Postgraduate Medicine
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Managing insulin-dependent diabetic patients Oliver E. Owen, Guenther Boden & Charles R. Shuman To cite this article: Oliver E. Owen, Guenther Boden & Charles R. Shuman (1976) Managing insulin-dependent diabetic patients, Postgraduate Medicine, 59:1, 127-134, DOI: 10.1080/00325481.1976.11716530 To link to this article: http://dx.doi.org/10.1080/00325481.1976.11716530
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• A fundamental princip le in the treatment of diabetes mellitus is the supply of enough insulin ta regulate the metabolism of glucose, lipid, and protein. lndividuals who do not have enough endogenous insulin ta prevent catabolism while their food consumption is adequate need supplementary insulin. This group includes patients with growth-onset diabetes and ali diabetics who are ketosis-prone with or without stress due ta trauma, surgery, or infection. In addition, adult diabetics with symptomatic hyperglycemia who respond inadequately ta oral hypoglycemie agents and dietary regulation need exogenous insulin. By contrast, diet rather than insulin is the treatment of choice for obese, hyperphagic patients with maturity-onset diabetes who have symptomatic hyperglycemia and who maintain or gain weight. Meeting the specifie needs of each insulin-dependent dia be tic patient requires knowledge of the time-activity course of the available insulin preparations. Factors influencing the choice of preparation include the response of blood glucose levels ta meals, quantity and distribution of dietary carbohydrate, physical activity, and individual response ta insulin. The most widely used insulin preparations are the intermediate-acting NPH insulin (isophane insulin suspension) and Lente insulin (insulin zinc suspension) and the rapid-acting Regular insulin and Semilente insulin (insulin zinc suspension prompt). Because of their activity curves, they are best suited for administration in single-dose, split-dose, or combined-splitdose schedules, which are satisfactory for the regulation of metabolism in nearly ali insulin-dependent diabetic patients.
• manag1ng insu lin-dependent diabetic patients Oliver E. Owen, MD Guenther Boden, MD Charles R. Shuman, MD Temple University Health Sciences Center Philadelphia
consider What three insulin preparations can be usecl to satisfactorily manage 95% of insulin-dependent diabetics?
Types of lnsulln
Data on the commercial insulin preparations available in the United States are given in table 1. Those readily available are mixtures of insulin obtained from beef and park pancreas. Special monospecies insulins made from beef or park pancreas are available. Purity and shelf life of commercial insulins have improved through the years. The purified insulins produced and distributed in the United States and Canada are greater than 98% pure insulin ("single peak"); those produced and distributed primarily in Europe are greater than 99% pure insulin (''monocomponent"). The insulins available at present do not require refrigeration
Vol. 59 o No. 1 o January 1976 o POSTOAADUATE MEDICINE
What are the most common causes of complications such as hypoglycemia, rebound hyperglycemia, and lipoatrophy? How can these complications be effectively managed? When is hospitalization advisable?
127
table 1. insulin preparations commercially available in the united states, classified according to approximate duration of action Classification
Rapid
lnsulln preparation•
Regular (neutral)
Action On set
Peak
Du ration
IV:t immediate
15-30 min 30-60 min 1-2 hr
1-2 hr 2-4 hr 5-10 hr
lM: 5-30 min SC: 30min
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lntermediate
Slow
Combinations
Semilente (insulin zinc suspension prompt)
SC:
1 hr
3-4 hr
10-16 hr
Globin zinc insulin NPH (isophane insulin suspension) Lente (insulin zinc suspension)
SC: SC:
2 hr 2 hr
6-8 hr 8-14 hr
12-18 hr 18-24 hr
SC:
2 hr
8-14 hr
18-24 hr
Protamine zinc insulin suspension Ultralente (insulin zinc suspension extended)
SC:
6 hr
16-20 hr
24-30 hr
SC:
6 hr
18-29 hr
3D-36 hr
SC: SC: SC: SC:
30 min 1 hr 1 hr 1 hr
2-10 2-10 4-10 2-24
18-24 18-24 18-24 30-36
Regular + N PH Regular + Lente Semilente + Lente Semilente + Ultralente
hr hr hr hr
hr hr hr hr
•Preparations are available in concentrations of 40. 80, and 100 units/ml in 10-ml vials. Regular (Concentrated) lletin is also available in a concentration of 500 units/ml in 20-ml vials. Regular, NPH, and Lente insulins are available as beef-pork insulin mixtures and as special monospecies insulins made exclusively from bee! or pork pancreas.
tiV, lM, and SC denote intravenous, intramuscular, and subcutaneous routes of administration.
but should not be exposed ta extreme temperature (be law freezing or above 120 F). Regular insulin manufactured since February 1973 has a neutra! pH and is sa identified on the vial. An advantage of Regular neutra! insulin is that it can be added in any proportion ta NPH or Lente insulin. 1 Single-peak insulins are marketed in the United States in concentrations of 40 (redcapped vial), 80 (green), 100 (orange), and 500 (brown) units per milliliter in l 0-rnl vials. Discontinuance of marketing of U-80 preparations is planned in the near future. The U-40 insulin preparations permit more accurate measurement of small doses. However, marketing ofU-40 insulin probably will cease as saon as accurate syringes for delivery of
small doses of U -100 insulin preparations become available. About 95% of insulin-dependent diabetic patients can be managed by using single doses, split doses, or combined-split doses of various combinations of three insulin preparations: single-peak U- 100 beef-pork NPH, Lente, and Regular insulins. In arder of increasing difficulty in management, schedules that will give satisfactory control in almost ali cases are: ( 1) single dose of 50 units or Jess of NPH or Lente insulin given before breakfast, (2) split dose of NPH or Lente insulin, with 60% ta 90% given before breakfast and 10% ta 40% given before the evening meal, and (3) combined-split dose, with a combinatian of NPH or Lente insulin and Regular in-
128
POSTGRADUATE MEDICINE • January 1976 • Vol. 59 • No. 1
sulin (combined dose) given before breakfast and with NPH, Lente, or Regular insulin (split dose) given before the evening meal.
