Pancreatic beta-cell glycosylation linked with diabetes
MedWire News: An animal study conducted by US researchers provides evidence of a pathway to diabetes resulting from high levels of dietary fat.
Increased fat in the bloodstream results in the attenuation of pancreatic beta-cell glycosylation and impaired glucose control, explain Jamey Marth (University of California, Santa Barbara, CA) and colleagues in the journal Nature Medicine.
Specifically, elevations in free fatty acids led to reduced GnT-4a glycotransferase expression in beta cells and this resulted in signs and symptoms of metabolic disease, they report.
"We were initially surprised to learn how much the pancreatic beta cell contributes to the onset and severity of diabetes," Marth said in a press release accompanying the study. "The observation that beta-cell malfunction significantly contributes to multiple disease signs, including insulin resistance, was unexpected."
It is known that a high-fat or Western-style diet is a contributing factor to disease onset, but it is unclear how diet and obesity trigger diabetic pathophysiology, note the researchers.
Past animal studies have shown that mice lacking GnT-4a glycotransferase have an impaired metabolic profile suggestive of Type 2 diabetes. GnT-4a glycotransferase is an enzyme that modifies various glycoproteins, including proteins responsible for glucose transport.
In this analysis, Marth and colleagues performed a series of experiments in mice and human tissue to identify factors controlling GnT-4a function.
Wild-type mice fed a high-fat diet became deficient in Mgat4a, the protein that encodes for GnT-4a glycotransferase, compared with mice fed a standard diet.
In the mice with reduced GnT-4a expression, evidence of metabolic syndrome, including hyperglycemia, impaired glucose tolerance, hyperinsulinemia, hepatic steatosis, and diminished insulin action was observed in muscle and fat tissues.
As a result of impaired GnT-4a expression, the researchers say the beta cells of mice fed a high-fat diet were unable to sense and respond to blood glucose.
Finally, the researchers preserved GnT-4a function in mice that were fed a high-fat diet, and obese mice, and found that these mice were protected against disease. In mice with enforced beta-cell specific GnT-4a protein glycosylation, glucose transport was maintained.
These new findings suggest that the disruption of beta-cell glycosylation and glucose transport contributes to disease onset, conclude the authors.
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