1. For patients with type 1 diabetes (T1D), the burden of constantly monitoring their blood sugar and judging when and how much insulin to self-inject, is bad enough. Even worse, a miscalculation or lapse in regimen can cause blood sugar levels to rise too high (hyperglycemia), potentially leading to heart disease, blindness and other long-term complications, or to plummet too low (hypoglycemia), which in the worst cases can result in coma or even death.
At time 0 mice with a diabetes-like condition were given a long-acting insulin that is currently prescribed to diabetics (blue), or Ins-PBA-F "smart" insulin (red) and compared to healthy mice that were not injected with insulin (black). At 3 hours, the mice were given a dose of sugar. Blood sugar returns to normal as quickly in diabetic mice treated with Ins-PBA-F "smart" insulin as in healthy mice.
Credit: Danny Chou
To mitigate the dangers inherent to insulin dosing, a University of Utah biochemist and fellow scientists have created Ins-PBA-F, a long-lasting "smart" insulin that self-activates when blood sugar soars. Tests on mouse models for type 1 diabetes show that one injection works for a minimum of 14 hours, during which time it can repeatedly and automatically lower blood sugar levels after mice are given amounts of sugar comparable to what they would consume at mealtime.
Ins-PBA-F, acts more quickly, and is better at lowering blood sugar, than long-acting insulin detimir, marketed as LEVIMIR. In fact, the speed and kinetics of touching down to safe blood glucose levels are identical in diabetic mouse models treated with Ins-PBA-F and in healthy mice whose blood sugar is regulated by their own insulin. A study showing these findings were published recently in PNAS Early Edition.
"This is an important advance in insulin therapy," says co-first author Danny Chou, Ph.D., USTAR investigator and assistant professor of biochemistry at the University of Utah. "Our insulin derivative appears to control blood sugar better than anything that is available to diabetes patients right now." He will continue evaluating the long-term safety and efficacy of Ins-PBA-F. The insulin derivative could reach Phase 1 human clinical trials in two to five years.
"At present, there is no clinically approved glucose-responsive modified insulin," says Matthew Webber, Ph.D., co-first author with Chou and Benjamin Tang, Ph.D., who performed the work together while postdoctoral fellows at MIT in collaboration with senior authors and MIT professors Robert Langer, Ph.D., and Daniel Anderson, Ph.D. "The development of such an approach could contribute to greater therapeutic autonomy for diabetic patients."
The hallmark symptom of diabetes is inadequate control of blood sugar. The deficit is most pronounced in type 1 diabetes, which develops when insulin-producing beta-cells of the pancreas are destroyed. Without insulin, there is no way to shuttle sugar out of the blood and into cells, where it is used for energy. T1D patients depend on daily insulin injections for survival.
Despite advances in diabetes treatment such as insulin pumps and the development of four types of insulin, patients must still manually adjust how much insulin they take on a given day. Blood sugar levels vacillate widely depending on a number of factors such as what someone chooses to eat and whether they exercise.
A glucose-responsive insulin that is automatically activated when blood sugar levels are high would eliminate the need for additional boosts of insulin, and reduce the dangers that come with inaccurate dosing. Various such "smart" insulins under development typically incorporate a protein-based barrier, such as a gel or coating, that inhibits insulin when blood sugar is low. However, such biologically based components are often sources of trouble, provoking unwanted side effects such as an immune response.
Ins-PBA-F differs in that it was created by chemically modifying insulin directly. Ins-PBA-F consists of a long-acting insulin derivative that has a chemical moiety, phenylboronic acid (PBA), added to one end. Under normal conditions, Ins-PBA-F binds to serum proteins that circulate in the bloodstream, blocking its activity. When blood sugar levels are high, glucose sugars bind PBA, which acts like a trigger to release Ins-PBA-F so it can get to work.
"Before, a 'smart' insulin really meant delivering insulin differently," says Chou. "Ins-PBA-F fits the true definition of 'smart' insulin, where the insulin itself is glucose responsive. It is the first in its class."
Chou explains that because Ins-PBA-F is a chemically modified version of a naturally occurring hormone, he thinks it is likely to be safe enough to use on a daily basis, similar to other insulin derivatives that are on the market today.
"My goal is to make life easier, and safer for diabetics," he says.
2. Applying lessons learned from autism to brain cancer, researchers at The Johns Hopkins University have discovered why elevated levels of the protein NHE9 add to the lethality of the most common and aggressive form of brain cancer, glioblastoma. Their discovery suggests that drugs designed to target NHE9 could help to successfully fight the deadly disease.
A summary of their work in human tumor cells and mice were published on recently in the journal Nature Communications.
"My laboratory's research on cargo transport inside the cells of patients with autism has led to a new strategy for treating a deadly brain cancer," says Rajini Rao, Ph.D., a professor of physiology at the Johns Hopkins University School of Medicine. "This is a great example of the unexpected good that can come from going wherever the science takes us."
All animal and human cells contain many "cargo packages" surrounded by membranes. These so-called endosomes carry newly minted proteins to specific destinations throughout the cell and haul away old proteins for destruction. Key to their "shipping speed" is the level of acidity inside the endosomes. This is controlled by balancing the activity of protein "pumps" that push protons into endosomes to increase their acidity with that of protein "leaks," like NHE9, that remove protons.
Rao says: "Endosomes are like buckets of water that have to be kept full despite the leaks in them. Altering either the faucet or the leak rate can dramatically change the water level in the bucket."
Rao's research group previously showed that autism-associated defects in the protein NHE9 are harmful because they "clog the leaks," leaving endosomes too acidic and making them race to remove cargo from the cell membrane, destroying proteins prematurely.
To better understand NHE9, graduate students and postdoctoral fellows in Rao's lab searched through patient databases to see if it had other effects on human health. To their surprise, they found that elevated levels of NHE9 are associated with resistance to radiation, chemotherapy and poorer prognoses for patients with glioblastomas.
Teaming up with Alfredo Quinones-Hinojosa, M.D., a professor of neurosurgery at Johns Hopkins, the researchers examined NHE9 in tumor cells from several patients. Cells with low levels of NHE9 grew the slowest, the team found, and those with the highest levels grew fastest. Similarly, the cells with the most NHE9 traveled fastest when placed on a surface mimicking that of the brain, suggesting a high potential for metastasis. And this was confirmed when the tumor cells, which were manipulated to have high or low NHE9, were transplanted into the brains of mice.
Based on their autism research, the team suspected that the boost NHE9 gave to glioblastomas was explained by abnormal endosome acidity. Further studies revealed that, in contrast to autism, NHE9 is overactive in brain cancer, causing endosomes to leak too many protons and become too alkaline. This slows down the "shipping rate" of cancer-promoting cargo and leaves them on the cell surface for too long.
Research from other laboratories suggested that one such cargo protein is EGFR, which maintains cancer-promoting signals at the cell surface and helps tumors become more robust so they grow and move faster. It is also found at elevated levels in more than one-half of patients with glioblastomas. Drugs targeting EGFR in these patients are sometimes effective.
As they suspected, the team found that alkaline endosomes slow down the removal of EGFR from cell surfaces. Lab-grown tumor cells were more readily killed when treated with both a drug countering NHE proteins and a drug against EGFR than when treated by the EGFR-targeting drug alone.
Quinones-Hinojosa says: "We are still five to 10 years away from testing this idea in patients, but these results are encouraging. They give us a better idea of what to target so that hopefully we can make this disease less aggressive and less devastating."