In the absence of acute illness (other than diabetes), insulin therapy can be started on an outpatient basis. (Exceptions are noted later.) After the his tory, physical examinatian, and blood glucose determinations have established the diagnosis of diabetes meiJitus and the need for exogenous insulin, education of the patient begins. It is essential to good management that the patient understand the balance among diet, insulin, and exercise. Unrestrained food ingestion is the primary cause of hyperglycemia in diabetics receiving insulin. Exercise potentiates the hypoglycemie action of insulin. Checking and recording urinary glucose reactions on double-voided specimens are very important. Techniques for self-administration of insulin are demonstrated. Insulin should be injected subcutaneously, using sterile technique. Sites for injection are the back of the arm in the deltoid area and in the crease between deltoid and triceps muscles, the anterior aspect of the thigh, the anterior and lateral aspects of the abdomen, and the buttocks. Alternation of these sites is essential, using each area as infrequently as possible. Glass syringes are Jess expensive than disposable plastic syringes. Glass syringes can be routinely stored in alcohol solution and periodically washed with soap and water and sterilized in boiling water (about once a month). Disposable needles on the glass syringes can be used repeatedly and are discarded when dull. Disposable syringes and needles for single use are convenient for travel and may be preferable for a patient whose skin is not kept clean. Air is added to the insulin vial to keep its contents under slight positive pressure and to facilitate withdrawal of solution. The initial dose of intermediate-acting insulin (NPH or Lente) is JO to 20 units, given about 20 minutes before breakfast. During the
early phase of management, the diabetic patient is told to check the urine for glucose before breakfast, lunch, dinner, and bedtime and to record daily insulin doses and urinary glucose reactions. If urine voided just before the evening meal is positive for glucose, the patient should increase the morning insulin dose by 4 units every other day. The urine tested should be urine obtained from a second or late voiding; the first urine specimen voided after a meal should not be used for regulation of insulin dosage because it may contain glucose accumulated in the bladder during the brief postprandial period and does not truly reflect the blood glucose leve) at the time of tes ting. At the end of one week, the physician checks the fasting blood glucose level, urinary glucose records, body weight, and general medical status and adjusts the insulin dosage as necessary. If the patient experiences episodes of hypoglycemia or if ali urine glucose tests are negative, the daily dose of insulin is reduced by 4 units every other day until about half of the urinary tests are nonreactive. Once the late-afternoon test is nonreactive, the test done before breakfast also may be nonreactive. However, many Americans eat their largest meal in the evening. Diabetics should distribute their food intake more evenly throughout the day, but many do not change their eating patterns. If a single dose of insulin given before breakfast fails to prevent nocturia secondary to glycosuria, a split-dose insulin regimen is recommended, with an appropriate amount of NPH, Lente, or Regular insulin given just before the evening meal. If urine voided before bedtime is nonreactive for glucose, a snack should be eaten to avoid nocturnal hypoglycemia. It should be recognized that the hypoglycemie effect of any insulin dose is related to the blood glucose concentration at the time of insulin administration. Insulin acts to decrease the blood levels of glucose and other oxidizable substrates that compete with glucose as body fuels. When the blood glucose leve) is low following administration of insulin, the levels of circulating free fatty acids
Vol. 59 • No. 1 • January 1976 • POSTGAADUATE MEDICINE
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Initiation of lnsulln Therapy ln Ambulatory Patients
Dr. Owen is professer of medicine; Dr. Boden is associate professer of medicine; and Dr. Shuman is professer of medicine, Temple University Health Sciences Center, Philadelphia.
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Oliver E. Owen
Guanther Bodan
Charlas R. Shuman
and ketone bodies are low. Thus, a diabetic who has an overnight fasting blood glucose level of 100 mg/ 100 ml without hyperlipidemia and hyperketonemia and who takes NPH or Lente insulin before breakfast is more likely to experience late-afternoon hypoglycemia than is a patient with an overnight fasting blood glucose concentration of 250 mg/ 100 ml wit.h accompanying hyperlipidemia and hyperketonemia. Therefore, if the split-dose insulin regimen is used to control overnight fasting hyperglycemia, the morning dose of insulin should be appropriately adjusted to prevent hypoglycemia from occurring before the evening meal. Once the late-afternoon and overnight fasting blood glucose concentrations are satisfactory, attention is directed to the period between breakfast and lunch. If the breakfast meal does not con tain excess carbohydrate, glycosuria occurring between breakfast and lunch is an indication for use of a combination of intermediate- and rapid-acting insulins. Usually, 4 to 6 units ofNPH or Lente insulin is subtracted from the morning dose, and 6 to 10 units of Regular insulin is added. The two insulins are drawn into the same syringe. Adding air to the vial before withdrawing the solution helps to avoid contamination of the second vial by insulin already in the syringe. Mixing of the insulins in the syringe is unnecessary. It is important to use syringes with minimal dead space and not to change brands of syringe. In general, the larger a patient's insulin requirement, the more Regular insulin and the less NPH or Lente insulin is used.
Advantages of outpatient treatment of dia be tes are simplicity and economy. Patients are encouraged to participate in their regular daily activities. A disadvantage is the require.ment of a considerable period of instruction. A small proportion of patients have bladder hypotonia or. abnormally high or low renal thresholds for glucose which preclude the use of simple uri-ne glucose testing as a guide to insulin dosage. In addition, the peak action ofNPH and Lente insulins occurs in the afternoon, and when aglycosuria prevails, the patient must make return visits so blood glucose concentrations can be measured.
Diabetics who should not be managed as outpatients but should be hospitalized during the initial phase of insulin therapy include pregnant women with newly discovered diabetes and children with the disease. Hospitalization is also indicated for ali diabetics with acute conditions complicating control, such as severe infection or trauma. During such acute situations, there are three cardinal objectives: Prevent dehydrating hyperglycemia; avoid hypoglycemia; prevent ketoacidosis. In treatment of hospitalized patients, only Regular insulin should be used initially. The amount of the first dose depends on the blood glucose and electrolyte concentrations and is 10 to 20 or more units. Subsequent doses are given every four to six hours, the intervals depending on seriai blood glucose responses. If blood for repeated analyses cannot be obtained, fractional urinary glucose reactions
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POSTORADUATE MEDICINE
Traatment of Hospltallzed Patients Wlthout Fulminant Ketoacldosls
o January 1976 o Vol. 59 o No. 1
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determined at four-hour intervals may be used as a guide for no more than 24 hours. For each one-digit rise in glucose reaction above 1 +, 4 to 6 units of Regular insulin is added. (If the reaction were 3+, for example, 8 to 12 units would be added.) On the next moming, NPH or Lente insulin is given instead of Regular insulin in a dose of about two thirds of the total quantity of Regular insulin gi ven during the previous 24 hours. If the acute process (infection, effects of trauma) continues, supplementary Regular insulin is given at intervals of four to six hours as needed to control hyperglycemia.
