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Type 2 diabetes (T2D) is a complex metabolic disorder characterized by impaired glucose metabolism and pancreatic β-cell dysfunction. No effective treatments are available for T2D, although there have been many developments in the therapeutic arena. Nitric oxide (NO) is an endocrine agent with multiple and important biological roles in most mammalian tissues. NO has emerged as a central regulator of energy metabolism and body composition. NO bioavailability is decreased in T2D. Several of the pharmaceuticals used in T2D affect the NO system and perhaps even more so by the drugs we use to treat diabetic cardiovascular complications. Experimental works in animal models of T2D show promising results with interventions aimed to increase NO signaling. However, translation into human studies has so far been less successful, but more large-scale prolonged studies are clearly needed to understand its role.
This book is a collection of reviews that deal with the role of nitric oxide in type 2 diabetes, providing a unique overview of NO signaling, and pointing out key areas for more detailed research. The book includes contributions about the pathophysiology of T2D, a brief history of discovery and timeline of NO research, a comprehensive overview of impaired NO metabolism in T2D, precursors of NO (i.e., L-arginine, L-citrulline, nitrate, nitrites, and NO donors), NO and T2D from genetic points of view, NO and diabetic wound healing, NO and osteoporosis, NO and hyperuricemia, NO and Alzheimer’s Disease, therapeutic applications of NO and NO donors in T2D. The compilation is of great value to anyone interested in the biochemistry of NO and its relationship to diabetes.
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The global obesity and overweight pandemic that causes the increasing number of patients with type 2 diabetes (T2D) is a major challenge for healthcare systems worldwide. With its cardiovascular complications, this metabolic disorder is one of the major causes of morbidity and mortality worldwide. On top of lifestyle and dietary recommendations to prevent or control T2D, a tremendous amount of research has been invested in understanding disease mechanisms better and developing novel drugs. Even if new pharmaceuticals have entered the clinical arena in recent years, metformin is still the first-line option, even after more than 60 years. This points to the necessity to develop therapeutic strategies based on biological pathways that have not previously been the center focus of diabetes research. Such an area is nitric oxide research.
Nitric oxide (NO) is one of the universal signaling molecules in mammalian species. When discovered in the 1980s, it portrayed a completely novel principle, where a small, unstable, and reactive free radical gas was involved in cell signaling. Its chemical nature makes it react with other radicals and transition metals; one example of the latter is how NO activates soluble guanylyl cyclase to generate cGMP, a classical form of NO signaling that, e.g., induces vasodilation. Binding to heme in cytochrome c oxidase, leading to inhibition of mitochondrial respiration, is another example. In addition, post-translational nitrosation of many proteins, which regulates their function, is another signaling modality of NO. This pluripotency of NO explains why it is involved in regulating such diverse processes as cardiovascular function, metabolism, inflammation, and nerve signaling. The canonical pathway for NO generation involves the substrates L-arginine and molecular oxygen and specific NO synthases (N.O.S.s), of which there are three isoforms. Two of them are more constitutively expressed (endothelial N.O.S. and neuronal N.O.S.), while an inducible isoform (inducible N.O.S.) is involved during inflammatory conditions. The half-life of NO is within seconds due to binding to heme or to rapid oxidation, which forms the inorganic anions nitrite and nitrate that are widely used both in vitro and in vivo as more stable surrogate measures of NO.
Interestingly, discoveries in the mid-1990s revealed that these supposedly inert anions could be recycled back to bioactive NO and other reactive nitrogen species. The first step in this nitrate-nitrate-NO pathway involves active uptake of circulating nitrate in the salivary glands, after which nitrate in the saliva is reduced to nitrite by oral commensal bacteria, a function that mammalian cells are poor in performing. Swallowed salivary nitrite is rapidly absorbed in the gut, and then there are several pathways for further reduction to NO. Of interest is that the nitrate-nitrite-NO pathway can be fueled by a diet where certain vegetables contain high levels of nitrate. This pathway can be viewed as a parallel backup system to the L-arginine-NOS-NO pathway, perhaps with more importance during hypoxic and ischemic conditions.
