Symposium on Diabetes Mellitus

Insulin Treatment in Diabetes John A. Galloway, M.D./ and Rubin Bressler, M.D.,:q

Since our discussion of insulin treatment in diabetes in this journal seven years ago,7 the efficacy of and indications for purer forms of insulin have been established. lo • 2.3. 73. 7.3. 76 Arguments showing the relation of blood glucose control to the development and progression of the complications have been strengthened,'" 12. I". 37. 40 but are still being challenged. 3s Since the balance has been in favor of control, new methods of monitoring the blood glucose level and delivering insulin are being developed. 3 , 4, I!. :10, 4:1. 4H New data on the bioavailability, pharll.lacokinetics, and time action of insulin are also now available. 26 . 31. 34, 41. 51 Finally, means for coping with a possible insulin shortage within the next few years is being considered,'!" In order to provide the medical practitioner with both a basis and method for managing diabetics who need insulin, this essay will update our earlier views on the clinical use of insulin. 7

EFFICACY OF AND INDICATIONS FOR THE USE OF PURER FORMS OF INSULIN In 1971, when "single peak" (SP) and "single component" (Se) insulins became available we initiated clinical studies to ascertain the efficacy of these insulins in insulin lipoatrophy, insulin allergy, insulin hypertrophy, insulin resistance, and labile diabetes. The term "single peak" is used to designate insulin which on gel chromatography yields a profile consisting chiefly of a single peak. The primary improvement seen in single peak insulin in comparison with those insulins commonly available in the early 1970's is a reduction of the amount of large molecular substances which elute as the A and B peaks. Disc-gel electrophoresis discloses in addition to insulin the presence of small amounts of desamido insulin and arginine insulins which have been shown to be intermediates in the conversion of proinsulin to insulin. "Senior Clinical Pharmacologist, Lilly Laboratory for Clinical Research and Associate Professor of Medicine, Indiana University School of Medicine, Indianapolis, Indiana ""Professor and Head Internal Medicine, Professor of Pharmacology and Chief, Clinical Pharmacology, University of Arizona College of Medicine, Tucson, Arizona

Medical Clinics of North America - Vo!. 62, No. 4, July 1978

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The single peak insulin used in our studies contains less than 0.1 per cent proinsulin and 0.02 per cent glucagon by weight. Single component insulin is single peak insulin which has been further purified by DEAE cellulose chromatography.,o,n] The chief difference between the two is that single component insulin is 99 per cent insulin and has only miniscule amounts of material of large molecular weight. (In this paper we assume that SCPI, manufactured by Lilly, and Novo's Monocomponent insulin are probably comparable.) Since the species from which the insulin has been derived has a bearing on the treatment of the complications of insulin therapy, it is helpful to know that over 95 per cent of insulin sold in this country is mixed beef-pork, the remainder being monospecies pork and monospecies beef material. The methods of preparation and chemical composition of single peak and single component insulin are summarized in Table 1. While generally single component insulin is less likely than single peak insulin to be associated with complications, the advantage of single component over single peak insulin is clearly demonstrated in only a minority of patients, those with allergy and lipoatrophy.

Insulin-Induced Lipoatrophy This complication of insulin therapy, which occurs most commonly in children and adolescent girls, consists of loss of fat at the site of injection of insulin. This condition should not be confused with classical atrophic diabetes. 5H Insulin lipoatrophy is a benign condition, but the cosmetic disfigurement may cause great concern to patients. While the cause of insulin lipoatrophy has not been established, the unique efficacy of purified insulins, particularly from pork, and especially SCI and monocomponent insulin, indicates that less pure insulins may contain a substance(s) which in susceptible patients is lipolytic. That insulin lipoatrophy has an immune component is suggested by (1) a high coincidence of local allergy and lipoatrophy (15 per cent); (2) the reduction in insulin lipoatrophy that results from the local use of Table 1.