Hypoglycemia-Exogenous insulin is the most common source of hypoglycemia in diabetic patients. Hypoglycemia is usually associated with insulin overdosage, omission or delay of meals, or unusual or unplanned physieal activity. Insulin overdosage can be avoided by seeking the lowest effective dose for maintaining satisfactory control of the blood glucose level. The omission of meals can be avoided by educating the patient on the importance of regular meals. Hypoglycemia secondary to physical activity can be avoided if patients check urine for glucose before and after the activity and consume extra food as needed. Such tes ting is easily done by using the available test strips. If the urinary glucose test is nonreactive before the patient plays squash or tennis, for example, or before he or she mows the grass or does comparable physical activities, 6 to 12 oz of Coca-Cola (20 to 40 gm of glucose) or a similar beverage, or food (candy), should be consumed. If the urinary glucose test is reactive before participation in heavy physical activity, an extra feeding after the exercise may be needed to prevent subsequent hypoglycemia. Most patients saon leam how much physical activity they can tolerate and how much extra food they need to forestall insulin reactions. The hypoglycemie effect of exercise is long-lasting, however, and may be retlected in the blood glucose concentration on the following day. Hypoglycemie signs and symptoms
(hunger, nausea, faintness, sweating, headache, rapid heart rate, double vision, slurred speech, mental obtundation) are easily cleared with 10 to 20 gm of glucose taken orally. Unless treatment is given prompt! y, unconsciousness and convulsions may ensue. In sorne patients a graduai decline in blood glucose level blunts the acute-phase signs and symptoms attributed to stimulation of the autonomie nervous system. A rapid decline occurring during strenuous physieal activity may be heralded by slow reaction time and poorly coordinated movements. Noctumal sweating and moming headaches are valuable elues to hypoglycemia in sorne patients. Hypothermia usually accompanies hypoglycemia and is a valuable sign, especially in hospitalized patients whose temperature is recorded frequently. In elderly patients, hypoglycemie coma may arouse suspicion of a cerebrovascular accident. Depression of cerebral centers is readily reversible by prompt intravenous administration of 25 or 50 ml of 50% dextrose in water. Permanent brain damage may be associated with hypoglycemia lasting for six hours or more. Development of renal insufficiency is frequently associated with a rise in frequency of hypoglycemie episodes in insulin-dependent diabetic patients. Diminished food intake and diminished renal clearance of insulin probably are underlying factors. The insulin dosage should be reduced. Rarely, hypoglycemia occurs as a manifestation ofpituitary or adrenal insufficiency in a diabetic patient. Replacement therapy for the pituitary or adrenal disorder will correct the hypoglycemia. Insulin-dependent patients should at ali times have immediate access to a source of carbohydrate and should carry identification denoting their diabetie status. Hypoglycemie symptoms may mimie intoxication with alcobol or drugs. A diabetie patient's family and close friends should know how to use glue agon and glucose in the event of hypoglycemie coma. Initiation of treatment should not be delayed. An unconscious patient should be given 0.5
Vol. 59 • No. 1 • January 1976 • POSTGRADUATE MEDICINE
131
Complications of lnsulin Therapy
lnsulin overdosage can be avoided by seeking the lowest effective dose for maintaining satisfactory control of the blood glucose level.
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lnsulin-dependent patients should at ali times have immediate access to a source of carbohydrate and should carry Identification denoting their diabetic status.
mg of glucagon subcutaneously, intravenously, or intramuscularly. The dose is repeated in 15 minutes if consciousness does not return. An insulin syringe is used to administer the glucagon. Once the patient is aroused, glucose should be given orally. Excess glucagon causes nausea and vomiting and, therefore, prevents the patient from taking carbohydrate orally. A patient should not be left in coma by family members or friends while they wait for professional help. They should be instructed to initiate treatment with glucagon and concentrated carbohydrate for severe hypoglycemia; then they should call for professional help as needed. This avoids the loss of valuable time and prevents brain damage due to prolonged hypoglycemia.
that insulin-induced hypoglycemia can result in rebound hyperglycemia. Thus, giving too much insulin can cause a form of brittle diabetes. Insulin's hypoglycemie action results in release of glucagon, catecholamines, cortisol, and growth hormone, which in tum act to mobilize body fuels, including glucose derived from glycogenolysis and gluconeogenesis. Hunger leads to additional carbohydrate intake. These physiologie defense mechanisms at times lead to overcompensation in diabetic patients who are devoid of endogenous insulin stores. The result is rebound hyperglycemia, or the Somogyi phenomenon. Although the Somogyi phenomenon does occur, 2 it is overemphasized as a cause of hyperglycemia. By far the most common cause in insulin-dependent diabetics is excessive carbohydrate intake. Nevertheless the Somogyi phenomenon usually escapes detection. Patients exhibiting the Somogyi phenomenon are usually nonobese, and many have a history of ketoacidosis. Clinical elues suggesting the Somogyi effect are aglycosuria and aketonuria followed in a few hours by strong reactivity of the urine for both glucose and acetoacetate (the ketone body in biologie fluids responsible for the positive nitroprusside reaction). The diagnosis of the
Somogyi phenomenon is documented by wide fluctuations in blood concentrations (eg, 40 to 400 mg/lOO ml) despite a lack of food intake. Additional evidence is a quantitative reduction in 24-hour urinary excretion of glucose following a reduction in insulin dosage. When the Somogyi effect is suspected, the patient should be hospitalized. Blood samples should be obtained frequently during the day (hourly, if possible) and at times during the night. Urine should be tested frequently for glucose and acetoacetate (ketone bodies), and a 24-hour specimen should be collected for quantitation of glucose. Oral temperature should be taken every four hours, and a blood glucose test obtained immediately if hypothermia is present. Management of rebound hyperglycemia involves an initial 25% to 30% reduction in insulin dosage, with subsequent adjustments to meet needs. Insu/in allergy-Local hypersensitivity reactions to insulin at the site of injection are common. Frequently, induration with stinging, burning, or itching occurs within an hour or so. Violaceous discoloration of the area persists for severa! days.These reactions may occur over severa! weeks and then may subside graduai! y. Rarely, patients continue to have them. The indurated lesions are palpated by running the fingers up and down the anterior aspects of the thighs over the sites of insulin injection. Local reactions usually are not serious clinical problems. Infrequently, generalized allergie reactions to insulin marked by urticaria, pruritus, and angioedema accompany local reactions. lmmediate anaphylactic reactions to insulin are rare. Allergie reactions to injected USP insulins have been thought to be due to protein contaminants. However, recent studies 3 show that single-peak U -lOO beef-pork insulins have no immunologie advantages over the less-purified standard USP insulins. IgE has been identified as the reaginic antibody associated with allergie reactions to insulin. The IgE is directed against the insulin molecule, not against protein contaminants. 4 • 5 Furthermore, concentrations of circulating IgE anti-
