Diabetes: the past, the present, and the challenging future

Diabetes testing can be traced back to medieval times-and innovations in testing are being developed today and tomorrow. In this article, we will look at the past, present, and challenging future for this disease state. Additionally, we will look at key risk factors and the changing landscape for diagnosis. Let's quickly review some basic information about diabetes.

Diabetes mellitus describes a group of metabolic diseases characterized by elevated blood glucose or hyperglycemia.1 (Please visit www-mlo-online.com/201405ce to read references for this story.) In persons with a normal metabolism, the consumption of food stimulates the pancreas to release an adequate amount of insulin to move glucose from the bloodstream into cells to produce energy. This mechanism maintains blood glucose levels with fairly tight control but allows flexibility for cells to receive sufficient glucose for all energy-requiring activities. In a person with diabetes, this mechanism fails, and levels of glucose in the blood rise due to the absence of insulin production or the inability of cells to respond properly to the insulin that is produced.

In the clinical laboratory, one of the most frequently requested tests is blood glucose. Uncontrolled, high glucose levels can lead to significant morbidity and premature mortality. Diabetes is the seventh-leading cause of death listed on death certificates in the United States,2 but its actual toll is much higher, because death certificates often fail to list underlying factors, including diabetes, that contributed to the ultimate cause of death, such as stroke or ischemic heart disease.

Currently, about 171 million people across the globe have been diagnosed with diabetes, and this number is calculated to double by the year 2030.2 In the U.S. alone, the number of people diagnosed with diabetes has risen from 1.5 million in 1958 to 25.8 million in 2011, an increase that is epidemic in proportion.1 The Centers for Disease Control and Prevention (CDC) additionally estimates that in 2011,79 million adults age 20 and over had prediabetes, in which blood glucose levels are higher than normal but have not reached the level required for a diagnosis of diabetes. Eleven percent of those with prediabetic readings of elevated blood glucose will develop diabetes within three years.1'2 It is important to note that these individuals are at increased risk of developing vascular disease, even if they do not develop frank diabetes.

Types of diabetes

Type 1 diabetes results from an autoimmune destruction of pancreatic beta cells, usually leading to absolute insulin insufficiency. Type 1 accounts for about 5% of diabetes in the U.S.3 Compared to type 2 diabetes, onset is rapid. Frequent urination, unusual thirst, unusual weight loss coupled with extreme hunger, and irritability are the most prominent symptoms. While all the causes of type 1 diabetes are not fully understood, its prevalence does not appear to be increasing significantly.3

Type 2 diabetes results from a progressive secretory defect on the background of insulin resistance.3 It is most often characterized by its lack of symptoms and gradual beta cell dysfunction. It is associated with increasing age, obesity, and physical inactivity and is more prevalent in certain ethnic groups, such as African Americans, Hispanics, and Native Americans, with Asians generally being at lower risk.4" However, as prevalence increases, a softening of ethnic disparity is noted, with increased numbers of cases noted in all groups.

One of the most disturbing increases in type 2 diabetes is seen in youth. Prior to 1980, this disease was rarely seen in children, but 3,600 cases a year were seen between 2002 and 20055 (Figure 1). Type 2 diabetes in this age group is also more difficult to treat. In addition to compliance issues, hormonal changes, the onset of puberty, childhood illnesses, and infections make successful control a challenge.

Gestational diabetes is a form of glucose intolerance that occurs during pregnancy. It affects about 4% of pregnant women and can result in fetal complications if not treated. While it usually recedes following delivery, the presence of gestational diabetes increases a woman's risk for developing type 2 diabetes to about 40% within five to 10 years of giving birth.3

Other types of diabetes can result from specific genetic defects that destroy beta cells or prevent them from secreting insulin. Some individuals develop diabetes following pancreatic disease or infection. Additionally, certain medications, such as immunosuppressive drugs or those used to combat HIV, can target and destroy insulinsecreting cells.3

Risk factors

Ethnic origin, family history, and specific gene mutations are risk factors beyond our control. However, many lifestyle choices have great influence over the risk of developing type 2 diabetes. The most prominent are obesity and physical inactivity. Additional risk factors for type 2 diabetes include low HDL (<35mg/dL) and high triglycerides (>250 mg/dL) as well as elevated blood pressure or having given birth to a child over 9 lb.4a These risk factors may be present in a person presenting with prediabetes, in which the blood glucose level is higher than normal but not yet diagnostic of type 2 diabetes.2 The good news for people with prediabetes is that a weight loss of only 5% of body weight can prevent or delay the onset of disease.

