Young Blood Vessels Rejuvenate Aged Insulin-Producing Beta Cells

Professor Per-Olof Berggren Rolf Luft at the Research Center for Diabetes and Endocrinology at Karolinska Institutet has led an important study in collaboration with Alejandro Caicedo at University of Miami Miller School of Medicine and Hong Gil Nam at DGIST from the Republic of Korea that demonstrates that young capillary vessels can rejuvenate aged pancreatic islets. This study was published in the Proceedings of the National Academy of Sciences, USA and challenges prevailing views on the causes of age-dependent impaired glucose balance regulation, which often, in older patients, develops into type 2 diabetes mellitus.  These results suggest that treating inflammation and fibrosis in the small blood vessels of the pancreatic islets might provide a new way to treat age-dependent dysregulation of blood glucose levels.

“This is an unexpected but highly important finding, which we expect will have a significant impact on diabetes research in the future. The results indicate that beta cell function does not decline with age, and instead suggest that islet function is threatened by an age-dependent impairment of vessels that support them with oxygen and nutrients”, says Berggren.

Pancreatic beta cells are in the pancreatic islets and secrete the hormone insulin, which regulates blood glucose levels and also is one of the most important anabolic hormones of the human body.  Ageing may lead to a progressive decline in glucose regulation which may contribute to the onset of diabetes.  Generally, it has been assumed that this is due to reduced capacity of the beta cell to secrete insulin or multiply.

“In the study we challenged the view that the age-dependent impairment in glucose homeostasis is solely due to intrinsic, dysfunction of islet cells, and hypothesized that it is instead affected by systemic aging factors”, says first author Joana Almaça at the Diabetes Research Institute, University of Miami.

Even though the common wisdom in modern medicine is that insulin-producing pancreatic beta cell lose function through the constant demands on them,  Berggren and his collaborators showed that mouse and human beta cells are fully functional at advanced age.  When they replaced the islet vasculature in aged islet grafts with young capillaries, the investigators found that the islets were rejuvenated and glucose homeostasis fully restored.

“While expanding beta cell mass may still be desirable for future diabetes therapy, improving the local environment of the otherwise healthy aged beta cell could prevent age-associated deterioration in glucose homeostasis and thereby promote healthy ageing, which is conceptually novel and highly exciting”, says Per-Olof Berggren.


Directly Reprogramming Gut Cells into Beta Cells to Treat Diabetes

Type 1 diabetes mellitus results from destruction of insulin-producing beta cells in the pancreas. Diabetics have to give themselves routine shots of insulin. The hope that stem cells offer is the production of cells that can replace the lost beta cells. “We are looking for ways to make new beta cells for these patients to one day replace daily insulin injections,” says Ben Stanger, MD, PhD, assistant professor of Medicine in the Division of Gastroenterology, Perelman School of Medicine at the University of Pennsylvania.

Some diabetics have had beta cells from cadavers transplanted into their bodies to replace the missing beta cells. Such a procedure shows that replacement therapy is, in principle possible. Therefore, transplanting islet cells to restore normal blood sugar levels in type 1 diabetics could treat and even cure disease. Unfortunately, transplantable islet cells are in short supply, and stem cell-based approaches have a long way to go before they reach the clinic. However, Stanger and his colleagues have tried a different strategy for treating type 1 diabetes. “It’s a powerful idea that if you have the right combination of transcription factors you can make any cell into any other cell. It’s cellular alchemy,” comments Stanger.

New research from Stanger and a postdoctoral fellow in his laboratory, Yi-Ju Chen that was published in Cell Reports, describes the production of new insulin-making cells in the gut of laboratory animals by introducing three new transcription factors. This experiment raises the prospect of using directly reprogrammed adult cells as a source for new beta cells.

In 2008, Stanger and others in Doug Melton’s laboratory used three beta-cell reprogramming factors (Pdx1, MafA, and Ngn3, collectively called PMN) to convert pancreatic acinar cells (the cells in the pancreas that secrete enzymes rather than hormones) into cells that had many of the features of pancreatic beta cells.

Following this report, the Stanger and his team set out to determine if other cells types could be directly reprogrammed into beta cells. “We expressed PMN in a wide spectrum of tissues in one-to-two-month-old mice,” says Stanger. “Three days later the mice died of hypoglycemia.” It was clear that Stanger and his crew were on to something. Further work showed that some of the mouse cells were making way too much extra insulin and that killed the mice.

When the dead mice were autopsied, “we saw transient expression of the three factors in crypt cells of the intestine near the pancreas,” explained Stanger.

