Opinion
Innate immunity, insulin resistance and type 2 diabetes

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Recent evidence has disclosed previously unrecognized links among insulin resistance, obesity, circulating immune markers, immunogenetic susceptibility, macrophage function and chronic infection. Genetic variations leading to altered production or function of circulating innate immune proteins, cellular pattern-recognition receptors and inflammatory cytokines have been linked with insulin resistance, type 2 diabetes, obesity and atherosclerosis. Cellular innate immune associations with obesity and insulin resistance include increased white blood cell count and adipose tissue macrophage numbers. The innate immune response is modulated possibly by both predisposition (genetic or fetal programming), perhaps owing to evolutionary pressures caused by acute infections at the population level (pandemics), and chronic low exposure to environmental products or infectious agents. The common characteristics shared among innate immunity activation, obesity and insulin resistance are summarized.

Introduction

Type 2 diabetes mellitus is one of the world's most important diseases. Few healthcare professionals or, indeed, members of the general public are unaware that there is a global epidemic of type 2 diabetes, fuelled by population growth, aging, urbanization and increasing obesity and inactivity. [1] It is estimated that, in many countries, including those, such as India, China and the USA, that have the highest numbers of diabetic patients currently (>90% of these with type 2 diabetes), the prevalence will double in the next 20 years or so [2]. The disease is, in short, common, costly and associated with devastating complications and is yet of uncertain origin.

It is well established that type 2 diabetes is caused by a combination of insulin resistance at skeletal muscle, liver and adipose tissues and impaired insulin secretion from the pancreatic islets [3]. A model for the development of the disease that fits our present understanding is shown in Figure 1. In this formulation, environmental trigger factors, such as overeating and underactivity, are thought to cause decreased insulin release and action in individuals with a susceptibility to the disease. Passing first through a stage of impaired glucose tolerance and/or impaired fasting glucose concentration, frank type 2 diabetes eventually develops, in association with a varying number of other clinical and biochemical features, which are themselves cardiovascular risk factors and are together called the metabolic syndrome [4].

In this article, we update an hypothesis that was proposed a decade ago 5, 6: that a disorder of the innate immune system underlies the pathophysiology of type 2 diabetes, insulin resistance and several other chronic non-communicable diseases, such as atherosclerosis. This theory is of interest in clinical chemistry for several reasons, including the identification of new circulating biomarkers of diabetes and its clinical status and identification of predictors of diabetes development, as well as furthering understanding of its pathophysiology.

Section snippets

The classical (acquired) immunology of type 1 diabetes

Unlike type 1 diabetes, type 2 diabetes is not caused by autoimmune destruction of the islet cells and is not therefore associated with circulating immune markers, such as autoantibodies to islet cells, glutamic acid decarboxylase and insulin. Furthermore, susceptibility to type 2 diabetes is not associated with the human leukocyte antigen (HLA) genes within the major histocompatibility complex, which, in type 1 diabetes, have a role in presenting foreign and self antigens and in initiating

Type 2 diabetes: a disease of the innate immune system

The innate immune system is the body's first line of defense against microbial, chemical, physical and psychological injury, whereby various reactions repair damage, avoid or isolate threats and restore homeostasis. The systemic component of innate immunity or systemic inflammation is called the ‘acute-phase response’ (somewhat misleadingly because it is chronic in the case of diabetes). Here, sentinel trouble-shooting cells throughout the body, such as macrophages, adipocytes and endothelial

New evidence for genetic influences in innate immunity

The fact that blood concentrations of inflammatory markers of innate immunity predict diabetes [11] but are not related to the duration of diabetes [25] suggests that individuals might have a pre-set or inherited level of the innate immune response at birth (as the name innate suggests), which determines their lifetime risk of developing diabetes in the face of adverse environmental stimuli.

Genetic influence on innate immunity was first suggested from studies of the main proinflammatory

A disease of macrophages?

The host needs to not only sense but also kill microbes. In vertebrates, innate immunity is dependent in large part on myeloid cells, the professional immunocytes that engulf and destroy pathogens 38, 39. Myeloid cells include mononuclear phagocytes, the macrophages that are derived from blood monocytes; and polymorphonuclear phagocytes. A higher peripheral white blood-cell count has been associated with insulin resistance and with atherosclerosis [40]; white blood cell count correlates

Chronic inflammation resulting from chronic infection?

Further evidence for a link between the innate immune system and insulin sensitivity comes from recent observations regarding exposure to infection. Apparently healthy men with exposure to common pathogens (herpes virus 1, herpes virus 2, enteroviruses and Chlamydia pneumoniae), all of which are characterized by high frequency of exposure in the general population and persistent and chronic infection, showed increased fat mass and insulin resistance. The greater the exposure to these pathogens

Conclusions

The ability to mount a prominent inflammatory response to pathogens confers an advantage in innate immune defense. Several factors seem to be implicated simultaneously in the recognition and elimination of microbial surfaces and of different external and endogenous ligands. These pathways are involved simultaneously in metabolic pathways and tissue responses, such as atherosclerosis. Various innate immune metabolic pathways might have evolved in adipose tissue in parallel with several

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