Previous Article |
Table of Contents
| Next Article 
COMMENTARY
Type 1, type 1.5, and type 2 diabetes: NOD the diabetes we thought it was
Clinic for Endocrinology and Diabetes, University Hospital Zurich, CH-8091 Zurich, Switzerland
Diabetes is defined as a metabolic disease characterized by hyperglycemia. Current classifications distinguish between type 1 diabetes, characterized by autoimmune 
cell destruction, and the broader type 2 diabetes, which ranges "from predominantly insulin resistance with relative insulin deficiency to predominantly an insulin secretory defect with insulin resistance" (1). Increasing clinical evidence is emerging that highlights marked overlap between these two diabetic conditions. For example, immunological phenomena (e.g., anti-islet cell antibodies, elevated circulating cytokines and chemokines) classically associated with type 1 diabetes are present in many patients with type 2 diabetes (2, 3), and obesity, which is associated with insulin resistance and type 2 diabetes, shows strong correlations with the recent increased incidence of type 1 diabetes (4–6). Not surprisingly, therefore, the classification of diabetes into two main types has been challenged (7, 8). Through differential gene expression analysis, the study by Chaparro et al. (9) in this issue of PNAS provides strong genetic evidence for the overlap in pathologies and thus strongly impacts this debate. Changes in the classification may influence both diabetes research and guidelines for therapy.
For the last 30 years, the classical model for type 1 diabetes research has been the nonobese diabetic (NOD) mouse. Notwithstanding several issues regarding its relevance toward human disease, the NOD mouse has generally been accepted as a valuable tool in the study of type 1 diabetes (10). In the study by Chaparro et al., NOD/severe combined immunodeficient (scid) mice were used to investigate intrinsic target-tissue abnormalities in the absence of B and T cell immune effects. Analyzing the gene expression patterns of various tissues in NOD/scid mice (the pancreas and the submandibular and lacrimal glands) versus C57BL/6 (B6)/scid mice, Chaparro et al. have made the unexpected observation that numerous genes differentially regulated in the NOD mouse are more commonly associated with type 2 rather than type 1 diabetes (9). These include changes in gene expression related to insulin resistance, vascular pathology, altered cell-to-cell and cell-to-extracellular matrix interactions, and endoplasmic reticulum stress. Furthermore, the authors show support for these gene changes by confirming that the NOD/scid mice were insulin-resistant at 6 weeks of age, before the onset of hyperglycemia, a finding that rules out indirect effects of elevated glucose on the system. Based on these findings, the authors propose to reclassify the NOD mouse from being a model of type 1 diabetes to a model of type 1.5, as an interface between type 1 and type 2 diabetes. In support of this animal study, interesting reports have shown familiar clustering of type 1 and type 2 diabetes mellitus genes (11, 12), and recent studies suggest that selected susceptibility gene variants may be involved in the pathogenesis of type 1 and type 2 diabetes (13–15).
Similarly, recent investigations into the pathogenesis of cell dysfunction in type 2 diabetes have uncovered factors classically associated with type 1 diabetes. Indeed, type 2 diabetes manifests itself in individuals who lose the ability to produce sufficient quantities of insulin to maintain normoglycemia in the presence of insulin resistance. The failure of the cell is probably due to both a defect in secretory function and a decrease in cell mass (16–18). Whereas insulin resistance in patients remains relatively constant with time, cell functional mass is more plastic, first increasing (compensation for insulin resistance in prediabetics) and later decreasing, accounting for onset and progression of the disease. Thus, decreased functional cell mass is a hallmark not only of type 1 diabetes but also of type 2 diabetes. Furthermore, it is becoming increasingly apparent that many factors classically deemed type 1 diabetes-specific are also integral to the process of cell failure in type 2 diabetes patients. These include the effect of IL-1, Fas, and nuclear factor-
B, endoplasmic reticulum stress, and increased expression of c-Myc (19–22). Interestingly, polymorphisms in the Fas pathway have been associated recently with type 2 diabetes (23). Moreover, recent studies have shown immune-cell infiltration in islets of type 2 diabetic patients (our unpublished work). Consequently, the mechanisms leading to cytokine-induced cell dysfunction in type 1 diabetes and to nutrient-induced cell dysfunction in type 2 diabetes share the activation of common final pathways, including IL-1 signaling (24).
Therefore, the current classification of diabetes into two distinct diseases likely does not reflect the true nature of most cases. Classically defined type 1 and type 2 diabetes may merely reflect two extremes of a continuum, connected by the central role of the cell but defined by predisposition and the profile of numerous pro- and anti- cell factors. At one end of the spectrum, diabetes involves a strong predisposition to autoimmunity with high sensitivity toward "triggering factors," whereas at the other end, the disease entails the response of a relatively robust cell pool to the inflammatory and metabolic stresses associated with obesity and insulin resistance. The central role of the failing cell at both extremes, and likely at every point in between, connects both diseases. Given this continuum, it may be that the classical events of antigen presentation and autoimmunity associated with type 1 diabetes could also be triggered by metabolic stress-induced cell apoptosis and necrosis.
Hence, although both diabetes types share similar characteristics, no single feature clearly discriminates the two (Table 1). Perhaps as an alternative to adding decimals to the categories of diabetes classification, researchers and clinicians should simply approach their respective "patients" with no categorical prejudice. With an open mind, Chaparro et al. have highlighted that the NOD mouse may NOD represent the type of diabetes we thought it did.
|
Footnotes
Author contributions: M.Y.D. and J.A.E. wrote the paper.
Conflict of interest statement: No conflicts declared.
See companion article on page 12475.
*To whom correspondence should be addressed at: Clinic for Endocrinology and Diabetes, Department of Medicine, University Hospital Zurich, CH-8091 Zurich, Switzerland. E-mail: marc.donath{at}usz.ch
© 2006 by The National Academy of Sciences of the USA
References
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg What's this?
Companion article to this Commentary:
This article has been cited by other articles in HighWire Press-hosted journals:
|
|
 |
|
  M. Y. Donath, D. M. Schumann, M. Faulenbach, H. Ellingsgaard, A. Perren, and J. A. Ehses Islet Inflammation in Type 2 Diabetes: From metabolic stress to therapy Diabetes Care, February 1, 2008; 31(Supplement_2): S161 - S164. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E.-G. Hong, D. Y. Jung, H. J. Ko, Z. Zhang, Z. Ma, J. Y. Jun, J. H. Kim, A. D. Sumner, T. C. Vary, T. W. Gardner, et al. Nonobese, insulin-deficient Ins2Akita mice develop type 2 diabetes phenotypes including insulin resistance and cardiac remodeling Am J Physiol Endocrinol Metab, December 1, 2007; 293(6): E1687 - E1696. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
