Scientists discover why and how diabetes damages the heart

by Barbara Hewitt on July 2, 2015

Scientists in the United States have discovered a potential new treatment for diabetes-related heart damage after finding out how too much blood sugar affects this vital organ.

The team at John Hopkins University Medical Centre have located what they describe as the ‘epicentre of mischief’ wreaked by too much blood sugar. Working with diabetic rats, they have used a sugar-eating enzyme to restore normal function in the glucose damaged cells.


Scientists have discovered a potential new treatment for diabetes-related heart damage

‘Glucose toxicity in the heart is one of the gravest complications of diabetes and one whose mechanisms are poorly understood,’ said lead investigator Genaro Ramirez-Correa, an instructor of paediatric cardiology at the Johns Hopkins Children’s Centre.

Scientists have known for some time that hearts affected by diabetes conduct electrical signals abnormally and contract aberrantly, both problems believed to stem from the cells’ inability to properly respond to calcium, the chief trigger of cardiac and other muscle contraction.

But how and why heart cells in diabetics fail to respond to contraction-fuelling calcium has been a puzzle until the researchers found that a sugar molecule and an enzyme charged with regulating the molecule’s levels inside cells appears to be at the root of calcium insensitivity and poor contraction.

The sugar molecule, called O-GlcNAc, and one of its handler enzymes OGT, get shuffled around the cell and end up in the wrong location. From there, the researchers observed, they interfere with the work of proteins that control muscle contraction.

Using a sophisticated laser microscope to obtain detailed images of the cells’ interiors, researchers focused on the areas within heart cells that control muscle contraction, which are tiny muscle units known as sarcomeres.

Scientists noticed that in diabetic heart muscle cells, O-GlcNAc and one of its chaperone enzymes, OGT, move away from the sarcomere’s border and toward the middle where various proteins normally connect with each other and form chains that pull the ends of the sarcomere closer together, the essence of muscle contraction.

Normally, flow of calcium into the heart cells is a call to action for muscle proteins to form a cross-bridge and initiate contraction. But when O-GlcNAc and OGT insert themselves in the middle, like struts, the researchers found, they prevented contractile proteins from cross bridging properly with one another in response to calcium. That, the researchers say, fuels the calcium insensitivity seen in diabetic hearts and causes abnormal muscle contraction.

In further experiments, researchers used an enzyme, OGA, whose sole job is to break down O-GlcNAc. Harnessing the enzyme’s appetite for O-GlcNAc, they introduced a bacterial form of this sugar gobbler into the muscle cells of diabetic hearts.

The cells’ ability to respond to calcium was restored and so was their normal contraction, the researchers observed, and Ramirez-Correa explained that when they exposed healthy heart muscle cells to the same enzyme, nothing changed.

The team believes that if their observations are confirmed in larger animals and then in humans, the findings could lead to the development of drugs that inhibit the toxic reshuffling of sugar molecules and enzymes inside heart cells. The results could also form the basis for a clinical biomarker that heralds the onset of diabetic cardiomyopathy before irreversible damage occurs.

The opinions expressed in this article do not necessarily reflect the views of the Community and should not be interpreted as medical advice. Please see your doctor before making any changes to your diabetes management plan.

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