When Aretaeus of Cappadocian described and coined the term “diabetes”, he was describing excessive urination (“…it is impossible to put any restraint to the patient's drinking or making water”). Nowadays diabetes means increased levels of blood glucose, the marker of many different diseases with different etiologies and mechanisms that have in common hyperglycemia and, in many cases, the long-term consequences of the disease. By now, high levels of blood sugar are easily treated and it is very rare to die directly from it, but the consequences of uncontrolled diabetes and its associated problems result in a large number of blindness, renal failure, amputations, and especially cardiovascular problems. Diabetes is bad because it is diabetes but it is worse because of the bad companies it keeps!
The diagnosis of diabetes mellitus-1 (DM-1) is usually straight forward because the blood sugar levels are quite high, has a rapid onset, and the patients are symptomatic. DM-2, on the other hand, has an insidious onset, mostly asymptomatic, and frequently is an incidental finding during a routine physical examination (Box 1.1). The transition from normal to pre-diabetes and then to established diabetes is slow and may have improvements and aggravations over the years. During this gradual aggravation of the metabolic process, some of the complications including the cardiovascular may have already started even though the diagnostic glycemic levels may not have been reached, or have not been found.
These diagnostic criteria are general guidelines indicating important steps in the pathogenesis of diabetes but the patient has to be considered as a whole—not just an isolated blood glucose value—contemplating also past medical and family history, associated conditions, and cardiovascular risk factors (Box 1.2). In patients at risk the time for medical intervention should be much earlier that in the past.
The diagnostic criteria at the present time are based on the determination of fasting plasma glucose level, glycohemoglobin A1c, and/or less common, an oral glucose tolerance test (OGTT). Each one of these methods has advantages and disadvantages, with variable clinical acceptance depending on their availability and reliability in different parts of the world. Thiazide diuretics, glucocorticoids and atypical antipsychotic medications should be taken into consideration while performing these tests.
Fasting plasma glucose can be obtained with dependable results in most of the world, but note that for diagnostic purposes the plasma glucose must be measured in a laboratory with well calibrated instruments. Home glucose meters measure whole blood glucose and have a variability range of 10–15% or more in the same sample so that they are absolutely not recommended for diagnosis, and they should be used only for glycemic control. It may sound redundant but we urge you to find the best available laboratory to do these tests, and it is always wise to repeat the test on a different day – and may be in a different laboratory. The fasting plasma glucose is a direct indication of the hepatic glucose production that occurs during the night and with the “Dawn phenomenon”, which are exaggerated because of insulin resistance at the level of the liver.
The advantages and disadvantages of fasting plasma glucose are listed in the Table 1.1.
Glycohemoglobin A1c: Initially, after its standardization, it seemed to be a better and more simple test to diagnose diabetes but it was later found to be not as sensitive as the fasting plasma glucose determination. There are about 30% of patients with elevated fasting plasma glucose who have a hemoglobin A1c less than 6.5%.
On the other hand, it is quite specific, and in most clinical situations it has very rare false positives. One advantage is that it represents the previous glycemic levels of about three months. This becomes very useful in situations of hyperglycemias found in acutely ill patients (Infections, acute myocardial infarctions, surgery, trauma etc.) who were not known to have diabetes (Table 1.2). The differential diagnosis is between an unknown diabetes of longer duration, or an acute “stress” diabetes. If the level of hemoglobin A1c is elevated it indicates that the patient has had diabetes in the past. If the level of A1c is normal it becomes a clear indication of acute “stress” diabetes. But, there are some disadvantages also which are listed in the Table 1.2.
The process of hemoglobin glycation is non-enzymatic and depends on the level of hyperglycemia, time, and a less known factor that is the rate of glycation of each protein. The longer the red cells stay in circulation and the higher the glycemic levels, the higher the A1c. The attachment of glucose to the hemoglobin seem to be different in some individuals, and there “High Glycators” (Highher A1c levels for the same levels of glycemia) and “Low Glycators” (Table 1.3).
Oral Glucose Tolerance Test (OGTT): It is still used in some parts of the world as the gold standard for the diagnosis of DM-2, and is routinely used for the diagnosis of gestational diabetes (Although with a different technique). Again, the measurements should be as plasma glucose, and done with laboratory equipment. It is very sensitive, and gives a very good idea of both fasting and post-prandial levels but it requires a prolonged visit, at least two venipunctures and the ingestion of a standardized glucose load of 75 g. Usually two samples are obtained, fasting and two hours. Plasma glucose levels at one hour are usually not necessary since they are highly variable according to the rate of gastric emptying. Blood sugar levels two hours after a glucose load are mostly related to the prandial insulin secretion of the beta cells, particularly to the first phase that normally prepares the cells to take up the carbohydrates coming from the intestinal absorption. Occasionally, patients become nauseated and are unable to drink the entire volume, or they start vomiting. In these cases, the test should be stopped and repeated two or three weeks later.
Each test has advantages, disadvantages and pitfalls so that they have to be utilized according to the patient and their availability and reliability in every part of the world (Table 1.4). With any of the tests if the results are inconclusive or the patient is at high-risk, it is important to repeat the same test or obtain another one to confirm or not the diagnosis. Even with one positive diagnostic test, it is recommended to obtain a confirmation with the same or one of the other tests.
