Targeting Angiogenesis, Inflammation and Oxidative Stress in Chronic Diseases: Angiogenesis, Inflammation and Oxidative Stress in Chronic Diseases

Targeting Angiogenesis, Inflammation and Oxidative Stress in Chronic Diseases presents recent advances in the vivid molecular pathways targeting angiogenesis, inflammation and oxidative stress that contribute very widely to the genesis of chronic diseases. The books will also highlight the drugs from natural and synthetic origin in the management/prevention/treatment of diseases along with the drug delivery approaches. The book’s authors from various key institutions around the globe will deliver well-structured and well-designed chapters. The systematic presented information and knowledge will surely aid consistency and continuity. The multifaceted book is enriched with deep scientific contents. Each chapter will clearly define the facts, emerging role of molecular pathways and the targets and focus will be imparted on key challenges associated and the future directions that will provide torch bearer thing for the researchers to explore new targets in the domain.

• Focuses on the pathogenesis of the disease, along with the molecular mechanism of action
• Includes updates on strategic design/delivery of drugs targeting angiogenesis, inflammation, and oxidative stress
• Provides recent advancements in the field of pathogenesis of chronic diseases

• Language: English
• Publisher: Academic Press
• Release date: Jan 10, 2024
• ISBN: 9780443135880

Book preview

1 Understanding the role of angiogenesis, inflammation and oxidative stress in diabetes mellitus: Insights into the past, present and future trends

Sandeep Rathora; Sukhbir Singha; Neelam Sharmaa; Ishrat Zahoora; Bhupinder Bhyanb    a Department of Pharmaceutics, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, Haryana, India

b Department of Pharmaceutics, Swift School of Pharmacy, Rajpura, Punjab, India

Abstract

The objective of this chapter is to understanding different roles in diabetes mellitus type 2, one of the most universal metabolic diseases, is the result of incorrect insulin response in insulin-sensitive tissues and inappropriate insulin synthesis by pancreatic cells. The primary cause of diabetes type 2, a metabolic clinical syndrome defined by hyperglycemia and insulin resistance, is thought to be oxidative stress. Both obesity and diabetes prevalence are rising everywhere in the world. It poses a significant financial burden due to the increasing expenses of its complications and maintenance. A persistent state of inflammation associated with aging, known as inflammation, has been hypothesized to have a role in several diseases frequently seen in the senior population. Inflammation is linked to an excess of reactive oxygen species (ROS) in the cell, which can cause cellular components to oxidize and become damaged, experience increased inflammation and activate cell death pathways. In this chapter, we go through what is currently known about how oxidative stress, mitochondrial stress, and inflammation are related to diabetes mellitus type 2. We discuss the role of angiogenesis as an essential stage in the development of many life-threatening disorders, vascular dysfunction, and nearly all human cancers. An innovative and successful method for treating illnesses including cancer, diabetic retinopathy, and age-related macular degradation that depend on angiogenesis is antiangiogenic therapy. Traditional dosage forms have flexible bioavailability, short half-lives, need frequent administrations, and increase side effects despite the great therapeutic benefits. These factors make therapy ineffective and lead to patient noncompliance. Nanotechnology-based approaches are more appealing due to the added benefit of site-specific medicine administration with enhanced bioavailability and a more variable dosing schedule.

Keywords

Angiogenesis; Diabetes mellitus; Epidemiology; Insulin resistance; Inflammation and novel drug delivery system; Mitochondria; Oxidative stress

1 Introduction

Diabetes is a group of metabolic disorders marked over time by an excessive increase in blood glucose levels and becomes a serious health illness with considerable social and economic complications. Diabetes mellitus type 1 and type 2 are dangerous long-term conditions in which the body is unable to make any or enough insulin or fails to utilize the insulin that is generated properly [1,2]. Hyperglycemia, hyperlipidemia, abnormalities in the metabolism of glucose and lipids, and changed liver enzyme levels are all related to diabetes. Diabetes has now been linked to chronic hyperglycemia, which is recognized by persistently and abnormally high postprandial blood glucose levels [3]. With a population of 77 million, the International Diabetes Federation evaluated that the prevalence of diabetes will be 7.7% in 2019 and will rise to 9.5% in 2045 [4,5]. Diabetes primarily affects Western nations, although it is becoming more common in emerging Asian countries such as China and India [6]. It is the seventh leading reason of death in the United States due to its several severe side effects, which include neuropathy, nephropathy, high blood pressure, cardiovascular risk, an unbalanced lipid profile, and retinopathy [7]. Around 90% of all instances of diabetes were in adults with type 2 diabetes mellitus. In addition to reduced pancreatic insulin secretion, type 2 diabetes mellitus is a metabolic condition marked primarily by insulin resistance and limited insulin action in the muscle and liver cells [8,9]. The prevention and treatment of type 2 diabetes mellitus are therefore one of the most important issues of the 21st century to diminish complications, death, and healthcare costs [10]. It also produces polyuria, polydipsia, and polyphagia as symptoms which are characterized by high blood glucose levels.

