Abstract

It is a well-known clinical observation that inflammatory diseases are accompanied by metabolic implications such as hyperglycemia, insulin resistance and increased fatty acids. On the other hand, metabolic diseases have inflammatory implications. There is a chronic and low-grade state of inflammation in obesity and type 2 diabetes. Physiological insulin resistance during infection or inflammation re-distributes glucose and fatty acids to immune cells. On the basis of systemic and adipose tissue inflammation such as MCP-1/TLR-4-driven macrophage infiltration and pro-inflammatory polarization of these cells, this lecture will give a summary of anti-diabetic effects of anti-inflammatory drugs used in rheumatology.

What is the evidence from clinical studies using anti-inflammatory approaches to treat patients with type 2 diabetes mellitus?

Basically, TNF plays an important role in insulin resistance in rodents. Blocking TNF in rodents reverses obesity-related diabetes. There are no state of the art clinical studies showing convincing evidence of an anti-diabetic potential due to underpowered cohorts and short duration of the studies. Only one single study over 6 months showed a 10% improvement of fasting glucose levels in 40 prediabetic obese patients.

Diacerein belongs to the chemical group of anthranoids. Although the mechanism of action is unknown, diacerein decreases the levels of TNF and of IL1b and has therefore been used in rheumatic diseases. Diacerein has potent effects on insulin secretion and glycemic control with a reduction of HBA1c level by 1.6%.

IL-1 receptor antagonists such as anakinra (a recombinant human IL-1 receptor antagonist) have also been studied in diabetes. Anakinra was able to improve glycemia, inflammation and insulin secretion. Two additional studies in patients with impaired glucose tolerance or prediabetes demonstrated positive effects of anakinra on beta cell secretory capacity. Since anakinra requires daily injections and often causes adverse effects at the injection site, humanized antibodies against IL1b have been developed. Each of these antibodies had beneficial effects in patients with type 2 diabetes. However, studies were either underpowered or showed only little improvements of glycosylated HBA1c levels, probably due to low pre-study levels.

Inhibition of the IKK/NFkB pathway might also be of benefit in insulin resistance. Salsalate improves insulin sensitivity, insulin secretion and glycemic control to a moderate extent of 0.4–0.5%. Salsalate also has effects in prediabetic patients and in drug-naive type 2 diabetic patients.

There is upcoming evidence of potential benefical effects of CCR2 antagonism in diabetes.

Obesity causes an increased flux of fatty acids into muscle and liver with an accumulation of DAG in these organs. DAG activates specific isoforms of protein kinases, that is PKC T in muscle and PKC E in the liver. These isoforms cause an inhibitory phosphorylation of IRS-1 and the insulin receptor itself leading to insulin resistance. Weight reduction by diet, physical activity and bariatric surgery remove ectopic fat and are able reverse diabetes. Most interestingly, PKC-isoform specific inhibitors such as FGF-21 might represent new drug targets.

Finally, targeting ectopic fat is more close to the pathophysiology of diabetes than anti-inflammatory therapy.