Scientists identify third critical hormone in Type 2 diabetes

April 3, 2014 by Helen Jones, Johns Hopkins University
Scientists identify third critical hormone in Type 2 diabetes
Mehboob Hussain, M.D.

(Medical Xpress)—Working with mice and human blood and liver samples, scientists from the Johns Hopkins Children's Center have identified a previously unsuspected liver hormone as a critical player in the development of type 2 diabetes, a condition that affects nearly 26 million people in the United States and is a leading cause of heart disease and stroke, as well as kidney, nerve and eye damage.

Results of the research, to be published April 1 in the journal Cell Metabolism, show that the hormone, kisspeptin 1, or K1—up until now known for its regulation of puberty and fertility—also slows down the production of insulin, the sugar-regulating hormone secreted by the pancreas, and in doing so fuels the development of .

The findings provide what researchers consider a missing link in understanding the origins of type 2 diabetes. Two hormones, glucagon and insulin, must work in synchrony to maintain healthy sugar levels in the bloodstream. Secreted when sugar levels drop, glucagon causes the liver to release its strategic reserves of glucose into the bloodstream. When sugar levels rise, insulin acts as an antidote to glucagon, helping the body lower blood sugar by transporting it out of the bloodstream and into organs and tissues as fuel. In type 2 diabetes, secrete too little or no insulin at all, leading to a dangerous buildup of sugar in the blood. People with type 2 diabetes and those with early forms of the disease known as pre-diabetes have abnormally high levels of the sugar-boosting hormone glucagon even in the presence of insulin and even when the body doesn't need more sugar. Researchers have long wondered if abnormal glucagon levels somehow affect the insulin-secreting cells of the pancreas. The prevailing wisdom has been that exposure to chronically elevated glucagon and blood sugar levels take a gradual toll on the pancreas, and its overworked beta cells slowly decrease insulin output until they stop making insulin altogether.

The new findings, however, show that the pancreatic cells don't just get tired; their function is directly suppressed by K1. Specifically, the researchers found that the liver, stimulated by high levels of glucagon, releases K1 into the bloodstream. K1 then homes in on pancreatic beta cells, where it suppresses insulin secretion.

"Our findings suggest that glucagon issues the command, but K1 carries out the orders, and in doing, so it appears to be the very cause of the declining seen in type 2 diabetes," says lead investigator Mehboob Hussain, M.D., an endocrinologist and metabolism expert at the Johns Hopkins Children's Center.

"Glucagon and insulin alone never really made complete sense," Hussain adds. "There was always something missing and, we feel, kisspeptin 1 is a very good candidate to be that missing part. All our findings point in this direction."

In one set of experiments, the researchers fattened a group of mice by feeding them calorie-rich food. Predictably, the mice developed diabetes, their declined and K1 levels in their blood shot up, the researchers found. When the investigators chemically altered the livers of the diabetic mice to make them incapable of K1 production, the animals' insulin levels returned to healthy ranges. Next, the researchers engineered mice whose pancreatic cells were lacking receptors for K1. Those mice, even when they feasted on high-fat food, maintained healthy insulin production and blood sugar levels. In other words, the missing K1 receptor rendered these animals' insulin-secreting cells immune to the effects of K1.

Moreover, the researchers found, K1 levels were notably increased in blood and liver samples obtained from people with type 2 diabetes. Additionally, when researchers exposed mouse pancreatic cells to K1-rich blood plasma obtained from people with type 2 diabetes, the insulin production of these cells dropped.

The identification of K1 as a key player in diabetes, the research team says, offers a possible new treatment target that can lead to the development of drugs that restore the function of the insulin-secreting cells. Currently, diabetes therapy is based on injecting synthetic insulin to maintain blood sugar levels. However, restoring natural insulin production could, in theory, cure diabetes, instead of simply mitigating its symptoms.

The Johns Hopkins team says it has already identified a hormone-like substance that blocks the K1 receptor in the pancreatic cells of mice. The investigators will next study whether this receptor-blocker can restore the function of human pancreatic cells.

The identification of K1 also makes evolutionary sense, Hussain adds, and may explain why diabetes is an ancient disease common across species. Hussain and colleagues believe that K1 may have evolved to play an insulin-blunting role and prevent sharp falls in sugar levels during fight-or-flight situations.

"Sugar provides critical fuel when an animal enters combat or is trying to run away from a predator," Hussain says. "The high levels of insulin after a meal can cause dangerously low levels of , which would render the animal weak and vulnerable. So our theory is that K1 is a defense mechanism that halts the sugar-reducing effects of insulin in such life-and-death situations."