2 Types of diabetes mellitus

2.1 Type 1 diabetes mellitus (T1DM)

The primary cause of type 1 diabetes mellitus is the demolition of pancreatic cells, which leads to an insufficient amount of insulin being produced. Juvenile-onset diabetes was formerly the name given to it since it typically develops in children. The onset often happens throughout childhood, peaking between the ages of 5–7 and during puberty, but it can happen at any age. Commonly, it is an endocrine autoimmune metabolic condition occurring mainly during childhood [11]. The loss of β-cells in the massive majority of patients (70%–90%) is the consequence of type 1 diabetes mellitus autoimmunity nevertheless in a smaller set of the population, no autoantibodies or immune responses are noticed, and the root of β-cell destruction is unknown (idiopathic type 1b diabetes mellitus). It is associated with the presence of autoantibodies many months or years before the onset of symptoms. These autoantibodies act as a biomarker for the development of autoimmunity. The autoantibodies associated with T1DM are those directed against insulin, 65 kDa glutamic acid decarboxylase, insulinoma-associated protein 2, or zinc transporters. The first β-cell autoantibody to appear in early childhood is usually directed against insulin or GAD65 (i.e., antiinsulin or antiGAD65 autoantibodies), however, these autoantibodies can each be present, whereas it is far uncommon to look at islet antigen-2 (IA-2) or zinc transporter (ZNT) autoantibody first. What triggers the appearance of a first-appearing β-cell-targeting autoantibody is doubtful but is beneath scrutiny in several studies of kids who are being followed up since birth [12–14]. The different causes of type 1 diabetes mellitus are autoimmune diseases, endocrine disease, viruses and infection, destruction of the pancreas, environmental factors, drug and chemical toxins, autoimmune destructions of β-cells, etc. [11].

2.2 Type 2 diabetes mellitus (T2DM)

In type 2 diabetes mellitus (T2DM) there is dysregulation of carbohydrate, protein, and fat metabolism leading to decreased insulin secretion, insulin resistance, or a combination of both. Of the three main categories of diabetes, T2DM is more common (in more than 90% of all cases) than type 1 diabetes mellitus or gestational diabetes. Over the past few decades, our understanding of the course and development of T2DM has evolved rapidly. It has become more prevalent between children and adolescents, partly due to an increase in the number of overweight or obese young people. Compared to type 1 diabetes, type 2 diabetes is more strongly associated with family history and heredity. Twin studies have shown that genetics contribute significantly to the occurrence of T2DM [14]. Its chief basis is gradually decreased insulin secretion through pancreatic β-cells, the individual who has a preexisting background of insulin resistance in skeletal muscle, adipose tissue, and liver. Obvious hyperglycemia a high-risk condition preceded by prediabetes that predisposes individuals to T2DM development. Prediabetes is described by one of the following: Impaired fasting glucose (IFG) levels, impaired glucose tolerance (IGT), or elevated level of glycated hemoglobin A1c (HbA1c) [15,16]. Impaired fasting glucose levels are assessed with fasting plasma glucose levels that are higher than normal, while IGT is characterized by insulin resistance in muscle and impaired late (second-phase) insulin secretion after a meal. Individuals with IFG levels manifest hepatic insulin resistance and impaired early insulin secretion. Annual conversion rates of prediabetes to T2DM range from 3% to 11% per year [17].

Finding persons who have prediabetes and intervening with lifestyle changes (weight reduction and exercise) as well as antidiabetic and antiobesity drugs are necessary for the prevention of diabetes. According to the American Diabetes Association (ADA) Consensus Conference, metformin, pioglitazone, and a combination dosage of metformin and rosiglitazone should be used to treat high-risk patients with IGT and IFG levels (HbA1c > 6.5%; BMI 30 kg per m²; age 60 years). However, prediabetic people can be anticipated to benefit from a lowered chance of acquiring diabetes, a better lipid profile, and a decreased cardiovascular risk, including a reduced risk of developing hypertension, if they can effectively lose weight and continue physical activity plan. T2DM is a complex chronic disorder that necessitates ongoing medical attention, patient self management for control of abnormal glucose levels, and multifactorial risk reduction strategies to normalize blood glucose, lipid profiles, and blood pressure to prevent or minimize acute and long-term macrovascular complications (such as a heart attack or stroke) and microvascular complications (including retinopathy, nephropathy, and neuropathy) [18,19].