Comparison of Lilly "Single Peak" and "Single Component" lnsulins SINGLE PEAK

SINGLE COMPONENT

Method of purification

Molecular sieve

Molecular sieve and ion exchange chromatography

Composition

99 per cent insulin and insulin-like materials. Less than 1 per cent other materials of higher molecular weight

99 per cent insulin. Miniscule quantities of other substances of higher molecular weight

Commercial availability

All Lilly insulins (V-40, V-80, V-100, and V-500) are single peak (mixed beef-pork and monospecies beef and pork insulin)

Supplied as investigational drug as V-100 pork Lente and Regular only

INSULIN TREATMENT

665

steroids;~2. 7~ and (3) the occurrence of insulin lipoatrophy in one of our patients treated with SCBI (beef being more immunogenic than pork, a phenomenon ascribed to the fact that beef differs from human insulin at positions 8 and 10 on the A-chain whereas pork is the same as human insulin). Thus, it is possible that lipoatrophy results from the initiation of a clinically inapparent immune-type response by materials of large molecular weight present in the less pure forms of insulin. This in turn triggers local lipolysis, the mechanisms of which are unknown but may be due to the local release of catecholamines secondary to the immunologic stimuli. In our series 7:l of over 300 patients, more than 80 per cent improved on mixed beef-pork SPI injected into the affected areas. About a fourth of the remainder noted filling in when placed on monospecies pork SPI. The remainder responded to single component pork insulin (SCPI) with two exceptions, in one the patient being lost to follow-up. The other failure was in a patient, age 14, who had dramatic improvement when placed on SCPI. Because of a temporary hiatus in supplies the patient had to take single peak pork insulin (SPPI) following which multiple areas of atrophy which had filled in with SCPI excavated. Reinstitution of treatment with SCPI has resulted in only very slow improvement of the insulin lipoatrophy. Based on our data and the findings of others,28 we conclude that SCPI and its foreign counterpart (MC-pork insulin, Novo) are virtually 100 per cent effective in the management of patients with insulin lipoatrophy. Four additional points should be considered in managing patients with insulin liopatrophy: 1. As noted above, about 15 per cent of patients have co-existing local allergy. The insulin lipoatrophy will not respond until the allergy has been effectively treated (see below). 2. Areas that fill in with whatever insulin is found to be effective early in the period of resolution first have a "doughy" consistency, "Normal" tissue apparently takes 2 to 4 weeks to develop. 3. Areas that have filled in may tend to re-excavate unless they are reinjected every two to four weeks. However, too frequent injections may result in the development of insulin hypertrophy. Consequently, except for occasional "maintenance" injection of former areas of atrophy once resolution has occurred, the areas of injection of insulin should be rotated. 4. Based on our patient who was a secondary failure with SCPI, we believe that patients with lipoatrophy who are started on SCPI should be continued on it indefinitely.

Allergy to Insulin Insulin allergy occurs in two readily recognizable forms-local and systemic. The local allergic response may be immediate (onset within 15 minutes to 2 hours after the injection of insulin) or a delayed (onset 4 hours or more after the injection of insulin). Systemic allergy and local allergy of the immediate type are thought to be IgE mediated. H• 49 Delayed local allergy is mediated by IgG antibody. Some patients have both systemic and local allergy and in some severe local allergy progresses to systemic allergy.

