When Does Type 2 Diabetes Attack the Liver?

The Context: When someone builds up excess fat around their liver, they can develop a condition called non-alcoholic fatty liver disease (NAFLD). Those with type 2 diabetes can have increased risk of developing NAFLD, and the combination of both conditions can lead to nonalcoholic steatohepatitis (NASH). Those with NASH can have life-threatening liver inflammation, scarring, and liver cancer. But not everyone with type 2 diabetes gets NAFLD, and not everyone with NAFLD gets NASH. Scientists have long suspected a genetic component is involved, but have been unable to pinpoint specific risk factors.

The Study: Using 3D models of liver tissue made from stem cells called organoids, scientists led by NYSCF – Robertson Stem Cell Investigator Alumnus Takanori Takebe, MD, of Cincinnati Children’s Hospital discovered a certain gene that can trigger dangerous NAFLD-associated fat accumulation in those with type 2 diabetes. The study appears in Cell.

The Importance: This study establishes an improved model for studying type 2 diabetes and NASH, and NAFLD, and could help doctors predict and treat the people most at-risk for severe complications. 

The team began by growing liver organoids from the cells of 24 donors, and examined their gene activity.

The researchers identified a variant in one gene – GCKR-rs1260326 TT – that when exposed to conditions associated with diabetes (like high glucose and high insulin levels) can accelerate NAFLD fat accumulation. 

What’s interesting is that this same variant typically helps prevent liver scarring in someone with healthy blood sugar. So it seems that in those with an already at-risk liver, this variant turns from good to bad, essentially betraying the organ it is meant to protect. 

“It is very exciting to be able to recapitulate genetically-determined individual’s phenotype in an organoid model,” remarked first author Masaki Kimura, PhD, in an article from Cincinnati Children’s. “Our series of experiments using data from organoids and patients are further leveraged to disentangle the puzzling role of GCKR-rs1260326, revealing this variant exerts NASH protection and promotion depending on diabetes complications.”

Toward Better Treatments

One promising aspect of organoids is that they can be used as material for drug testing, and because they are made from actual human patients rather than the mouse models frequently used in drug discovery, the results could be much more informative of how a real patient would respond.

The scientists decided to see whether metformin—a widely prescribed diabetes treatment—made any difference for liver function when the NAFLD variant was present. It did, but not in a good way.

The organoids revealed that in those with the gene variant, metformin made liver function even worse. However, replacing metformin with a combination of two drugs, nicotinamide riboside and nitazoxanide, appears to stabilize the organoids’ function.

Why is metformin failing in organoids? The scientists suspect that the drug is slowing already weakened metabolic rates that occur when diabetes and NAFLD are combined.

The team then decided to look at HbA1c levels (a common test used to gauge diabetes control). They found that when HbA1c values were within normal ranges, several scores of liver function were better when someone carried the gene variant.

Conversely, when HbA1c values were in the diabetic range, those carrying the variant scored much lower.

“We found that en masse population-based analysis under insulin insensitive conditions predicted key non-alcoholic steatohepatitis (NASH) factors, opening up a door for an array of future personalized medicine applications propelled by human organoids,” said Dr. Takebe. 

“We also found, in collaboration with industry collaborators, that drugs that can uncouple oxidative mechanisms within cells helped improve mitochondrial function and may help livers adapt to the presence of increased fat. This suggests new potential ways to manage diabetic NASH.”

Bringing Findings to the Clinic

Dr. Takebe is leveraging his organoid platform to develop treatments for severe metabolic disorders – like diabetes, severe dyslipidemias, lipodystrophies, and NASH – via his recently-launched biotech company OrsoBio. This company’s pipeline consists of two clinical and two preclinical programs. 

Journal Article:

En masse organoid phenotyping informs metabolic-associated genetic susceptibility to NASH
Masaki Kimura, Takuma Iguchi, Kentaro Iwasawa, Andrew Dunn, Wendy L. Thompson, Yosuke Yoneyama, Praneet Chaturvedi, Aaron M. Zorn, Michelle Wintzinger, Mattia Quattrocelli, Miki Watanabe-Chailland, Gaohui Zhu, Masanobu Fujimoto, Meenasri Kumbaji, Asuka Kodaka, Yevgeniy Gindin, Chuhan Chung, Robert P. Myers, G. Mani Subramanian, Vivian Hwa, Takanori Takebe. Cell. 2022. DOI: https://doi.org/10.1016/j.cell.2022.09.031

Cover image: Liver organoids. Credit: Takebe lab.