Tuesday, June 2, 2015

Metformin use linked to risk of low Thyroid Hormone Levels

Metformin is a drug commonly used to treat type 2 diabetes by controlling the amount of sugar in the blood. Now, a new study suggests patients with under-active thyroids who take metformin have an increased risk of low levels of thyroid-stimulating hormone.


Metformin, a commonly used medication for type 2 diabetes, could increase risk of low levels of TSH, researchers say.
Having an under-active thyroid - also known ashypothyroidism - means that the thyroid gland does not make enough thyroid hormone to meet the body's needs. The thyroid hormone regulates the metabolism, affecting almost every organ in the body.
Low levels of thyroid-stimulating hormone (TSH), which is excreted by the pituitary gland, can cause serious damage, including cardiovascular conditions and fractures.
Metformin is used either alone or in combination with other medications, such as insulin, to treat type 2 diabetes by decreasing the amount of sugar absorbed from food and the amount made by the liver.
Long-term diabetes and high blood sugar can develop into serious or life-threatening complications, such as heart disease, stroke, kidney problems, nerve damage and eye problems.
However, previous research has suggested that metformin could lower TSH levels, potentially exposing patients to harmful effects of subclinical hyperthyroidism.
As such, the researchers of this latest study, led by Dr. Laurent Axoulay of McGill University in Montréal, Canada, examined data on 74,300 patients who received metformin and sulfonylurea - another common drug for diabetes - over a 25-year period.
They publish their results in the Canadian Medical Association Journal (CMAJ).

'Metformin linked to 55% increased risk of low TSH levels'

Of the study participants, 5,689 had been treated for hypothyroidism, while nearly 60,000 had normal thyroid function. Among the hypothyroidism group, there were 495 cases of low TSH per year, compared with 322 in the normal group.
The researchers found that in patients with treated hypothyroidism, metformin use was linked with a 55% increased risk of low TSH levels, compared with the use of sulfonylurea.
Fast facts about hypothyroidism
  • Without enough thyroid hormone, the body's functions slow down
  • In the US, around 4.6% of the population over 12 years old have hypothyroidism
  • Symptoms include fatigue, weight gain, cold intolerance,constipation, impaired fertility and depression.
The team adds that use of metformin did not appear to affect those with normal thyroid function.
They conclude that their findings "support the hypothesis that metformin may lead to reductions in TSH levels in patients with treated hypothyroidism."
Dr. Axoulay adds:
"Given the relatively high incidence of low TSH levels in patients taking metformin, it is imperative that future studies assess the clinical consequences of this effect."
Though their study had a large sample size, there were certain limitations. For example, their data showed records of prescriptions written by physicians, but it is unknown whether the patients followed the treatment. However, the researchers say prescription renewals were "likely good indicators of adherence."
They add that given the observational nature of the study, residual confounding needs to be considered, despite the fact that consistent results were observed.
Medical News Today recently reported on a study that suggested metformin could increase the lifespan of non-diabetic individuals.

Thyroid stimulating hormone - video

Written by Marie Ellis
source : http://www.medicalnewstoday.com/articles/282854.php

Study uncovers why statins increase Diabetes Risk and Offers Solution

Statins are drugs that lower cholesterol in the body by interfering with the production of cholesterol in the liver. Though they lower bad cholesterol and raise good cholesterol, one side effect is that they increase risk of diabetes. Now, researchers have discovered why and offer a way to suppress this side effect.
One of the world's most widely used drugs, statins have been hailed by the medical community for their ability to prevent heart disease.
Still, the researchers, who have published their findings in the journal Diabetes, were confused as to why diabetes was linked to statin use.
"Recently, an increased risk of diabetes has been added to the warning label for statin use," says lead author Jonathan Schertzer, assistant professor of Biochemistry and Biomedical Sciences, and Canadian Diabetes Association Scholar.
"This was perplexing to us," he continues, "because if you are improving your metabolic profile with statins you should actually be decreasing the incidence of diabetes with these drugs, yet, the opposite happened."
According to the team, around 13 million people could be prescribed a statin drug at some point in their lives.
In January of this year, the Food and Drug Administration (FDA) released a Consumer Update outlining some of the risks associated with taking statins, which included an increased risk of raised blood sugar levels and the development of type 2 diabetes.
At that time, Dr. Amy G. Egan, deputy director for safety in the FDA's Division of Metabolism and Endocrinology Products, said:
"Clearly we think that the heart benefits of statins outweighs this small increased risk. But what this means for patients taking statins and the health care professionals prescribing them is that blood-sugar levels may need to be assessed after instituting statin therapy."
But until Prof. Schertzer and his team conducted their latest research, the pathway linking statins to diabetes was unknown.

