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EPIDEMIOLOGY OF DIABETES MELLITUS

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2 EPIDEMIOLOGY OF DIABETES MELLITUS
Chapter 32 EPIDEMIOLOGY OF DIABETES MELLITUS

3 Type 1 & 2 Diabetes Diabetes Mellitus is a complex chronic metabolic disease characterized by high fasting blood glucose. The two major forms of diabetes, type 1 and type 2, arise by different mechanisms. Elevated blood glucose, or hyperglycemia, arises when insulin, a key hormone produced by the beta (b) cells of the Islets of Langerhans of the pancreas, is either no longer secreted (diabetes type 1) or no longer able to adequately facilitate glucose entry into the cells for energy production (diabetes type 2).

4 History of Diabetes Mellitus
Diabetes mellitus has an ancient recorded history dating to 5th century BC Indian texts. Early historical writings show that tasting urine was the first diagnostic diabetes test. In the 19th and early 20th centuries, the first quantitative clinical and diagnostic tools were developed to test for elevated sugar in the urine (glycosuria) and blood (hyperglycemia). The later discovery of insulin forever transformed type 1 diabetes from a rare and fatal disease to one where prolonged survival was possible. Henschen, 1969; Guthrie & Humphreys, 1988; Eknoyan & Nagy, 2005

5 Role of Insulin in Diabetes
Diabetes mellitus is a disease state of persistent inappropriate excess blood glucose (hyperglycemia) caused by the inability of endogenous insulin to adequately mediate glucose uptake for the target cells that require it. Reasons for inadequate insulin action include lack of insulin production by the β-cells of the pancreas (insulin insufficiency) and reduced, downregulated, or dysregulated insulin receptor signaling (insulin resistance).

6 Role of Insulin in Diabetes
Glucose is the primary sugar metabolized for energy. Insulin is synthesized and secreted by the beta (β) cells of the endocrine pancreas within specialized areas called the Islets of Langerhans. Insulin induces glucose uptake for energy production in muscle cells and storage in fat cells. Glucose transporter 4 (GLUT-4) is the gateway for insulin-mediated cellular glucose uptake (Kandror & Pilch, 1996; Pessin et al., 1999; Czech & Corvera, 1999).

7 Diagnosis of Diabetes Several blood glucose tests are available for the diagnosis of diabetes. A diagnosis is made when the blood glucose exceeds a clinically identified threshold level or diagnostic cut point for the particular test in use. Diagnosis Fasting glucose 2 hour glucose from an OGTT HbA1c levels

8 Diagnosis of Diabetes Hemoglobin A1c test (HbA1c)
Hemoglobin A1c (HbA1c) assesses average glucose levels over a two to three month period. Fasting is not required for the test. Traditionally, HbA1c is used by diabetics to monitor blood glucose levels. In this capacity, the level of HbA1c can be used as an indicator of treatment effectiveness. A diagnosis of diabetes is made when the HbA1c is 6.5% or higher (Kilpatrick, 2000; Gomero, 2008).

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10 Types of Diabetes There are two major types of diabetes mellitus (type 1 and type 2), which are differentiated, in large part, by their underlying etiologies. In type 1 diabetes, the pancreas no longer produces insulin, primarily due to autoimmune destruction of the β-cells. Type 1 diabetes is therefore characterized as insulin dependent. It develops primarily in children and accounts for about 5-10% of all diabetics.

11 Types of Diabetes In classic type 2 diabetes, insulin is still produced and secreted, but because of insulin resistance of target cells coupled with relative insulin insufficiency, blood glucose is not adequately controlled. Type 2 diabetes develops primarily in adults and accounts for 90-95% of all diabetics.

12 Types of Diabetes A third type of diabetes, gestational diabetes, is diagnosed during pregnancy. Pregnancy increases the metabolic workload of the maternal pancreas and heightens both insulin resistance and insulin insufficiency (Homko, 2010). Other etiologic forms of diabetes are due to rare genetic defects of the β-cells and defects in insulin action, signaling, or secretion.

