By Gary Wolfe and Marleen Wolfe

 When a person of great fame and stature dies as a result of complications from diabetes—singer Johnny Cash, for example—the notoriety of the event suddenly elevates public awareness about a disease that has scourged humanity since ancient times. As sad as such losses may be, however, one of the more tragic aspects of the disease is that in many cases the suffering and deaths are needless and preventable. In large measure this is because diabetes is easy to diagnose with widely available laboratory blood tests and manageable with proven drugs (notably insulin), simple self-administered blood tests, and commonsense lifestyle changes.

This is not to say that diabetes is easy to bear for either the patients or their families. Along with the diagnosis of the disease must also come the recognition that it will intrude, often painfully, into all facets of a diabetic’s life with daily finger sticks, blood tests, and insulin injections; meticulous daily routines to plan and monitor diet and physical activity; and enormous psychological stress in worrying about possible long-term complications. Fortunately, continued research into the disease, coupled with new technological developments and disease management strategies, promises to make the disease easier to live with in the future.

An Ancient Disease
There is ample evidence to suggest that ancient physicians could recognize diabetes and differentiate two forms. For example, Robert Rizza, MD, an endocrinologist and professor of medicine in the Division of Endocrinology, Diabetes, Metabolism and Nutrition, at the Mayo Clinic, in Rochester, Minn, and on the board of the American Diabetes Association (ADA), explains that the name “diabetes” comes from the Greek word meaning “sweet urine” because the ancients associated the disease with sugar in the urine.

Rizza says, “The ancients knew that one form–now called Type 1–was invariably fatal (and would remain so until the discovery of insulin in 1922) and that the other form–now called Type 2–was treatable. They also understood some of the major complications that could result from the disease and even prescribed healthy regimens (involving eating less, exercising more, and avoiding certain substances) to help alleviate the less severe form of the disease.”

In our own society, public awareness about diabetes is essential because the incidence of the disease is increasing as the general population gets older, heavier, and more sedentary. Statistics from the ADA in 2000 indicate that of the estimated 17 million Americans who have the disease, 5.9 million—1/3 of cases—are still undiagnosed; and each year more than a million people 20 years or older become new cases. The ADA also notes “the risk of death from diabetes is about twice that of people without diabetes” and that “diabetes was the sixth leading cause of death in the United States in 1999." Besides Type 1 and Type 2, a third category, “Gestational Diabetes affects about 4% of all pregnant women (about 135,000 cases in the United States annually).” Moreover, there are another estimated 16 million Americans with prediabetic conditions in which their “blood glucose levels are higher than normal but not high enough for a diagnosis of Type 2 diabetes.”

“Early diagnosis is vital because diabetes itself often displays no outward symptoms,” says Rizza. If detected and treated soon, the disease can be controlled with relative ease. If not, it will gradually wreak havoc on most of the body’s major organs, leading to a multitude of serious, often fatal, complications, which may not become evident until years after the disease’s onset. “By then,” says Rizza, “treatment is usually too late to reverse the complications, some of which may include vascular and tissue damage leading to amputations; renal, respiratory, and circulatory failure; high blood pressure; stroke; heart disease; nervous system damage; dental disease; blindness; pregnancy complications; and other metabolic damage.”He also notes that the specific mechanisms that cause such extensive damage are not fully understood yet and remain subjects of active research.

Preliminary Diagnosis
Insulin is a pancreatic hormone essential for regulating almost every tissue in the body. If the body’s insulin supply is inadequate or absent, the insulin-dependant regulatory function is compromised or lost altogether, and various potentially fatal complications will arise. Rizza says, “The principal indicator of an insulin deficiency is an elevation in blood glucose (hyperglycemia). Related conditions that suggest a heightened risk of diabetes include high blood pressure and a high concentration of blood lipids.”

“The criterion for establishing that a person has diabetes is a fasting blood glucose concentration that routinely exceeds 125 mg/dL versus a normal concentration in the 80 – 100 mg/dL range for a healthy individual,” says Rizza. Complementing blood glucose testing, glucose tolerance testing is also used to confirm the presence of diabetes. He explains, “A positive indication of diabetes would be a concentration of more than 200 mg/dL for 1 hour after drinking 75 grams of glucose. If the concentration remains at more than 200 mg/dL for 2 hours, then a subsequent fasting glucose tolerance test would be used to verify the high concentration.”

 Pointe Scientific’s Direct HbA1c product is a latex-enhanced immunoturbidimetric assay for the automated determination of hemoglobin A1c (HbA1c) in human blood.

Either blood glucose or glucose tolerance testing alone can identify the presence of diabetes in about 80% of cases according to Rizza, but using both tests as a means of verifying each other enables diabetes to be detected effectively in all instances.

