Diabetes is not so much being cured as it is being surrounded. Researchers are coming at this common disorder from a number of different perspectives, and some of their discoveries are finding their way, or soon might find their way, into clinical practice. Here’s a roundup of some recent scientific approaches regarding type 1, type 2, and gestational diabetes mellitus (GDM), as well as an exciting recent FDA approval of a needle-free glucose testing device that may make life easier for people with diabetes.
Biosensor to monitor glucose in tears/sweat
We may be one step closer to providing people with diabetes with an improved monitoring tool that continuously tracks their glucose levels through their tears or sweat. Researchers report in the journal ACS Nano the development of an ultra-thin, flexible sensor that could be incorporated into contact lenses or on the backs of watches for real-time glucose tracking.
Wearable sensors are part of an increasingly digitized world. But those that are commercially available typically monitor physical activities by measuring steps taken, for example, or heart rate. Creating ways to measure health markers on a molecular level has been far more challenging, but the benefits could be life-changing for some patients. Diagnosing and tracking conditions are often done by analyzing a sample of someone’s blood. The pain of pricking fingers or drawing blood, however, can deter people from vigilantly monitoring conditions such as diabetes that require regular checks. To take the sting out of the process, wearable glucose sensors are in development but have been hampered by several factors. Some devices can’t detect the low levels of glucose that are in sweat and tears, or they stop working when they are bent.
The researchers created a biosensor using nanoribbons of indium oxide, an enzyme glucose oxidase, a natural chitosan film, and single-walled carbon nanotubes. When glucose is present in a test sample, it interacts with the enzyme, setting off a short chain of reactions and ultimately creating an electrical signal. Testing showed that the device could detect a range of glucose concentrations from 10 nanomolar to one millimolar, which is sensitive enough to cover typical glucose levels in sweat, saliva, and tears in people with and without diabetes. Bending the film 100 times didn’t noticeably affect its performance.
Women who have GDM risk future health issues
Women who have gestational diabetes mellitus during pregnancy have a higher risk than other women of developing type 2 diabetes, hypertension, and ischemic heart disease in the future, according to new research led by the University of Birmingham (UK). The retrospective cohort study was published in PLOS Medicine.
The researchers studied the incidence of type 2 diabetes, hypertension, and ischemic heart and cerebrovascular diseases in a UK primary care database that included more than 9,000 women diagnosed with GDM between 1990 and 2016.
The study found that women diagnosed with GDM were more than 20 times more likely to be diagnosed with type 2 diabetes later in life, more than two-and-a-half times more likely to develop ischemic heart disease, and almost twice as likely to develop hypertension.
Dr. Krish Nirantharakumar, of the University of Birmingham’s Institute of Applied Health Research, says: “Results showed women diagnosed with GDM were significantly more likely to develop hypertension and ischemic heart disease at a relatively young age compared with women without a previous diagnosis of GDM in addition to the established risk of developing diabetes. The risk was greatest for type 2 diabetes in the first year following diagnosis of GDM and persisted throughout the follow-up period.”
The findings add an important insight into the trajectory of the development of type 2 diabetes, hypertension, and cardiovascular disease in the early and latter post-partum periods.
“Furthermore, the findings are the first to report on a large UK population and identify an at-risk group of relatively young women ideally suited for targeting risk factor management to improve long-term metabolic and cardiovascular outcomes,” says Nirantharakumar.
The study also found that follow-up screening in women diagnosed with GDM for diabetes as well as cardiovascular risk factors was low. With the exception of blood pressure, less than 60 percent of women were screened in the first year after giving birth, and that decreased to less than 40 percent by the second year after having their baby.
Barbara Daly, of the Faculty of Medical and Health Sciences at the University of Auckland (New Zealand), says the research was especially important given that the prevalence of GDM is increasing rapidly in most developed countries.
New findings in early-stage islet autoimmunity
Type 1 diabetes is the most common metabolic disease in childhood and adolescence. In this disease, the body’s immune system attacks and destroys the insulin-producing cells of the pancreas. Regulatory T cells (Tregs) play an important role in this process: in healthy people, they suppress excessive immune reactions and thus prevent autoimmune diseases.