2.3 Gestational diabetes mellitus (GDM)

The term gestational diabetes was first introduced by Carrington in 1957. This type of high blood sugar occurs during pregnancy and is usually detected in the later stage of the second trimester or early in the third trimester, this condition is typically resolved after delivery. Therefore, the term GDM refers to a wide range of hyperglycemia that includes mild forms like IGT or IFG during late pregnancy to severe forms like those observed in early pregnancy indicative of overt diabetes. While diabetes-related hyperglycemia was initially rare, it has gained prevalence with the global epidemics of diabetes and obesity, as well as the trend of delayed childbearing, especially in regions where early-onset diabetes and obesity are also common [20].

In the current epidemic of hyperglycemia outside of pregnancy, probably, some cases diagnosed as gestational diabetes mellitus (GDM) are undiagnosed prepregnancy hyperglycemia with varying degrees of severity. There is no universal agreement on a single diagnostic protocol or criteria for GDM, which makes international comparisons challenging. GDM poses risks to both the mother, mainly hypertensive disorders of pregnancy, and the fetus, mainly excessive fetal growth and adiposity. A diagnosis of GDM can indicate a higher risk of diabetes, obesity, and premature cardiovascular disease in women and their offspring over the long-term [21].

3 National and international prevalence

More than 37 million adults in the United States have diabetes, which has more than doubled over the past 20 years. Diabetes may lead to major health concerns that can harm the eyes, kidneys, and nerves, among other sections of the body, if it is not managed. Diabetes mellitus type 1 and diabetes mellitus type 2 are the two primary subtypes. When a person has diabetes type 1, their body is unable to produce insulin. The most prevalent kind of diabetes type 2 is characterized by the body’s inability to use insulin suitably. According to the International Diabetes Federation, there are 537 million diabetics worldwide. The International Diabetes Federation projects that by 2045, 783 million people worldwide will have diabetes, a 46% rise from the current number of cases [4,6].

India has been the second-highest number of diabetics worldwide. Furthermore, 40 million people in India have impaired glucose tolerance, which places them at a high-risk of emergent diabetes type 2. This is the second-highest total in the entire world. More than half (53.1%) of diabetics in India do not have a diagnosis. When diabetes is not adequately diagnosed or managed, it can have catastrophic and occasionally deadly effects, such as heart attack, stroke, renal failure, blindness, and lower limb amputation. They have the result of reducing living quality and increasing healthcare costs, which heightens the need for treatment availability. Diabetics of type 2 make up around 90% of the population. In 2008, there were 347 (314–382) million cases of diabetes globally, with 90% of those cases being type 2 diabetes, up from 153 (127–182) million in 1980 due to changes in lifestyle and an increase in obesity [22]. According to conservative estimates, 429–552 million people worldwide will develop diabetes by 2030 as a result of being overweight, obese, and having an extended life expectancy [23,24]. Obesity is defined as having a body mass index of more than 30 kg/m² [25]. According to epidemiology research, those who are obese have a much higher chance of developing diabetes [26]. T2DM has been identified as an obesity-related condition as a result [27].

4 Pathophysiology of diabetes mellitus

The body breaks down the food it consumes and absorbs it into circulation through the digestive system. While some of the food is consumed right once, the majority is preserved for later use. It serves as a fuel, particularly for the brain cells, which are dependent on glucose for their operation. It is stored as glycogen in the liver and muscle cells. The islets of Langerhans of the pancreas create insulin, which is required for the transportation of glucose into the cells for utilization as fuel. A protein hormone, insulin is released into the intracellular environment by the beta cells before entering the circulation to be used. It interacts with the insulin receptor protein, which in turn triggers a series of intracellular events, at the cellular level. In response to this contact, a new protein known as a glucose transporter (GLUT4 in muscle cells) is produced. This protein moves to the cell surface and facilitates the entry of bigger molecular nutrients like protein and glucose [28,29].

Insulin serves a variety of purposes, including facilitating the intake of nutrients and stimulating the production of fat and glycogen while suppressing the breakdown of fat and glycogen-producing enzymes. It is natural for storage compounds to break down, and this process is essential to metabolism. The biological system cannot use the generated metabolites in the absence of insulin, which results in a catabolic condition. The most crucial mechanisms leading to the hyperglycemia of diabetes, whether from insulin insufficiency or insulin resistance, occur in the liver, which is also capable of producing fresh glucose (gluconeogenesis) from protein [30].

