[PHNUTR-L] Abnormal fat metabolism underlies heart problems in diabetic patients

[Kathrynne Holden]

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Public release date: 10-Aug-2007
http://www.eurekalert.org/pub_releases/2007-08/wuso-afm081007.php

Contact: Gwen Ericson
314-286-0141
Washington University School of Medicine

Abnormal fat metabolism underlies heart problems in diabetic patients

St. Louis, Aug. 10, 2007 — Heart disease hits people with diabetes twice 
as often as people without diabetes. In those with diabetes, 
cardiovascular complications occur at an earlier age and often result in 
premature death, making heart disease the major killer of diabetic 
people. But why is heart disease so prevalent among diabetics?
To help answer that question, researchers at Washington University 
School of Medicine in St. Louis have been analyzing the fat (lipid) 
composition of heart tissue from laboratory mice with diabetes. They 
have found that heart cells of diabetic mice lose an important lipid 
from cellular components that generate energy for the heart, and their 
latest research shows this happens at the very earliest stages of diabetes.

"Diabetic hearts run mostly on fats for fuel because glucose isn't 
readily available to them," says Richard Gross, M.D., Ph.D., director of 
the Division of Bioorganic Chemistry and Molecular Pharmacology and 
professor of medicine, of chemistry and of molecular biology and 
pharmacology. "Unfortunately, this change in metabolism distorts the 
lipid composition of cell membranes causing abnormal physical properties 
and cellular dysfunction."

The important lipid that the researchers found to be decreased in 
diabetes is cardiolipin. "Cardiolipin" literally means heart fat, and 
the term was coined because cardiolipin was first discovered in beef 
hearts and is one of the most abundant lipids in heart tissue. This 
lipid has unusual physical properties that are essential for the 
operation of the energy-producing cell structures called mitochondria.

When mitochondria lose a lot of their cardiolipin, they malfunction. 
Their malfunction not only interferes with the energy supply of heart 
muscle cells, it also increases the amount of damaging oxygen-containing 
substances in the cells, creating unhealthy conditions that can lead to 
heart problems.

Interestingly, a rare genetic disorder — Barth syndrome — held a key to 
identifying cardiolipin decrease in diabetic hearts. Children born with 
Barth syndrome have weak hearts and often die young from heart failure. 
These children have mutations that prevent cells from producing enough 
cardiolipin. The connection between cardiolipin and heart disease in 
Barth syndrome led the Washington University researchers to wonder if 
cardiolipin was also affected in diabetic hearts.

But in order to measure cardiolipin, the researchers needed a way to 
distinguish it from the numerous other lipids found in heart cells. 
Fortunately, Gross and his colleagues have been developing and refining 
a highly sophisticated set of techniques that allow them to separate and 
quantify thousands of different lipids based on their subtle structural 
differences. The set of techniques has been termed "shotgun lipidomics" 
because they very rapidly determine which lipids are in tissues and blood.

"Shotgun lipidomics provide a precise way to measure changes in heart 
lipid content," says first author Xianlin Han, Ph.D., assistant 
professor of medicine. "We found a dramatic depletion of cardiolipin in 
heart muscle as early as five days after diabetes was induced in mice."

"These results suggest that cardiolipin alterations underlie heart 
dysfunction in diabetic heart disease and may be a useful biomarker for 
diagnosing cardiovascular disease in diabetes," Gross says. "Measuring 
alterations may be a way to tell the severity of heart disease and to 
evaluate how well therapies work. In addition, these findings suggest 
potential new therapeutic approaches."

Even though the research team found a depletion of an important type of 
lipid in diabetic heart tissue, diabetic heart muscle cells actually 
take in excess lipids. But as these lipids enter cells they activate 
lipid-digesting enzymes. In previous studies, Gross and colleagues 
identified a particular lipid-digesting enzyme that becomes more active 
in diabetic heart muscle and contributes to the breakdown of cardiolipin.

Recently, Gross and his colleague David Mancuso, Ph.D., member of the 
division, found that mice engineered to produce too much of this enzyme 
in their hearts developed defects in mitochondrial function which became 
worse when they were fasted — a condition that, like diabetes, causes 
the heart to use lipids for fuel. A 16-hour fast caused significant 
problems with the mouse hearts' ability to pump blood, again implicating 
altered lipid metabolism, cardiolipin scarcity and mitochondrial 
impairment in heart disease using lipid as predominant fuel.

Gross adds that in addition to the effects on mitochondria, many of the 
membranes in heart cells, which are built from fatty molecules, are also 
adversely affected by the diabetic heart's abnormal lipid metabolism. 
Furthermore, because fatty molecules are part of cells' signaling 
mechanisms, numerous aspects of cellular physiology become altered.

"The pieces of the puzzle of diabetic heart disease are now rapidly 
falling into place," Gross says. "By exploiting the novel technology of 
shotgun lipidomics, we have identified the increased activation of 
certain lipid-digesting enzymes and the decrease of cardiolipin as 
central aspects of this disorder. We hope that these kinds of studies 
will enable physicians to diagnose diabetic cardiovascular disease 
sooner and treat it earlier."
###

Han X, Yang J, Yang K, Zhao Z, Abendschein DR, Gross RW. Alterations in 
myocardial cardiolipin content and composition occur at the very 
earliest stages of diabetes: a shotgun lipidomics study. Biochemistry 
2007;46:6417-6428.

Mancuso DJ, Han X, Jenkins CM, Lehman JJ, Sambandam N, Sims HF, Yang J, 
Yan W, Yang K, Green K, Abendschein DR, Saffitz JE, Gross RW. Dramatic 
accumulation of triglycerides and precipitation of cardiac hemodynamic 
dysfunction during brief caloric restriction in transgenic myocardium 
expressing human calcium-independent phospholipase A2γ. Journal of 
Biological Chemistry 2007 Mar;282(12):9216-9227.

Funding from the National Institutes of Health supported this research.

Washington University School of Medicine's full-time and volunteer 
faculty physicians also are the medical staff of Barnes-Jewish and St. 
Louis Children's hospitals. The School of Medicine is one of the leading 
medical research, teaching and patient care institutions in the nation, 
currently ranked fourth in the nation by U.S. News & World Report. 
Through its affiliations with Barnes-Jewish and St. Louis Children's 
hospitals, the School of Medicine is linked to BJC HealthCare.
-- 
Kathrynne Holden, MS, RD < fivestar at nutritionucanlivewith.com >
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