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LOCAL REACTIONS. Local allergy consists of a hard, indurated area at the injection site involving just the subcutaneous tissues or extending to the overlying tissues, producing a brawny or erythematous rash. Local reactions ordinarily come on within 1 to 4 weeks after the initiation of insulin treatment. However, because a large number of patients have been sensitized by previous exposure to insulin, local reactions are now being seen within the first few days of reinstitution of insulin therapy. Some local reactions will improve if the patient is switched from mixed beef-pork to monospecies pork insulin. Barring a history of allergy to beef protein, patients whose allergy worsens on SPPI should be tried on "single peak" beef insuli12- (SPBI). Patients who respond to SPPI about the same as they did to mixed beef-pork SPI should be tried on SCPI. The use of multiple doses of Regular Insulin or the use of steroids with the insulin may be considered for a small minority of patients, particularly those in whom the local reaction occurs 6 to 24 hours after the injection of insulin.';' A suitable starting dose is in the range of 0.1 to 0.5 mg of steroid per dose. In using this approach one should be aware that a dose of 0.75 mg per day is likely to suppress adrenal function. Some patients will persist with small, but to the patients troublesome, local reactions which do not improve for several months. In two of seven such patients we observed local allergy to SC Human Regular Insulin. 17 In about half of our cases of persistent local allergy of the immediate-type, desensitization seems to have been helpful. Since in some patients protamine is a significant antigen,65 the intermediate-acting insulin of choice for all patients with insulin allergy, both local and systemic, is Lente. SYSTEMIC REACTIONS AND DESENSITIZATION. Systemic allergic reactions to insulin range from generalized hives (with or without local allergy) to angioedema and anaphylaxis. Intermittent insulin therapy was present in over 60 per cent of the 129 patients in our series, and 30 per cent of patients were overweight by at least 20 per cent.73 A history of penicillin allergy was obtained in 37 per cent of the patients. While a diagnosis of resistance was established in only 15 per cent of our patients before we became involved in their management, either at the Lilly Clinic or through their local physicians, subsequent measurement of serum antibody titers disclosed that in over 40 per cent the degree of serum binding of beef insulin was in the range we ordinarily see in patients with immunologic insulin resistance. The treatment of systemic allergy to insulin is desensitization.';'" We have modified the methods of Corcoran 15 and of Marble47 and use Insulin Allergy Desensitization Kits for SPP, SPB, and SCP insulins, prepared by Eli Lilly and Company. To prevent binding of low concentrations of insulin to the walls of the glass vials, human serum al':'We recommend Decadron which stability studies have demonstrated to be compatible with insulin. "':'Occasionally we have encountered patients who were allergic to monospecies beef and pork SPI and tolerated SCPI without desensitization, suggesting that the allergy was to non-insulin materials in the SPPI. However, like Goldman et al.,'" we have also treated patients with systemic allergy to insulin who demonstrated marked reactivity to SCPI.

667

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bumin, 0.1 per cent, has been added to the diluent. The dilutions of these kits are listed in Table 2. Because of the high frequency of elevated antibody titers to beef insulin (IgG) associated with systemic allergy to insulin, suggesting that many patients would be resistant to beef insulin even if they were adequately desensitized to it, as recommended by Mattson et al.,." we ordinarily suggest desensitization to commercially available SPPI. However, if intradermal testing (1/1000 and 1/500 unit in 0.1 ml volume, Bottles A and B in the Lilly kits may be used) or the clinical history suggests a greater sensitivity to pork than to beef insulin, then desensitization to beef insulin is undertaken. SCPI is recommended for (1) patients who cannot be desensitized to monospecies pork or beef insulin; (2) patients who have been desensitized to and then develop local allergy to SPPI; and (3) patients who have strong histories of insulin allergy and/or marked reactivity to intradermal tests with monospecies pork and beef insulin. The desensitization procedure is initiated after the patient has been off all insulin for at least 12 and preferably 24 to 48 hours. When necessary, sodium bicarbonate, 1.0 gm 4 times daily, is used to delay the development of ketoacidosis. No drugs (e.g., antihistamines or steroids) which might mask an allergic reaction are given during the procedure. Epinephrine, 0.1 to 0.3 ml of a 1/1000 solution, is used if required. The first 10 desensitizing doses are given in 0.1 ml volumes every 30 minutes. The first three dilutions are ordinarily given intradermally and the subsequent ones subcutaneously. If a positive reaction occurs we drop back two dilutions. Occasionally it is necessary to increase the interval from 112 to 2 hours and interpolate additional doses between those provided in the Insulin Allergy Desensitization Kit. This can be done most conveniently by mixing in a U-100 (1 ml) syringe 0.1 ml of material from any of the prepared dilutions with 0.9 ml of saline and

The Dilutions of Regular Insulin Found in the Insulin Allergy Desensitization Kits Prepared by Eli Lilly and Company

Table 2.

BOTTLE LABEL LETTER

A B

C D

E F G

H J K

UNIT/0.1 ML

DILUTION (IN DECIMAL)

UNITS/ML

1/1000 1/500 1/250 1/100 1/50 1/25 1/10 1/5 1/2

0-0.01 0-0.02 0-0.04 0-0.10 0-0.20 0-0.40 0-1 0-2 0-5 0-10

1/100 1/50 1/25 1/10 1/5 2/5 1 2 5 10

':'Supplied on a complimentary basis on request of the physician.

