Researchers found that controlling obesity and type 2 diabetes should begin in the gastrointestinal tract (image: Wikimedia Commons)

Gastrointestinal tract is linked to insulin resistance
2015-06-10

Gut microbiota in obese individuals and type 2 diabetics induces the production of higher bacterial membrane lipid levels and lower levels of fatty acids that are involved in insulin intolerance, studies show.

Gastrointestinal tract is linked to insulin resistance

Gut microbiota in obese individuals and type 2 diabetics induces the production of higher bacterial membrane lipid levels and lower levels of fatty acids that are involved in insulin intolerance, studies show.

2015-06-10

Researchers found that controlling obesity and type 2 diabetes should begin in the gastrointestinal tract (image: Wikimedia Commons)

 

By Elton Alisson, in Buenos Aires

Agência FAPESP – The gastrointestinal tract is linked to insulin resistance in patients with obesity and type 2 diabetes, which is the most common form of the disease.

This is the main finding of a series of studies that were performed by different research groups around the world and corroborated by Brazilian researchers at the National Institute of Obesity and Diabetes (INOD) and the multidisciplinary Obesity and Comorbidities Research Center (OCRC). INOD is one of the National Science and Technology Institutes that are supported by FAPESP and the National Council for Scientific and Technological Development (CNPq). OCRC is one of the Research, Innovation and Dissemination Centers (RIDCs) that are funded by FAPESP.

Select findings from the Brazilian researchers were presented in a panel session on health during FAPESP Week Buenos Aires, which was held on April 7-10 in the capital of Argentina by FAPESP in partnership with Argentina’s National Scientific & Technological Research Council (CONICET).

“What we’re seeing is that besides the central nervous system, muscles, liver and adipose tissue, among other organs, the gastrointestinal tract also appears to be involved in insulin resistance,” said Mário Saad, a professor at the University of Campinas School of Medical Sciences (FCM-UNICAMP) in São Paulo State, Brazil and the principal investigator of the project.

“We’re now starting to understand that the control of obesity and type 2 diabetes should begin with the gastrointestinal tract.”

According to Saad, insulin resistance at the molecular level occurs when this hormone (which is produced by the pancreas, stimulates glucose uptake by cells and acts in the metabolism of lipids and proteins) cannot properly transmit signals to cells to activate receptors that phosphorylate (add a phosphate group to) tyrosines on the insulin receptor substrate proteins IRS1 and IRS2.

Tyrosine phosphorylation stimulates both of these proteins to activate members of the PI3K family of enzymes, which in turn activate AKT, a protein kinase that plays a key role in multiple cellular processes, including glucose metabolism, Saad explained.

“The effects triggered by insulin, in terms of enhancing muscle tissue glucose intake, boosting fatty tissue lipid synthesis and blocking glycogenesis in the liver, depend basically on cellular insulin receptor activation mechanisms, tyrosine phosphorylation of IRS1 and IRS2, and the activation of AKT,” he said. Glycogenesis is the formation of glycogen, which is the primary type of carbohydrate that is stored in the liver and muscle cells, from glucose.

In experiments on obese mice, the researchers observed that adipose tissue produces interleukins and fatty acids, in addition to other compounds that activate serine protein kinases.

When serine protein kinases are activated, they phosphorylate serine residues in IRS1 and IRS2, which leads to changes in the structures of these proteins such that they can no longer interact with insulin receptors and therefore tyrosine phosphorylation cannot take place.

“Insulin resistance at the molecular level is neither more nor less than prior serine phosphorylation of IRS1 and IRS2,” Saad concluded.

Role of microbiota

To evaluate how long an animal takes to develop insulin resistance, Saad’s research group performed an experiment in which mice were fed a hyperlipid diet (with very high levels of fat).

The results of the experiment showed that the mice developed insulin resistance after three days.

“They developed insulin resistance before becoming obese, suggesting that this condition precedes obesity,” Saad noted. “Their muscles captured less glucose after the onset of the hyperlipid diet.”

According to Saad, tyrosine phosphorylation of IRS1 was lower and AKT was less active in mice that were fed a hyperlipid diet.

“After three days of being fed a hyperlipid diet, the animal already presents with insulin resistance, meaning the hormone can’t adequately transmit its signal to cells,” he said.

One of the possible keys to the development of insulin resistance in these mice prior to their becoming obese is lipopolysaccharide (LPS), an important component of the outer membranes of gram-negative bacteria, which are found in the gut microbiota of mammals. LPS can activate the serine protein kinases that are responsible for serine phosphorylation of IRS1 and IRS2, inducing insulin resistance, Saad explained.

The consumption of a hyperlipid diet for three days caused an increase in LPS circulation and absorption by gram-negative bacteria in the animals’ gut microbiota, according to the findings of experiments performed by Saad’s research group.

“When we fed these mice a hyperlipid diet, we apparently modulated their gut microbiota,” he said. “This modulation caused an increase in LPS intake and consequently induced insulin resistance before the animals developed obesity.”

The researchers verified these findings by performing another experiment in which mice treated with antibiotics to reduce gut microbiota, and a control group with normal gut flora was fed a hyperlipid diet.

The results of this study, which are published in the journal Diabetologia, showed that after three days of being fed a hyperlipid diet the mice with normal gut flora developed insulin resistance, whereas the mice treated with antibiotics displayed normal phosphorylation of IRS1 and IRS2, as well as AKT activation, and did not present with insulin resistance.

“LPS levels in the mice treated with antibiotics were lower than in the mice with normal gut flora, showing that gut microbiota are essential to the development of insulin resistance,” Saad noted.

The researchers also measured levels of short-chain fatty acids produced by gut bacteria, such as acetate, again comparing mice treated with antibiotics to those that had normal gut flora; both groups were fed a hyperlipid diet.

The analysis showed that mice with normal gut microbiota presented with lower levels of acetate, which activates AMPK, an enzyme that increases glucose transport and uptake as well as enhancing lipid oxidation.

“Increased circulating levels of LPS in conjunction with reduced levels of acetate contribute to the development of insulin resistance,” Saad explained.

Intestinal barrier

According to Saad, the short-chain fatty acids and toxins that are produced by bacteria modulate the expression of intestinal epithelial proteins, altering the permeability of the intestinal barrier.

The hyperlipid diet that was fed to the animals that were treated with antibiotics reduced the expression of ZO-1, which is an intestinal epithelial protein that has an important role in reducing intestinal absorption of toxins that can induce insulin resistance.

“Our research shows that an alteration in gut microbiota occurring at the onset of obesity and type 2 diabetes is capable of weakening the intestinal barrier so that more insulin resistance-inducing substances are absorbed, along with fewer substances that could prevent the development of insulin resistance,” he said.

The researchers also conducted a study of HIV-infected patients who were treated with an AIDS medication cocktail to evaluate LPS levels in this population, as they tend to develop insulin resistance during disease treatment.

Their findings showed that LPS levels in these patients were as high as in people with obesity and type 2 diabetes.

“The high levels of LPS observed in HIV-infected patients point to an alteration in their microbiota and to permeability of the intestinal barrier, which leads to insulin resistance,” Saad concluded.

 

  Republish
 

Republish

The Agency FAPESP licenses news via Creative Commons (CC-BY-NC-ND) so that they can be republished free of charge and in a simple way by other digital or printed vehicles. Agência FAPESP must be credited as the source of the content being republished and the name of the reporter (if any) must be attributed. Using the HMTL button below allows compliance with these rules, detailed in Digital Republishing Policy FAPESP.