Oregon State University researchers have used a new analytical method to shed light on an enduring mystery in type 2 diabetes: why some obese patients develop diabetes and others don’t. The reason is down to a genetic pathway linking diet and gut microbiota to macrophages and white adipose tissue. Their findings appear in the Journal of Experimental Medicine.
Type 2 diabetes is frequently associated with obesity. Ins some patients, that means insulin resistance. Later stages of the disease sees the pancreas producing insufficient insulin to maintain normal glucose levels.
In either case, hyperglycaemia is the result, which, if left untreated, impairs many major organs, sometimes to disabling or life-threatening degrees. Overweight status is a key risk factor for type 2 diabetes, often a result of eating too much fat and sugar in combination with low physical activity.
Associate Professors 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.
The findings showed that a particular type of gut microbe leads to white adipose tissue containing macrophage cells 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. “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 is incredibly complex, comprising more than 10 trillion microbial cells from about 1000 different bacterial species.
Associate Profs Morgun and Shulzhenko, 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,” Associate Prof 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 made use of transkingdom network analysis and multi-organ network analysis. Mouse experiments examined the intestine, liver, muscle and white adipose tissue, and the molecular signature (gene expression) of white adipose tissue macrophages in obese human patients.
“Diabetes induced by the western diet is characterised by microbiota-dependent mitochondrial damage,” Associate Prof Morgun said. “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 likely not the only microbial regulator for expression for the genetic pathway they discovered, 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.
Source: Oregon State University
