Diabetes and inflammation

# Overview
In 1923, when Banting and Bests were awarded the Nobel Prize for insulin discovery, most researchers thought that diabetes in a solved problem.  However despite the advances in the blood glucose management, there is no cure for diabetes and preventing its major complications. Scientists observed that people with type 2 diabetes have overly active and sometimes dysfunctional immune system, which are linked to these complications. Nowadays diabetes is merely the disease of high blood glucose, or lack of insulin, but chronic inflammatory state and the overabundance of reactive oxygen species (ROS).

# Pathophysiology

## What is chronic inflammation?
Inflammation is part of a healthy immune response, an orchestrated onslaught of cells and chemicals that heal injury and fight infection. Chronic inflammation is a process occurs throughout the body when something activated the immune system and this trigger is long enough that certain stop signals are not able to prevent it. This inflammation results into the cascade of reactive oxygen species and further damage   . In 1993, scientists showed that the tumor necrosis factor  (TNF-) expression was up-regulated in the adipose tissue of obese mice with type 2 diabetes . When they breed mice that were deficient in TNF-, diabetes did not develop. So it seems that inflammation precede diabetes, long before diagnosis.

## Obesity is the link between diabetes and inflammation
Leukocytes and innate immunity is the main source of inflammation in humans. So why is inflammation increased in diabetes? In lower species, adipose tissue is the mediator of innate immunity. In insects, adipocytes have a receptor for the cell wall of bacteria and fungi, called toll like receptor. It is responsible for nuclear factor 1  (NF1) activation which induces the secretion of antibacterial peptides and other defense mechanisms. This induce the inflammatory cascades. Fat tissue also manages the storage of lipids in the liver . During evolution, in the vertebrates a third organ was developed that protect the body against foreign attack. However some aspects of innate immunity are still preserved in the adipocytes. Moreover adipose tissue is populated with tissue resident macrophages, which is significantly increase by diet induced weigh gain .
How fat tissue is the source of inflammation in obesity? The first theory is that there is an overabundance of energy in the form of glucose and lipid in obesity. This leads to mitochondrial dysfunction and ROS production from the adipocytes. ROS can activate the immunity by inducing the NF1 and hence secretion of the inflammatory cytokines .  The second one is hypoxia theory reported by Trayhurn and Wood . The fat cells expand in weight gain. They sometimes do not get enough oxygen .In response to hypoxia; they induce cytokines, which activate the angiogenesis, metabolism and cellular stress. These cytokines induce  insulin resistance and hence  result into diabetes. The adipose tissue is not usually considered as an immune or inflammatory organ, however these observations provide evidence for the link between obesity and inflammation.

## Systemic Inflammation in diabetes
A growing body of evidence demonstrates that the adipose tissue inflammation results into the systemic inflammation. C reactive protein (CRP) is an inflammatory marker produced by the liver in response to TNF and Interleukin-6. CRP has been shown to precede diabetes years before diagnosis. Elevated CRP levels are unquestionably associated with obesity and increased risk of cardiovascular disorders. Patients with a high CRP levels are at a higher mortality risk from heart disease. Other inflammatory markers are also disproportionately elevated in diabetes which results into systemic inflammation. The systemic inflammation result into insulin resistance and insulin resistance results into obesity. Hence both diabetes and inflammation reinforce each other via a positive feedback .

## Age
Aging increases inflammatory cytokines and hence the ROS.

## Gender
While population based studies have shown a higher risk of cardiovascular disorders in men , women with diabetes are faced with a higher risk of dyslipidemia and cardiovascular disorders than men with diabetes. This seems to be irrespective of menopausal status. This could be partially explained by a higher fat tissue and a hyperactive immune system in women with diabetes.

## Future or Investigational Therapies
Recent studies have shown that treatment with antiinflamatory drugs such as Hydroxychloroquine  and TNF- inhibitors  reduce the risk of diabetes. However there is not any preventive or screening strategy to find people at a higher risk of diabetes.