15: Diabetes Mellitus


CHAPTER 15
Diabetes Mellitus


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).

Schematic illustration of the prevalence of diabetes by age and gender in 2021.

FIGURE 15.1 The prevalence of diabetes by age and gender in 2021.


Source: (Sun et al., 2022 / with permission of Elsevier).


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).


Table 15.1 Estimated prevalence of diabetes of any type for adults 20 to 79 years.


Source: (Adapted from Saeedi et al., 2019).



















Year Estimate number of cases worldwide
2019 463 million
2030 578 million
2045 700 million
Annual deaths due to diabetes 4 million (in 2017)

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.

Schematic illustration of people (20 to 79 years) with diabetes according to region in 2019, 2030, and 2045.

FIGURE 15.2 People (20 to 79 years) with diabetes according to region in 2019, 2030, and 2045.


Source: (International Diabetes Federation, 2021).


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.


Table 15.2 Clinical features distinguishing type 1 diabetes, type 2 diabetes, and monogenic diabetes.


Source: (Punthakee, Goldenberg, & Katz, 2018).

















































Clinical features Type 1 diabetes Type 2 diabetes Monogenic diabetes
Age of onset (years) Most <25 but can occur at any age (but not before the age of 6 months) Usually >25 but incidence increasing in adolescents, paralleling increasing rate of obesity in children and adolescents Usually <25; neonatal diabetes <6 months*
Weight Usually thin, but, with obesity epidemic, can have overweight or obesity >90% at least overweight Similar to the general population
Islet autoantibodies Usually present Absent Absent
C‐peptide Undetectable/low Normal/high Normal
Insulin production Absent Present Usually present
First‐line treatment Insulin Noninsulin antihyperglycemic agents, gradual dependence on insulin may occur Depends on subtype
Family history of diabetes Infrequent (5–10%) Frequent (75–90%) Multigenerational, autosomal pattern of inheritance
DKA Common Rare Rare (except for neonatal diabetes1)

1 Neonatal diabetes is a form of diabetes with onset at <6 months of age, requires genetic testing, and may be amenable to therapy with oral sulfonylurea in place of insulin therapy. DKA = diabetic ketoacidosis


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).

Schematic illustration of insulin requirements for normal, prediabetes, and diabetes.

FIGURE 15.3 Insulin requirements for normal, prediabetes, and diabetes. FPG = fasting plasma glucose.


Source: (Bar‐Tana, 2020 / with permission of Springer Nature).


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.

Schematic illustration of types of diabetes according to the 2019 WHO report on the classification of diabetes mellitus.

FIGURE 15.4 Types of diabetes according to the 2019 WHO report on the classification of diabetes mellitus.


Source: (World Health Organization, 2019).


Table 15.3 Diabetes and prediabetes diagnostic criteria.


Source: (American Diabetes Association, 2020).































Biochemical marker Normal levels Prediabetes Diabetes mellitus
Hemoglobin A1C [HbA1c (%)] <5.7%
(39 mmol/mol)
5.7–6.4%
(39–47 mmol/mol)
≥6.5%
(48 mmol/mol)

Impaired fasting glucose (IFG) Impaired glucose tolerance (IGT)
Fasting plasma glucose (FPG) <100 mg/dL (5.6 mmol/L) 100 to
125 mg/dL (5.6–6.9 mmol/L)

≥126 mg/dL (7.0 mmol/L)
Oral glucose tolerance test
(OGTT)
<140 mg/dL (7.8 mmol/L)
140 to 199 mg/dL (7.8‐11.0 mmol/L)
after a glucose load of 75 g anhydrous glucose dissolved in water
≥200 mg/dL (11.1 mmol/L)
Random plasma glucose
≥200 mg/dL (11.1 mmol/L)

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).


HEART DISEASE AND STROKE



  • According to the National Institute of Diabetes and Digestive and Kidney Diseases, people with diabetes tend to develop heart disease at a younger age compared to people without diabetes (Barrett‐Connor, Wingard, Wong, & Goldberg, 2018), while they have twice the risk of heart disease or stroke as adults without diabetes.
  • Based on statistics published by the WHO, adults with diabetes have heart disease and stroke death rates about 2 to 3 times higher than adults without diabetes (WHO, 2018).
  • In patients with diabetes, cardiovascular disease is a major cause of death and disability (IDF Diabetes Atlas ‐ 8th Edition, 2017).

HIGH BLOOD PRESSURE



  • Hypertension is a major risk factor for atherosclerotic cardiovascular disease and microvascular complications (American Diabetes Association, 2020).
  • In patients with diabetes, sex (male), family history, age, and body‐mass index (BMI) continue to be independent risk factors. The duration of diabetes increases the risk, whereas good renal function is protective (Tsimihodimos, González‐Villalpando, Meigs, & Ferrannini, 2018).
  • About two‐thirds of adults with diabetes have a blood pressure greater than 130/80 mm Hg or use prescription medications for hypertension.