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adjusting the dose given to the patient by changing the volume administered. About 90 per cent of patients with systemic insulin allergy can be desensitized to pork insulin', and in about 80 per cent of these SPPI gives satisfactory results. About 10 per cent of patients require desensitization to beef insulin. Patients with marked systemic allergy need to be maintained on two doses of Lente or Lente and Regular insulin in order to maintain the desensitized state. Because of the relative rarity of the need for SCBI, this material is not supplied in desensitization kit form. U sing the above procedures, we have noted only 6 treatment failures in 129 patients (5 per cent). Two of the patients who failed to be desensitized to SPI no longer require insulin, a third one needs it but fears the procedure, having had two episodes of anaphylaxis. A fourth patient intermittently demonstrates evidence of continued allergy to SCPI in spite of desensitization. The other two have juvenile-type diabetes and desensitization to SPPI in one and SPBI in the other apparently failed. The allergic manifestations in the last two patients have been reduced by antihistamines. We have not used steroids in the management of patients with chronic insulin allergy. However, the experience of Cockel and Mann ' l indicates that this is an effective adjunct for patients who need insulin and cannot be adequately or fully desensitized by methods outlined above. With the removal of phenformin from the United States market, we anticipate that a number of patients who have been previously sensitized to insulin will be returned to insulin treatment and many will develop local and/or systemic allergy. This possibility needs to be carefully considered by physicians and patients alike before reinstituting insulin therapy, especially where other measures such as weight reduction can be used.

Antibodies to Insulin Virtually all patients receiving insulin daily for over 4 to 6 weeks develop antibodies to insulin. 6 Since former insulin preparations contained a number of protein impurities,'U a study of the significance of these antibodies per se could not be undertaken. However, with the availability of the purified insulins'iJ. (;2, n. 7(; it has been possible to quantify the immunogenic properties of monospecies pork and beef insulins under a variety of conditions. Accordingly, studies in patients who have never received insulin and then are treated with former commercial, SP, and SC monospecies pork and beef insulins disclose the following observations:'; 1. The most immunogenic of insulins, regardless of purity, are those of beef source, single component beef insulin (SCBI) being as immunogenic as former commercial and SPBI. This finding is compatible with the differences in amino acid sequence between beef and human insulin, Mixed beef-pork SPI is no less immunogenic than former commercial mixed insulin6 or monospecies SPBI. 2, While SCPI is the least immunogenic of all insulins, antibodies to it do develop.6,7:; There is little difference in immunogenicity between SPI and former commercial pork insulin, a finding which sug!)

INSULIN TREATMENT

669

gests that even though the content of non-insulin materials is low in SPPI, they are sufficient to produce serum antibodies in patients. 3. Multiple doses of SCBRI (e.g., Neutral Regular Insulin) produce antibody titers about half as high as those which are found in patients who are treated with single component Beef Lente (SCBL). We ascribe this to the adjuvant effect of the Lente form. Preliminary results in 5 patients who have been treated only with a single component Pork Regular Insulin (SCPRI) in multiple doses indicate that this dose form produces lower antibody titers than those seen with single component Pork Lente (SCPL).'i() 4. While SCPI is less immunogenic than SPPI in patients who have never received insulin, neither our experience,44 nor that of Yue and Turtle,7n has demonstrated that SCI is superior to other porcine insulin preparations in management of immunologic insulin resistance. In evaluating insulin immunogenicity it is important to recognize that the immune response of patients to beef or to pork insulin is controlled by response genes whose function is poorly understood. Since loss of specificity in the immune response has been shown to occur with continued exposure to the antigen (insulin) resulting in the development of high affinity cross-reactive antibodies, it follows that diabetics with an allergic diathesis who are chronically exposed to insulin from one species may be expected eventually to demonstrate antibodies recognizing the other. Since the world-wide supply of pork insulin is quite limited and preparation of SCPI results in substantial wastage of units, it is essential to determine the specific indications for SCPI. Based on the foregoing, we recommend SCPI for those patients who develop insulin lipoatrophy on mixed beef-pork, who do not respond to monospecies pork SPI, for patients who have been desensitized to SCPI, or who have local allergy and tolerate this insulin better than monospecies SPB or SPPI. There are no data demonstrating the unique efficacy of single component pork insulin in immunologic insulin resistance, insulin hypertrophy, or labile brittle diabetes. Other indications for SCPI have been suggested but thus far have not been established. For instance, since interruption of insulin therapy augments the immune response, patients in whom insulin therapy is likely to be discontinuous, such as those with mild diabetes or women with gestational diabetes, might derive unique benefit from the use of SCPI. It has also been suggested that since insulin antibodies cross the placental barrier, SCPI should be used in all diabetic women of child-bearing age. (Acceptance of this as an indication for SCPI requires that the pathological significance of maternal insulin antibody in the fetus be better understood.) However, the demonstrated immunogenicity of SCPpH. :W. 70. 76 suggests that even this highly purified form may be too immunogenic to prevent antibody formation unless administered solely as multiple doses of Regular Insulin. SCPI has been proposed as a possible means of preventing the nodular lesion of diabetic glomerulosclerosis. Specifically, Wehner et al. 71 immunized rabbits with "a" and "b" component from commercial

