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.

Betatrophin, a New Liver Protein that Increases the Number of Insulin-Making Cells

Douglas Melton’s laboratory at the Harvard University Stem Cell Institute in Cambridge, Massachusetts has discovered a liver hormone that stimulates the growth of insulin-secreting beta cells in the pancreas. This discovery could very well lead to new treatments for diabetes.

This hormone, betatrophin, was induced in mice by treating them with a peptide that binds to insulin receptors. The insulin-occupied insulin receptors were unable to bind insulin, and that caused the animals to be resistant to insulin. Under these conditions, the livers of these mice produced betatrophin, which caused the animals’ insulin-secreting pancreatic β cells to proliferate. Melton and others searched for genes that showed increased activity under these insulin-resistant conditions, which allowed Melton and colleagues to isolate and identify betatrophin.

According to Melton and his co-workers, “Transient expression of betatrophin in mouse liver significantly and specifically promotes pancreatic β cell proliferation, expands β cell mass, and improves glucose tolerance” (from the abstract of the paper).

Further experiments showed that when eight-week-old mice injected with betatrophin there was an average 17-fold rise in the proliferation of their insulin-secreting pancreatic β cells. Melton and others published these results in the journal Cell. Fortunately, betatrophin is also found in the human liver, according to Melton and others.

“It’s rare that one discovers a new hormone, and this one is interesting because it’s so specific,” says Melton. “It works only on β cells and it’s so robust and so potent.”

Pancreatic β cells replicate rapidly during embryonic and neonatal stages in both mice and humans, but beta cell growth decreases dramatically in adults. A decrease in the function of beta cells late in life is the main cause of type 2 diabetes. Type 2 diabetes is a metabolic disorder that affects more than 300 million people worldwide. In the United States alone, the two forms of diabetes — type 2 and type 1— account for US$176 billion in direct medical costs each year.

Melton hypothesized that injections of betatrophin once a month, or even once a year, could potentially induce enough activity in pancreatic β cells to provide the same level of blood-sugar control for people with type 2 diabetes as do daily insulin injections. According to Melton, betatrophin would cause fewer complications, since the body would make its own insulin. He also hopes that betatrophin will be able to help people with type 1 diabetes.

Matthias Hebrok, director of the University of California, San Francisco, Diabetes Center, says that the work “is a great advance”. “The findings are very interesting,” he says, although he would like to see the experiments repeated in older mice. “Do mice that are on their way to becoming diabetic at an advanced age truly have an increase in proliferative capacity upon treatment with betatrophin?” he asks. This is a fair question.

Henrik Semb, managing director of the Danish Stem Cell Center in Copenhagen, says that “the identification of a factor, betatrophin, that stimulates mouse β-cell replication with remarkable efficiency is a very important discovery, because it provides the starting point for further studies to elucidate the underlying mechanism of β-cell replication.”

β-cell replication has proved difficult to control in humans, but producing enough betatrophin for testing in human clinical trials will take about two years, according to Melton, who is also working to identify the hormone’s receptor and its mechanism of action.

References: Yi, P., Park, J.-S. & Melton, D. A. Cell (2013).

No Evidence of Regeneration of Insulin-Making Cells in the Pancreas

Type 1 diabetics and severe type 2 diabetics show reduction of insulin secretion as a result of destruction of the specific cells in the pancreas that produce insulin. These cells, the so-called beta cells, suffer destruction from the patient’s immune system (type 1 diabetes) or from overwork (type 2 diabetes). The holy grail of diabetes treatment is the regeneration of lost beta cells.

pancreas beta cells

Several reports have marshaled evidence that the pancreatic beta cells do regenerate, but the constant assault by the immune system eventually destroys all the beta cells. Other reports have argued that a stem cell population in the ductal system of the pancreas can replenish the beta cells. Thus, augmenting beta cell regeneration seemed to be simply a matter of employing the already-present regenerative properties of the pancreas.

Unfortunately, a recent study seems to put the kibosh on any hope that the pancreatic beta cells regenerate. This new study was published in the Journal of Clinical Investigation. In this paper, researchers at Children’s Hospital of Pittsburgh report were unable to find signs of new beta cell production in several common models of pancreatic injury (see Xiao, X., et al. 2013. No evidence for beta-cell neogenesis in murine adult pancreas. J Clin Invest., 123(5):2207-17).

“Overall, the paper puts one more nail in what was already becoming an increasingly tight coffin for what had been the prevailing hypothesis about β-cell neogenesis in adult mice,” said Fred Levine, who studies β-cell regeneration at Sanford Burnham Medical Research Institute in La Jolla, California and was not involved in the study. Still, Levine cautions that this negative result does not completely rule out adult regeneration of β-cells in other injury models.

To detect the formation of new beta cells, George Gittes and his colleagues used an old cell tracking method, but applied it in a different manner. They used two fluorescent tags in transgenic mice: a red tag that targets a protein in the cell membrane of most cells in the body, except for insulin producing cells, and a green tag that only tagged pancreatic beta cells. Gittes team looked for cells that turned on their insulin genes for the first time during a 40–48 hour window. The cells, therefore, would express both tags and, as a result, appeared yellow.

The yellow transition was detected in embryonic mice, where neogenesis (new beta cell production) is expected to occur. But when the researchers examined adult cells, they saw no yellow cells—meaning no evidence of neogenesis. They repeated this experiment in several common models of pancreatic damage. For example, the pancreatic duct ligation model (PDL damages other pancreatic cell types but not β-cells. The absence of detectable neogenesis in these models “puts pressure on us to find models in which there is neogenesis,” said Gittes. But he remains “very confident” that there are other models in which neogenesis occurs.

In fact, several models not tested in this paper have shown evidence of neogenesis, including one of Gittes’ own. In 2011, in which his team found evidence of neogenesis in a mice who beta cells were engineered to express diphtheria toxin receptors, that led to their death (see Criscimanna, A., et al. 2011. Duct cells contribute to regeneration of endocrine and acinar cells following pancreatic damage in adult mice. Gastroenterology, 141(4):1451-62). In 2010, two other research groups, including one headed by Levine, also demonstrated neogenesis in adult mice through trandifferentiation of preexisting α-cells in pancreatic islets into β-cells (Thorel, F., et al. 2010. Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss. Nature,464(7292):1149-54 and Chung, C.H., et al. 2010. Pancreatic β-cell neogenesis by direct conversion from mature α-cells. Stem Cells, 28(9):1630-8).

“Overall, I believe that the pathway by which β-cell regeneration occurs…is likely to vary depending on the stimulus for regeneration,” said Levine. Therefore, the current work does not rule out neogenesis, even from duct cells, in other models. “I would argue that the old cliché, ‘Absence of evidence is not evidence of absence’ should be kept in mind when evaluating studies like this.”