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31. Current Advances in the Management of Diabetes Mellitus
Guided by – Osmonova Gulnaaz Zh.,Department of Child Diseases, Osh, Kyrgyzstan
Sekhsaria Manas, Ghuraiya Uditya Raj Singh, Kalaivanan Nevelan, Sameer Saifi
Osh State University International Medical Faculty,Osh, Kyrgyzstan
Abstract: It is a chronic metabolic disease that affects children and is typified by ongoing hyperglycemia brought on by either reduced insulin action or secretion, or both. While type 2 diabetes mellitus (T2DM) is being diagnosed more frequently as a result of increased obesity rates, type 1 diabetes mellitus (T1DM), an autoimmune loss of pancreatic β-cells, makes up the majority of cases in children. Polyuria, polydipsia, weight loss, and diabetic ketoacidosis (DKA) are common symptoms of the condition.
Diabetes mellitus (DM) is a growing epidemic that is causing a significant socioeconomic burden on nations all over the world. Since traditional treatment approaches have not fully addressed the underlying causes of the disease and are fraught with serious side effects, new treatment options for the management of diabetes mellitus are developing quickly. Thus, this narrative review explores different treatment regimens in DM management and the associated challenges. A literature search for pub - lished articles on recent advances in DM management was completed with search engines including Web of Science, Pubmed /Medline, Scopus, using keywords such as DM, management of DM, and gene therapy.
According to our research, significant advancements have been made in the treatment of diabetes mellitus, with encouraging outcomes when employing various treatment approaches such as gene therapy, nanotechnology, stem cells, medical nutrition therapy, and lifestyle change. Numerous obstacles have been faced when employing these methods, such as optimizing them to guarantee the best possible glycemic, lipid, and blood pressure control to reduce complications, enhancing patient adherence to pharmacologic and lifestyle interventions, safety, ethical concerns, and an efficient delivery system, among other things. In conclusion, an efficient and secure clinical treatment strategy depends on lifestyle management in addition to pharmaceutical treatments and the optimization of these strategies.
Keywords: diabetes mellitus; nanotechnology; stem cell; gene therapy; glycemic.
Introduction
One of the most prevalent chronic endocrine conditions in children and adolescents, diabetes mellitus (DM) has a substantial impact on long-term health, growth, and development. Chronic hyperglycemia brought on by deficiencies in insulin production, action, or both is what is known as this metabolic condition. Type 2 diabetes mellitus (T2DM) is becoming a major public health concern among adolescents, primarily because of rising rates of childhood obesity, sedentary lifestyles, and genetic predispositions. In contrast, type 1 diabetes mellitus (T1DM) still accounts for nearly 90–95% of cases in children.
Children's diabetes frequently develops suddenly, and many of them first exhibit the potentially fatal complication of diabetic ketoacidosis (DKA). Diabetes can cause significant morbidity and death if it is not identified early and treated promptly. Inadequate management of hyperglycemia over time increases the risk of microvascular and macrovascular problems, which start in childhood but become more severe in maturity.
Diabetes mellitus (DM) is a chronic, complex, and non-transmissible endocrine disease that is expanding quickly and has presented therapeutic difficulties all over the world. It is frequently associated with risks related to patients' complex metabolic development. It is characterized by high blood levels of lipids and glucose as well as oxidative stress, which leads to long-term problems with many body organs, primarily the kidneys, eyes, nerves, and blood vessels.
According to the World Health Organization (WHO), diabetes mellitus is a disease that can cause severe illness and even death. Approximately 387 million people worldwide suffer with this illness, and by 2040, that number is expected to rise to over 640 million.
More than 90 percent of the 425 million people with diabetes mellitus are adults, and 352 million of them have impaired glucose tolerance (IGT), according to a 2017 report by the International Diabetes Federation (IDF). Hyperglycemia is not the sole symptom of type II diabetes mellitus (T2DM); the condition also includes a number of consequences, including kidney failure, blindness, heart attacks, strokes, and lower limb amputations. Epidemiological research has provided growing evidence that type 2 diabetes is a condition with several origins linked to both polygenic and various environmental factors. T2DM is thus too complicated to cure due to genetic polymorphism and other numerous risk factors.
Insulin-like drug injections and oral hypoglycemic medication are currently the primary treatment approaches for type 2 diabetes. Though they have several negative effects, these medications are essential in the treatment of type 2 diabetes. Since its creation, insulin has been the mainstay of treatment for uncontrolled insulin-deficient diabetes mellitus. It is true that the injection of exogenous insulin is essential for survival because of the acute shortage of beta cells. Even with the advancements in our understanding of the causes, consequences, and persistence of diabetes mellitus, as well as the development of insulin and its analogs, maintaining strict glycemic control without adverse side effects like low blood glucose and weight gain continues to present formidable challenges. Therefore, this emphasizes even more how important it is to use methods other than insulin.