DIABETIC RETINOPATHY



  • Diabetes is the main cause of new cases of blindness among adults aged 20 to 74 years (Centers for Disease Control and Prevention, 2011).
  • The incidence of diabetic retinopathy ranges from 2.2% to 12.7% among patients with diabetes, while the annual progression estimates a range from 3.4% to 12.3% with the highest ranges found in US after 2000 (Sabanayagam et al., 2019).
  • Optimization of glycemic control, blood pressure, and lipid profile may help reduce the risk or slow the progress of the diabetic retinopathy (American Diabetes Association, 2020).

DIABETIC KIDNEY DISEASE



  • According to the National Kidney Foundation, 30% of patients with T1D and 10% to 40% of those with T2D will suffer from kidney failure.
  • In high‐income countries, 50% of cases of end‐stage kidney disease are attributed to diabetic kidney disease (Tuttle et al., 2014).
    Schematic illustration of chronic complications of diabetes.

    FIGURE 15.5 Chronic complications of diabetes.


    Source: (International Diabetes Federation, 2019).


  • The prevalence of end‐stage kidney disease is 10 times higher in individuals with diabetes (IDF Diabetes Atlas ‐ 8th Edition, 2017).
  • According to a meta‐analysis of cohort studies (8 cohorts of general population [1,285,045 participants] and five cohorts of chronic kidney disease [CKD; 79,519 participants] with a mean follow up of 4 years), patients with diabetes were at a higher risk of developing acute kidney injury compared to individuals without diabetes (James et al., 2015).

DIABETIC NEUROPATHY



  • About 60% to 70% of people with diabetes in the US have mild to severe forms of nervous system damage. The results include damage to sensory, motor, and autonomic nerves causing symptoms such as numb, tingling, or burning feet, one‐sided sharp pain (National Institute of Neurological Disorders and Stroke, 2022) as well as other problems such as depression, anxiety, and memory impairments. Gut microbiota seems to influence the release of some of the major brain neurotransmitters that act in the gut‐brain axis (Thakur, Tyagi, & Shekhar, 2019).
  • Gastrointestinal neuropathies include esophageal dysmotility, gastroparesis, constipation, diarrhea, and fecal incontinence (American Diabetes Association, 2020).
  • Severe forms of diabetic nerve disease lead to the development of ulcers (IDF Diabetes Atlas ‐ 8th Edition, 2017) and therefore, are a major contributing cause of lower‐extremity amputations.

AMPUTATIO\NS



  • The global prevalence of the diabetic foot is 6.4%, and it is higher for men. In high‐income countries, the annual incidence of the disease is 2% (IDF Diabetes Atlas ‐ 8th Edition, 2017).
  • Among patients with diabetes, after a 43% decline between 2000 and 2009, amputation (both major and minor) rates increased by 50% from 2009 to 2015 (Creager et al., 2021).

DENTAL DISEASE



  • Periodontal (gum) disease is more common in people with diabetes. Among young adults, those with diabetes compared to those without diabetes have about twice the risk (Centers for Disease Control and Prevention, 2011).
  • Almost one‐third of people with diabetes have severe periodontal diseases with loss of attachment of the gums to the teeth measuring 5 mm or more (Centers for Disease Control and Prevention, 2011).
  • Periodontal disease is a major cause of tooth loss and is associated with an increased risk of cardiovascular disease (IDF Diabetes Atlas ‐ 8th Edition, 2017).

COMPLICATIONS OF PREGNANCY



  • High blood glucose during pregnancy may have consequences for both the mother and the offspring. It is possible to increase the risk for fetal loss, congenital malformations, stillbirth, perinatal death, preeclampsia, eclampsia, obstetric complications, and maternal morbidity and pregnancy related mortality. Concerning the baby, high blood glucose can cause macrosomia, or low birth weight, and shoulder dystocia during delivery (IDF Diabetes Atlas ‐ 8th Edition, 2017).
  • Poorly controlled diabetes before conception and during the first trimester of pregnancy can cause major birth defects in 5% to 10% of pregnancies and spontaneous abortions in 15% to 20% of pregnancies (Centers for Disease Control and Prevention, 2011).
  • Poorly controlled diabetes during the second and third trimesters of pregnancy can result in excessively large babies, posing a risk to both mother and child (Centers for Disease Control and Prevention, 2011).
  • Children of women with diabetes during pregnancy are at high risk of suffering from transgenerational effects such obesity, diabetes, hypertension, and kidney disease (IDF Diabetes Atlas ‐ 8th Edition, 2017).

OTHER COMPLICATIONS



  • Biochemical imbalances caused by uncontrolled diabetes can lead to acute life‐threatening events, such as diabetic ketoacidosis and coma (Centers for Disease Control and Prevention, 2011).
  • People with diabetes are more vulnerable to many other illnesses and often with worse prognoses. For example, they are more likely to die with pneumonia or influenza than people who do not have diabetes (Centers for Disease Control and Prevention, 2011).
  • Diabetes is associated with an increased risk of cancer, cognitive impairment, dementia, and autoimmune diseases (for T1D only), such as autoimmune thyroid disease and celiac disease (American Diabetes Association, 2020).
  • People with diabetes aged 60 years or older are 2–3 times more likely to report an inability to walk one‐quarter of a mile, climb stairs, or do housework compared with people without diabetes in the same age group.

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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Jun 25, 2023 | Posted by in CARDIOLOGY | Comments Off on 15: Diabetes Mellitus

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