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POSTGAADUATE MEDICIIIE • January 1976 • Vol. 59 • No. 1
Rebound hyperglycemia (the Somogyi phenomenon)-lt is important to recognize
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body correlate reasonably weil with the clinical allergie states. 4 Local allergie rea:tions can be blunted by use of antihistamine. Diphenhydramine (Benadryl), 25 mg, should be given about 30 minutes before an insulin injection and every four hours as needed. If generalized allergie reactions occur and insulin cannat be discontinued, desensitization is required. Before desensitization is started, insulin is withheld for at least 12 and preferably for 24 hours. Seriai dilutions of U-100 single-peak monospecies beef or park insulin (Regular, NPH, or Lente) are used (writtencommunication, Dr. J. A. Galloway, 1975). The insulin is diluted in normal saline solution to which 0.5% human albumin has been added. The large skin areas of the abdomen, thighs, or arms are the sites of injection. The species causing the lesser skin reactions is determined by giving single test doses of monospecies beef and park insulins. Saline solution is used as a control. For desensitization, the insulin with the lower reoctivity (usually park) is used. If the reoctions are identical, beef-pork insulin is used. The following amounts of insulin are given (in volumes of 0.1 ml) at 20- to 30-minute intervals: intradermally, 0.001, 0.002, and 0.004 unit; subcutaneously, 0.01, 0.02, 0.04, 0.1, 0.2, 0.5, 1, 2, 8, and 10 units. Desensitization should be achieved in less than eight hours. Epinephrine should be on hand for use in case of anaphylactic reaction, and a source of carbohydrate should be available to co un ter hypoglycemia. On the first day after desensitization, Regular insulin should be given at four- to six-hour intervals. Thereafter, two daily doses ofRegular, NPH, or Lente insulin may be needed to maintain desensitization. Patients are advised of the risk of becoming resensitized if insulin doses are omitted. Insulin resistance-About 0.1% of diabetic patients are insulin-resistant. 6 Insulin resistance has been defined arbitrarily as the state of requiring more than 200 units of insulin daily for a period longer than two days in the absence of ketoacidosis or acute infection. The current estimate of the amount of en-
dogenous insulin secreted by a normal adult is about 40 to 50 units/day. Nevertheless the old definition of insu lin resistance remains clinically valid; patients requiring more than 200 units/day almost invariably are found to have high titers of insulin-neutralizing antibodies. In ali persans receiving exogenous insulin daily, antibodies to insulin develop after five to six weeks. The titers usually are law and clinically insignificant. On rare occasions, high titers of IgG antibodies develop, necessitating administration of hundreds to thousands of units of insulin to control the diabetic state. 7 A diagnosis of insulin resistance due to IgG antibodies is made by determining the serum insulin-binding capacity. 8 Regular insulin preparations (U-100, U-500, U-5,000) should be used instead of modified insulins; Regular monospecies park or beefpork insulin is preferred. Patients failing to respond to Regular insulin and requiring more than 200 units/day should be given a glucocorticoid. We prefer prednisone in a dosage of 60 to 80 mg/day initially. After a week or two, the blood glucose level may decrease, probably owing to a reduction in insulin-binding antibodies. Regular insulin and prednisone dosages are reduced accordingly. After se veral months of prednisone therapy with maintenance doses of 10 to 15 mg/day, the glucocorticoid can be discontinued. After the insulin requirement has been reduced to less than 100 units/day,
Vol. 59 • No. 1 • January 1976 • POSTGAADUATE MEDICINE
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Regular insulin in combination with a modified insulin (NPH or Lente) often is necessary to achieve optimal control. Lipodystrophy-Two forms of lipodystrophy complicating the management of diabetic patients are recognized. In one, fibrofatty masses develop (lipohypertrophy). In the other, subcutaneous fat appears to melt away (lipoatrophy). Lipohypertrophy is generally seen in patients who favor particular sites for insulin injections. The masses that develop, usually in the thigh or deltoid area, can become very large, but the thigh masses frequently are not visible to inspection unless the patients are standing. Absorption of insulin from the hypertrophie areas may be unpredictable and slow. The masses regress slowly when the affected areas are avoided as sites of injection. Lipoatrophy used to occur in about 50% of children, 20% of adult females, and 5% of adult males who received insulin, 8 • 9 developing after three to six months of treatment in most cases and subsiding after two or three years. A recent report 9 suggests that the incidence is going dawn (perhaps because contaminants have been removed from commercial insulins). However, this must be confirmed by further observation. Cosmetic disfigurement of thighs, abdomen, buttocks, and arms secondary to this form of lipodystrophy has be en disturbing to diabetic patients, especially women. It was
recently observed 1 that lipoatrophic areas disappeared in 86% of cases when single-peak or single-component insulin was injected into the affected areas or adjacent to them. For treatment of patients who do not respond to mixed beef-pork single-peak insulin, Galloway and co-workers 1 have recomlnended use of monospecies single-peak insulin or, if this fails, of single-component pork insulin. Summary
About 95% of insulin-dependent diabetics can be managed satisfactorily with one or a combination of the following insulin preparations: single-peak U-100 beef-pork NPH, Lente, and Regular. Complications of insulin therapy are commonly attributable to poor regulation of insulin dosage, irregular or excessive food intake, or unusual physical activity. One form of hyperglycemia is induced by insulin. Generalized allergie reactions to insulin sometimes require desensitization. Insulin-resistant patients are treated with a glucocorticoid. • This work was supported in part by re se arch grants 5 RO 1 AM 16102-02 MET, 1 ROI AM 16348·02 MET, and 5 MOI RR 349-09 from the National Institutes of Health. Address reprint requests to Oliver E. Owen, MD, General Clinical Research Center, Temple University Health Sciences Center, Philadelphia, PA 19140. Re ad ySource on diabetes appears on page 179. CME Credit Quiz on diabetes begins on page 185.
References 1. Galloway JA, Root MA, Chance RE, et al: New forms of insulin. In Kryston U, Shaw RA (Editors): Endocrinology and Diabetes. New York, Grune & Stranon, 1975, p 329 2. Blood ME, Mintz DH, Field JB: lnsulin-induced posthypoglycemie hyperglycemia as a cause of "brinle" diabetes. Am J Med 47:891, 1969 3. Tantillo JJ, Karam JH, Burrill KC, et al: Immunogenicity of "single peak" beef-pork insulin in diabetic subjects. Diabetes 23:276-281, 1974 4. Patterson R, Mellies CJ, Roberts M: Immunologie reactions against insulin. Il. IgE anti-insulin, insulin allergy and combined IgE and IgC immunologie insulin resistance. J ImmunolliO:II35, 1973 5. Mattson JR, Patterson R, Roberts M: Insulin therapy in
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6.
7.
8.
