To date, the underlying causes of inflammation in obesity and type 2 diabetes mellitus (T2DM) have remained unclear, which has hampered efforts to develop preventive treatments. Now, Barbara Nikolajczyk and Douglas Lauffenburger show that changes to mitochondria drive inflammation in cells that have been exposed to fatty acid derivatives, which are elevated in obesity and T2DM. These data provide new insights into the causes of inflammation in T2DM and suggest that lipids could continue to drive inflammation (and thus metabolic dysfunction) in patients who have responded well to treatments that target glucose levels.

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“We were initially interested in investigating whether changes in the metabolism of immune cells contributed to T2DM-associated chronic inflammation,” explains Nikolajczyk. “Based on the importance of non-mitochondrial glycolysis in other types of inflammation, we hypothesized that immune cells from patients with T2DM would generate ATP by burning glucose by non-mitochondrial glycolysis — we were wrong.”

In their study, the investigators used immune cells from patients with T2DM. As a marker for inflammation, the authors used a specific T cell inflammatory profile, which consists of predominantly CD4+ type 17 T helper cells (TH17 cells).

Nikolajczyk and colleagues found that non-mitochondrial glycolysis failed to drive the T2DM-associated inflammatory signature. Other major pathways of ATP generation, including fatty acid oxidation and glutaminolysis, were similarly unable to activate TH17 cells. Instead, a combination of mitochondrial defects and fatty acid derivatives associated with T2DM were the cause of inflammation. “We combined siRNA-mediated knockdown of mitochondrial transporters (which was only partially effective) with higher concentrations of fatty acid derivatives that are naturally elevated in T2DM, to partially recapitulate TH17 function in cells from lean healthy participants,” adds Nikolajczyk. “Although it seems obvious that complete knockdown of mitochondrial transporters only partially recapitulates human disease, a rather clever integration of findings in the literature led lead author Dequina Nicholas to consider the possibility that partial defects might combine to generate T cell-associated inflammation.”

Nikolajczyk and colleagues found that non-mitochondrial glycolysis failed to drive the T2DM-associated inflammatory signature

The team is now interested in developing new analytical approaches that leverage ongoing lipidomics findings to further understand the pathology of T2DM. “This direction might begin to address the questions in the community regarding tight glycaemic control as the treatment goal for people with T2DM,” concludes Nikolajczyk.