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A Mini-Review of Current Treatment Approaches and Gene Therapy as Potential Interventions for Diabetes Mellitus Types 1
Hoda Mohammad Dezashibi, Aliakbar Shabani
Department of Medical Biotechnology, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| Date of Submission | 10-Jun-2023 |
| Date of Acceptance | 10-Jul-2023 |
| Date of Web Publication | 31-Aug-2023 |
Correspondence Address:
Aliakbar Shabani
Education and Research Campus of University of Medical Sciences and Health Services, 5th Kilometer of Damghan Road, Semnan Province, Semnan - 3513138111
Iran
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/abr.abr_201_23
Diabetes mellitus type 1 is a chronic condition characterized by the loss or dysfunction of β-cells in the pancreas, resulting in insufficient insulin production. This mini-review examines current treatment approaches and explores the potential of gene therapy as interventions for type 1 diabetes mellitus. The discussed strategies include β-cell sensitization, β-cell regeneration from various cell sources, stem cell therapies, and the promotion of β-cell replication. The article emphasizes the importance of understanding the pathways involved in β-cell proliferation and the factors influencing their replication. Stem cell therapies, particularly using embryonic stem cells and induced pluripotent stem cells, hold promise for generating β-cells and replacing damaged or lost cells. Additionally, gene therapy offers a novel approach by manipulating genes involved in insulin production and glucose metabolism. However, ethical considerations, tumorigenic risks, and the translation of these therapies into clinical trials pose challenges. Nonetheless, the ongoing research and advancements in these areas provide hope for improved management and treatment of type 1 diabetes mellitus.
Keywords: Diabetes mellitus type 1, Gene therapy, Induced pluripotent stem cells, Insulin-secreting cells, Pancreas
How to cite this article:
Dezashibi HM, Shabani A. A Mini-Review of Current Treatment Approaches and Gene Therapy as Potential Interventions for Diabetes Mellitus Types 1. Adv Biomed Res 2023;12:219 |
How to cite this URL:
Dezashibi HM, Shabani A. A Mini-Review of Current Treatment Approaches and Gene Therapy as Potential Interventions for Diabetes Mellitus Types 1. Adv Biomed Res [serial online] 2023 [cited 2023 Sep 26];12:219. Available from: https://www.advbiores.net/text.asp?2023/12/1/219/384990 |
| Introduction | |  |
Diabetes, a metabolic disorder, is considered one of the oldest diseases known to humans. This condition is characterized by elevated levels of glucose in the bloodstream, requiring regular monitoring and effective management. Insulin, a hormone produced by pancreatic beta cells (β-cells), plays a crucial role in facilitating glucose absorption for energy production and various other bodily functions. The occurrence of diabetes arises from inadequate insulin production or reduced insulin sensitivity. Type 1 diabetes (T1DM) typically emerges when pancreatic β-cells (β-cells) are destroyed by T cell-mediated autoimmunity, leading to insulin deficiency.[1] Diabetic nephropathy, retinopathy, neuropathy, cardiovascular disease, and diabetic foot ulcers can be prevented or slowed down by early detection and management.[2]
Due to its significant socioeconomic impact on numerous nations,[3] addressing diabetes mellitus (DM) requires continuous scientific and technological progress for the identification of innovative treatment approaches.[4] Consequently, this has led to the emergence of novel therapeutic categories such as gastric inhibitory peptide (GIP) analogs, amylin analogs, and incretin mimetics. Furthermore, potential drug targets for diabetes treatment, specifically peroxisome proliferator-activated receptor (PPAR) and dipeptidyl peptidase-4 (DPP4) inhibitors, have been established.[5]
Promoting the regeneration of β-cells by means of trans-differentiation or stem cell techniques has a direct impact on improving the function and structure of these cells.[6] However, the field of gene therapy has recently emerged as a promising approach for managing diabetes, with numerous clinical studies demonstrating its safety and effectiveness in treating various complex diseases. Both viral and non-viral approaches to gene therapy have shown encouraging outcomes. For instance, gene therapy utilizing adeno-associated viral (AAV) vectors has been applied, and research indicates its potential for long-term regulation of blood glucose levels and prevention of diabetes-related complications.[7]
Overall, the purpose of this study is to provide an up-to-date, comprehensive overview of current treatment approaches for type 1 diabetes while also examining the potential of gene therapy as a novel intervention strategy. The findings of this study may contribute to further understanding the role of gene therapy in the management of type 1 diabetes and potentially pave the way for future research and therapeutic developments in this field.
