Successful lifestyle modifications may underlie umbilical cord-mesenchymal stromal cell effects in type 2 diabetes mellitus

Abstract

Type 2 diabetes mellitus (T2DM) is a lifelong condition and a grave threat to human health. Innovative efforts to relieve its detrimental effects are acutely needed. The sine qua non in T2DM management is consistent adherence to a prudent lifestyle and nutrition, combined with aerobic and resistance exercise regimens, together repeatedly shown to lead to complete reversal and even long-term remission. Non-adherence to the above lifestyle adjustments condemns any treatment effort and ultimately the patient to a grim fate. It is thus imperative that every study evaluating the effects of innovative interventions in T2DM objectively compares the novel treatment modality to lifestyle modifications, preferably through double-blind controlled randomization, before claiming efficacy.

Key Words: Type 1 diabetes mellitus, Type 2 diabetes mellitus, Human umbilical cord mesenchymal stem cells, Diabetes remission, Diabetes reversal, Lifestyle modifications.

Core Tip: The role of human umbilical cord-mesenchymal stem cells in type 2 diabetes mellitus (T2DM) could at best be seen as supportive to the irreplaceable role of consistent lifestyle modifications that, at a minimum, must include nutritional and exercise interventions. Combination of newer pharmacological treatments in T2DM, such as semaglutide or tirzepatide, with cellular components is worth exploring.

TO THE EDITOR

Type 2 diabetes mellitus (T2DM) is a grave threat to human health, and until recently, was considered a lifelong and irreversible condition[1]. Diabetes mellitus (DM) currently afflicts over 500 million individuals, and this number is projected to rise to nearly 800 million by 2045[1]. T2DM, which affects over 90% of diabetic patients, is caused by a complex interplay of genetics and lifestyle that leads to metabolic perturbations, insulin resistance (IR), loss of pancreatic β-cell identity and β-cell dedifferentiation, to ultimately failure of insulin-secreting pancreatic β-cells[2,3]. If left uncontrolled, T2DM results in a myriad of severe health complications and significantly contributes to the premature demise of the diabetic patient[3]. The syndemic of coronavirus disease 2019 and T2DM has horribly confirmed the latter’s dismal effect on lethality[4]. Innovative, preventative, mitigatory, and therapeutic interventions are acutely needed, and cell-based therapies appear promising in the treatment of both types of diabetes[5]. In this context, Lian et al[6] present a small cohort of 16 T2DM patients that received intravenous infusions of allogeneic human umbilical cord-mesenchymal stromal cells (hUC-MSC) at a dose of 1×10⁶ cells/kg per week for 3 consecutive weeks and were followed up for 12 wk. They conclude that allogeneic hUC-MSC can improve glycemia, restore islet β-cell function, and reduce the dosage of hypoglycemic agents without serious adverse events[6].

We would like to offer additional explanations to their conclusions. In preparation for the hUC-MSC intervention, Lian et al[6] submitted the enrolled participants to a 16-wk-long wash-in period with a daily diet not exceeding 25-30 kcal/kg body weight, and an exercise routine, composed of walking or similar exercise, for 30 min 3 times per week. These recommendations were monitored at their diabetic outpatient clinic and maintained throughout the 16-wk wash-in and the 12-wk follow-up periods. It also appears that, throughout the initial 16-wk period, fasting plasma glucose and 2-h postprandial plasma glucose were tested 7 times per week, consequently imposing an additional layer of accountability. Peculiarly, no clinical characteristics of the cohort, such as body weight (BW), body mass index (BMI), glycated hemoglobin (HbA1c), and C-peptide, at the start and at the end of the 16-wk wash-in intervention period, are given. Without these parameters, it is impossible to evaluate the effects of the ensuing three allogeneic hUC-MSC infusions in the 3 consecutive weeks, and premature to claim efficacy, particularly while the plausibly successful lifestyle modification intervention continued in parallel for another 12 wk to a total of at least 28 wk! The proper way to conduct this study would have been in a randomized controlled trial (RCT) setting, with a T2DM patient group with lifestyle modifications alone as the comparator. In our opinion, and in view of the mean duration of the cohort’s diabetes (10.06 ± 5.74 years), and HbA1c (8.01 ± 0.63) values, the stringent dietary and exercise interventions during the 16-wk wash-in period, per se, could restore near-normal pancreatic function in several of the participants[2,7,8]. There are currently ample data through the Diabetes Remission Clinical Trials (DiRECT) supporting the notion that weight loss through very low energy diets can successfully and sustainably reverse T2DM in any ethnic population[2,8,9]. Indeed, an impressive 61% remission rate at 12 mo and an average weight loss of over 10 kg achieved at 1 year in the DiRECT study are utterly convincing[10]. The DiRECT diet entails consumption of not over 853 calories a day, mainly from soups or shakes, for up to 5 mo[9]. As patient BW in the current study[6] is not given, it is impossible to comment on the total caloric energy of the diets Lian et al[6] offered their patients during the 16-wk-long wash-in period[6]. Mechanistically, reducing intra-organ fat content (liver and pancreas) through weight loss-inducing low-calorie diets is able to reinstate a lost pancreatic β-cell phenotype, especially with T2DM durations of less than 11 yr[2,11,12]. It is thus highly plausible that the improvements noted in Lian et al[6] represent the action of a 28-wk lifestyle modification intervention.

