Sensitive acid sensor controls insulin production

August 11, 2014
An implant constantly monitors the blood’s acidity and responds to diabetic acidosis by producing insulin. Credit: ETH Zurich

Many human metabolic functions only run smoothly if the acid level in the body remains neutral and stable. For humans, normal blood pH values lie between 7.35 and 7.45. By way of comparison, an empty stomach is extremely acidic, with a pH value of 1.5.

The body constantly monitors this narrow pH band and quickly restores the ideal pH values in the event of any deviations. This is because many proteins cease to function properly if fluids in the body become even slightly more acidic. These proteins become unstable and alter their structure or interactions with other proteins, causing entire metabolic pathways to break down.

People with are particularly at risk of high acid levels. Their bodies produce no insulin, the hormone that regulates , so their cells cannot absorb any glucose from the blood and have to tap into another energy source: fat reserves. In doing so, the liver produces beta-hydroxybutyrate, an acid which supplies the muscles and brain with energy via the bloodstream. If the body continues to use fat reserves for energy, however, this produces so much acid that the blood's pH value plummets while the sugar molecules circulate in the blood unused. If the lack of insulin is not noticed or treated in time, people with type 1 diabetes can die from ketoacidosis – metabolic shock resulting from an excess of beta-hydroxybutyrate.

Sensor measures acidity

A team of bioengineers from ETH Zurich's Department of Biosystems Science and Engineering (D-BSSE) in Basel have now developed a new implantable molecular device composed of two modules: a sensor that constantly measures blood pH and a gene feedback mechanism that produces the necessary amount of insulin. They constructed both modules from biological components, such as various genes and proteins, and incorporated them into cultivated renal cells. The researchers then embedded millions of these customised cells in capsules which can be used as implants in the body.

The heart of the implantable molecular device is the pH sensor, which measures the blood's precise acidity and reacts sensitively to minor deviations from the ideal pH value. If the pH values falls below 7.35, the sensor transmits a signal to trigger the production of insulin. Such a low pH value is specific for type 1 diabetes: although blood pH also drops due to alcohol abuse or exercise on account of the overacidification of the muscles, it does not fall below 7.35. The hormone insulin ensures that the normal cells in the body absorb glucose again and switch from fat to sugar as their energy source for metabolism, and the pH value rises again as a result. Once blood pH returns to the ideal range, the sensor turns itself off and the reprogrammed cells stop producing insulin.

Insulin level back to normal

The researchers have already tested their invention on mice with type 1 diabetes and related acidosis. The results look promising: mice with the capsules implanted produced the amount of insulin appropriate to their individual acid measurements. The hormone level in the blood was comparable to that of healthy mice that regulated their insulin levels naturally. The implant also compensated for larger deviations in blood sugar.

"Applications for humans are conceivable based on this prototype, but they are yet to be developed," says Martin Fussenegger. "We wanted to create a prototype first to see whether molecular prostheses could even be used for such fine adjustments to metabolic processes," he says. Preparing a product like this for the market, however, is beyond the scope of his institute's staff and financial resources, Fussenegger says, and would thus have to be pursued in collaboration with an industrial partner.

Extensive experience in metabolic diseases

Researchers in Fussenegger's group have already made headlines several times with similar synthetic networks. For instance, they developed an implant with genes that could be activated with blue light, thereby producing GLP-1, which regulates . They also put together a network that eliminates metabolic syndrome, a process set in motion by an authorised blood-pressure medicine. All of these networks respond to a signal and produce a hormonally active substance. The special thing about the new feedback mechanism, however, is that the body itself produces the signal, which is then detected by a sensor that triggers a fine-tuned therapeutic reaction.

Three groups from the D-BSSE worked on the present project. Fussenegger's group developed the genetic network; Professor of Biosystems Engineering Andreas Hierlemann and his team tested the acidity sensor with the aid of microfluidic platforms; and Jörg Stelling, a professor of computational systems biology, modelled it in order to estimate the dynamics of the production.

Explore further: Novel drug target linked to insulin secretion and type 2 diabetes treatment

More information: Ausländer D, Ausländer S, Charpin-El Hamri G, Sedlmayer F, Müller M, Frey O, Hierlemann A, Stelling J, Fussenegger M. A synthetic Multifunctional Mammalian pH Sensor and CO2 Transgene-Control Device. Molecular Cell, available online 10 July 2014. DOI: 10.1016/j.molcel.2014.06.007

Related Stories

Novel drug target linked to insulin secretion and type 2 diabetes treatment

May 26, 2014
A signal that promotes insulin secretion and reduces hyperglycemia in a type 2 diabetes animal model is enhanced by the inhibition of a novel enzyme discovered by CHUM Research Centre (CRCHUM) and University of Montreal researchers. ...

A new way to generate insulin-producing cells in Type 1 diabetes (w/ Video)

July 31, 2014
A new study by researchers at Sanford-Burnham Medical Research Institute (Sanford-Burnham) has found that a peptide called caerulein can convert existing cells in the pancreas into those cells destroyed in type 1 diabetes-insulin-producing ...

New culprit identified in metabolic syndrome

August 8, 2014
A new study suggests uric acid may play a role in causing metabolic syndrome, a cluster of risk factors that increases the risk of heart disease and type 2 diabetes.

Researchers discover that brown fat protects against diabetes and obesity in humans

July 23, 2014
Researchers at the University of Texas Medical Branch at Galveston have shown for the first time that people with higher levels of brown fat, or brown adipose tissue, in their bodies have better blood sugar control, higher ...

Researchers discover new link between obesity, inflammation, and insulin resistance

July 17, 2014
A new study by researchers at Sanford-Burnham Medical Research Institute (Sanford-Burnham) has identified a new signal that triggers the events leading to insulin resistance in obesity. The signal causes inflammation in adipose ...

Growth hormone defect may protect against diabetes, cancer in unique ecuador population

June 23, 2014
People who lack growth hormone (GH) receptors also appear to have marked insulin sensitivity that prevents them from developing diabetes and lowers their risk for cancer, despite their increased percentage of body fat, new ...

Recommended for you

Want to win at sports? Take a cue from these mighty mice

July 20, 2017
As student athletes hit training fields this summer to gain the competitive edge, a new study shows how the experiences of a tiny mouse can put them on the path to winning.

'Smart' robot technology could give stroke rehab a boost

July 19, 2017
Scientists say they have developed a "smart" robotic harness that might make it easier for people to learn to walk again after a stroke or spinal cord injury.

Engineered liver tissue expands after transplant

July 19, 2017
Many diseases, including cirrhosis and hepatitis, can lead to liver failure. More than 17,000 Americans suffering from these diseases are now waiting for liver transplants, but significantly fewer livers are available.

Lunatic Fringe gene plays key role in the renewable brain

July 19, 2017
The discovery that the brain can generate new cells - about 700 new neurons each day - has triggered investigations to uncover how this process is regulated. Researchers at Baylor College of Medicine and Jan and Dan Duncan ...

New animal models for hepatitis C could pave the way for a vaccine

July 19, 2017
They say that an ounce of prevention is worth a pound of cure. In the case of hepatitis C—a disease that affects nearly 71 million people worldwide, causing cirrhosis and liver cancer if left untreated—it might be worth ...

Omega-3 fatty acids fight inflammation via cannabinoids

July 18, 2017
Chemical compounds called cannabinoids are found in marijuana and also are produced naturally in the body from omega-3 fatty acids. A well-known cannabinoid in marijuana, tetrahydrocannabinol, is responsible for some of its ...

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.