The Heterogeneity of Diabetes

Abstract

Diabetes is an emblematic example of a heterogeneous disease. Systemic inflammation has emerged as a prominent factor in the type 2 diabetes pathoetiology, but it remains ill-defined in type 1 diabetes. There is a wide spectrum of associations between inflammatory responses and diabetic syndromes. At one end of this spectrum, there is type 1 diabetes for which there is convincing evidence that chronic inflammation of pancreatic islets is a central aspect of disease pathogenesis. At the opposite end, is type 2 diabetes that is clearly associated with systemic inflammation, which could be either the cause or simply mark the underlying pathology. Accumulating evidence has substantiated that a subgroup of adult patients clinically diagnosed with type 2 diabetes exhibit autoantibody responses to islet autoantigens. The presence of these immunologic abnormalities is associated with a severe insulin secretory defect and the absence of signs of systemic inflammation as documented by plasma C-reactive protein and fibrinogen levels that are comparable with those of control populations. Islet autoantibody evaluation should be part of the diagnostic assessment for clinically diagnosed type 2 diabetes not only because it might predict the rate of progression to insulin requirement in adult populations but also to identify a pathogenically distinct disease phenotype characterized by the absence of systemic inflammation and its related disorders. A more appropriate characterization of this subgroup of clinically diagnosed type 2 diabetes, diabetes of autoimmune pathogenesis, will promote future research into the etiology, natural history, and treatment.

Diabetes classification: grey zones, sound and smoke: Action LADA 1

“…Only selected cytokines are mildy upregulated in association with the autoimmune process in type 1 diabetes [52]. Thus it seems fair to conclude that type 1 and type 2 diabetes differ with respect to systemic low grade inflammation [53]. LADA is not well studied in this regard, but the available data from a large study suggest that LADA patients do not exhibit systemic low grade inflammation as seen in type 2 diabetes [53] which fits with the lower body mass index of this patient group.…”

Metabolic Syndrome and Autoimmune Diabetes: Action LADA 3

“…Nevertheless, the metabolic syndrome was not originally introduced to identify a feature of autoimmune diabetes but to capture the clustering of a group of continuous variables associated with cardiovascular risk. That cluster has subsequently been extended to include measures of endothelial dysfunction and low-grade inflammation, but it remains unclear whether these new parameters are also features of autoimmune diabetes; for example, type 2 diabetes is associated with increased levels of proinflammatory serum cytokines and acute-phase proteins, especially in association with obesity, whereas in type 1 diabetes such inflammatory changes are mild or nonexistent (18). Patients with LADA have not been consistently found to exhibit the systemic low-grade inflammation previously identified in type 2 diabetic patients (18).…”

“…That cluster has subsequently been extended to include measures of endothelial dysfunction and low-grade inflammation, but it remains unclear whether these new parameters are also features of autoimmune diabetes; for example, type 2 diabetes is associated with increased levels of proinflammatory serum cytokines and acute-phase proteins, especially in association with obesity, whereas in type 1 diabetes such inflammatory changes are mild or nonexistent (18). Patients with LADA have not been consistently found to exhibit the systemic low-grade inflammation previously identified in type 2 diabetic patients (18). Thus, it is reasonable to conclude that autoimmune diabetes, whether type 1 diabetes or LADA, differs from type 2 diabetes with respect to systemic low-grade inflammation, as it does with metabolic syndrome.…”

Humoral Autoimmunity in Type 1 Diabetes: Prediction, Significance, and Detection of Distinct Disease Subtypes

“…The presence of GAD65 and/or IA-2 autoantibodies in T2D patients diagnosed by conventional criteria (ADA or WHO) is not uncommon among older diabetics, being 5% -10% or higher, especially in those on insulin therapy (Barinas-Mitchell et al 2004Leslie et al 2006;Pietropaolo et al 2007). Thus, there may be as many GAD65 antibody-positive older diabetics as there are children affected by T1D.…”