Differentiating Diabetes Types
Diabetes occurs in at least two forms: Type 1 (afflicting about 10% of diabetics and believed to be caused by an alteration in immunity) and Type 2 (afflicting about 90% of diabetics). “In many instances,” says Rizza, “patients have a strong genetic predisposition for the disease, further aggravated by environmental challenges, such as diet and lifestyle. Certain populations in areas such as Southeast Asia and India apparently have an easier time acquiring the disease even with modest weight gains, whereas people of European origin seem to be able to gain more weight before the problems arise.”

Type 1 Diabetes
Formerly called juvenile diabetes, Type 1 diabetes results when a person’s pancreas cannot secrete any insulin even though the pancreas may otherwise function normally. Typical causes may be autoimmune destruction of the insulin-secreting cells; diseases, traumas, or other external causes that prevent the organ from functioning properly; or surgical removal of the organ.

Regardless of the cause, Type 1 diabetes patients require daily insulin injections to survive. Moreover, they must conscientiously check their blood glucose levels on arising and before every meal, closely follow the treatment plan prescribed for them, and carefully monitor their diets and general physical condition at all times.

Type 2 Diabetes
Type 2 diabetes is commonly acquired as people age and gain weight, although it also appears in children. It may result from a combination of factors–often lifestyle related–such as obesity, overeating, sedentary work habits, and lack of exercise. In these in
stances, although the pancreas still secretes insulin, the concentration is inadequate to meet the body’s requirements

“With Type 2,” says Rizza, “physicians have the options of prescribing drugs to stimulate the pancreas to secrete more insulin, to cause the body to make less glucose, and to make the naturally available insulin work more effectively in the patient’s body. If these drugs cannot adjust insulin production and use, then insulin injections may be necessary.”

With proper treatment, weight loss, and physical exercise, Type 2 diabetics can often reestablish normal metabolic functions and lower the risk of diabetic complications, but, according to Rizza, “the disease never really goes away. Patients will maintain a lifelong predisposition for the disease, especially if they gain weight, overeat, and stop exercising.”

 Metrika’s A1cNow test quantitatively measures the percentage of glycated hemoglobin (%HBA1c) in capillary (fingerstick) or venous blood samples.

Growing Importance of A1c Testing
Recent advances in diabetes management involve new POC and clinical laboratory technologies and more effective analyzers for performing hemoglobin A1c measurements, which in the past were quite difficult to perform quickly and accurately. According to Rizza, "The A1c results correspond to the amount of glucose molecules attaching themselves to the hemoglobin in red blood cells. They provide an index of how well blood sugars are being controlled and help physicians adjust medication levels.”

Examples of A1c Assays
A number of A1c assays are commercially available: for example, the Direct HbA1c™ product (from Pointe Scientific Inc of Lincoln Park, Mich) for automated central lab use and the A1cNow™ product (from Metrika, Inc. in Sunnyvale, Calif) for point-of-care applications and patient self-test.

The Direct HbA1c product is a latex-enhanced immunoturbidimetric assay for the automated determination of hemoglobin A1c (HbA1c) in human blood. A new offering, it was submitted to the FDA in May 2003 and received its 510k clearance in early August. Presented in a convenient liquid stable format, the reagent may be used on virtually any chemistry analyzer capable of handling at least two reagents. To ensure integrity of each determination, a calibrator and control set are available; these are correlated with other national glycohemoglobin standards program (NGSP)–certified methods.

Stats
  • Total Number of People With Diabetes in the US: Approx. 17 million
    (5%—10%, Type 1; 90%—95%, Type 2)
  • Total Number of Cases Diagnosed: Approx. 11.1 million
  • Total Number of Cases Not Diagnosed: Approx. 5.9 million
  • Total Number of People with Prediabetes in the US: Approx. 16 million
    (in addition to those who already have the disease)
  • Total Annual Costs of Diabetes in the US in 2002: Approx. $132 billion for direct and indirect costs (10% of US health care dollars)
* Source: American Diabetes Association
(www.diabetes.org). All statistics are estimates.

According to Bill Walters, vice president and technical director of Pointe Scientific, “We offer a simplified methodology that measures A1c directly. This differs from other techniques that require two different determinations–one of total hemoglobin and one of A1c in mass concentration units–followed by complicated calculations to determine percentage of HbA1c. Our HbA1c method employs a straightforward competitive binding principle that needs only one assay instead of two, only one channel instead of two, and no calculations.”

Walters says, “By eliminating any additive error that might have resulted from the second assay, our HbA1c assay can correspondingly improve accuracy and precision. Also important, laboratories can consolidate our HbA1c product directly onto the analyzer workstations they already use for routine chemistry testing. So there is no need for them to buy and maintain an additional dedicated analyzer for HbA1c assays.”

