beta cells

New Research Proves the Pancreas Can Regenerate

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Beta cell regeneration – progenitor cells (green) can become insulin-producing cells (red) [courtesy of the Diabetes Research Institute]

Type 1 diabetes is caused by an autoimmune attack that destroys the beta cells, the part of the body that produces the essential hormone insulin. It is generally supposed that once these cells have been lost, they are gone forever. In the search for a cure, the most advanced research has concentrated on the transplantation of new beta cells — either from an organ donor or grown in a laboratory — to replace the cells that have been irrevocably lost.

But what if your body could be directed to regrow its own new beta cells? A lead investigator at the Diabetes Research Institute believes that the pancreas can regenerate beta cells, and that his lab has discovered how to make it happen.

A Century of Questions

Many human cells can regenerate themselves. You may have heard that, due to constant cell regrowth, the entire human body is replaced every seven years. That’s not quite right — while most of your skin cells turn over within months, you also have brain cells that never have been and never will be replaced.

The pancreas, like most other internal organs, is slow to regenerate and has a very limited ability to heal itself. But doctors have long suspected that the pancreas harbors the ability to regenerate the islet cells, which contain the insulin-producing beta cells. “The concept has been around for more than 100 years,” since even before the discovery of insulin, says Juan Dominguez-Bendala, PhD. It’s always been a controversial idea, but he believes that the debate has now been settled.

Dr. Dominguez-Bendala is the Director of Stem Cell & Pancreatic Regeneration and Research at the Diabetes Research Institute. His team, in a collaborative effort with his colleague Dr. Ricardo Pastori, recently published a report in Cell Metabolism that finally proves that the adult human body is capable of growing new beta cells:

“I think that this is very definitive. We’re looking at regeneration in the real thing, the real human pancreas. We see this happening in real-time. It’s unequivocal.”

New Evidence

The islet cells that contain both the beta cells and other important exocrine cells only make up a small minority of the pancreas’ mass. Most of the organ is devoted to a ductal system that helps synthesize digestive juices and transport them to the intestines. In the embryo, though, this part of the pancreas also creates the islet cells.

“There are lots of people that don’t believe that this is a process that happens during normal adult life. But what we and others contend is that when there’s extensive damage to the pancreas, there’s a partial reactivation of the embryonic program that brought about islet cells in the first place. There are stem cells in the ducts that give rise to new islets.”

For years, however, the evidence in favor of human islet regeneration only came in the form of samples from the pancreases of deceased people. It had never been possible to observe the regeneration of islet cells in real-time, and “the evidence was rather circumstantial.” There was supporting evidence from mouse models, but Dominguez-Bendala admits that this was of limited value: “We have cured diabetes in mice hundreds of different ways, and none of them have ever worked in humans.”

Scientists received a new tool with the establishment of nPOD, the Network for Pancreatic Organ Donors with Diabetes. Founded and supported by the leading charity JDRF, nPOD encourages people with diabetes to sign up as organ donors and donate their pancreases to science. This national network is the only way for American researchers to receive a reliable supply of viable organs from people with type 1 diabetes.

Dominguez-Bendala’s lab began receiving donations of pancreas slices in 2018. It took some tinkering, but they found a medium that “could extend the life and functionality in vitro for about two weeks, which was plenty for us to start seeing if there’s regeneration.” It provided, for the first time, “a window into the real pancreas.”

How to Stimulate Beta Cell Regeneration

If pancreatic regeneration does occur naturally, it’s obviously not enough to substantially heal people with diabetes or pancreatitis. To make a difference, Dominguez-Bendala would have to find a way to accelerate and amplify the regeneration process. His secret ingredient may be a natural human growth factor named BMP7.

BMP7 is “like a fuel for stem cells across the body,” and Dominguez-Bendala wanted to see if it could have the same effect in the pancreas. The substance is well-studied and is already approved for an unrelated condition: “It’s already in clinical use. It regrows bone, and is used to fuse vertebrae when you have spinal surgery.”

The team at Dominguez-Bendala’s lab would take multiple pancreatic slices from a single donor and treated some with BMP7. When they took a closer look, they saw exactly what they had hoped: new hybrid cells emerging from the ductal mass of the pancreas and creating a bridge towards the area where islet cells are born. A trajectory analysis showed that some of the new hybrid cells “became new islet cells.”

“We showed for the first time, in a human-based model, how regeneration works.”

“We discovered that progenitor cells inside the ducts respond to BMP7 by proliferating, and then when you remove the BMP7, they differentiate into all the different cell types of the pancreas.”

“To me, it doesn’t get any more promising than that,” Dominguez-Bendala said. “You can cure diabetes left and right in mice, but to show that you can induce beta cell regeneration in a type 1 diabetes donor? That’s something really major.”

