US researchers explore link between sugar, insulin, keto, and cancer

The groundbreaking work of US cancer researcher Lewis Cantley, PhD, linking the ketogenic diet to an anti-cancer drug, is receiving prominent coverage in the medical media.

Dr. Cantley, who is based at Weill Cornell Medicine in New York City, is leading a research program in which a powerful anti-cancer drug is paired with the ketogenic diet in effort to starve cancer cells of the glucose and insulin they need to grow and spread. His work, now in clinical trials with women with endometrial cancer, was detailed in a new feature in The Medical Express this week.

A number of years ago, Cantley discovered a special enzyme, called PI3 kinase, which some are calling “the master switch for cancer.” As the article notes:

It turned out that the gene that encodes PI3K is the most frequently mutated cancer-promoting gene in humans — and in the years since Dr. Cantley’s revolutionary discovery, it has been implicated in as many as 80 percent of cancers, including those of the breast, brain and bladder.

Cantley is touted to be in contention for the Nobel Prize in medicine for his discovery. But now Cantley and his team have created drugs that inhibit PI3K. However, their research also found that despite the new drug’s ability to inhibit PI3K, the continuing presence of high insulin drives further cancer growth. How to get the insulin levels down? The ketogenic diet!

His groundbreaking work, in which PI3K inhibitors plus the ketogenic diet shrank cancers in mice, received prominent coverage in pre-eminent journal Nature in July 2018. Now the work has moved into clinical trials in humans.

In December, Dr. Bret Scher wrote about this promising avenue of research in a column for Diet Doctor. Dr. Scher’s post was a summary of a larger piece written by famous oncologist and author Dr. Siddhartha Mukherjee in The New York Times Magazine, which also describes Dr. Cantley’s ground-breaking work. Mukherjee was a co-author with Cantley on the Nature publication and a leading clinical researcher involved in the clinical trials of keto plus the PI3K inhibitor.

Said Dr. Scher of the work, and Mukherjee’s involvement:

How wonderful that this mainstream trial is about to get underway, especially with a curious and open-minded researcher at the helm. Knowledge is power, and shining the bright light of mainstream attention and resources on the potential of keto diets as an adjuvant cancer therapy is very good news indeed.

In a second story in the medical news this past week, a team of researchers, including post-doctoral fellows who had been working in Cantley’s lab at Weill Cornell Medicine, has discovered that high-fructose corn-syrup increases intestinal tumor growth in mouse models of colon cancer. The cancer growth was independent of obesity in the mice.

The study was published in the leading journal Science this past week. While the team of authors conclude the results are too early to translate into human cancer growth “these mouse studies support the hypothesis that the combination of dietary glucose and fructose, even at a moderate dose, can enhance tumorigenesis [tumor growth].”

In short, while much more research needs to be done, these are exciting times for novel cancer research, helping us better understand the role of glucose and insulin in cancer growth and using the ketogenic diet as a potentially powerful addition to new cancer therapies.

(Source: Diet Doctor)

Insulin pill instead of shot: How close are we for diabetes patients?

Daily insulin shots for the management of Type 1 and Type 2 diabetes could become a thing of the past, and insulin pills could someday be another option for diabetes patients.

In people with Type 1 diabetes, the pancreas does not make insulin -- a hormone that helps glucose get into your cells to give them energy -- which is why they take insulin. In people with Type 2 diabetes, the body does not make or use insulin well, and so insulin therapy may be needed.

Insulin can be administered using a needle and syringe, a pen injection, a pump through a needle, an inhaler, an injection port or what's called a jet injection, which sends a spray of insulin into the skin at high pressure.

Yet there have been several research efforts around the world to develop pills as another way to take insulin. These efforts are ongoing, but if any are found to be safe and effective, they could change the daily well-being of the more than 400 million people living with diabetes worldwide. About 40% of them rely on insulin injections.

"Insulin is currently given primarily by injections, which is a challenge for Type 1 diabetics and a deterrent for Type 2 diabetic patients to switch to insulin. An oral pill for insulin will make it easier for the patients to take insulin," said Samir Mitragotri, a professor of bioengineering and biologically inspired engineering at the Harvard John A. Paulson School of Engineering and Applied Sciences.