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insulin and noted the formation of serum antibodies to insulin and material in the renal glomeruli which morphologically resembled nodular glomerulosclerosis. The lesions were demonstrated to contain insulin: insulin antibody complexes. Neither monocomponent insulin nor diluting fluid for insulin produced these lesions. Since patients who have never received insulin develop nodular glomerulosclerosis, and since control of the diabetes is apparently a critical factor in the development of the renal complications of diabetes in humans, we concur with Yue and Turtle 76 who state, "Although definitive conclusions cannot be reached for another 10 or 15 years, it appears unlikely at this stage that purified insulins will prevent diabetic complications." Finally, highly purified pork insulin has been used in patients with markedly unstable diabetes. Neither we nor Yue and Turtle in their review,16 as well as in their own practice,75 were able to demonstrate any advantage with the purified insulins in patients with unstable diabetes. Labile diabetes is a multifactorial disorder which may involve a total absence of endogenous insulin and glucagon,39 renal wastage of insulin,4ti and immunologic phenomenaY' 18 Therefore, it should not be expected that an insulin of reduced immunogenicity by itself will significantly ameliorate diabetes instability." Because of the absence of effective measures for the management of labile diabetics, it is likely that many patients with this problem will be treated with SCPI and the results will be disappointing.

THE CLINICAL USE OF INSULIN The proper use of insulin requires an awareness of the pharmaceutical composition and the clinical advantages and limitations of the various preparations. We 2 (;.51 and others have evaluated the bioavailability2H,:11 and pharmacokinetics:l4 of insulin in several situations in normal human beings, but space limitations do not permit a detailed discussion here. The basic information on the various insulin preparations is presented in Table 3. Although an occasional patient will derive unique benefit from PZI or from Semilente or Ultralente, we find that NPH or Lente alone or in combination with Regular constitutes the best treatment for the majority of our patients. Although many insulin-dependent patients can be adequately controlled with a single daily dose of NPH or Lente insulin, a vexing minority cannot be regulated by this means. Since the response of individual patients may be highly variable, it is important to consider factors which may influence the blood glucose response to exogenous insulin: "A recent report" indicates that increased levels of insulin antibodies are associated with unmeasurable quantities of fasting serum C-peptide in juvenile-type diabetics and suggests a deleterious effect of insulin antibodies on the preservation of endogenous insulin secretion. This possibility needs to be pursued in a large series of patients in which both basal and stimulated serum C-peptide are measured.

Turbid

Ultralente

Prolonged

Rapid Intermediate

Turbid Turbid

Semilente Lente

Rapid Intermediate

ACTION

Prolonged

Clear Turbid

APPEARANCE

Protamine Zinc Turbid

Regular Crystalline NPH

INSULIN

TYPE OF

Table 3.

18-24

2-4 6-12

14-24

2-4 6-12

(Hours)

ACTIVITY

PEAK

36+

12-16 24-28

36+

5-7 24-28

(Hours)

DURATION

0.14-0.25

0.14-0.25 0.14-0.25

0.15-0.25

0.01-0.04 0.01-0.04

(mg/lOO units)

ZINC CONTENT

None 7.2 Phosphate 7.2 Phosphate 7.2 Acetate Acetate 7.2 Acetate 7.2

BUFFER

pH

Insulin Preparations Used in the United States

None

None None

Protamine

None Protamine

Type

1-1.5

0.4

mg/100 units

PROTEIN

~

O'l

...