Molecular mechanisms of type 1 diabetes
The development of type 1 diabetes (T1D) involves a complex interplay between genetic and environmental factors.[8] Genetic susceptibility plays a significant role in T1D pathogenesis, as evidenced by the increased risk of diabetes observed among siblings and the higher concordance rate in monozygotic twins compared to dizygotic twins.[9] Extensive research has identified over 50 susceptibility regions associated with T1D, with particular emphasis on the major histocompatibility complex (MHC) region.[9] The MHC region, located on chromosome 6p21.3, encompasses genes encoding human leukocyte antigen (HLA) proteins. HLA molecules are crucial for immune recognition of self and non-self-antigens.[9] Polymorphisms within HLA genes have been extensively studied in relation to T1D, as they influence immune responses. HLA class I (A, B, and C) and class II (DP, DQ, and DR) molecules, encoded by HLA genes, play pivotal roles in presenting antigens to CD8+ and CD4+ T cells, respectively.[10] Among the HLA genes, HLA class II genes, particularly DRB1 and DQB1, exhibit the strongest association with T1D susceptibility, contributing approximately 40–50% of the overall risk.[11] Specific combinations of alleles, genotypes, and haplotypes of class II genes have been found to be associated with T1D in various populations. For instance, the DRB10301-DQB10201 (DR3-DQ2) and DRB10401-DQB10302 (DR4-DQ8) haplotypes consistently show associations with T1D in Caucasian individuals.[12],[13] The precise mechanisms by which HLA class II genes confer susceptibility to beta cell loss in T1D are not fully elucidated. It is believed that the binding properties of peptides derived from proinsulin, insulinoma-associated antigen 2 (IA-2), glutamic acid decarboxylase (GAD), and zinc transporter 8 (ZnT8) to antigen-presenting cells play a role in this process.[14],[15] The association between HLA and latent autoimmune diabetes in adults (LADA) is not as well understood as in classic T1D. Nevertheless, studies have revealed similarities in HLA genetics between LADA and T1D, suggesting shared genetic backgrounds. Some distinctions have been noted, such as a lower frequency of the highest risk genotype DQ2/DQ8 in LADA compared to juvenile-onset T1D.[16],[17]
Alternative approaches to promote healing and provide treatment
Gene therapy
To deliver the insulin gene to different tissues such as adipocytes, pancreas, livers, and muscles, viral methods such as lentivirus, adenovirus, and AAV have been used as well as non-viral techniques such as liposomes and naked DNA.[18] Enteroendocrine K-cells in the intestines share similarities with pancreatic β-cells by producing GIP. Both cell types secrete GIP, which regulates insulin release in response to elevated blood glucose levels. Additionally, they possess comparable glucose-sensing mechanisms, shared transcription factors, and signaling pathways. This convergence highlights the interconnectedness of the gut and pancreatic endocrine systems in glucose regulation. Understanding these similarities can aid in managing metabolic disorders like type 2 diabetes. Further research may lead to innovative therapeutic strategies for improving glucose homeostasis.[19] The transplantation of K-cells has therefore failed to reverse diabetes effectively, despite attempts to manipulate them in vitro to produce and release insulin. After being induced with diabetes by streptozotocin (STZ), transgenic mice engineered to express insulin under the GIP promoter displayed normal glucose levels. This suggests that K-cells produce adequate amounts of insulin to maintain glucose homeostasis.[20] Recently, gene manipulation techniques have been introduced for managing diabetes mellitus, utilizing adeno-associated viral (AAV) vectors to achieve the co-expression of insulin and glucokinase genes in skeletal muscles. Notably, this approach has demonstrated long-term effectiveness in achieving normo-glycemia without the need for exogenous insulin.[7] AAV vectors possess favorable characteristics for gene therapy, including minimal immune response, infectivity in both dividing and dormant cells, and absence of genome integration. AAV vectors are characterized by these attributes, which make them particularly suitable for gene therapy applications. Mice with diabetes induced by STZ were given AAV vectors that contained the insulin and glucokinase genes. When these two genes are co-expressed, glucose transporter protein 4 (GLUT4) and glucokinase enzymes are translocated to the modified muscle cells, increasing glucose absorption. As a result of the expression of the glucokinase enzyme, glucose phosphorylation was alleviated and insulin production was regulated, resulting in normo-glycemia.[21]
