Type II Diabetes Treatment with Stem Cells
Prior to the discovery of insulin in 1921, everyone with type I diabetes died within a few years after diagnosis. At that time, what is today known as type II diabetes was extremely rare. Although insulin in and of itself does not constitute a cure for diabetes, its discovery represented a major breakthrough in the management of the disease. Stem cell therapy, however, offers the first real treatment for diabetes.
Type II diabetes, also known as non-insulin dependent diabetes mellitus (NIDDM), and formerly known as adult-onset diabetes, initially occurs because tissue becomes resistant to insulin. The body needs insulin so that it can uptake glucose - sugar - so the first problem that occurs is that the tissue stops responding to insulin. The pancreas continues to make insulin, such as after a meal, for example, but the tissue stops taking up the glucose in response to the insulin signal, and the body cannot use the glucose. As a result, the pancreas tries to compensate by producing more insulin in order to overcome the initial resistance. At some point, the cells in the pancreas are overworked and cannot make any more insulin, so they start dying.
Therefore, there are 3 main steps that lead to type II diabetes, which are:
1/ insulin resistance,
2/ increased production by the pancreas of insulin,
3/ the pancreatic beta cells which produce the insulin start to die.
After the 3rd step has begun, the patient becomes dependent upon insulin from exogenous sources, such as from intramuscular shots. But these injections of exogenous insulin are not biologically regulated by the body, but rather they occur in spikes: so, for example, you administer the shot and your body is flooded with insulin, which is then used up by the body, so that later there is no more insulin available for your body. Because of these spikes of concentrated amounts of insulin in the blood, the body itself starts degenerating, which results in secondary complications such as any or all of the following:
1/ peripheral neuropathy,
2/ vascular disease, in which endothelial cells in the blood vessels don't function properly, which leads to heart disease and peripheral artery disease, and
3/ renal disease - which leads to kidney failure.
How exactly do adult stem cells work to correct all of this?
Adult stem cells work in a number of ways, so let's look at each mechanism individually. Let's also look at the obvious reasons for why current medical therapies for type II diabetes do not work effectively.
Current treatments for type II diabetes are based on chemical methods that increase the body's tissue sensitivity to insulin, however, these therapies do not address the underlying causes of the disease, specifically, the pancreatic beta cell dysfunction and the insulin resistance. Additionally, secondary complications such as those mentioned above, namely, peripheral neuropathy, organ dysfunction and peripheral vascular disease, also are not improved by current approaches. In this chapter we describe how adult stem cell therapy is an ideal treatment for type II diabetes, because it is the only therapy that addresses all of these issues. Through inhibiting the production of inflammatory mediators such as TNF-alpha, adult stem cells contribute to increasing insulin sensitivity. The additional ability of adult stem cells to directly differentiate into beta cells, as well as to induce endogenous insulin secretion, has also been demonstrated in several scenarios. Furthermore, the regenerative ability of adult stem cells is not limited only to increasing endothelial health and organ function but also to decreasing neuropathic pain. Let's look at each of these properties individually.
Increasing insulin sensitivity with adult stem cells:
The insulin receptor signaling pathway is very sensitive to inflammatory mediators. Specifically, cytokines such as TNF-alpha inactivate the insulin receptor through mechanisms such as phosphorylation of serine on the insulin receptor substrate. Clinical support for the role of TNF-alpha in insulin resistance comes from studies demonstrating positive correlations between this cytokine and the severity of type II diabetes. The primary source of TNF-alpha in type II diabetic patients is adipose tissue. For example, large volume liposuction has been demonstrated to temporarily reduce TNF-alpha levels as well as the extent of insulin resistance. Various types of adult stem cells have demonstrated a highly potent ability to block the production of TNF-alpha, and it is also known that the blood-making compartment in the bone marrow is very sensitive to TNF-alpha. Accordingly, one of the natural functions of the mesenchymal stem cell, which resides in the bone marrow, is to inhibit production of this cytokine from other cells. Mesenchymal stem cells produce a variety of TNF-alpha inhibitor compounds such as IL-10 (interleukin 10) and TGF-beta. The potency of mesenchymal stem cells to shut down TNF production has therefore been well established by a number of researchers.
