Is Type II diabetes mellitus a disease of the innate immune system?

Abstract

The cause of the common type of Type II (non-insulin-dependent) diabetes mellitus, which affects at least 100 million people throughout the world, is not known. One of the foremost challenges we face is to account mechanistically for not only the defining hyperglycaemia but also for the myriad of other biochemical and physiological abnormalities which are characteristic of this disease. For example, it is now clear that Type II diabetes and lesser degrees of glucose intolerance commonly occur together with a collection of clinical and biochemical features which have been called metabolic syndrome X [1, 2].These features include central obesity, hypertension, accelerated atherosclerosis, hypertriglyceridaemia and low serum concentrations of high-density lipoprotein (HDL) cholesterol. Though insulin resistance seems to be a central abnormality, the origin of the impaired insulin action and how it explains the many other abnormalities of Type II diabetes is not known.In recent years, we have been gathering evidence that in Type II diabetes there is a cytokine-associated acute-phase reaction, part of the innate immune response. As an alternative direction for research into the aetiology of Type II diabetes, we propose that it may be helpful to consider whether the mechanisms involved in the acute-phase response can be major contributors to the pathophysiology of many of the features of Type II diabetes and syndrome X, including glucose intolerance, insulin resistance, impair- Diabetologia (1998) Summary Type II (non-insulin-dependent) diabetes mellitus is associated with increased blood concentrations of markers of the acute-phase response, including sialic acid, a-1 acid glycoprotein, serum amyloid A, C-reactive protein and cortisol, and the main cytokine mediator of the response, interleukin-6. The dyslipidaemia common in Type II diabetes (hypertriglyceridaemia and low serum levels of HDL cholesterol) is also a feature of natural and experimental acutephase reactions. We review evidence that a long-term cytokine-mediated acute-phase reaction occurs in Type II diabetes and is part of a wide-ranging innate immune response. Through the action of cytokines on the brain, liver, endothelium, adipose tissue and elsewhere, this process could be a major contributor to the biochemical and clinical features of metabolic syndrome X (glucose intolerance, dyslipidaemia, insulin resistance, hypertension, central obesity, accelerated atherosclerosis) but also provides a mechanism for many other abnormalities seen in Type II diabetes, including those in blood clotting, the reproductive system, metal ion metabolism, psychological behaviour and capillary permeability. In the short-term, the innate immune system restores homeostasis after environmental threats; we suggest that in Type II diabetes and impaired glucose tolerance long-term lifestyle and environmental stimulants, probably in those with an innately hypersensitive acute-phase response, produce disease instead of repair. [Diabetologia (1998

Walking and inflammatory markers in individuals screened for type 2 diabetes

“…As chronic low-grade inflammation is thought to play an important role in the pathogenesis of type 2 diabetes and cardiovascular disease (Libby et al, 2002, Pickup & Crook 1998, Xu et al 2003, this study suggests that increased walking activity may reduce the risk of developing a debilitating chronic disease through reduced systemic inflammation. This is clinically important as, for the majority of individuals, walking is the most accessible form of physical activity.…”

“…Markers of chronic low-grade inflammation, such as tumor necrosis factor-α (TNFα) , interleukin-6 (IL-6), and C-reactive protein (CRP), have been shown to predict the risk of developing type 2 diabetes and cardiovascular disease and are thought to be directly involved in the pathogenesis of these chronic diseases (Libby et al 2002, Pickup & Crook 1998, Xu et al 2003. TNFα and IL-6 are cytokines which are predominantly secreted from adipose tissue while CRP is the principal downstream mediator of the acute phase response and is secreted by the liver in response to TNFα and IL-6 stimuli (Du Clos 2000).…”

Relationships among acylation stimulating protein, adiponectin and complement C3 in lean vs obese type 2 diabetes

“…This may have pathophysiological and clinical relevance. Recently, it has been suggested by Pickup and Crook 55 and Pickup et al 56 as well as others, 57,58 that insulin resistance, and ultimately type 2 diabetes, may in part be a manifestation of a chronic acute-phase response. This concept was largely developed from the observations that plasma concentrations of other inflammatory cytokines and acute-phase proteins such as TNF-a, IL-6, and/or CRP are increased in individuals with type 2 diabetes.…”

Low adiponectin concentration during pregnancy predicts postpartum insulin resistance, beta cell dysfunction and fasting glycaemia

“…In the past decade, a growing body of evidence has identified two pathological sequelae of obesity that may link adiposity to diabetic risk: (1) chronic subclinical inflammation, as characterised by increased serum levels of inflammatory biomarkers such as C-reactive protein (CRP); and (2) dysregulation of adipokines, including increased serum leptin and low circulating levels of the insulin-sensitising protein adiponectin [7,8]. Indeed, CRP, leptin and hypoadiponectinaemia have each emerged as novel risk factors for type 2 diabetes mellitus in the general population [8][9][10][11].…”