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Reversing Oxidative Stress and Inflammation in Diabetes

Subcutaneous insulin infusion is the gold standard for type 1 diabetic therapy, but this approach may induce glycemic variability in some patients.

Targeting oxidative stress and inflammation could be a new therapeutic approach to diabetes since conventional insulin therapy does not allow protection of the liver from chronic diabetes effects, according to a new study.

Subcutaneous insulin infusion is the gold standard for type 1 diabetic patient therapy. The subcutaneous route is less physiological than intraperitoneal administration, and may induce glycemic variability in some patients, which is a powerful enhancer of reactive oxygen species (ROS) production. Oxidative stress plays a role in diabetes and its complications, but has not been fully characterized, especially in the liver, the target organ for insulin sensitivity.

Long-term insulin delivery can reduce blood glucose variability in diabetic patients, stated the researchers, led by Stéphanie Dal of the University of Strasbourg in Strasbourg, France. They observed the rapid increase of hepatic oxidative stress and inflammation biomarkers, which is associated with drastic decrease of glycogen storage and protein synthesis, in a diabetic rat model.

The researchers published their results in Experimental Biology and Medicine.

Hepatic injury was determined through the measurement of glycogen content, ROS production, and macrophage infiltration. Liver oxidative stress status was evaluated through the measurement of superoxide dismutase (SOD), catalase (CAT), and nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase) expression, and mitogen-activated protein kinase (MAPK) activation.

They found that induction of diabetes led to increased plasma oxidative stress and inflammation. Also, ROS production and macrophage infiltration increased in addition to SOD, CAT, and NADPH oxidase expression.

“Intensive insulin therapy improved metabolic control in diabetic animals as seen by a restoration of hepatic glycogen, plasma IGF-1 levels, and a decrease in plasma oxidative stress,” they stated. However, insulin treatment did not result in a decrease in acute inflammation.

“These results suggest that the onset of diabetes induces liver oxidative stress and inflammation, and that subcutaneous insulin administration cannot completely reverse these changes,” the researchers stated.

Under physiological conditions, an endogenous antioxidant system ensures the oxidative balance. Host survival depends upon the ability of cells and tissues to adapt to or resist the stress and repair or remove damaged molecules and cells.

Continuous administration of insulin subcutaneously, using an osmotic mini-pump, rapidly decreased oxidative stress in liver and plasma, but failed after longer diabetes status. Also, hepatic and systemic inflammation was not prevented and there was a high variability of glycogen content.

Subcutaneous insulin infusion was not able to preserve the balance of anti-oxidant and pro-oxidant species. “Favoring a more physiological pathway for insulin administration would be a real advantage for better glycemic control, preserving organs from glucotoxicity-induced disorders and oxidative stress,” the researchers stated.

Dr. Steven R. Goodman, Editor-in-Chief of Experimental Biology and Medicine, stated that these results support for the first time “the need for consideration of combining insulin with therapeutics directed towards inflammation and oxidative stress for diabetics.”

Reference: Dal S, et al. Oxidative stress status and liver tissue defenses in diabetic rats during intensive subcutaneous insulin therapy. Exp Biol Med (Maywood). 2016 Jan;241(2):184-192.