Diabetes: Epidemiology, Etiology, and Diagnosis

Diabetes results from a complex interaction of genetic, environmental, and lifestyle factors. In type 1 diabetes, an autoimmune-mediated process triggered by an environmental factor and occurring in genetically susceptible people causes destruction of the pancreatic β cells. People with type 1 diabetes do not produce insulin and they must receive daily injections of insulin to survive. Type 2 diabetes is caused by lifestyle factors (obesity being the most important) and, to a small degree, by genetic factors. The pancreatic β cells are not destroyed, but they do not produce sufficient insulin to maintain healthy glycemic control, and people with type 2 diabetes also do not utilize the insulin they do produced. Type 2 diabetes can initially be managed with a special diet, some lifestyle changes, and oral medications, but most patients will eventually need insulin.

Case Study #1: A 13-year-old male with no prior medical history (PMH) is noticed by his parents to have an increased appetite, excessive thirst, and excessive urination. He has been in his usual state of health and maintaining his normal activities. He has two older siblings and both are healthy. His mother is healthy, but his father has type 1 diabetes. Laboratory tests show fasting plasma glucose of 145 mg/dL and one week later, 151 mg/dL, and his HbA1C is 7.3%. He is started on intensive insulin therapy (basal insulin plus as needed short-acting insulin through the day) and exercise and diet prescriptions are made.

Case Study #2: A 57-year-old female with a PMH of HTN visits her primary care physician because she has developed an ulcer on her foot (the result of an injury) that does not seem to be healing, and pins and needles sensation in the same extremity. She currently takes lisinopril and HCTZ for HTN; her blood pressure is 166/88 mm Hg. She does not smoke or use alcohol. Her body weight is 125 kg (classifying her as obese), and she never exercises. Her fasting plasma glucose is 191 mg/dL, and one week later, 211 mg/dL, her HbA1C is 8.1%, and her total serum cholesterol is 246 mg/dL. She is diagnosed with diabetic neuropathy, hypercholesterolemia, metabolic syndrome, type 2 diabetes, and uncontrolled hypertension.

Learning Break: Diabetes is diagnosed and monitored using three tests: fasting plasma glucose, oral glucose tolerance test, and glycated hemoglobin (HbA1C). Normal fasting plasma glucose is 70-99 mg/dL. A normal oral glucose tolerance test should be ≤ 140 mg/dL two hours after receiving 50 grams of glucose. The HbA1C test reflects the average amount of glucose in the blood over a period of weeks, so it is a useful test for monitoring the effectiveness of therapy and assessing the long-term risk for complications. The HbA1C should be ≤ 6%.

The epidemiology of diabetes is best understood in the context of these categories: diabetes in the population, type 1 diabetes, type 2 diabetes, diabetes and age, diabetes and gender, diabetes and ethnic background, and morbidity and mortality associated with diabetes.

Learning Break: Diabetes is typically classified as either type 1 or type 2, but there are actually many other types of diabetes (e.g., gestational, drug-induced, infection-induced, or disease-induced, etc.). However, these represent a very, very small minority of the total number of cases of diabetes and they will not be discussed here. There is also a condition called pre-diabetes. Pre-diabetes is a condition in which the HbA1C, the plasma glucose, and other markers of diabetes are persistently elevated, but are not high enough to require treatment. People with pre-diabetes have an increased risk of developing type 2 diabetes, heart disease, and stroke.