13 Global Pandemic of Diabetes Mellitus
The beginning of the 21st century marked a profound increase in the global burden of diabetes which is now described as a pandemic. Heightened levels of obesity and greater longevity are clearly important determinants of this worldwide phenomenon.

14 Global Pandemic of Diabetes Mellitus
The web of causation is complex and involves multiple factors including fetal and childhood growth and development, maternal biology and influence, genetics, nutrition, urbanization, automation, perceptions of weight gain, changes in food costs, greater access to foods high in fat and calories, and proclivity to lack of exercise through a sedentary lifestyle (Narayan et al., 2006).

15 Global Prevalence of Diabetes Mellitus
Diabetes mellitus is currently the most frequently diagnosed of non-communicable diseases and the fastest-growing chronic disease in the world. More than 285 million people had diabetes in 2010, a 67% increase from the estimated 171 million people with diabetes in 2000 (Shaw, Sicree & Zimmit, 2010).

16 Global Prevalence of Diabetes Mellitus
Across all age groups, the worldwide prevalence of diabetes more than doubled in the first decade of the 21st century, rising from 2.8% in 2000 to 6.4% in 2010. The greatest increase in prevalence has occurred among the elderly, rising from <5% in 1970 to nearly 15% in 2010 for adults 65 years or older (Wild et al., 2004).

17 Global Prevalence of Diabetes Mellitus
Longitudinal data reflect an alarming 4% annual increase in the worldwide prevalence of adult diabetes over the past 15 years. If this steep trajectory continues, the worldwide number of diabetics is expected to exceed 400 million by 2025, effectively doubling the absolute number of diabetics within a 30 year period. The global pandemic of diabetes is largely due to type 2 diabetes that predominantly strikes in adulthood (Roglic & Unwin, 2005; Roglic & Unwin, 2010).

18 Figure 32.2 Global Trends in the Prevalence of Diabetes

19 Global Prevalence of Diabetes Mellitus
The prevalence is highest (>75 cases per 1,000) in developed countries of North America and Western Europe and lowest (<15 cases per 1,000) in developing countries of Southeast Asia and Central Africa. This global pattern is similar to that of obesity and energy consumption (Roglic & Unwin, 2005, Roglic & Unwin, 2010).

20 Figure 32.3 Prevalence of Diabetes, 2000

21 Distribution of Diabetes by Gender and Age
The prevalence increases exponentially by age reaching a maximum of approximately 14% in adults, 80 years and older. Age-specific prevalence rates are similar for men and women becoming only slightly higher in elderly women due to their greater longevity.

22 Figure 32.4 Age-Specific Prevalence of Diabetes Mellitus

23 Global Deaths Attributable to Diabetes
During 2010, 3.96 million deaths were attributable to diabetes or approximately 6.8% of all-cause global mortality. In recent years, significant increases in relative mortality have been noted in both developed and developing nations. Population surveys indicate that diabetes is a leading cause of premature death worldwide, and the death toll is expected to rise further, particularly in developing countries where the prevalence is increasing and access to health care is limited (Roglic & Unwin, 2010).

24 Undiagnosed Diabetes In many developing countries, up to 90% of people with adult onset diabetes are undiagnosed. In China, roughly 6 out of 10 diabetics are undiagnosed. Lack of public awareness and diagnostic opportunities are cited as reasons for the high percentage of undiagnosed diabetes in poor and developing countries.

25 Burden of Diabetes in the United States
The prevalence of diabetes across all age groups has risen more than 7-fold in the United States in the past half century, from less than 1% in 1960 to approximately 7% in 2010. The greatest absolute increase occurred among the elderly. The prevalence of diabetes increased from approximately 8% to nearly 20% for adults 65 years and older during

26 Burden of Diabetes in the United States
The incidence and prevalence rates of diabetes are continuing to rise among US adults, particularly among Hispanic and African Americans. Nearly 20% of diabetics remain undiagnosed. Clearly, diabetes has reached epidemic proportions in the US population (Mokdad et al., 2000; Mokdad et al., 2001; CDC, 2010; Cowie et al., 2010).

