Introduction
Diabetes is an ancient disease, with records dating back to over 2,000 years ago. Early descriptions of diabetes mentioned symptoms like excessive thirst and urination, and even in 600 BC, people distinguished between two main types of diabetes. One of the most well-known descriptions was by Arateus the Cappadocian, who talked about the body turning flesh into urine and the disease progressing quickly. (Decoding Diabetes)
Over the centuries, there were sporadic mentions of diabetes, with some attributing it to a loss of salt in the body. However, the sweet taste of the urine was known. These early accounts mainly referred to what we now call type 1 and late type 2 diabetes.
In the 17th and 18th centuries, diabetes was better recognized, and some cases were associated with obesity. The breakthrough came when excess glucose was discovered in the urine and later in the blood.
In the 19th century, the presence of excess ketones was also identified. It wasn’t until the end of the 19th century that we had a clear description of the two main types of diabetes. One was seen in young people and progressed quickly to ketoacidosis, while the other was found in older obese individuals. These were later called juvenile-onset diabetes and maturity-onset diabetes, with the latter considered milder.
Diagnosis depended on measuring blood glucose levels, and there were no standardized criteria at first. Diagnosis usually happened after the onset of symptoms, along with high blood glucose or sugar in the urine, and ketones in the urine for the juvenile-onset type.
A significant breakthrough occurred in 1936 when Himsworth’s work showed that people with diabetes could be divided into insulin-resistant and insulin-sensitive types, with the former being more common in those with maturity-onset diabetes. The development of the radioimmunoassay for insulin allowed clear demonstration of insulin deficiency in those with juvenile-onset diabetes while insulin levels were normal or high in those with maturity-onset diabetes.
Until the mid-20th century, diabetes was considered relatively rare and mostly seen in people of European descent. It wasn’t until 1964 that the World Health Organization (WHO) started paying more attention to diabetes. The real turning point for diagnosis and classification came in 1980 with the publication of the second WHO Expert Committee report, along with a report from the National Diabetes Data Group (NDDG) in the USA in 1979. These events laid the foundation for the diagnostic criteria and classifications used today.
Definition of Diabetes
Diabetes is a health problem with many possible causes. It’s marked by high blood sugar and issues with how your body handles carbohydrates, fats, and proteins. These problems happen because of trouble with insulin, a hormone that regulates blood sugar. The exact mix of these issues can vary among different types of diabetes.
Diabetes can lead to specific complications, like eye problems that might cause blindness, kidney issues that could lead to kidney failure, and nerve problems that might result in foot ulcers or loss of feeling. It also increases the risk of heart and blood vessel diseases.
Typically, diabetes shows up with symptoms like excessive thirst, frequent urination, blurred vision, and weight loss. In some cases, it can even lead to severe conditions like ketoacidosis. But sometimes, the signs are very subtle, or you might not have any symptoms at all while your blood sugar stays high and causes damage over time.
Classification of Diabetes
The classification of diabetes has evolved over time. For centuries, people recognized different levels of severity in diabetes, but it wasn’t until the early 20th century that they started to see two distinct types. However, they didn’t really understand the causes.
In the 1930s, a researcher named Harold Percival Himsworth suggested there were two different forms of diabetes. The first official classification attempt came with the first WHO Expert Committee on Diabetes Mellitus. They divided diabetes into juvenile-onset and maturity-onset based on the age when it usually showed up. At that time, there were other terms like brittle, gestational, pancreatic, endocrine, insulin-resistant, and iatrogenic diabetes, but the causes were not clear.
In the 1970s, there was more clarity when they discovered certain genetic factors (HLA genotypes) in younger patients with diabetes and found islet cell antibodies, showing that these individuals had an autoimmune disorder.
The modern era of classification began with the second WHO Expert Committee, which reviewed and modified the classification from the National Diabetes Data Group. They introduced two main categories: insulin-dependent diabetes mellitus (Type 1) and non-insulin-dependent diabetes (Type 2). There were also “other types” and gestational diabetes, along with two risk classes.
The 1980 classification was updated in 1985, emphasizing clinical descriptions and introducing malnutrition-related diabetes mellitus, which is seen more in certain regions. They also introduced impaired glucose tolerance (IGT) as a high-risk category.
