Nanoscience Applications in Diabetes Treatment

Nanotechnology has shown immense promise for advancing blood glucose control. This technology offers the potential to safeguard pancreatic cells from autoimmune destruction by driving the creation of innovative therapeutic agents that can be delivered to specific targets.
In this book, you will find a comprehensive exploration of diabetes and its approved medical treatments. The book delves into how nanotechnology can amplify the efficacy of current treatment modalities, potentially paving the way for a gene therapy solution to combat this disease. Starting with the history of diabetes treatment, the book explains treatment challenges for diabetes before getting into the three ways nanoscience is helping in diabetes treatment: insulin delivery, drug delivery and nucleotide delivery. Each chapter is contributed by accomplished experts in their respective fields, who strive to offer a thorough, yet accessible discussion of the subject.

Readership
General readers, science enthusiasts and scholars interested in diabetes medicine.

• Language: English
• Publisher: Bentham Science Publishers
• Release date: Mar 11, 2001
• ISBN: 9789815196535

Book preview

The Story of Diabetes and its Causes

Ramin Malboosbaf¹, *, Neda Hatami¹

¹ Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, Tehran, Iran

Abstract

Diabetes mellitus (DM) is a complex metabolic disorder whose rising prevalence is terrible. A deeper knowledge of the pathophysiology of diabetes could assist in discovering possible therapeutic targets for treating diabetes and its associated problems. The common feature of diabetes, regardless of the specific pathology involved, is hyperglycemia brought on by the death or dysfunction of β-cell. As insulin deficiency gets worse over time, dysglycemia progresses in a continuum. This chapter has provided a brief review of the pathophysiology of diabetes. Also, the roles of genetics and environmental factors have been emphasized.

Keywords: Diabetes, Disease, Factor, Glucose, Pathophysiology.

---

* Corresponding author Ramin Malboosbaf: Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, Tehran, Iran; E-mail: [e-mail]

INTRODUCTION

Diabetes mellitus is a complex metabolic disorder whose principal clinical and diagnostic feature is hyperglycemia [1]. Diabetes has reached epidemic proportions; the global diabetes prevalence in 20-79-year-old in the latest reports was estimated to be 10.5% (536.6 million people), rising to 12.2% (783.2 million) in 2045 [2]. Over the next 20 years, its prevalence is expected to double, affecting more than half a billion people, with more than 75% of patients living in low- and middle-income countries [3]. Additionally, the increase in prevalence in developing countries is believed to be greater due to the widespread adoption of Western lifestyle habits, such as sedentary behavior, inactivity, and a high-energy diet [4, 5].

The risk of a variety of cardiovascular disorders is roughly doubled by diabetes, particularly type 2 diabetes mellitus (T2DM) [6]. In addition, a wide range of non-vascular diseases, such as cancer, infections, liver disease, and mental and nervous system disorders, are linked to T2DM [7]. In a similar vein, type 1 diabetes mellitus (T1DM) is linked to an increased risk of both vascular and non-

vascular complications. A deeper knowledge of the pathophysiology of diabetes could assist in discovering possible therapeutic targets for treating diabetes and its associated problems [8, 9].

TYPE 1 DIABETES

The prevalence of T1DM is increasing worldwide. Although T1DM is often diagnosed in childhood, 84% of people living with T1DM are adults [10]; 62% of all new T1D cases in 2022 were in people aged 20 years or older [11]. T1DM affects men and women equally [12] and reduces life expectancy by an estimated 13 years [9]. With some exceptions, the incidence of T1DM is positively related to geographic distance north of the equator [13]. Colder seasons correlate with the diagnosis and progression of T1DM. Both disease onset and the incidence of islet autoimmunity appear to be higher in autumn and winter than in spring and summer [14-16].

Role of Genetics

The higher prevalence of T1DM in a family suggests a hereditary risk, which increases with the proband's degree of genetic similarity. Human leukocyte antigen (HLA) gene variations alter how the HLA protein binds to antigenic peptides and how the antigen is presented to T cells, contributing to 50-60% of the gene risk. Cell surface proteins involved in antigen presentation and self-tolerance are encoded by HLA genes, which are essential for controlling the immune response. As a result, genetic variations in these proteins' amino acid sequences may alter the repertoire of presented peptides and result in self-tolerance loss [17].