27 Figure 32.6 Prevalence of Diabetes in the United States, 1960-2010

28 Mortality from Diabetes in the United States
Concurrent with the dramatic increase in the prevalence of diabetes in the United States during the past three decades, the death toll has also accelerated. Proportionate estimates of relative mortality reflect at least a 4-fold increase in deaths from diabetes since 1960 (Kung et al., 2008).

29 Figure 32.7 Relative Mortality of Diabetes in the United States, 1960-2010

30 Population-Based Models of Diabetes
The Thrifty Genotype Hypothesis postulated by James Neel implicates the evolutionary selection of “thrifty genes” which facilitate efficient storage of fat during times of nutritional abundance, and which helped hunter-gatherer populations survive times of famine and food scarcity. Neel postulated that the genetic selection that served human populations so well in the past have been “rendered detrimental by progress”. According to this theory, an abundance of food that is perpetually available will inevitably lead to obesity and obesity-related chronic diseases, such as type 2 diabetes (Neel, 1962).

31 Microvascular Complications of Diabetes
Undetected or uncontrolled type 2 diabetes often results in silent pathology that can do irreparable damage at the microvascular (small blood vessel) level. Progression of microvascular disease results in irreversible consequences to health and quality of life such as diabetic retinopathy and blindness, diabetic nephropathy and kidney failure, and/or diabetic neuropathy and amputation (Moss, Klein & Klein, 1991; Fowler 2008).

32 Macrovascular Complications of Diabetes
Extended duration of undiagnosed or uncontrolled hyperglycemia increases the risk for macrovascular (large blood vessel) complications. There is a 2-fold increase in overall premature mortality, a 4-fold increase in deaths due to cardiovascular disease (CVD), and a 4-fold increase in stroke deaths among diabetics compared to non-diabetics. CVD is the primary cause of death among both type 1 and type 2 diabetics, eventually killing one out of every two patients (Fowler, 2008).

33 Macrovascular Complications of Diabetes
Hyperglycemia and insulin resistance often go unrecognized for many years in adults, and as a consequence, the presence of microvascular and macrovascular disease is a near certainty when type 2 diabetes is finally diagnosed (Sheehy et al., 2010). In contrast, the prominent clinical signs and symptoms of type 1 diabetes usually lead to a prompt diagnosis, and with effective treatment (insulin replacement) and glycemic control, the risk of long term sequelae can be ameliorated (Moore et al., 2009).

34 Epidemiology of Type 1 Diabetes
Type 1 diabetes, previously called insulin-dependent diabetes mellitus or juvenile-onset diabetes, is characterized by a lack of endogenous insulin production. It is the major form of diabetes in children and young adults and accounts for 5-10% of all diabetics.

35 Epidemiology of Type 1 Diabetes
There are two subforms of type 1 diabetes. Type 1a is caused by auto-immune destruction of the β-cells of the pancreas, confirmed by the presence of β-cell auto-antibodies. Type 1b is non-autoimmune pancreatic β-cell destruction that is idiopathic or of unknown origin. Serum auto-antibodies reactive against the pancreatic β-cells are detectable in approximately 90% of patients diagnosed with type 1 diabetes (Eisenbarth et al., 2010).

36 Epidemiology of Type 1 Diabetes
The incidence of type 1 diabetes has increased markedly in the world population during the past fifty years, especially among children under 5 years of age. Globally, the average annual rate of increase is approximately 3% and there are no signs that the trend is abating (Krolewski et al., 1987; Bingley & Gale, 1989; Gale, 2002; Gillespie et al., 2004; Patterson et al, 2009).