Thus by inhibiting TNF alpha and releasing numerous anti-inflammatory mediators, mesenchymal stem cells offfer the possibility of decreasing insulin resistance by targeting the underlying inflammatory cause. Such anti-inflammatory activities of mesenchymal stem cells have also been demonstrated in other conditions associated with pathological immune activation. For example, U.S. FDA-approved Phase III clinical trials are currently being performed for the treatment of graft-versus-host-disease and Crohn's disease by the company Osiris Therapeutics.
Restoration of insulin production by adult stem cells:
Adult stem cells are known to differentiate into a variety of different cell types. The public media discusses at length the possibility of being able to use embryonic stem cells, perhaps, some day, at some distant time in the future, to generate new tissue, however, embryonic stem cells are well known to be tumor-causing, by definition, and they have never actually been used clinically, for this as well as numerous other inherent risks. In sharp contrast, adult stem cells such as bone marrow and cord blood stem cells, which have been administered to thousands of patients without adverse effects, are already recognized as being capable of differentiating into therapeutic cells such as insulin producing cells. The production of insulin has already been demonstrated in animal models in which mesenchymal stem cells were administered into mice whose beta cells had been damaged by the administration of the toxic compound streptozoicin, after which, increased insulin production was measured in the mice as a direct result of the mesenchymal stem cells.
The use of adult stem cells to induce islet regeneration is also currently undergoing U.S. FDA approved clinical trials at the University of Miami. Additionally, results from numerous clinical studies involving the administration of bone marrow stem cells by physicians outside of the U.S. have been very promising. For example, one group in Argentina has reported that 85% of Type II diabetic patients who were treated with their own mesenchymal stem cells were able to stop using insulin. The possibility of stimulating islet regeneration does not necessarily depend on differentiation of the adult stem cells into new islet cells but may also occur through the production of growth factors made by the stem cells and which allow endogenous pancreatic stem cells to start proliferating, thereby healing the injured area. For example, from a mouse study in which chemically labeled bone marrow stem cells were administered into mice with injured beta cells, the stem cells were actually found to stimulate the islet activating pancreatic duct stem cell proliferation. The possibility of stimulating endogenous pancreatic duct stem cells by pharmacological means is currently under investigation by the company Novo Nordisk, who has administered a combination of EGF and gastrin to diabetic patients in Phase II clinical trials. However, given that adult stem cells produce a "symphony of growth factors", including gastrin and EGF, the administration of stem cells seems to possess a higher possibility of success. Regardless of whether stem cells directly differentiate into pancreatic cells, or activate endogenous pancreatic stem cells, from the preclinical and clinical data available, there is strong evidence to indicate that these cells are therapeutic for the restoration of insulin production.
Reversing secondary complications:
Uncontrolled blood glucose levels are associated with a variety of complications such as peripheral vascular disease, neuropathic pain and the dysfunction of various organs, for example, renal failure. It is known that stem cell therapy can ameliorate, or in some cases, reverse these pathologies. Peripheral vascular disease, for example, is caused by endothelial dysfunction, but we also know that there is a constant migration of endothelial progenitors from bone marrow sources to the periphery. This migration can be measured through the quantification of the content of endothelial progenitor cells in peripheral blood, and in this manner it has been observed that patients who are diabetic and who have higher levels of circulating endothelial progenitors usually have a lower risk of coronary artery disease.
The administration of adult stem cells is known to rejuvenate old or dysfunctional endothelial cells, and to increase responsiveness to vasoactive stimuli. On the other hand, neuropathy, which is a major cause of persistent, chronic pain in diabetic patients, has been reversed in patients who were treated with various adult stem cell populations. This was further documented in highly defined animal models of pain in which bone marrow stem cell administration was found to accelerate nerve healing and to reduce chronic pain. The ability of stem cells to naturally repair injured organs has similarly been described for the heart, the liver and the kidneys. Mechanistically, injured organs transmit elaborate chemical signals, such as SDF-1, which attract stem cells and induce cellular differentiation of the required tissue. Accordingly, based upon the above discussion, adult stem cell therapy also offers the ideal treatment of secondary complications associated with diabetes.
An adult patient with advanced type II diabetes and a specific level of insulin requirement had been previously treated with metformin. Upon deciding to receive stem cell treatment, the patient received 3 million mesenchymal stem cells which were administered once every two days for the period of a week. No treatment-associated adverse events were reported. Subsequently the patient reported improved movement and increased cognitive activity as well as decreased neuropathic pain and insulin requirements.
This is just one example of the successful ability of adult stem cells to treat type II diabetes.