Next, they had to prove that the new islet cells were actually functional. Could they respond to high blood sugar levels, secrete insulin, and correct hyperglycemia? “When we look at the neogenic cells, the cells that have been formed as a result of BMP7 stimulation, we can see that they respond to glucose stimulation by making insulin.”

It will take several years and “a lot of boring experiments” to convince the FDA that the therapy is safe to try in humans. Studies of mice, at least, show that BMP7 causes no other dysfunctional tissue growth. It also doesn’t stimulate islet cell growth in healthy mice, suggesting that the substance naturally targets injuries: “We think it takes an extreme degree of damage to the pancreas for this very primitive regeneration program to be activated.” Studies in humans help show that BMP7 is safe for general use, including when used to help heal kidney disease.

The Immunity Problem

Beta cell regeneration has the same big problem that every other proposed type 1 diabetes cure has: the immune system. Transplanted islet cells — whether they come from an organ donor or a laboratory manufacturing process — can correct hyperglycemia and grant insulin independence, but thus far nobody has figured out how to protect them from the immune system without the use of powerful drugs (with potentially powerful side effects).

“This doesn’t work unless we do something about the immune system, or else the new cells will be destroyed again and again,” says Dominguez-Bendala. “We envision this as a combination therapy alongside immunotherapies.”

Dominguez-Bendala is gambling, along with the rest of the diabetes world, that better immunotherapies are coming soon. In the meanwhile, the first patient population likely to benefit from any beta cell regeneration therapy are people who have received a kidney transplant, patients who therefore already require anti-rejection medications.

There is at least some hope, however, that naturally regenerated beta cells will be easier to protect from the immune system than transplanted cells, which the body’s defenses identify as foreign. We won’t know yet how the body will respond to neogenic cells: “The truth is that we don’t know. I have spoken to immunologists who believe that the new cells may be able to sneak in and won’t be destroyed as quickly as the ones that were destroyed in the first place. I’m hopeful that it will happen, but I’m not counting on that.”

Timeline

Beta cell regeneration is in its infancy as a therapy, and will require many years of experimentation before it gets anywhere close to FDA approval. I asked Dominguez-Bendala if a more advanced potential cure — such as Vertex’s VX-264 — might succeed first and render his work obsolete. Dominguez-Bendala doesn’t see Vertex as a competitor — his lab has helped contribute to progress in the field of stem cell differentiation — but he is emphatic that VX-264 will not be a full cure and will not end the search for better type 1 diabetes remedies:

“It’s not a cure by any stretch of the imagination. It’s a brute force strategy, putting things in the body, and the body is attacking them. What we are proposing is fundamentally different, to harness the very natural ability of the pancreas to heal itself. That’s a much more holistic approach.”

Several other research groups are investigating parallel therapies. In France, a startup named DiogenX believes it has found another way to regenerate the beta cells. And just last week, an Australian team published a study of another method that could stimulate beta cell regeneration.

“I’m hopeful that it will be available sooner rather than later. We could spend twenty years exploring the little details of the mechanisms, but that’s not what the Diabetes Research Institute is about. We want to have therapies in the clinic as soon as possible. That’s our mission, and that’s what we are going to do.”

Disordered Eating with Diabetes

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eating disorder with diabetes

 

“Are you hungry?” my husband asked me after a particularly difficult hike in the Rocky Mountains last summer that lasted over 12 hours, where all we ate during the day was trail mix and some dried fruit. He was starving.

“I’m fine,” I replied. “My blood sugar is 115.”

He looked at me quizzically, and lovingly reminded me that blood sugar and hunger are not the same thing.

As a person with diabetes, I have had to separate my hunger from my need of food. There have been countless instances when at dinner time my blood sugar was over 400, and I had to wait until insulin brought me down to a safe level before digging in. Conversely, there have been many times (too many to count) where I was not hungry at all, but of course had to eat something because my blood sugar was under 60. I am always cognizant of my blood sugar, but not always of the crucial hunger and fullness cues. This is problematic.

People with diabetes have a tricky relationship with food. Diabetes requires one to be diligent when it comes to tracking what and how much they eat. There is also constant monitoring of food intake (carbohydrates in particular), exercise, and insulin. Additionally, people with type 1 diabetes, whose beta cells have been destroyed by the body’s immune system, secrete none of the hormone called amylin at all. Amylin is a peptide hormone that is co-secreted with insulin, and inhibits glucagon secretion, delays gastric emptying, and acts as a satiety agent. This may be why some people with diabetes struggle to feel full after meals. As a result of all of this constant tracking of food, plus the inability to regulate our hunger cues, people with diabetes may be inherently more prone to issues around disordered eating.

