about the etiology of type 1 diabetes mellitus?
Although the exact etiology of T1DM remains yet to be elucidated by leveraging human-based technologies, genomic studies indicate that genetics plays a major role in the development of pancreatic islet autoimmunity. Genetic factors that increase the risk of developing T1DM include polymorphisms in human leukocyte antigen (HLA) and other immune system-related genes. In over 50 associated loci identified by GWAS and other genetic association studies, the majority of T1DM-associated variants are non-protein coding regulatory genes and only a few protein-coding genes, like HLA-II, INS, CTLA4 and PTPN22, show substantial effects on T1DM.
Both endogenous factors, such as dietary content and intestine microbiota, and exogenous factors, such as environmental toxins and viral infections, are believed to play a role in the triggering of the autoimmune attack and progression to overt T1DM in genetically susceptible individuals.
Within T1DM patient populations, epidemiological, clinical, genetic, immunological, histological, and metabolic differences suggest heterogeneity in pathophysiological mechanisms.
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How similar are human and animal endocrine systems?
Below are some of the examples of species-specific differences that are expected to impact the face, construct, and predictive validity of animal models of T1DM.
Species-specific differences in structure and function of pancreatic islets
Inter-species differences in the cytoarchitecture of the pancreatic islets of Langerhans have consequences on the function of islets, susceptibility to diabetes, and disease pathophysiology. For example, the mouse differs from humans in aspects such as the proportion of beta versus alpha cells, alignment of endocrine cells relative to blood vessels, beta-cell network dynamics and insulin release patterns.
Species-specific differences in genetics and gene expression
Inter-species differences between human and rodent in regard to genetics is found both at the level of non-protein and protein-coding genes. For instance, humans have a single insulin gene while rodents have two non-allelic insulin genes, affecting how insulin transcriptionally regulates the expression of other genes. There are also marked divergences across species in cis regulatory elements and trans regulatory elements that affect how glucose related-genes respond to insulin.
Species-specific differences in glucose regulation
Even though insulin is essential for maintaining optimum blood glucose levels in all vertebrate species, its function has evolved in species-specific manners. The two most frequently used species to model diabetes, mice and rats, differ significantly from humans at gene, protein, pathway, cellular, tissue, organ and organism levels of glucose regulation, which has major implications for safety of patients and success of therapies to treat diabetes.
Species-specific immunological and genetic differences in T1DM
A notable example of the manner in which species-specific features of the immune system negatively affect the predictive validity of T1DM animal models is the multiple T cell antigens-targeting antithymocyte globulin therapy that caused severe adverse effects in T1DM patients, despite encouraging safety and efficacy findings in preclinical animal testing. This section explores several of the marked inter-species differences in immunity between T1DM patients and the gold standard non-obese diabetic (NOD) mouse model of T1DM, which illustrate why it is difficult to pin translational gaps to single immune components.
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Face validity - How well do animal models replicate the human type 1 diabetes mellitus phenotype?
Since the end of the 19th century, numerous attempts were made to model T1DM in several dozen animal species by employing chemical, viral, and surgical induction, selective breeding of strains with spontaneous symptoms, and gene editing. However, as a few select examples illustrate below, these T1DM animal models did not faithfully recapitulate the clinical features and pathophysiology of T1DM.
Chemically-induced T1DM animal models - While streptozotocine (STZ) can induce a moderate beta cell toxicity and T-cell mediated immune response at low dose and rapid beta cells death at high dose, the symptoms were not irreversible. Moreover, autoimmunity and immune cell infiltration (insulitis) were absent in this method, hindering the development of immune-modulating therapies for T1DM.
Spontaneous and genetic T1DM animal models - The gold standard NOD mouse displays hyperglycemia, insulitis, destruction of beta cells as well as several diabetic complications, such as neuropathy, nephropathy, and retinopathy. In contrast to T1DM patients, NOD mice appear to be resistant to development of ketoacidosis and can remain alive several weeks after disease onset even in absence of insulin administration.
Virally-induced T1DM animal models - Infection with encephalomyocarditis, coxsackie and lymphocyte choriomeningitis viruses was shown to induce immune-mediated destruction of beta cells in mouse, rat, hamster and NHP models of T1DM. Nonetheless, the ability of the viral induction method to trigger symptoms of T1DM was found to vary according to the susceptibility of the host species and strain to the virus.
Surgically-induced T1DM animal models - Surgical procedures, such as pancreatectomy, islet transplantation and thymectomy employed to induce T1DM in mice, rats, rabbits, dogs, pigs, and NHP mostly elicit moderate hyperglycemia followed by pancreatic regeneration, and without immune-mediated beta cell destruction and insulitis.
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Construct validity - How well do the mechanisms of disease induction in animals reflect the currently understood etiology of human type 1 diabetes mellitus?
The above described species-specific differences and limitations inherent to experimental induction methods both stand in the way of achieving robust construct validity of animal models of human T1DM.
