Preface

Nitric oxide (NO) is a colorless, odorless, primordial flammable gas that has been present in the earth's atmosphere from the beginning of time. Historically, NO was regarded as an industrial toxin or pollutant generated in many industries; however, it is now well recognized that NO is endogenously produced and has an important biological role in most mammalian tissues. The vital role of NO in human biology was recognized in 1992 when the journal Science introduced NO as the “Molecule of the Year” [1] and in 1998 when the Nobel Prize in Physiology and Medicine was awarded to Robert F. Furchgott, Louis J. Ignarro, and Ferid Murad for the major discoveries surrounding it and establishing its role as a messenger molecule.

According to the World Health Organization (WHO), the prevalence of obesity across the globe has approximately doubled since 1980. In the U.S., about one-third of the adult population is obese, and an additional one-third is overweight [2]. Obesity is the fastest-growing lethal disease in Western and developing countries. People do not die due to obesity itself but from its complications, which shorten the life span [3, 4]. In addition, obesity leads to many other diseases, including type-2 diabetes (T2D) and its complication. T2D, which used to be referred to as adult-onset or non-insulin-dependent diabetes, accounts for over 90–95% of all diabetes; T2D is a complex metabolic disorder essentially characterized by alterations in lipid metabolism, insulin resistance, and pancreatic β-cell dysfunction [5]. Unfortunately, there are no effective treatments available for T2D, although there have been many developments in the therapeutic arena [6]. Hence there is an urgent need to develop new preventative and/or therapeutic strategies to combat T2D.

Over the past three decades, NO has emerged as a central regulator of energy metabolism and body composition. NO bioavailability is decreased in animal models of diet-induced obesity and in obese and insulin-resistant patients, and increasing NO output has remarkable effects on obesity and insulin resistance [7]. This volume is a collection of reviews dealing with The Role of Nitric Oxide in Type 2 Diabetes”. These reviews provide a unique overview of NO signaling, pointing out key areas for more detailed research. We hope that the breadth of the topics covered in this volume will provide new perspectives and help to stimulate research towards unanswered questions.

Chapter 1 is an overview of the pathophysiology of T2D by Drs. Ghasemi and Kashfi entitled, “Pathophysiology of Type 2 Diabetes: A General Overview of Glucose and Insulin Homeostasis”. A better understanding of the pathophysiology of T2D provides an opportunity for revising the current therapeutic modalities, from a primary glycemic control to a pathophysiological-based approach. This chapter provides essential information on glucose homeostasis and the pathophysiology of T2D. Chapter 2 by Drs. Ghasemi and Kashfi is entitled “Nitric oxide: A Brief History of Discovery and Timeline of its Research.” This chapter highlights the discovery of NO in mammals and its role as a signaling molecule. The overview describes the chronological development of NO, emphasizing the events in the last two decades of the 20th century. Chapter 3 is a review by Drs. Bahadoran, Carlström, Mirmiran, and Ghasemi entitled, “Impaired Nitric Oxide Metabolism in Type 2 Diabetes: At a Glance”. Abnormal NO metabolism is associated with the development of insulin resistance and T2D, which in turn can lead to impaired NO homeostasis. The concept of NO deficiency is supported by results from human studies on polymorphisms of endothelial NO synthase (eNOS) gene, animal knockout models for NO synthase isoforms (N.O.S.s), and pharmacological inhibitors of N.O.S. This chapter focuses on the role of impaired NO metabolism in T2D.

Chapter 4 by Drs. Bahadoran, Carlström, Mirmiran, and Ghasemi is entitled “Asymmetrical Dimethyl Arginine, Nitric Oxide, and Type 2 Diabetes”. Asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of nitric oxide synthases. Over-production leads to decreased NO bioavailability and diabetes complications, including cardiovascular diseases, nephropathy, and retinopathy, with increased mortality risk. This chapter discusses how disrupted ADMA metabolism contributes to the development of T2D and its complications. Chapter 5 is a contribution by Drs. Bahadoran, González-Muniesa, Mirmiran, and Ghasemi is entitled, “Nitric Oxide-Related Oral Microbiota Dysbiosis in Type 2 Diabetes”. This chapter gives an overview of oral microbiota dysbiosis in T2D, focusing on nitrate-reducing bacteria and their metabolic activity.