According to the National Institutes of Health, adolescents (ages 12-21) with type 1 diabetes experience elevated rates of disordered eating behaviors in 37.9% of females and in 15.9% of males. For adolescents without diabetes, the rates are 3.8% and 1.5%, respectively. The most common type of disordered eating among people with type 1 diabetes is a little known condition called diabulimia, where people intentionally reduce their insulin intake to lose weight. This is a serious condition that leads to diabetic ketoacidosis (DKA) and even death, if not treated.

One in three teenagers (more often than not a girl) will face disordered eating in her lifetime with type 1 diabetes. We’re bombarded with magazines and ads, fad diets and “quick fixes.” We also have to maintain a healthy HbA1c, measure every portion of food we eat, and make sure we get adequate exercise and take our insulin appropriately. It’s stressful. And how “normal” is it that every 12 year old with diabetes knows the carb counts for not only every sandwich they eat, but all of the snacks they eat at sleepovers, as well as their birthday cake?

Holding all of that healthy knowledge inside is overwhelming, especially in a society that values thinness over all else. It is also powerful that every diabetic holds the keys to their health literally in their hands. If they mismanage their diabetes, they will lose weight (losing weight is also a classic symptom of diabetes, so it stands to reason that diabulimia and the mismanagement of the condition leads to weight loss). People with diabetes face many tough battles, and food is a major source of stress for most people with the condition.

Since many people’s relationship to food is warped, it’s important to note the symptoms of diabulimia if your loved ones are showing any of the following signs, and to seek help if you think they have a problem:

According to the National Eating Disorder Association, signs of diabulimia include:

  • Hemoglobin A1c level of 9.0 or higher on a continuous basis
  • Unexplained weight loss
  • Persistent thirst/frequent urination
  • Preoccupation with body image and a fear that insulin will cause weight gain
  • Blood sugar records that do not match hemoglobin A1c results (falsifying sugar logs)
  • Depression
  • Secrecy about blood sugars, shots, and eating
  • Repeated bladder and yeast infections
  • Low sodium/potassium
  • Increased appetite especially in sugary foods
  • Cancelled doctors’ appointments

If you think that you or someone you know is struggling with disordered eating or diabulimia, contact the diabulimia helpline or call their hotline, open 24 hours a day: (425) 985–3635.

Have you seen drastic dietary or behavioral changes in someone you love that has diabetes? Do you recognize any of the aforementioned symptoms in your own life? If so, please seek the help you need. Your diabetes and your life depend on it.

 

Diabetes Management: A Work in Progress

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 snow footprint

 

 

There’s a blizzard outside and today we’re snowed in. In Rochester, NY where I grew up, we rarely had snow days. Being close to Canada and having snow for almost 8 months of the year meant the city was well equipped to meet extreme weather.

But here in New York state, it’s been snowing in snowballs. It’s been too cold to go outside, too cold to go anywhere and did I mention… it’s frigging cold out there! I am not sure what I was thinking leaving behind endless summers ,but it’s been quite a shock to my blood sugar levels. I really thought I had things down but I’ve realized that my diabetes management is still a work in progress.

In spite of the cold, I went into the city this week to meet with Craig Kasper the creator of the Bravest Podcast. Craig also lives with type 1 and created the podcast so he could learn and explore what it is that enables people to live extraordinary lives in spite of their diabetes.

In the interview, we talked about levels of bravery. As our discussion progressed I shared that acceptance continues to be a process. There was that moment of diagnosis, where I felt like I had to swallow a bitter pill, the long years of denial where I kept thinking that controlling my diet and walking up hills would cure me, the moment where I gave myself my first injection through a rain of tears, the day where I knew I needed to change my management strategy by splitting my basal dose and finally yesterday pulling up a ½ unit of bolus insulin into a syringe and taking the plunge.

insulin pen

Living with Latent Autoimmune Diabetes in Adults (LADA) is no picnic. A friend recently commented that it’s easier to calculate your insulin to carb ratio when your beta cells don’t produce any insulin. Living with LADA is like playing roulette. Some days the ball lands on the money and other days I leave the table in despair.

The only way I get through each and every wonky moment is with the varied practices of yoga. I love working with the medium of sound in my practice because sound is so direct and immediately calms and centers me.

Working with sound in yoga is called mantra. The word mantra comes from two words, manas, meaning mind and trayati meaning freedom. A mantra is a sound, which frees the mind by giving the mind a focus so it’s naturally drawn out of its preoccupation with thoughts, ideas, and beliefs.

I know it’s natural to be obsessed with thoughts about the ins and outs of daily management. In working up to that first bolus injection I would sit down to meditate and replay worst case scenarios over and over.

That thought loop went on for days until I caught myself. It’s up to me to stop my need to identify with the thought by asking myself; what kind of investment do I have in that thought? Can a thought make me happy? How can a thought, which has no substance or dimension get the better of me?