As a result, this narrative review explores many alternative treatment regimens, such as gene therapy, medical
nutrition therapy, nanotechnology, stem cell technology, lifestyle change, and the difficulties involved with these
approaches, for the treatment of two types of diabetes mellitus.
Methods
Several search engines, including Scopus, Google Scholar, Pubmed/Medline, and the Web of Science databases, were used in the literature search for this narrative review in order to find published publications on recent developments in the management of DM. Diabetes mellitus, hyperglycemia, diabetes management, type 2 diabetes, nanotechnology in diabetes, gene therapy in diabetes management, current treatment, etc. are some of the keywords and subject titles used. To choose which articles were suitable for full-text reading, the search results' titles and abstracts were meticulously vetted. After retrieving the eligible articles, three authors independently conducted full-text screening to choose which research would be included in the final analysis. Included were original research and review articles written in English and published between 1993 and 2022.
Risk Factors of Diabetes
Diabetes is linked to a number of risk factors. The development of diabetes is considerably accelerated by these risk factors. Age, weight, a family history of diabetes, smoking, and race/ethnicity are a few of these. T2DM is a disorder that affects adults, whereas T1DM is primarily encountered in young people. Age-related insulin secretion deficiencies and increasing insulin resistance brought on by changes in body composition enhance the risk of type 2 diabetes. Disability is a disorder that is closely linked to diabetes and an increase in body weight that results in obesity. This is because rising body weight causes insulin resistance to rise.
The FDA estimates that smokers have a 30–40% higher risk of developing type 2 diabetes than nonsmokers. Additionally, smoking can lead to an increase in insulin resistance, which increases the amount of insulin needed by patients to control their blood sugar levels. Diabetes is inherited. It is recommended that those with the family history follow lifestyle choices that lower their chance of developing diabetes.
Management of Diabetes
The treatment of diabetes involves a number of contemporary strategies. However, reaching any goals stated for DM management depends on early diagnosis. Every patient receives care with the goal of reaching a specific result. These goals are established on the first day of the clinic appointment to provide a customized approach to diabetes care.
Internet Intervention for Lifestyle Modification in Diabetes
A key component of managing diabetes is changing one's lifestyle. Both individuals with pre-diabetes and those with diabetes are advised to take it. Among the suggested lifestyle changes are healthier meals, more physical activity, and a less sedentary lifestyle. The patient's condition may influence the appropriate workout. Exercise aids in lowering plasma glucose levels.
Diabetic people should restrict foods high in fat and sugar, prefer lean meats and nonfat dairy products, and consume a lot of fruits, vegetables, and whole grains for a healthy diet. Reducing alcohol consumption and quitting smoking are further lifestyle modifications. Usually, each person's lifestyle adjustments are unique.
Although the aforementioned techniques aid in the efficient treatment of diabetes, it may be difficult to communicate with or remind the subjects to perform them on a regular basis. Programs that are web-based or internet-based have been implemented to increase compliance with the lifestyle modifications.
These online techniques offer a practical way to support diabetic self-management.
Internet Intervention Types
1. Web portals and mobile applications
• Applications for monitoring physical activity, food, and carbohydrate intake.
• Online educational resources for families and kids.
2. Remote monitoring and telemedicine
• Online consultations with diabetes educators, nutritionists, and endocrinologists.
• Using cloud-based technologies to integrate data from continuous glucose monitoring (CGM).
3. Gamification & Interactive Learning: Online exercises and games that promote a balanced diet and regular exercise.
• Reward schemes to boost adherence and motivation.
4. Peer Support & Social Media: Online support groups for parents and kids.
• Exchanging experiences to boost interaction and lessen loneliness.
Medical Nutrition Therapy in Diabetes
A "nutrition-based treatment provided by a registered dietitian nutritionist" is known as medical nutrition therapy (MNT). In order to help manage diabetes mellitus, it includes dietary diagnosis as well as therapeutic and expert counseling services. MNT is essential to managing and educating people with diabetes. International collaborative groups have attempted to reform and offer courses for adverse nutritional transition in their recommendations on MNT for diabetes treatment. For example, because of its effect on glycaemia, MNT has been used to treat GDM, where carbohydrate (CHO) is the primary causal agent. Pregnant women need at least 175 g of CHO daily, according to the Institute of Medicine, and low-CHO diets that have been used historically to treat GDM have shown promise.