Glyburide taken with statins suppressed immune response

After investigating further, the research team found that statins "activated a very specific immune response, which stopped insulin from doing its job properly," says Prof. Schertzer.
After "connecting the dots," he and his team discovered that taking another drug - called glyburide - alongside statins suppressed this immune response.

Though statins can prevent heart disease by lowering cholesterol, they also increase risks for developing type 2 diabetes.
This finding could yield the development of new targets for this immune pathway that do not interfere with the positive effects of statins, they say.
For future research, Prof. Schertzer and colleagues want to understand how statins advance diabetes by understanding how the drugs work in the pancreas, an organ that secretes insulin. Other side effects include muscle pain and muscle breakdown, and the team hopes to understand whether the immune pathway is involved in such side effects.
"It's premature to say we are going to change this drug," says Prof. Schertzer, "but now that we understand one way it can cause this side effect, we can develop new strategies to minimize side effects."
He adds that they could even possibly use natural products or strategies involving nutrition to counter these side effects.
Because statins are so widely prescribed, the researchers say understanding how they prompt adverse effects could lead to vital improvements in the drug, which could ultimately affect a large portion of the population.
Prof. Schertzer concludes by noting:
"With the new federal warning label on the risk of diabetes with statin usage, people are heavily debating its pros and cons. We think this is the wrong conversation to have. Statins are a great drug for many people. What we really should be talking about is how to make them better, and we are beginning to understand the basic biology of statins so we can do just that."
Medical News Today recently reported on a study that suggested patients with terminal illnesses benefit from stopping statins. Researchers from that study said patients in late stages of cancer or other terminal illnesses may extend their lives by discontinuing use of the drug.
Written by Marie Ellis
source : http://www.medicalnewstoday.com/articles/278164.php

Type 1 Diabetes Reversed in Mice

Type 1 diabetes accounts for about 5% of all diabetes and is usually diagnosed in young people. There is no cure for the disease - which happens when the immune system destroys pancreatic beta cells and the body's only source of insulin, a hormone that controls blood sugar. Now researchers report they have successfully tested a new therapy that appears to reverse new onset type 1 diabetes in mice.
Investigators from the University of Cincinnati (UC) presented their findings at the 74th Scientific Sessions of the American Diabetes Association in San Francisco on 14 June 2014.
There are two parts to the immune system: the innate immune system, which we are born with and attempts to fight infection straight away; and the adaptive immune system, which takes time to mount a response that is more specific to the particular pathogen.
The innate immune system includes a group of cells known as dendritic cells that send messages to the adaptive immune system. Dendritic cells are important antigen processors - they have receptors on their cell surface that react to pathogens and present their antigens to the adaptive immune cells such as immature T cells to develop a more precise response.
Most previous attempts to combat type 1 diabetes have aimed at reducing an overzealous adaptive immune response by eliminating the auto-reactive T cells directly. But in this new study, the researchers used an approach that tackles T cells indirectly, as study leader William Ridgway, a professor in medicine at UC, explains:
"We are targeting a receptor that is found mostly on the innate immune cells, such as dendritic cells."
He and his team decided to tackle a receptor on dendritic cells called TLR4. Previous studies have already established that non-obese diabetic mice have faulty innate immune cells, and that this could be partly due to a defect in TLR4, which many suspect helps to prevent type 1 diabetes when it functions normally.

Antibody that boosts TLR4 reversed new onset type 1 diabetes in mice

The researchers found when they used an agonistic monoclonal antibody, UT18, to boost the activity of TLR4 in mice with new onset type 1 diabetes, it reversed the disease in a high percentage of them.