Another approach to gene therapy for diabetes management involved the use of a humanized liver mouse model. Researchers utilized AAV serotype 2 (AAV2) to transfer the pancreatic and duodenal homeobox 1 (PDX1) gene, an enzyme that is involved in the development and maturation of pancreatic β-cells. It was confirmed that green fluorescent protein was present and the liver cells containing the PDX1 gene secreted insulin, leading to glycemic control.[22] Adenovirus-mediated transfection of hepatic cells with neurogenin 3 (Ngn3) resulted in insulin production and trans-differentiation of oval cell populations.[23],[24] Introducing neuronal differentiation 1 (NeuroD1) into the liver of mice with STZ-induced diabetes upregulated various pancreatic transcription factors without causing significant liver damage. Furthermore, NeuroD1 had a strong effect on inducing insulin expression in primary pancreatic duct cells. Researchers suggested targeting promoters in specific cell types, such as liver-type pyruvate kinase (L-PK), glucose 6-phosphatase (G6Pase), phosphoenolpyruvate carboxykinase (PEPCK), albumin, and insulin-like growth factor binding protein-1 (IGFBP-1), to enhance hepatic insulin gene therapy.[25] While liver-specific promoters showed insulin secretion, their activity was weaker compared to strong constitutive promoters like cytomegalovirus. Modifications using L-PK led to glucose responsiveness and restored normo-glycemia for a limited period[26] [Figure 1]. | Figure 1: Gene therapy approaches for diabetes management: Viral and non-viral methods for insulin gene delivery to different tissues show promise in regulating glucose homeostasis. Adeno-associated viral (AAV) vectors co-expressing insulin and glucokinase genes in cells demonstrate long-term effectiveness in achieving normo-glycemia. GLUT4: glucose transporter protein 4, Ngn3: neurogenin 3, PDX1: pancreatic and duodenal homeobox 1
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In the non-viral gene delivery method, insulin fragments were combined with plasmid DNA and administered via intravenous injection. This approach involved injecting the plasmid into the liver and muscles of rats with STZ-induced diabetes. The result of the study is that normo-glycemia has been achieved in the subjects for one week and for thirty weeks, respectively. To address the issue of short-term liver expression, the DNA transposon system was employed, enabling the integration of the gene into the host chromosome. Furthermore, co-injecting plasmid DNA containing insulin with furin significantly enhanced the production of active insulin within the muscle.[27]
In a study, a non-viral plasmid, pBudCE4.1, was engineered to carry the genes for proinsulin (PI) and pancreatic regenerating (Reg) III protein. Findings were revealed that the introduction of pReg/PI effectively ameliorated streptozotocin-induced type 1 diabetes mellitus (T1DM) by promoting the regeneration of beta cells and inducing immunological self-tolerance.[28] Additionally, the use of pVAX plasmid has been explored as another plasmid vector for gene transfer. This non-viral approach allows transient expression of target genes in both liver parenchymal and non-parenchymal cells. In a specific study, researchers successfully expressed the insulin-like growth factor 1 (IGF-1) gene using the pVAX plasmid. Notably, after receiving ten administrations, mice with normal blood glucose levels achieved prolonged therapeutic effects and did not require further treatment.[29] Another study utilized a bioreducible cationic polymer called poly-(cystamine bisacrylamide-diamino hexane) (p(CBA-DAH)) to deliver RAE-1 to pancreatic islets in their study. The treatment group receiving polyplexes containing RAE-1 demonstrated an improvement in insulitis levels.[30]
In addition, pancreatic or liver cells were transfected with the human insulin gene ex vivo and then autologous grafts were performed. Over the course of 47 weeks, this method was shown to improve insulin secretion, hyperglycemia, and diabetic complications in pigs. However, gene silencing eventually occurred, though the underlying mechanism remains unclear. Lentivirus vectors carrying the modified human insulin gene were also injected into the portal system of the livers of diabetic rats, enabling liver cells to sense glucose and respond by synthesizing, releasing, and storing human insulin[31],[32] [Figure 1].