9.
patients with systemic insulin allergy. Arch Intern Med 135:818, 1975 Shipp JC, Cunningham RW, Russell RO, et al: Insulin resistance: Clinical features, natural course and effects of adrenal stei'oid treatment. Medicine 44:165-186, Mar 1965 Patterson R, D'Rourke J, Roberts M, et al: Immunologie reactions against insulin. 1. lgG anti-insulin and insulin resistance. J Immunol 110:1126, 1973 Marble A: Insulin in the treatment of diabetes. In Marble A, White P. Bradley RF, et al (Editors): Joslin's Diabetes Mellitus. Ed. Il. Philadelphia, Lea & Febiger, 1971, p 287 Teuscher A: Treatment of insulin lipoatrophy with monocomponent insulin. Diabetologia 10:211, 1974
POSTGRADUATE MEDICINE o January 1976 o Vol. 59 • No. 1
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Managing insulin-dependent diabetic patients Oliver E. Owen, Guenther Boden & Charles R. Shuman To cite this article: Oliver E. Owen, Guenther Boden & Charles R. Shuman (1976) Managing insulin-dependent diabetic patients, Postgraduate Medicine, 59:1, 127-134, DOI: 10.1080/00325481.1976.11716530 To link to this article: http://dx.doi.org/10.1080/00325481.1976.11716530
Published online: 07 Jul 2016.
Submit your article to this journal
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ipgm20 Download by: [University of Calgary]
Date: 06 August 2017, At: 00:04
Downloaded by [University of Calgary] at 00:04 06 August 2017
• A fundamental princip le in the treatment of diabetes mellitus is the supply of enough insulin ta regulate the metabolism of glucose, lipid, and protein. lndividuals who do not have enough endogenous insulin ta prevent catabolism while their food consumption is adequate need supplementary insulin. This group includes patients with growth-onset diabetes and ali diabetics who are ketosis-prone with or without stress due ta trauma, surgery, or infection. In addition, adult diabetics with symptomatic hyperglycemia who respond inadequately ta oral hypoglycemie agents and dietary regulation need exogenous insulin. By contrast, diet rather than insulin is the treatment of choice for obese, hyperphagic patients with maturity-onset diabetes who have symptomatic hyperglycemia and who maintain or gain weight. Meeting the specifie needs of each insulin-dependent dia be tic patient requires knowledge of the time-activity course of the available insulin preparations. Factors influencing the choice of preparation include the response of blood glucose levels ta meals, quantity and distribution of dietary carbohydrate, physical activity, and individual response ta insulin. The most widely used insulin preparations are the intermediate-acting NPH insulin (isophane insulin suspension) and Lente insulin (insulin zinc suspension) and the rapid-acting Regular insulin and Semilente insulin (insulin zinc suspension prompt). Because of their activity curves, they are best suited for administration in single-dose, split-dose, or combined-splitdose schedules, which are satisfactory for the regulation of metabolism in nearly ali insulin-dependent diabetic patients.
• manag1ng insu lin-dependent diabetic patients Oliver E. Owen, MD Guenther Boden, MD Charles R. Shuman, MD Temple University Health Sciences Center Philadelphia
consider What three insulin preparations can be usecl to satisfactorily manage 95% of insulin-dependent diabetics?
Types of lnsulln
Data on the commercial insulin preparations available in the United States are given in table 1. Those readily available are mixtures of insulin obtained from beef and park pancreas. Special monospecies insulins made from beef or park pancreas are available. Purity and shelf life of commercial insulins have improved through the years. The purified insulins produced and distributed in the United States and Canada are greater than 98% pure insulin ("single peak"); those produced and distributed primarily in Europe are greater than 99% pure insulin (''monocomponent"). The insulins available at present do not require refrigeration
Vol. 59 o No. 1 o January 1976 o POSTOAADUATE MEDICINE
What are the most common causes of complications such as hypoglycemia, rebound hyperglycemia, and lipoatrophy? How can these complications be effectively managed? When is hospitalization advisable?
127
table 1. insulin preparations commercially available in the united states, classified according to approximate duration of action Classification
Rapid
lnsulln preparation•
Regular (neutral)
Action On set
Peak
Du ration
IV:t immediate
15-30 min 30-60 min 1-2 hr
1-2 hr 2-4 hr 5-10 hr
lM: 5-30 min SC: 30min
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lntermediate
Slow
Combinations
Semilente (insulin zinc suspension prompt)
SC:
1 hr
3-4 hr
10-16 hr
Globin zinc insulin NPH (isophane insulin suspension) Lente (insulin zinc suspension)
SC: SC:
2 hr 2 hr
6-8 hr 8-14 hr
12-18 hr 18-24 hr
SC:
2 hr
8-14 hr
18-24 hr
Protamine zinc insulin suspension Ultralente (insulin zinc suspension extended)
SC:
6 hr
16-20 hr
24-30 hr
SC:
6 hr
18-29 hr
3D-36 hr
SC: SC: SC: SC:
30 min 1 hr 1 hr 1 hr
2-10 2-10 4-10 2-24
18-24 18-24 18-24 30-36
Regular + N PH Regular + Lente Semilente + Lente Semilente + Ultralente
hr hr hr hr
hr hr hr hr
•Preparations are available in concentrations of 40. 80, and 100 units/ml in 10-ml vials. Regular (Concentrated) lletin is also available in a concentration of 500 units/ml in 20-ml vials. Regular, NPH, and Lente insulins are available as beef-pork insulin mixtures and as special monospecies insulins made exclusively from bee! or pork pancreas.
tiV, lM, and SC denote intravenous, intramuscular, and subcutaneous routes of administration.
but should not be exposed ta extreme temperature (be law freezing or above 120 F). Regular insulin manufactured since February 1973 has a neutra! pH and is sa identified on the vial. An advantage of Regular neutra! insulin is that it can be added in any proportion ta NPH or Lente insulin. 1 Single-peak insulins are marketed in the United States in concentrations of 40 (redcapped vial), 80 (green), 100 (orange), and 500 (brown) units per milliliter in l 0-rnl vials. Discontinuance of marketing of U-80 preparations is planned in the near future. The U-40 insulin preparations permit more accurate measurement of small doses. However, marketing ofU-40 insulin probably will cease as saon as accurate syringes for delivery of
small doses of U -100 insulin preparations become available. About 95% of insulin-dependent diabetic patients can be managed by using single doses, split doses, or combined-split doses of various combinations of three insulin preparations: single-peak U- 100 beef-pork NPH, Lente, and Regular insulins. In arder of increasing difficulty in management, schedules that will give satisfactory control in almost ali cases are: ( 1) single dose of 50 units or Jess of NPH or Lente insulin given before breakfast, (2) split dose of NPH or Lente insulin, with 60% ta 90% given before breakfast and 10% ta 40% given before the evening meal, and (3) combined-split dose, with a combinatian of NPH or Lente insulin and Regular in-
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sulin (combined dose) given before breakfast and with NPH, Lente, or Regular insulin (split dose) given before the evening meal.