While the TLR4 pathway in humans is similar to that of mice, there are some differences, so further study is required to see if the treatment will work in humans.
Prof. Ridgway says the cause of the reversal was the "preservation of the endocrine pancreatic beta cells that produce insulin. These cells are preserved from the autoimmune attack which is the hallmark of Type 1 diabetes."
He points out that the key to reversing type 1 diabetes in the mice was catching the disease right at the onset, which has only a very short time window. The window is likely to be longer in humans, he says, but it is still relatively short before end-stage type 1 diabetes sets in.
While the TLR4 pathway in humans is similar to that of mice, there are some differences, so further study is required to see if the treatment will work in humans.
Prof. Ridgway says there is also a chance, if the therapy works in humans, that it will do so with an agonistic anti-TLR4 agent that is already approved, or under development.
Meanwhile, Medical News Today reported on another study presented at the same conference by researchers from the Intermountain Heart Institute at Intermountain Medical Center in Murray, UT. The Intermountain study explains how type 2 diabetes risk in prediabetics may be combated by periodic fasting to work against the effects of insulin resistance.
Written by Catharine Paddock PhD
source : http://www.medicalnewstoday.com/articles/278289.php

Periodic Fasting may protect against Diabetes in At-Risk Groups

At the 2014 American Diabetes Association Scientific Sessions in San Francisco, CA, researchers present new findings on how diabetes risk in prediabetics may be combated by periodic fasting.
In people who have prediabetes, the amount of glucose in the blood is higher than normal but is not high enough to be classed as diabetes.
In 2011, researchers at the Intermountain Heart Institute at Intermountain Medical Center in Murray, UT, investigated how glucose levels and weight were effected by 1 day of water-only fasting in healthy people.
"When we studied the effects of fasting in apparently healthy people, cholesterol levels increased during the one-time 24-hour fast," says Benjamin Horne, PhD, director of cardiovascular and genetic epidemiology at the Intermountain Medical Center Heart Institute and lead researcher on the new study.
"The changes that were most interesting or unexpected were all related to metabolic health and diabetes risk," he adds.
"Together with our prior studies that showed decades of routine fasting was associated with a lower risk of diabetes and coronary artery disease, this led us to think that fasting is most impactful for reducing the risk of diabetes and related metabolic problems."
Consequently, Dr. Horne and team began investigating the effects of fasting in prediabetics. Although Medical News Today does not have details on the number of participants included in the new study, the team has revealed that participants were between the ages of 30 and 69, and each subject also had at least three metabolic risk factors, such as:
  • A large waistline
  • A high triglyceride level
  • A low HDL cholesterol level
  • High blood pressure
  • High fasting blood sugar.

Body 'feasts' on bad cholesterol in fat cells, negating insulin resistance effects

The researchers found that during fasting days, the participants' cholesterol went up slightly, as it had done in the previous study of healthy people. However, over a 6-week period, the cholesterol levels of the prediabetic participants actually decreased by about 12%.
"Because we expect that the cholesterol was used for energy during the fasting episodes and likely came from fat cells," says Dr. Horne, "this leads us to believe fasting may be an effective diabetes intervention."
After 10-12 hours of fasting, the body begins to scavenge other sources of energy throughout the body in order to sustain itself. The benefit to prediabetics, Dr. Horne's team believes, is that because the body feasts on the LDL (or "bad") cholesterol in fat cells it negates the effect of insulin resistance.
diagram depicting diabetes mechanisms

Insulin resistance is when insulin production becomes so high that the pancreas can no longer produce the body's required levels of insulin, which causes blood sugar to rise. The researchers believe fasting may prevent this.
Insulin resistance is when insulin production becomes so high that the pancreas can no longer produce the body's required levels of insulin, which causes blood sugar to rise.
"The fat cells themselves are a major contributor to insulin resistance, which can lead to diabetes," Dr. Horne explains. "Because fasting may help to eliminate and break down fat cells, insulin resistance may be frustrated by fasting."
Although fasting may protect against diabetes, Dr. Horne reminds that it is important to keep in mind that fasting did not achieve overnight results. He adds that more in-depth study is needed to define what the optimum length and frequency of fasting should be in prediabetics.
"Fasting has the potential to become an important diabetes intervention," he says. "Though we've studied fasting and its health benefits for years, we didn't know why fasting could provide the health benefits we observed related to the risk of diabetes."
Recently, Medical News Today reported on a study conducted by the University of Southern California in Los Angeles that suggested prolonged fasting may "reboot" the immune system - protecting against the toxic effects of chemotherapy and triggering stem cell regeneration of new immune cells, as well as clearing out old and damaged cells.
Written by David McNamee
source : http://www.medicalnewstoday.com/articles/278264.php

Discovery of Glucose sensor in brain may lead to New Diabetes Treatments

There is an enzyme in the brain that plays a key role in sensing and controlling levels of glucose in the blood. The underlying mechanism that it triggers appears to link to both type 1 and type 2 diabetes, according to US researchers, who suggest the discovery could lead to new treatments for diabetes.