Treating diabetes by specifically targeting and regenerating β-cells
Trans-differentiation
Drugs currently used for diabetic treatment primarily focus on enhancing the sensitivity of β-cells to produce insulin to lower blood glucose levels. However, these medications often come with unwanted side effects, prompting research into alternative treatment approaches. Bonner-Weir et al.[33] demonstrated that in cases of β-cell depletion in diabetes, the increased proliferation of remaining β-cells contributes to β-cell regeneration. In light of these findings, further investigation has been conducted into the neogenesis of insulin-producing cells from other types of cells, as observed in various injury models.[34] Recent studies have focused on inducing β-cell regeneration through the trans-differentiation of different cell types. Researchers believe in the potential of pancreatic progenitor cells in the pancreas to undergo trans-differentiation and regenerate into β-cells.[35] Among the relevant cell types for β-cell regeneration, pancreatic exocrine cells such as acinar cells and ductal epithelial cells have gained attention due to their pancreatic lineage and differentiation potential. It has been hypothesized that β-cell neogenesis from pancreatic progenitor cells can occur within the pancreatic ducts after birth. Some studies have provided evidence of β-cell generation from ductal tissue in the adult pancreas, particularly in response to injury-induced β-cell depletion resulting from duct ligation.[35] However, recent studies utilizing labeling experiments of the ductal lineage have failed to conclusively demonstrate the formation of β-cells derived from ductal cells.[21]
It is important to note that the clinical application of these findings is limited by factors such as organ shortage for transplantation and the need for immune-suppressant drugs, which have primarily been studied in animal models rather than in a human microenvironment. In addition to pancreatic progenitor cells, researchers have explored the potential of α-cells to convert into β-cells. Studies conducted using zebrafish models and β-cell ablation have shown promising results, but further research is required.[36]
Stem cells
Stem cells have been investigated as alternative sources for β-cells due to limitations in the trans-differentiation of pancreatic progenitor cells. One alternative is the use of embryonic stem cells (ESCs) obtained from human embryos.[37] However, ethical concerns arise due to their embryonic origin. Using somatic cell nucleus reprogramming, induced pluripotent stem cells (iPSCs) have been generated to overcome this limitation.[38] iPSCs share comparable characteristics with ESCs and can be generated using small molecules and RNA. They offer the advantage of patient-specific cell replacement therapy.[39] A lack of pancreatic differentiation in ESCs and iPSCs may be addressed by pancreatic progenitor cells (PPCs).[35] Mesenchymal stem cells (MSCs) have shown promise in diabetic therapy due to their immunomodulatory effects. They create a microenvironment that promotes β-cell regeneration while suppressing destructive T-Helper1 (Th1) cells.[40] However, it is preferable to use MSCs therapy in combination with other treatment approaches. Undifferentiated MSCs do not directly generate new β-cells for regeneration.[36] The media obtained from MSC culture has demonstrated therapeutic effects when injected into diabetic mice.[41] This approach avoids issues of autoimmunity and oncogenesis, as it is cell-free in nature.
