Rats dying from type 1 diabetes restored to health without insulin
24 February 2009
Terminally ill rodents with type 1 diabetes have been restored to
full health with a single injection of a substance other than insulin by
University of Texas Southwestern Medical Center scientists. The rats
were given a single injection of the hormone leptin.
Since the discovery of insulin in 1922, type 1 diabetes
(insulin-dependent diabetes) in humans has been treated by injecting
insulin to lower high blood sugar levels and prevent diabetic coma.
New findings by UT Southwestern researchers, which appears in the
Proceedings of the National Academy of Sciences, suggest that
insulin isn’t the only agent that is effective. Leptin, a hormone
produced by the body’s fat cells, also lowers blood glucose levels and
maintains them in a normal range for extended periods, they found.
“The fact that these animals don’t die and are restored to normal
health despite a total lack of insulin is hard for many researchers and
clinicians to believe,” said Dr Roger Unger, professor of internal
medicine and senior author of the study.
“Many scientists, including us, thought it would be a waste of time
to give leptin in the absence of insulin. We’ve been brainwashed into
thinking that insulin is the only substance that can correct the
consequences of insulin deficiency.”
The mechanism of leptin’s glucose-lowering action appears to involve
the suppression of glucagon, a hormone produced by the pancreas that
raises glucose levels. Normally, glucagon is released when the glucose,
or sugar, level in the blood is low.
In insulin deficiency, however, glucagon levels are inappropriately
high and cause the liver to release excessive amounts of glucose into
the bloodstream. This action is opposed by insulin, which tells the
body’s cells to remove sugar from the bloodstream.
In type 1 diabetes the pancreatic islet cells that produce insulin
are destroyed. Type 1 diabetics must take insulin multiple times a day
to metabolize blood glucose and regiment their diets. In comparison,
patients with non-insulin dependent, or type 2, diabetes make insulin,
but their bodies don’t respond well to it. Type 1 diabetes affects about
1 million and type 2 diabetes between 18 million and 20 million people
in the US.
In the current study, researchers tested for the first time whether a
single injection of the leptin gene given to insulin-deficient mice and
rats on the verge of death from diabetic coma could reverse the severe
condition and prevent the animals from dying.
The animals that received the leptin gene began producing excessive
amounts of leptin, which reversed all the measurable consequences of
type 1 diabetes including weight loss, hyperglycemia and ketoacidosis, a
potentially fatal condition that develops when the body doesn’t have
enough insulin to meet basic metabolic requirements.
Much of the effect was mediated by complete suppression of the high
glucagon levels, said Dr Xinxin Yu, assistant instructor of internal
medicine and lead author of the study.
“These animals were actually dying,” Dr. Yu said. “But if we gave
them the leptin gene, within two weeks, the terminally ill rodents were
restored to full health without any other treatment.”
Dr Unger said it’s too premature to know whether leptin might someday
replace insulin as a treatment for diabetic patients, but this study
demonstrates that leptin could at least handle some of insulin’s job
requirements and do it for longer periods of time. Injected insulin is
biologically active for only three to four hours.
“My hope is that you could give leptin for one type of action —
glucagon’s suppression, for example — and insulin for another. Or
perhaps give a substance other than insulin entirely,” Dr Unger said.
“What would be a tremendous advance would be the ability to give an oral
agent that suppresses glucagon without injections.”
Dr Yu said the research team hypothesizes that leptin combats
diabetes not only by suppressing glucagon’s action on the liver, but
also by boosting the insulin-like actions of IGF-1 (insulin-like growth
factor-1), a hormone that promotes growth and mimics insulin.
“One of the things that happens when a child gets type 1 diabetes is
their growth is stunted until they’re given insulin,” Dr Unger said.
“The same is true with mice. However, we found if you take a diabetic
rat that’s not receiving insulin and make it hyperleptinemic, it almost
catches up growthwise.”
While the treated animals’ blood glucose levels inched back up over
time, their hyperglycemia (high blood sugar) consistently remained well
below the elevated pre-treatment levels. The untreated rodents, on the
other hand, died within two or three days. The researchers tracked the
treated rodents for 25 weeks.
The next step is to study other potential glucagon suppressants and
begin leptin clinical trials within the next year.
Other UT Southwestern researchers involved in the study were Dr. May-Yun
Wang, assistant professor of internal medicine; Dr. Zhao Wang,
postdoctoral researcher in internal medicine; and former postdoctoral
fellow Dr. Byung-Hyun Park.
The work was supported by the National Institute of Diabetes and
Digestive and Kidney Diseases, the Department of Veterans Affairs, and
the Juvenile Diabetes Research Foundation.
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