They report how they discovered the part played by the enzyme - known as prolyl endopeptidase (PREP) - in the Proceedings of the National Academies of Sciences (PNAS).
There are two types of diabetes. Type 1 is where the body's ability to make insulin - an enzyme that helps cells convert glucose into energy - is impaired due to loss of insulin-producing cells in the pancreas. Type 2 arises not through lack of insulin, but because cells lose their ability to use it properly and become insulin-resistant.
The study found PREP links to both types of diabetes - one way involves communication with the pancreas, and the other way involves sensing levels of glucose in the blood.

Enzyme triggers series of steps that control glucose levels

Lead author Sabrina Diano, a professor in the Departments of Obstetrics, Gynecology & Reproductive Sciences, Comparative Medicine, and Neurobiology at Yale University School of Medicine, New Haven, CT, says they discovered that PREP - found in a part of the hypothalamus known as the ventromedial nucleus - triggers a series of steps that control glucose in the blood.

brain illustration
Researchers say they have discovered an enzyme in the brain that plays a key role in sensing and controlling levels of glucose in the blood.
The team already knew that the ventromedial nucleus has brain cells that are capable of sensing glucose, and wanted to find out more about the link to PREP.
They discovered that PREP gives brain cells in this part of the brain the ability to sense glucose. When the cells detect rising glucose levels, they instruct the pancreas to secrete more insulin, which keeps glucose in check and prevents diabetes.
When they genetically engineered mice with low levels of the enzyme, they found the mice had high levels of blood glucose and developed diabetes.
They confirmed the effect of reduced PREP by treating normal mice with a PREP inhibitor. The mice showed decreased insulin levels and impaired glucose tolerance.
And when they restored PREP function in the mice bred to have low PREP - by injecting them with a virus that causes the relevant gene to be switched on again - they found it reversed the glucose intolerance the mice had shown before.

Low levels of PREP prevent neurons sensing increases in glucose

Prof. Diano says the low levels of enzyme prevented the neurons from sensing increased levels of blood glucose, which in turn meant they could not control release of insulin from the pancreas, which led the mice to become glucose intolerant and diabetic.
She and her colleagues conclude that:
"Taken together, our results unmask a previously unknown player in central regulation of glucose metabolism and pancreatic function."
If they find the targets in the enzyme that make the neurons sense changes in glucose levels, then the researchers believe it could lead to a new type of drug to regulate insulin secretion. Such a drug could not only treat type 2 diabetes, but perhaps even prevent it, says Prof. Diano.
Funds from the National Institutes of Health and the American Diabetes Association helped to finance the study.
Meanwhile, another recently published study from China found that shift work may increase risk for type 2 diabetes, particularly in men. While the researchers who carried out the meta-analysis did not examine why the risk is higher in men, they suggest it could be that repeated disruption of the body's internal clock affects levels of testosterone in men. Other studies have shown low levels of the male hormone are linked to insulin resistance and diabetes.

How sugar affect the brain? - video

Written by Catharine Paddock PhD
source : http://www.medicalnewstoday.com/articles/280465.php

Could artificial sweeteners promote Diabetes and Obesity?

For those who are diabetic or dieting, you may think artificial sweeteners are your best friend. They allow you to get the taste of sugar from foods and beverages without the elevated blood sugar levels or calories. But a new study suggests this may not be the case; artificial sweeteners could actually promote obesity and diabetes.

Rather than aiding weight loss and treatment of type 2 diabetes, researchers say consumption of artificial sweeteners may have the opposite effect.
The research team, including Eran Elinav of the Department of Immunology at the Weizmann Institute of Science in Israel, recently published their findings in the journal Nature.
Discovered more than a century ago, artificial sweeteners are now found in an abundance of foods and drinks labeled "diet" or "sugar-free," including chewing gum, soft drinks, ice cream and yoghurt.
Because artificial sweeteners are low calorie and do not contain carbohydrates like sugar (meaning they are less likely to increase blood sugar levels), they are often recommended to help with weight loss or to treat or prevent metabolic disorders, such as type 2 diabetes.
However, Elinav and colleagues note that, although some studies support such recommendations, others have indicated that artificial sweeteners actually increase weight gain and raise the risk of metabolic disorders. For example, a study from Washington University School of Medicine reported by Medical News Today last year claimed the artificial sweetener sucralose is linked to increased glucose and insulin levels.
"Despite these controversial data, the Food and Drug Administration (FDA) approved six NAS (non-caloric artificial sweetener) products for use in the US," the researchers note. These are saccharin, sucralose, aspartame, advantame, neotame and acesulfame potassium.

