Emerging technology in diabetes mellitus: glucose monitoring and new insulins. (Review Article).ABSTRACT
Modern diabetes management requires intensive self-monitoring of blood glucose levels, often coupled with a multicomponent insulin program. Recent advances include alternate site blood glucose blood glucose Diabetology The principal sugar produced by the body from food–especially carbohydrates, but also from proteins and fats; glucose is the body's major source of energy, is transported to cells via the circulation and used by cells in the presence testing devices, which facilitate more frequent sampling by individuals with diabetes. Continuous glucose monitoring glucose monitoring Lab medicine The periodic evaluation of any analyte abnormal in Pts with DM, to assess short and long-term control with antiglycemic agents. See Glucose, Glycated hemoglobin. through interstitial fluid interstitial fluid
The fluid in spaces between the tissue cells.
The fluid between cells in tissues. Referred to as the liquid subtance of the body.
Mentioned in: Lymphedema analysis is now available and appears to give a more representative picture of the glycemic Glycemic
The presence of glucose in the blood.
Mentioned in: Cholesterol, High
pertaining to the level of glucose in the blood. variations typical for type 1 diabetes type 1 diabetes
See diabetes mellitus. . Recombinant DNA technology recombinant DNA technology
Recombining of DNA molecules from two different species that are inserted into a host organism to produce new genetic combinations that are of value to science, medicine, agriculture, or industry. has led to the development of new insulin analogs that provide more physiologic insulin delivery. Inhaled and oral insulin formulations may replace multiple injections in future insulin therapy regimens.
THE Diabetes Control and Complications Trial The Diabetes Control and Complications Trial, or DCCT, was the largest, most comprehensive diabetes study ever conducted at the time.
The U.S. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) conducted this clinical study of 1,441 volunteers (1) and the UK Prospective Diabetes Study (2) have clearly established the benefit of near-normalization of blood glucose levels to reduce the risk of chronic complications in individuals with diabetes mellitus diabetes mellitus
Disorder of insufficient production of or reduced sensitivity to insulin. Insulin, synthesized in the islets of Langerhans (see Langerhans, islets of), is necessary to metabolize glucose. In diabetes, blood sugar levels increase (hyperglycemia). . An integral part of the treatment program for all affected individuals is self-monitoring of blood glucose (SMBG SMBG Self-Monitoring of Blood Glucose ). (3) This requires lancing the fingertip fin·ger·tip
The extreme end or tip of a finger. , applying a blood sample to a test strip, and recording the result from a portable meter. Patients must learn problem-solving skills regarding daily events, and health care professionals must be able to accurately interpret glucose data and provide meaningful feedback in the setting of a brief office visit. Patients complain about the discomfort, inconvenience, and expense of testing. Self-reported data are not necessarily a reliable and accurate representation of the patient's true glycemic pattern. (4,5) However, with the current treatment trends of more flexible diets and complex medication schedules, SMBG is absolutely essential to achieve the ADA Ada, city, United States
Ada (ā`ə), city (1990 pop. 15,820), seat of Pontotoc co., S central Okla.; inc. 1904. It is a large cattle market and the center of a rich oil and ranch area. standards of glycemic control. (3) For those patients on multicomponent intensive insulin regimens, multiple daily tests both before and after meals are necessary. The quest for noninvasive monitoring and more comprehensive glucose data collection has provided new monitoring technologies to assist the health care professional and the patient. (6) Recombinant DNA technology has facilitated the development of new insulin analogs that provide more physiologic delivery of insulin. These advances will enable more individuals with diabetes to approach optimal glucose control in the future. This discussion will review new glucose monitoring devices, products in development, and the status of new insulin analogs.
