Biochemical Immunology of Diabetes and Associated Complications

Biochemical Immunology of Diabetes and Associated Complications offers in-depth coverage of the association of biochemical and immunological aspects of the human body in diabetes. It discusses the suppression and modulation of the immune system and the impact of immunochemicals on the biochemical pathways in diabetes, and associated complications. It enumerates the exigency in knowledge about the immunomodulators as therapeutic targets to cure the syndrome. This book will serve as an important reference for medical practitioners, researchers, medical students, masters and doctoral students of life sciences background. It could also be used as a reference book for science graduates, science teachers and researchers from academia and industry.

• Presents information on Immunosuppression and Immunomodulation that directly or indirectly affects the biochemistry underlying diabetes
• Highlights the association of immunological and biochemical aspects in diabetes to gain a better understanding in handling the disease
• Presents the latest research on inflammatory-mediated responses in the development of diabetes
• Includes a chapter of Case studies related to the diseases in question

• Language: English
• Publisher: Academic Press
• Release date: Mar 15, 2024
• ISBN: 9780443131967

Book preview

Chapter 1: Types of diabetes mellitus, mechanism of insulin resistance and associated complications

Arvind Singh Jadon¹, Mahabir Parshad Kaushik¹, Kuttiappan Anitha², Shvetank Bhatt³, Poonam Bhadauriya⁴, and Manoj Sharma⁵     ¹Amity Institute of Pharmacy, Amity University Madhya Pradesh (AUMP), Gwalior, Madhya Pradesh, India     ²Department of Pharmacology, School of Pharmacy and Technology Management (SPTM), SVKM’s Narsee Monjee Institute of Management Studies (NMIMS) Deemed-to-University, Shirpur, Maharashtra, India     ³School of Health Science and Technology, Dr. Vishwanath Karad MIT World Peace University, Pune, Maharashtra, India     ⁴Institute of Professional Studies, College of Pharmacy, Gwalior, Madhya Pradesh, India     ⁵School of Studies in Pharmaceutical Sciences, Jiwaji University, Gwalior, Madhya Pradesh, India

Abstract

Diabetes mellitus is a metabolic condition caused by a decrease in insulin release or insulin resistance. Insulin may be released in normal amounts in type 2 diabetes mellitus; however receptor desensitization is observed which leads to insulin resistance. Insulin resistance, also known as decreased insulin sensitivity, occurs when cells in your muscles, fat, and liver do not respond properly to insulin, a hormone produced by your pancreas that is necessary for survival and regulates blood glucose (sugar) levels. Insulin resistance can be temporary or chronic, and in some circumstances, it can be treated. Insulin resistance often leads to an increase in insulin synthesis (hyperinsulinemia) in order for your body to maintain healthy blood sugar levels. Elevated insulin levels can lead to weight gain, which exacerbates insulin resistance. Various studies have reported that the diabetic patients are more susceptible to several infections. Diabetic subjects are more prone to infections as a result of hyperglycemia-induced dysfunction of immune system. People with diabetes have increased risk of lower respiratory tract infections like pulmonary tuberculosis and pneumonia, urinary tract infections, and skin and soft tissue infections. Moreover, consumption of food with high glycemic index causes the worsening of symptoms of diabetes mellitus. This chapter mainly put a light on better understanding of type of diabetes mellitus, insulin resistance, mechanism of insulin resistance, monitoring of insulin secretion and resistance as well as complications associated with insulin resistance.

Keywords

Cellular process; Clinical endocrinology; Diabetes; Diabetes mellitus; Diabetic complications; Endocrine disorder; Insulin receptor; Insulin resistance; Metabolism; Pathological process; Therapeutic procedure; Type of diabetes

1. Introduction to diabetes mellitus

Diabetes mellitus (DM) is a metabolic disorder characterized by abnormally increased blood glucose levels. Diabetes mellitus is derived from the Greek term diabetes, which means to pass through, and the Latin word mellitus, which means sweet (Mering & Minkowski, 1890).

Diabetes is a collection of metabolic illnesses characterized by hyperglycemia caused by insulin production, insulin action, or both. Diabetes-related chronic hyperglycemia is linked to long-term damage, malfunction, and failure of several organs, including the eyes, kidneys, nerves, heart, and blood vessels.

