How stem cells may offer a new therapeutic approach to treating type 2 diabetes mellitus (T2DM)
The use of stem cells in treating diseases and disorders has become the most idealised solution for many due to its regenerative ability, as well as its capabilities in differentiating into a variety of different cell types (Chagastelles & Nardi 2011). Stem cells can provide more long-term treatment for many diseases and disorders and thus, can revolutionise the way patients receive treatment. In general, diabetes mellitus is a commonplace disorder of the feedback mechanisms controlling blood glucose levels. Normally, there is a tight control of plasma glucose levels to maintain this within a narrow range despite oscillations of glucose intake (Kahn et al. 2014). However, in cases of type 2 diabetes mellitus (T2DM), there is a combined effect of insulin resistance and -cell dysfunction (pancreatic cells which are insulin producing), and makes T2DM a dual defect disease. (Leahy 2005). Therefore, there is increasing interest in using stem cells in the therapy of diabetes, as stem cells show the potential of differentiating into insulin-producing cells (IPCs) as well providing additional therapeutic effects (Zang & Hao et al. 2017).
Pathophysiology and pathogenesis of type II diabetes mellitus.
-cell dysfunction and insulin resistance work alongside each other in the pathogenesis of T2DM (Kahn et al. 2014). Firstly, -cell dysfunction occurs early on in the onset of type II diabetes, where the patient is transitioning from having normal glucose tolerance to insufficient glucose tolerance (IGT), and is described as the "key pathogenic event" which leads to the further progression of the disorder (Leahy 2005). In normal glucose homeostasis, -cells (of the pancreatic islets) secrete insulin to target tissues to regulate increased glucose levels, and does so by the coupling of insulin secretion with changes in intracellular ATP levels. The release of insulin is important in mediating glucose levels in the blood, as well as reducing hepatic glucose production and increasing glucose uptake by the skeletal muscle and adipose tissue (Sesti 2006). When glucose levels increase, most of the glucose undergoes oxidative phosphorylation and thus, increases intracellular ATP levels (Cantley & Ashcroft 2015). This triggers insulin secretion by the -cells in two distinct phases called the ‘first phase’ where insulin release lasts for 5 – 10 minutes, and the ‘second phase’ which is sustained until normal glucose is reached and hyperglycaemia no longer present (Leahy 2005). This homeostatic process is vital in maintaining euglycaemia, and in cases of type II diabetes, becomes compromised as the patient shows a decrease in -cell mass and a loss of the ‘first phase’ function which is characteristic to T2DM. This decrease in -cell mass is due to apoptosis causing cell death; this is thought to be worsened by insulin resistance increasing the demand for insulin secretion which, as a consequence, leads to the progression of -cell dysfunction (Cernea & Dobreanu 2013). As a result, action of facilitative glucose transporters (such as GLUT4 which acts primarily on adipose tissue and skeletal muscle) and the homeostasis of blood glucose levels becomes compromised (Figure 1) (Guillausseau et al. 2008).
Figure 1: comparisons between normal glucose homeostasis and affected glucose homeostasis in type 2 diabetes. In the normal regulation of blood glucose levels (a), -cells are important in the detection of heightened glucose levels and in the subsequent mechanisms of glucose transporter action, increased ATP levels from glucose glycolysis and opening of voltage dependent Ca+ levels which triggers biphasic insulin release (Röder et al. 2016). In cases of type 2 diabetes (b), the decrease in -cell mass and function causes compromised glucose transporter expression and glucose stimulated insulin release, so that rather than blood glucose levels being regulated back to normal, hyperglycaemia occurs (Guillausseau et al. 2008), due to the resistance of primary target tissues to the insulin-mediated response and hepatic glucose production not being halted (Sesti 2006).
It is evident how IPCs such as -cells play a vital role in the regulation of blood glucose levels due to their role in sensing an increase in blood glucose levels, and acting upon this change. The release of insulin to reduce these increased levels is key; however, the sensitivity of target tissues to the effect of insulin in lowering glucose levels is also of importance for the normal functioning of the insulin-mediated response (Leahy 2005). Therefore, in T2DM, sufferers are unable to make proper use of insulin which leads to increased insulin secretion – this is not efficient as primary target tissues (such as skeletal muscle, adipose tissue, liver and cardiac muscle) have become resistant to insulin and glucose uptake by these tissues is not adequate (Sesti 2006), and as T2DM progresses, -cell function and mass becomes reduced significantly.