Dr. Carolin Daniel’s team is investigating why Tregs fail to protect the islet cells in type 1 diabetes. She is a group leader at the Institute for Diabetes Research (IDF) of Helmholtz Zentrum München (Germany). In the current study, her team elucidated a mechanism that causes fewer Tregs to be produced during islet autoimmunity onset and therefore allows the immune system to get out of control and attack.
According to study findings miRNA181a and NFAT5 molecules play a key role. Says Daniel: “We showed that miRNA181a leads to the activation of the transcription factor NFAT5 during islet autoimmunity onset. The consequence is an inhibition of Treg induction and thus increased immune activation.”
To test the suitability of this new finding for possible therapeutic approaches, the scientists investigated a preclinical model with early-stage islet autoimmunity. When they interrupted the miRNA181a/NFAT5-axis, they observed a significantly lower activation of the immune system and an increased formation of Tregs. This was achieved by the pharmacological inhibition of both miRNA181a and NFAT5.
“The targeted inhibition of miRNA181a or NFAT5 could open up new approaches to reduce the activity of the immune system against its own islet cells,” says Professor Anette-Gabriele Ziegler, director of the IDF. “The combination with other immune-modulating therapeutic approaches would also be conceivable as an intervention.”
In the future, the researchers want to further investigate these findings in preclinical tests. To this end, humanized models will be used to test whether the combination of insulin vaccination and inhibition of the miRNA181a/NFAT5 axis leads to an immune system that is more tolerant toward insulin-producing cells.
Immune system could regulate insulin
Inflammation processes are responsible for the failure of insulin production in diabetes patients, but patients’ own immune systems could contribute to treatment of this disease. Researchers at the University of Basel and University Hospital Basel (Switzerland) have found a feedback mechanism that could help maintain insulin production in overweight sufferers, they report in the journal Immunity.
In their study, the researchers focused specifically on recently discovered ILC2 immune cells in the pancreas, where, under diabetic conditions, the protein IL33 is activated, among others. This protein stimulates the ILC2 cells, which trigger the release of insulin in overweight individuals using retinoic acid and could therefore be used to inhibit the failure of insulin production.
The research gives an insight into an inflammatory network that could contribute to the maintenance of insulin production in diabetics. The complex interactions between endocrine cells and immune cells are clearly significant for the maintenance of insulin release.
It is already known that obesity and diabetes lead to an excessive, pathological activation of the immune system in which the messenger substance IL1-beta plays a central role. This results in the death of insulin-producing cells. However, if IL1-beta is blocked, diabetes and its complications—in particular cardiovascular diseases—can be inhibited. Diabetic inflammatory reactions are already finding use in clinical applications.
Gene causes low and high blood sugar in family
A study of families with rare blood sugar conditions has revealed a new gene thought to be critical in the regulation of insulin. The research, carried out at Queen Mary University of London, University of Exeter, and Vanderbilt University and published in the journal PNAS, could lead to the development of novel treatments for both rare and common forms of diabetes.
In addition to the more common forms of diabetes (type 1 or type 2), in about one to two percent of cases diabetes is due to a genetic disorder. A defective gene typically affects the function of insulin-producing cells in the pancreas, known as beta cells.
The research team studied the unique case of a family in which several individuals suffer from diabetes, while other family members have developed insulin-producing tumors in their pancreas. These tumors, which are known as insulinomas, typically cause low blood sugar levels, in contrast to diabetes, which leads to high blood sugar levels.
Lead author Professor Márta Korbonits says: “We were initially surprised about the association of two apparently contrasting conditions within the same families—diabetes, which is associated with high blood sugar, and insulinomas, associated with low blood sugar. Our research shows that, surprisingly, the same gene defect can impact the insulin-producing beta cells of the pancreas to lead to these two opposing medical conditions.” The team also observed that males were more prone to developing diabetes, while insulinomas were more commonly found in females.
“One exciting avenue to explore will be seeing if we can use this finding to uncover new ways to help regenerate beta cells and treat the more common forms of diabetes,” Professor Korbonits adds.
The researchers identified a genetic disorder in a gene called MAFA, which controls the production of insulin in beta cells. Unexpectedly, this gene defect was present in both the family members with diabetes and those with insulinomas, and was also identified in a second, unrelated family with the same unusual dual picture.