ALTERNATE-SITE TESTING DEVICES
Avoiding the pain associated with lancing the fingertips for blood glucose sampling has led to the development of several devices that obtain samples from other less-sensitive areas of the body, hence the term "alternate-site" or "off-site" testing. Examples of these areas include the forearm and thigh. Alternate-site testing is also desirable for individuals in occupations such as health care and certain industrial workers. The first such device available in early 2000 was the AtLast meter (Amira Medical, Scotts Valley, Calif). This device is a single unit that uses a custom lancet to obtain a small blood sample from the desired site. The opposite end of the AtLast holds a test strip that acquires the blood sample for glucose analysis. Clinical studies show an excellent correlation with venous glucose readings. Patients surveyed have indicated a distinct preference for the forearm as a test site. (7)
In mid-2000 the Freestyle meter (TheraSense Inc, Alameda, Calif) became available. This system includes a lancet device that produces a "pin-head" sized blood sample painlessly from the forearm. The blood sample is analyzed by a separate meter unit to provide a glucose result. Figure 1 shows forearm testing with the Freestyle meter, and the inset shows the small blood sample (0.3 [micro]L) obtained with the Freestyle lancet. Lifescan (Milpitas, Calif) has introduced a new FastTake test strip, which has the approval of the Food and Drug Administration (FDA FDA
Food and Drug Administration
n.pr See Food and Drug Administration.
n.pr the abbreviation for the Food and Drug Administration. ) for use on alternate sites such as the forearm because of its required small sample size and capillary action. Recently, Lifescan has introduced the ONE TOUCH Ultra, and MediSense (Abbott Laboratories, Abbott Park, Ill) has introduced the Soft-Tact meter for alternate-site testing.
Many patients prefer an alternate site to traditional fingertip testing, but bruising can occur at the site of sampling and there is evidence that rapid changes in glucose levels are more accurately reflected in the fingertip than in the forearm or thigh. Therefore, some manufacturers recommend fingertip testing if rapidly changing glucose levels are suspected.
CONTINUOUS GLUCOSE MONITORING
Current SMBG systems provide only limited data that may not be representative of the glucose excursions typical for the individual with type 1 diabetes. (8) Blood glucose levels change from minute to minute, and frequent insulin injections or an insulin infusion pump infusion pump A device designed to deliver drugs and/or 'biologicals', at low doses and at a constant or controllable rate; ↑ rates of delivery in such devices may be associated with local hemolysis, compromising the potential benefits of a calibrated delivery are necessary to achieve near-normal glucose 1evels. (9) Hypoglycemia hypoglycemia: see diabetes.
Below-normal levels of blood glucose, quickly reversed by administration of oral or intravenous glucose. Even brief episodes can produce severe brain dysfunction. is a major risk, especially in patients who lack awareness and require assistance to recover from such episodes. (10) Intense efforts in recent years have been directed toward developing methods of continuous glucose monitoring to provide a more accurate view of the glycemic changes seen in type I diabetes Type I diabetes
Also called juvenile diabetes. Type I diabetes typically begins early in life. Affected individuals have a primary insulin deficiency and must take insulin injections.
Mentioned in: Diabetic Ketoacidosis . Such a system is also a necessary component to make the artificial pancreas a reality. (11) Many of these systems measure interstitial fluid glucose levels that correlate with capillary glucose levels, with minimal differences only when there are abrupt changes in serum glucose levels. (12-14)
In early 2000, MiniMed Inc (Northridge, Calif) gained FDA approval to market the Continuous Glucose Monitoring System. (15) The key components are a pager-sized monitor; small implantable sensor, communication station, and computer software for data analysis. Figure 2 shows an implanted sensor and a monitor clipped to a belt. The sensor samples interstitial fluid glucose continuously, usually from the abdominal wall, sending an electrical signal to the monitor every 10 seconds. The monitor converts the signal to a glucose value that is averaged every 5 minutes. As a result, the monitor provides 288 glucose values per 24-hour period. The monitor must be calibrated cal·i·brate
tr.v. cal·i·brat·ed, cal·i·brat·ing, cal·i·brates
1. To check, adjust, or determine by comparison with a standard (the graduations of a quantitative measuring instrument): with a capillary glucose value at least four times a day. The current monitor does not have a visual display of the monitored values. The usual life span of the implanted sensor is 72 hours. The monitored data are downloaded to a computer via the communication station and are then organized for analysis by a software program. Figure 3 provides a dram atic display of the glucose excursions provided by the continuous monitor during a 24-hour period in an individual on an intensive insulin regimen for type 1 diabetes. The top portion of the Figure shows the patient's entered capillary glucose values; the curve in the bottom part of the Figure represents the continuous monitor data. During the period of monitoring, the patient maintains an event diary of meals, activity, and insulin doses, which is critical to data interpretation.
Preliminary reports indicate that most patients benefit from a single session of monitoring with a reduction in hemoglobin [A.sub.1c] levels and hypoglycemic hypoglycemic /hy·po·gly·ce·mic/ (-gli-sem´ik)
1. pertaining to, characterized by, or causing hypoglycemia.
