Researchers Track Metabolic Link Between Type 2 Diabetes and Fatty Liver Disease

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A new study utilized electronic medical records and genotype data to reveal three patient subtypes of type 2 diabetes. [iStock/dml5050]

Having an accumulation of fat in your liver cells may raise your risk of developing type 2 diabetes regardless of the fat in other places of your body. What links fatty liver and diabetes remains unknown. However, a new study from the Faculty of Health and Medical Sciences at the University of Copenhagen shows that glucagon resistance may be the link between the two diseases.

The study, “Glucagon acutely regulates hepatic amino acid catabolism and the effect may be disturbed by steatosis,” is published in Molecular Metabolism and led by Nicolai J. Wewer Albrechtsen, assistant professor at the Novo Nordisk Center for Protein Research and resident at the department of clinical biochemistry, Rigshospitalet.

The association between non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes is strong. Up to 70% of obese patients with type 2 diabetes have NAFLD. The spectrum of NAFLD ranges from simple steatosis to non-alcoholic steatohepatitis with variable degrees of fibrosis and cirrhosis.

Glucagon is a hormone that is produced by alpha cells in a part of the pancreas known as the islets of Langerhans. In people with diabetes, glucagon’s presence can raise blood glucose levels too high. The reason for this is either because not enough insulin is present or, as is the case in type 2 diabetes, the body is less able to respond to insulin.

“Glucagon is well known to regulate blood glucose but may be equally important for amino acid metabolism. Plasma levels of amino acids are regulated by glucagon-dependent mechanism(s) while amino acids stimulate glucagon secretion from alpha cells, completing the recently described liver-alpha cell axis. The mechanisms behind the cycle and the possible impact of hepatic steatosis are unclear,” noted the researchers.

The research team assessed amino acid clearance in vivo in mice treated with a glucagon receptor antagonist (GRA), transgenic mice with 95% reduction in alpha cells, and mice with fatty liver disease.

“The reduced glucagon sensitivity means that the secretion of glucagon is increased via a so-called feedback system between the liver and the pancreas. An elevated level of glucagon is undesirable as it increases sugar production in the liver and thus creates a high blood sugar level.”

The researchers also performed RNA sequencing on livers from glucagon receptor knock-out mice and mice with fatty liver disease. “Finally, we measured individual plasma amino acids and glucagon in healthy controls and in two independent cohorts of patients with biopsy-verified non-alcoholic fatty liver disease (NAFLD),” the researchers noted.

The researchers observed reduction in amino acid clearance in mice treated with GRA and mice lacking loss of alpha cells along with reduced production of urea. Administering glucagon altered the secretion of rat liver metabolites. Within minutes, the researchers observed increased urea formation in mice, in perfused rat liver, and in primary human hepatocytes.

Their study demonstrates that lack of glucagon signaling as well as fatty liver disease results in impaired amino acid metabolism. Glucagon plays a role in the minute-to-minute regulation of amino acid turnover and formation of urea, which is impaired in fatty liver disease.

“Our study points to a new biomarker (the glucagon-alanine index) that may be useful in identifying persons with impaired glucagon sensitivity,” explained Marie Winther-Sørensen, a PhD student at the Novo Nordisk Foundation Center for Protein Research and the department of biomedical sciences. “If we can detect glucagon resistance from a blood test, we can start treatment early and thus prevent the development of type 2 diabetes.”

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