Insulin resistance reversed by removal of Gal3 protein

By removing the protein galectin-3 (Gal3), a team of investigators were able to reverse diabetic insulin resistance and glucose intolerance in mice used as models of obesity and diabetes.

Binding to insulin receptors on cells, Gal3 prevents insulin from attaching and resulting in insulin resistance. Led by Jerrold Olefsky MD, professor of medicine in the Division of Endocrinology and Metabolism at University of California San Diego School of Medicine, this investigation revealed how genetically removing Gal3 — or using pharmaceutical inhibitors — insulin sensitivity and glucose tolerance could be returned to normal, even among older mice. However, their obesity remained unchanged.

"This study puts Gal3 on the map for insulin resistance and diabetes in a mouse model. Our findings suggest that Gal3 inhibition in people could be an effective anti-diabetic approach."

Jerrold Olefsky MD, Professor of Medicine, Associate Dean for Scientific Affairs, Division of Endocrinology and Metabolism, University of California San Diego School of Medicine, and senior author of the study.

Olefsky and other researchers are studying how chronic tissue inflammation leads to insulin resistance in type 2 diabetes. The paper, published in the journal Cell on November 3, explains why inflammation requires macrophages — specialized cells that destroy targeted cells. In fat — 40 percent of cells are macrophages. Macrophages secrete Gal3, which acts as a signal to attract more macrophages — which results in even more Gal3.

Investigators were able to identify bone marrow-derived macrophages as the source of Gal3 that leads to insulin resistance.

More importantly, researchers found that Gal3 is secreted by macrophages, and can cause insulin resistance in liver, fat cells, and muscle cells independent of inflammation.

Gal3 has previously been connected to other diseases. Olefsky will continue to study Gal3 depletion as a possible therapeutic target for nonalcoholic steatohepatitis (a type of fatty liver disease, characterized by inflammation of the liver with fat accumulation) as well as heart and liver fibrosis.

Abstract Highlights
•Galectin-3 blood levels are elevated in human and rodent obesity
•Galectin-3 directly impairs insulin action in myocytes, adipocytes, and hepatocytes
•Galectin-3 treatment causes systemic insulin resistance in vivo
•Galectin-3 loss of function improves insulin sensitivity in obesity

Summary
In obesity, macrophages and other immune cells accumulate in insulin target tissues, promoting a chronic inflammatory state and insulin resistance. Galectin-3 (Gal3), a lectin mainly secreted by macrophages, is elevated in both obese subjects and mice. Administration of Gal3 to mice causes insulin resistance and glucose intolerance, whereas inhibition of Gal3, through either genetic or pharmacologic loss of function, improved insulin sensitivity in obese mice. In vitro treatment with Gal3 directly enhanced macrophage chemotaxis, reduced insulin-stimulated glucose uptake in myocytes and 3T3-L1 adipocytes and impaired insulin-mediated suppression of glucose output in primary mouse hepatocytes. Importantly, we found that Gal3 can bind directly to the insulin receptor (IR) and inhibit downstream IR signaling. These observations elucidate a novel role for Gal3 in hepatocyte, adipocyte, and myocyte insulin resistance, suggesting that Gal3 can link inflammation to decreased insulin sensitivity. Inhibition of Gal3 could be a new approach to treat insulin resistance.

Keywords:
galectin-3, insulin resistance, inflammation

Study co-authors include: Pingping Li, Chinese Academy of Medical Sciences, Peking Union Medical College and UC San Diego; Shuainan Liu, Zhufang Shen, Bing Cui, Lijuan Kong, Shaocong Hou, Xiao Liang, Chinese Academy of Medical Sciences, Peking Union Medical College; Min Lu, UC San Diego, and Merck Research Laboratories; Gautum Bandyyopadhyay, Dayoung Oh, Andrew M. Johnson, Dorothy Sears, Wei Ying, Olivia Osborn, Joshua Wollam, UC San Diego; Takeshi Imamura, Shiga University of Medical Science; Salvatore Iovino, Martin Brenner, Merck Research Laboratories; Steven M. Watkins, Lipomics Technologies, Inc.

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Chronic tissue inflammation leads to insulin resistance in type 2 diabetes.
Binding to insulin receptors on the cell membrane, Gal3 attracts inflammed macrophages.
Image Credit: University of California San Diego School of Medicine