To date, the underlying causes of inflammation in obesity and type 2 diabetes mellitus (T2DM) have been poorly understood, which has hampered efforts to develop treatments to prevent complications from a disease that is the third leading cause of death in the US. But research at the University of Kentucky shows that changes to mitochondria – the powerhouse of cells – drive chronic inflammation from cells exposed to certain types of fats, shattering the prevailing assumption that glucose was the culprit.
Chronic inflammation fuels many of the devastating complications of type 2 diabetes, including cardiovascular, kidney, and periodontal diseases, and is thus one of the key targets for therapy development. This new data may enlighten the conversation about tight glycaemic control as the dominant treatment goal for people with diabetes.
The research was by a team led by Barbara Nikolajczyk (UK Barnstable Brown Diabetes Centre, department of pharmacology and nutritional sciences) and Douglas Lauffenberger (Massachusetts Institute of Technology (MIT) department of biological engineering).
Nikolajczyk and Lauffenberger didn't set out to disprove the glucose-inflammation causation theory. Based on the importance of glycolysis – a 10-reaction sequence that produces energy – in other types of inflammation, the team hypothesized that immune cells from patients with type 2 diabetes would produce energy by burning glucose. "We were wrong," Nikolajczyk said.
"We exclusively used immune cells from human subjects for all of the work, " Nikolajczyk explained, noting that humans, but not animal models of type 2 diabetes, have the specific pro-inflammatory T cell profile her team had identified in earlier research.
The team was surprised to find that glycolysis wasn't driving chronic inflammation. Instead, a combination of defects in mitochondria and elevated fat derivatives were responsible.
Nikolajczyk said she sees applications for this research in both basic and clinical sciences. She hopes to precisely define pro-inflammatory lipid types and explore associations between circulating and/or tissue-associated lipids and insulin resistance, one key feature of type 2 diabetes. She is also interested in contributing to the development of new analytical approaches, spearheaded by Lauffenburger's team, that leverage ongoing lipid-related findings into a new understanding of pathology in type 2 diabetes.
"Aggressive blood glucose control to lower the risk of diabetic complications has been the goal for most people with type 2 diabetes for decades," Nikolajczyk said. "Our data provide an explanation for why people with tight glucose control can nonetheless have disease progression."
Mechanisms that regulate metabolites and downstream energy generation are key determinants of T cell cytokine production, but the processes underlying the Th17 profile that predicts the metabolic status of people with obesity are untested. Th17 function requires fatty acid uptake, and our new data show that blockade of CPT1A inhibits Th17-associated cytokine production by cells from people with type 2 diabetes (T2D). A low CACT:CPT1A ratio in immune cells from T2D subjects indicates altered mitochondrial function and coincides with the preference of these cells to generate ATP through glycolysis rather than fatty acid oxidation. However, glycolysis was not critical for Th17 cytokines. Instead, β oxidation blockade or CACT knockdown in T cells from lean subjects to mimic characteristics of T2D causes cells to utilize 16C-fatty acylcarnitine to support Th17 cytokines. These data show long-chain acylcarnitine combines with compromised β oxidation to promote disease-predictive inflammation in human T2D.
Dequina A Nicholas, Elizabeth A Proctor, Madhur Agrawal, Anna C Belkina, Stephen C Van Nostrand, Leena Panneerseelan-Bharath, Albert R Jones, Forum Raval, Blanche C Ip, Min Zhu, Jose M Cacicedo, Chloe Habib, Nestor Sainz-Rueda, Leah Persky, Patrick G Sullivan, Barbara E Corkey, Caroline M Apovian, Philip A Kern, Douglas A Lauffenburger, Barbara S Nikolajczyk
[link url="https://www.sciencedaily.com/releases/2019/08/190821082238.htm"]University of Kentucky material[/link]
[link url="https://www.sciencedirect.com/science/article/abs/pii/S1550413119303778?via%3Dihub"]Cell Metabolism abstract[/link]