The Liver Runs Through It: New Scientific Evidence of the Central Role Obesity Plays in the Development of Type-2 Diabetes

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Research that tightened the focus on a PTP protein that attaches to liver cells hints at new treatments for obesity-induced diabetes.

The Liver Runs Through It: New Scientific Evidence of the Central Role Obesity Plays in the Development of Type-2 Diabetes

The fact that a research result is unsurprising in no way makes it unimportant. The liver’s prominent place in the physiological chain of events associated with the acquisition of type-2 diabetes is well-known and –documented.

Put simply, the liver both stores (from the food we eat) and produces glucose and, absent available sugar, ketones. What is also well known is that diseases and malfunctions of the liver can cause type-2 diabetes—and type-2 diabetes can cause diseases and maladies of the liver. Of late there has been much attention called to the phenomenon of fatty-liver disease, its causes, and ways to prevent and treat it.

Motivated by their concerns about the “epidemic” of obesity worldwide, scientists at Switzerland’s University of Geneva claim to have made a significant step further into understanding the place of the liver—and obesity—in the diabetes equation. In a report published in November, the deciphered the ways the protein PTPR-γ, which obesity appears to promote, inhibits insulin receptors on the surface of liver cells.

The Research

The scientists sought a clearer, more precise understanding of the mechanism by which the inflammation brought on by obesity triggers a transcription factor (NF-kβ) that seems to play a central role in the development of diabetes. Roberto Coppari, a professor at the University of Geneva’s Faculty of Medicine Diabetes Centre and a co-author of the study, focused on Protein Tyrosine Phosphatase Receptor Gamma, or PTPR-γ.

Preliminary human studies indicated that the content of that protein increases with liver inflammation, “an effect that could directly affect insulin receptors by inhibiting insulin action”, in Coppari’s words. The researchers tested their hypothesis by modifying the expression of the protein in mice—by suppressing and over-expressing, as well as well as normally expressing it.

Initially, there did not appear to be a difference in resulting insulin resistance. Then they tightened their focus on the normally expressed protein, but only in liver cells (hepatocytes). In the summary in the online ScienceMag, “The mice were again prone to insulin resistance, indicating the pivotal role of the liver.” 

Earlier studies of PTP proteins as the bases for potential diabetes therapies had proved unproductive. The protein studied and measured in Geneva proved different in important ways.

In ScienceMag’s summary (verbatim): “Contrary to some of its family members that are intracellular, the protein identified in Geneva is located on the cell membrane. It is therefore of much easier access for therapeutic molecules.

“Interestingly, the very form of this protein allows for potential inhibition strategies: when two independent PTPR-γ molecules are brought together by a ligand, they cannot act any more. The researchers are now working on identifying the endogenous ligand produced by the body, or on developing molecules that could mimic its function.”

Additional details of the research and its results are presented in more technical language in the study published in Nature Communications. A knowledgeable (and determined) lay reader can follow it.

The implications for diabetes treatments

In their own summary, the researchers wrote that they “propose hepatic PTPR-γ as a link between obesity-induced inflammation and insulin resistance and as potential target for treatment of T2DM….

“Here we show that PTPR-γ is a negative regulator of hepatic insulin signaling in both physiological and obesity/inflammation contexts. Importantly, our results suggest a model in which PTPR-γ links hepatic inflammation with insulin resistance and glucose imbalance associated with obesity.”

Perhaps it warrants noting that the Geneva research was carried out to address the “epidemic” of obesity worldwide, and suggested that its findings could lead to advances in treatment of resulting type-2 diabetes.

What went unsaid by the researchers is the greater desirability of preventing or reversing obesity. To that end, the treatment remains the same: appropriate diet and regular exercise. 


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