This book, to my knowledge, is the first of its kind, Asghar Ghasemi and collaborators present a comprehensive and detailed overview of our current knowledge on the role of NO in T2D. The rationale for this book is the growing evidence of the involvement of the NO system in diabetes. An impressive amount of research has clarified that NO is deeply involved on many levels to uphold metabolic homeostasis and that NO signaling is negatively affected in T2D. Of interest is that several of the pharmaceuticals used in T2D affect the NO system and perhaps even more so by the drugs we use to treat diabetic cardiovascular complications. Experimental works in animal models of obesity or T2D show promising results with interventions aimed to increase NO signaling. However, translation into human studies has so far been less successful, but larger and more prolonged studies are clearly needed. There is an intriguing dietary aspect here since NO bioavailability can be boosted by nitrate in our diet, which is supported by epidemiological studies showing that green leafy vegetables, which are high in nitrate, stand out as particularly protective against the development of T2D and cardiovascular disease. Clearly, more research on the role of NO in metabolic regulation and T2D is needed, and in this context, the present book is of great value to anyone interested in this field of research.
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.
The prevalence of diabetes is increasing worldwide, and this disease has a tremendous financial burden on most countries. Major types of diabetes are type 1 diabetes and type 2 diabetes (T2D); T2D accounts for 90-95% of all diabetic cases. For better management of diabetes, we need to have a better understanding of its pathophysiology. This chapter provides an overview of glucose homeostasis and the underlying pathophysiology of T2D.
Diabetes is the largest epidemic in human history [1], and there is currently a rapid-growing diabetes pandemic [2]. From 1980 to 2014, the total number of subjects with diabetes has quadrupled [3, 4]. More than 70% of global mortality is attributed to non-communicable diseases, including diabetes [5, 6]. Diabetes is the ninth leading cause of death [7], and in 2017, it caused one death every eight seconds (2.1 and 1.8 million in women and men aged 20–79 years, respectively) [2]. On average, healthcare expenditures for diabetic subjects are two-fold higher than those without diabetes [2]; in addition, approximately 79.4% of people with diabetes live in low- and middle-income countries [8]. Hyperglycemia is the third leading modifiable cause of death after high blood pressure and tobacco use [3]. A better understanding of the pathophysiology of type 2 diabetes (T2D) provides
an opportunity for revising the current therapeutic modalities in the management of T2D, from a primary glycemic control to a pathophysiological-based approach. This chapter provides essential information on glucose homeostasis and the pathophysiology of T2D.
Amongst adults aged 20–79 years, the worldwide prevalence of diabetes in 2019, was 9.3% (9.0% in women and 9.6% in men), and unfortunately, this is expected to rise to 10.2% (578.4 million) and 10.9% (700.2 million) in 2030 and 2045, respectively [8]. There is considerable geographical/cultural heterogeneity relating to the incidence of diabetes. For example, the crude incidence of diabetes ranges from 2.9 per 1000 population in France to 23.5 per 1000 population in the Pima Indians of the United States [9]. Also, the incidence of diabetes increases with age because of decreased ability of the β-cells to compensate for insulin resistance [10]. Major types of diabetes are type 1 and type 2. Type 1 diabetes accounts for 5-10% of all diabetes [2], and patients require insulin therapy. Type 2 diabetes, which used to be referred to as adult-onset or non-insulin-dependent diabetes, accounts for over 90–95% of all diabetes [11]; T2D is a complex metabolic disorder essentially characterized by alterations in lipid metabolism, insulin resistance, and pancreatic β-cell dysfunction [12, 13].
Worldwide, the prevalence of prediabetes is also increasing [14]. Prediabetes is defined as a state of higher than normal glycemia that does not meet the established criteria for diabetes diagnosis and includes subjects with impaired fasting glycemia (IFG), impaired glucose tolerance (IGT), or both [11]. Prediabetes can predict the risk of developing diabetes [11, 15], and in some subjects, it can be alleviated by lifestyle modifications or pharmacological interventions, such as metformin administration [16]. Table 1 summarizes some statistical data about diabetes according to the International Diabetes Federation (IDF) report.
Diabetes is diagnosed using glucose-based criteria, i.e., fasting plasma glucose (FPG) levels or 2-h plasma glucose (2-hPG) levels during a 75-g oral glucose tolerance test; hemoglobin A1c (HbA1C) levels are also used as an indicator [11, 17]. Table 2 provides diagnostic criteria for T2D according to the World Health Organization (WHO) and the American Diabetes Association (ADA).