Developing insulin that patients can ingest remains a scientific challenge because insulin can be degraded in the stomach by acids and enzymes before it's used in the body, Mitragotri said.

In other words, insulin has to survive the hostile environment of your digestive system.

"Even if some insulin makes it into the intestine, it cannot cross the intestinal wall, since the wall is designed to prevent the transport of proteins," Mitragotri said.

"The mucus layer present on the wall of the intestine also makes transport of insulin from the intestine into the blood stream very challenging," he said. "Collectively, these hurdles make oral delivery of insulin very difficult."

The science behind insulin you can swallow
Mitragotri was senior author of a study published Monday in the Proceedings of the National Academy of Sciences that described how a new liquid formulation of insulin inside an enterically coated capsule was capable of lowering blood glucose levels in rats.

Enterically coated means the coating can be dissolved only in the body's small intestine.

For the study, researchers gave six nondiabetic male rats an oral insulin capsule and three nondiabetic male rats traditional injections of insulin.

The researchers found that blood glucose levels rapidly dropped 38% in the rats given capsules within two hours and slowly but steadily continued to fall, dropping 45% by 10 hours.

In comparison, blood glucose levels sharply dropped 49% within one hour in the rats given injections. Levels then rose, which is a typical response in nondiabetic rats, before continuing to decrease in a typical pattern.

"Oral delivery of insulin has been challenging. The study demonstrates a new technology to overcome these challenges," Mitragotri said.

"The next step is to perform longer-term safety studies and efficacy testing in larger animals," he said.

"These studies will provide the necessary information to support human clinical testing, which we hope will begin in three to five years."

That study was just the latest to experiment with creating an insulin pill; many others do involve testing in humans.

Last month, Oramed Pharmaceuticals launched its largest and most advanced clinical trial of its own oral insulin pill, under the direction of the US Food and Drug Administration. The trial involves 240 patients with Type 2 diabetes.

"A year from now we will better know the potential of our drug to control and maintain blood glucose levels and will have further proof of the longer-term benefits of taking an oral pill versus an injection," Oramed CEO Nadav Kidron said in a news release in May.

Other experimental oral insulin pills are Capsulin by the company Diabetology and HDV-Insulin by the company Diasome, which was the first oral insulin approved for phase three testing by the FDA, according to the company's website.

Insulin you can swallow also has been studied as a possible way to either hold off or prevent the development of Type 1 diabetes, but this approach has been found to be ineffective in human clinical studies.

In a separate study published in the journal JAMA in November, researchers examined whether a type of oral insulin capsule can delay or prevent the development of Type 1 diabetes in the relatives of patients with the disease, who are therefore themselves at a higher risk of developing it, over a 2.7-year period.

That study involved 560 people, some of whom were given an insulin capsule and others who were were given a placebo pill.

Though some participants given the insulin capsule had a longer time before being diagnosed with diabetes, overall, "these findings do not support oral insulin as used in this study for diabetes prevention," the researchers wrote.

Many questions remain
The future of insulin therapy is among the research topics on the agenda at the annual scientific conference of the American Diabetes Association this week in Florida.

Research on the oral administration of insulin dates back decades.

One study published in the journal Diabetes in 1988 involved administering nanocapsules of insulin to rats. It found that the capsules preserved the therapeutic effect of insulin when administered.

Still, more research is needed to better understand the possible risks that could come with insulin pills. In general, insulin therapy causes changes in blood sugar, so symptoms of low and high blood sugar could emerge, as seen with insulin injections.

Some studies suggest that use of insulin might be linked with increased risk of cancer, but of course more research is also needed to determine whether such a relationship could emerge with the use of insulin pills.

These pills are far from proven, but they are staking a claim as a possible new avenue for diabetes care.

(Source: CNN)

New implant for Type 1 diabetes could eliminate the insulin shots

For the more than 1 million Americans who live with type 1 diabetes, daily insulin injections are literally a matter of life and death. And while there is no cure, a Cornell-led research team has developed a device that could revolutionize management of the disease.