Adult stem cells inhibit the mediators that cause insulin resistance. As previously described, one of these mediators, which causes the body to resist insulin, is called TNF-alpha (tumor necrosis factor alpha). It has been demonstrated that patients with type II diabetes have abnormally high levels of TNF-alpha, and it is also known that the amount of TNF-alpha in the plasma is known to correlate with extensive insulin resistance. In other words, the more TNF alpha is in a person's blood plasma, the greater is that person's insulin resistance.
Mesenchymal stem cells have been found to shut down TNF-alpha production, thereby shutting off inflammation. A number of studies have documented this fact, one of which was published by Aggarwal et al., in 2005 in the journal Blood, entitled, "Human mesenchymal stem cells modulate allogeneic immune cell response." So there is a great deal of evidence documenting the ability of mesenchymal stem cells to correct the body's resistance to insulin.
But what about the other problem inherent in diabetes, regarding the dead pancreatic beta islet cells?
Many studies have demonstrated that adult stem cells can actually become pancreatic-like stem cells. One such study, conducted by Sun et al., was published in 2007 in the Chin Med J., entitled, "Differentiation of bone marrow-derived mesenchymal stem cells from diabetic patients into insulin-producing cells in vitro." In this and other similar studies it was demonstrated that stem cells derived from bone marrow can produce insulin in vitro after a "glucose challenge", in which glucose is given to mesenchymal stem cells that were treated to become similar to pancreatic cells. The results consistently indicate that the mesenchymal stem cells are in fact becoming cells which produce insulin in response to the glucose - but this is in vitro. What about in vivo?
Another study was conducted by Lee et al., and published in 2006 in the Proceedings of the National Academies of Science, entitled, "Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/scid mice." In this study, the investigators used the streptozoacin toxin to kill the beta cells in the pancreas of mice, and when mesenchymal stem cells were administered to the mice, insulin production was shown to increase.
Another study was conducted by Tang et al., and published in the journal Diabetes, entitled, "In vivo and in vitro characterization of insulin-producing cells obtained from murine bone marrow." In this study, the investigators took stem cells from bone marrow, cultured them, and made cells that appeared to be the beta islet cells.
Specifically, the scientists took mesenchymal stem cells, cultured them in glucose, and added nicotinamide, which is an agent that is known to assist in pancreatic regeneration. The result was the formation of a group of cells that look and behave like pancreatic beta islet cells. The phenotypic expression of these cells does not include CD34 or CD45, therefore these cells are not hematopoietic, but their genotypic expression includes genes that are specific to the pancreas, such as PDX-1, insulin, glucose transporters, etc., so these cells would appear to resemble pancreatic beta islet cells in behavior and function.
The question still remains: do these cells actually produce insulin in vivo?
The pancreas of mice were destroyed by the administration of streptozoacin, after which glucose concentrations were found to rise in accord with the destruction of the beta islets. When differentiated bone marrow cells were implanted under the kidney capsule, in the treated mice there was found to be a reduction in the glucose level, but not in the control (untreated) mice. These mice were then found to be non-diabetic, but is their insulin really controlled by glucose?
A "glucose challenge" was conducted, in which glucose was administered systemically, after which blood levels of glucose were then measured. The results indicated that the levels in the "control" mice were much higher than in the mice that had been treated with the bone marrow-derived stem cells.
At the University of Alberta in Canada, Dr. Greg Korbutt directs the human islet quality control laboratory where he was part of a team which discovered pancreatic stem cells in mice. From these cells the scientists were then able to develop not only insulin-producing cells but also neurons, which suggests not only the possible existence of pancreatic stem cells in humans, but also the pluripotential nature of such cells. Dr. Korbutt was one of the original doctors who developed the Edmonton Protocol, and as he explains, "One of our limitations is the amount of human donor organs that are available for recipients" of the Edmonton Protocol. Thus this new discovery of pancreatic stem cells in mice "could be a potential way of overcoming the supply problem," although he adds that it is "very likely" that pancreatic stem cells will be found to exist in humans.
At the University of Wisconsin at Madison, researchers have constructed a new model of the stages of normal pancreatic development from studying embryonic stem cells in mice. The new model identifies the differentiation of the stem cells into pancreatic precursor cells and the various islet cell types, the precise development of which has not yet been fully elucidated. A cellular understanding of these mechanisms of development should shed some light on the precise nature of human pancreatic stem cells.