Diabetes is characterized by anomalies in glucose, lipid, and protein metabolism caused by insulin's ineffective action on target tissues. Inadequate insulin action is caused by insufficient insulin production and/or decreased tissue responses to insulin at one or more locations along the complicated hormone action pathways. Insulin secretion and insulin action deficiencies commonly occur in the same patient, and it is sometimes unclear which anomaly, if either alone, is the major cause of hyperglycemia.

Clinical features similar to diabetes mellitus were described 3000 years ago by the ancient Egyptians. In Greek, diabetes means to go through. According to historical records, Greek physician Apollonius of Memphis coined the name diabetes approximately 250–300 BCE, for its top symptom: a disease that drains patients of more fluid than they can consume. The sweet flavor of urine in this ailment was discovered by ancient Greek, Indian, and Egyptian civilizations, and so the term Diabetes Mellitus was born. They tested for diabetes which they called honey urine by determining if ants were attracted to a person's urine (Lakhtakia, 2013). In earlier times, a diagnosis of diabetes was likely a death sentence. The investigations of Minkowski and von Mering in 1889 were a watershed moment in the history of diabetes mellitus. They established the involvement of the pancreas in diabetes etiology (Mering & Minkowski, 1890). At the University of Toronto, Banting, Best, and Collip isolated the hormone insulin from the cow pancreas, resulting in the availability of a successful diabetic medication in 1922 (Banting et al., 1922). Frederick Banting and John MacLeod were given the Nobel Prize in Medicine in 1923 for discovering insulin. To address this expanding problem, the excellent effort has been done throughout the years, as well as several discoveries and management solutions. Unfortunately, diabetes remains one of the most common chronic diseases in the country and throughout the world. It is still the seventh greatest cause of mortality in the United States.

1.1. Type of diabetes mellitus

The great majority of diabetes patients fit into one of two basic etiopathogenetic groups. The etiology of one kind of diabetes, type 1, is an utter lack of insulin secretion. Serological evidence of an autoimmune pathologic process occurring in the pancreatic islets and genetic markers may typically identify individuals at elevated risk of developing this kind of diabetes. Type 2 diabetes, on the other hand, is caused by a combination of insulin resistance and an insufficient compensatory insulin secretory response. A level of hyperglycemia sufficient to produce pathologic and functional alterations in many target tissues, but without clinical symptoms, may exist for a long time before diabetes is diagnosed. During this asymptomatic time, an imbalance in carbohydrate metabolism can be demonstrated by measuring plasma glucose in the fasting state or following a challenge with an oral glucose load (Nathan et al., 2009).

The factors that existed at the time of a person's diagnosis typically define their type of diabetes, and many diabetics do not neatly fall into a single class. A woman with gestational diabetes mellitus (GDM), for example, may continue to have high blood sugar levels after delivery and be diagnosed with type 2 diabetes. Alternatively, a person who develops diabetes as a result of high doses of exogenous steroids may become normoglycemic if the glucocorticoids are stopped, but then develop diabetes many years later as a result of recurrent pancreatitis. Another example might be a thiazide-treated person who gets diabetes years later. Because thiazides seldom induce significant hyperglycemia, such people most likely have type 2 diabetes that is aggravated by the medicine. Thus, for the physician and patient, understanding the pathophysiology of hyperglycemia and treating it successfully is more essential than labeling a specific kind of diabetes (Genuth et al., 2003).

The list shown in Table 1.1 is not all-inclusive but reflects the more commonly recognized drug-, hormone-, toxin-induced, and other forms of diabetes (Genuth et al., 2003; Kahn, 1997).

Table 1.1

a In the absence of unequivocal hyperglycemia, criteria 1-3 should be confirmed by repeat testing.