37 Risk Factors for Type 1 Diabetes
Risk factors for type 1 diabetes include genetic propensity and family history, environmental and/or dietary factors or triggers, ethno-racial distribution, and geography. Definitive linkages between these factors and molecular mechanisms of pathogenesis have not been fully clarified and remain under intense study.

38 Genetics of Type 1 Diabetes
A modest genetic risk of developing type 1 diabetes has been confirmed by twin and family studies. However, the absolute risk attributable to genetics per se is small since only 10-15% of cases have an affected first degree relative and the risk to offspring with an affected parent or sibling is less than 10% (Warram, Krolewski & Kahn, 1988; Redondo et al., 1999). Certain alleles of the Major Histocompatibilty Complex (Human Leukocyte Antigen, HLA) appear to modulate the risk (Eisenbarth et al., 2010).

39 Environmental Factors & Type 1 Diabetes
Viral infections, particularly mumps, Coxsackie virus B, Epstein-Barr virus, congenital rubella syndrome, and cytomegaloviruses have been implicated as possible triggers for β-cell autoimmunity Dorman, LaPorte, & Songer, 2003 In the US, Caucasians have the highest risk for the development of type 1 diabetes. Multiple factors may contribute to the increased risk for developing type 1 diabetes among Caucasians compared to other ethnic groups Lambert et al., 2004

40 Type 1 Diabetes in Sardinia
Sardinia has one of the highest incidence rates of type 1 diabetes in the world (approximately 39 cases per 100,000 among children under 15 years of age) which is nearly seven times higher than in comparable regions on the west coast of Italy. Recent studies of Sardinian children have focused on an increasing trend in the prevalence of obesity as a possible reason for the high rate (Sanna et al., 2006).

41 Type 1 Diabetes in Sardinia
These trends are consistent with the hygiene hypothesis which proposes that the absence of immunogenic stimuli early in life may heighten the risk of developing autoimmune diseases. The Sardinian population has been described as a genetic isolate and certain genes that predispose to diabetes or other autoimmune conditions may have reached high frequencies due to natural selection and/or inbreeding (Marrosu et al., 2002).

42 Type 1 Diabetes in Sardinia
In addition to having high rates of type 1 diabetes, the Sardinian population also has higher incidence and prevalence rates of multiple sclerosis than other European and Italian populations (Rosati et al., 1995). Since both conditions involve autoimmune reactions (destruction of neurons in multiple sclerosis and pancreatic b-cells in diabetes), they may have genetic and/or environmental risk factors in common (Marrosu et al., 2004).

43 Birth Weight, Obesity & Type 1 Diabetes
In a recent meta-analysis of data from multiple epidemiologic studies, the combined odds of developing type 1 diabetes increased by 2-fold in obese children compared to normal weight children (Veberteen et al., 2011). High birth weight and excess weight gain during the first postnatal year also increase the risk of developing type 1 diabetes (Harder et al., 2009).

44 Pre-diabetes Pre-diabetes is defined as impaired fasting glucose and/or impaired glucose tolerance. In this condition, blood glucose is higher than normal, but not high enough to meet the diagnostic criteria for type 2 diabetes. A number of studies conducted in a wide range of populations provide clear evidence that pre-diabetes is a significant risk factor for the development of type 2 diabetes, microvascular, and macrovascular disease (Gerstein et al., 2007; Wang et al., 2010).

45 Risk Factors for Type 2 Diabetes
The known major risk factors for type 2 diabetes include family history, age, ethnicity, obesity, and pre-diabetes. Family history is one of the strongest predictors of type 2 diabetes. The risk of developing diabetes is doubled if one first degree relative (parent or sibling) has the disease and is increased over 4-fold if two or more first degree relatives have the disease (Valdez et al., 2007).