In 1999, WHO and the American Diabetes Association revisited the classification, realizing that terms like IDDM and NIDDM were sometimes confusing. They wanted a classification that considered both the causes and the clinical stages of the disease. This classification includes Type 1 diabetes (T1DM), Type 2 diabetes (T2DM), other specific types, and gestational diabetes.
T2DM is mainly classified by excluding other causes, and new causes are added under “other specific types” as they are discovered.
The classification was revisited again in 2006 with minor changes. IGT was no longer considered a type of diabetes but was retained as a risk category. Impaired fasting glycemia (IFG) was introduced as another risk category, which is important in places where glucose tolerance tests are not commonly done.
In simple terms, the way we categorize diabetes has evolved over time as we’ve learned more about its different types and causes. The goal is to create a classification that helps doctors understand and treat the disease better.
Type 1 Diabetes
Type 1 diabetes (T1DM) is mainly caused by the destruction of insulin-producing cells in the body. After a certain point, people with T1DM need insulin to stay alive. In people of European descent, over 90% of them have signs of their immune system mistakenly attacking these insulin-producing cells. They have antibodies like anti-glutamine acid decarboxylase (anti-GAD), anti-insulin, and islet cell antibodies. Certain gene variations in the HLA complex are linked to T1DM. But not everyone with T1DM symptoms has these immune-related signs, although they tend to be young, not overweight, and often under 30 years old.
In non-European populations, up to 80% of people with T1DM may not have these immune-related antibodies. We call this idiopathic T1DM. However, like autoimmune T1DM, there is a clear loss of insulin-producing cell function. When diabetes appears before the age of 6 months, it’s more likely to be a rare type called monogenic neonatal diabetes.
Apart from the young people who get T1DM suddenly, there is an older group who develop it more slowly. They might seem to have Type 2 diabetes initially but show signs of immune-related issues when we check for GAD antibodies. Eventually, they become dependent on insulin. This is known as latent autoimmune diabetes of adults (LADA).
Type 2 Diabetes
Most people around the world who have diabetes, have Type 2 diabetes (T2DM). In T2DM, the body’s cells don’t use insulin properly, and over time, the body can’t make enough insulin to overcome this problem. People with T2DM usually don’t need insulin to stay alive, but they might require it to control their blood sugar as the condition progresses.
We don’t fully understand the exact reasons behind T2DM, but we know it’s strongly linked to factors like being overweight, not getting enough exercise, and adopting a more Westernized lifestyle. The sharp increase in T2DM over the past two decades is closely connected to the rise in obesity worldwide. Both being overweight, especially having fat around the belly, and not being physically active make the body resistant to insulin, which can eventually lead to diabetes in people who can’t produce enough insulin.
T2DM becomes more common as people get older because age often brings less physical activity and muscle mass. However, it’s also increasingly seen in younger people, including teenagers from various ethnic backgrounds.
T2DM tends to run in families. If you have a close relative with diabetes, you have a nearly 50% chance of developing it at some point in your life. Certain ethnic groups, like Polynesian, Micronesian, South Asian, sub-Saharan African, Arabian, and Native American, are more prone to T2DM than people of European descent.
T2DM is diagnosed by ruling out other possible causes, and as we discover more causes, the number of T2DM cases might decrease, but this is a slow process.
Gestational Diabetes Mellitus
Gestational diabetes mellitus (GDM) is a condition where high blood sugar levels are first found during pregnancy. It’s different from women who already had diabetes before getting pregnant. Typically, blood sugar levels in early pregnancy are lower, so if they become elevated during this time, it’s likely a sign of preexisting Type 2 diabetes.
Doctors usually check for GDM at around 28 weeks of pregnancy. GDM can lead to various complications, including problems with the baby like stillbirth, birth defects, low blood sugar, jaundice, premature birth, and having a very large baby. Some factors that increase the risk of GDM include certain ethnic backgrounds, a history of GDM or glucose problems, older age, being overweight, and having had a big baby in a previous pregnancy.
Other Specific types of Diabetes
Diabetes can show up due to specific genetic issues or in various other situations. One well-known group of genetic problems is called MODY, where diabetes starts at a young age but is usually not severe. For example, a common one is caused by a gene mutation on chromosome 12.
Diabetes can also be linked to problems with how insulin works in the body. Some diseases, like type A insulin resistance, leprechaunism, and lipoatrophic diabetes, have insulin-related issues. Diseases of the pancreas, like pancreatitis from excessive alcohol consumption, can lead to diabetes by damaging the insulin-producing cells. Conditions like hemochromatosis and cystic fibrosis are also known to cause diabetes.