DM-1 is preceded by a prediabetic state that may last for several years, and is only diagnosed by checking the specific autoantibodies. Not all the individuals with positive antibodies will develop this form of diabetes. The more positive antibodies, the more the likelihood of developing DM-1.
DM-2 also has a very prolonged and asymptomatic prediabetic stage that is characterized by insulin resistance and beta cell hypersecretion initially completely euglycemic. The progression from normoglycemia to dysglycemia may be faster for certain ethnic groups like Asian-Indians. Once the process of beta cell fatigue ensues—usually starting with the loss of the first phase of prandial secretion—progressive increases in glycemic levels appear. There are fluctuations in these metabolic parameters but, if there are no lifestyle or therapeutic interventions, the glycemic levels slowly increase to attain diagnostic levels. Lifestyle modifications, especially weight loss, at this stage can prevent the progression towards diabetes, but they are not easy to implement and maintain over the years. Earlier screening and diagnose permits better results in prevention and in future treatments. Also, the higher the levels of any of these tests there is a continuous increase in the risk of new diabetes.
Diagnostic criteria for prediabetes are discussed in the Box 1.3.
IMPAIRED GLUCOSE TOLERANCE
Impaired glucose tolerance is a prediabetic stage characterized by a 2-hour plasma glucose level between 140 and 199 mg/dL (7.8 and 11 mmol/L) during an OGTT. It indicates a failure of the beta cell secretion after a meal, particularly a decrease or absence in the first phase, and accompanied also by delayed hypersecretion due to the persistent post-prandial hyperglycemia.
Impaired fasting glucose is diagnosed when the fasting levels are between 100 and 125 mg/dL (5.6–6.9 mmol/L) and it represents mostly inappropriately increased hepatic glucose production during an overnight fast. It is not uncommon for patients with DM-2 after the disease has been diagnosed to have fasting glucose levels that are higher than during the rest of the day (“Reverse diabetes”). This explains why the determination of fasting glucose levels is so sensitive for the diagnosis of diabetes. Individuals with impaired fasting or glucose tolerance have a risk of developing new diabetes at a rate of 5–10% per year. The risk is even greater when both abnormalities are present. Nevertheless, impaired glucose tolerance tends to be more frequent, and has a greater association with cardiovascular mortality later on.
Increased glycohemoglobin A1c: Prediabetes may also be diagnosed with levels of A1c between 5.7 and 6.4%, with the risk increasing with values closer to 6.5%. Again, the determination of A1c is not as sensitive as the other methods for the diagnosis of prediabetes.
Our scientific knowledge has progressed enormously with the new tools of genetics and molecular biology in the last few years but we still have a lot to learn. With the discovery of the genomic sequence many of us thought that we soon will be able to understand the predisposition, causes and mechanisms of many common conditions. So far, only very few, uncommon, usually monogenic, diseases have been elucidated leaving the majority of the common clinical problems we see daily in our clinics and hospitals still without clear explanations. We desperately need ways to understand the different types and etiologies of the diabetes that today we simply classify as type 1 and type 2. In particular, we urgently need simple methods to quantify insulin resistance and beta cell mass in our patients to be able to direct our treatments according to the particular mechanisms that are abnormal in each patient.
An important stimulus to try to diagnose diabetes earlier has to do with the protection of the beta cells. Blood glucose control is much better and easier when there is a considerable residual mass of beta cells in the pancreatic islets able to secrete variable amounts of insulin. The more functioning beta cells the less hyper- and hypoglycemia our patients will have. Aging, glucose toxicity, chronic hypersecretion, fatigue and apoptosis keeps decreasing the viable beta cells in the pancreas day by day. In DM-1, we have to add the autoimmune attack or insulitis. The earlier we intervene to normalize the blood glucose levels and avoid the fatigue caused by the constant hypersecretion the more beta cells that we save for the future. At the same time—even though we still do not know exactly the mechanisms—euglycemia improves insulin resistance, which in turn helps to put the beta cells to rest decreasing their tendency to fatigue. Recent epidemiological studies in Europe have shown that earlier diagnosis and intervention are more important than the improvements later obtained in glycemia, blood pressure and lipid control.
Prevention and early diagnosis: We all know that the best treatment is prevention but at the present time we are still waiting too long to diagnose and treat DM-2. It is relatively easy for an experienced physician to forecast the appearance of hyperglycemia in an obese, sedentary individual with a strong family history of diabetes, several components of the metabolic syndrome, polycystic ovaries, or with a past history of gestational diabetes. Approximately, 50% of persons with DM-2 around the world are undiagnosed. Why do we have to wait for the blood glucose or the glycohemoglobin A1c to increase above an arbitrary level when we know that at the time of the diagnosis of type 2 diabetes half of the patients (in developed countries where they have more frequent medical encounters and interventions) already have signs and symptoms of chronic complications and the blood vessels show already changes of arteriosclerosis?
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- An excellent review of all the technical and biological variations in the measurement of A1c
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- A complete review of the tests and criteria of the diagnosis.
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- A genome-wide study of a very large population looking for insulin resistance.
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