>-l

Z

a:t>l

> >-l

~

51

t"'

Z rn C1

-

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1. Antibodies and the time action of insulin. The time action of any of the insulins in Table 3 may be markedly distorted by serum antibodies to insulin. As a result, Regular Insulin, commonly thought to have an onset within 2 to 4 hours and a peak activity 6 to 8 hours, may in some patients not have an effect for 4 hours and the full impact of a dose not be observed for 8 to 10 hours. This phenomenon impugns the rationality of adjusting doses of Regular Insulin by the so-called "sliding scale," for additional insulin may be ordered because of a 4+ urine glucose 4 hours after a dose before the effect of that dose can be fully exerted. As a result, hypoglycemia may occur. Because of antibody binding of insulin, in some patients post-cibal hyperglycemia can be managed by giving Regular Insulin 1 to 11/2 hours before meals. 2. Because one or even two injections of insulin, either as Regular or Regular and Lente or NPH, cannot simulate in timing or amounts secreted the insulin response of normal subjects to food, it is absolutely essential that the food challenge to insulin be distributed to at least three meals and a snack, and in the case of adolescents requiring high caloric diet (e.g., 3000 calories containing 300 gm of carbohydrate) to6 feedings with 2/9 for each main meal and 1/9 between meals and at bedtime. 3. In unstable diabetes, although the mean daily blood glucose level may be reduced by the use of multiple doses of Regular Insulin, this procedure will not decrease the fluctuations in the blood glucose and will increase the frequency of hypoglycemic reactions. H4 4. The natural history of diabetes affects insulin requirements. In managing the insulin-dependent diabetic it is essential to recognize three periods of change in the insulin requirements. These are (1) the so-called honeymoon stage which occurs one to six months after the onset of insulin-dependent diabetes; (2) adolescence; and (3) diabetes complicated by end-stage renal disease. The so-called honeymoon stage occurs more commonly in overweight adolescent girls but occurs probably in all insulin-dependent diabetics to one degree or another. Jackson's data;)f; indicate that the duration of the honeymoon stage apparently is a function of the promptness with which the diagnosis of diabetes is made and the adequacy of early treatment. Because blood sugars may be normal or slightly higher than normal without treatment with insulin, the tendency of most physicians is to discontinue insulin during the honeymoon phase. However, if the patient has a history of allergy and is mildly hyperglycemic, treatment with insulin is probably indicated to decrease the blood sugar and prevent the development of allergy to insulin. During adolescence the insulin requirements may rise to as high as 200 units per day. This increased need tends to coincide with the growth spurt which may occur as early as 10 or 11 and last as long as 18 or 19 years of age. A 50 to 100 per cent increase in the insulin dose may be required for the patient to maintain normal growth and development. For reasons which are not entirely clear, as abnormal renal function develops in diabetics (creatinine in excess of 1.2 and BUN over 20

673

INSULIN TREATMENT

mg per 100 ml), clinical insulin requirements diminish, and even if the patient has had labile diabetes the blood glucose level usually is managed on one dose of insulin a day. While the mechanism of the fall in insulin requirements is not fully understood, reduction in renal clearance of insulin has been postulated as being a contributing factor. In the care of patients with long-standing diabetes and early renal failure, it is important to anticipate that the reduction of dose by 25 to 50 per cent may be required, otherwise hypo glycemia will occur.

Blood Glucose Response to NPH and Lente Insulin Hallas-Moller12 has identified three types of responses to intermediate-acting insulins. These are depicted in Figure l. The response of the patient who has fasting hyperglycemia, who is hyperglycemic during the morning and during the evening, is designated as an "A" or transient response. Frequently, these patients have periods of normoglycemia in the afternoon, developing their hypoglycemic reactions at this time of the day. In this type of patient, if the NPH or Lente dose is increased, severe afternoon hypo glycemia occurs. To overcome this the addition of a second dose of NPH or Lente Insulin is needed before supper. More often, however, not only is intermediate-acting insulin required before breakfast and supper, but a substantial portion of the insulin dose needs to be given as Regular insulin:

Regular NPH

Before Breakfast

Before Lunch

Before Supper

2 parts 1 part

o

1 part 1 part

o

There is a group of patients who demonstrate a transient CA) response to a single dose of intermediate-acting insulins but who are well

A

B Normal

Transient

C

Dela ed

400

Figure 1. Three types of blood glucose responses of insulin-dependent diabetics to intermediate-acting insulin.