The impact of obesity on developing diabetes has been demonstrated in data taken from the National Health and Nutrition Examination Survey of 2006. In Figure 2, these data show the lifetime risk of developing diabetes based on weight categories at 18 years of age. It is striking to note that a female who is classified as obese at 18 years of age has more than a 50% risk of developing diabetes over her lifetime. This risk jumps to more than 75% in a female classified as very obese.2,6

Complications of diabetes

Since diabetes is a chronic illness that varies in severity across patients, the effects on major organ systems also vary according to patient control of blood glucose, coexistent diseases, medications, and duration of disease.7 Diabetes affects all major organ systems through its effects on the micro- and macrovasculature. Retinopathy, neuropathy, and nephropathy are the most common organ-specific complications of diabetes, while heart and blood-vessel disease results in acute coronary syndrome and strokes.8,9

Diabetes is the leading cause of blindness in adults 20 to 74 years of age. More than four million people with diabetes over the age of 40 have diabetic retinopathy, which appears in 28% of diagnosed cases. Diabetes is also the leading cause of kidney failure, with 202,290 people in the United States having been diagnosed with end-stage kidney disease due to diabetes in 2008. With the potential for earlyin-life complications such as kidney disease, blindness, and vascular disease, the impact of type 2 diabetes in youth will be profound in terms of morbidity and early mortality.5

Nervous system damage includes impaired sensation in the feet or hands, gastroparesis, or slowed digestion of food in the stomach, carpel-tunnel syndrome, and erectile dysfimction.4b Sixty-five percent of long-term diabetics have nerve damage, and 30% of those over 40 have impaired sensation in their feet. This nerve damage is a major cause of lower-extremity amputations. In fact, more than half of all nontraumatic lower-limb amputations occur in people with diabetes.10

Compared to the general population, people living with diabetes have death rates from heart disease and stroke that are two to four times higher.11 More than 75% of diabetics are treated for hypertension, and the majority also present with dyslipidemia, greatly increasing their risk for stroke and heart disease.7 One startling statistic: deaths from heart disease in women with diabetes have increased 23% over the past 30 years, compared to a 27% decrease in women without diabetes.

Diagnosing diabetes

Rudimentary forms of diagnostics for diabetes have existed for millennia. Around 600 B.C., a Hindu physician described the sweet taste of urine in people with extreme thirst. Diagnosis as we know it dates to medieval times, when urine was routinely collected in a flask and examined for sediment related to disease said to be in different parts of the body.

Just over 100 years ago, Benedict developed a standardized method to measure glucose in urine.12 In 1921, at the Annual Meeting of the Association of Life Insurance Medical Directors, Dr. Elliott Joslin extended the use of Benedict's method in the "glucose diet test." This version of the glucose tolerance test required the patient to eat two meals, each containing 125 grams of carbohydrate, including apple pie and ice cream, followed by collection of urine for the following two hours. He stated that this was the most rehable method for diagnosis of diabetes.13 He also noted that blood tests for glucose were not satisfactory due to complicated methods that resulted in high error rates. Today, this would be known as unacceptable coefficients of variation.

Changing criteria for diagnosis

For the past several decades, diagnosis of diabetes has been based on blood glucose criteria, either a fasting sample or the two-hour value in the 75-g oral glucose challenge test. Several recent studies have shown the limited usefulness of glucose testing in the diagnosis of adolescents.14 In this population, the glucose tolerance test can give misleading results due to the effects of puberty and hormones, according to a recent presentation at the Excellence in Diabetes Conference, February 28 through March 2, 2014, in Doha, Qatar.

The upper limit of normal used to diagnose diabetes has been reduced, and an intermediate category of impaired glucose has been added to the diagnostic algorithm.7 Numerous research studies have confirmed that lowering the acceptable levels of blood glucose assists with earlier diagnosis and reduces the morbidity associated with this disease.15,16 However, another impact of the lower limits is the diagnosis of diabetes in people who would have been excluded earlier.3 Therefore, the large rise in cases in recent years results from this reclassification as well as actual numbers of people presenting with diabetes.

In 2009, an International Expert Committee recommended the use of hemoglobin Ale (HbA1c) to diagnose diabetes.4" The American Diabetes Association adopted this criterion in 20104" (Table 1, page 10). HbA1c had been recognized for its clinical utility in diabetes management as early as the 1980s, but it had not been recommended for diagnosis. This marker is a stable adduct where glucose binds to the N-terminal valine of the hemoglobin B chain. The tight binding gives it a lifespan coincident with that of the erythrocyte, about 120 days. When the recommendation was made for the use of HbA1c in diagnosis, it was with the understanding that the test be performed by a method that is certified by the National Glycohemoglobin Standardization Program (NGSP) or traceable to the Diabetes Control and Complications Trial reference assay. Earlier methods to measure HbA1c showed wide variability, but with the NGSP and proficiency testing, standard deviations have been reduced considerably.7

The HbA1c test has several advantages over blood glucose testing. These include patient convenience, since fasting is not required; greater analytical stability for laboratory measurement; and less dayto-day change due to illness or stress.17 Blood glucose measures can contribute to misclassification due to diurnal variation as well as pre-analytical factors, particularly in vitro glycolysis.