Maintaining blood glucose concentrations within a physiologic range, either in a fasted state or excess nutrient availability, is essential for keeping normal bodily functions [18]. This critical homeostasis is achieved through a complex network involving hormones and neuropeptides released mainly from the brain, pancreas, liver, intestine, adipose tissue, and skeletal muscle [19].
Nutrient sensing and hormonal signaling regulate glucose homeostasis, controlling tissue-specific glucose utilization and production [18]. With the use of homeostatic mechanisms, the body protects itself against either hyperglycemia (and its complications, i.e., retinopathy, neuropathy, nephropathy, premature atherosclerosis, diabetic ketoacidosis, and hyperosmolar hyperglycemic state) or hypoglycemia, which can cause cardiac arrhythmias, neurological dysfunction, coma, and death [20]. Fig. (1) shows how circulating glucose concentrations are determined by the balance changes of plasma glucose concentrations in normal subjects.
Fig. (1)) Variations of plasma glucose concentrations in normal subjects. Normal range of circulating fasting glucose concentration is 70-100 mg/dL [21]. Plasma glucose concentrations range from a minimum of 55 mg/dL during fasting to a maximum of 160 mg/dL after a meal [20, 22, 23], and its daily average is ~85-90 mg/dL [22, 24] as shown by blue point. The glucose concentration at which glucose first appears in the urine (the renal threshold for glucose) occurs at a venous plasma glucose concentration of ~180 mg/dL [25]. To convert glucose concentration from mg/dL multiplied by 0.05551. Created with BioRender.com.As shown in Fig. (2) in the post-absorptive state (i.e., 12-16 h after the last meal), the rate of endogenous glucose production (EGP) is about 1.8–2 mg/kg/min (10-11 μmol/kg/min) in humans and is equal to the rate of basal glucose utilization [20, 26, 27]; this compares with maximal insulin-stimulated glucose utilization that is ~10-11 mg/kg/min [28]. Rate of EGP in post-absorptive state is about 10% lower in elderly (75±4 y) than young (24±3 y) subjects (2.18 vs. 2.41 mg/kg/min) [29].
Fig. (2)) Glucose homeostasis in the fasted state. Endogenous glucose production (EGP), mainly by the liver and to a lesser extent by the kidney, is precisely matched with glucose utilization. Hepatic glucose production (HGP), the primary determinant of fasting blood glucose concentration, is equally derived from glycogenolysis and gluconeogenesis. Lactate is the most important gluconeogenic substrate. After overnight fasting, ~80% of glucose is used via insulin-independent pathways, and the brain uses about half of the total glucose. Reproduced with permission and modifications from [35], Ghasemi, A and Norouzirad, R, Critical Reviews in Oncogenesis, 2019; 24(2): p. 1-10.During fasting, about 75-85% of EGP (or even up to 100% in short fasting) that is about 1.8-2 mg/min, occurs in the liver and about 15% (5-20%) in the kidneys [22, 26, 30]. Hepatic glucose production (HGP) is the main determinant of fasting glycemia [31, 32]. The rate of liver glycogen depletion during fasting is about 100 mg/min or 9% per hour [33]; after a 48-h fasting period, all released glucose is provided through gluconeogenesis by the liver and the kidneys [20]. However, after >8 hours of fasting, gluconeogenesis progressively replaces glycogenolysis to preserve glycogen stores; and following 10-hour of fasting, gluconeogenesis and glycogenolysis account for 70% and 30% of total HGP, respectively [33]. Renal gluconeogenesis takes place in the proximal tubular cells and contributes 0, 5, and 10% to the overall glucose production after overnight fasting (10-16 h), moderate fasting (30-60 h), and prolonged fasting (>1 week), respectively [22]. In post-absorptive state, substrate for hepatic gluconeogenesis are lactate (40%), alanine (27%), glycerol (13%), glutamine (10%), and other amino acids (10%) [27]. In the case of renal gluconeogenesis, substrates include lactate (50%), glutamine (20%), alanine (15%), glycerol (10%), and other amino acids (5%) [27].
Overall, the rate of glucose release into the circulation in the fasting state is about 1.8–2.0 mg/kg/min, supported by hepatic glycogenolysis (45-50% by rate of 0.8-0.9 mg/kg/min), hepatic gluconeogenesis (25-30%, 0.45-0.55 mg/kg/min), and renal gluconeogenesis (20-25%, 0.35-0.45 mg/kg/min) [20].
