A new analytical technique developed by researchers at Oregon State University provides insight into a longstanding type 2 diabetes mystery: Why some obese individuals get the disease while others don’t.
One in ten Americans has type 2 diabetes, a serious metabolic disease. It is a condition that impacts how the body metabolizes glucose, a sugar that is a major source of energy. The condition was once known as adult-onset diabetes. This kind of diabetes is frequently associated with obesity.
For some people, this means that their body does not react to insulin as it should. Instead, it fights against insulin’s effects. Insulin is a hormone generated by the pancreas that facilitates the entry of sugar into cells. When the pancreas is worn down in the latter stages of the disease, individuals are unable to generate enough insulin to keep their blood sugar levels within the normal range.
In either scenario, blood sugar levels rise, and if ignored, the consequence weakens several important organs—sometimes severely or even fatally. Being overweight, which is often brought on by consuming excessive amounts of fat and sugar together with little physical exercise, is a major risk factor for type 2 diabetes.
To investigate the processes behind early-stage systemic insulin resistance, Andrey Morgun, Natalia Shulzhenko, and Giorgio Trinchieri of the National Cancer Institute created a novel analytical method known as multi-organ network analysis.
The scientists wanted to know what organs, biological pathways, and genes were involved.
The results, which demonstrate how a certain kind of gut microbe causes white adipose tissue to contain macrophage cells—large immune system cells—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 analysis predict that a high-fat/high-sugar diet primarily acts in white adipose tissue by driving microbiota-related damage to the energy synthesis process, leading to systemic insulin resistance,” said Morgun, associate professor of pharmaceutical sciences at the OSU College of Pharmacy. “Treatments that modify a patient’s microbiota in ways that target insulin resistance in adipose tissue macrophage cells could be a new therapeutic strategy for type 2 diabetes.”
The human gut microbiome features more than 10 trillion microbial cells from about 1,000 different bacterial species.
Morgun and Shulzhenko, an associate professor in OSU’s Carlson College of Veterinary Medicine, in earlier research developed a computational method, transkingdom network analysis, that predicts specific types of bacteria controlling the expression of mammalian genes connected to specific medical conditions such as diabetes.
“Type 2 diabetes is a global pandemic, and the number of diagnoses is expected to keep increasing over the next 10 years,” Shulzhenko said. “The so-called ‘western diet’ – high in saturated fats and refined sugars – is one of the primary 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 transkingdom network analysis and multi-organ network analysis. They also conducted experiments in mice, looking at the intestine, liver, muscle, and white adipose tissue, and examined the molecular signature – which genes were being expressed – of white adipose tissue macrophages in obese human patients.
“Diabetes induced by the western diet is characterized by microbiota-dependent mitochondrial damage,” Morgun said. “Adipose tissue has a predominant role in systemic insulin resistance, and we characterized the gene expression program and the key master regulator of adipose tissue macrophage that is associated with insulin resistance. We discovered that the Oscillibacter microbe, enriched by a western diet, causes an increase of the insulin-resistant adipose tissue macrophage.”
The researchers add, however, that Oscillibacter is likely not the only microbial regulator for the expression of the key gene they identified – Mmp12 – and that the Mmp12 pathway, while clearly instrumental, is probably not the only important pathway, depending on which gut microbes are present.
“We previously showed that Romboutsia ilealis worsens glucose tolerance by inhibiting insulin levels, which may be relevant to more advanced stages of type 2 diabetes,” Shulzhenko said.
Reference: “Microbiota and adipocyte mitochondrial damage in type 2 diabetes are linked by Mmp12+ macrophages” byZhipeng Li, Manoj Gurung, Richard R. Rodrigues, Jyothi Padiadpu, Nolan K. Newman, Nathan P. Manes, Jacob W. Pederson, Renee L. Greer, Stephany Vasquez-Perez, Hyekyoung You, Kaito A. Hioki, Zoe Moulton, Anna Fel, Dominic De Nardo, Amiran K. Dzutsev, Aleksandra Nita-Lazar, Giorgio Trinchieri, Natalia Shulzhenko and Andrey Morgun, 3 June 2022, Journal of Experimental Medicine.
The study was funded by the NIH/National Institutes of Health and the Oregon Medical Research Foundation.
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