46 Risk Factors for Type 2 Diabetes
Nevertheless, the profound increase in diabetes incidence and prevalence within the past several decades rules out a genetic basis for the excess burden of the disease, and points to insidious environmental factors that most likely play a permissive role in the etiology of diabetes.

47 Obesity & Type 2 Diabetes
Obesity is the strongest modifiable predictor of type 2 diabetes. The cause and effect relationship between obesity and type 2 diabetes is dramatically illustrated by studies of US men and women. Compared with a BMI of 21, the relative risk of developing type 2 diabetes rises exponentially with increasing BMI. The relative risk rises to more than 40 for gravidly obese men and more than 90 for gravidly obese women. Multi-fold risk elevations are notable even for modest increases in body mass (Chan et al., 1994; Colditz et al., 1995).

48 Dietary Factors & Type 2 Diabetes
Dietary factors have also been found to influence the risk of developing type 2 diabetes. The glycemic index, glycemic load, type of fat, type of carbohydrate, dietary fiber, magnesium, and an emerging potential risk factor, high fructose corn syrup, have all been investigated in experimental and epidemiologic studies.

49 Glycemic Index & Type 2 Diabetes
The glycemic index is a measure of postprandial increase in blood glucose due to intake of a specific food relative to that induced by glucose per se. The glycemic index ranks foods on the basis of their acute glycemic impact relative to glucose (Jenkins, 1981; Brand-Miller, 1994). Jenkin’s glycemic index and the related measurement, the glycemic load, have been widely used in epidemiologic and clinical investigations.

50 Glycemic Index & Type 2 Diabetes
Several large prospective cohort studies have found positive associations between the glycemic index or the glycemic load and the risk of type 2 diabetes. In general, high intake of foods with a high glycemic index or a high glycemic load have been found to increase the risk of developing type 2 diabetes (Barclay et al., 2008).

51 Dietary Fiber & Type 2 Diabetes
Some epidemiologic studies have found that certain types of dietary fiber protect against the development of type 2 diabetes. Dietary fiber consists of both soluble and insoluble forms. Soluble fiber has been shown to inhibit macronutrient absorption, reduce postprandial glucose responses and beneficially influence blood lipids. Nevertheless, it is primarily insoluble (cereal) fiber that has consistently been found associated with reduced diabetes risk (Weickert et al., 2005).

52 Dietary Fat & Type 2 Diabetes
Dietary fat has also been implicated as a potential risk factor for type 2 diabetes. The Pima Indians of Arizona have the highest reported incidence and prevalence rates of type 2 diabetes in the United States (Knowland et al., 1978). The traditional diet of native Pima Indians living in Mexico consists of 8-12% fat, 70-80% carbohydrate and 12-18% protein.

53 Dietary Fat & Type 2 Diabetes
In contrast, the modern day diet of Pima Indians who migrated to Arizona is comprised of approximately 50% carbohydrate, 40% fat and 10% protein. Results suggest that the traditional Pima lifestyle characterized by a low fat high carbohydrate diet and regular energy expenditure in physical labor protects against the development of type 2 diabetes and related diseases (Ravussin et al., 2002).

54 High Fructose Corn Syrup & Type 2 Diabetes
High fructose corn syrup has recently attracted attention as a potential risk factor in the development of type 2 diabetes, possibly through its effects on weight gain and obesity. Recent short term studies found that consuming a high level of fructose by drinking beverages sweetened with high fructose corn syrup increased insulin resistance and decreased insulin senstivity (Swarbrick et al., 2008 Stanhope et al., 2009). Additional studies are needed to confirm that intake of high fructose corn syrup increases the risk of developing insulin resistance and type 2 diabetes.

55 Ethnic Disparities in Type 2 Diabetes
Type 2 diabetes disproportionately affects Asians, Hispanics, Native Americans, Pacific Islanders, and African Americans. Asians, although phenotypically leaner than members of most other ethnic groups, have been found to be at high risk for developing type 2 diabetes at relatively low levels of body mass (Shai et al., 2006).

