Excess fat disrupts heart cell's energy system

January 05, 2018

A University of Iowa study has identified how excess fat in the heart, a common feature in diabetes and obesity, can harm the cells' essential ability to produce energy. Researchers believe the mechanism may contribute to the two- to five-fold increased risk of heart failure in people with diabetes.

The heart is the most energy-hungry organ in the body. Just like a combustion engine burning fuel to power the pistons, healthy heart cells consume fuel molecules to create the necessary energy to keep the heart pumping. This essential energy production takes place inside mitochondria, the self-contained "powerplant" organelles inside cells.

Although mitochondria in a healthy heart primarily use fatty acids as fuel, they can easily adapt to use other fuel molecules as needed, including glucose, lactate, and ketone bodies. Diabetes, however, reduces the heart muscle's metabolic adaptability and causes heart cells to overuse fat as a metabolic fuel.

The study, published in Circulation Research, found that this cardiac lipid overload leads to numerous small, misshapen mitochondria that don't produce energy as efficiently as normal mitochondria. Previous research from the UI team has suggested that problems with mitochondrial energy production may play a role in heart failure associated with diabetes.

"Diabetes, which affects almost 30 million Americans, significantly increases the risk of heart failure, and one of the cardinal manifestations of the hearts of people with diabetes is the tendency to overuse fat as a metabolic fuel, which ultimately leads to mitochondrial and cardiac damage," explains study leader E. Dale Abel, MD, PhD, professor and departmental executive officer of internal medicine at the UI Carver College of Medicine and director of the Fraternal Order of Eagles Diabetes Research Center at the UI. "We have demonstrated and detected how increasing the amount of fat (lipid) that the heart consumes leads to dramatic changes in the structure and function of the mitochondria in the heart. These studies provide a new window into how these changes to mitochondria could occur in the lipid-overloaded heart."

The UI team used genetically modified mice that mimic the increased fatty acid uptake (lipid overload) that characterizes diabetes to investigate the consequences of cardiac lipid overload on mitochondria. A novel 3-D electron microscopic cellular imaging technique developed by colleagues in Germany allowed the researchers to directly observe the structural changes to the mitochondria - rather like putting on a virtual reality headset inside the cardiac muscle cell, says Abel. In the mouse model, lipid uptake to heart is doubled. This modest increase resulted in mitochondria that became thinner and more twisted than mitochondria in healthy heart cells. These structural changes (almost like a noodle snaking through the heart) lead to an appearance of mitochondrial fragmentation when imaged by conventional electron microscopy.

The study also revealed the molecular cause of the change in mitochondrial structure. Prolonged lipid overload leads to increased levels of damaging substances called reactive oxygen species (ROS). The excess ROS disrupts the mitochondrial network by altering the activity of several important proteins that help control the size and shape of mitochondria.

Removing the excess ROS by overexpressing a molecule that helps "mop up" ROS molecules restored normal-looking mitochondria, which worked properly, despite the lipid overload.

Surprisingly, using the same approach to remove ROS in normal heart cells led to mitochondria that were four times as large as normal, suggesting that ROS levels are inversely proportional to mitochondria size.

The findings suggest that cardiac lipid overload disrupts normal mitochondrial structure, which may impair energy production and compromise heart function.
-end-
In addition to Abel, the team included UI researchers Kensuke Tsushima, Jamie Soto, Gregory Jenson, Austin Tor, Rose McGlauflin, Helena Kenny, Yuan Zhang, Rhonda Souvenir, Renata Pereira and Vitor Lira. The team also included Heiko Bugger, Eva Rog-Zielinska and Peter Kohl from the University Freiburg in Germany; Adam Wende from the University of Alabama at Birmingham; Crystal Black, Sharon Hu, and Ken Spitzer from the University of Utah; Terry Sharp, Koresh Shoghi and Jean Schaffer from Washington University; Genevieve Sparagna from the University of Colorado Boulder; and Oleh Khalimonchuk from the University of Nebraska.

The research was funded in part by grants from the National Institutes of Health, the American Heart Association, the Juvenile Diabetes Research Foundation, the Japan Heart Foundation, Deutsche Forschungsgemeinschaft and the European Research Council.

University of Iowa Health Care

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.