In the fasted state, glucose utilization (~1.8-2.0 mg/kg/min), which is mainly insulin-independent, mostly occurs in the brain (40-45%), muscle (15-20%), liver (10-15%), gastrointestinal tract (5-10%), and kidney (5-10%) Fig. (2). In the basal state, the central nervous system accounts for a large percentage of glucose utilization [29]. In both absorptive and post-absorptive states, the brain utilizes glucose at a rate of 1-1.2 mg/kg/min, mostly insulin-independent [26] and, therefore, is not affected by diabetes [26]. Because of low plasma insulin concentration in the fasted state (5-10 μU/mL), skeletal muscle glucose uptake during fasting is low and insulin-independent [34]. In the post-absorptive state, glucose taken up by tissues is completely oxidized to CO2 or released back into the circulation as lactate, alanine, and glutamine to participate in gluconeogenesis, and there is no net storage of glucose [27].
For 4-6 h on three occasions in a day, most people are in the post-prandial state [20]. During the post-prandial period, digested nutrients are the major source of circulating glucose [36]. Following glucose ingestion, circulating glucose levels peak in 60-90 minutes and return to basal levels within 3-4 h [20]. During the post-prandial period, HGP decreases by about 67-80%, but renal glucose release increases [27, 37]. After a meal, EGP is decreased by ~61%, with hepatic glycogenolysis ceasing for 4-6 h to replenish hepatic glucose stores and limit post-prandial hyperglycemia [20]. Hepatic gluconeogenesis decreases by ~82%, and glucose generated by gluconeogenesis is largely converted to glycogen [20]. Renal gluconeogenesis increases by about 2-fold and is responsible for approximately 60% of EGP, probably to facilitate efficient repletion of hepatic glycogen stores [20]. In summary, EGP decreases to ~0.8 mg/kg/min after a meal, of which 60% is produced by renal gluconeogenesis and 40% by liver gluconeogenesis.
Post-prandial glucose utilization rate is ~10 mg/kg/min and mostly insulin-dependent [20]. In post-prandial state, glucose uptake are 30-35% in skeletal muscle, 25-30% in liver, 10-15% in gastrointestinal tract, 10-15% in kidney, 10% in brain, 5% in adipose tissue, and 5-10% in the other tissues (e.g., skin, blood cells) [20, 26]. After a meal, the skeletal muscles take up 80-90% of the available glucose, thus representing a major site of uptake [26, 34]. Of the glucose taken up by the skeletal muscle, about 70% is converted to glycogen, and approximately 30% enters glycolysis, of which 90% represents glucose oxidation, and 10% goes towards lactate release [34].
Of ingested glucose, ~45% is converted to glycogen in the splanchnic tissues, 27% is taken up by skeletal muscle and converted to glycogen, 15% is taken up by the brain, 5% by the adipose tissue, and 8% by the kidneys [20, 27]. However, splanchnic glucose uptake after oral glucose has been estimated to be from < 25% to 60% [37]. In fact, about 30% of ingested glucose is extracted by splanchnic tissues. Of 70% of which enter the systemic circulation, about 21% is extracted by the liver, 40% is taken up by the skeletal muscle, 21% by the brain, 11% by the kidneys, and 7% by the adipose tissue [27].
Glucose homeostasis is regulated by peripheral and central mechanisms [38], balancing glucose production and utilization. As shown in Table 3., glucose-sensing cells are found in the taste buds of the tongue, intestinal and pancreatic endocrine cells, and the CNS [39]. Integrated information received from these cells is used to control glucose homeostasis and maintain normoglycemia [39].
In the mid-19th century, Claude Bernard showed that brain stimulation of the fourth ventricle increases plasma glucose levels [41]. Glucose-sensing neurons are mostly found in the hypothalamus and the brain stem [39]; the hypothalamus is the brain region that contributes the most to glucose homeostasis [41].
Amongst the nuclei of the hypothalamus, the arcuate nucleus (ARC), ventromedial nucleus (VMN), and lateral hypothalamic (LH) nucleus have the most important roles in glucose regulation [39, 41]. In the brainstem, dorsal vagal complex [area postrema (AP), the nucleus tractus salitarius (NTS), and the dorsal motor nucleus of the vagus (DMNX)], and ventral part of medulla or basolateral medulla (BLM) express glucose-sensing neurons [39].
