Discovery could change treatments for type 2 diabetes

Monday, 9 March 2020

Today, many health problems appear to stem from the disruption the metabolic balance between glucose production and energy utilization in the liver.  Now, Yale scientists have reported (in JAMA surgery) the discovery of the molecular mechanisms that trigger the imbalance between these two processes.

A finding with implications for future treatments of type 2 diabetes and non-alcoholic fatty liver disease.

About the research

The hormone glucagon, secreted by the pancreas, plays an essential role in our metabolism. In times of food scarcity, it can jump-start the liver’s production of glucose, an essential fuel for the brain, in a process called gluconeogenesis. In diabetes, which is marked by an excess of blood glucose, this process is disrupted.

By applying novel methods to assess liver metabolism they have been able to delineate the molecular mechanisms by which glucagon works.

In the past, researchers have previously focused on glucagon in attempts to reduce elevated blood glucose in diabetes. But those experimental treatments led to potentially serious side effects, including a build-up of liver enzymes indicating fatty liver disease.

The new research zeroed in on the role of calcium signalling within the mitochondria, the cell’s energy-producing factory.

What the research found

The Yale team led by two senior endocrinologists discovered that a protein called inositol triphosphate receptor 1 (INSP3R1) regulates both gluconeogenesis and fat oxidation in the liver in response to glucagon. The group found that INSP3R1 influences gluconeogenesis by regulating calcium signalling within the cell and fat oxidation by influencing calcium signalling within the mitochondria.

They identified mitochondrial calcium transport as a potential target to promote the good effects of glucagon to promote mitochondrial fat oxidation in the liver and reverse NAFLD without the bad effects of stimulating gluconeogenesis.

When obese rodents were treated chronically with glucagon, the hormone reversed NAFLD and improved the body’s response to insulin. However, when obese mice without INSP3R1 were chronically treated with glucagon, the hormone had no effect.

What the results mean

These results provide new insights into glucagon biology and suggest that mitochondrial calcium transport, mediated by INSP3R1, may represent a novel target for treatments that aim to reverse NAFLD and type 2 diabetes.

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