The Blood Sugar in Office Practice: Practical and Laboratory Aspects

The Blood Sugar in Office Practice: Practical and Laboratory Aspects CHARLES T. LEE, JR., M.D. Associate in Medicine, University of Pennsylvania School of Medicine; Assistant in Medicine, Pennsylvania and Chestnut Hill Hospitals, Philadelphia

test for blood sugar level is done more frequently than any othcr blood chemical test, but the results of the test are used probably to less purpose than any other. It seems surprising that, after almost three decades of insulin therapy, there is still confusion about the method to be used, what constitutes normal and abnormal results, and the best time of day to do the test. The first source of confusion is that the methods of determining blood sugar have become progressively more refined as the pitfalls and inaccuracies in the older methods are eliminated; the second is that the diagnosis of clinical diabetes as opposed to chemical diabetes is still in doubt in many physicians' minds. As Dr. Levine pointed out in these pages a few months ago, the diagnosis of the diabetic state in the earliest or latent stage may allow us to modify the severity of the disorder when it becomes overt and may postpone for sometime its emergence.! The emphasis today is on the earliest possible diagnosis of diabetes, and to accomplish this we must pay attention to minor variations from the normal blood sugar levels. There are certain practical advantages in performing blood sugar tests in the office. Any physician who follows and attempts to manage patients with diabetes mellitus can attest to this. If either the patient or his blood has to be sent to an outside laboratory, both the doctor and the patient are inconvenienced. The results of such tests are not immediately available, and this means extra visits by the patient or time-consuming telephone calls and letters by the doctor, a nuisance to both. Ideally, one would like an office blood sugar test which is rapid, accurate and reproducible over a wide range of values, inexpensive, requiring a minimum of equipment, and easy to perform. Unfortunately, no single test now available fulfills all these criteria, but we are now approaching the ideal more closely than ever before. As an office procedure, blood sugar determination can be done for one of three purposes: to detect diabetes mellitus, to detect hypoglycemic

THE

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state,; and to follow the control of diabetic patients. Each of these purposes requires that the blood sugar be drawn at a different time and that each result be interpreted according to it,; own set of "normal limits." Routine ordering of fasting or postprandial blood sugars without considering what specific information one wants is a waste of time and effort. FASTING BLOOD SUGAR

This determination accounts for approximately 80 per cent of all blood sugars ordered routinely in hospital and commercial laboratories. It is the most abused and least useful of all blood sugar determinations. Table 1.

Comparison of Fasting and 2-Hour Blood Sugar Levels in 1045 Consecutive Glucose Tolerance Tests 2-HOUR BLOOD SUGAR I,EVEL ISO mg. per 100 140 to 180 mg. per 100 m!. m!. or more (161 tests) (181 tests)

FASTING

BLOOD SUGAR

Under 120 mg. per 100 m!.

Under 140 rng. per 100 m!. (683 tests)

Number Per cent Number Per cent Number Per cent. of tests of tests of tests of tests of tests of tests 121

75%

173

96%

-----~---

679

99+%

--------

Under 100 mg. per 100 m!.

47

30%

127

70%

601

88%

Under SO mg. per 100 m!.

9

5.6%

15

S.2%

145

21%

--

I helieve that the management of most diabetic patients would probably he as good, if not better, if dependence on fasting blood sugars was done away with, and certainly many more patients with mild diabetes would be discovered if fasting levels were never ordered for this purpose. The futility of determining the fasting sugar for the detection of mild diabetes is illustrated in Table 1, which shows the results of the last 1045 routine glucose tolerance tests done at the Pennsylvania Hospital and compares the fasting blood sugar levels with the two-hour blood levels. In the group of 161 patients showing a definite diabetic curve (two-hour sugar of 180 mg. per 100 ml. or more) 75 per cent of the fasting sugars were under 120 mg. per 100 ml. and 30 per cent were under 100 mg. per 100 ml. Taking all the results considered diabetic, 50 per cent of the fasting levels were under 100 mg. per 100 ml., and, if 120 mg. per 100 ml. were taken as the upper limit of normal, in only 54 of 368 patients would diabetes have been suspected if fasting levels alone had been done. Yet