Bone marrow stem cells (BMSCs) have been utilized to replace damaged β-cells but produce low levels of insulin. Adipose tissue-derived stem cells (ADSCs) offer advantages such as low immunogenicity, higher immunomodulatory properties, and a higher capacity for stem cell proliferation compared to BMSCs.[42] ADSCs can differentiate into insulin-producing cells (IPCs) and, when transplanted into the pancreas of STZ rats, have shown induction of pancreatic regeneration.[43] In diabetic rats, the transplantation of differentiated IPCs improved the morphology and function of islet cells.[44] ADSCs have also shown benefits in islet angiogenesis enhancement, reduced cell apoptosis, and improved insulin sensitivity.[43]
The ability of human placenta-derived MSCs (PD-MSCs) to produce insulin has attracted attention. After intravenous injection of PD-MSCs, glycosylated hemoglobin levels were significantly decreased and insulin and C-peptide levels were significantly increased in type 2 diabetes mellitus T2DM patients. As far as cardiac and renal function is concerned, no side effects, immune rejection, or changes have been observed.[43]
Efforts to enhance the efficiency of generating functional stem cell (SC) β-cells necessitate a comprehensive understanding of the extracellular signals governing cell fate determinations during embryonic and postnatal development. However, the complete comprehension of the cues required to fully control the differentiation of embryonic stem cells (ESCs) into all islet endocrine cell types remains elusive. Presently, SC islet clusters typically contain a significant proportion of undesired non-pancreatic endocrine cells and progenitor cells that fail to undergo terminal differentiation, resulting in a limited number of desired endocrine cells. To address this, methods such as fluorescence-activated cell sorting (FACS) and magnetic bead sorting are employed to enrich β- and α-cells and minimize the presence of undesired cells within SC islet clusters. Nonetheless, these sorting methods are accompanied by substantial cell loss, significantly reducing the overall efficiency of β-like cell production.[45]
The optimal mimicry of human islet function necessitates precise regulation of the β to non-β endocrine cell ratio within the clusters. Existing differentiation protocols primarily prioritize the generation of β-like cells, leading to fewer α- and δ-like cells. The extent to which a pure population of β-like cells or the presence of other endocrine cells is advantageous for achieving optimal β-cell function and sufficient insulin secretion remains uncertain.[46]
Although SC β-cells generated in vitro closely resemble mature human β-cells, they lack the expression of crucial maturation markers, namely UCN3, MAFA, and SIX3. Furthermore, their capacity for glucose-stimulated insulin secretion does not match that of fully mature human β-cells. The inability to fully replicate in vitro functionality can be attributed to a dearth of knowledge concerning the factors governing β-cell maturation during neonatal development in vivo.[47],[48] The impact of nutritional and metabolic changes on the β-cell niche, which play pivotal roles in in vivo maturation, remains inadequately understood and cannot be faithfully recapitulated in SC β-cell differentiation protocols. Remarkably, the expression of maturation markers becomes evident after transplantation, indicating the influence of the in vivo environment. Mature β-cells exhibit glucose-dependent insulin secretion, responding comparably to glucose and potassium, whereas fetal β-cells and SC β-cells demonstrate substantially lower insulin secretion in response to glucose. Furthermore, SC β-cells secrete insulin in response to amino acids, which typically fail to induce insulin secretion in mature β-cells. These functional disparities may reflect the role of fetal β-cells in embryonic growth, wherein continuous insulin secretion is required, as opposed to mature β-cells that primarily secrete insulin postprandially. Recent investigations have shed light on the distinctions between fetal and mature β-cells in terms of glucose metabolism, mitochondrial activity, and nutrient sensing. Inducing metabolic maturation through endocrine cell clustering or the expression of mitochondrial activity regulators facilitates insulin secretion via mitochondrial oxidative respiration, a process critical for insulin secretion in mature β-cells. These findings offer promise, as the generation of cells exhibiting heightened functionality could potentially reduce the number of transplanted cells necessary for diabetes treatment and expedite diabetes reversal.[49]
The transplantation of SC β-cells into individuals with type 1 diabetes (T1D) faces the significant challenge of immune rejection. Physical protection through the encapsulation of SC β-cells using alginate microspheres or macrodevices has exhibited promise. Macroencapsulation devices, in combination with SC progenitor cells, have demonstrated the ability to regulate blood glucose levels in immunocompromised mice. Encouragingly, modified alginate spheres containing SC β-cells, transplanted into diabetic rodents without the use of immunosuppressants, have achieved sustained blood glucose control through the production of human insulin.[50],[51]