The autoimmune nature of diabetes is primarily due to its strong connection to HLA, the DQA and DQB genes, and its direct influence through the DRB genes [18]. Genome-wide association studies have demonstrated a strong link with the HLA-DR3 and HLA-DR4 haplotypes, as well as an exclusive link between the autoimmune destruction of β-cells and the DR4-DQB1I0302 haplotype [19-21].

Smaller effects are caused by about additional 50 genes individually [22, 23], including gene variants that modulate immune regulation and tolerance, viral responses [24-29], responses to environmental signals, and endocrine function [30]. Some variants are expressed in pancreatic β-cell [31]. In relatives, the onset and progression of islet autoimmunity are influenced by genetics [32, 33]. These gene variants collectively are responsible for 80% of T1DM inheritance [34]. A patient's risk, C-peptide decline rates, and response to various therapies can all be predicted by genetic variants [35]. With a deeper comprehension of heredity profiles, new goals for individualized interventions may be realized.

Role of the Environment

Numerous pieces of evidence suggest that environmental and genetic factors interact to cause autoimmunity and the development of T1DM, such as T1DM discordance rates in twins, the variance in geographic prevalence, and the adjustment of disease incidence rates as individuals migrate from low to high-incidence countries. The fact that most patients with the highest risk HLA haplotypes do not develop T1DM lends credence to this gene-environment interaction. Timing of environmental trigger exposure can also be very important. The investigation of environmental exposures is made more challenging by the variation in disease onset age. However, the early onset of islet autoantibodies linked to T1DM in children raises the possibility that early environmental exposures may play a role [10].

Infection

Congenital rubella infection has strong evidence to raise the possibility of T1DM development [36]. Enteroviruses are also thought to be associated with T1DM [37]. These infections are considered to alter gut microbiome composition [10].

Dietary Factors

β-cell autoimmunity can be affected by the timing of exposure to foods like grains and nutrients like gluten [10], as some studies show that early initiation of (<3 months) cereals may have this effect [38]. Retrospective studies led to the hypothesis that early initiation of cow's milk or less breastfeeding could increase the risk of T1DM. However, it was not confirmed by prospective studies [39]. Vitamin D deficiency and low levels of omega-3 fatty acids have been probably linked to an increased risk of T1DM [40].

Natural History and Prognosis

The common feature of diabetes, regardless of the specific pathology involved, is hyperglycemia brought on by the death or dysfunction of β-cell. As insulin deficiency gets worse over time, dysglycemia progresses in a continuum. The ability to categorize diseases and determine where and how to intervene best to stop or halt disease progression and complications depends on understanding the natural history of β-cell mass and function [10]. T1DM pathogenesis is influenced by both humoral and cellular immunity [41]. There is increasing evidence of significant overlap across the entire spectrum of diabetes, even though T1DM is caused by the immune system's destruction of beta cells, and T2DM is mostly associated with glucose-specific insulin secretion problems [42]. In both types of diabetes, the hyperglycemia-induced stress response may contribute to β-cell apoptosis [43]. The changes in β-cell phenotype that are the consequence of hyperglycemia may reflect the dedifferentiation of β-cell, which are important to the natural history and staging of diabetes [44].

Long before the diagnosis, abnormal insulin secretion can start [45-48], with a gradual decrease that starts at least two years before the diagnosis and accelerates immediately after diagnosis [49, 50]. In a similar time frame, a decrease in β-cell sensitivity seems to take place [51]. The late insulin response increases as the early insulin response subsides, suggesting a potential compensatory mechanism [52]. It has been said that the a decrease in insulin secretion in the first year after diagnosis is biphasic, steeper in the first year than in the second. Additionally, the data imply that adults experience a slower rate of decrease [53]. Until there is little to no insulin secretion, the loss of insulin secretion can persist for years after diagnosis. Though, even after 30 years of T1DM, the majority of patients still have low C-peptide levels [54]. Usually, glucose levels are high years before T1DM is diagnosed. Higher glucose levels, even within the normal range, signify T1DM [54-57]. There are significant fluctuations in glucose during the progression to T1DM [58]. Metabolic progression markers could be used to predict more accurately when people at risk will develop diabetes [35, 59]. Prediction can be further enhanced by combining dynamic glucose and C-peptide changes into risk scores [60, 61].