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many physicians still feel that they have ruled out diabetes if a normal fasting blood sugar value is obtained. In suspected hypoglycemic states, a fasting blood sugar or a blood sugar done at the time that symptoms occur is the simplest determination that is likely to be of value. The ordinary glucose tolerance test may show an abnormally low value at two or three hours in functional hypoglycemia, but a test at six hours or longer may be necessary to detect organic hypoglycemia. In patients with diabetes mellitus, a fasting sugar should occasionally be done together with postprandial or late afternoon tests to check on the state of diabetic control. Generally, patients taking insulin should have the blood sugar determined at the times of day when the extremes of blood sugar are likely to be found. Patients taking only protamine zinc insulin are likely to show the lowest levels on the fasting sugar; those taking intermediate-acting insulin run the greatest risk of hypoglycemia in the late afternoon or early evening. To assume that good diabetic control has been achieved because the fasting blood sugar level is normal may be to overlook a marked postprandial hyperglycemia later in the day, especially in patients with milder diabetes who are not taking insulin. POSTPRANDIAL OR POSTGLUCOSE BLOOD SUGARS

The value of postprandial blood sugar levels for both the detection and the control of diabetes is becoming better recognized, although I have already pointed out that most tests done in the Philadelphia area are on fasting specimens. For these tests, the blood sugar is taken either two hours after a meal high in carbohydrate or two hours after drinking a standard 100 gram glucose dose. For discovering new cases of diabetes, postprandial and postglucose determinations are infinitely superior to fasting levels. It is true that discordant results are frequently obtained and that abnormally high levels on such determinations may not be confirmed when a subsequent glucose tolerance test is done. 2 Despite these false positive and false negative results, many more patients with mild diabetes will be discovered if these methods are routinely employed in preference to the fasting sugar. In managing patients with diabetes, a one- or two-hour postprandial blood sugar will show the highest levels that the blood sugar is likely to reach. If such determinations are in the range of 160 mg. per 100 ml. or less and hypoglycemic symptoms at other times of the day are absent, good or excellent control is assured. Random blood sugar levels can be performed on any patients with or without diabetes whenever they come into the office. In diabetic patients, they are of value in checking the degree of control at various times during

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the day. For detecting new cases of mild diabetes, they are more valuable than fasting determinations but not as effective as postglucose or postprandial levels. BLOOD SUGAR (GLUCOSE) TESTS

There are many methods available for doing blood sugar determinations, but I shall discuss only three in any detail and I shall try to point out their individual advantages, disadvantages and limitations. The three methods are the Dextrotest, * the quickest and easiest but a semiquantitative method; the Folin-Wu, perhaps the most widely used of the standard methods; and the Somogyi-Nelson, a test which determines the true glucose level of the blood. All three methods utilize the same basic principles but the complexity of the tests and the reagents used vary. In each, a protein-free filtrate of the blood is prepared. To this is added a copper reagent. The resulting mixture is heated and the color reaction produced is compared with standard colors or standard glucose solutions. There is no single "best test" which will suit all physicians under all circumstances. Furthermore, it is essential that the results of any of the methods be checked against known standards at frequent intervals. Disregard of this principle will inevitably result in serious errors. Dextrotest Method

The Dextrotest has been a real step forward in managing diabetic patients in the office. For the physician who does not have or does not want the equipment necessary to perform the more complex chemical determinations, it provides a simple method which can be of great value when it is correctly used. The kit for performing the test is a small self-contained unit which includes everything necessary except tap-water and a syringe and needle for drawing the blood. A pipette or other measuring apparatus is not necessary since the tubes are accurately calibrated. The method is adequately described on the insert which comes with the set as well as in several previous papers on the subject3- 6 so that it does not have to be repeated here. However, I do have some suggestions and comments about the use of the Dextrotest. If the deproteinizing solution in tube A is prepared before the blood sample is drawn, the blood may be emptied directly into the tube from the syringe without having to use an anticoagulant or otherwise preserving the blood. If it is inconvenient to do the test immediately or if the same sample is to be used for additional tests, it may be added to an oxalate or fluoride tube in the usual manner. As in all laboratory tests, the results are more consistent if the determinations are done repeatedly by the same person. In general, the correlation between this method and a standard chemical determination is sufficiently good that the results

* Ames Co., Inc., Elkhart, Indiana.