Mesenchymal stem cells (MSCs) and their potential for the treatment of type 2 diabetes mellitus (T2DM)
Existing treatment for T2DM is based on oral anti-diabetic drugs, but T2DM progresses to cause further -cell degeneration and insulin resistance, which could potentially go on to cause kidney failure and blindness. Albeit helpful for controlling blood glucose levels in T2DM patients, stem cells provide the potential for improved treatment as they have the ability to promote the regeneration of insulin producing cells (IPCs) in patients with type 2 diabetes and help improve insulin resistance simultaneously (Zang & Hao et al. 2017). In particular, mesenchymal stem cells (MSCs) are of particular interest due to not only their multipotent abilities to regenerate pancreatic -cells (Shen et al. 2013), but also their potential ability to prevent the apoptosis of existing -cells and to have positive paracrine effects on insulin resistance (Zang & Hao et al. 2017). The effects of MSCs on regenerating -cells has been found to have positive therapeutic effects in lowering glucose levels in mice with streptozotocin (STZ) induced T2DM. MSCs were infused in two phases: the ‘early phase’ (7 days after initial SZN administration) and the ‘late phase’ (21 days after initial SZN administration). This shows how MSCs can significantly improve hyperglycaemia following MSC infusion in T2DM mice, as blood glucose levels decreased by 34.6% following first infusion, and by 25% following the second infusion (Figure 2).
Figure 2: (Si et al. 2012) Lowered blood glucose levels following ‘early phase’ (7 days) MSC infusion, as well as in second infusion at 42 days. After initial infusion of MSCs into mice with T2DM, blood glucose decreased significantly with this effect lasting for a period of four weeks before glucose levels increased once again. After this four-week period, MSCs were infused and the decrease in blood glucose levels seen once again.
Research by Ho et al. (2012) using mice with SZN induced T2DM also looked into the use of MSCs transplanted into these subjects intravenously: the study looks into overcoming the issue of hyperglycaemia reoccurring a short period following MSC transplantation, and shows how multiple MSC transplantations performed every 2 weeks stabilised blood glucose levels and restored its homeostasis after 3 doses by reducing oxidative stress (Figure 3). Moreover, whilst Si et al.’s (2012) research looked into the differentiation of MSCs into -cells, Ho et al. (2012) looked into how MSCs showed potential in differentiating into insulin-producing cells (IPCs) within the liver with 51% of transplanted MSCs successfully differentiating into IPCs in of the recipient STZ injected mice.
Figure 3: (Ho et al. 2012) Blood sugar levels become stabilised after 3 doses of MSCs transplanted bi-weekly. Following initial STZ injection and thus, initiation of T2DM, MSCs were transplanted every two weeks for a total period of 16 weeks. In just after 3 bi-weekly doses, blood sugar levels showed a gradual decrease to levels close to that of the non-T2DM control.
MSCs are also known to have anti-inflammatory effects both in vivo and in vitro and has shown potential in improving insulin resistance in a model involving adipose tissue derived MSCs. In this model, MSCs showed improvements in glucose uptake via the glucose transporter GLUT4, as well restoring insulin in insulin resistant cells (Zang et al. 2017). This provides a positive outlook towards the effects of MSCs in ameliorating the issue of insulin resistance in cases of T2DM, although more research in this area is required.
Conclusions
In both Ho et al. and Si et al.’s studies, comparisons of STZ + MSC mice with non-STZ controls and STZ only mice showed similar results in terms of hyperglycaemia persisting and STZ + MSC mice showing a decrease in blood glucose levels following infusion of MSC. It is significant how in Ho et al.’s study, glucose levels reduced to a level close to that in the non-STZ mice after a 16-week period of bi-weekly MSC transplantations as this suggests the ability of MSCs in regulating blood glucose levels with longer term effects as to prevent re-occurring hyperglycaemia. MSCs therefore show potential in differentiating into insulin-producing cells for the improvement of glucose homeostasis otherwise compromised by T2DM. MSCs also show the potential of ameliorating the combined issue of insulin resistance in research models proposed by Zang et al. (2017); however, this area of research requires further study. Nevertheless, the ability of MSCs to differentiate into pancreatic -cells (Ho et al. 2012) which are important in the glucose homeostasis and triggering an insulin response, as well as their potential in differentiating into liver IPCs (Si et al. 2012) and stabilising hyperglycaemia shows great potential for a more long-term T2DM treatment. This alone provides a positive future for the use of stem cells in T2DM treatment.