In the absence of acute illness (other than diabetes), insulin therapy can be started on an outpatient basis. (Exceptions are noted later.) After the his tory, physical examinatian, and blood glucose determinations have established the diagnosis of diabetes meiJitus and the need for exogenous insulin, education of the patient begins. It is essential to good management that the patient understand the balance among diet, insulin, and exercise. Unrestrained food ingestion is the primary cause of hyperglycemia in diabetics receiving insulin. Exercise potentiates the hypoglycemie action of insulin. Checking and recording urinary glucose reactions on double-voided specimens are very important. Techniques for self-administration of insulin are demonstrated. Insulin should be injected subcutaneously, using sterile technique. Sites for injection are the back of the arm in the deltoid area and in the crease between deltoid and triceps muscles, the anterior aspect of the thigh, the anterior and lateral aspects of the abdomen, and the buttocks. Alternation of these sites is essential, using each area as infrequently as possible. Glass syringes are Jess expensive than disposable plastic syringes. Glass syringes can be routinely stored in alcohol solution and periodically washed with soap and water and sterilized in boiling water (about once a month). Disposable needles on the glass syringes can be used repeatedly and are discarded when dull. Disposable syringes and needles for single use are convenient for travel and may be preferable for a patient whose skin is not kept clean. Air is added to the insulin vial to keep its contents under slight positive pressure and to facilitate withdrawal of solution. The initial dose of intermediate-acting insulin (NPH or Lente) is JO to 20 units, given about 20 minutes before breakfast. During the
early phase of management, the diabetic patient is told to check the urine for glucose before breakfast, lunch, dinner, and bedtime and to record daily insulin doses and urinary glucose reactions. If urine voided just before the evening meal is positive for glucose, the patient should increase the morning insulin dose by 4 units every other day. The urine tested should be urine obtained from a second or late voiding; the first urine specimen voided after a meal should not be used for regulation of insulin dosage because it may contain glucose accumulated in the bladder during the brief postprandial period and does not truly reflect the blood glucose leve) at the time of tes ting. At the end of one week, the physician checks the fasting blood glucose level, urinary glucose records, body weight, and general medical status and adjusts the insulin dosage as necessary. If the patient experiences episodes of hypoglycemia or if ali urine glucose tests are negative, the daily dose of insulin is reduced by 4 units every other day until about half of the urinary tests are nonreactive. Once the late-afternoon test is nonreactive, the test done before breakfast also may be nonreactive. However, many Americans eat their largest meal in the evening. Diabetics should distribute their food intake more evenly throughout the day, but many do not change their eating patterns. If a single dose of insulin given before breakfast fails to prevent nocturia secondary to glycosuria, a split-dose insulin regimen is recommended, with an appropriate amount of NPH, Lente, or Regular insulin given just before the evening meal. If urine voided before bedtime is nonreactive for glucose, a snack should be eaten to avoid nocturnal hypoglycemia. It should be recognized that the hypoglycemie effect of any insulin dose is related to the blood glucose concentration at the time of insulin administration. Insulin acts to decrease the blood levels of glucose and other oxidizable substrates that compete with glucose as body fuels. When the blood glucose leve) is low following administration of insulin, the levels of circulating free fatty acids
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Initiation of lnsulln Therapy ln Ambulatory Patients
Dr. Owen is professer of medicine; Dr. Boden is associate professer of medicine; and Dr. Shuman is professer of medicine, Temple University Health Sciences Center, Philadelphia.
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Oliver E. Owen
Guanther Bodan
Charlas R. Shuman
and ketone bodies are low. Thus, a diabetic who has an overnight fasting blood glucose level of 100 mg/ 100 ml without hyperlipidemia and hyperketonemia and who takes NPH or Lente insulin before breakfast is more likely to experience late-afternoon hypoglycemia than is a patient with an overnight fasting blood glucose concentration of 250 mg/ 100 ml wit.h accompanying hyperlipidemia and hyperketonemia. Therefore, if the split-dose insulin regimen is used to control overnight fasting hyperglycemia, the morning dose of insulin should be appropriately adjusted to prevent hypoglycemia from occurring before the evening meal. Once the late-afternoon and overnight fasting blood glucose concentrations are satisfactory, attention is directed to the period between breakfast and lunch. If the breakfast meal does not con tain excess carbohydrate, glycosuria occurring between breakfast and lunch is an indication for use of a combination of intermediate- and rapid-acting insulins. Usually, 4 to 6 units ofNPH or Lente insulin is subtracted from the morning dose, and 6 to 10 units of Regular insulin is added. The two insulins are drawn into the same syringe. Adding air to the vial before withdrawing the solution helps to avoid contamination of the second vial by insulin already in the syringe. Mixing of the insulins in the syringe is unnecessary. It is important to use syringes with minimal dead space and not to change brands of syringe. In general, the larger a patient's insulin requirement, the more Regular insulin and the less NPH or Lente insulin is used.
Advantages of outpatient treatment of dia be tes are simplicity and economy. Patients are encouraged to participate in their regular daily activities. A disadvantage is the require.ment of a considerable period of instruction. A small proportion of patients have bladder hypotonia or. abnormally high or low renal thresholds for glucose which preclude the use of simple uri-ne glucose testing as a guide to insulin dosage. In addition, the peak action ofNPH and Lente insulins occurs in the afternoon, and when aglycosuria prevails, the patient must make return visits so blood glucose concentrations can be measured.
Diabetics who should not be managed as outpatients but should be hospitalized during the initial phase of insulin therapy include pregnant women with newly discovered diabetes and children with the disease. Hospitalization is also indicated for ali diabetics with acute conditions complicating control, such as severe infection or trauma. During such acute situations, there are three cardinal objectives: Prevent dehydrating hyperglycemia; avoid hypoglycemia; prevent ketoacidosis. In treatment of hospitalized patients, only Regular insulin should be used initially. The amount of the first dose depends on the blood glucose and electrolyte concentrations and is 10 to 20 or more units. Subsequent doses are given every four to six hours, the intervals depending on seriai blood glucose responses. If blood for repeated analyses cannot be obtained, fractional urinary glucose reactions
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determined at four-hour intervals may be used as a guide for no more than 24 hours. For each one-digit rise in glucose reaction above 1 +, 4 to 6 units of Regular insulin is added. (If the reaction were 3+, for example, 8 to 12 units would be added.) On the next moming, NPH or Lente insulin is given instead of Regular insulin in a dose of about two thirds of the total quantity of Regular insulin gi ven during the previous 24 hours. If the acute process (infection, effects of trauma) continues, supplementary Regular insulin is given at intervals of four to six hours as needed to control hyperglycemia.