2. an agent that lowers blood glucose levels. events. (16-18)
Our early experience with the first 12 patients receiving intensive insulin therapy at the University of Kentucky showed patterns of glycemic excursions not previously recognized with usual SMBG in all patients. Previously unrecognized events included unsuspected hypoglycemia requiring a change in basal insulin rates (7 of 12 patients), inappropriate insulin dosing for meals or The University of Kentucky, also referred to as UK, is a public, co-educational university located in Lexington, Kentucky. hyperglycemia hyperglycemia: see diabetes. (5 of 12 patients), and improper food choices noted on the event diary (3 of 12 patients). The average [HbA.sub.1c] of the patients studied decreased from 8.1% to 7.2% (P < .0017, t test) after implementation of changes based on the continuous monitor data.
Reviewing the glucose data and the event diary is a time consuming, challenging task aided by modal day glucose curves provided by the accompanying computer software program. Limitations include premature sensor failure with loss of data and discordant glucose curves on successive days, making therapeutic recommendations difficult. It is anticipated that improvements in sensor stability and other technical advances, including alarm capacity and visual display for the user, will be available in the near future. Software improvements are also needed to assist the health care professional in data analysis. We are in the process of developing a quantitative data instrument based on an area under the curve analysis that will facilitate data interpretation, and we plan to include that in future analyses.
The Glucowatch Biographer (Cygnus Inc, Redwood City, Calif) has been tested extensively in clinical trials and has recently received FDA approval. (19,20) The device consists of an oversized o·ver·size
1. A size that is larger than usual.
2. An oversize article or object.
adj. o·ver·size also o·ver·sized
Larger in size than usual or necessary. watch that calculates and displays glucose values and an autosensor that extracts interstitial glucose readings transdermally from the forearm tissues by means of reverse iontophoresis iontophoresis /ion·to·pho·re·sis/ (i-on?to-fah-re´sis) the introduction of ions of soluble salts into the body by means of electric current.iontophoret´ic
n. . A low electrical current facilitates the migration of glucose molecules through the skin to the gel disk in the autosensor. The autosensor measures glucose values every 10 minutes for up to 12 hours and gives an immediate visual display as well as storing those values for later analysis. An alarm capability can alert the user to abnormal high or low glucose values. The Glucowatch also requires periodic calibration with capillary glucose values and can give false readings if the user is sweating excessively. The first commercial units have been shipped to the United Kingdom, and it is anticipated that the device will be available in the Uni ted States in mid-2002.
MONITORING TECHNOLOGIES IN DEVELOPMENT
Several laboratories are working intensively to develop noninvasive glucose monitoring using novel technologies such as infrared radiation spectroscopy, Raman (vibrational) spectroscopy, polarized A one-way direction of a signal or the molecules within a material pointing in one direction. light rotation, and miniaturized systems to harvest interstitial fluid glucose. (6,21) Near-infrared and mid-infrared spectroscopy uses an external light source to measure glucose transcutaneously. Many technical problems must be overcome before such technology can be perfected for clinical use. Numerous companies are developing systems to extract interstitial fluid glucose through minimally invasive methods such as transdermal patches similar to the Glucowatch and microneedles. (22,23) The interstitial fluid extraction devices are being applied in clinical testing, whereas most noninvasive infrared technology requires further refinement. (24-26) The implantable glucose sensor with long-term stability is still in its infancy but is a necessary component to the future artificial pancreas. (27,28)
Basal insulin glargine insulin glargine (rDNA origin) Warning - High-alert drug!