Consumption of artificial sweeteners 'interferes with gut bacteria'

In this latest study, the team investigated how artificial sweeteners affected the metabolism of mice.
For 11 weeks, some mice were supplied with drinking water supplemented with an artificial sweetener - either saccharin, sucralose or aspartame - and glucose, while others drank just water alone or water containing only sugar.
The team found that the mice that drank the water containing glucose and an artificial sweetener developed glucose intolerance - elevated blood sugar levels - whereas the mice that drank water alone or water containing only sugar did not.
They found that this effect was brought on by interferences in gut bacteria. "Notably," the researchers say, "several of the bacterial taxa that changed following NAS consumption were previously associated with type 2 diabetes in humans."
Furthermore, on studying the fecal samples of mice that consumed saccharin, the team found that these mice demonstrated an increase in specific pathways, including the glycan gradation pathway. This is where glycans (polysaccharides) are fermented to produce certain compounds, including short-chain fatty acids. Such pathways, the researchers say, have been previously linked to obesity and diabetes in both mice and humans.

Artificial sweeteners 'may have enhanced the epidemics they were intended to fight'

Elinav and colleagues then assessed the effect of long-term consumption of artificial sweeteners on humans by analyzing the data of an ongoing clinical trial involving 381 non-diabetic participants.
From this, they found several associations between long-term consumption of artificial sweeteners and increased weight, increased waist-to-hip ratio (an indicator of abdominal obesity), higher fasting blood glucose levels and increased glycosylated hemoglobin levels.
The researchers note that artificial sweeteners were widely introduced into our diets to help reduce caloric intake and normalize blood glucose levels. But they say these findings indicate that they may be having the opposite effect:
"Together with other major shifts that occurred in human nutrition, this increase in NAS consumption coincides with the dramatic increase in the obesity and diabetes epidemics. Our findings suggest that NAS may have directly contributed to enhancing the exact epidemic that they themselves were intended to fight.
Moreover, our results point towards the need to develop new nutritional strategies tailored to the individual while integrating personalized differences in the composition and function of the gut microbiota."

Are Artificial Sweeteners Really Safe? - video

Written by Honor Whiteman
source : http://www.medicalnewstoday.com/articles/282604.php

Blood sugar measured by laser may do away with Pin Pricks

Researchers are working on a way to use laser technology to measure blood glucose non-invasively. While there is still a way to go before they have a laser device that is portable and suitable for home use, they believe one day it will replace the need for diabetics to draw blood to test their glucose levels.

In the journal Biomedical Optics Express, the team of electrical engineers, from Princeton University, NJ, describes how they used their prototype device to measure blood sugar by directing the laser at a person's palm.
Senior author Claire Gmachl, the Eugene Higgins Professor of Electrical Engineering at Princeton, says:
"With this work we hope to improve the lives of many diabetes sufferers who depend on frequent blood glucose monitoring."

Laser beam penetrates skin and is absorbed by glucose

The device works by sending a laser beam through skin cells - without causing damage - to be absorbed by sugar molecules. The target is not blood sugar as such, but the sugar content of dermal interstitial fluid, which has a strong correlation with blood sugar.

The new monitor uses a laser, instead of blood sample, to read blood sugar levels. The laser is directed at the person's palm, passes through skin cells and is partially absorbed by sugar molecules, allowing researchers to calculate blood sugar levels.
Image credit: Princeton
The amount of absorption of the laser beam is thus an indicator of the amount of glucose in the blood.
The team was surprised at how accurate the readings turned out to be. Current glucose monitors that patients use at home are required to show readings within 20% of the patient's actual blood level.
Lead author Sabbir Liakat, a graduate student in electrical engineering, says even their early version of the laser system met this requirement, and the latest version is 84% accurate.
The challenge now is to improve the technology - and not least to bring down the scale.
When they started working on the idea, the device covered an average lab bench and needed an elaborate system to keep it cool.
Prof. Gmachl says they have solved the cooling problem - the system now works at room temperature - but they still have to work out how to make the technology smaller.
They aim to develop a mobile device they can take to clinics and put through more tests and collect a larger set of data to work with.