Potential enzyme as therapeutic target
Abnormalities in glucose uptake by the liver (or hepatic glucose uptake, HGU) cause elevations in blood glucose levels following meals, a state that is known as postprandial hyperglycemia. Such abnormalities are observed in obesity and type 2 diabetes and result in an increased risk of cardiovascular complications. Although the exact mechanism of HGU impairment is unknown, there is evidence that it is mediated by abnormal regulation of the enzyme hepatic glucokinase and the glucokinase regulatory protein (GKRP).
Now, a team of Japanese researchers has identified a sirtuin enzyme (Sirt2) as a key player in regulating hepatic glucokinase through modifying GKRP, suggesting that this mechanism offers a potential therapeutic target for type 2 diabetes.
Previous reports show that the signaling molecule nicotinamide adenine dinucleotide (NAD+) governs glucose metabolism. In this paper, the researchers used in vitro experiments to identify Sirt2 as a mediator of NAD+-dependent HGU. However, Sirt2 did not influence the gene expression levels of glucokinase and glucose-6-phosphatase. This implies that Sirt2 affected HGU through post-translational modifications.
In normal cells, glucokinase binds to GKRP in low glucose conditions, while the two proteins dissociate in response to elevation of glucose levels. In cells derived from diabetic mice, however, this does not take place even under high glucose concentrations. In the current study, researchers were able to reverse this perturbation by overexpressing Sirt2 and showed that Sirt2 can regulate the dissociation by directly binding to GKRP and deacetylating it (at residue K126) in a NAD+-dependent manner.
The researchers also performed experiments in mice and found that expressing a form of GKRP that could not be acetylated perturbs HGU, suggesting that acetylation of GKRP is involved in HGU and the maintenance of normal glucose levels. They also found that a decrease in NAD+-dependent Sirt2 activity and defective Sirt2-dependent deacetylation of GKRP were responsible, at least in part, for the HGU abnormality observed in obese diabetic mice.
Overall, the results indicate that NAD+ and Sirt2 regulate HGU and that Sirt2 acts through deacetylating GKRP. The authors conclude that “these findings suggest that NAD +/Sirt2-dependent GKRP deacetylation regulation plays an important role in HGU control and that this regulation is a novel therapeutic target in type 2 diabetes and obesity and is responsible for HGU impairment.”
FDA clears first continuous glucose monitoring system
The U.S. Food and Drug Administration has approved the FreeStyle Libre Flash Glucose Monitoring System, the first continuous glucose monitoring system that can be used by adult patients to make diabetes treatment decisions without calibration using a blood sample from the fingertip.
The system reduces the need for fingerstick testing by using a small sensor wire inserted below the skin’s surface that continuously measures and monitors glucose levels. Users can determine glucose levels by waving a dedicated, mobile reader above the sensor wire to determine if glucose levels are too high (hyperglycemia) or too low (hypoglycemia), and how glucose levels are changing. It is intended for use in people 18 years of age and older with diabetes; after a 12-hour start-up period, it can be worn for up to 10 days.
“The FDA is always interested in new technologies that can help make the care of people living with chronic conditions, such as diabetes, easier and more manageable,” says Donald St. Pierre, acting director of the Office of In Vitro Diagnostics and Radiological Health and deputy director of new product evaluation in the FDA’s Center for Devices and Radiological Health. “This system allows people with diabetes to avoid the additional step of fingerstick calibration, which can sometimes be painful, but still provides necessary information for treating their diabetes—with a wave of the mobile reader.”
People with diabetes must regularly test and monitor their blood sugar to make sure it is at an appropriate level, which is often done multiple times per day by taking a fingerstick sample and testing it with a blood glucose meter. Typically patients use results of a traditional fingerstick test to make diabetes treatment decisions; however, fingerstick testing is not needed to inform appropriate care choices or to calibrate glucose levels with this system.
The FDA evaluated data from a clinical study of individuals aged 18 and older with diabetes, and reviewed the device’s performance by comparing readings obtained by the FreeStyle Libre Glucose Monitoring System to those obtained by an established laboratory method used for analysis of blood glucose.
Risks associated with use of the system may include hypoglycemia or hyperglycemia in cases where information provided by the device is inaccurate and used to make treatment decisions, as well as mild skin irritations around the insertion site. It does not provide real-time alerts or alarms in the absence of a user-initiated action; for example, it cannot alert users to low blood glucose levels while they are asleep.
The FreeStyle Libre Flash Glucose Monitoring System is manufactured by Abbott Diabetes Care Inc.