In Type 1 diabetes, insulin-producing pancreatic cell clusters (islets) are destroyed by the body’s immune system. The research group, led by assistant professor Minglin Ma from the Department of Biological and Environmental Engineering in the College of Agriculture and Life Sciences, has devised an ingenious method for implanting hundreds of thousands of islet cells into a patient. They are protected by a thin hydrogel coating and, more importantly, the coated cells are attached to a polymer thread and can be removed or replaced easily when they have outlived their usefulness.

The findings were published in Proceedings of the National Academy of Sciences.

Transplantation of stem cell-derived, insulin-producing islet cells is an alternative to insulin therapy, but that requires long-term immunosuppressive drug administration. One well-researched approach to avoid the immune system’s response is to coat and protect the cells in tiny hydrogel capsules, hundreds of microns in diameter. However, these capsules cannot be taken out of the body easily, since they’re not connected to each other, and there are hundreds of thousands of them.

And the ability to remove the transplant is key because of the potential of tumors forming when stem cell-derived, insulin-producing cells – the most promising cell source for type 1 diabetes cell therapies – are used.

“When they fail or die, they need to come out,” Ma said. “You don’t want to put something in the body that you can’t take out. With our method, that’s not a problem.”

Taking inspiration from the way water beads on a spider’s web, Ma and his team first attempted to connect the islet cell-containing capsules through a string but realized that it would be better to put the hydrogel layer uniformly around a string instead.

That string: an ionized calcium-releasing, nanoporous polymer thread. The device starts with two sterile nylon sutures twisted in a helix, then folded over to facilitate the subsequent nanoporous structure coatings. Placed onto that thread is a thin layer of islet cell-containing alginate hydrogel, which adheres to the helical, nanoporous thread, similar to dew drops sticking to the spider silk. Alginate is a seaweed extract commonly used in encapsulated cell transplantation.

Doctoral students Alan Chiu, left, and Duo An hold a sample of TRAFFIC (Thread-Reinforced Alginate Fiber for Islets enCapsulation). In the background, left to right, are Minglin Ma, Dan Luo, Meredith Silberstein and Dr. James Flanders.

This thread – which the group has dubbed TRAFFIC (Thread-Reinforced Alginate Fiber For Islets enCapsulation) – was inspired by a spider’s web but, according to Ma, is even better because the hydrogel covers the thread uniformly.

“You don’t have any gaps between capsules,” he said. “With a spider’s silk, you still have gaps between the water beads. In our case, gaps would be bad in terms of scar tissue and the like.”

And since the thread is twisted and porous, the hydrogel won’t slip off as it would on a single, smooth piece of material. Fan and Silberstein were instrumental in modeling different options for the thread configuration.

This therapy would involve minimally invasive laparoscopic surgery to implant approximately six feet of hydrogel-coated thread into the patient’s peritoneal cavity.

“We only need two quarter-inch-long incisions,” Flanders said. “We inflate the abdomen with carbon dioxide, which gives us room to work, and then put in two ports – one for a scope that’s hooked to a camera, so we can see what we’re doing, and the other for a grasping device, which is how we introduce the implant.”

TRAFFIC’s large surface area promotes better mass transfer, Ma said, and diffusion is good because all the islet cells are near the surface. Current life span estimates for the thread are between six and 24 months, although more testing is necessary.

In mice, blood glucose levels were returned to normal two days after implantation of a one-inch length of TRAFFIC, and remained normal for at least three months when the experiment ended. Retrievability was tested in multiple dogs, with 10-inch samples being successfully implanted and removed laparoscopically.

Flanders, who performed surgical implantation in canines, said among the different dogs and devices tested there was either no or only minimal adhesion of the device to surrounding tissue upon removal.

This collaboration has produced a potentially game-changing medical device, he said.

“When Minglin first told me about this, I thought it was brilliant,” Flanders said. “There have been other devices sort of like this, but this one seems to have so much promise. It’s minimally reactive, it protects the islet cells, it allows them to sense glucose, they don’t attach to anything, and it can be easily removed. To me, it sounded like a win-win.”

(Source: Daily Accord)