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can be depended upon after one has become familiar with the technique. 4 Most inaccurate results stem from either of two sources. The first is not having the bottom of the meniscus for the water and then for the blood come exactly to the line in tube A. The second is not comparing the color reaction in tube B with the color chart at exactly 30 seconds, an oversight which can result in as much as 50 per cent error. The limitations of the method must be mentioned. First, since no color change occurs below 100 mg. per 100 ml., the test is useless for detecting hypoglycemia. Second, the limits of accuracy are insufficient to allow this test to be used routinely as a substitute for a regular glucose tolerance test unless the results are grossly abnormal-200 mg. per 100 ml. or more at the two-hour determination. Third, and I feel that this is a minor objection, values over 200 mg. per 100 ml. cannot be estimated with the standard Dextrotest method. Others have shown that a reasonable approximation of higher values can be obtained by using more water (2.5 ml. instead of 2 ml.) and less blood (0.5 ml. instead of 1 ml.) and multiplying the final result by 2, but I think this is of little practical value. For general use, any blood sugar over 200 mg. per 100 ml. is too high and the diabetic state is poorly controlled. Whether the absolute value of the blood sugar is 280 or 350 mg. per 100 ml. makes little difference, since in either instance control must be improved considerably. I use the following normal values with the Dextrotest: Fasting blood sugars in either diabetics or normals should show a blue reaction (100 mg. per 100 ml. or less). Postglucose or postprandial blood sugars used for screening purposes in nondiabetic patients should be blue, preferably, or a minor dirty green (100 to 125 mg. per 100 ml.). Values above this are an indication for repeated more accurate testing with conventional methods (see Table 2). Random blood sugars should give a blue reaction. Table 2.

Normal Blood Sugar Values TEST USED

BLOOD SPECIMEN

Dextrotest

Folin-Wu

Somogyi-Nelson

Fasting

100 or less

80 to 110

60 to 100

2 hr. Postprandial

100 to 125

100 to 140

70 to 120

Postglucose

125 or less

140 or less

120 or less

Random

100 or less

120 or less

100 or less

-

Under 60

Under 50

Hypoglycemia

-

All blood sugar values in mg. per 100 m!. "2 hr. postprandial"-after a meal high in carbohydrate. "Postglucose"-2 hours after a standard 100 gram glucose load taken fasting.

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My reason for interpreting the results so strictly is that false high values may be easily checked and discovered for what they are, but false low values or a more liberal interpretation of the results may cause one to overlook an early or mild diabetic patient. Keeping in mind these few limitations, the Dextrotest is an extremely useful aid for every practicing physician. Folin-Wu and Somogyi-Nelson Methods

The use of a standard chemical method such as either of these should be considered only if one tests a large number of blood sugars or if the routine blood chemistries are being performed. Since the introduction of the Dextrotest, using one of these other techniques to perform eight or ten blood sugar tests a week seems needlessly complex and expensive. Furthermore, using either of these methods requires more time and effort on the part of the physician or technician as well as a constant check on the accuracy of the results. Since some type of photoelectric colorimeter is necessary, adequate repair and control service for the instrument must be available, something which may not be easily found away from the metropolitan centers. The Folin-Wu method is "by no means the most economical, the most convenient, the easiest, the most specific, or the most reproducible method."6 Nonetheless, it is still perhaps the most widely used test throughout the world. When the common tungstic acid filtrate is used, the Folin-Wu test gives not only the level of the blood glucose but also includes other nonglucose reducing substances which increase the value by 15 to 30 mg. per] 00 m!. or, in extreme cases, by 5 to 65 mg. per 100 m!. or more. Additional disadvantages are that the special Folin-Wu tube should be used and that the readings should be done promptly to prevent excessive reoxidation of the cuprous oxide and fading of the molybdenum blue color. If one is already using it and is accustomed to the results, it is worth while keeping on, but I should not advise putting it in the laboratory as the method of choice today. Part of the present confusion in interpreting blood sugar results stems from the fact that the normal values with the Folin-W u technique are higher than with other methods; the limits for fasting blood sugar of 80 to 120 mg. per 100 m!. (Folin-Wu) would be abnormally high with the true glucose method. A postprandial or postglucose blood sugar of more than 150 mg. per cent with the Folin-Wu is definitely suspect and should be repeated. The Somogyi-Nelson technique utilizes a zinc sulfate-barium hydroxide method of protein precipitation which removes the nonglucose reducing substances. The results with this method are correspondingly lower than when a tungstic acid filtrate is employed. However, the solutions of zinc sulfate and barium hydroxide must be accurately titrated so that they neutralize each other exactly or errors will result. 7 An advantage of the method is that the color reaction produced with the Somogyi-