These are just some of many in vivo studies in animals showing that bone marrow stem cells can become "pancreatic-like" cells, which is a carefully chosen name since it is not known whether or not they are actually pancreatic cells but we do know that the cells produce insulin and that they are regulated by glucose, so they behave in the same manner as pancreatic cells.
Previous studies have indicated progress in the treatment of diabetes with autologous stem cells (stem cells for which the donor and recipient are the same person), and some recent research in Argentina has shown particular promise. In this technique, stem cells are administered to the patient via a catheter which is directed through the endovascular arteries directly to the pancreatic parenchyma. The catheterization is employed via an arterial route since arteries deliver oxygenated blood to the organs of the body. The catheter is inserted through a puncture in the groin under local anesthesia, and no stitches are required. More than 70 cases of diabetes have been treated according to this technique, with some of these patients having had diabetes for as long as 30 years, and with many of them exhibiting minimal response to conventional treatment. After receiving treatment by this procedure, 90% of these patients have exhibited significant progress which has even led to the complete withdrawal of original medication in these instances. No complications have been seen in any of the patients, even 9 months after treatment.
Similar techniques at other laboratories for the treatment of type II diabetes use the patient's own stem cells which are derived from the patient's own bone marrow. These bone marrow-derived stem cells are extracted from the patient's hip and are then separated and expanded in the laboratory, after which time they are injected back into the patient through an arterial catheter in the groin with the use of local anesthesia, as described above.
It is therefore now known that mesenhcymal stem cells can correct the two underlying mechanisms of diabetes, namely, the progression of insulin resistance and pancreatic cell death. Now let's consider the secondary complications, specifically, peripheral neuropathy and neuropathic pain.
Numerous case reports have documented the neurogenerative abilities of stem cells, and many animal studies have proven that stem cells can prevent neuropathic pain through a direct analgesic effect: One such study was conducted by Klass et al., and published in 2007 in the journal Anesth. Analg., entitled "Intravenous mononuclear marrow cells reverse neuropathic pain from experimental mononeuropathy." Many other clinical reports have also supported the fact that stem cells can help regenerate neurons.
In peripheral artery disease, endothelial dysfunction often results because patients with type II diabetes have low concentrations of circulating endothelial progenitor cells, which are the cells that make new endothelium. Circulating endothelial cells correlate with vascular health, and bone marrow stem cells are rich in endothelial precursor cells. The administration of bone marrow stem cells can therefore improve endothelial health by increasing vascular endothelial function.
Another major complication of type II diabetes is kidney failure. This topic was addressed in the same study cited above, conducted by Lee et al., and published in 2006 in the Proceedings of the National Academies of Science, entitled, "Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/scid mice." In this study, the mice had been induced to become diabetic through streptozoacin, and the kidneys were examined for inflammatory macrophage infiltration. As with pancreatic tissue, the stem cells were found to home-in on and repair the damaged renal tissue.
Type II diabetes is becoming an increasingly common problem throughout the world, especially in industrialized nations. Although type I diabetes is not as common as type II diabetes, clinical studies have also shown success in treating type I diabetes with adult stem cells. In a study conducted in 2007 by J.C. Voltarelli of Brazil, fourteen patients with type I diabetes were treated with autologous bone marrow stem cells that had been mobilized into the peripheral blood circulation from which they were collected. During follow-up procedures that were conducted between 7 and 36 months, all fourteen of the patients were able to discontinue insulin use.
Type II diabetes is a potentially fatal disease that is characterized by a progressive worsening of the following 3 conditions:
1/ resistance to insulin by tissue throughout the body,
2/ increased production by the pancreas of insulin,
3/ death of the pancreatic beta cells which produce insulin.
Secondary complications often include any or all of the following:
1/ peripheral neuropathy,
2/ vascular disease which may develop into heart disease and peripheral artery disease, and
3/ renal disease which may ultimately lead to kidney failure.
As such, type II diabetes could most logically be treated with a therapy that would simultaneously correct the underlying physiological mechanisms which lead to the disease, while also correcting and preventing secondary complications. Thus far, the only type of therapy which has been shown to accomplish these objectives is adult stem cell therapy.
Adult stem cells have been shown to reverse diabetes by stopping insulin resistance, inhibiting inflammation, and by regenerating the insulin-producing pancreatic beta islet cells. Additionally, these stem cells have also been shown to control the secondary complications of type II diabetes by correcting the underlying mechanisms of these abnormalities.