An alternative strategy involves utilizing engineering techniques to confer immune protection. Proposed gene modifications in transplanted cells, aimed at inducing immune tolerance, include the incorporation of tolerogenic cytokines and immunomodulatory proteins such as HLA-G, PD-L1, and CTLA-4, as well as reducing HLA expression. Such modifications could enhance tolerance to β-cell antigens without adversely affecting the recipient's immune system through the administration of immunosuppressive drugs. Additionally, a complementary approach involves attenuating the T cell-specific attack on β-cells by manipulating Treg cells.[52],[53]
Improving the ability of β-cells to reproduce themselves
Promoting the replication or expansion of β-cells through self-replication is a potential future therapy for diabetes. β-cells remain inactive during infancy.[34] However, certain conditions such as obesity and pregnancy can still induce β-cell replication.[54],[55] Different species differ in their proliferative capacities, which are dependent on their age. It is possible to stimulate the regeneration of these cells by targeting the pathways that control their growth. Signaling through the ERK pathway is enhanced when specific receptors are activated. Insulin and glucose, glucagon-like peptide-1 (GLP-1), have demonstrated the ability to trigger mitogenic signaling via the PI3K/Akt/mTOR pathway. Glucose signaling also involves the calcineurin/NFAT and ERK pathways, while GLP-1 signaling stimulates cyclic adenosine monophosphate (cAMP) generation to promote β-cell proliferation.[56] Many circulating factors, including GLP-1 from intestinal cells, osteocalcin derived from osteoblasts, and thyroid hormone, are known to promote the proliferation of cell types present in the body. The MAPK and PI3K/Akt pathways play key roles in regulating β-cell proliferation. The activation of ERK1/2 through the MAPK pathway is the main mitogenic pathway that distinguishes β-cell function from metabolic regulation, as it does not play a role in insulin secretion.[57] The MAPK pathway also influences the mitogenic effects of growth factors, nutrients, and hormones. The PI3K/Akt/mTOR pathway is a significant signaling pathway responsible for transmitting signals that promote β-cell proliferation. It can be activated by insulin, GLP-1, and glucose and plays a crucial role in regulating cellular processes related to growth and proliferation in β-cells.[58]
| Conclusion | | |
In conclusion, this mini-review explores various treatment approaches and potential interventions for type 1 diabetes mellitus. The current strategies discussed include β-cell sensitization to insulin production, β-cell regeneration through different cell sources, stem cell therapies, and the promotion of β-cell replication. These approaches offer promising avenues for future diabetic therapies. The article emphasizes the importance of understanding the pathways that regulate β-cell proliferation and the factors that influence their replication. By targeting these pathways and utilizing circulating factors such as GLP-1, osteocalcin, and thyroid hormone, researchers aim to enhance β-cell regeneration and expansion. Additionally, stem cell therapies, including the use of embryonic stem cells and induced pluripotent stem cells, hold the potential for generating β-cells and replacing damaged or lost cells. Gene therapy is also highlighted as a potential intervention for type 1 diabetes mellitus. The ability to modify or introduce genes that regulate insulin production and glucose metabolism opens up new possibilities for treatment. Advances in gene therapy techniques, such as clustered regularly interspaced short palindromic repeats-CRISPR-associated protein 9 (CRISPR-Cas9), offer hope for precise genetic modifications to correct underlying genetic defects associated with diabetes. While these approaches show promise, challenges remain. The ethical considerations surrounding the use of embryonic stem cells and the tumorigenic risk associated with undifferentiated stem cells need to be addressed. Furthermore, the optimization of differentiation protocols and the translation of these therapies from animal models to human clinical trials are essential steps in their development. Overall, this mini-review provides insights into the current treatment approaches and gene therapy as potential interventions for type 1 diabetes mellitus. Continued research and advancements in these areas have the potential to revolutionize diabetes management and improve the lives of individuals living with this chronic condition.
Acknowledgment
we would like to acknowledge the individuals and institutions who generously provided resources, data, or access to research facilities. Their support has been essential in conducting our experiments. While it is not possible to mention everyone individually, we sincerely appreciate all those who have contributed to our research in various ways.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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