Chemically-induced T1DM animal models - In chemically-induced animal models of T1DM, beta cells are degraded through direct cytotoxic action of glucose analogues STZ and alloxan, rather than through immune-mediated mechanisms. To prevent cytotoxic damage to other organs, T1DM was induced in dogs and primates by low dose of STZ combined with partial pancreatotomy, however, this method still falls short of recapitulating human-relevant mechanisms of T1DM.
Spontaneous and genetic T1DM animal models - Despite the fact that the NOD mouse carries several dozen insulin-dependent diabetes loci, its genetic background, gene expression regulation, glucose metabolism, microbiome, and immune pathways differ from those of humans, affecting their predictive validity. In addition, NOD mice do not capture patient-specific interactions between genetic susceptibility and environmental factors.
Virally-induced T1DM animal models - To experimentally induce symptoms of T1DM in animals, encephalomyocarditis (EMCV), coxsackie, and lymphocyte choriomeningitis (LMCV) viruses are typically used. However, there is no evidence that EMCV and LMCV cause diabetes in humans. These viruses may act through pathways that differ in human T1DM.
Surgically-induced T1DM animal models - Surgical induction does not correspond to any of the causes of T1DM observed in patient populations and does not allow to better understand the autoimmune mechanisms of T1DM.
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Predictive validity - How well do animal models predict safety and efficacy of therapies in patients with type 1 diabetes mellitus?
While the discovery of the insulin therapy through experiments in dogs marked a landmark breakthrough more than 100 years ago, it stands as a rare exception. In the decades since, research in animals to discover new treatments for diabetes has not led to medical advances of added value for T1DM patients.
Insulin administration through daily injections, or an insulin pump, remains to date the mainstay of treatment. The insulin therapy itself aims to compensate for the missing insulin but does not halt the autoimmune-mediated destruction of pancreatic beta cells. Despite glucose control with insulin therapy, many T1DM patients develop cardiovascular disease, neuropathy, retinopathy, chronic kidney disease, and chronic skin wounds.
Numerous pharmaceutical agents prevented and even reversed T1DM in NOD mice, yet, these successes were not replicated in clinical trials. To date, prevention and treatment of T1DM remain suboptimal, with large inter-individual variations in responses to treatments. In clinical trials for antithymocyte globulin, for instance, half of participants with stage 2 T1DM remained diabetes-free for up to four years, while the other half progressed to stage 3 T1DM within two months. This inter-patient variability in drug response suggests that a personalized medicine approach to T1DM would help determine which patients are most likely to benefit from specific drug candidates.
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Ethical validity - How well do animal experiments align with human ethical principles?
Preclinical - Animal research is unethical in essence by human standards, since it involves physical constraint, psychological suffering and deprivation of freedom, social interactions, natural environment, and life purpose. In addition to this baseline, experiments inflict severe clinical harm in animals.
Clinical - Statistics consistently show that clinical success rates of drugs developed and tested in animals is very low, raising the question of whether it is ethical to put the health of patients at risk.
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Intrinsic validity - How well do animal models capture the clinical heterogeneity of type 1 diabetes mellitus?
The heterogeneity in disease phenotypes, pathomechanisms and responses to treatments is not recapitulated in animal models of T1DM.
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Extrinsic validity - How well does animal experimentation generate reliable and reproducible outcomes?
In spite of significant investment in dissemination, various incentives and training of animal researchers, the ARRIVE - Animal Research: Reporting of In Vivo Experiments - guidelines remain poorly implemented and the majority of animal experiments irreproducible. While in vitro methods are not immune to issues of reproducibility, the moral weight of irreproducible animal studies is not the same.
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Key takeaways
Type 1 Diabetes Mellitus (T1DM) is an autoimmune disease characterized by chronic hyperglycemia. It is associated with an increased risk of cardiovascular disease, nephropathy, retinopathy, diabetic wounds, psychiatric disorders, dental issues and peripheral neuropathy, even in individuals receiving insulin therapy. Within T1DM patient populations, clinical, genetic, immunological, histological and metabolic differences suggest heterogeneity in pathophysiological mechanisms.
In vivo modeling of T1DM causes severe suffering in animals. Yet, owing to human-specific features of pancreatic anatomy and function, glucose regulation, genetic background, gene expression regulation, and immune system, animal models of T1DM do not faithfully recapitulate the T1DM phenotypes, pathophysiology, and responses to treatments.
To date, there is no cure for T1DM and treated patients often go on to develop complications with potentially severe consequences. A human-centric approach to research is needed to advance understanding of disease mechanisms and discovery of innovative treatments to prevent, treat, and reverse heterogenous T1DM endotypes.
How is human-based in vitro the answer to advance biomedical research into type 1 diabetes mellitus?
The following section explores the creative ways in which researchers can leverage human-based in vitro technologies to develop effective treatments for T1DM and pave the way for personalized medicine solutions tailored to T1DM endotypes. The list of over 15 examples and suggestions include employing patient-derived pancreatic 3D tissues to model heterogenous disease pathophysiology, dissect the effect of external risk factors on patient-specific genetic backgrounds, determine the capacity of T1DM-associated viruses to trigger T-cell mediated autoimmunity and high-throughput screen drug candidates.
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