Diabetic ketoacidosis (DKA), as the first onset of the disease, can occur when there is sudden β-cell death in children and adolescents. In some, the course of the illness is prolonged, with a slight increase in fasting blood glucose that only becomes severe with or without ketoacidosis in the presence of physiological stresses like severe infections. Patients with this form of diabetes, despite the variable course, require insulin treatment for survival when they develop severe or complete insulin deficiency in early, middle, or even late life. Low or undetectable plasma C-peptide levels are a sign of severe or complete insulin deficiency, regardless of the age of onset [62 - 64]. Fig. (1) depicts the natural history of T1DM [64].

Before a clinical diagnosis of T1DM is made, circulating autoantibodies against insulin, glutamic acid decarboxylase (GAD), the protein tyrosine phosphatase IA-2, and the zinc transporter eight can be found [65]. Reversion is uncommon in people with multiple autoantibodies, while individuals with single autoantibodies often become negative [66]. Anti-GAD-65 is the most important, detectable in approximately 80% of patients at the time of clinical diagnosis, followed by Islet cell antibodies (ICAs) and IA-2, which are present in 69-90% and 54-75%, respectively. In T1DM, Anti-GAD-65 gradually decreases over time. In high-risk populations, the presence of anti-GAD antibodies is a strong predictor of T1DM development in the future [67]. About 70% of all infants and young children at the diagnosis have insulin autoantibodies (IAAs), which also play a significant inhibitory role in insulin function in patients receiving insulin therapy [18].

Fig. (1))

Pathophysiological mechanisms in common for NADLD and T2DM. LPS: lipopolysaccharides; CRP: C reactive protein; TNF-α: tumor necrosis factor; IL-6: interleukin-6; ROS: reactive oxygen species; TLR: toll-like receptor [119].

Children with HLA risk genotypes in relatives with T1DM who have two or more islet autoantibodies have a 75% chance of developing clinical diabetes in the next ten years [68]. As an increasing number of autoantibodies are found, the risk increases [68-70]. Today, a diagnostic stage of T1DM is thought to be a positive test for at least two autoantibodies [35]. Although autoimmunity in T1DM has a significant prognostic value, there is no effective treatment or prevention strategy [71].

It is interesting to note that 5% of T2DM patients have autoantibodies to GAD. These patients have a lower BMI and less residual β-cell function than patients with T2DM who do not have a GAD antibody. Additionally, they have a genetic profile that is more in line with that of T1DM patients and a previous need for insulin therapy, indicating that adult autoimmune diabetes may be a form of T1DM with a slower course and a later onset age [72].

Effects on Glucose Metabolism

While insulin insufficiency is the main flaw in T1DM, insulin operation is also flawed. The expression of multiple genes is required for target tissues to correctly respond to insulin, including glucokinase in the liver and the GLUT-4 class of glucose transporters in adipose tissue. Lack of insulin causes unregulated lipolysis and high plasma-free fatty acid levels, which inhibit the metabolism of glucose in peripheral tissues like the skeletal muscle [73].

Hepatic glucose output is increased in uncontrolled T1DM at first through glycogenolysis, followed by gluconeogenesis. Insulin also controls hepatic glucokinase. So, decreased glucose phosphorylation induces a higher glucose transport into the blood [73]. Additionally, non-hepatic tissues' glucose utilization is affected by insulin deficiency. Adipose tissue and skeletal muscle are particularly affected by insulin's effect on glucose uptake. This is done by transporting glucose transporter proteins to the plasma membrane of these organs, which is mediated by insulin [73].

Effect on Lipid Metabolism

After eating, the main function of insulin is to promote the storage of dietary energy in the form of glycogen in hepatocytes and skeletal muscle. Additionally, insulin causes hepatocytes to produce triglycerides and store them in adipose tissue. Normally, insulin is required for lipoprotein lipase (LPL) to act on plasma triglycerides. Fatty acids can be extracted from circulating triglycerides and stored in adipocytes by LPL, a membrane-bound enzyme on the surface of the endothelial cells that line the vessels. The lack of insulin leads to hypertriglyceridemia [73]. Triglycerides quickly mobilize in uncontrolled T1DM, raising plasma-free fatty acid concentrations. Except for the brain, many tissues absorb the free fatty acids and convert them to produce energy [73].

Malonyl-COA levels decrease, and fatty acetyl-COA transport into mitochondria rises in the absence of insulin. Acetyl-COA is produced when fatty acids are oxidized by mitochondria, which can be further oxidized during the tricarboxylic acid (TCA) cycle. Most of the acetyl-COA found in hepatocytes is metabolized into the