Cell-based treatment modalities do indeed have a place in the treatment armamentarium against DM. Numerous proof of concept studies demonstrating efficacy of cell-based therapies in DM have instilled hope in addressing the intricate pathophysiology of both type 1 (T1) and T2DM[13,14]. Autologous hematopoietic stem cell (AHSC) bone marrow (BM) transplantation (AHSC-BMT) can lead to complete and durable remission in patients with new-onset T1DM[15-18]. Moreover, confirming earlier studies, early autologous MSC transplantation in newly-diagnosed T1DM children is reported as a promising, safe, and effective treatment, significantly improving HbA1c and C-peptide levels and shifting pro-inflammatory cytokines to anti-inflammatory cytokines, ultimately mitigating hypoglycemic episodes[19,20]. In T2DM, Bhansali et al[21,22] showed that autologous BM-MSCs (BM-AMSCs) and autologous BM-mononuclear cells (BM-AMNCs) result in sustained reduction in insulin doses, with improvement in insulin sensitivity with MSCs and increase in C-peptide response with MNCs[21-23]. Similarly, Nguyen et al[24] recently showed short-term therapeutic effects with autologous administration of BM-MSCs in T2DM patients with T2DM duration less than 10 years and no obesity. Evidently, the best cell-based therapeutic outcomes are achieved by transplantation of BM-AHSCs for T1DM and BM-AMNCs along with BM-AMSCs for T2DM. Moreover, targeted rather than intravenous infusions for autologous MSC sources appear to be more effective[14]. The use of allogeneic sources, such as cadaveric pancreas and β-cell transplantation in T1DM, however, has led to variable results due to donor tissue scarcity and complications related to immunosuppression and immune rejection[5]. Allogenic MSCs have also been employed in the treatment of T2DM; Zang et al[25] showed modest short-term response in 20% vs 4.55% in the placebo arm, measured as percentage of patients reaching HbA1c levels of < 7.0% at 48 wk, clearly lower than the over 60% remission rates in the DiRECT studies[9]. Compared with allogeneic MSCs, autologous MSCs are safer, more ethical, more homogenous, have better secretome and epigenome synchronicity with the recipient, are not prone to immune rejection, and are without unknown potential candidate disease genes[26]. Allogeneic sources may elicit complications, such as pulmonary micro-embolism and other coagulation disorders, especially with increasing production passage (often seen in industrially-produced high passage allogeneic MSCs) that increase MSC size and predispose to microthrombus formation[13,27].

Human studies indicate no significant β-cell neogenesis in adults, thus any improvements in T2DM using lifestyle modifications and/or stem cell-based treatment modalities are not due to a de novo increase in β-cell mass[11]. In fact, Lian et al[6] themselves also indicate that de novo β-cell proliferation is not considered to be the reason for their observed improvements[6]. Instead, MSC paracrine effects on insulin sensitivity, intrahepatic/pancreatic lipid accumulation, relief of oxidative stress, and reduction of systemic inflammation might represent mechanisms by which MSCs may ameliorate T2DM[13]. Evidence shows that infusion of MSCs activates protein kinase B and adenosine monophosphate-activated protein kinase signaling pathways. MSCs also inhibit nucleotide oligomerization domain-like receptor protein 3 inflammasome formation, subsequently enhancing the function of insulin receptor substrate 1 and glucose transporter-4 (GLUT4), both crucial for modulation of glucose uptake and IR in hepatic cells[13]. Importantly, these mechanisms (and many more) described in MSC infusions are robustly stimulated through consistent aerobic and resistance exercise regimens, that, in combination with nutritional modifications, can lead to T2DM reversal and remission[4,28-30].

In general, despite the initial enthusiasm and reports of success, MSCs from diverse sources have shown underwhelming and mostly short-term therapeutic results in controlled human clinical trials, a far cry from the remission/reversal results of the DiRECT studies[2,9,10,13,31]. Most allogeneic MSC studies are performed in patients with marginally abnormal BMI and HbA1c, and include diverse cell types, sources, passage numbers, and mode of administration. These are several of the issues that make it impossible to evaluate efficacy such studies. The above issues need to be resolved via rigorous RCTs before making further claims of efficacy[13]. Moreover, MSC pharmacokinetics, which are intimately related to the mode of administration, need to be clarified as they are with common pharmaceutical drugs[13]. Finally, instilling unrealistic hopes that MSCs can replace a prudent lifestyle with a regular exercise regimen and mindful nutritional habits, is another perilous layman conclusion.

Weight loss and DM duration are the two most important parameters influencing T2DM reversal/remission and the probability of success of cell-based interventions[8,24,32]. There are no human studies showing efficacy of MSCs in weight loss but preconditioning with metformin or in combination with liraglutide, a glucagon-like peptide-1 (GLP-1) agonist, leads to improvements in T2DM[13,33]. The potential synergism between cell-based therapies and the newer, more effective pharmacological weight loss treatments in T2DM is worth exploring. Examples of such drugs include GLP-1 agonists (e.g., semaglutide), or tirzepatide, a dual agonist of glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptors[34,35]. In view of the exceptional improvements in the key components related to diabetes pathophysiology (e.g., β-cell function, insulin sensitivity, glucagon secretion with GIP/GLP-1 agonists), it is highly improbable that MSC-based therapies alone will have a meaningful prospect of success in T2DM cure[35]. The use of teplizumab in delaying T1DM onset while preparing for an AHSC-BMT could plausibly lead to T1DM remission[15-18,36].

ACKNOWLEDGEMENTS

We are thankful to James TA, Marshall for his invaluable editorial assistance.