However, these advantages of HbA1c testing must be weighed against its greater cost and limited availability, especially compared to standardized methods.7 While point-of-care HbA1c tests may be NGSP-certified, proficiency testing is not currently mandated for those performing this test. Participation in proficiency testing can strengthen the utility of this assay in several diagnostic locations, including clinics and physician offices.18

The HbA1c level reflects the integrated glucose value over the preceding 12 weeks. Epidemiological studies have shown that HbA1c values are superior to glucose in estimating the risk of microvascular complications.16 Subjects with well-controlled HbA1c levels exhibited reduced risk for proteinuria and subsequent nephropathy. Well-controlled HbA1c levels have also been associated with a reduction and/or delay in the development of retinopathy and neuropathy. The use of HbA1c to monitor glucose control can assist in reduction of the development of neuropathy and retinopathy by as much as 60%.16

However, HbA1c levels may vary with patients' race or ethnicity. Glycation rates may be higher in some racial groups, but this is controversial.18 Also, whether the cut point for diagnosis should be the same for children and adolescents as it is for adults is unclear.11 For conditions with abnormal red cell turnover, such as pregnancy, recent blood loss or transfusion, and some anemias, the diagnosis of diabetes must rely on blood glucose and not HbA1c.7

Understanding the need for an NGSP-certified method and the limitations of the test, what should the level of HbA1c be? The American Diabetes Association suggests less than 7%, while the International Diabetes Federation uses 8%.7 These are values for adults, while in children and adolescents, the levels should be a point higher, since they are more likely to experience hypoglycemia if their blood glucose levels are very tightly controlled.

Because HbA1c reflects average glycemia over several months and has strong predictive value for diabetes complications, testing should be performed routinely at the initial assessment and at continuing-care visits.17 The measurement of HbA1c has been the primary index of glycemia in the Diabetes Control and Complications Trial, the United Kingdom Prospective Diabetes Study, and many other studies. It is therefore the basis upon which glycémie control is known to be a mediator of diabetic complications. The Diabetes Control and Complications Trial reduced mean HbA1c by 1.8% in the intensively treated group (7.3% vs. 9.1%), and this difference resulted in a 76% decrease in the development of new retinopathy and a 60% decrease in the development of clinical neuropathy.7 Similarly, in type 2 diabetes, the United Kingdom Prospective Diabetes Study found a 25% decrease in microvascular complications associated with the 10% reduction in HbA1c achieved in the intensively treated group.3

Recently, NGSP-certified rapid HbA1c assays have become available, allowing office and home testing. Point-of-care HbA1c testing at the clinic visit gives patients immediate feedback and allows the physician to make timely therapy changes. Evidence suggests that point-of-care HbA1c testing may be superior to central laboratory testing in decreasing HbA1c levels in type 1 and type 2 diabetes.19'21 Benefits of home testing, including increased patient autonomy and self-knowledge, must be weighed against the possibility of misuse, misinterpretation, and avoidance of the regular medical-care system. No evidence exists to evaluate the efficacy of home HbA1c testing. (See Figure 3.)

By providing office-visit feedback, point-of-care testing for HbA1c as well as glucose can allow the physician to make immediate changes in medications and/or lifestyle management.19'20 This might be especially important in younger patients with type 2 diabetes for whom the cardiovascular risk rises to high levels early in life.2

In addition to HbA1c, two other long-term indices of glycemia-fructosamine and 1,5 anhydroglucitol (1,5-AG)-are available but less widely used. Fructosamine, the product of post-translational glycation of serum proteins, predominantly albumin, provides a reflection of glycemia over a shorter time frame than does HbA1c. The reliability of the fructosamine assay is variable, bringing into question its clinical utility. One study found the mean glycemia over a prior two-week period was better predicted by HbA1c than fructosamine.22 Even as an adjunct to home blood glucose monitoring, weekly fructosamine testing did not improve HbA1c levels.

Facing a challenging future

The CDC estimates that in 2011 more than seven million people in the U.S. had diabetes and did not know it. Diabetes imposes a financial burden on both our healthcare system and the individuals living with the disease. The CDC estimates the cost of diabetes in the U.S. was $194 billion in 2011 and will increase to more than $250 billion in 2014.3 This is unsustainable, with many predictions that the epidemic will impact one out of three Americans by midcentuiy. Diabetes treatment, including medications and monitoring supplies, costs each patient about $11,700 annually. If he or she develops one diabetic complication, such as retinopathy, the individual cost rises to an average of $20,700 per year.63

An important question that needs to be answered as we attempt to further reduce the complications arising from undiagnosed diabetes is whether we should screen the general population for diabetes using tests such as HbA1c. An answer to this question continues to be discussed; yet as the number of undiagnosed patients continues to grow, the impact of the disease on patient quality of life and the overall cost of diabetes to healthcare cannot be ignored.

By Nancy Haley, PhD, and Martu Richards

Nancy Haley, PhD, serves as Senior Clinical Consultant for Siemens Healthcare Diagnostics and is a member of the Siemens Healthcare Diagnostics Scientific Marketing team, where she conducts seminars on emerging technologies and cardiovascular, oncological, and infectious diseases. Martu Richards serves as Marketing Manager, POC Business Management, for Siemens Healthcare Diagnostics, providing marketing and business management support for Siemens customers.