It’s like trying to catch a snowflake. Impossible!

And it’s not about stopping the thought either. Try and banish any thought, another impossible task.

Mantra is such a profound way to bring the mind into a one-pointed focus, it can be chanted out loud or internally. Each nuance has a different effect on the mind and body. Chanting audibly affects the pituitary gland, the master gland in the body. It vibrates during chanting which tones and tunes all the other glands in the body. It also affects the vagus nerve which is responsible for increasing immunity

Chanting out loud increases the length of exhalation too. The longer the exhale the calmer the nervous system. Finally, mantra increases our ability to recognize that moment of getting lost in a thought. Thoughts come and go. It’s the thinker of the thoughts that matters.

For today’s practice join me in a simple chanting practice with the sound, om.

URL: https://soundcloud.com/the-flying-yogini/om-chanting-for-health-and-wellbeing

Diabetes Discovery: Heart Drug Spares Beta Cells in Lab

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Patients with type 1 diabetes — and their doctors — dream of a life without insulin injections. Our long-term goal is to make that desire a reality, and we’ve started by looking for potential factors that were involved in the death of insulin-producing beta cells.

Our lab is targeting a specific protein, TXNIP, which seems to induce beta cell death when it’s over-expressed.

The good news is that we may not have to wait for the painstakingly long process of developing a new drug to act on TXNIP. A cheap old calcium channel blocker may do the trick, at least for now.

In several studies, my colleagues at the UAB Comprehensive Diabetes Center and I demonstrated that TXNIP plays a central role in mediating the response of beta cells to stressful stimuli. We found that overexpression of this protein in beta cells occurs during the development of diabetes and, if left unchecked, leads to death of these cells. Conversely, we were able to show that reducing TXNIP levels in beta cells could prevent development of diabetes in mouse models.

Through our research, we noted that the the calcium channel blocker verapamil, used to treat hypertension and various heart conditions, could also lower TXNIP levels in beta cells. We showed that this drug could both prevent and reverse diabetes in mouse models.

Since verapamil is an FDA-approved drug with a clear safety profile, we were able to quickly advance this research to the clinical trial stage where we are testing the drug’s effectiveness in patients who have recently (i.e. within 3 months) been diagnosed with T1D. In this current study, we are asking if verapamil can promote beta cell survival and slow progression of T1D, potentially reducing insulin requirements and improving glucose control in patients with the disease.

Several previous studies came into play in helping us identify verapamil as a potentially beneficial therapy for blocking TXNIP and preventing beta cell death. Our research team had noticed that, based on its ability to lower cellular calcium levels, use of verapamil is associated with a decrease in TXNIP levels in both mouse and human beta cells. Previously, we had also shown that genetic deletion of TXNIP in mouse models was able to prevent diabetes by promoting beta cell survival and beta cell function.

Based on this information, we tested the ability of oral verapamil to block TXNIP expression and reverse diabetes in already diabetic mice. While blood glucose got worse in the control group that didn’t receive the drug, those receiving verapamil reduced their blood glucose to normal levels, had normal insulin-producing beta cells, and completely reversed their diabetes.

We do not expect such dramatic effects in our current human trial, and no reports of diabetes reversal are available despite some patients with diabetes receiving verapamil for other reasons. However, verapamil treatment is typically initiated later in the disease process when beta cell mass may already be severely compromised, and most studies focus on cardiovascular events rather than diabetes. Spinoff studies from the International Verapamil SR/Trandolapril Study (INVEST) show, however, that verapamil reduced the risk of new-onset type 2 diabetes, supporting a potential beneficial effect in humans.

The primary goal of the newly launched human clinical trial is to assess the safety and efficacy of using oral verapamil to prevent beta cell death, increase insulin production, and improve blood glucose control in patients with recent-onset T1D. The double-blind study will enroll approximately 52 volunteers between the ages of 19 and 45 who will be randomized to receive either verapamil or a placebo once a day for a year while continuing insulin pump therapy.

Researchers will track participants’ C-peptide levels following meal ingestion (an indirect measure of beta cell function), as well as their blood sugar control and insulin requirements in order to measure any impact on their beta cell mass, function, and related insulin production. Recruitment of patients will continue until spring of 2016, and initial results from the trial are expected in early 2018.

If this trial suggests that verapamil can be effective at slowing progression of T1D and protecting beta cells, a larger trial will be needed to confirm the drug’s usefulness in a broader population of individuals with T1D. It is also possible that the drug might need to be paired with other therapies to regenerate beta cells or provide more robust control of the immune system attack.

If successful, however, verapamil therapy would target the underlying cause of T1D — beta cell loss — which current treatments aren’t able to do.