"'"oo

iD

IOOf-+-+---I f----....

t

It-----iri

674

JOHN Brtsl.

Lu ch

Supper

A.

GALLOWAY AND RUBIN BRESSLER Snack

Brts!.

BLOOD

SUGAR

TREND

REGULAR

INSULIN NPH

OR LENTE

INSULIN HOUR 1 8

MEAl Brtsl.

12

lunch

6

Supper

10

Snack

8

Brts!.

Figure 2. Rationale for the use of two doses daily of regular (short-acting) and intermediate-acting insulin for the control of juvenile-type diabetes. The top lines depict the basal tendency to hyperglycemia, which is increased with meals. The diamonds and ellipses represent the duration of action of the insulin dose indicated, and the density of the vertical lines is intended to demonstrate the intensity of action (dose) of insulin usually needed.

controlled without the use of Regular insulin. Such patients are able to demonstrate excellent control on injections of intermediate-acting insulin before breakfast and before supper. This group may represent an early transition from the normal or "B" response (see below). A rare patient with transient response to intermediate-acting insulin may also be treated with mixtures of Lente and Ultralente insulin in one daily injection. In this regimen the prolonged action of UItralente insulin serves to afford sufficient retarded release of insulin to obviate the need for a second dose of Lente or NPH before supper. The patient who remains essentially normoglycemic throughout the 24 hour period on diet and a single dose of NPH or Lente is designated a "B" or normal response. Such patients require special attention only when late afternoon or early evening hypo glycemia occurs. Treatment usually consists of reducing the morning dose with or without the addition of a pre-supper dose .. The patient who is hyperglycemic during the day and normal to hypoglycemic at night is designated a "C" or delayed response. These patients have a delayed onset of action following the administration of NPH or Lente Insulin, a phenomenon which leads to a displacement to the right of the standard time activity curve of intermediate-acting insulin. The patient with the "C" response needs to have a portion of the NPH or Lente replaced by Regular Insulin before breakfast. Occasionally an additional dose of Regular Insulin before supper is necessary. Since the response of patients to NPH or Lente Insulin may change with time, it is important in the longitudinal management of patients to be alert to the possibility that the various patterns described may evolve one from another. Overall, in our view, the use of 1:1 or 2:1 combinations of NPH or Lente and Regular twice a day is a highly successful program for a majority of patients (Figure 2). The advantages of this type of program are (1) that it reduces basal hyperglycemia and hyperglycemia in relation to meals and (2) it makes it easier to anticipate physical activity and food-intake and progressively change insulin doses.