Glucose sensing by the brain occurs through glucose-excited (GE) and glucose-inhibited (GI) neurons [39, 41]. GI neurons are mostly found in the medial ARC, whereas GE neurons are mostly found in lateral ARC [41]. An increase in extracellular glucose concentration leads to an increase in the firing of GE neurons and a decrease in the firing of GI neurons [39, 41]. Brain glucose levels usually are 20-30% lower than that in the plasma, and compared to the other regions of the brain, GE neurons in ARC are exposed to higher glucose levels [41]. Glucose-sensing neurons in the hypothalamus and brainstem control the activity of peripheral organs involved in glucose homeostasis, including the liver, adipose tissue, muscles, and pancreatic islets through the activity of the autonomic nervous system (ANS) [39, 40, 42].
Pancreatic islets are richly innervated by sympathetic and parasympathetic nervous systems [19, 39, 40]. Nerve fibers from hypothalamic nuclei, PBN, LC, and BLM, reach the intermediolateral cell column of the spinal cord, from which sympathetic efferents project to the peripheral organs [39]. Increased sympathetic activity stimulates glucagon secretion, inhibits insulin secretion, enhances lipolysis in white adipose tissue (WAT), increases thermogenesis in brown adipose tissue (BAT), stimulates epinephrine secretion by the adrenals, and regulates hepatic glucose output [39]. Norepinephrine/epinephrine inhibits insulin secretion by activating α2-adrenergic receptors in the β-cells and stimulates glucagon secretion by activating β2-adrenergic receptors in the α-cells [40].
Parasympathetic efferents originate from DMNX and are controlled by NTS and some hypothalamic nuclei [39]. Parasympathetic stimulation increases insulin secretion from the β-cells in hyperglycemic conditions and increases glucagon secretion during hypoglycemia [40]. The effect of parasympathetic activation in increasing insulin secretion from the β-cells is achieved via type 3 muscarinic acetylcholine receptor activation by acetylcholine (ACh); neuropeptides released from parasympathetic endings, including vasoactive intestinal peptide (VIP), pituitary adenylate-cyclase activating peptide (PACAP), and gastrin-releasing peptide (GRP) potentiate the ACh effects [40]. Increased parasympathetic activation also stimulates β-cell proliferation [40].
High glucose levels depolarize GE neurons [42]. In GE neurons, glucose sensing is similar to that in the pancreatic β-cells in which glucose enters the cell via glucose transporter (GLUT)-2 (GLUT-2) and is phosphorylated by glucokinase (hexokinase IV) [39]. A high ATP/ADP ratio closes KATP channels and causes membrane depolarization, facilitating Ca2+ entry through voltage-dependent calcium channels [39]. Low glucose levels depolarize GI neurons [42]. In GI neurons, hypoglycemia decreases ATP production, which in turn decreases the activity of Na+/K+–ATPase and causes membrane depolarization through increased intracellular Na+ and closure of the cystic fibrosis transmembrane regulator (CFTR) chloride channels [39]. Hypoglycemia also activates AMP-activated protein kinase (AMPK), which suppresses CFTR activity; AMPK activates the NO-cGMP pathway, further activating the AMPK [39].
The pancreas contributes to glucose homeostasis mainly through the secretion of insulin and glucagon [19]. Between meals, when blood glucose levels are low, increased glucagon secretion promotes glycogenolysis and stimulates hepatic and renal gluconeogenesis during prolonged fasting [19]. In the fed state, increased circulating insulin alongside a decrease in circulating glucagon decreases EGP and promotes glucose utilization [22, 26]. About half of HGP suppression following a meal is due to stimulation of insulin secretion, and the other half is due to inhibition of glucagon secretion, indicating the importance of the insulin-to-glucagon ratio [24]. Following glucose ingestion, plasma insulin increases by 4-fold, and plasma glucagon decreases by 50% [20]. Only 30% of glucose disposal is insulin-dependent in the post-absorptive state, increasing to 85% in the post-prandial state [43]. Insulin increases muscle and adipose tissue clearance rate by 10-fold [33]. The principal fuel source of skeletal muscle is free fatty acids (FFA) and glucose in fasted and fed states, respectively; the ability of the skeletal muscle to change oxidation pattern is termed metabolic flexibility [34, 43]. Insulin also promotes glycogenesis, lipogenesis, and protein synthesis [19].
