Stem Cells and Diabetes: Can Regenerative Medicine Replace Insulin?

Diabetes mellitus (DM) is a chronic metabolic disorder with characteristic features like destruction of β pancreatic cells which results in insufficient insulin production. Generally, decrease in insulin production leads to altered blood glucose levels. Globally, DM affects about 200 million people.

Type 1 DM occurs due to autoimmune destruction of β pancreatic cells producing insulin and type 2 DM occurs due to insulin resistance. Moreover, both the types results in inadequate insulin levels which leads to hyperglycemia.

Overview:

Currently, clinicians treat type 1 DM with insulin coupled with lifestyle modifications and oral hypoglycemic agents are the main stay for the treatment of type 2 DM. However, these therapies not only are limited in efficacy but also pose financial burden. According to some reports, even after lifelong insulin therapy, only about less than 40% of the patients are able to manage glucose levels.

Above all, pancreas transplantation is another option, but the need to take immunosupressants continuously doesn’t make it a desirable option.

Regenerative medicine therapy is a considerable option as the stem cell therapy not only regenerates the healthy cells, it also improves various functions like maintaining blood glucose levels and countering autoimmunity.

Types of stem cells producing insulin:

Bone marrow derived stem cells: many studies reports that these stem cells differentiate into insulin producing cells by Pdx-1 overexpression and transplantation of these cells improves hyperglycemia i.e. it reduces blood glucose levels.

Adipose tissue derived stem cells: adipose tissue derived stem cells first differentiate into definitive endoderm, then to pancreatic endoderm and finally to islet cells aggregate which secrete c-peptide. These cells increase c-peptide levels and reduce glucose levels.

Umbilical cord derived stem cells: these stem cells express stage-specific antigen 4 (SSEA4), octamer 4 (Oct4) and differentiate into islet cells capable of producing insulin. The islet cells produce insulin and c-peptide.

Hepatic cells: with the help of β cell transcription factors and several growth factors, hepatic cells differentiate into insulin producing cells. These cells produce insulin and prevents progression of diabetes.

How does stem cell therapy manage diabetes?

In diabetes, autologous bone marrow derived stem cells, adipose tissue derived stem cells and mesenchymal stem cells reduce requirement of insulin overtime by

1. Decreasing HbA1c levels
2. Reducing and reversing anti-pancreatic antibody formation in type 1 DM
3. Reducing inflammation and glucose levels
4. And increasing c-peptide levels.

Mesenchymal stem cells treat diabetes by various mechanisms:

1. Prevents the destruction of β cells by inhibiting proliferation of T cells.
2. Generates Treg cells (regulatory T cells) to prevent autoimmune destruction on β cells.
3. Stimulates M2 macrophages to reduce inflammation and enhance insulin sensitivity.
4. Promotes glucose uptake which reduces insulin resistance.
5. And also promotes and differentiates into insulin producing cells.

How does MSC derived cells work:

Mesenchymal stem cells stimulate β cell regeneration.

• Bone marrow derived mesenchymal stem cells enhances insulin levels whereas umbilical cord derived mesenchymal regenerates islet cells, and maintains blood glucose levels by reversing autoimmunity.
• Stem cells umbilical cord derived exosomes increase insulin sensitivity.

Exosomes and diabetes:

Type 1 DM:

• Exosomes reduce inflammatory response and autoimmunity by increasing the number of islet cells and reducing blood glucose levels.
• MSC derived exosomes prevents Th1 and Th17 cells differentiation, which reduces T cell activation. Furthermore, this inturn enhances IL-10 production which reduces inflammation of islet cells, increase insulin levels and delays progression of type 1 diabetes.

Type 2 DM:

• MSC derived exosomes has an indirect action on insulin resistance. The exosomes decrease β cell destruction, increases metabolism of glucose and enhances glycogen storage which improves insulin resistance.
• The exosomes also enhance proliferation of islet cells which increases production of insulin and decreases blood glucose.

Stem cells in managing diabetic complications:

Apart from treating diabetes, stem cell therapy also has the potential to treat and suppress diabetic complications. They are:

1. Diabetic neuropathy: the stem cells enhance nerve conduction, blood flow, improves inflammation of nerves and sensory functions.
2. Diabetic nephropathy: MSC’s reduces cytokine levels and inflammation in kidneys, improves glomerular filtration rate, decreases serum creatinine levels and presence of microalbuminuria.
3. Diabetic retinopathy: in diabetic retinopathy, the stem cells enhance retinal dysfunction, increases levels of retinal neurotrophic factor and improves retinal leakage.

Groundbreaking case:

According to the journal Cell, a 25-year-old woman with type 1 DM undergoes stem cell therapy and within 3 months of the therapy the woman starts to produce insulin and later after 1 year of treatment she did not require insulin injections.

