Fatty Liver, Fatty Acids, Fetuin-A: Parameters for Improved Identification of Risk Patients

Researchers at Tübingen University Hospital showed last year that the concomitant presence of elevated fetuin-A and fatty acid levels increased the risk for the development of insulin resistance. The decreased insulin action in the body is seen as a very important common cause of widespread diseases such as type 2 diabetes and cardiovascular diseases or certain types of cancer. Recent studies have shown that the concomitant occurrence of a third parameter – significant fatty liver disease – further increases the risk for insulin resistance.

Patients who have all three risk factors (fatty liver, increased fetuin A, high concentrations of free fatty acids (FFAs), may therefore benefit from a drug to lower fetuin-A levels. The results of the Tübingen study strongly suggest that, prior to a lifestyle intervention, body fat distribution and metabolism should be precisely characterized in order to identify patients at high risk for metabolic disease and, if appropriate, to provide them with drug treatment.
In the December 4th issue of the New England Journal of Medicine ** the DZD Professor Norbert Stefan and his research team have now presented new findings. The data of 280 test subjects with a risk for type 2 diabetes show that the concentration of the fatty liver hormone fetuin-A in the blood determined insulin resistance in people with fatty liver disease far more than in people without fatty liver disease. “Thus, we have found both a marker and a mechanism of insulin resistance that allows us to identify patients who need personalized prevention and treatment to protect them against an elevated risk for type 2 diabetes and cardiovascular diseases,” said Stefan. He is Heisenberg Professor of Clinical Experimental Diabetology at Tübingen University Hospital and head of the Department of the Pathophysiology of Prediabetes at the Institute for Diabetes Research and Metabolic Diseases (IDM) of Helmholtz Zentrum München, a partner of the German Center for Diabetes Research (DZD).
“An overweight individual is not necessarily a risk patient, and a person of normal weight is not per se protected against insulin resistance and its complications. Only the precise diagnosis of fatty acid levels, the fetuin-A level and the fat status of the liver enable a more accurate assessment of the disease risk. Then a lifestyle intervention or targeted drug therapy can be beneficial,” Stefan said.

Role of fatty liver in the pathogenesis of type 2 diabetes and cardiovascular diseases
Previously it was assumed that the main reason for the increasing incidence of type 2 diabetes and cardiovascular diseases was that the population was increasingly overweight. In recent years, scientists in Tübingen discovered that fatty liver also plays an important role in the pathogenesis of these diseases. Over a period of many years, Professor Stefan and his research team have studied hormones secreted from the liver into the blood in varying concentrations, depending on whether the test subject suffered from fatty liver or was healthy. The researchers were thus able to show how a fatty liver alters its secretion behavior and secretes varying quantities of proteins into the bloodstream. These proteins reach other organs where they subsequently exercise their effect. One of the most important of these proteins is fetuin-A. Its determination in the blood not only serves to diagnose a fatty liver at an earlier stage, but rather serves to predict the risk for metabolic disorders (such as insulin resistance) especially in normal to slightly overweight people.

Interaction of various factors
Type 2 diabetes, cardiovascular diseases and certain types of cancer often occur concomitantly. The decreased insulin action in the body that is associated with subclinical inflammation is viewed as a very important common cause.
For many years, elevated fatty acid concentrations in the blood have been under suspicion as the primary culprit. However, the study of the Tübingen scientists revealed that body fat mass and adipose tissue hormone concentration in the blood can predict insulin resistance in humans and the risk for type 2 diabetes and cardiovascular diseases only under certain conditions – when at the same time high levels of the fatty liver hormone fetuin-A are produced . This confirms that fetuin-A needs the fatty acids for its pathogenic properties with regard to metabolic diseases.


Original publication
Stefan N, Schick F, Häring HU. Ectopic Fat in Insulin Resistance, Dyslipidemia and Cardiomettabolic Disease. N Engl J Med. 2014 Dec 4;371(23):2236-2238. doi: 10.1056/NEJMc1412427