Type 1 diabetes mellitus known as an autoimmune condition causes the death of insulin-producing cells in the pancreas by invading macrophages and CD4+ and CD8+ T lymphocytes. Majorities of patients who previously had insulin treatment and those with circulating islet cell antibodies both have these antibodies. A lack of insulin secretion may result from the autoimmune destruction of pancreatic β-cells, which results in metabolic abnormalities linked to T1DM. Additionally, individuals with T1DM secrete an excessive amount of glucagon and have decreased insulin production, which might disrupt pancreatic α-cell function [31]. The metabolic problems brought on by low insulin are made worse by the incorrect rise of glucagon levels. Lack of insulin results in unchecked lipolysis and excessive plasma levels of free fatty acids, which inhibit glucose utilization in peripheral tissues including skeletal muscle. A variety of genes, including glucokinase in the liver and the GLUT 4 class of glucose transporters in adipose tissue, are required for target tissues to respond to insulin correctly, and an insulin shortage may reduce their expression. Impaired protein, glucose, and lipid metabolism are the main metabolic abnormalities caused by insulin insufficiency in T1DM [32,33].

Insulin resistance and decreased insulin production due to pancreatic beta-cell dysfunction are the two primary pathophysiological abnormalities associated with type 2 diabetes [34]. Although relative to the degree of insulin resistance, the plasma insulin concentration (both fasting and meal stimulated) is elevated in an absolute sense. Normal glucose homeostasis cannot be sustained by elevated plasma insulin levels. It is essentially difficult to distinguish the contribution of each to the etiopathogenesis of T2DM because of the close association between the production of insulin and the sensitivity of hormone action in the complex management of glucose homeostasis. Impaired glucose tolerance eventually results from insulin resistance and hyperinsulinemia [35].

5 Oxidative stress in diabetes mellitus

Both diabetes mellitus type 1 and diabetes mellitus type 2 have incorrectly managed blood sugar levels that rise to high levels over extended periods. One of diabetes’ many consequences, persistent hyperglycemia, is also one of the disease’s hallmarks. Even though there are still many unresolved questions about the physiopathology of oxidative stress, it is widely recognized that it plays a crucial role in the development and progression of diabetes. Oxidative stress is a condition when there is an imbalance in the creation and elimination of ROS, which promotes the synthesis of oxidants. ROS include the hydroxyl radical (OH), superoxide anion (O2), and peroxynitrite (ONO2) among other oxygen-free radicals. Because it produces free radicals so easily, hydrogen peroxide (H2O2), one of oxygen’s nonradical byproducts, is also categorized as ROS. Excessively nicotinamide adenine dinucleotide hydrogen phosphate (NADPH) is generated when cells have an excessively high protein biosynthetic load, which increases the production of superoxide anion radicals (O2) and causes cells more susceptible to oxidative damage [36].

Organelles like mitochondria are necessary for energetic metabolism because they allow oxidative phosphorylation, which releases energy in the form of adenosine triphosphate (ATP). In this process, NADH and FADH2, which are produced when nutrients are oxidized, by the electron transport chain (ETC), produce ATP, ROS, and mostly O2. Although mitochondria are the primary generator of intracellular ROS, these organelles also have antioxidant enzymes that, under normal circumstances, control the cellular redox imbalance. The manganese superoxide dismutase (MnSOD), a superoxide dismutase that is specific to mitochondria and suppresses O2, is shown in Fig. 1 and highlights the crucial function that mitochondria play as a source of ROS in maintaining them under homeostatic processes [37].

Fig. 1

Fig. 1 Mitochondria play a source of ROS and in keeping them under homeostatic regulation.

The primary nutritional origin of energy for the transport chain is glucose, which is produced as NADH and FADH2. This makes it understandable why ROS are linked to the physiopathology of diabetes. There is proof that people with type 2 diabetes have changed antioxidant enzymes [38], and several investigations have found that people with diabetes mellitus generally exhibit oxidative stress. Additionally, diabetes has been linked to malfunction of the mitochondrial ETC in terms of mitochondrial disorders [39]. It is known very well that abnormalities in the mitochondrial genome predispose individuals to diabetes. Proteins that are encoded by the mitochondrial genome are required for the synthesis of ATP and are a component of the ETC. For example, recent prospective research conducted on people with mitochondrial dysfunction discovered a greater risk of endocrine illnesses like diabetes mellitus [40].

High-level oxidative stress and mitochondrial disorders have also been linked, according to research [41]. It has been hypothesized that mitochondria are significant in the etiology of diabetes and the subsequent ROS production, which is a significant trigger of the implications of the diseases [42], according to the body of evidence linking T2DM and oxidative stress affecting mitochondria. Advanced glycation metabolites, glucose oxidation, and lipid peroxidation are all increased by hyperglycemia inside cells [43], which causes the production of ROS [44], which reduces insulin release.

