DEFINITION

According to the WHO 2019 updated and published guidance on how to classify diabetes mellitus (DM) (World Health Organization, 2019) and the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (“Diagnosis and Classification of Diabetes Mellitus,” 2014; “Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus,” 1998), DM can be defined as a group of metabolic disorders characterized by chronic hyperglycemia (i.e., high concentrations of blood glucose) resulting from defects in insulin production, insulin action, or both and associated with disturbances in glucose, lipid, and protein metabolism. As it will be discussed below in this chapter, long‐term effects of the chronic hyperglycemia on health include damage, dysfunction, and failure of organs like the eyes, kidneys, nerves, heart, and blood vessels.

EPIDEMIOLOGY

According to the 2017 Atlas of the International Federation of Diabetes, almost 50% of the adults 20 to 79 years old living with diabetes are undiagnosed. This translates to 212.4 million people who are uninformed about their disease. Approximately 27.7 million Americans have diabetes are unaware of the diagnosis. In the last few decades, the prevalence of type 2 diabetes (T2D) has alarmingly grown in children and adolescents. Physical inactivity, adherence to bad dietary habits, and obesity are the culprits for this increase (IDF Diabetes Atlas ‐ 8th Edition, 2017).

In 2019, the prevalence of diabetes for adults aged 20 to 79 years old worldwide was estimated to be 9.3% and is projected to be 10.2% in 2030 and 10.9% in 2045 (Saeedi et al., 2019). The prevalence of diabetes by age and gender in 2021 is shown in Figure 15.1 (Sun et al. 2022).

The total number of patients worldwide with diabetes over the next two to three decades is projected to rise from 463 million in 2019 to 700 million in 2045 (Table 15.1) (Saeedi et al., 2019).

The number of patients aged 20 to 79 years with diabetes, according to region, in 2019 and the projection in 2045, is presented in Figure 15.2 (International Diabetes Federation, 2021).

In 2019, diabetes was the ninth leading cause of death with an estimated of 1.5 million deaths directly attributed to diabetes (WHO, 2018). Overall, the risk for death among people with diabetes is about twice that of people without diabetes of similar age.

In 2017, the IDF estimates that the total medical cost attributable to diabetes was USD $850 billion, for patients older than 18 years, of which USD $727 billion were spent for patients aged 20 to 79 years old. Specifically in the US, healthcare expenditure for diabetes was $348 billion dollars (IDF Diabetes Atlas ‐ 8th Edition, 2017). In 2045, global healthcare expenditure on diabetes is expected to reach USD $958 billion for adult patients (IDF Diabetes Atlas ‐ 8th Edition, 2017).

TYPES OF DIABETES

According to published clinical practice guidelines from several organizations [e.g., American Diabetes Association (ADA), WHO, Canadian Diabetes Association], most cases can be classified into two categories, type 1 and type 2 DM, although gestational DM (i.e., diabetes with onset or first recognition during pregnancy in the second or third trimester), and other uncommon types also exist (“2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes‐2019,” 2019; Adler et al., 2021; American Diabetes Association, 2020; World Health Organization, 2019):

1. Type 1 diabetes mellitus (T1D)
   
2. Type 2 diabetes mellitus (T2D)
   
3. Gestational diabetes mellitus (GDM)
   
4. Specific types of diabetes due to other causes

More specifically, T1D, formerly referred to as insulin‐dependent diabetes mellitus (IDDM), accounts for 5% to 10% of all diagnosed cases of diabetes. It typically occurs in children and adolescents. However, new onset T1D can occur in all age groups with a global prevalence of 5.9 per 10,000 (Holt et al., 2021). It is an autoimmune disease and most often the result of irreparable damage to the insulin‐producing cells (β‐cells) of the pancreas from antibody attacks (Atkinson & Maclaren, 1994). It is characterized by an absolute deficiency of insulin, the hormone that regulates blood glucose. The rate of the pancreatic β‐cell destruction varies between individuals; it occurs rapidly, mainly in infants and children, or slower, mainly in adult patients (“2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes‐2019,” 2019). The symptoms of T1D usually include abnormal thirst and dry mouth, frequent urination, constant hunger, lack of energy and fatigue, sudden weight loss, and blurred vision (IDF Diabetes Atlas ‐ 8th Edition, 2017). The clinical features distinguishing T1D, T2D, and monogenic diabetes are shown in Table 15.2.

T2D, formerly referred to as non‐insulin‐dependent diabetes mellitus (NIDDM), accounts for about 90% to 95% of diagnosed diabetes cases, usually after the age of 40 and in families. In prediabetes, characterized by insulin resistance, the insulin signaling leading to efficient transport glucose across the cell membrane is diminished. Consequently, the amount of insulin required to transport a certain amount of glucose into the cells is higher and insulin levels in these individuals are elevated (Figure 15.3) (Bar‐Tana, 2020). As the degree of resistance increases, the need for insulin also rises. Gradually, the pancreas loses its ability to produce it. By the time T2D has appeared, insulin secretion has become defective and is not adequate to compensate for the insulin resistance (Polonsky, Sturis, & Bell, 1996). Most of the individuals with T2D are suffering from obesity, which, at least in part, is responsible for some degree of insulin resistance (Bogardus, Lillioja, Mott, Hollenbeck, & Reaven, 1985; Kolterman et al., 1981). The symptoms of T2D may be excessive thirst and dry mouth, frequent and abundant urination, lack of energy and extreme tiredness, tingling or numbness in hands and feet, frequent fungal skin infections, slow healing wounds, and blurred vision (IDF Diabetes Atlas ‐ 8th Edition, 2017).