1.1.1. Etiologic classification of diabetes mellitus

1. Type 1 diabetes mellitus (β-cell destruction, usually leading to absolute insulin deficiency)

a. Immune-mediated diabetes mellitus

b. Idiopathic diabetes mellitus

2. Type 2 diabetes mellitus (may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance)

3. Other specific types of diabetes mellitus

a. Genetic defects of β-cell function

i. Chromosome 12, HNF-1α (MODY3)

ii. Chromosome 7, glucokinase (MODY2)

iii. Chromosome 20, HNF-4α (MODY1)

iv. Chromosome 13, insulin promoter factor-1 (IPF-1; MODY4)

v. Chromosome 17, HNF-1β (MODY5)

vi. Chromosome 2, NeuroD1 (MODY6)

vii. Mitochondrial DNA

b. Genetic defects in insulin action

i. Type A insulin resistance

ii. Leprechaunism

iii. Rabson-Mendenhall syndrome

iv. Lipoatrophic diabetes

c. Diseases of the exocrine pancreas

i. Pancreatitis

ii. Trauma/pancreatectomy

iii. Neoplasia

iv. Cystic fibrosis

v. Hemochromatosis

vi. Fibrocalculous pancreatopathy

d. Endocrinopathies

i. Acromegaly

ii. Cushing's syndrome

iii. Glucagonoma

iv. Pheochromocytoma

v. Hyperthyroidism

vi. Somatostatinoma

vii. Aldosteronoma

e. Drug or chemical-induced diabetes mellitus

i. Vacor

ii. Nicotinic acid

iii. Pentamidine

iv. Glucocorticoids

v. Thyroid hormone

vi. Diazoxide

vii. β-Adrenergic agonists

viii. Thiazides

ix. Dilantin

x. ϒ-Interferon

f. Diabetes induced by infections

i. Congenital rubella

ii. Cytomegalovirus

g. Uncommon forms of immune-mediated diabetes

i. Stiff-man syndrome

ii. Anti-insulin receptor antibodies

h. Other genetic syndromes, sometimes associated with diabetes

i. Down syndrome

ii. Klinefelter syndrome

iii. Turner syndrome

iv. Wolfram syndrome

v. Friedreich ataxia

vi. Huntington chorea

vii. Laurence-Moon-Biedl syndrome

viii. Myotonic dystrophy

ix. Porphyria

x. Prader–Willi syndrome

xi. Others

4. Gestational diabetes mellitus (GDM)

1.1.1.1. Type 1 diabetes mellitus (β-cell destruction, usually leading to absolute insulin deficiency)

1.1.1.1.1. Immune-mediated diabetes mellitus

This kind of diabetes, which affects only 5%–10% of persons with the condition and was previously known as type 1 diabetes, juvenile-onset diabetes, or insulin-dependent diabetes, is caused by an autoimmune reaction that destroys pancreatic beta cells via molecular processes. Islet cell autoantibodies, insulin autoantibodies, GAD (GAD65) autoantibodies, and autoantibodies to the tyrosine phosphatases IA-2 and IA-2β are all markers of immunological destruction of β-cells. When fasting hyperglycemia is first discovered, one or more of these autoantibodies are present in 85%–90% of people. Furthermore, the illness has substantial HLA correlations, with DQA and DQB gene links, and it is impacted by the DRB genes. These HLA-DR/DQ alleles can be protective or predisposing. The pace of β-cell death in this kind of diabetes is extremely diverse, being quick in some persons (mostly babies and children) and moderate in others (primarily adults). Ketoacidosis may be the initial symptom of the illness in certain people, particularly children and adolescents. Furthermore, some people have mild fasting hyperglycemia, which can quickly progress to severe hyperglycemia and/or ketoacidosis in the presence of illness or other stress. Others, particularly adults, may have residual β-cell activity for many years, allowing them to avoid ketoacidosis; nonetheless, such people eventually become insulin-dependent and are at danger of ketoacidosis. At this stage of the illness, there is little or no insulin production, as evidenced by low or undetectable plasma C-peptide levels. Immune-mediated diabetes is most frequent in childhood and adolescence, although it can strike at any age, including the eighth and ninth decades of life. Autoimmune destruction of β-cells has numerous genetic predispositions and is also linked to unknown environmental variables. Although people with this form of diabetes are rarely obese, the presence of obesity is not incompatible with the diagnosis. Other autoimmune conditions that these people are prone to include Graves' disease, Hashimoto's thyroiditis, Addison's disease, vitiligo, celiac sprue, autoimmune hepatitis, myasthenia gravis, and pernicious anemia (Kahn,