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Nelson copper reagents does not reoxidize or fade as readily as that produced by the Folin-Wu reagents so that the readings do not have to be taken as rapidly nor special tubes used. The blood levels reported with a true glucose method may seem horrifyingly low at times to someone familiar with Folin-Wu results. The fasting blood sugar typically ranges between 60 to 100 mg. per 100 ml., and a postprandial or postglucose test should be below 120 mg. per 100 ml. Levels between 120 and 140 mg. per 100 ml. warrant a subsequent glucose tolerance test. With the Somogyi-Nelson method, it is not unusual to see a glucose tolerance test in which all of the values are below 100 mg. per 100 ml. OTHER METHODS AND MISCELLANEOUS TIPS

Microtechniques for numerous blood chemistries including sugar will soon become more popular and more widely used. The advantages in being able to use only 0.1 ml. of blood drawn from a fingertip are obvious to anyone who has perspired over drawing blood from an obese arm with tiny veins which have been punctured too many times in the past. The blood sugar levels obtained with this capillary blood are essentially the same as arterial levels and the results must be interpreted as such. In general, capillary blood samples taken in the fasting or postabsorptive state (more than four hours after eating) will not give significantly different results from ordinary venous blood sugar levels. Samples taken after a meal or a load of glucose may be 20 to 40 mg. per 100 ml. higher than simultaneous venous levels because of the active utilization of glucose by the peripheral muscles. There is also some evidence that glucose is irregularly released by the liver in such circumstances so that it enters the hepatic venous blood and then the arterial circulation in surges rather than as a steady dribble. 8 This makes the interpretation of the results more difficult. However, I think that capillary blood will be the commonest source of blood sugar determinations within the next few years. Preservation of the blood samples sometimes causes concern because it is usually more convenient and economical to do a group of blood sugars than to run them one at a time. If sodium fluoride is used as the anticoagulant, there will not be any significant lowering of the blood sugar if the treated blood is allowed to stand in the tube a few hours or even overnight in the refrigerator. This is not true if the common oxalate anticoagulant is used, but these samples may be safely kept for three or four hours if they are refrigerated promptly after being drawn. SUMMARY AND CONCLUSIONS

The management of diabetic patients and the discovery of new cases of diabetes would be easier and simpler if blood sugar tests could be per-

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formed in the physician's office. Although there is no test available today which fulfills the ideal criteria, the use of the Dextrotest method will enable many more physicians to do a rapid semi-quantitative estimation of the blood sugar while the patient is still in the office. Within the limitations of the method, the results with the Dextrotest are reasonably accurate and of great help. For those physicians who see many diabetic or potentially diabetic patients or who perform other blood chemistries in the office, one of the standard blood sugar methods permits more flexibility and greater accuracy. A true glucose method such as the Somogyi-Nelson test is preferable. The Folin-Wu type of test, although still widely used, is becoming obsolete. The blood sugar of the future will probably be determined on capillary blood by a microtechnique. The confusion which still exists concerning normal and abnormal blood sugar values and the diagnosis of diabetes arises from the varying normal ranges of blood sugar results with different tests. The fasting blood sugar determination is of limited value and is largely a waste of time except in searching for hypoglycemia. This test should be used much less frequently than it is now, and postprandial and post glucose levels should be done more often. REFERENCES

1. Levine, R.: The Early Manifestations and the Diagnosis of Diabetes Mellitus.

M. CLIN. NORTH AMERICA 44: 203,1960. 2. Unger, R. H.: Standard Two-Hour Oral Glucose Tolerance Test in Diagnosis of Diabetes Mellitus in Subjects Without Fasting Hyperglycemia. Ann. Int. Med. 47: 1138, 1957. 3. Moss, J. M.: The Clinical Use of Dextrotest. Virginia M. Month. 85: 255, HJ58. 4. Moss, J. M.: Clinical Studies with Dextrotest. J.A.M.A. 164: 762, 1957. 5. Lancaster, W. M.: A Simple Method of Blood-Sugar Estimation. Brit. M. J. 2: 83,1957. 6. Young, N. F. and Sobel, A. E.: Glucose (Folin-Wu). In: Reiner, M. (ed.): Standard Methods of Clinical Chemistry. New York, Academic Press, Inc., 1953, vol. 1, pp. 60-64. 7. Reinhold, J. G., Vanderau, M. and Halpern, P. E.: Glucose (Nelson-Somogyi). In: Reiner, M. (ed.): Standard Methods of Clinical Chemistry. New York, Academic Press, Inc., 1953, vol. 1, pp. 65-70. 8. Anderson, G. E.: The Diabetic Problem. Penna. M. J. 59: 317,1956. 33 East Chestnut Hill Avenue Philadelphia 18, Pennsylvania