First and foremost, MNT maintains euglycemia by ensuring enough weight gain throughout pregnancy and fetal growth while avoiding metabolic acidosis and ketogenesis. However, among other things, MNT has not yet determined the ideal diet for DM in terms of energy content and the distribution, quality, and quantity of macronutrients [37]. According to reports, when the carbohydrate intake of GDM patients is specifically considered, their nutritional needs are the same for all pregnant instances. Although the evidence is still limited, a low-glycemic index diet has been suggested to be more effective in the treatment of GDM than the conventional intervention of carbohydrate restriction [37]. Limiting calories is essential for managing overweight or obesity.
Indications show that MNT may be a potent, easily avail- able, and cheap therapeutic technique and could be an essential tool for DM prevention and management [35]. Reports have charged MNT with the design of signature diet strategies that will be suitable medically as well as patient focused. By this, it is hoped that practicing diabetologists and registered dieticians (RDs) will partner to furnish nutritional guide- lines based on evidence for use by MNT for the prevention and management of DM and related comorbid conditions.
Gene Therapy and Diabetes Mellitus
The process of restoring the symptoms of a disease caused by a faulty gene by introducing the external normal gene is known as gene therapy. Its benefit is that any condition can be cured with a single treatment, and gene therapy is currently creating new therapeutic choices across various medical specialties. Currently, gene manipulation includes not only adding a gene but also editing and modifying it. The goal of this strategy is to correct faulty genes that have been identified as the cause of any disease and to effectively stop the disease's onset or progression. Three main intervention techniques are used in gene therapy: (i) introducing a new gene into the body; (ii) replacing the defective gene with a functional one; and (iii) turning off the malfunctioning genes that cause the disease. Somatic gene therapy and germline gene therapy are two further subcategories of gene therapy. Germline gene therapy targets the reproductive cells, whereas somatic gene therapy primarily targets the somatic cells, also known as the sick cells. In succeeding generations, germline treatment prevents the disease from developing. Because gene therapies have the potential to treat a wide range of illnesses, such as diabetes mellitus, autoimmune disorders, heart problems, and malignancies, among others, they are being used as trends in emerging treatments.
T1DM is an autoimmune ailment marked by T-cell-orchestrated self-damage of the islet beta cells responsible for the secretion of insulin. Its management is problematic and complex, particularly using conventional drugs. Thus, gene therapy is partly an emerging promising therapeutic alternative in its treatment . The etiology of T1DM is multi- factorial involving both environmental and genetic factors akin to any other autoimmune disease. In the recent past, researchers have favorably pointed out many genes accountable for the evolution of T1DM . Thus, alteration or grappling with these genes employing gene therapy techniques will probably foster better comprehensible management of the ailment or even cure T1DM.
Although T1DM is the primary focus of gene therapy for diabetes mellitus, numerous genes have been considered as a potential treatment for T2DM due to the disease's strong genetic predisposition [48]. Through genetic linkage investigations, over 75 distinct genetic loci have been found for type 2 diabetes, and other potential treatment targets have also been identified [46]. Unlike the frequency and development of diseases with limited impacts, genetic loci may have a significant influence on treatment responsiveness [49]. There are numerous genetic loci with potential for gene therapy for type 2 diabetes. An excellent example is nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3). Inhibition of NLRP3 reduces inflammation, protects against pancreatic b-cell apoptosis, and stops mice from developing type 2 diabetes.
Stem Cell Therapy in Diabetes
The traditional methods of treating diabetes mellitus have many negative consequences and don't address the root causes of the condition. Therefore, there is a search for an acceptable alternative treatment plan. The pancreatic or islet-cell transplantation is the basis for the cellular-based treatment approach now used in the management of diabetes mellitus in order to restore the beta cells' ability to secrete insulin. The scarcity of donor organs limits this strategy. These issues prompt research into the potential use of stem cells to create beta cells. Stem cells' unique capacity for reconstruction may make them a valuable tool for the treatment of diabetes mellitus.
Development of replenishable islets source using stem cells might avert the recent supply/demand problems in the transplantation of islet and furnish DM subjects with a prolonged source of beta cells for insulin secretion. Hence, in the management of DM, stem cell investigation has become a promising approach.
The goal of stem cell DM treatment is to use pluripotent or multipotent stem cells to replace damaged or dysfunctional pancreatic cells. The ability of several types of stem cells, such as induced pluripotent stem cells (iPSCs), embryonic stem cells (ESCs), and adult stem cells, to generate surrogate beta cells or restore the physiologic function of the beta cell has been utilized in this technique in a variety of ways.