6 Inflammation in diabetes mellitus

The microvascular disorders of diabetes (such as renal disease, nerve, and retinal) are heavily influenced by inflammation at the vascular level, while the macrovascular complications of diabetes are strongly influenced by oxidative stress (such as peripheral arterial disease, coronary artery disease, and stroke). Hence, it is clear that obesity has a role in the development of both insulin resistance and diabetes. A rise in blood levels of free fatty acids (FFA) is another effect of poor insulin sensitivity, particularly as a result of the disruption of insulin’s antilipolytic effect on adipocytes. In reaction, fat cells release large amounts of FFA into the bloodstream, which leads to more insulin release interference and ectopic lipid deposition, among other systemic lipotoxic effects. In this regard, lipotoxicity is now recognized as a major factor in insulin resistance [45].

6.1 Relationship between oxidative stress and inflammation

A high-calorie diet, exposure to immunological, chronic, radioactive, toxic chemicals, allergies, illnesses, obesity, and pathogenic diseases like cancer are all linked to inflammation, which is the body’s natural defensive mechanism against pathogens. Oxidative stress and other protein oxidations are the results of several chronic illnesses associated with the increased generation of ROS [46]. Peroxiredoxin 2 has been identified as an inflammatory signal and protein oxidations cause the production of inflammatory signal molecules. Several researchers have investigated the connection between oxidative stress and inflammation. There is proof that oxidative stress contributes to the pathogenesis of chronic inflammatory disorders. The following are the results of the investigation. By altering synaptic and nonsynaptic transmission between neurons, ROS produced in brain tissues may act as the origin for neuroinflammation and cell death, which in turn leads to neurodegeneration and loss of memory [47,48]. Hyperglycemia causes significant cellular damage to the brain due to the increased production of oxidative stress. Many disorders, including insulin resistance, diabetes mellitus type 2, and cardiovascular diseases, are influenced by chronic inflammation [47,49].

6.2 Important roles for oxidative stress and inflammation in vascular failure

Because of the failure to regulate intracellular glucose content about blood glucose levels and their inability to prevent glucose from entering when blood glucose levels are high, vascular endothelial cells are a common target of hyperglycemic injury [50]. Endothelial cells store a lot of glucose in this circumstance (during hyperglycemia) and may suffer considerable oxidative damage. Both direct advanced glycation end product (AGE) damage caused by glycation and indirect ROS damage caused by hyperglycemia can trigger an inflammatory response in the endothelium. It appears that the immune system alters the integrity of the endothelium by generating ROS through a pulmonary explosion [51]. All of these components cause endothelial tissue to experience oxidative stress and ROS, which encourages inflammation and damages the vascular endothelium. Additionally, ROS contributes to inflammation by increasing inflammatory cytokine levels and upregulating the expression of growth factors and cellular adhesion molecules at the beginning of cardiovascular issues linked to T2DM [52,53]. Fig. 2 explains the mechanisms of hyperglycemia-induced endothelial dysfunction.

Fig. 2

Fig. 2 Mechanisms of hyperglycemia-induced endothelium dysfunction.

7 Role of angiogenesis in diabetes mellitus

The complex process of angiogenesis, which leads to the formation of capillaries, includes the interaction of many vascular endothelial growth factors. The development of new blood vessels from the existing vasculature is known as angiogenesis. It starts in utero and lasts all the way through old age, happening in both health and illness. The distance between a blood capillary, which is created by the angiogenesis process, and any metabolically active tissue in the body is less than a few hundred micrometers. Several molecules are needed for angiogenesis to function effectively, including adhesion receptors, extracellular matrix proteins, angiogenic agents, and proteolytic enzymes [54,55]. The balance of positive and negative angiogenic modulators in the vascular milieu is also necessary for angiogenesis. A few of the linkages between abnormal angiogenesis and the development of chronic diabetic complications are shown in Fig. 3.

Fig. 3

Fig. 3 The interaction between aberrant angiogenesis in different tissues and the emergence of problems from chronic diabetes. VEGF , vascular endothelial growth factor.

Excessive or defective angiogenic processes have been linked to diabetes mellitus, and both of these factors are important contributors to the development of chronic diabetic problems with serious clinical repercussions. The driving factors and key clinical repercussions of diabetes’ impact on angiogenesis are diabetic retinopathy is a neurovascular disorder of the retina associated with diabetes that is marked by the development of new blood vessels. Ischemia can result from vascular alterations in the preproliferative phases, which in turn can cause angiogenesis in the retina and vitreous invasion. Because of the lack of strong intercellular connections, newly created blood vessels are young and brittle, making them vulnerable to ruptures that might result in sight-threatening hemorrhages. The angle of the eye’s anterior chamber may neovascularize, which might lead to retinopathy glaucoma [56,57].

