Deleting a liver enzyme lowers the health risk of sweet treats (at least in mice)

October 24, 2019

Tsukuba, Japan - Excessive sugar and fat in the diet can lead to hepatic (liver) insulin resistance. Often seen in people who are obese, hepatic insulin resistance leads to unhealthy levels of fatty lipids in the liver and is a risk factor for serious illnesses like type 2 diabetes and cardiovascular disease. Researchers at the University of Tsukuba are attempting to unravel the complicated physiology of insulin resistance, and in a new study published in Hepatology, they show how one gene can have a major impact on insulin resistance in the liver.

A therapy that prevents hepatic insulin resistance would go a long way toward addressing the many health issues stemming from the rise in obesity worldwide. Such a therapy does not yet exist, largely because the links between diet and liver physiology are poorly understood.

Hitoshi Shimano, corresponding author of the study and head of the Department of Metabolism and Endocrinology at the University of Tsukuba Hospital, has spent many years unpacking the mechanisms of lipid metabolism. Several years back, his research team discovered that deleting a single gene--Elovl6, which codes for an enzyme that makes lipids--protects mice that are on a high-sugar, high-fat diet from developing insulin resistance.

"Our prior work showed that deleting the Elovl6 gene protects mice from several hallmark signs of diabetes, including insulin resistance," says Shimano. "However, this was done by removing the gene from every cell in the mouse body. We're now interested in understanding the role of Elovl6 in a more targeted setting, by deleting the gene specifically in liver and seeing its effect on insulin resistance in hepatic cells. This will give us a better picture of what's happening in the liver, which will aid downstream efforts to develop targeted therapies."

While the prospect of a targeted therapy for insulin resistance is tantalizing, the team's latest study shows that the story gets more complicated in the liver.

"We assumed that mice with a liver-targeted deletion of Elovl6 would be protected from hepatic insulin resistance," says Takashi Matsuzaka, professor of medicine at the University of Tsukuba and lead author of the study. "We instead found a more nuanced effect, in that only mice that were fed a high-sugar diet were protected. The deletion had no effect on mice that were given a high-fat diet."

What explains the selective impact of Elovl6 in the liver? After a great deal of molecular digging, the researchers uncovered a potential answer. They found that removing Elovl6 changes the balance of many lipids in the liver. Notably, they discovered that one lipid in particular--in a class of lipids called ceramides--was much higher in liver cells that were missing Elovl6. The team found that this ceramide sets off a cascade of molecular signals that protects mice from insulin resistance due to an excessively sweet diet.

"Although the mechanism is more complex than we initially predicted, the findings confirm our hypothesis that Elovl6 plays a critical role in hepatic insulin resistance," Shimano concludes. "Targeting Elovl6 is an effective method of protecting against insulin resistance, so we're hopeful that delineating the underlying molecular pathways of Elov6 will aid in the development of treatments for this condition."
-end-


University of Tsukuba

Related Diabetes Articles from Brightsurf:

New diabetes medication reduced heart event risk in those with diabetes and kidney disease
Sotagliflozin - a type of medication known as an SGLT2 inhibitor primarily prescribed for Type 2 diabetes - reduces the risk of adverse cardiovascular events for patients with diabetes and kidney disease.

Diabetes drug boosts survival in patients with type 2 diabetes and COVID-19 pneumonia
Sitagliptin, a drug to lower blood sugar in type 2 diabetes, also improves survival in diabetic patients hospitalized with COVID-19, suggests a multicenter observational study in Italy.

Making sense of diabetes
Throughout her 38-year nursing career, Laurel Despins has progressed from a bedside nurse to a clinical nurse specialist and has worked in medical, surgical and cardiac intensive care units.

Helping teens with type 1 diabetes improve diabetes control with MyDiaText
Adolescence is a difficult period of development, made more complex for those with Type 1 diabetes mellitus (T1DM).

Diabetes-in-a-dish model uncovers new insights into the cause of type 2 diabetes
Researchers have developed a novel 'disease-in-a-dish' model to study the basic molecular factors that lead to the development of type 2 diabetes, uncovering the potential existence of major signaling defects both inside and outside of the classical insulin signaling cascade, and providing new perspectives on the mechanisms behind insulin resistance in type 2 diabetes and possibly opportunities for the development of novel therapeutics for the disease.

Tele-diabetes to manage new-onset diabetes during COVID-19 pandemic
Two new case studies highlight the use of tele-diabetes to manage new-onset type 1 diabetes in an adult and an infant during the COVID-19 pandemic.

Genetic profile may predict type 2 diabetes risk among women with gestational diabetes
Women who go on to develop type 2 diabetes after having gestational, or pregnancy-related, diabetes are more likely to have particular genetic profiles, suggests an analysis by researchers at the National Institutes of Health and other institutions.

Maternal gestational diabetes linked to diabetes in children
Children and youth of mothers who had gestational diabetes during pregnancy are at increased risk of diabetes themselves, according to new research published in CMAJ (Canadian Medical Association Journal).

Two diabetes medications don't slow progression of type 2 diabetes in youth
In youth with impaired glucose tolerance or recent-onset type 2 diabetes, neither initial treatment with long-acting insulin followed by the drug metformin, nor metformin alone preserved the body's ability to make insulin, according to results published online June 25 in Diabetes Care.

People with diabetes visit the dentist less frequently despite link between diabetes, oral health
Adults with diabetes are less likely to visit the dentist than people with prediabetes or without diabetes, finds a new study led by researchers at NYU Rory Meyers College of Nursing and East Carolina University's Brody School of Medicine.

Read More: Diabetes News and Diabetes Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.