• Diabetes in the population: A 2011 report from the Centers for Disease Control (CDC) estimated that approximately 26 million Americans have diabetes, and an estimated 79 million Americans have pre-diabetes (US Department of Health and Human Services, 2011). Diabetes affects 8.3% of all Americans and 11.3% of people aged 20 years and older and pre-diabetes affects approximately 35% of people aged 20 years and older. There are also millions of people who do not know they have pre-diabetes or dont know they have type 2 diabetes.
• Type 1 diabetes: Type 1 diabetes accounts for approximately 5%-10% of all cases of the disease (Khardori, 2011).
• Type 2 diabetes: Type 2 diabetes accounts for approximately 90%-95% of all cases of the disease (Khardori, 2011).
• Diabetes and age: Type 1 diabetes typically develops in children aged 4 years and older, and the peak incidence in children occurs between the ages of 11 and 13 years (Khardori, 2011). Some cases of type 1 diabetes occur in adults, and cases of type 1 diabetes have been reported in people in the 8th and 9th decade of life. Almost all cases of type 1 diabetes are caused by autoimmune destruction of the pancreatic β cells, but there are a small number of patients (mostly African-American or Asian) that develop idiopathic type 1 diabetes. This form of the disease is not caused by an autoimmune process, it is strongly inherited, and the need for insulin tends to wax and wane (American Diabetes Association, 2010). The incidence of type 2 diabetes increases with increasing age.
• Diabetes and gender: Type 1 diabetes is approximately 1.5 times more common in men than in women (Khardori, 2011). In the US, approximately 11.8% of all men 20 years of age or older have diabetes, and approximately 10.8% of all women 20 years of age or older have diabetes (US Department of Health and Human Services, 2011).
• Diabetes and ethnic background: In descending order, diabetes affects 12.6% of non-Hispanic blacks, 11.8% of Hispanics, 8.4% of Asian-Americans, and 7.1% of non-Hispanic whites (US Department of Health and Human Services, 2011). Type 1 diabetes is more common in whites; it is much less common in African-Americans and Asian-Americans (Khardori, 2011). Type 2 diabetes is more common in African-Americans, Native Americans, and Hispanics than among whites (Khardori, 2011).
• Diabetes and morbidity and mortality: Diabetes is the seventh leading cause of death in the US (US Department of Health and Human Services, 2011). It is the leading cause of kidney failure, neuropathy, non-traumatic amputations, and blindness in adults. In addition, diabetes is considered to be a major risk factor for the development of cardiovascular disease and stroke.

Type 1 diabetes is caused by autoimmune destruction of the β cells of the pancreas. This process occurs in genetically susceptible people and is (presumably) triggered by an environmental factor or factors (Skyler, Ricordi, 2011). When the majority (approximately 80%-90%) of the β cells have been destroyed, a normal level of serum glucose cannot be maintained and signs and symptoms of type 1 diabetes will become evident.

Learning Break: Type 1 diabetes is caused by an interaction of genetics and environment, and there are multiple genetic and environmental factors that may contribute to the development of the disease.

• Environmental factors: Environmental factors especially certain viruses are thought to play a role in the development of type 1 diabetes, and there is epidemiological evidence that supports this theory. For example, the incidence of the disease has been increasing rapidly worldwide, especially in very young children. However, although there are certainly regional differences in the incidence of type 1 diabetes, the genetic risk profile for type1 diabetes does not differ greatly from area to area (Hober, Sane, 2010), suggesting the possibility of an environmental influence on the development of the disease (Ilonen, Vaarala, Akerblom, Knip, 2009). Environmental triggers that may initiate the autoimmune destruction of pancreatic β cells include chemicals, dietary factors in early life (e.g. exposure to cows milk, vitamin D deficiency), cytotoxins, enteroviruses, and other infections. However, aside from the enteroviruses there is little convincing evidence that at this point that these or other environmental factors are responsible for causing the large increase in the number of cases of type 1 diabetes (TEDDY Study Group, 2008, Vehik, Dabelea, 2011).


• Environmental factors/enteroviruses: Enteroviruses are very common viruses. They are spread through infected respiratory particles and infected stool, and they are second only to rhinoviruses (the common cold viruses) in the number of infections caused. Epidemiological studies have shown a significant association between the incidence of enterovirus infections and the development of type 1 diabetes and/or autoimmunity (Yeung, Rawlinson, Craig, 2011), especially in genetically susceptible individuals (Hober, Sane, 2010). A review and meta-analysis of observational studies showed that children with type 1 diabetes were 9 times more likely to have had an enteroviral infection, and children with autoimmunity that could affect the pancreas were 3 times as likely to have had an enteroviral infection (Yeung, Rawlinson, Craig, 2011).   


