2. Epidemiology The worldwide prevalence of diabetes mellitus (DM) has risen dramatically over the past two decades, from an estimated 30 million cases in 1985 to 177 million in 2000. Based on current trends, >360 million individuals will have diabetes by the year 2030. Although the prevalence of both type 1 and type 2 DM is increasing worldwide, the prevalence of type 2 DM is rising much more rapidly because of increasing obesity and reduced activity levels as countries become more industrialized. This is true in most countries, and 6 of the top 10 countries with the highest rates are in Asia. In the United States, the Centers for Disease Control and Prevention (CDC) estimated that 20.8 million persons, or 7% of the population, had diabetes in 2005 (~30% of individuals with diabetes were undiagnosed). 1

3. Epidemiology Approximately 1.5 million individuals (>20 years) were newly diagnosed with diabetes in 2005. DM increases with aging. In 2005, the prevalence of DM in the United States was estimated to be 0.22% in those 20 years. In individuals >60 years, the prevalence of DM was 20.9%. The prevalence is similar in men and women throughout most age ranges (10.5% and 8.8% in individuals >20 years) but is slightly greater in men >60 years. Worldwide estimates project that in 2030 the greatest number of individuals with diabetes will be 45–64 years of age. 1

4. Epidemiology There is considerable geographic variation in the incidence of both type 1 and type 2 DM. Scandinavia has the highest incidence of type 1 DM (e.g., in Finland, the incidence is 35/100,000 per year). The Pacific Rim has a much lower rate (in Japan and China, the incidence is 1–3/100,000 per year) of type 1 DM; Northern Europe and the United States have an intermediate rate (8–17/100,000 per year). Much of the increased risk of type 1 DM is believed to reflect the frequency of high-risk HLA alleles among ethnic groups in different geographic locations. The prevalence of type 2 DM and its harbinger, impaired glucose tolerance (IGT) is highest in certain Pacific islands, intermediate in countries such as India and the United States, and relatively low in Russia. This variability is likely due to genetic, behavioral, and environmental factors. 1

5. Epidemiology

6. DM prevalence also varies among different ethnic populations within a given country. In 2005, the CDC estimated that the prevalence of DM in the United States (age > 20 years) was: 13.3% in African Americans, 9.5% in Latinos 15.1% in Native Americans (American Indians and Alaska natives) 8.7% in non-Hispanic whites Individuals belonging to Asian-American or Pacific-Islander ethnic groups in Hawaii are twice as likely to have diabetes compared to non-Hispanic whites. The onset of type 2 DM occurs, on average, at an earlier age in ethnic groups other than non-Hispanic whites. Diabetes is a major cause of mortality, but several studies indicate that diabetes is likely underreported as a cause of death. In the United States, diabetes was listed as the sixth-leading cause of death in 2002; a recent estimate suggested that diabetes was the fifth leading cause of death worldwide and was responsible for almost 3 million deaths annually (1.7–5.2% of deaths worldwide). 1

7. Types of Diabetes Currently, DM is classified by the pathogenesis that leads to hyperglycemia. Pre-diabetes is characterized by: Plasma glucose levels elevated (2-hour postprandial >140 mg/dL), but not diagnostic of DM Type 1 Diabetes is characterized by: Complete or near-total insulin deficiency Type 2 Diabetes is characterized by: Variable degrees of insulin resistance, impaired insulin secretion, and increased glucose production Gestational Diabetes is characterized by: Development during pregnancy Insulin resistance related to the metabolic changes of late pregnancy Increased insulin requirements that may lead to IGT Reversion to normal glucose tolerance post-partum for most women, but with a substantial risk (30–60%) for development of DM later in life

8. Anatomy and Physiology Diabetes (DM) is a disease of the endocrine system that alters the metabolism of all of the energy nutrients in the body and whose sequelae impacts most organ systems in the body. The pancreas is an organ that has both endocrine and exocrine functions. We will concern ourselves here with the endocrine function of the pancreas. The videos should have given you an idea of how the absolute insulin deficiency of type one DM and the insulin resistance of type two DM affects the level of serum glucose in the body. We will now discuss how this elevation in serum glucose impacts the various organ systems of the body. The chronic complications of DM are responsible for the majority of morbidity and mortality associated with the disease.

10. Chronic Complications Two types of complications: 1. Vascular 2. Nonvascular Subdivisions of the two types of complications 1. Vascular a. Microvascular (retinopathy, neuropathy, nephropathy) b. Macrovascular [coronary vascular disease (CAD), peripheral vascular disease (PVD), cerebrovascular disease]

11. Chronic Complications 2. Nonvascular a. Gastroparesis b. Infections c. Skin changes d. Possible hearing loss The risk of chronic complications increases as a function of the duration of hyperglycemia; they usually become apparent in the second decade of hyperglycemia. Since type 2 DM often has a long asymptomatic period of hyperglycemia, many individuals with type 2 DM have complications at the time of diagnosis.

12. Chronic Complications Before we consider each of these complications in detail, let’s explore the underlying reasons for these complications. In other words, what is it about hyperglycemia that causes these complications? In order to answer this question, we need to go back and refresh our memories about the anatomy of capillary walls. In particular, let us consider the structure and function of the basement membrane of the blood vessels and nerves.