GDM is a type of diabetes first diagnosed in the second or third semester of pregnancy without any prior diagnosis of T1D or T2D. Pregnant women who have not had diabetes before pregnancy should be tested for GDM at 24 to 28 weeks of pregnancy. Those diagnosed with GDM should be screened for diabetes or prediabetes at least every 3 years during their lifetime (“2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes‐2019,” 2019).

Diabetes may be related to other causes, such as specific diseases or health conditions. Disease of the exocrine pancreas, such as pancreatitis and cystic fibrosis are examples of such diseases (“2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes‐2019,” 2019). Cystic fibrosis‐related diabetes is very common in patients with the disease, especially in adults (Moran et al., 2018), and it is mainly linked to loss of pancreatic cells resulting in both insulin and glucagon deficiency (“2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes‐2019,” 2019). Diabetes following an organ transplant is another cause of the disease. The use of glucocorticoids after a transplant, for example, or for the treatment of HIV/AIDS may contribute to drug‐ or chemical‐induced diabetes. Finally, monogenic diabetes syndromes, such as neonatal diabetes and maturity‐onset diabetes of the young (MODY) count for a small percentage of the diabetes cases.

As many people do not fit into one category, the 2019 WHO guidance for diabetes suggested a classification system aiming in clinical care and in helping health professionals to choose appropriate treatments (Figure 15.4).

DIAGNOSIS OF DIABETES MELLITUS

Diagnosis of diabetes is based on blood‐glucose levels. Fasting plasma glucose (FPG) or plasma glucose (PG) after a 2‐hour, 75‐g oral glucose tolerance test (OGTT) or HbA1c, criteria are used for setting the diagnosis with equal effectiveness, at least for T2D (“2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes, 2019).

To assess FPG, there should be at least an 8‐hour fast. Measurements of FPG ≥126 mg/dL (7.0 mmol/L) can set the diagnosis of diabetes. OGTT should be performed in accordance with the instruction for OGTT by the WHO. Glucose should be 75 g of anhydrous glucose and dissolved in water. If 2‐h PG is ≥ 200 mg/dL (11.1 mmol/L) during OGTT, the individual is diagnosed with diabetes. When measuring HbA1c, an National Glycohemoglobin Standardization Program (NGSP)‐certified and standardized, or traceable to the diabetes control and complications trial (DCCT) assay is needed to avoid variations between different laboratories. An HbA1c ≥ 6.5% (48 mmol/mol) is the cutoff point for diabetes. Finally, when the patients has symptoms of classic hyperglycemia or a hyperglycemic crisis, the diagnosis may be set when a random PG measurement is ≥ 200 mg/dL (11.1 mmol/L) (Table 15.3) (“2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes, 2019).

PREDIABETES

Prediabetes is a condition characterized by blood‐glucose levels that are higher than normal, but not high enough to be classified as diabetes. Individuals with prediabetes have impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) and/or an HbA1c of 5.7% to 6.4% (39–47 mmol/mol). This condition may lead to T2D and may contribute to an increased risk of cardiovascular disease (“2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes, 2019).

IFG is a condition in which the fasting blood‐glucose level is 100 to 125 milligrams per deciliter (mg/dL), after an overnight fast (“Diagnosis and Classification of Diabetes Mellitus,” 2014; “Follow‐up Report on the Diagnosis of Diabetes Mellitus,” 2003). The level is higher than the normal blood‐glucose levels of 70 to 99 mg/dL, but not high enough to be classified as diabetes.

IGT is a condition in which the blood‐glucose level is 140 to 199 mg/dL (7.8 to 11.0 mmol/L) after a 2‐hour OGTT. This level is higher than normal but not high enough to be classified as diabetes (“Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus,” 1997). The risk for progression to diabetes among those with prediabetes is high, but not inevitable.

Diabetes and prediabetes diagnostic criteria are summarized in Table 15.3 (American Diabetes Association, 2020).

COMPLICATIONS

The National Institute of Diabetes and Digestive and Kidney Diseases, the International Diabetes Federation, and the ADA list several co‐morbidities attributed to diabetes that include, but are not limited to, heart disease and stroke, high blood pressure, diabetic retinopathy, kidney disease, nervous system disease, amputations, dental disease, and complications of pregnancy. These complications can be categorized as chronic macrovascular complications, such as cardiovascular disease and diabetic foot, or chronic microvascular complications, such as kidney disease, neuropathy, and retinopathy (International Diabetes Federation, 2021; IDF Diabetes Atlas ‐ 8th Edition, 2017) (Figure 15.5).

PHYSIOLOGY AND PATHOPHYSIOLOGY

The last century has been characterized by remarkable advances in our understanding of the mechanisms that lead to hyperglycemia in DM. A pathophysiological view that overcomes the historical and simplistic ‘glucocentric’ view could result in a better patient phenotyping and therapeutic approach (Zaccardi, Webb, Yates, & Davies, 2016).

In T2D, a combination of genetic, metabolic, and environmental factors that interact with one another including non‐modifiable (ethnicity and family history/genetic predisposition) and modifiable risk factors (obesity, low physical activity, and an unhealthy diet) result in a complex network of pathological changes leading to insulin dysfunction (Figure 15.6).

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