• Genetic factors: Type 1 diabetes is definitely in part a genetic disease. At least 18 regions of the genome have been linked with a risk for developing type 1 diabetes. A lot of research has examined the IDDM1 region, a region of the genome that contains the HLA (human leukocyte antigen) genes, and the greatest genetic risk for type 1 diabetes is related to alleles, genotypes, and haplotypes of the HLA Class II genes (Pociot, Akolkar, Concannon, et al, 2010). The HLA is a region of genes that is located on chromosome 6. These genes encode MHC (major histocompatability complex) immune response proteins that are located on cell membranes; these proteins are used by the immune system to identify antigenic material (Dean, McEntyre, 2004). The genes that encode the MHC proteins that are most strongly associated with type 1 diabetes are HLA-DR, HLA-DQ, and HLA-DP, and they have alleles that affect the coding of the proteins in a way that makes them appear as foreign to the immune system. An autoimmune response is initiated, and the pancreatic β cells are destroyed. Other genes in other areas are also thought to be genetic factors that contribute to the development of type 1 diabetes. The IDDM2 region contains the insulin gene that affects the production of insulin, and the IDDM3-IDDM18 regions contain genes that may act as susceptibility genes (Dean, McEntyre, 2004), and it is possible that variations in the CTL4 gene (a gene that encodes a molecule that inhibits the autoimmune response) also can influence susceptibility to type 1 diabetes. However, although genetics are an important risk factor for type 1 diabetes, there are many genes that may be involved and how, why, and when genetics influences the development of type 1 diabetes is still far from clear. For example, in identical twins the risk for one sibling developing type 1 diabetes if the other has the disease is approximately 33%, and children whose parents have type 1 diabetes only have a 3%-6% risk of developing type1 diabetes.

Type 2 diabetes is characterized by insulin resistance and a progressive decline in pancreatic β cell insulin production. There is no autoimmune-mediated pancreatic β cell damage and most patients with type 2 diabetes do not need insulin during the initial stages of the disease.

Insulin resistance is a condition in which insulin is produced, but is not used properly: a given amount of insulin does not produce the expected result. In people who are obese it may be that the chronic inflammation associated with obesity affects the function of the insulin receptors on the cells in the liver, muscles, etc., decreases the number of insulin receptors, affects insulin signaling pathways, or inactivates insulin receptors (Allende-Vigo, 2010; Olatunbosun, 2011).

The progressive decline in pancreatic β cell function is due to decreased β cell mass caused by apoptosis (Butler, Janson, Bonner-Weir, Ritzel, Rizza, Butler, 2003); this may be a consequence of aging, genetic susceptibility, and insulin resistance itself (Unger, Parkin, 2010). The etiology of type 2 diabetes is complex and involved genetic and lifestyle factors.

• Genetic factors: There are susceptibility genes that definitely play a role in the development of type 2 diabetes, but their contribution appears to be small. The effect of the known, common gene variants in creating a pre-disposition to type 2 diabetes is approximately 5%-10% (McCarthy, 2010), so unlike some inherited diseases, being homozygous for these susceptibility genes does not typically result in a case of type 2 diabetes unless certain environmental (in this case lifestyle) factors are present.


• Lifestyle factors/demographics: Obesity is definitely a major risk factor for the development of type 2 diabetes (Li, Zhao, Luan, et al, 2011), and the greater the degree of obesity, the higher the risk (Nguyen, Nguyen, Lane, Wang, 2011). Excess adipose tissue is typically in a state of chronic inflammation, and this inflammation is thought to cause insulin resistance in the adipose tissue and in other organs (Gutierrez, Puglisi, Hasty, 2009). Other factors that increase the risk of developing type 2 diabetes are the presence of the metabolic syndrome (Eckel, 2008), age, and a sedentary lifestyle. Type 2 diabetes is much more common in African-Americans than other ethnic groups. There may be a genetic explanation for this, but socio-economic factors are probably to blame (Link, McKinlay, 2009).

