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Why all patients with obesity do not develop T2DM

Updated: Jun 8, 2022

Researchers at Oregon State University (OSU) have invented a new analytical method that sheds light on an enduring mystery regarding type 2 diabetes: Why some patients with obesity develop the disease and others do not?

Drs Andrey Morgun and Natalia Shulzhenko of OSU and Giorgio Trinchieri of the National Cancer Institute developed a novel analytical technique, multi-organ network analysis, to explore the mechanisms behind early-stage systemic insulin resistance. The scientists sought to learn which organs, biological pathways and genes are playing roles. Reporting their findings in the paper, ‘Microbiota and adipocyte mitochondrial damage in type 2 diabetes are linked by Mmp12+ macrophages’, in the Journal of Experimental Medicine, they show that a particular type of gut microbe leads to white adipose tissue containing macrophage cells - large cells that are part of the immune system -associated with insulin resistance.

"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 in 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 ten years," said Shulzhenko. "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 characterised by microbiota-dependent mitochondrial damage," added Morgun. "Adipose tissue has a predominant role in systemic insulin resistance, and we characterised the gene expression program and the key master regulator of adipose tissue macrophage that are 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 unlikely to be the only microbial regulator for 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 concluded.

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