56 Ethnic Disparities in Type 2 Diabetes
The physiological basis for this ethnic differential in risk may relate to body composition and the distribution of body fat. On average, persons of Asian origin have a higher level of visceral/abdominal fat at the same level of BMI than subjects of other ethnicities (Tanaka, Horimai & Katsukawa, 2003; Deurenberg-Yap & Deurenberg, 2003).

57 The Metabolic Syndrome (Syndrome X)
The constellation of symptoms defining the Metabolic Syndrome (Syndrome X) consists of abdominal obesity (increased waist circumference), atherogenic dyslipidemia (increased triglycerides and decreased HDL-cholesterol), hypertension, insulin resistance (impaired glucose uptake in the presence of normal or elevated insulin levels), a pro-inflammatory state (elevated C-reactive protein), and a prothrombotic state (increased plasminogen activator inhibitor). The clinical diagnosis is made when any three of these conditions exist in the same individual (Phillips, 1977; Reaven, 1988).

58 The Metabolic Syndrome (Syndrome X)
Currently, it is estimated that nearly one-third of US adults (66 million) are afflicted by the Metabolic Syndrome (Ervin, 2009). There is debate regarding whether obesity and/or insulin resistance cause the Metabolic Syndrome or if they are consequences of other metabolic abnormalities. One pathogenic sequence involves the initial development of obesity and excess adiposity. Adipocytes that have reached their threshold of fat storage respond by secreting inflammatory substances called adipokines that interfere with the insulin-driven glucose transport system.

59 Gestational Diabetes Mellitus
Gestational diabetes mellitus refers to hyperglycemia that arises during pregnancy. The condition is detected in approximately 200,000 pregnant women annually in the United States or about 7.5% of pregnancies. In addition to fetal risk, the health consequences of diabetes, retinopathy, nephropathy, neuropathy, and cardiovascular disease, are all accentuated by pregnancy. Women with a history of gestational diabetes mellitus are at 2-3-fold elevated risk of developing type 2 diabetes (Lawrence et al., 2008).

60 Economic Impact of Diabetes
The predicted health care burden and profound economic implications of the long-term management of diabetes is staggering and unsustainable. Worldwide, the annual estimated cost is $490 billion. Clearly, the cost of effective treatment and management has outstripped the resources of health care systems worldwide, underscoring the critical need for more cost-effective strategies for the primary, secondary and tertiary prevention of diabetes and its complications (Permutt, Wasson & Cox, 2005).

61 Prevention of Diabetes Mellitus
The American Diabetes Association recommends specific lifestyle practices including sustained weight control through restriction of caloric intake and regular daily physical exercise. Blood lipids, blood pressure, blood glucose and other vital signs should be checked by a physician on a regular basis and maintained within normal limits.

62 Prevention of Diabetes Mellitus
A remarkable and disturbing statistic is that nearly 25% of people with type 2 diabetes in the United States are undiagnosed. Adult onset disease is often not detected until clinically overt complications are present. Relatively simple tests are available to detect preclinical disease (pre-diabetes) and effective non-pharmacologic interventions have proven effective in preventing the progression of pre-diabetes to diabetes.

63 Prevention of Diabetes Mellitus
Well designed population screening programs coupled with effective lifestyle changes and therapy could substantially reduce the overwhelming health burden of type 2 diabetes (American Diabetes Association, 2010). Approximately 7% of all pregnancies in the United States are complicated by gestational diabetes (200,000 cases annually).

64 Prevention of Diabetes Mellitus
Because the risks to the mother and the neonate are significant, screening for diabetes is warranted based on the presence of any one of the following risk factors: obesity, prior history of disease, delivery of a large-for-gestational-age baby, presence of glycosuria, diagnosis of polycystic ovarian syndrome, and family history of type 2 diabetes American Diabetes Association, 2010


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