The human pancreas weighs around 90 g and contains about one million islets, each of which has ~1000 β-cells, and its insulin content is about 200-250 units [44, 45]. Each β-cell has 5-10,000 dense-core granules containing insulin, and each granule has ≥300,000 molecules of insulin [45]. Even in normoglycemic subjects, the β-cell number varies from 0.3-2.0% of the pancreatic mass [45]. Under physiological conditions, with maximal glucose concentrations, only a fraction of the granules release their insulin, estimated to be around 2%/hour [45]. Basal insulin secretion accounts for approximately 50% of insulin secretion [31], and the remainder is secreted in response to increased portal plasma glucose levels following a meal [31].
Insulin secretion in response to hyperglycemia is biphasic [2, 45]; a nadir follows the first phase, which lasts for 3-10 min and then the second phase gradually increases, lasting 60 min or more [45]. The first phase of glucose-induced insulin secretion (GSIS) is a measure of the β-cell function [46] and is preferentially impaired in T2D [45, 47] or is almost abolished [2, 48]. The second phase of insulin secretion also decreases in T2D [2].
As shown in Fig. (3), glucose enters the β-cells via GLUT2 and is phosphorylated to glucose-6-phosphate by GK. Following glycolytic and oxidative glucose metabolism, the ATP/ADP ratio increases and closes the KATP channels; this results in depolarization and opening of the voltage-dependent calcium channels, and calcium entry is followed by insulin secretion [45].
Fig. (3)) A schematic illustration representing the mechanism for insulin secretion in pancreatic β-cells. Glucose enters the cell primarily by glucose transporter-2 (GLUT-2) and to a lesser extent by GLUT-1 and GLUT-3 (step 1) and is converted to glucose-6-phosphate by glucokinase (step 2). Glucose metabolism increases ATP/ADP ratio in the cytoplasm (step 3), which closes the ATP-dependent potassium channels (KATP) and depolarizes the cell membrane (step 4). Depolarization opens voltage-dependent calcium channels (VDCC) and causes Ca2+ entry (step 5) that facilitates insulin secretion by exocytosis (step 6). Created with BioRender.com.GLUT2, located within the pancreatic β-cell membrane, has a high Km for glucose (15-20 mM) [49], allowing for rapid equilibration between extra- and intracellular glucose levels [45, 50]. GLUT2 has a low affinity for glucose and is not saturated even at high glucose levels [33]; therefore, hepatocytes and pancreatic β-cells that express GLUT2 experience a rise in intracellular glucose levels following increased plasma glucose and can sense glucose [33]. Under physiological conditions, the rate of glucose transport has little effect on insulin secretion [45]. In human β-cells, GLUT1 and GLUT3 are also involved in glucose entry [40, 45, 51].
Glucokinase (hexokinase IV, Km≈ 8-10 mM, 144-180 mg/dL) in the β-cells acts within the normal range of plasma glucose concentrations and phosphorylates glucose [45, 50]. Glucose phosphorylation is a critical step in controlling glycolytic flux, as it traps the glucose molecule within the cell by placing a charge on it; the capacity of glucose transport is higher than glucose phosphorylation [51].
KATP channels couple cell metabolism to electrical activity [52]. A KATP channel in the pancreatic β-cells has four Kir6.2 subunits and four SUR1 subunits [52, 53]. Antidiabetic drugs such as sulfonylureas (e.g., glipalamide) and glinides (e.g., repaglinide) inhibit KATP channels and increase insulin secretion [53]. Voltage-dependent calcium channels that are found in the pancreatic β-cells are L-type calcium channels (CaV1.2 and CaV1.3), P/Q-type channels (CaV2.1), and T-type channels (CaV3.2) [53].
In addition to triggering the insulin secretion pathway described above, glucose can activate a metabolic amplifying pathway whereby it modulates insulin secretion independently from its action on KATP channels by generating signals (NADPH, hormones, neurotransmitters) that amplify the action of Ca2+ on insulin granule exocytosis, provided that Ca2+ influx is already stimulated and [Ca2+]i is high [54].