The A1cNow test quantitatively measures the percentage of glycated hemoglobin (%HBA1c) in capillary (fingerstick) or venous blood samples. Designed to provide results in only 8 minutes, the test is typically administered at 3-month intervals to monitor the long-term effectiveness of glycemic control in people with diabetes. According to Roseann Burhenne, a registered nurse and director of marketing for Metrika, “The measure of successful glycemic control, as defined by the American Diabetes Association, is a value 7% or lower. This was determined from the landmark diabetes complications and controls studies (DCCT) published in the 1990s. At higher values the risk of diabetic complications increases.”

To perform the A1cNow test, the user simply collects a fingerstick sample, dilutes the sample, and applies the sample to the sample port. Once the sample is applied, the monitor activates itself. After 8 minutes, numerical results automatically appear on the monitor’s LCD screen. Burhenne explains, “During this time, the monitor actually runs over 25 internal quality checks, then runs duplicate measures, averaging the results to attain optimal performance. The test is certified to have a coefficient of variation less than 4% compared with the NGSP standard.”

The A1cNow test employs a proprietary micro-optical detection method performed with a self-contained, integrated, single-use monitor. Only about the size of a pager, the monitor incorporates a combination of microelectronics, micro-optics, a multibeam reflectometer, and dry reagent chemistry strips. Both immunoassay and chemistry technologies are used to measure HBA1c and total hemoglobin, respectively. CLIA and FDA cleared for consumer home testing, the test is kitted in two versions: one exclusively for professional POC use and the other exclusively for consumer use.

Testing for Diabetic Complications: Microalbumin as an Indicator
Another important area of testing involves assays to detect the onset of diabetic complications as early as possible. Such knowledge facilitates proactive treatment and helps prevent the complications from progressing to potentially life-threatening stages.

Kamiya Biomedical Company of Seattle, Wash, offers the K-ASSAY® microalbumin assay reagent. This allows minute traces (0.5 to 30 mg/dL) of albumin in the urine to be detected on automated central laboratory chemistry analyzers using the immunoturbidimetric assay method.

According to Colin Getty, vice president of marketing at Kamiya Biomedical and a microbiologist with both research and clinical experience, “The normal range of albumin in urine is approximately 0 to 2 mg/dL for random specimens. Higher values generally indicate some kind of kidney damage and possible renal disease. The disease may result from diabetic complications; this is
a major reason why the American Diabetes Association advocates this type of testing. However, it is important to note that renal disease may also be attributable to other sources, such as alcoholism and cirrhosis.”

Getty says, “The ability to detect such low concentrations of albumin in the urine is advantageous because the earlier that renal disease can be detected, the better the chances are that it can be treated successfully before damage to the kidneys becomes too extensive. By contrast, the urine protein dipsticks used in most POC settings can detect albumin only down to the 20—30 mg/dL range, a concentration at which the renal disease is likely to be already far advanced.”

Kamiya provides the K-ASSAY microalbumin assay reagent in bottled kits, each capable of about 200 tests. The stability of the reagent ensures that assays are reproducible. Kamiya also offers associated calibrators and controls.

Examples of Other Advances in Diabetes Testing
Other important advances cited by Rizza relate to easier and more accurate patient self-administered blood sugar tests, which are essential for diabetics who need to adjust their daily medication dosages and diets and which may now be performed with miniscule amounts of blood (about a thousandth of a mL) obtained by less painful fingersticks. Still other advances are apparent in wider varieties of insulin and other drugs that stimulate insulin secretion, and in the use of programmable automatic pumps to infuse the medication more precisely according to specific patient requirements.

Looking Toward the Future
Ongoing research is continuing to delve into the many remaining mysteries of diabetes. For example, Rizza says some current topics of interest include “what makes some people resistant to insulin, what causes insulin-secreting beta cells to die in people with diabetes, how can beta cells be regenerated, what are the best therapies for diabetes, and many more. There is tremendous reason for optimism. Much of what is done as standard practice today was research 10 to 15 years ago.”

For more information, contact:

American Diabetes Association, 1701 North Beauregard Street, Alexandria, VA 22311; (800) DIABETES; (800) 342-2383; www.diabetes.org

Pointe Scientific Inc, 1025 John A. Papalas Drive, Lincoln Park, Mich 48146; (313) 383-7220; (800) 445-9853; www.pointescientific.com

Metrika Inc, 510 Oakmead Parkway, Sunnyvale, Calif 94085; (408) 524-2255; (877) METRIKA; www.a1cnow.com

Kamiya Biomedical Company, 910 Industry Drive, Seattle, Wash 98181; (206) 575-8068; www.kamiyabiomedical.com