The device uses a 'quantum cascade laser' to produce mid-infrared light

The system uses infrared laser light, which is just beyond the spectrum light visible to the human eye. Medical devices currently use near-infrared, a band that has slightly longer wavelengths than the red that the human eye can see. Near-infrared is not blocked by water and can thus be used in the body.
close up of Princeton laser device
The quantum cascade laser allows the team to select the frequency they need in the mid-infrared region, and also because of recent improvements in the technology, it provides the increased power and stability needed to penetrate the skin.
Image credit: Princeton
But near infrared does not interact with chemicals in the skin - for that you have to move to slightly longer wavelengths in the mid-infrared region. At this wavelength, the laser light is absorbed by blood sugar and is not much affected by other chemicals in the skin.
However, mid-infrared laser light is more difficult to harness with standard lasers, and it also requires higher power and stability in order for the beam to penetrate the skin and scatter off bodily fluid.
But as sometimes happens in projects where people work tirelessly to achieve their goals - there was a breakthrough. This came when they tried a new type of device called a 'quantum cascade laser.'
The quantum cascade laser allows the team to select the frequency they need in the mid-infrared region, and also because of recent improvements in the technology, it provides the increased power and stability needed to penetrate the skin.

Small study shows average readings meet required clinical accuracy

In their study paper they describe how they measured the blood sugar of three healthy volunteers before and after they each ate 20 jellybeans. The researchers also measured the resulting rise in blood sugar with the conventional finger-prick test.
The team repeated the experiment and took measurements several times over several weeks. The results showed that while the laser device's average readings had errors larger than standard blood sugar monitors, they were within the range required for clinical accuracy.
The team is excited by the potential their discovery offers because, as Prof. Gmachl explains, "the quantum cascade laser can be designed to emit light across a very wide wavelength range, its usability is not just for glucose detection, but could conceivably be used for other medical sensing and monitoring applications."
The National Science Foundation, the Wendy and Eric Schmidt Foundation, Daylight Solutions Inc., and Opto-Knowledge Systems helped to fund the study.
Recently, Medical News Today also learned how the discovery of a glucose sensor in the brain may lead to new diabetes treatments.

Non-Invasive Optical Blood Glucose Monitoring System - video

Written by Catharine Paddock PhD
source : http://www.medicalnewstoday.com/articles/281407.php

Fruit flies help researchers unlock mysteries of Human Diabetes

For the first time, the tiny fruit fly can be used to study how mutations associated with the development of diabetes affect the production and secretion of the vital hormone insulin.
The advance is due to a new technique devised by researchers at the Stanford University School of Medicine that allows scientists to measure insulin levels in the insects with extremely high sensitivity and reproducibility.
The experimental model is likely to transform the field of diabetes research by bringing the staggering power of fruit fly genetics, honed over 100 years of research, to bear on the devastating condition that affects millions of Americans. Until now, scientists wishing to study the effect of specific mutations on insulin had to rely on the laborious, lengthy and expensive genetic engineering of laboratory mice or other mammals.
Fruit flies