• Pre-diabetes is defined as a condition in which glucose levels and other markers of diabetes are abnormally high, but at a level that does not require treatment. People with pre-diabetes have a very high risk of diabetes. A fasting plasma glucose of 100 mg/dL to 125 mg/dL, or an oral glucose tolerance test of 140 mg/dL to 199 mg/dL is considered diagnostic for pre-diabetes (American Diabetes Association, 2010). An HbA1C level that is above the top normal of 6% and below the 6.5% level that is diagnostic for diabetes also represents a significant risk factor for developing diabetes (American Diabetes Association, 2010), although some authorities feel that the lower limit for HbA1C in pre-diabetes should be 5.7%.


• Diabetes is diagnosed when a) the HbA1C is ≥ 6.5%, or b) the fasting plasma glucose is ≥ 126 mg/dL on two occasions, or c) the oral glucose tolerance test is ≥ 200 mg/dL, or d) the patient has classic symptoms of hyperglycemia (e.g., polydipsia, polyphagia, polyuria) or had a hyperglycemic crisis, and has a random plasma glucose ≥ 200 mg/dL (American Diabetes Association, 2010). 


• If the patients laboratory values are high, the risk of developing microvascular complications such as retinopathy and neuropathy increase, and the risk of developing cardiovascular complications increases, as well. There is a direct linear relationship between abnormal fasting plasma glucose and HbA1C and diabetic complications; the worse the glycemic control and the higher the levels, the greater the risk. There are some questions about which test HbA1C, fasting plasma glucose, or oral glucose tolerance test is best for diagnosing diabetes. There is no definite answer at this point; the provider should use the test he/she feels is best and use confirmatory tests as needed.

The question of who to test for type 1 diabetes usually resolves itself. People with type 1 diabetes present with signs and symptoms that are distinctive and the fasting plasma glucose is markedly elevated, so most cases are diagnosed very soon after onset. Autoantibody levels can be measured and this might be advisable in high-risk individuals.

Testing for type 2 diabetes should be performed in any asymptomatic adult, regardless of age, who is obese or has one or more risk factors such as sedentary lifestyle, ethnic risk factor, a first-degree relative who has diabetes, an HbA1C ≥ 5.7%, hypertension, etc. (American Diabetes Association, 2010). People who are not obese and do not have risk factors should be tested starting at age 45. Fasting plasma glucose, oral glucose tolerance test, or HbA1C testing can be used and if the values are normal, the tests can be repeated in three years. Adults should also have serum lipids measured, blood pressure should be checked, an evaluation for the presence of cardiovascular disease should be performed, and if needed, evaluation for the presence/possibility of diabetic nephropathy, neuropathy, and retinopathy. Children who are obese and who have risk factors should be evaluated starting at age 10.

Diabetes can be a devastating disease, it is a progressive disease, and there is no cure. Patients with diabetes must monitor their diet, their activity level, their plasma glucose, and almost without exception they must take medications forever.

Type 1 diabetes cannot be prevented or (effectively) cured; it can only be managed. However, with conscientious effort patients can delay the onset and/or slow the progression and severity of the complications of the disease.

But type 2 diabetes can, in many instances, be prevented. It has clearly been shown that lifestyle alterations such as diet, exercise and weight loss especially weight loss can prevent the development of type 2 diabetes; unfortunately, it is well known that many people find initiating and maintaining an exercise and weight loss program very difficult. So with the incidence of obesity at epidemic proportions and predicted to increase, the population getting older and more sedentary, the already very high incidence of type 2 diabetes is going to become even higher.

Given these facts, identification of people at risk and vigorous screening of these people is essential, and health care professionals need to know who these people are and provide them with education and testing.

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