Type 2 diabetes, which is closely associated with high-fat and high-sugar diets and sedentary lifestyles, is the predominant form of the disease, accounting for more than 90 percent of all diabetes cases. While previously seen mostly in middle-aged and older adults, type 2 diabetes is now increasingly common in younger people and children, a phenomenon fueled by growing obesity rates, experts say.

FAST FACTS:

  • It is well established that two hormones, glucagon and insulin, must work in perfect unison to maintain healthy in the body.
  • Type 2 diabetes typically develops when glucagon, which stimulates sugar secretion, and insulin, which stimulates sugar absorption, are off balance.
  • Now, scientists at Johns Hopkins have discovered a third critical "player" in the development of type 2 —a hormone called kisspeptitn-1, which apparently carries out commands issued by and directly interferes with insulin production in the pancreas.
  • The discovery may prove to be a long-missing link in the understanding of the origins of the disease.
  • The researchers are currently designing therapies that block kisspeptin-1 from entering the -producing cells of the pancreas.

Explore further: Researchers find new pathway connected to type 2 diabetes

Related Stories

Researchers find new pathway connected to type 2 diabetes

March 19, 2014
Scientists at the Children's Hospital of Eastern Ontario (CHEO) Research Institute have discovered a cellular pathway that is responsible for keeping blood sugar levels low in obese or pre-diabetic people, and may prevent ...

Loss of function of a single gene linked to diabetes in mice

January 4, 2014
Researchers from the University of Illinois at Chicago College of Medicine have found that dysfunction in a single gene in mice causes fasting hyperglycemia, one of the major symptoms of type 2 diabetes. Their findings were ...

Cause for exaggerated insulin response in subset of bariatric surgery patients identified

March 27, 2014
University of Cincinnati (UC) researchers have discovered that altered islet cell function and reduced insulin clearance contribute to excessive post-meal insulin response in patients experiencing low blood sugar symptoms ...

Researchers discover protein that may represent new target for treating type 1 diabetes

January 4, 2012
Researchers at Wake Forest Baptist Medical Center's Institute for Regenerative Medicine and colleagues have discovered a new protein that may play a critical role in how the human body regulates blood sugar levels. Reporting ...

New inflammation hormone link may pave way to study new drugs for Type 2 diabetes

May 15, 2012
A new link between obesity and type 2 diabetes found in mice could open the door to exploring new potential drug treatments for diabetes, University of Michigan Health System research has found.

Unusual suspect: Scientists find 'second fiddle' protein's role in Type 2 diabetes

April 11, 2013
A team of researchers at the Johns Hopkins Children's Center has found that a protein long believed to have a minor role in type 2 diabetes is, in fact, a central player in the development of the condition that affects nearly ...

Recommended for you

Genetic discovery may help better identify children at risk for type 1 diabetes

January 17, 2018
Six novel chromosomal regions identified by scientists leading a large, prospective study of children at risk for type 1 diabetes will enable the discovery of more genes that cause the disease and more targets for treating ...

Thirty-year study shows women who breastfeed for six months or more reduce their diabetes risk

January 16, 2018
In a long-term national study, breastfeeding for six months or longer cuts the risk of developing type 2 diabetes nearly in half for women throughout their childbearing years, according to new Kaiser Permanente research published ...

Women who have gestational diabetes in pregnancy are at higher risk of future health issues

January 16, 2018
Women who have gestational diabetes mellitus (GDM) during pregnancy have a higher than usual risk of developing type 2 diabetes, hypertension, and ischemic heart disease in the future, according to new research led by the ...

Diabetes gene found that causes low and high blood sugar levels in the same family

January 15, 2018
A study of families with rare blood sugar conditions has revealed a new gene thought to be critical in the regulation of insulin, the key hormone in diabetes.

Discovery could lead to new therapies for diabetics

January 12, 2018
New research by MDI Biological Laboratory scientist Sandra Rieger, Ph.D., and her team has demonstrated that an enzyme she had previously identified as playing a role in peripheral neuropathy induced by cancer chemotherapy ...

Enzyme shown to regulate inflammation and metabolism in fat tissue

January 11, 2018
The human body has two primary kinds of fat—white fat, which stores excess calories and is associated with obesity, and brown fat, which burns calories in order to produce heat and has garnered interest as a potential means ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.