Diabetic kidney disease (DKD) is marked by excessive and aberrant angiogenesis, a defective vasculature has been observed to promote glomerular enlargement by forming new blood vessels with blood capillaries. For instance, the generation of vascular endothelial growth factor (VEGF)-A may have proangiogenic effects as well as concurrently cause dysfunction in glomerular endothelial cells. The initial step of angiogenesis that VEGF-A induces is the weakening of endothelial cell connections to enable sprouting; this may enhance the permeability of the ultrafiltration barrier and endorse albuminuria [58,59].

It was commonly seen that newly formed arteries connected to peritubular capillaries bypass the glomerulus. However, it is conceivable to consider the overexpression of VEGF-A in DKD caused by hyperglycemia and shear stress as a compensatory effort to lower intraglomerular pressure. The aberrant control of angiogenesis by VEGF-A in DKD has been linked to angiopoietin-1 and angiopoietin-2 abnormalities, and their suppression may have therapeutic implications [60].

Acute hyperglycemia can cause nerve damage without causing vascular alterations, the clinical data supported the theory that diabetic neuropathy is dependent on an inadequate angiogenic response. Uncertainty exists about the precise processes by which diabetes damages the vasa nervorum, including whether these mechanisms are exclusive to neuropathy or mimic the broad mechanisms by which hyperglycemia damages endothelial cells [61]. It has been hypothesized that excessive glucose stimulates the creation and expression of VEGF by Schwann cells, which may then cause vasa nervorum endothelial cell failure. Reducing or preventing VEGF overexpression can indeed improve diabetic neuropathy-related symptoms [62,63].

The presence of hyperglycemia considerably slows the healing of cutaneous lesions. Diabetic individuals may develop persistent, nonhealing ulcers that are confined to certain pressure areas on their feet, such as the metatarsophalangeal joints, ankles, and heels. The process of healing a wound must include angiogenesis [64]. Insufficient angiogenesis in diabetes individuals manifests as reduced endothelial cell proliferation and diminished cell and growth aspect receptiveness at the site of the lesion. For instance, the synthesis of VEGF by wild-type fibroblasts is enhanced threefold in response to hypoxia, but the production of VEGF by diabetic fibroblasts is not upregulated in hypoxia situations [65].

8 Management of diabetes mellitus

8.1 Nutritional management

Consuming enough dietary fiber, the treatment of cardiovascular risk factors and glycemic control, in particular, fiber-containing natural resources, have been reported to be improved, reducing the risk of cardiovascular death in diabetics [66–68]. It is generally advised that diabetic patients consume fiber and whole grains in amounts that are at least comparable to those advised for the general population; approximately 30 g/d for women and 38 g/d for men, or 14 g per 1000 kcal. This is to account for the modest beneficial effects on cardiovascular risk factors. Consuming carbohydrates containing meals such as fruits, vegetables, legumes, whole grains, and dairy is quite valuable for the diabetic patient [69,70].

According to epidemiological research, fats increase the chance of acquiring obesity and cardiovascular disease [71]. As with the other primary principles, there is no ideal fat proportion. Instead, diabetic patients often follow the guidelines for the overall population (between 20% and 35%), especially if the patients are overweight, in that instance, the percentage must be kept within reasonable limits. According to certain research studies examining the Balanced diet pattern, monounsaturated fatty acids can reduce cardiovascular risk factors and improve glycemic control, particularly if saturated fatty acids are substituted. Eating omega-3-rich food, however, may help to reduce the risk of cardiac disease [72].

8.2 Physical activity

The simplest and most fundamental methods for treating diabetes are physical activity and exercise. General benefits of encouraging exercise within a specific strategy include improvements in glycemic control [73], blood pressure and cholesterol profiles, cardiovascular health advantages, enhanced quality of life, psychological well-being, and treatment of depression only a few of the benefits. Choose an aerobic activity you enjoy doing, such as walking, running, biking, or swimming. People should try to exercise for 150 min a week, or 30 min or more of moderate aerobic activity, on average. Resistance exercise increases your ability for daily chores, balance, and strength. Resistance training includes activities like yoga, dance, and grappling. Those with type 2 diabetes should make an effort to perform two to three resistance exercises per week [74,75].

