Why do only some people get type 2 diabetes? A study sheds new light

A study from Oregon State University explains why not all overweight patients get type 2 diabetes.

A new analysis technique developed by researchers at Oregon State University sheds light on a long-standing mystery of type 2 diabetes: why some obese people get the disease and others don’t.

One in ten Americans has type 2 diabetes, a serious metabolic disease. It’s a condition that affects how the body metabolizes glucose, a sugar that’s an important source of energy. The condition was formerly known as adult-onset diabetes. This type of diabetes is often associated with obesity.

For some people, this means their body isn’t responding to insulin the way it should. Instead, it fights the effects of insulin. Insulin is a hormone made by the pancreas that facilitates the entry of sugar into cells. When the pancreas wears out in the latter stages of the disease, people can no longer produce enough insulin to keep their blood sugar levels within the normal range.

In both scenarios, blood sugar levels rise, and if ignored, the result weakens several important organs — sometimes seriously or even fatally. Obesity, which is often caused by excessive fat and sugar consumption combined with little physical activity, is a major risk factor for type 2 diabetes.

To study the processes behind early-stage systemic insulin resistance, Andrey Morgun, Natalia Shulzhenko and Giorgio Trinchieri of the National Cancer Institute developed a novel analytical method known as multi-organ network analysis.

The scientists wanted to know which organs, biological pathways and genes are involved.

The results, showing how a certain type of gut microbe causes white adipose tissue to contain macrophage cells – large cells in the immune system – that have been linked to insulin resistance were published in Journal of Experimental Medicine.

White adipose tissue is the main type of fat in the human body.

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

The human gut microbiome contains more than 10 trillion microbial cells from approximately 1,000 different bacterial species.

Morgun and Shulzhenko, associate professors at OSU’s Carlson College of Veterinary Medicine, in previous research developed a computational method, Transkingdom Network Analysis, that predicts specific types of bacteria that control the expression of mammalian genes linked to certain diseases, such as diabetes .

“Type 2 diabetes is a global pandemic and the number of diagnoses is expected to continue to increase over the next 10 years,” Shulzhenko said. “The so-called ‘Western diet’ – high in saturated fats and refined sugars – is one of the main contributors. But gut bacteria play an important role 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, examining the gut, liver, muscles and white adipose tissue, and examining the molecular signature – which genes were being 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 dominant role in systemic insulin resistance, and we have characterized the gene expression program and key master regulator of adipose tissue macrophages associated with insulin resistance. We have discovered that the Oscillibacter microbe enriched by a Western diet causes an increase in insulin-resistant adipose tissue macrophages.”

However, the researchers add that Oscillibacter is unlikely to be the only microbial regulator for the expression of the key gene they have identified – Mmp12 – and that the Mmp12 pathway, while clearly instrumental, is unlikely to be the only important pathway depending on, which gut microbes are present.

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

Reference: “Microbiota and mitochondrial adipocyte damage in type 2 diabetes are linked through Mmp12⁺ Macrophages” by Zhipeng 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, June 3, 2022, Journal of Experimental Medicine.
DOI: 10.1084/jem.20220017

The study was funded by the NIH/National Institutes of Health and the Oregon Medical Research Foundation.