Pharmacologic class: Pancreatic hormone
Therapeutic class: Hypoglycemic
(Lantus, Aventis Pharmaceuticals) became available in mid-2001. This insulin analog is produced by recombinant DNA technology with 2 changes from the human insulin human insulin
A protein that has the normal structure of insulin produced by the human pancreas but that is prepared by recombinant DNA techniques and by semisynthetic processes. structure: substitution of glycine glycine (glī`sēn), organic compound, one of the 20 amino acids commonly found in animal proteins. Glycine is the only one of these amino acids that is not optically active, i.e. for asparagine asparagine (əspâr`əjēn), organic compound, one of the 20 amino acids commonly found in animal proteins. Only the l-stereoisomer participates in the biosynthesis of mammalian proteins. at position 21 in the A chain and the addition of 2 arginine arginine (är`jənĭn), organic compound, one of the 20 amino acids commonly found in animal proteins. Only the l-stereoisomer participates in the biosynthesis of proteins. molecules to the end of the B chain. This chemical change results in a less soluble insulin, which is absorbed slowly from the subcutaneous injection site. The resulting pharmacokinetic properties include an onset within 2 hours, a flat or square wave action profile, and a 24-hour duration of action, making it an ideal basal insulin. (29,30) Absorption of injected glargine did not vary by injection site, leading to less intrasubject variability than with typical intermediate insulins. In clinical trials, patients have had fewer hypoglycemic events and achieved lower fasting glucose levels than those treated with NPH insulin. (31,32) More frequent injection site discomfort has been noted, but this did not lead to disc ontinuance of therapy. Glargine insulin appears to offer great promise as a basal insulin component to an intensive insulin program for type 1 diabetes and may also be a superior insulin for people who need an extra complement of insulin to combine with oral hypoglycemic therapy for type 2 diabetes type 2 diabetes
See diabetes mellitus. .
Insulin aspart (Novolog, Novo Nordisk Pharmaceuticals) is a rapid-acting analog produced by substitution of aspartic acid for proline proline (prō`lēn), organic compound, one of the 20 amino acids commonly found in animal proteins. Only the l-stereoisomer appears in mammalian protein. at position B28. This alteration leads to more rapid absorption, with an onset of action onset of action Pharmacology The length of time needed for a medicine to become effective. See Therapeutic drug monitoring. within 10 to 20 minutes and peak within 45 minutes, corresponding with the postprandial postprandial /post·pran·di·al/ (-pran´de-al) occurring after a meal.
Following a meal, especially dinner. blood glucose peak. (33) Clinical trials have shown reduced postprandial hyperglycemia with improved hemoglobin [A.sub.1c] levels and no increase in hypoglycemic events when compared with human regular insulin. (34,35) This rapid-acting insulin became available in late 2001.
Many patients find multiple daily insulin injections painful and inconvenient and therefore unacceptable. This has spurred intense efforts to develop alternate systems of insulin delivery. Clinical trials have shown inhaled insulin to be as effective as injected regular insulin in both type 1 and type 2 diabetes. (36,37) Pulmonary safety has been shown for up to 2 years. (36) Orally ingested insulin in its native unmodified form is degraded in the upper gastrointestinal tract and shows no metabolic activity. An oral insulin spray (Oralin, Generex Biotechnology) that is absorbed rapidly through the buccal mucosa is currently in clinical trials and may also provide an alternative to injected insulin.
The new insulins will be important components to insulin treatment programs in the near future, improving our ability to simulate endogenous insulin action. The inhaled/oral formulations promise to provide patient acceptable systems that will translate to improved glycemic control for greater numbers of people with diabetes mellitus.
[FIGURE 3 OMITTED]
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der·mal or der·mic
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CGMS Copy Generation Management System
CGMS Coordination Group for Meteorological Satellites
CGMS Crop Growth Monitoring System
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NITF National Imagery Transmission Format
NITF National Insurance Task Force
NITF Nuclear Instrument Test Facility
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(37.) Pfutzner AHT AHT Animal Health Trust (Suffolk, England)
AHT American Hairless Terrier (dog breed)
AHT After Hours Trading
AHT Animal Health Technician
AHT Anchor Handling Tug , Steiner S, Heinemann L, et al: Inhaled Technosphere/Insulin shows a low variability in metabolic action in type 2 diabetic patients. Diabetes 2000; 49(suppl 1):492
RELATED ARTICLE: KEY POINTS
* The quest for noninvasive monitoring and more comprehensive glucose data collection has provided new monitoring technologies to assist the health care professional and the patient.
* Recombinant DNA technology has facilitated the development of new insulin analogs that provide more physiologic delivery of insulin.
* These advances will enable more individuals with diabetes to approach optimal glucose control in the future.
From the Department of Internal Medicine, Division of Endocrinology and Molecular Medicine, University of Kentucky Medical Center, Lexington.
Reprint requests to L. Raymond Reynolds, MD, University of Kentucky Medical Center, Division of Endocrinology and Molecular Medicine, 800 Rose St, MN 525, Lexington, KY 405346-0298.