Encapsulation technology:

It is a technology where beta cells are encapsulated around a biocompatible membrane to prevent it from the immune response while ensuring sufficient insulin secretion. Via-Cyte is a company which delivers products by PEC-Direct™ and PEC-Encap™ (VC-01™) technologies. The US FDA provided approval in the year 2014 to the company to conduct clinical trials.

PEC-Direct™: a macro device that vascularizes pancreatic progenitor cells so that they differentiate into insulin-producing cells. But the major problem with the product is that the cells that we transplant come in direct contact with the circulating cells leading to immune attack. So, the need for immunosuppressive therapy arises.

PEC-Encap™ (VC-01™): to counter the problem with the PEC-Direct™ product, PEC-Encap™ (VC-01™) product has a permeable membrane which allows vascularization and prevents the contact of transplant cells with circulating cells.

The ideal properties of an encapsulation device are:

1. Should be biocompatible
2. Should be able to provide sufficient blood supply to β cells
3. Should secrete insulin sufficiently from the device
4. Should prevent any immune rejection.

Existing conventional treatment options of diabetes:

Generally, management of DM involves lifestyle modifications like including physical activity, taking healthy diet and taking insulin and oral hypoglycemic agents. However, in conditions where the above treatment options fail, clinicians recommend pancreas transplantation.

Healthy diet: Avoid excess sugar, fats and carbohydrate intake. Instead, eat foods rich in nutrition and fiber like fruits, vegetables, nuts and grains.

Physical activity: Engage in physical activity to reduce sugar levels. Because, physical activity like exercises improves sugar utilization in the body which in turn reduces blood glucose levels.

Insulin: In type 1 DM, exogenous insulin is the preferred choice. Depending on the condition, the clinicians decide duration and dose of insulin. The types of insulin are rapid, short, intermediate and long-acting insulin.

Oral hypoglycemic agents: These agents reduce blood sugar levels in the body and stimulate the cells to produce insulin which promotes glucose uptake and reduces glucose levels in the blood. Eg: Biguanides, Sulphonylureas, α glucosidase inhibitors.

Pancreas transplantation: Generally, in conditions where patients do not respond to other therapies, doctors suggest pancreas transplant. The benefit of pancreas transplant is that the patient will further not need any insulin therapy. However, the major disadvantage with transplant is that the patient will need to take immunosuppressive therapy for lifetime.

Evidence based studies on stem cell efficacy:

To determine the efficacy of mesenchymal stem cells therapy in type 1 and type 2 diabetic patients, researchers carried out a meta-analysis. The results of the meta-analysis are that the MSC:

1. decrease HbA1c levels
2. increase c-peptide levels
3. Reduce requirement for insulin therapy.

New regenerative medicine/therapy:

In diabetic wounds, instead of regulating immune response the macrophages cause inflammation and the wounds do not heal properly. And the reactive oxygen species that the body releases due to inflammation makes the healing of wound tougher.

To counter these problems and to treat the diabetic wound, researchers from Icahn School of Medicine (Mount Sinai), developed new regenerative medicine.

Type 1 & Type 2 Diabetes Success Stories

In this Personalized regenerative medicine therapy, the researchers load lipid particles with RNA encoding IL-4. This therapy tackles dysfunctional macrophages and reduces inflammation and reactive oxygen species. In conclusion, the regenerative medicine accelerates the repair process of diabetic wound.

Conclusion

There are several treatment options for diabetes but regenerative medicine edges other therapies because of the numerous advantages. Moreover, the conventional treatment options do not cure diabetes instead it only helps in managing symptoms. Whereas the regenerative medicine with stem cells can help in restoring the destructed β cells.

The stem cells possess the ability to differentiate into insulin producing cells and maintain euglycemia state. It also overcomes the problem of long-term therapies. In conclusion, with the development of new technologies and novel approaches, regenerative medicine can revolutionize the treatment of diabetes.

FAQ’s

Q: What are the types of diabetes mellitus?

Diabetes mellitus is a chronic metabolic disorder with characteristic features like destruction of β pancreatic cells which results in insufficient insulin production. Decrease in insulin production leads to altered blood glucose levels. Type 1 diabetes occurs due to autoimmune destruction of β pancreatic cells producing insulin and type 2 diabetes occurs due to insulin resistance.

Q: How does exosome treat type 1 diabetes:

MSC derived exosomes prevents Th1 and Th17 cells differentiation, which reduces T cell activation. This in turn enhances IL-10 production which reduces inflammation of islet cells, increase insulin levels and delays progression of type 1 diabetes.

Q: How does stem cell therapy work in diabetes?

In diabetes, stem cells reduce requirement of insulin overtime by decreasing HbA1c levels, reducing and reversing anti-pancreatic antibody formation in type 1 diabetes, reducing inflammation and glucose levels and increasing c-peptide levels.

Q: What is encapsulation technology?

It is a technology where beta cells are encapsulated around a biocompatible membrane to prevent it from the immune response while ensuring sufficient insulin secretion.