IATA study finds that gut microbiota produces enzymes that inactivate hormones responsible for blood glucose control

A study by the Institute of Agrochemistry and Food Technology (IATA-CSIC), located at the University of Valencia Science Park, reveals that certain microorganisms produce a homologue that affects the mechanism that lowers blood glucose

The intestinal microbiota, the set of microorganisms that inhabit our intestine, controls several aspects related to human metabolism and eating behavior. It is also closely linked to the development of metabolic pathologies such as diabetes or obesity. A study led by the Institute of Agrochemistry and Food Technology (IATA), of the Spanish National Research Council (CSIC), now reveals that some intestinal bacteria produce substances with a function identical to the human enzyme DPP-4, responsible for the degradation of incretins, the hormones that control blood glucose. This finding, published in the journal Genome Biology, opens the door to develop drugs against bacterial enzymes and improve treatments for type 2 diabetes.

Incretins are the hormones that cause the secretion of insulin by the pancreas when food is ingested and are therefore responsible for lowering blood glucose levels. The two main incretins are gastric inhibitory polypeptide (GIP) and glucagon-like peptide type 1 (GLP-1), hormones with which DPP-4 interacts directly. The IATA research shows that enzymes produced by bacteria, with identical behavior to DPP-4, also interact with these hormones.

“Until now we knew that dipeptidyl peptidase-4 or DPP-4 activity produced by human cells worsened glucose response because it cleaves and inactivates incretins, which are responsible for insulin release after food intake. We have now detected that some intestinal bacteria produce a DPP-4 homologue. This is a mechanism through which the microbiota can worsen our metabolic health,” explains Marta Olivares, CSIC researcher at IATA and one of the authors of the study.

Pharmaceutical research for the treatment of type 2 diabetes has focused on the interaction between DPP-4 and incretins, trying to increase the lifespan of incretins by inhibiting the activity of the DPP-4 enzyme. “These drugs have been designed to act on human DPP-4, but we did not know that some intestinal bacteria produce enzymes that act in an identical way”, says Alfonso Benítez, CSIC scientist at IATA and author of the study.

"These drugs have been designed to act on human DPP-4, but we did not know that some intestinal bacteria produce enzymes that act in an identical way", Alfonso Benítez, CSIC scientist at IATA and author of the study

The results of the work show that, while some drugs are effective in preventing the action of DPP-4 homologous enzymes of bacteria of the genus Parabacteroides merdae, other drugs have no effect on their behavior. In other words, the inhibitors commonly used in antidiabetic therapies vary in their ability to act against bacterial enzymes.

The research team stresses the importance of developing treatments that act against enzymes of bacterial origin. “Our finding shows the need to incorporate this factor to achieve more effective therapies for type 2 diabetes,” concludes Benítez.

Intestinal hormones in diabetes

The abuse of foods rich in carbohydrates or sugars, often associated with overweight and obesity, is related to higher blood glucose levels. Glucose, our main source of energy, enters the cells thanks to insulin, a hormone released by the pancreas after food intake.

Overweight and obese individuals have excess blood glucose as a result of unhealthy diets, and require increased insulin secretion so that glucose, after food intake, enters the interior of the cells and blood glucose levels are reduced.

Obesity is the main risk factor for type 2 diabetes, which accounts for 90% of diabetes cases. It is a metabolic disorder characterized by hyperglycemia, a high level of sugar in the blood.

Different studies point to an increase in DPP-4 activity in individuals with obesity and type 2 diabetes, which causes inactivation of the hormones responsible for insulin release by the pancreas and, consequently, an increase in blood glucose.

“Our study provides scientific evidence on the possible causal role of the microbiota in the development of type 2 diabetes, and highlights the need to address not only dietary factors, but also the composition and functionality of intestinal bacteria in this disease,” say the authors of the publication, from the Microbiome, Nutrition and Health research group at IATA-CSIC. Researchers from the Centro de Investigación Príncipe Felipe de Valencia (CIPF) also participate in the study.