New research dispels the prevalent notion that glucose drives inflammation in obesity-related type 2 diabetes. The findings may explain why so many treatments to prevent complications in type 2 diabetes have failed.

scientist performing cell culture experimentsShare on Pinterest
Researchers used cell culture experiments to reveal that defects in the cells' mitochondria, along with exposure to certain types of fats, drive inflammation in type 2 diabetes.

Chronic inflammation is the root cause of many of diabetes' complications, including cardiovascular and kidney disease.

Until now, the scientific consensus has been that glucose drives inflammation in type 2 diabetes.

But new research counters this popular notion and points instead to high levels of lipids and defects in mitochondria — the tiny energy-reducing organelles inside cells.

Barbara Nikolajczyk from the Department of Pharmacology and Nutritional Sciences at the University of Kentucky Barnstable Brown Diabetes Center in Lexington is the lead author of the new study.

Nikolajczyk and her team started from the hypothesis that immune cells from people with type 2 diabetes would produce energy by breaking down glucose through the process of glycolysis.

Glycolysis is a series of reactions that turn glucose into energy. Other types of inflammation also rely on this process.

However, the results of the new research — appearing in the journal Cell Metabolism — disproved the scientists' premise.

Experiments reveal surprising results

"We exclusively used immune cells from human subjects for all of the work," Nikolajczyk explains.

She adds that she and her team have previously identified pro-inflammatory T cells with a profile specific to humans, which explains why animal models would not have been helpful for the current research.

The researchers compared samples from 42 people with obesity who did not have type 2 diabetes with samples from 50 people who had both obesity and diabetes.

The scientists excluded samples from people who were smokers, used insulin, had taken antibiotics or anti-inflammatory medication, as well as those who had a medical history of other inflammatory or autoimmune conditions.

Nikolajczyk and team isolated immune cells called CD4+ T cells and performed several cell culture experiments that revealed glycolysis does not drive chronic inflammation.

"[A]ctivated immune cells and purified CD4+ T cells" from people with type 2 diabetes are "strongly biased" towards glycolysis, write the authors. However, glucose starvation experiments designed to steer cells from people with type 2 diabetes "away from glycolysis and toward alternative fuel sources " did not normalize the inflammatory profile of T cells, as the researchers expected.

This unexpected result, explain the authors, shows that "glycolysis parallels, but does not fuel, [type 2 diabetes] inflammation."

Instead, the experiments revealed that T cells from people with type 2 diabetes had a range of mitochondrial defects. They also found that alterations in the "import or oxidation of fatty acids" trigger inflammation in healthy cells.

Nikolajczyk and colleagues conclude:

"Mitochondrial changes combine with fatty acid metabolites to activate inflammation."

Study may explain why treatments fail

The authors expand on the importance of their findings. They write that identifying the main driver behind obesity-associated inflammation is critical for preventing or treating metabolic disorders in people with obesity.

"Our data unexpectedly show that glucose, which drives inflammation in other contexts, is dispensable for type 2 diabetes-associated inflammation."

"Instead, partial defects in the cell's power plant, or mitochondria, fuel inflammation, but only in cells further stressed by the types of lipids that are elevated in obesity and type 2 diabetes," they explain.

Because current standard treatments for diabetes focus on glucose control, the surprising findings "raise clinical concerns that lipids will continue to drive inflammation, and thus metabolic dysfunction," even in diabetes patients with good glucose control.

"Aggressive blood glucose control to lower the risk of diabetic complications has been the goal for most people with type 2 diabetes for decades," stresses Nikolajczyk.

"Our data provide an explanation for why people with tight glucose control can nonetheless have disease progression."

Barbara Nikolajczyk