They dubbed these beta-like, transformed cells “neoislet” cells. These neoislet cells express insulin and show outward structural features akin to beta cells. These neoislets also respond to glucose and release insulin when exposed to glucose. The cells were also able to improve hyperglycemia in diabetic mice.

Stanger and his co-workers also figured out how to turn on the expression of PMN in only the intestinal crypt cells to prevent the deadly whole-body hypoglycemia side effect that first killed the mice.

In culture, the expression of PMN in human intestinal ‘‘organoids,’ which are miniature intestinal units grown in culture, also converted intestinal epithelial cells into beta-like cells.

“Our results demonstrate that the intestine could be an accessible and abundant source of functional insulin-producing cells,” says Stanger. “Our ultimate goal is to obtain epithelial cells from diabetes patients who have had endoscopies, expand these cells, add PMN to them to make beta-like cells, and then give them back to the patient as an alternate therapy. There is a long way to go for this to be possible, including improving the functional properties of the cells, so that they more closely resemble beta cells, and figuring out alternate ways of converting intestinal cells to beta-like cells without gene therapy.”

This is hopefully a grand start to what might be a cure for type 1 diabetes.

Adult Stem Cells to Cure Diabetes?

Type 1 diabetics must inject themselves with insulin on a daily basis in order to survive. Without these shots, they would die.

Insulin injection

In most cases, type 1 diabetics have diabetes because their immune systems have attacked their insulin-producing cells and have destroyed them. However, a recent study at the University of Missouri has revealed that the immune system-dependent damage to the pancreas in type 1 diabetics goes beyond direct damage to the insulin-producing cells in the pancreas, The immune response also destroys blood vessels that feed tissues within the pancreas. This finding could provide the impetus for a cure that includes a combination of drugs and stem cells.

Habib Zaghouani and his research team at the University of Missouri School of Medicine discovered that “type 1 diabetes destroys not only insulin-producing cells but also blood vessels that support them,” explained Zaghouani. “When we realized how important the blood vessels were to insulin production, we developed a cure that combines a drug we created with adult stem cells from bone marrow. The drug stop the immune system attack, and the stem cells generate new blood vessels that help insulin-producing cells to multiply and thrive.”

Type 1 diabetes or juvenile diabetes, can lead to numerous complications, including cardiovascular disease, kidney damage, nerve damage, osteoporosis and blindness. The immune response that leads to type 1 diabetes attacks the pancreas, and in particular, the cell clusters known as the islet of Langerhans or pancreatic islets. Pancreatic islets contain several hormone-secreting cells types, but the one cell type in particular attacked by the immune system in type 1 diabetics are the insulin-secreting beta cells.

Pancreatic islets
Pancreatic islets

Destruction of the beta cells greatly decreases the body’s capability to make insulin, and without sufficient quantities of insulin, the body’s capability to take up, utilize and store sugar decelerates drastically, leading to mobilization of fats stores, the production of acid, wasting of several organs, excessive water loss, constant hunger, thirst, urination, acidosis (acidification of the blood), and eventually coma and death if left untreated.

The immune system not only destroys the beta cells, it also causes collateral damage to small blood vessels (capillaries) that carry blood to and from the pancreatic islets. This blood vessel damage led Zaghouani to examine ways to head this off at the pass and heal the resultant damage.

In previous studies, Zaghouani and others developed a drug against type 1 diabetes called Ig-GAD2. Treatment with this drug stops the immune system from attacking beta cells, but, unfortunately too few beta cells survived the onslaught from the immune system to reverse the disease. In his newest study, Zaghouani and his colleagues treated non-obese diabetic (NOD) with Ig-GAD2 and then injected bone marrow-based stem cells into the pancreas in the hope that these stem cells would differentiate into insulin-secreting beta cells.

“The combination of Ig-GAD2 and bone marrow [stem] cells did result in production of new beta cells, but not in the way we expected,” explained Zaghouani. “We thought the bone marrow [stem] cells would evolve directly into beta cells. Instead, the bone marrow cells led to growth of new blood vessels, and it was the new blood vessels that facilitated reproduction of the new beta cells. In other words, we discovered that to cure type 1 diabetes, we need to repair the blood vessels that allow the subject’s beta cells to grow and distribute insulin throughout the body.”

Zaghouani would lie to acquire a patent for his promising treatment and hopes to translate his preclinical research discovery from mice to larger animals and then to humans. In the meantime, his research continues to be funded by the National Institutes of Health and the University of Missouri.