Fibrocalculous pancreatitis is another type. It was once considered a form of diabetes linked to malnutrition and pancreas issues, but it’s now grouped with “other specific types.”
Certain hormonal disorders, like Cushing syndrome and acromegaly, can lead to diabetes, but treating the underlying hormone problem often resolves the diabetes. Some drugs and chemicals can cause diabetes by either harming insulin-making cells or making the body more resistant to insulin.
Infections, such as mumps, congenital rubella, coxsackie B, and cytomegalovirus, have been linked to diabetes development. Many genetic syndromes are also associated with diabetes.
There are some types of diabetes that don’t neatly fit into the usual categories. One is called “Flatbush” diabetes, found in African Americans. Another is ketosis-prone T2DM seen in sub-Saharan Africa. These types involve periods of high ketones and absolute dependence on insulin, alternating with times when diet alone can control the diabetes.
Risk States
Before 1979 and 1980, there was a category known as “borderline” diabetes. It applied to cases where there was uncertainty about whether someone had diabetes, but their blood sugar levels were higher than what’s considered normal. This was later defined by the NDDG and WHO as Impaired Glucose Tolerance (IGT), which means having higher-than-normal blood sugar levels two hours after drinking a sugary solution, but not high enough to be considered diabetes.
Later on, both the ADA and WHO introduced another concept called Impaired Fasting Glucose (IFG), which means having higher-than-normal blood sugar levels when you haven’t eaten for a while but still not high enough to be called diabetes.
Both IFG and IGT are associated with a two- to threefold increased risk of developing diabetes. IGT is also a sign of potential heart problems. IFG is useful because it can signal that someone is at risk of developing diabetes without needing a full glucose tolerance test.
Together, IFG and IGT are sometimes called “pre-diabetes,” but that’s a bit misleading because not everyone with pre-diabetes goes on to develop diabetes. It’s also important to consider other risk factors like family history. The term “intermediate hyperglycemia” is preferred by WHO.
IGT and IFG are more common in older people, those who are overweight, certain ethnic groups with a higher risk, and people with heart disease or other signs of the metabolic syndrome, like problems with cholesterol, high blood pressure, or excess belly fat.
Diagnostic Criteria of Diabetes
Diagnosing diabetes is a big deal because it affects a person’s life. It’s crucial to be absolutely sure about the diagnosis. When someone has symptoms like excessive thirst, frequent urination, weight loss, or recurring infections, it’s easier to confirm diabetes. A single high blood sugar test is enough to diagnose it. If the venous blood glucose level is higher than 11.1 mmol/L (200 mg/dL) or 12.2 mmol/L (220 mg/dL) in capillary blood, it’s a clear diagnosis. Values between 5.0 and 11.0 mmol/L are uncertain, and further testing is needed.
For people without symptoms, diagnosing diabetes is a bit more complicated. This is especially important because many people with Type 2 diabetes don’t have any symptoms and don’t know they have it.
In those with symptoms, one high blood sugar test is enough. But for those without symptoms, they need more testing. One common test is called the Oral Glucose Tolerance Test (OGTT). This test has been around for a long time, and it involves drinking a sugary solution, then measuring blood sugar levels at 1 and 2 hours afterward. If the 2-hour value is 130 mg/dL (7.2 mmol/L) for venous blood, it suggests diabetes.
There’s also a concept called “borderline” diabetes, which is similar to what we now call Impaired Glucose Tolerance (IGT). It means having blood sugar levels above normal but not high enough to be called diabetes, typically between 110 mg/dL (6.1 mmol/L) to 129 mg/dL (7.2 mmol/L) for venous blood 2 hours after the glucose solution.
One important note is that people need to prepare for the OGTT by consuming at least 250 grams of carbohydrates for three days before the test. This is often not followed, which can lead to older people having normal fasting blood sugar but high 2-hour values. Many of them might actually have “starvation” diabetes rather than genuine diabetes.
Modern Times
The way we diagnose diabetes has evolved over the years. In 1979 and 1980, NDDG and WHO looked at a lot of data and decided that a 75-gram sugar solution should be consumed over 5 minutes. They set fasting and 2-hour blood sugar levels at 140 mg/dL and 200 mg/dL. These numbers were later rounded up to 8 mmol/L and 11 mmol/L. They defined Impaired Glucose Tolerance (IGT) as a fasting blood sugar level below 8 mmol/L with a 2-hour level between 8 and 11 mmol/L. This caused some confusion, and in 1985, WHO adjusted its values to match NDDG’s exactly.