Basal (fasting) insulin levels is about 11 µU/mL [24] or 2-12 µU/mL [55]. The insulin concentration in portal blood is approximately two-fold higher than peripheral circulation because of hepatic clearance of insulin [31]. The half-life of insulin is about 5 min in the blood, and insulin is degraded by insulin-degrading enzymes mostly in the liver (~80%) and kidney (~20%) as well as also in other tissues [44, 56]. In the insulin breakdown in the liver, insulin enters hepatocytes by receptor-mediated endocytosis and is degraded in the lysosomes [44]. The maximal effect of insulin on total body glucose metabolism, which includes suppression of glucose production and stimulation of glucose utilization (assessed by exogenous glucose infusion rate during euglycemic hyperinsulinemic clamp), is seen at plasma insulin concentrations between 200 and 700 μU/mL and is ~10-11 mg/kg/min [28]; the half-maximal effect is observed at ~60 μU/mL [28]. In subjects with T2D, the percentage of basal insulin secretion rate relative to total insulin secretion rate increases and GSIS decreases; the ratio of GSIS to basal insulin secretion rate are 3.7 and 0.78 in lean healthy and diabetic subjects, respectively [57]. Glucose production is more sensitive than glucose utilization to plasma insulin levels [28, 33]; plasma insulin levels for half-maximal suppression of glucose production (30 μU/mL) is approximately half of those for half-maximal stimulation of glucose utilization (60 μU/mL) [28]. Insulin completely blocks glucose production at a plasma concentration of 50-60 μU/mL [28]. A 10-20 μU/mL increment of plasma insulin concentrations (from basal insulin levels 11±1 μU/mL) can cause half-maximal suppression of glucose production, whereas a 40-50 μU/mL increment is needed for half-maximal stimulation of glucose utilization [28]. 10-15 µU/mL (60-90 pM) of serum insulin could prevent hydrolysis of triglycerides [31]. EC50 of plasma insulin concentrations for decreasing plasma non-esterified fatty acids is ~20 μU/mL [58]. Hepatic insulin resistance and hepatic glucose resistance cause fasting plasma insulin concentration to be higher in type 2 diabetic subjects [26]. EC50 of plasma insulin concentrations for glucose uptake in skeletal muscle is ~60 μU/mL in healthy subjects and much higher (~120-140 μU/mL) in type 2 diabetic subjects [34]. ED50 of portal insulin concentration to inhibit HGP in the basal state is higher in type 2 diabetic subjects than normal subjects, indicating hepatic insulin resistance in type 2 diabetic subjects with mild fasting hyperglycemia [59]. It has been reported that when plasma insulin concentration is < 50 μU/mL, impaired suppression of HGP compared to decreased glucose uptake, contributes more quantitatively to disturbed glucose homeostasis [59].
For interpreting circulating insulin levels, two technical points need to be considered: (1) assay-dependent variability and (2) converting insulin values from the bioefficacy-based traditional unit (µU/mL) to mass-based SI (Système International) unit (pM) [60]. Currently, there is no standard method for insulin measurement; in addition, circulating insulin assay using different methods shows ~2-fold difference [61]; this point should be considered in the interpretation and comparison of circulating insulin levels [61].
Converting insulin values from conventional (µU/mL) to SI (pM) units is a challenging issue, and conversion factors range from 5.99-7.174 [62-65]. Based on the molecular weight of human insulin (5808) and potency of insulin standard (24 U/mg, 4th International Standard of Insulin, 1959), it was concluded that 1 unit of insulin equals 7.174 nmol (yielding a conversion factor of 7.174) [63]. Since insulin standard contains some water and salts, using quantitative amino acid analysis and the potency of an insulin standard of 26 U/mg (WHO, 1987), it was concluded that 1 unit of insulin equals 6 nmol (yielding a conversion factor of 6.00) [63], which translates to 28.696 U/mg pure insulin [66]. Compared to the new conversion factor of 6.00, recommended by the ADA [62, 67], using other conversion factors including 7.174 and 6.945, which is recommended by the American Medical Association [62], ~20% and ~15% higher insulin values are obtained, respectively [63, 67], a factor that itself contributes to inter-assay variation [68] and potential clinical implications [60]. A commentary by Knopp et al. states that the correct conventional factor for human insulin is 1 μU/mL=6.00 pM [60].