In contrast, tiny, short-lived fruit flies can be bred in dizzying combinations by the tens of thousands in just days or weeks in small flasks on a laboratory bench.
"I normally avoid the term, but I think Dr. Park's new technique is a true breakthrough," said Seung Kim, MD, PhD, professor of developmental biology. "Only in selected mammals can researchers measure insulin with this degree of sensitivity."
Kim, who is also a Howard Hughes Medical Institute investigator, is the senior author of the paper describing the research. Research associate Sangbin Park, PhD, is the lead author of the paper, which was published inPLOS Genetics.
The power of a tiny model system
Insulin is an ancient molecule used by nearly all animals to regulate metabolism, growth and development. Diabetes in humans occurs when insulin-making cells in the pancreas fail to produce the hormone or when other cells in the body grow resistant to its effects. In 2002, Kim, his lab team and fellow Stanford researchers discovered that fruit flies develop a diabetes-like condition when their insulin-producing cells are destroyed.
"Studies of diabetes in fruit flies represent a relatively new area of investigation," said Carl Thummel, PhD, professor of human genetics at the University of Utah School of Medicine. Thummel uses the insect to study energy metabolism and metabolic disorders.
"Needless to say, fruit flies are very small, and only tiny amounts of blood can be extracted from their bodies," he said. "Our inability to measure the amounts of circulating insulin has been a major drawback in the field. The technique developed by Dr. Kim's group will allow researchers to rapidly test the effect of diabetes risk factors, and establishes fruit flies as an effective tool for studies of diabetes."
Developed by Park, the new technique uses a chemical tag to label an insulin-like peptide called Ilp2 in fruit flies. The tag allows researchers to use an antibody-based assay to measure insulin concentrations in the insect's blood and cells at the picomolar level - the level at which insulin concentrations are measured in humans.
Using the technique, the researchers were able to quickly identify what a mutation associated with type-2 diabetes in humans actually does: It regulates insulin secretion, but not production.
Understanding the effect of each mutation
Parsing the effect of each mutation on the way the body produces, secretes and responds (or not) to insulin is critical to further understand the disease and to devise new therapeutic approaches. "I was stunned that this technique worked so well to identify the effect of specific mutations," said Park. "Many of the genes we studied seem to have similar functions in governing insulin production or secretion in flies and in humans."
Previous efforts to tag Ilp2 have been hampered by the fact that the protein undergoes a complex series of modifications and folding events on its way to becoming the active form of the molecule. Tags that disrupt this process can cause inappropriate expression of the molecule or render it inactive, interfering with the very metabolic pathway researchers want to study.
Park capitalized on the knowledge that overexpression of the active form of the Ilp2 protein is lethal. He then randomly inserted chemical tags along the length of the molecule to create a panel of molecules tagged in many different places. Testing them individually, he looked for those that were still able to kill the flies - indicating that the molecule's activity had not been compromised. Eventually he found two locations on Ilp2 that were ideal. He could then use antibodies that recognized the tags to quantify levels of Ilp2 with the antibody-based assay.
"Once you know that the modifications, or tags, don't affect the expression or activity of the molecule, you have a lot more power to interpret your experiments," said Kim. "You can begin to track the insulin assembly line, from the transcription of RNA from the gene, to the production of the protein, to the storing and eventual secretion of the protein in response to metabolic signals. You have the opportunity to figure out the mechanisms controlling each of those steps in detail."
In flies, Ilp2 is produced and secreted by specialized neurons in the brain. This makes it relatively easy to compare levels of circulating Ilp2 with the amount of mature but unsecreted Ilp2: simply compare the amount of Ilp2 in the insects' bodies to the amount in their brains.
Park found that the amount of secreted Ilp2 increased from about 0.1 percent to about 0.35 percent of the total available during the first three days of a fruit fly's life. Furthermore, like in humans, circulating Ilp2 concentrations were relatively low in fasting flies, but peaked and then declined after a subsequent meal. Finally he showed that, in flies with only one working copy of the insulin receptor gene (they normally have two, as do humans), insulin secretion was increased in an apparent attempt to compensate for the deficiency - mirroring the development of insulin resistance in humans and mice.
Park and his colleagues then turned their attention to mutations associated with type-2 diabetes in genome-wide studies in humans. These studies don't reveal how a specific mutation might work to affect development of a disease; they show only that people with the condition are more likely than those without it to have certain mutations in their genome. Hundreds of candidate-susceptibility genes have been identified in this way.
Tip of the iceberg
The researchers found that blocking the expression of a fly version of a human protein called GLIS3, known to affect insulin production in mammals, and linked both to type-2 and type-1 diabetes in humans, also affected the production of Ilp2 in flies. A mutation in another protein, BCL11A, was known to be associated with the development of the disease in humans, but its mechanism of action was unclear. Park and his colleagues found that blocking the expression of the fly version of BCL11A did not affect the flies' ability to make Ilp2, but caused it to secrete abnormally high levels of Ilp2 into the bloodstream.
The researchers emphasize that these findings are just the tip of the iceberg. Many more mutations can be studied alone and in combination under a myriad of experimental conditions. A single fruit fly can lay several hundred eggs during its approximately 40-day life span; eggs develop into adults in only 10 days. They plan to continue to use the fruit fly system to complement and inform their ongoing studies in mammals and humans.
"We're really taking advantage of a century of work done by generations of other researchers," said Kim. "Historically the fly has been used to understand developmental biology by looking at its genes and its cells and observing how they change over time. Now we've shown we can accurately and precisely measure levels of a crucial hormone in these insects, and use that to identify new targets for diabetes investigation in mice and humans."

source : http://www.medicalnewstoday.com/releases/280778.php