In 1997 and 1999, ADA and the new WHO report used more data to determine the risk of retinopathy (an eye problem) at different glucose levels. They found reasonable agreement between studies from Egypt, the US, and the Pima Indians. The 2-hour cut-off of 11.1 mmol/L seemed reasonable, but they lowered the fasting value to 7.0 mmol/L. They also introduced the concept of Impaired Fasting Glucose (IFG), which is like IGT but for fasting blood sugar, indicating a risk for diabetes. The values for IFG were 6.1 to 6.9 mmol/L.
One major difference was that ADA suggested using fasting glucose alone for diagnosis and screening, avoiding the need for an Oral Glucose Tolerance Test (OGTT). WHO continued to support the use of OGTT when necessary because some people with diabetes have normal or IFG values when fasting.
In 2003, ADA recommended lowering the threshold for IFG to 100 mg/dL, but WHO didn’t agree with this change in 2006.
Problems with Glucose Tests
Measuring blood sugar has been the main way to diagnose diabetes for a century, but it has its issues. Initially, the tests were not very specific, but modern enzyme-based tests have improved that. In well-run labs with proper quality checks, accuracy and precision are not problems.
However, the introduction of glucose meters has brought challenges. These devices can be accurate when used carefully and well-controlled, but in the field, their reliability can be as low as 20%, making them unsuitable for diagnosis.
There are also concerns about handling the blood samples. If the blood isn’t separated right after it’s taken, there can be a gradual loss of glucose, ranging from 5% to 20%, even with preservatives.
Another set of issues revolves around the person being tested. Fasting blood sugar levels can vary, influenced by medications, other health conditions, or whether the person fasted properly. The Oral Glucose Tolerance Test (OGTT), which is considered the standard but has its variability from day to day in the same person, making it unreliable when someone is close to the diabetes threshold. These concerns are becoming more critical as more screening programs look for asymptomatic diabetes.
HbA1c as a diagnostic test for Diabetes
Using HbA1c as a diagnostic test for diabetes has become a game-changer in patient care. It’s a reliable way to determine someone’s blood sugar control over weeks, and it doesn’t require fasting or an OGTT (Oral Glucose Tolerance Test). This test is less prone to individual errors, although it can be influenced by certain conditions like anemia or hemoglobin issues.
In the past, there were concerns about the standardization and quality of HbA1c tests, as well as their cost and limited availability in many parts of the world. However, things have improved. There’s now an international standard, and reliable assays are used in good labs with minimal variation.
Many experts believe that HbA1c could be a valuable addition to diabetes diagnosis, used alongside fasting glucose. An Expert Committee led by the ADA supports the use of HbA1c for diagnosing diabetes, with a suggested diagnostic level of 6.5% (47.5 mmol/mol).
It’s worth noting that HbA1c might identify different individuals compared to glucose tests, and the prevalence of diabetes might vary. In some countries like the USA, Australia, Japan, and Northern European countries, HbA1c is likely to become the preferred test for diabetes diagnosis. However, glucose tests will continue to be used in most places for this purpose.
Gestational Diabetes Mellitus
There are two common tests used to diagnose gestational diabetes mellitus (GDM).
First Test (Recommended by WHO):
- After fasting overnight, a 75-gram glucose load is given.
- If the results show either impaired glucose tolerance (IGT) or diabetes based on non-pregnant criteria, the individual is diagnosed with GDM.
Second Test (Used in the USA):
- Initially, a 50-gram glucose load is given.
- If the 1-hour venous plasma glucose level is equal to or greater than 140 mg/dL (7.8 mmol/L), the patient returns for another test.
- In the follow-up test, either a 100-gram or 75-gram glucose load is used.
- The cutoff values for venous plasma glucose in the follow-up test are as follows: 95 mg/dL (5.3 mmol/L) for fasting, 180 mg/dL (10 mmol/L) at 1 hour, and 155 mg/dL (8.6 mmol/L) at 2 hours, regardless of which glucose load is administered.
The WHO’s protocol is simpler and widely accepted, but new recommendations are expected soon based on recent research findings from the Hyperglycemia and Pregnancy Outcomes Study.