9 Treatment of diabetes mellitus

9.1 Insulin treatments

Insulin was discovered in 1921, and human clinical trials in 1922 by Banting and Best. It is made up of the peptide chains chain A and chain B. Disulfide bridges bind these two chains together. Connecting-peptide can produce immunogenic reactions. The first diabetic medication was insulin. Different types of insulin based on the onset of time and duration of action are shown in Table 1. The best way to lower hyperglycemia is with insulin treatment, which helps control glucose metabolism. It also raises high-density lipoprotein and lower triglycerides [76–82].

Table 1

9.2 Noninsulin treatments

9.2.1 Insulin secretagogues

Some medications, primarily sulfonylureas and meglitinides work by interacting with the sulfonylurea receptor present in the pancreatic cells, which increases insulin release from the pancreas [83]. Tolbutamide, chlorpropamide, tolazamide, and acetohexamide are examples of first-generation sulfonylurea whereas glibenclamide, glipizide, and glimepiride are examples of second-generation sulfonylurea [84]. The development of second-generation sulfonylurea was aided by improved efficacy, a faster onset of action, reduced plasma half-lives, and a longer duration of activity. Sulfonylurea’s side effects may include symptoms of low sugar levels such as perspiration, disorientation, and agitation [85].

9.2.2 Biguanides

It acts by boosting the body’s responsiveness to natural insulin, decreasing gastrointestinal glucose absorption, and lowering hepatic glucose synthesis. By preventing gluconeogenesis and promoting glycolysis, biguanides reduce hepatic glucose production. They increase insulin receptor activation, which enhances insulin signaling [86]. These compounds do not directly affect the production of insulin-like insulin secretagogues. Metformin, phenformin, and buformin are examples of various compounds in this group. Biguanides have antihypertriglyceridemic and vasoprotective characteristics, none of which result in hypoglycemia or weight gain. Nevertheless, biguanides frequently have gastrointestinal side effects, such as diarrhea, vomiting, cramps, nausea, and increased flatulence. Vitamin B12 absorption is thought to be diminished with long-term usage [87–89].

9.2.3 Alpha-glucosidase inhibitors

Alpha-glucosidase inhibitors are mostly not suggested for those with inflammatory bowel diseases like Crohn’s disease or ulcerative colitis, intestinal blockages, gastrointestinal disorders, or diabetic ketoacidosis, which causes the body to burn fat for energy instead of carbohydrates [90]. If a patient has a big intestinal ulcer, liver cirrhosis, or is pregnant, acarbose is not advised [91].

9.2.4 Incretin mimetics

The incretins or peptides produced by the gut include glucagon-like peptides and insulinotropic polypeptides that are glucose-dependent. A decrease in blood glucose levels is encouraged by a group of naturally occurring metabolic hormones known as incretins [92]. These hormones are released following a meal. The gut’s L cells release a peptide of 36 amino acids called glucagon-like peptide-1 after the introduction of a meal. Glucagon-like peptide-1 secretion from pancreatic beta cells is equivalent to insulin secretion [93]. In response to glucagon-like peptide-1, the pancreatic beta cells start to make and secrete insulin. The strategy utilized for treating diabetes type 1 and diabetes type 2 may be the creation of glucagon-like peptide-1 analogs with a longer half-life [94].

9.2.5 Amylin analogs

The hormone amylin is composed of a single chain of 37 amino acids. By way of insulin, pancreatic beta cells release it. By slowing stomach emptying and preventing glucagon release, it keeps blood glucose levels stable throughout fasting and after meals. It regulates how much food is ingested by adjusting the brain’s center for appetite [95]. As both diabetes type 1 and diabetes type 2 lack amylin, research, and development of amylin analogs that maintain the homeostasis of glucose. Amylin cannot be used as a medication because it aggregates and is insoluble in solution; thus, chemical analogs that can mimic the effects of amylin were created. The parenteral administration of amylin analogs is utilized to treat both diabetes mellitus type 1 and diabetes mellitus type 2 [96]. The only medication in this family is pramlintide acetate, which is sold under the trade name Symlin and is taken subcutaneously [97].

10 Innovative drugs delivery systems for treatment of diabetes mellitus

Traditional drug delivery methods are subject to several drawbacks, including ineffectiveness brought on by poor or inadequate doses, decreased potency or altered effects brought on by drug metabolism, and a lack of target selectivity [98–100]. Novel drug delivery systems (NDDSs) are emerging fields in recent years due to their advantages in reduced dosing frequency, increased bioavailability, prevention from degradation in acidic gastric environments, targeted therapeutic efficacy with a decrease in associated side effects, and more [101]. Although several NDDSs are being investigated for the treatment of various ailments, only a small number, such as microparticulate and nanoparticulate systems, have been reported for the treatment of diabetes mellitus type 2.