Chapter 6, entitled “Nitric oxide and Type 2 Diabetes: Lessons from Genetic Studies”, is a contribution by Drs. Bahadoran, Mirmiran, Carlström, and Ghasemi. They discuss current genetic data linking NO metabolism to metabolic disorders, especially insulin resistance and T2D. Chapter 7 is a contribution by Dr. Afzali, Miss Ranjbar, and Drs. Kashfi and Ghasemi entitled, “Role of Nitric Oxide in Diabetic Wound Healing.” NO deficiency is an important mechanism responsible for poor healing in diabetic wounds. The beneficial effects of NO in wound healing are related to its antibacterial properties, regulation of inflammatory response, stimulation of proliferation, differentiation of keratinocytes and fibroblasts, and promotion of angiogenesis and collagen deposition. In this chapter, the function of NO in diabetic wound healing and the possible therapeutic significance of NO in the treatment of diabetic wounds are discussed.

Chapter 8 is entitled “Role of Nitric Oxide in Type 2 Diabetes-Induced Osteoporosis” by Drs. Yousefzadeh, Jeddi, Kashfi, and Ghasemi. Diabetoporosis, which is osteoporosis in type 2 diabetic patients, contributes to and aggravates osteoporotic fractures. Decreased eNOS-derived NO and higher iNOS-derived NO are some of the critical mechanisms in diabetoporosis. This chapter closely examines the role of NO in diabetoporosis. Chapter 9 by Drs. Bahadoran, Mirmiran, Kashfi, and Ghasemi is entitled, “Hyperuricemia, Type 2 Diabetes and Insulin Resistance: Role of Nitric Oxide”. Hyperuricemia is a risk factor for developing hypertension, cardiovascular diseases, chronic kidney disease, and T2D. It leads to the development of systemic insulin resistance, impaired NO and glucose metabolism, with induction of inflammation and oxidative stress. This chapter highlights the mediatory role of NO metabolism on hyperuricemia-induced dysglycemia and insulin resistance. Chapter 10 is entitled “Therapeutic management of type 2 diabetes: The nitric oxide axis,” by Ms. Ranjbar, O’Connor, and Dr. Kashfi. Current drugs approved for the management of T2D include biguanides, thiazolidinediones, sulfonylureas, meglitinides, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, alpha-glucosidase inhibitors, and sodium-glucose co-transporter 2 (SGLT2) inhibitors. In this chapter, the authors discuss these drugs, examine their mechanism of action, and present evidence that these drugs directly or indirectly modulate NO metabolism.

In Chapter 11, “Brain Insulin Resistance, Nitric Oxide and Alzheimer’s Disease Pathology,” Drs. Pei, Lee, Khan, and Wang discuss the role of NO availability in brain insulin resistance in dementia associated with Alzheimer’s disease. Chapter 12 by Drs. Mirmiran, Bahadoran, Kashfi, and Ghasemi, and is entitled “Arginine, Nitric Oxide and Type 2 Diabetes”. In this chapter, the authors provide an overview of the potential efficacy of L-arginine (Arg) as an NO precursor and its effects on glucose and insulin homeostasis and diabetes-induced cardiovascular complications. Chapter 13 is also by Drs. Mirmiran, Bahadoran, Kashfi, and Ghasemi and is entitled “Citrulline, Nitric Oxide and Type 2 Diabetes”. L-Citrulline (Cit) is a precursor of Arg and is involved in NO synthesis. Oral ingestion of Cit effectively elevates total Arg flux and promotes NO production. In this chapter, the authors discuss the potential use of Cit as an effective anti-diabetic agent.

Recent data suggest the utility of the nitrate-nitrite-nitric oxide (NO₃-NO₂-NO) pathway in treating T2D. Supplementation with inorganic NO₃-NO₂ in animal models of T2D resulted in improved hyperglycemia, insulin sensitivity, and glucose tolerance [8-10]. However, the efficacy of NO₃-NO₂ supplementation on glucose and insulin homeostasis in humans is unproven. In chapter 14, entitled “Nitrate, Nitrite, and Type 2 Diabetes’, Drs. Bahadoran, Mirmiran, Kashfi, and Ghasemi review the animal experiments and human clinical trials, addressing the potential effects of inorganic NO₃/NO₂ on glucose and insulin homeostasis in T2D. They also provide several plausible scenarios to address the challenge of lost-in-translation of beneficial effects of inorganic NO₃ and NO₂ from bench to bedside.

The final chapter of this book, chapter 15, is a review by Drs. Bahadoran, Mirmiran, Bahmani, and Ghasemi entitled, “Potential Applications of Nitric Oxide Donors in Type 2 Diabetes”. NO-donors have increasingly been studied as promising therapeutic agents for insulin resistance and T2D. This chapter reviews the effects of sodium nitroprusside, S-nitrosothiols, and N-diazeniumdiolates on glucose and insulin homeostasis.

We hope that the breadth of topics covered in this volume will provide the readers with new perspectives, give some food for thought, and stimulate more research into major unanswered questions.