13. Anatomy and Physiology of Chronic Complications

16. Chronic Complications Sustained hyperglycemia creates an imbalance of substances used for making the extracellular matrix. So, in order to answer our earlier question regarding why hyperglycemia causes vascular and non- vascular complications: Sustained hyperglycemia creates an imbalance of substances used for making the extracellular matrix. Enzyme systems normally convert glucose to other sugars, such as sorbitol and fructose to decrease serum glucose. Sorbitol, fructose, and glucose accumulate in the basement membrane of the cell and between the cells, causing intracellular edema and affecting function. This “clogging up” of the basement membrane by sugars, restricts the free flow of oxygen, nutrients, and wastes across the cell membrane and alters the structure of the membranes themselves. Remember: Structure equals function! Cells are impeded in ridding themselves of their waste material and in taking up oxygen and nutrients— therefore, cells malfunction and die.

17. Chronic Complications Vascular MICROVASCULAR: Retinopathy DM is the leading cause of blindness between the ages of 20 and 74 in the United States, and individuals with DM are 25 times more likely to become legally blind than individuals without D. Blindness is primarily the result of progressive diabetic retinopathy and clinically significant macular edema. Diabetic retinopathy is classified into two stages: nonproliferative and proliferative. Nonproliferative diabetic retinopathy usually appears late in the first decade or early in the second decade of the disease and is marked by retinal vascular microaneurysms, blot hemorrhages, and cotton wool spots. The pathophysiologic mechanisms invoked in nonproliferative retinopathy include loss of retinal pericytes, increased retinal vascular permeability, alterations in retinal blood flow, and abnormal retinal microvasculature, all of which lead to retinal ischemia. Remember the basement membrane??

18. Chronic Complications Vascular MICROVASCULAR: Retinopathy The appearance of neovascularization in response to retinal hypoxia is the hallmark of proliferative diabetic retinopathy. These newly formed vessels appear near the optic nerve and/or macula and rupture easily, leading to vitreous hemorrhage, fibrosis, and ultimately retinal detachment. Not all individuals with nonproliferative retinopathy develop proliferative retinopathy, but the more severe the nonproliferative disease, the greater the chance of evolution to proliferative retinopathy within 5 years.

19. Chronic Complications - Vascular Diabetic retinopathy results in scattered hemorrhages, yellow exudates, and neovascularization. This patient has neovascular vessels proliferating from the optic disc, requiring urgent pan retinal laser photocoagulation.

20. Chronic Complications Vascular MICROVASCULAR: Retinopathy: TREATMENT The most effective therapy for diabetic retinopathy is prevention. Intensive glycemic and blood pressure control will delay the development or slow the progression of retinopathy in individuals with either type 1 or type 2 DM. Individuals with known retinopathy are candidates for prophylactic photocoagulation when initiating intensive therapy. Once advanced retinopathy is present, improved glycemic control imparts less benefit, though adequate ophthalmologic care can prevent most blindness. Regular, comprehensive eye examinations are essential for all individuals with DM. Most diabetic eye disease can be successfully treated if detected early. Routine, nondilated eye examinations by the primary care provider or diabetes specialist are inadequate to detect diabetic eye disease, which requires an ophthalmologist for optimal care of these disorders. Laser photocoagulation is very successful in preserving vision. Proliferative retinopathy is usually treated with panretinal laser photocoagulation, whereas macular edema is treated with focal laser photocoagulation.

21. Chronic Complications Neurological MICROVASCULAR: Neuropathy Diabetic neuropathy occurs in ~50% of individuals with long-standing type 1 and type 2 DM. As with other complications of DM, the development of neuropathy correlates with the duration of diabetes and glycemic control. Additional risk factors are BMI (the greater the BMI, the greater the risk of neuropathy) and smoking. The presence of cardiovascular disease, elevated triglycerides, and hypertension is also associated with diabetic peripheral neuropathy. Both myelinated and unmyelinated nerve fibers are lost. The American Diabetic Association (ADA) recommends screening for distal symmetric neuropathy beginning with the initial diagnosis of diabetes and screening for autonomic neuropathy 5 years after diagnosis of type 1 DM and at the time of diagnosis of type 2 DM. All individuals with diabetes should then be screened annually for both forms of neuropathy.

22. Chronic Complications Neurological MICROVASCULAR: Neuropathy The most common form of diabetic neuropathy is distal symmetric polyneuropathy. It most frequently presents with distal sensory loss, but up to 50% of patients do not have symptoms of neuropathy. Hyperesthesia, paresthesia, and dysesthesia also may occur. Symptoms may include a sensation of numbness, tingling, sharpness, or burning that begins in the feet and spreads proximally. Neuropathic pain typically involving the lower extremities, is usually present at rest, and worsens at night. Both an acute (lasting <12 months) and a chronic form of painful diabetic neuropathy have been described. As diabetic neuropathy progresses, the pain subsides and eventually disappears, but a sensory deficit in the lower extremities persists. Physical examination reveals sensory loss, loss of ankle reflexes, and abnormal position sense.

23. Work in Progress New slides will appear here.