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Researchers Find Potential New Non-Insulin Treatment for Type 1 Diabetes

1-Apr-2011

March 2011 - Researchers at UT Southwestern Medical Center have discovered a

hormone pathway that potentially could lead to new ways of treating type 1

diabetes independent of insulin, long thought to be the sole regulator of

carbohydrates in the liver. Results of this new study will be published

March 25 in Science.

Another hormone, fibroblast growth factor 19 (FGF19), has insulin-like

characteristics beyond its role in bile acid synthesis. Unlike insulin,

however, FGF19 does not cause excess glucose to turn to fat, suggesting that

its activation could lead to new treatments for diabetes or obesity.

" The fundamental discovery is that there is a pathway that exists that is

required for the body, after a meal, to store glucose in the liver and drive

protein synthesis. That pathway is independent of insulin, " said Dr.

Mangelsdorf, chairman of pharmacology at UT Southwestern.

Naturally elevating this pathway, therefore, could lead to new diabetes

treatments outside of insulin therapy. The standard treatment for type 1

diabetes, which affects about 1 million people in the U.S., involves taking

insulin multiple times a day to metabolize blood sugar.

Dr. Mangelsdorf and Dr. Kliewer, professor of molecular biology and

pharmacology at UT Southwestern, are co-senior authors of the study. Dr.

Kliewer has been studying the hormone FGF19 since he discovered its

involvement in metabolism about eight years ago.

Fibroblast growth factors control nutrient metabolism and are released upon

bile acid uptake into the small intestine. Bile acids, produced by the

liver, break down fats in the body.

Researchers studied mice lacking FGF15 - the rodent FGF19 hormone

equivalent. These mice, after eating, could not properly maintain blood

concentrations of glucose and normal amounts of liver glycogen. Glycogen is

a form of glucose storage found mainly in liver and muscle tissue. The mice

were then injected with FGF19 to evaluate its effects on metabolism in the

liver.

FGF19 restored glycogen levels in the mice lacking FGF15. When administered

to diabetic mice lacking insulin, FGF19 also corrected the loss of glycogen.

" FGF19 does not make fat, and that's one of the effects that separates it

from insulin. Insulin also does not really have a dramatic effect on bile

acid synthesis. So, the two pathways are different even though they both

function in glycogen and protein synthesis, " said Dr. Mangelsdorf, a

Medical Institute investigator at the medical center.

Manipulating FGF19 as an alternative to insulin therapy remains a daunting

challenge, however, given some unwelcome side effects. In some studies, he

said, activating the hormone in rodents caused the liver to grow and develop

cancer.

One promising diabetes treatment route could involve the nuclear bile acid

receptor FXR, which Dr. Mangelsdorf said induces expression of FGF19.

Modulators of FXR (farnesoid X receptor) have been shown to lower

triglycerides and improve cholesterol profiles in preclinical models.

The study's lead author is Serkan Kir, a UT Southwestern graduate student in

pharmacology. Also involved in the study were researchers from Yale

University School of Medicine; Case Western Reserve University; Van Andel

Research Institute; and the Medical Institute.

The work was supported by the National Institutes of Health, HHMI, the

Welch Foundation and the Yale and Case Western Reserve University

Mouse Metabolic Phenotyping Centers.

Source: UT Southwestern Medical Center