Is Systemic Inflammation Related to Islet Autoimmunity?
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 is a heterogeneous dysregulation of carbohydrate metabolism, and there is no doubt that we are in the midst of an epidemic of this disease. The pathogenic equation for diabetes mellitus presents a complex interrelation of metabolic, genetic, and environmental factors as well as inflammatory mediators and, for most of which, is unclear if they reflect the disease processes or are simply measures of systemic or local responses to the disease. Since it is not entirely clear if systemic inflammation and the activation of the acute-phase responses are involved in the pathogenesis of type 1 diabetes as well as latent autoimmune diabetes of the adult (LADA), we will discuss its role in the pathoetiology of the latter two disorders and review background data on inflammation in type 1 and type 2 diabetes. We will pose the question as to whether or not markers of chronic inflammation are related to islet cell autoimmunity in older individuals clinically diagnosed with type 2 diabetes.
Type 1 diabetes, or insulin-dependent diabetes, is a chronic T-cell-mediated autoimmune disease characterized by selective destruction/dysfunction of pancreatic insulin-secreting cells. Type 1 and type 2 diabetes have distinct genetic bases. Although the association of specific HLA alleles and haplotypes with type 1 diabetes is very strong, this genetic locus is estimated to account for <50% of genetic contributions to disease susceptibility. Diabetogenic alleles are not fully penetrant, implying that not every individual who inherits the gene develops the disease.
Type 2 diabetes is another heterogeneous disease, and it is the most common form of diabetes, accounting for ~90% of cases and in many industrialized countries affecting 10-20% of individuals over the age of 45 years. In type 2 diabetes, both relative loss of ß-cell mass and intrinsic ß-cell secretory defects, including selective loss of sensitivity to glucose, may explain the failure of pancreatic ß-cells to meet the increased secretory demand caused by insulin resistance. While there is a wealth of data indicating that systemic inflammation plays a role in the chain of events leading to type 2 diabetes, atherosclerosis, obesity, and fatty liver disease, it is not clear whether systemic inflammation and acute-phase proteins emerge as important elements of type 1 diabetes pathoetiology.
Inflammation is a complex response that includes accumulation and activation of leukocytes and plasma proteins in and around the site of cell injury. The principal signs of inflammation consist of tumor, calor, rubor, and dolor (swelling, heat, redness, and pain) and are caused by vasodilatation, increased capillary permeability, local accumulation of leukocytes, and interstitial fluid and abnormal stimulation of nerve endings. Inflammation represents a protective response to control infections and promotes tissue repair, but it can also contribute to local tissue damage in a broad spectrum of inflammatory disorders.
The vast majority of investigations have demonstrated associations between systemic inflammation, also termed low-grade inflammation, and cardiovascular disease (CVD). Other studies have also shown relationships between systemic inflammation and diabetes, insulin resistance, osteoarthritis, osteoporosis, Alzheimer's disease, muscle wasting, cancer, and rheumatoid arthritis and aging. The classic paradigm of inflammation reveals that traditional inflammatory processes, such as those involved in immunity, complement activation, and coagulation, are interrelated. Because of this interrelationship, it has been difficult to establish whether inflammatory mediators directly cause disease or whether they are merely markers of the underlying disease.
Abstract and Introduction
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.
Introduction
Diabetes is a heterogeneous dysregulation of carbohydrate metabolism, and there is no doubt that we are in the midst of an epidemic of this disease. The pathogenic equation for diabetes mellitus presents a complex interrelation of metabolic, genetic, and environmental factors as well as inflammatory mediators and, for most of which, is unclear if they reflect the disease processes or are simply measures of systemic or local responses to the disease. Since it is not entirely clear if systemic inflammation and the activation of the acute-phase responses are involved in the pathogenesis of type 1 diabetes as well as latent autoimmune diabetes of the adult (LADA), we will discuss its role in the pathoetiology of the latter two disorders and review background data on inflammation in type 1 and type 2 diabetes. We will pose the question as to whether or not markers of chronic inflammation are related to islet cell autoimmunity in older individuals clinically diagnosed with type 2 diabetes.
Type 1 diabetes, or insulin-dependent diabetes, is a chronic T-cell-mediated autoimmune disease characterized by selective destruction/dysfunction of pancreatic insulin-secreting cells. Type 1 and type 2 diabetes have distinct genetic bases. Although the association of specific HLA alleles and haplotypes with type 1 diabetes is very strong, this genetic locus is estimated to account for <50% of genetic contributions to disease susceptibility. Diabetogenic alleles are not fully penetrant, implying that not every individual who inherits the gene develops the disease.
Type 2 diabetes is another heterogeneous disease, and it is the most common form of diabetes, accounting for ~90% of cases and in many industrialized countries affecting 10-20% of individuals over the age of 45 years. In type 2 diabetes, both relative loss of ß-cell mass and intrinsic ß-cell secretory defects, including selective loss of sensitivity to glucose, may explain the failure of pancreatic ß-cells to meet the increased secretory demand caused by insulin resistance. While there is a wealth of data indicating that systemic inflammation plays a role in the chain of events leading to type 2 diabetes, atherosclerosis, obesity, and fatty liver disease, it is not clear whether systemic inflammation and acute-phase proteins emerge as important elements of type 1 diabetes pathoetiology.
Inflammation is a complex response that includes accumulation and activation of leukocytes and plasma proteins in and around the site of cell injury. The principal signs of inflammation consist of tumor, calor, rubor, and dolor (swelling, heat, redness, and pain) and are caused by vasodilatation, increased capillary permeability, local accumulation of leukocytes, and interstitial fluid and abnormal stimulation of nerve endings. Inflammation represents a protective response to control infections and promotes tissue repair, but it can also contribute to local tissue damage in a broad spectrum of inflammatory disorders.
The vast majority of investigations have demonstrated associations between systemic inflammation, also termed low-grade inflammation, and cardiovascular disease (CVD). Other studies have also shown relationships between systemic inflammation and diabetes, insulin resistance, osteoarthritis, osteoporosis, Alzheimer's disease, muscle wasting, cancer, and rheumatoid arthritis and aging. The classic paradigm of inflammation reveals that traditional inflammatory processes, such as those involved in immunity, complement activation, and coagulation, are interrelated. Because of this interrelationship, it has been difficult to establish whether inflammatory mediators directly cause disease or whether they are merely markers of the underlying disease.
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