Study Clarifies Insulin’s Role In Type II Diabetes

Chronically high levels of insulin, as is found in people with Type II diabetes, may block a specific hormone that is a trigger for releasing energy into the body. The research team, led by Roger Y. Tsien, Ph.D., professor of Chemistry and Biochemistry in UCSD’s Department of Pharmacology found that high levels of insulin can block the stress hormone catecholamines, which normally causes the release of cellular energy. For normal metabolism to occur, the body needs a balanced input of two types of hormones: insulin and catacholomines. Insulin, the main energy storage hormone, works by blocking activation of the protein kinase A (PKA) enzyme. After a meal, insulin levels go up, and the body stores energy to be used later. When energy is needed, the catacholomine triggers activation of the PKA, and energy is released. But in people with Type II diabetes, the hormonal balance has been thrown off, because the body continues to produce and store more and more insulin instead of releasing the energy.

"Somehow, insulin knows how to specifically block catecholamine-induced PKA, but not other molecules," said Christopher Hupfeld, assistant professor of Medicine in the UCSD Division of Endocrinology and Metabolism and a co-author of the paper. "When the body has a constantly high level of insulin, this energy- release stimulus is lost."

The team’s findings provide new understanding to the cause and effect occurring when insulin levels are too high. It also underscores the goal of physicians to bring down insulin levels in Type II diabetes using medicines called insulin sensitizers, so that the body becomes more sensitive to using its own insulin, rather than compensating for insulin resistance by making more.

In order to understand the mechanisms of insulin resistance present in Type II diabetes, the researchers used a new breed of cellular enzyme reporter to track PKA. The reporter is a "marker" protein, created with a special fluorescent tag so that scientists can physically view the protein under a microscope and watch how the live cell works in real time.

The PKA is activated inside the adipocyte cell, the major site of energy storage in the body where many aspects of metabolism are controlled. There, energy is stored in the form of triglycerides, commonly known as fat. If a person is obese, excess triglycerides are stored in the adipocytes.

"If insulin levels get too high for too long a time – which happens in type II diabetes -the normal catecholamine signal that triggers energy release can be drowned out. This can lead to excessive energy storage in the adipocyte," said Hupfeld. "This may be one reason why chronic obesity and Type II diabetes are often seen together."

"By correcting this hormonal imbalance, we may at some point improve treatment options," said Hupfeld.

journal Nature September 22.

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DID YOU KNOW:
Diabetes Becomes the 5th Leading Cause of Death: Diabetes may have killed nearly 3 million people in 2000, making it the world’s No. 5 cause of death, by a new estimate. The numbers, published in Sept, 2005 Diabetes Care, come from researchers including the World Health Organization.