Insulin receptors are found in the membranes of almost all mammalian cells [31]. The number of insulin receptors varies between < 50 per erythrocyte to > 20,000 on hepatocytes [31]. Maximal effects of insulin on glucose production and glucose utilization occur at 11% and 49% of insulin receptor occupancy, suggesting the presence of spare insulin receptors in humans [28].
Fig. (4)) Insulin signaling pathways. IRS, insulin receptor substrate; PI3K, Phosphatidyl inositol-3 kinase; Akt, thymoma in AK (aphakia) mice; PKB, protein kinase B; Grb2, growth factor receptor binding protein-2; SOS, son of sevenless; Ras, Rat sarcoma; Raf, Raf fibrosarcoma; MEK, mitogen-activated ERK (extracellular-regulated kinases) kinase; MAPK, mitogen-activated protein kinase. Created with BioRender.com.Insulin receptor, a receptor tyrosine kinase (RTK), is a tetrameric protein that has two extracellular α-subunits and two intracellular β-subunits [69]. In the absence of insulin, the α-subunit inhibits the intrinsic tyrosine kinase activity of the β-subunit [69]. Following the binding of insulin to α-subunits of the insulin receptor, the intracellular tyrosine kinase domains on the β-subunits of insulin receptor are activated, causing intramolecular autophosphorylation or transphosphorylation in which each β-subunit phosphorylates tyrosine residues on other β-subunit [24, 70-72]. Then, insulin receptor substrate (IRS) proteins bind to phosphotyrosine residues on the receptor and themselves are phosphorylated [24]. Phosphorylated IRS proteins activate two main insulin signaling pathways: (1) phosphatidylinositol 3-kinase (PI3K)-Akt pathway and (2) Ras (rat sarcoma) mitogen-protein kinase (MAPK) pathway Fig. (4) [24].
PI3K is a heterodimer consisting of a catalytic subunit (p110) and an SH2- containing regulatory subunit (p85) [69, 72]. PI3K binds to the phosphorylated IRS proteins via its regulatory subunit; then, the catalytic subunit of PI3K converts plasma membrane phosphatidylinositol 4,5 bisphosphate (PIP2) to phosphatidylinositol 3,4,5 triphosphate (PIP3), which is a lipid second messenger [69]. PIP3activates 3-phosphoinositide-dependent protein kinase 1 (PDK1), which in turn activates PKB (Akt) [69]. The insulin's metabolic actions are mainly achieved through the PI3K/Akt pathway [70, 72, 73]. These actions include promotion of glucose uptake in myocytes and adipocytes, suppression of gluconeogenesis in hepatocytes, increase in glycogen synthesis, and inhibition of lipolysis [70]. In T2D, the ability of insulin to phosphorylate IRS-1 is impaired [24].
The other pathway for insulin action, the MAPK pathway, is mainly involved in nonmetabolic processes such as growth and cellular proliferation [24, 70, 72]; this pathway retains its sensitivity and its excessive stimulation during insulin resistance involved in inflammation and atherogenesis [24].
Insulin signaling is complex, and the number of signaling combinations of signaling molecules probably exceeds 1000; in most cases of insulin resistance, there is partial resistance in some but not all insulin signaling pathways [72, 74]. To review the pertinent timeline for key events in insulin signaling, see Ref [71], and for a more comprehensive review on insulin signaling pathways, see Ref [72].
As shown in Fig. (5), lifestyle and genetic predisposition play important roles in the development of T2D [75]. In addition, microbiota, the assemblage of living microorganisms in a defined environment, is associated with T2D and dysbiosis; change in healthy microbiota can influence the development of T2D [76]. Risk factors of T2D can be categorized as genetic, metabolic, and environmental risk factors [77]. Obesity, aging, economic development, sedentary lifestyle, urbanization, unhealthy and energy-dense diets, family history of diabetes in first-degree relatives, history of cardiovascular diseases, hypertension, polycystic ovary syndrome in women, pregnancy, smoking, stress, and dyslipidemia are among the risk factor for T2D [2, 7, 11, 78]. Some of these (e.g., genetic predisposition, ethnicity, and family history of diabetes) are non-modifiable risk factors. In contrast, most of them (e.g