Hypoglycemia-Exogenous insulin is the most common source of hypoglycemia in diabetic patients. Hypoglycemia is usually associated with insulin overdosage, omission or delay of meals, or unusual or unplanned physieal activity. Insulin overdosage can be avoided by seeking the lowest effective dose for maintaining satisfactory control of the blood glucose level. The omission of meals can be avoided by educating the patient on the importance of regular meals. Hypoglycemia secondary to physical activity can be avoided if patients check urine for glucose before and after the activity and consume extra food as needed. Such tes ting is easily done by using the available test strips. If the urinary glucose test is nonreactive before the patient plays squash or tennis, for example, or before he or she mows the grass or does comparable physical activities, 6 to 12 oz of Coca-Cola (20 to 40 gm of glucose) or a similar beverage, or food (candy), should be consumed. If the urinary glucose test is reactive before participation in heavy physical activity, an extra feeding after the exercise may be needed to prevent subsequent hypoglycemia. Most patients saon leam how much physical activity they can tolerate and how much extra food they need to forestall insulin reactions. The hypoglycemie effect of exercise is long-lasting, however, and may be retlected in the blood glucose concentration on the following day. Hypoglycemie signs and symptoms
(hunger, nausea, faintness, sweating, headache, rapid heart rate, double vision, slurred speech, mental obtundation) are easily cleared with 10 to 20 gm of glucose taken orally. Unless treatment is given prompt! y, unconsciousness and convulsions may ensue. In sorne patients a graduai decline in blood glucose level blunts the acute-phase signs and symptoms attributed to stimulation of the autonomie nervous system. A rapid decline occurring during strenuous physieal activity may be heralded by slow reaction time and poorly coordinated movements. Noctumal sweating and moming headaches are valuable elues to hypoglycemia in sorne patients. Hypothermia usually accompanies hypoglycemia and is a valuable sign, especially in hospitalized patients whose temperature is recorded frequently. In elderly patients, hypoglycemie coma may arouse suspicion of a cerebrovascular accident. Depression of cerebral centers is readily reversible by prompt intravenous administration of 25 or 50 ml of 50% dextrose in water. Permanent brain damage may be associated with hypoglycemia lasting for six hours or more. Development of renal insufficiency is frequently associated with a rise in frequency of hypoglycemie episodes in insulin-dependent diabetic patients. Diminished food intake and diminished renal clearance of insulin probably are underlying factors. The insulin dosage should be reduced. Rarely, hypoglycemia occurs as a manifestation ofpituitary or adrenal insufficiency in a diabetic patient. Replacement therapy for the pituitary or adrenal disorder will correct the hypoglycemia. Insulin-dependent patients should at ali times have immediate access to a source of carbohydrate and should carry identification denoting their diabetie status. Hypoglycemie symptoms may mimie intoxication with alcobol or drugs. A diabetie patient's family and close friends should know how to use glue agon and glucose in the event of hypoglycemie coma. Initiation of treatment should not be delayed. An unconscious patient should be given 0.5
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Complications of lnsulin Therapy
lnsulin overdosage can be avoided by seeking the lowest effective dose for maintaining satisfactory control of the blood glucose level.
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lnsulin-dependent patients should at ali times have immediate access to a source of carbohydrate and should carry Identification denoting their diabetic status.
mg of glucagon subcutaneously, intravenously, or intramuscularly. The dose is repeated in 15 minutes if consciousness does not return. An insulin syringe is used to administer the glucagon. Once the patient is aroused, glucose should be given orally. Excess glucagon causes nausea and vomiting and, therefore, prevents the patient from taking carbohydrate orally. A patient should not be left in coma by family members or friends while they wait for professional help. They should be instructed to initiate treatment with glucagon and concentrated carbohydrate for severe hypoglycemia; then they should call for professional help as needed. This avoids the loss of valuable time and prevents brain damage due to prolonged hypoglycemia.
that insulin-induced hypoglycemia can result in rebound hyperglycemia. Thus, giving too much insulin can cause a form of brittle diabetes. Insulin's hypoglycemie action results in release of glucagon, catecholamines, cortisol, and growth hormone, which in tum act to mobilize body fuels, including glucose derived from glycogenolysis and gluconeogenesis. Hunger leads to additional carbohydrate intake. These physiologie defense mechanisms at times lead to overcompensation in diabetic patients who are devoid of endogenous insulin stores. The result is rebound hyperglycemia, or the Somogyi phenomenon. Although the Somogyi phenomenon does occur, 2 it is overemphasized as a cause of hyperglycemia. By far the most common cause in insulin-dependent diabetics is excessive carbohydrate intake. Nevertheless the Somogyi phenomenon usually escapes detection. Patients exhibiting the Somogyi phenomenon are usually nonobese, and many have a history of ketoacidosis. Clinical elues suggesting the Somogyi effect are aglycosuria and aketonuria followed in a few hours by strong reactivity of the urine for both glucose and acetoacetate (the ketone body in biologie fluids responsible for the positive nitroprusside reaction). The diagnosis of the
Somogyi phenomenon is documented by wide fluctuations in blood concentrations (eg, 40 to 400 mg/lOO ml) despite a lack of food intake. Additional evidence is a quantitative reduction in 24-hour urinary excretion of glucose following a reduction in insulin dosage. When the Somogyi effect is suspected, the patient should be hospitalized. Blood samples should be obtained frequently during the day (hourly, if possible) and at times during the night. Urine should be tested frequently for glucose and acetoacetate (ketone bodies), and a 24-hour specimen should be collected for quantitation of glucose. Oral temperature should be taken every four hours, and a blood glucose test obtained immediately if hypothermia is present. Management of rebound hyperglycemia involves an initial 25% to 30% reduction in insulin dosage, with subsequent adjustments to meet needs. Insu/in allergy-Local hypersensitivity reactions to insulin at the site of injection are common. Frequently, induration with stinging, burning, or itching occurs within an hour or so. Violaceous discoloration of the area persists for severa! days.These reactions may occur over severa! weeks and then may subside graduai! y. Rarely, patients continue to have them. The indurated lesions are palpated by running the fingers up and down the anterior aspects of the thighs over the sites of insulin injection. Local reactions usually are not serious clinical problems. Infrequently, generalized allergie reactions to insulin marked by urticaria, pruritus, and angioedema accompany local reactions. lmmediate anaphylactic reactions to insulin are rare. Allergie reactions to injected USP insulins have been thought to be due to protein contaminants. However, recent studies 3 show that single-peak U -lOO beef-pork insulins have no immunologie advantages over the less-purified standard USP insulins. IgE has been identified as the reaginic antibody associated with allergie reactions to insulin. The IgE is directed against the insulin molecule, not against protein contaminants. 4 • 5 Furthermore, concentrations of circulating IgE anti-