The development of stem cells from several tissue sources, including adipose tissue, skin, bone marrow, umbilical cord blood, periosteum, and dental pulp, has been made easier by technological advancements.
The pancreas is typically the first organ of choice when looking for promising stem cells. Studies with animal models have revealed that a modest quantity of pancreatic tissue when made available could restore back the ideal pancreatic beta-cell mass. This is a result of the pancreatic duct's differentiated beta cells going through dedifferentiation and replication, which creates pluripotent cells that produce more beta cells. According to further research, it may be possible to create these ductal cell populations in vitro and instruct them to form clusters that synthesize insulin.
Furthermore, mesenchymal stem cells (MSCs) and hemopoietic adult stem cells (HSCs) have the capacity to transdifferentiate into a wide variety of cell lineages, including those of the liver, lung, brain, and gastrointestinal tract. To increase the amount of beta cells in T1DM, a different team of researchers experimented with the multipotent differentiation of hemopoietic progenitors. According to a paper, mouse bone marrow underwent ex vivo differentiation into functional beta cells. Similarly, research employing the mouse model suggested that the pancreas could be able to target bone marrow cells and reduce increased blood glucose levels. An autologous HSC trial showed improvement in both T1DM and T2DM.
Drugs Recently Introduced
Tirzepatide: The FDA recently approved the medication, which is marketed under the name Mounjaro, to treat type 2 diabetes. Tirzepatide is an injectable that is administered subcutaneously once a week and targets hormone receptors that are essential for glucose metabolism. These hormones are glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). GIP enhances insulin release during hyperglycemia but also stimulates glucagon release during hypoglycemia, whereas GLP-1 lowers blood glucose through a number of mechanisms, including promoting insulin secretion and inhibiting glucagon release during hyperglycemia.
Tirzepatide extends the actions of its receptors by acting as an agonist, which leads to blood glucose regulation. When used alone or in conjunction with other antidiabetic medications, tirzepatide's effectiveness was demonstrated versus a placebo, semaglutide, a GLP-1 receptor agonist, and two long-acting insulin analogs. As monotherapy and combination therapy, it reduced the HbA1c by 11.6% and 1.5%, respectively, compared to the placebo. At the maximum dosage of 15 mg, it reduced the HbA1c by 0.5% more than semaglutide, 0.9% more than insulin degludec, and 1.0% more than insulin glargine when compared to other antidiabetic medications [64]. Due to its effectiveness and once-weekly dosage, Tirzepatide offers a desirable paradigm shift in the treatment of type 2 diabetes.
Discussion of Major Findings
Diabetes mellitus is a multifactorial, progressive, and intricate metabolic disease that requires increasingly sophisticated therapies over time. Researchers from all over the world have been hard at work discovering and creating new medications to treat diabetes. Research on the etiology and treatment of type 1 diabetes has advanced significantly. There is growing evidence that the long-term prognosis of type 1 diabetes has significantly improved when contemporary insulin therapy is combined with glucose self-monitoring, which includes blood pressure and cholesterol monitoring. Regular exercise and a healthier diet may improve the quality of life for diabetic patients, according to the research. However, if diet and exercise are inadequate, drugs may assist diabetics control their blood glucose levels. Additionally, implantation of cells that produce insulin may provide the baseline glucose level necessary for sustaining.
The development of safe, effective, and particular gene delivery vectors and/or a cell engineering technique, in which the stem cell appears to play a significant role, could help realize the full promise of the gene therapy technology. Therefore, the development of a safe and effective vector to enable diabetic gene therapy for clinical trials requires the design of a feedback system that is dependable, sensitive, and closely monitored. The initial clinical method of DM gene therapy is most likely the reduction of islet transplant rejection.
People with diabetes mellitus may be able to reach their metabolic objectives with the use of dietary therapy and physical exercise. Using a variety of lifestyle strategies could be beneficial. Determining the degree of treatment goals through lifestyle modifications requires careful consideration of metabolic markers, including blood pressure, glucose, glycated hemoglobin, lipids, and body weight, as well as the evaluation of life quality. Yet, other nations have concentrated on managing diabetes mellitus and its sequelae by normalizing glycemic control as measured by hemoglobin A1 or fasting blood glucose, which alone attends to the needs of individuals who were already diabetic. Designing procedures for the early identification of abnormal glucose metabolism and implementing effective strategies for the normalization of this altered state are therefore essential. Additionally,
by using strong preventative measures, improved diagnostic procedures, early.