The particulate system is made up of miniature structures that may carry drugs inside of cells, and attaching ligands to them causes them to be recognized by certain receptors. Thus, it is believed that these methods are the most ideal ones for delivering antidiabetic medications [102].

Drugs that are trapped in microparticles can be released selectively at the desired spot. By adjusting the medication’s release rate, these systems keep the drug concentration in plasma constant. Due to their smaller size and higher surface-to-volume ratio, microparticles are used to speed up the dissolving of insoluble medicines [103].

Transcellular transport by carrier- or receptor-mediated endocytosis is the method used to move microparticulate systems. Attributable to their size, microparticles cannot overcome the tight connections of the mucosal membrane to enter cells via paracellular transport, whereas nanoparticulate systems exhibit better intracellular uptake than microparticulate systems [104]. Polymeric nanoparticles (NPs), metallic NPs, lipid-based NPs, and biological NPs are the many subcategories of nanoparticles [105]. Via cellular absorption mechanisms such as transcellular and paracellular pathways, nanoparticles transport the medications they have captured [106]. In addition, the NPs exhibit enhanced mucoadhesion because they interact electrostatically with the negatively charged mucus and endothelium layer to remain in the gastrointestinal system.

The insoluble pharmaceuticals of Biopharmaceutical Classification System (BCS) classes II and IV are included in a liquid form of an oil-in-water nanoemulsion with a particle size of 200 nm or less [107]. It increases the solubility of medications and creates a broad interfacial area to speed up the pace at which insoluble pharmaceuticals are absorbed [108]. A different technique of administration of medication than oral and parenteral is the transdermal delivery system. A transdermal delivery system is a low-cost, noninvasive treatment that patients may administer themselves. A transdermal delivery system may solve the issue of medication first-pass metabolism metabolizing very quickly. With the aid of permeability enhancers, the transdermal delivery system may be a viable alternative for the administration of hydrophilic medications, macromolecules, and vaccinations [109] Table 2 summarizes research outcomes of various types of nanoparticles investigated for treatment of diabetes mellitus.

Table 2

11 Conclusion and future perspectives

Type 2 diabetes is a highly frequent chronic metabolic disease. Although being an important topic of research, there is still much to learn about the physiopathology of this condition because it is unknown what causes it and several factors seem to be involved. The reasons for molecular diabetes development are still being studied. Diabetic cardiovascular issues are the most frequent long-term diabetes complications, which are associated with death as well as disability. The rising costs of its complications and management make diabetes a huge financial burden as well. The development of diabetes and the course of the illness are both significantly influenced by oxidative stress, as is well documented in this chapter. Many inflammatory mediators implicated in several chronic illnesses are activated by oxidative stress. According to clinical data, oxidative stress and inflammation brought on by excessive ROS generation are likely to play a significant role in the development of a number of illnesses, including chronic disorders connected to inflammation. As a result, oxidative stress not only aids in the progression of the illness but also plays a role in it. To comprehend how ROS are engaged in the illness, we have concentrated on the most significant pathways implicated in ROS formation during the onset and progression of diabetes. As we have demonstrated, inflammaging is linked to vascular function decrease, a significant risk factor for the development of cardiovascular disease. Moreover, oxidative stress, which results from cellular senescence and a lack of adaptive immunological function (immunosenescence), is a hallmark of age-onset illnesses including cardiovascular disease. Even though ocular tissues from diabetes patients were discovered to have considerably higher amounts of VEGF. The principal treatments for type 2 diabetes include insulin secretagogues, biguanides, alpha-glucosidase inhibitors, incretin mimetics, amylin antagonists, and sodium-glucose co-transporter inhibitors. Dual drug regimens are typically advised for patients who are unable to accomplish treatment objectives with first-line oral hypoglycemic medications used as monotherapy. Traditional dosage formulations have variable bioavailability and brief half-lives, which need repeated dosing and amplify adverse effects despite the great therapeutic benefits. Nanotechnology-based approaches are more appealing due to the added benefit of site-specific medicine administration with enhanced bioavailability and a more variable dosing schedule, which is relevant given the pathological complexity of the aforementioned condition.

References

[1] Rathor S., Bhatt D.C. Formulation, characterization, and pharmacokinetic evaluation of novel glipizide-phospholipid nano-complexes with improved solubility and bio-availability. Pharm Nanotechnol. 2022;10(2):125–136. doi:10.2174/2211738510666220328151512.

[2] Arunachalam S., Gunasekaran S. Diabetic research in India and China today: from literature-based mapping to health-care policy. Curr Sci. 2002. ;9(10):1086–1097.