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Rebound hyperglycemia (the Somogyi phenomenon)-lt is important to recognize
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body correlate reasonably weil with the clinical allergie states. 4 Local allergie rea:tions can be blunted by use of antihistamine. Diphenhydramine (Benadryl), 25 mg, should be given about 30 minutes before an insulin injection and every four hours as needed. If generalized allergie reactions occur and insulin cannat be discontinued, desensitization is required. Before desensitization is started, insulin is withheld for at least 12 and preferably for 24 hours. Seriai dilutions of U-100 single-peak monospecies beef or park insulin (Regular, NPH, or Lente) are used (writtencommunication, Dr. J. A. Galloway, 1975). The insulin is diluted in normal saline solution to which 0.5% human albumin has been added. The large skin areas of the abdomen, thighs, or arms are the sites of injection. The species causing the lesser skin reactions is determined by giving single test doses of monospecies beef and park insulins. Saline solution is used as a control. For desensitization, the insulin with the lower reoctivity (usually park) is used. If the reoctions are identical, beef-pork insulin is used. The following amounts of insulin are given (in volumes of 0.1 ml) at 20- to 30-minute intervals: intradermally, 0.001, 0.002, and 0.004 unit; subcutaneously, 0.01, 0.02, 0.04, 0.1, 0.2, 0.5, 1, 2, 8, and 10 units. Desensitization should be achieved in less than eight hours. Epinephrine should be on hand for use in case of anaphylactic reaction, and a source of carbohydrate should be available to co un ter hypoglycemia. On the first day after desensitization, Regular insulin should be given at four- to six-hour intervals. Thereafter, two daily doses ofRegular, NPH, or Lente insulin may be needed to maintain desensitization. Patients are advised of the risk of becoming resensitized if insulin doses are omitted. Insulin resistance-About 0.1% of diabetic patients are insulin-resistant. 6 Insulin resistance has been defined arbitrarily as the state of requiring more than 200 units of insulin daily for a period longer than two days in the absence of ketoacidosis or acute infection. The current estimate of the amount of en-
dogenous insulin secreted by a normal adult is about 40 to 50 units/day. Nevertheless the old definition of insu lin resistance remains clinically valid; patients requiring more than 200 units/day almost invariably are found to have high titers of insulin-neutralizing antibodies. In ali persans receiving exogenous insulin daily, antibodies to insulin develop after five to six weeks. The titers usually are law and clinically insignificant. On rare occasions, high titers of IgG antibodies develop, necessitating administration of hundreds to thousands of units of insulin to control the diabetic state. 7 A diagnosis of insulin resistance due to IgG antibodies is made by determining the serum insulin-binding capacity. 8 Regular insulin preparations (U-100, U-500, U-5,000) should be used instead of modified insulins; Regular monospecies park or beefpork insulin is preferred. Patients failing to respond to Regular insulin and requiring more than 200 units/day should be given a glucocorticoid. We prefer prednisone in a dosage of 60 to 80 mg/day initially. After a week or two, the blood glucose level may decrease, probably owing to a reduction in insulin-binding antibodies. Regular insulin and prednisone dosages are reduced accordingly. After se veral months of prednisone therapy with maintenance doses of 10 to 15 mg/day, the glucocorticoid can be discontinued. After the insulin requirement has been reduced to less than 100 units/day,
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Regular insulin in combination with a modified insulin (NPH or Lente) often is necessary to achieve optimal control. Lipodystrophy-Two forms of lipodystrophy complicating the management of diabetic patients are recognized. In one, fibrofatty masses develop (lipohypertrophy). In the other, subcutaneous fat appears to melt away (lipoatrophy). Lipohypertrophy is generally seen in patients who favor particular sites for insulin injections. The masses that develop, usually in the thigh or deltoid area, can become very large, but the thigh masses frequently are not visible to inspection unless the patients are standing. Absorption of insulin from the hypertrophie areas may be unpredictable and slow. The masses regress slowly when the affected areas are avoided as sites of injection. Lipoatrophy used to occur in about 50% of children, 20% of adult females, and 5% of adult males who received insulin, 8 • 9 developing after three to six months of treatment in most cases and subsiding after two or three years. A recent report 9 suggests that the incidence is going dawn (perhaps because contaminants have been removed from commercial insulins). However, this must be confirmed by further observation. Cosmetic disfigurement of thighs, abdomen, buttocks, and arms secondary to this form of lipodystrophy has be en disturbing to diabetic patients, especially women. It was
recently observed 1 that lipoatrophic areas disappeared in 86% of cases when single-peak or single-component insulin was injected into the affected areas or adjacent to them. For treatment of patients who do not respond to mixed beef-pork single-peak insulin, Galloway and co-workers 1 have recomlnended use of monospecies single-peak insulin or, if this fails, of single-component pork insulin. Summary
About 95% of insulin-dependent diabetics can be managed satisfactorily with one or a combination of the following insulin preparations: single-peak U-100 beef-pork NPH, Lente, and Regular. Complications of insulin therapy are commonly attributable to poor regulation of insulin dosage, irregular or excessive food intake, or unusual physical activity. One form of hyperglycemia is induced by insulin. Generalized allergie reactions to insulin sometimes require desensitization. Insulin-resistant patients are treated with a glucocorticoid. • This work was supported in part by re se arch grants 5 RO 1 AM 16102-02 MET, 1 ROI AM 16348·02 MET, and 5 MOI RR 349-09 from the National Institutes of Health. Address reprint requests to Oliver E. Owen, MD, General Clinical Research Center, Temple University Health Sciences Center, Philadelphia, PA 19140. Re ad ySource on diabetes appears on page 179. CME Credit Quiz on diabetes begins on page 185.
References 1. Galloway JA, Root MA, Chance RE, et al: New forms of insulin. In Kryston U, Shaw RA (Editors): Endocrinology and Diabetes. New York, Grune & Stranon, 1975, p 329 2. Blood ME, Mintz DH, Field JB: lnsulin-induced posthypoglycemie hyperglycemia as a cause of "brinle" diabetes. Am J Med 47:891, 1969 3. Tantillo JJ, Karam JH, Burrill KC, et al: Immunogenicity of "single peak" beef-pork insulin in diabetic subjects. Diabetes 23:276-281, 1974 4. Patterson R, Mellies CJ, Roberts M: Immunologie reactions against insulin. Il. IgE anti-insulin, insulin allergy and combined IgE and IgC immunologie insulin resistance. J ImmunolliO:II35, 1973 5. Mattson JR, Patterson R, Roberts M: Insulin therapy in
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6.
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9.
patients with systemic insulin allergy. Arch Intern Med 135:818, 1975 Shipp JC, Cunningham RW, Russell RO, et al: Insulin resistance: Clinical features, natural course and effects of adrenal stei'oid treatment. Medicine 44:165-186, Mar 1965 Patterson R, D'Rourke J, Roberts M, et al: Immunologie reactions against insulin. 1. lgG anti-insulin and insulin resistance. J Immunol 110:1126, 1973 Marble A: Insulin in the treatment of diabetes. In Marble A, White P. Bradley RF, et al (Editors): Joslin's Diabetes Mellitus. Ed. Il. Philadelphia, Lea & Febiger, 1971, p 287 Teuscher A: Treatment of insulin lipoatrophy with monocomponent insulin. Diabetologia 10:211, 1974
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