In addition to glycemic management, multifactorial therapies utilizing various treatment regimens, such as gene therapy, nanotechnology, stem cells, medical nutrition therapy, and lifestyle change, have produced noteworthy outcomes in reducing the effects of diabetes mellitus, however not without some difficulties. Although nanotechnology is a promising technology with the potential to improve diabetes care, there are still some obstacles to overcome. The price is one of the main drawbacks. The majority of the devices needed for insulin administration and CGM are highly costly. Even while diabetes affects people from all socioeconomic backgrounds, this restricts their use to the wealthy. Furthermore, the insertion of sensors and cannulas raises the danger of infection, which can occasionally be alarming and increases inflammation.
Despite the advantages of the gene therapy strategy, there may also be drawbacks. Genes inserted by a viral vector, for instance, may trigger an immunological reaction and worsen the illness. Furthermore, the majority of gene therapy research is still conducted on animal models, and human safety has not yet been established.
It is well known that the main obstacle to effective gene therapy is gene delivery technology. The key components of a successful gene delivery method are convenience, safety, specificity, stability, and efficiency. Therefore, the safe and effective delivery of the corrected gene to the target region is the biggest challenge in gene therapy. Therefore, in order to provide the therapeutic potential where needed, a suitable gene delivery technique or vector is needed. Currently, viral and non-viral vectors are the two primary types of vectors used.
The non-viral vector has the advantages of low immunity, low cost, and easy production; nonetheless, the main barriers to its widespread usage stem from the ineffectiveness of the delivery mechanism and temporary gene expression. On the other hand, findings indicate that viral vectors are more effective at delivering genes because they employ different mechanisms to carry DNA to cells. Viral vectors are viral particles that contain all of the virus's genes removed and precisely the crucially altered sequences of the virus.
When properly prepared, these viruses have flaws that, in theory, prevent replication or infection after infecting the target cell. Strong therapeutic gene expression is made possible by the integration of viral DNA with the host cell's genome.
In spite of their superiority over non-viral vectors as gene delivery vehicles, viral vectors nonetheless have certain drawbacks, such as immunogenicity, cytotoxicity, and inflammation. Despite the significant and innovative advances in the relevant fields of stem cell biology, the treatment of diabetes mellitus is still in its infancy. Numerous obstacles continue to impede the ethical and technological advancement of stem cell research, such as: The usage of ESCs is challenged with the production of teratomas and the danger of cancer, generating safety concerns.
Autoimmune rejection is the main obstacle to transplantation. Because of this, a steady and suitable immunosuppressive regimen is required. Current transplantation procedures must be stabilized using the standard testing module. To evaluate the issues related to the stability, longevity, and survival of the transplanted cell with the proper vascular and neurological support in the new milieu, a few experimental studies are required before stem cell transplantation can proceed. Once the proper developmental processes have been optimized, scale-up issues become problematic.
The quantity of cells must be sufficient to meet the demands of upcoming studies, including clinical trials. Therefore, an effective technique is needed to maximize the yield by modifying the culture requirements. In order to balance demand and utilization, further research into the availability of excess transplanted cellular reserves will require the stem cells' capacity to scale up. The ESCs are the possible targets for the ethicists because of where they are sourced from. ESCs are typically extracted from embryos that are either not fertilized or utilized in hospital ex vivo fertilization procedures.
Before these ESCs can be used in clinical research, the donor's informed agreement is typically needed. The source of life and the moral justification for ending the pregnancy are called into doubt, nonetheless, because the embryo is tragically destroyed in most cases as the cells are being extracted. Since there is less debate regarding the use of adult stem cells than embryonic ones, they are preferred.
The use of one's own stem cells for a variety of purposes is made possible by the present technological advancements in induced pluripotent stem cell research [78]. In these situations, the adult cells undergo pluripotent reprogramming, which results in their transformation into functional beta cells. This strategy may ultimately break the deadlock surrounding ESCs and help address further safety concerns that will probably be addressed in the future.
Conclusions
Diabetes mellitus has emerged as a public health concern that demands immediate attention, and the rising number of cases is expected to last for many more decades. As of right now, DM has no known remedy. Numerous therapy plans have demonstrated encouraging outcomes in the management of DM. However, DM is still a significant problem that could endanger public health despite the promise of these massive treatment efforts. For a clinical management plan to be strong, effective, and safe, the issues with each of these techniques must be resolved. Optimal metabolic management of blood pressure, glucose, and body weight is required, necessitating appropriate education and support for dietary improvements, physical activity, and weight loss.
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