Research sheds light on why not all obese patients develop type 2 diabetes

PORTLAND, Ore. — Researchers at Oregon State University have invented a new testing method that sheds light on a lingering mystery about type 2 diabetes: why some obese patients develop the disease and others don’t.

Type 2 diabetes is a serious metabolic disease that affects approximately one in 10 Americans. Formerly known as adult-onset diabetes, it is a chronic disease affecting the way the body metabolizes glucose, a sugar that is an essential source of energy. This type of diabetes is frequently associated with obesity.

For some patients, this means their body is not responding properly to insulin – it is resisting the effects of insulin, the hormone produced by the pancreas that opens the door for sugar to enter cells. In the later stages of the disease, when the pancreas is exhausted, patients do not produce enough insulin to maintain normal blood sugar levels.

In either case, sugar builds up in the bloodstream and, if left untreated, the effect impairs many major organs, sometimes to disabling or life-threatening degrees. One of the main risk factors for type 2 diabetes is being overweight, often the result of excessive fat and sugar consumption combined with low physical activity.

Andrey Morgun and Natalia Shulzhenko of OSU and Giorgio Trinchieri of the National Cancer Institute have developed a new analytical technique, multi-organ network analysis, to explore the mechanisms underlying systemic resistance to insulin at an early stage.

Scientists have sought to find out which organs, biological pathways and genes play a role.

The findings, which show that a particular type of gut microbe leads to white fatty tissue containing macrophage cells – large cells that are part of the immune system – associated with insulin resistance, were published in the Journal of Experimental Medicine.

In the human body, white adipose tissue is the main type of fat.

“Our experiments and analyzes predict that a diet high in fat and sugar acts mainly in white adipose tissue by causing microbiota-related damage in the process of energy synthesis, leading to systemic insulin resistance”, said Morgun, associate professor of pharmaceutical sciences at OSU’s College of Pharmacy. “Treatments that alter a patient’s microbiota in ways that target insulin resistance in adipose tissue macrophage cells could provide a new therapeutic strategy for type 2 diabetes.”

The human gut microbiome includes over 10 trillion microbial cells from approximately 1,000 different bacterial species.

Morgun and Shulzhenko, an associate professor at OSU’s Carlson College of Veterinary Medicine, developed in previous research a computational method, cross-kingdom network analysis, that predicts specific types of bacteria controlling mammalian gene expression. related to specific medical conditions such as diabetes.

“Type 2 diabetes is a global pandemic, and the number of diagnoses is expected to continue to rise over the next 10 years,” Shulzhenko said. “The so-called ‘Western diet’ – high in saturated fats and refined sugars – is one of the main factors. But gut bacteria have an important role to play in mediating the effects of diet.

In the new study, the scientists relied on both cross-realm network analysis and multi-organ network analysis. They also conducted experiments in mice, looking at gut, liver, muscle, and white adipose tissue, and looked at the molecular signature — which genes were expressed — of white adipose tissue macrophages in obese human patients. .

“Western diet-induced diabetes is characterized by microbiota-dependent mitochondrial damage,” Morgun said. “Adipose tissue plays a prominent role in systemic insulin resistance, and we have characterized the gene expression program and major regulator of adipose tissue macrophages that are associated with insulin resistance. We found that the microbe Oscillibacter, enriched by a Western diet, causes an increase in macrophage of insulin-resistant adipose tissue.

The researchers add, however, that Oscillibacter is probably not the only microbial regulator of the expression of the key gene they identified – Mmp12 – and that the Mmp12 pathway, although clearly instrumental, is probably not the only pathway. important, according to gut microbes. present.

“We have previously shown that Romboutsia ilealis worsens glucose tolerance by inhibiting insulin levels, which may be relevant for later stages of type 2 diabetes,” Shulzhenko said.

Zhipeng Li, Manoj Gurung, Jacob W. Pederson, Renee Greer, Stephany Vasquez-Perez and Hyekyoung You from the Carlson College of Veterinary Medicine and Richard Rodrigues, Jyothi Padiadpu, Nolan Newman and Kaito Hioki from the College of Pharmacy also participated in this research. , as did scientists from the National Cancer Institute, the National Institute of Allergy and Infectious Diseases and Monash University in Australia.

The National Institutes of Health and the Oregon Medical Research Foundation supported this study.

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