INSULIN TREATMENT

675

THE USE OF INSULIN IN PATIENTS DURING STRESS Diabetic Ketoacidosis Presently one of the most actively investigated fields in therapeutics is that of doses and routes of administration of insulin in diabetic ketoacidosis. This is discussed in detail elsewhere in this symposium, but a few comments are warranted here. With the traditional method, 200 to 400 units of insulin are required for the management of most patients. Recently a number of investigators have reported on the use of significantly smaller doses in the treatment of diabetic ketoacidosis. ':' Patients with hyperosmolar coma generally have been treated with approximately half the quantity of insulin used for traditional therapy of diabetic ketoacidosis. 58 Our view is that the importance of the type of insulin regimen used is secondary to careful surveillance and proper attention to changing the treatment, e.g., insulin dose, fluid and electrolytes, according to the needs of the individual patient. If low-dose treatment is to be used, then the programs of Fisher l (0.33 U per kg intravenous bolus followed by 7 units per hour intramuscularly or subcutaneously) or Piters55 (10 units per hour by continuous intravenous infusion) should be used. If, however, definite metabolic improvement is not seen in four hours then the use of larger (conventional) doses of insulin by the intravenous route must be considered. While the above programs are well understood by most physicians, the transfer of patients from Regular to intermediate-acting insulin following recovery is least well understood. One method is to place such patients on Regular Insulin every 6 hours for 2 to 4 days after ketoacidosis has resolved, using roughly one third 11/2 hours before breakfast; one sixth 1 hour before lunch; one third 11/2 hours before supper, and one sixth at midnight. This timing of the administration of Regular insulin attempts to match the action of the insulin to the hyperglycemia following food intake. To avoid the danger of nocturnal hypo glycemia with Regular Insulin the midnight dose is limited to 5 units or replaced entirely with a full one sixth of the daily dose of NPH or Lente insulin. The total daily insulin dose is calculated on a weight basis: 0.75 to 1.0 units per pound. The well-controlled patient requires 0.25 to 0.5 units per pound. It is important to recognize that a poorly controlled patient who is brought under good control frequently will experience a marked fall in insulin requirement after several days to several weeks. Insulin Management During Surgery The management of the insulin-dependent diabetic about to undergo elective surgery depends upon the complexity of his insulin *Schwartz,63 in 1964, commented, "Since the advent of insulin diabeticians have been engaged in a friendly contest to see who can give the most insulin to a resistant diabetic." Times have changed and the artistic philosophy of Mies van der Rohe that "less is more" is now influencing the therapy of diabetic ketoacidosis. As a result, the use of small doses of insulin in the treatment of diabetic hyperglycemia is increasingly common." 21. 27. 33. 55. 68

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program preoperatively and the fluid and electrolyte requirements of the procedure. Patients on a single dose of intermediate-acting insulin ordinarily can be maintained on this the day of surgery with carbohydrate in the diet being replaced by 5 to 10 per cent dextrose in water in appropriate volumes with solutions running from 7:00 A.M. to midnight the day of surgery.2:1.;;7 Patients on more than one daily dose of intermediate-acting insulin may be managed with a 6-hour pro gram ,22 in which the preoperative carbohydrate and insulin is divided by four and given every six hours. The carbohydrate is administered intravenously as 5 or 10 per cent dextrose in water and Regular insulin is given subcutaneously. In both methods, supplemental Regular insulin may be given if necessary. It is important to recognize that the duration of hyperglycemia is a function of stress of surgery, i.e., the more severe the operation or the length of anesthesia, the greater the number of days the patient's insulin requirements are to be increased. 24 • 57 Absorbance of Insulin to Intravenous Infusion Equipment Since the glass and plastic surfaces of intravenous infusion equipment bind insulin, the degree varying with the particular infusion equipment and types of solutions used,44 it is nearly impossible to add a given quantity of insulin to an infusion system and at the conclusion of the injection know what fraction of the insulin dose was actually received by the patient. Nonetheless, most workers agree that the walls of glass flasks or of the polyvinyl infusion bags and most infusion sets bind 20 to 30 per cent of insulin introduced into them.14, 54, n Most also agree that the binding of insulin can be largely prevented by the use of human serum albumin, 0.1 per cent. Although clinical data/' 52, 55 suggest that human serum albumin is not needed, the recommendation of Alberti I that a small volume of the patient's own blood be added to the infusate appears to be a convenient, practical, and effective way in which to prevent insulin binding to infusion equipment. ShumanG6 recommends the use of 5 ml of whole blood from the patient, a quantity which is adequate to prevent insulin binding and imparts to the container a pink color. Whether one uses no preventive measures, or human serum albumin, or the patient's whole blood, the chief concern is to monitor the patient's response carefully and adjust the insulin and fluids and electrolytes accordingly. Insulin Resistance Insulin resistance':' is classically defined as "hyporesponsiveness to or a tolerance of 200 units of insulin daily over a period of time in the absence of infection or coma.""7 However, the mechanisms operative in patients with these high doses are frequently encountered in patients taking as few as 50 to 100 units. The following practical points need to be considered in treating patients with increased insulin requirements: 1. The most common cause of increased insulin requirement is ':'For detailed information on insulin resistance the reader may consult an excellent review by Field.")

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obesity. In the massively obese patient exceedingly large doses of insulin are needed to decrease the blood glucose. In most instances the best way to reduce the blood glucose is to reduce the body weight. 2. When dietary intake of carbohydrate exceeds 300 gm per day it is very difficult to control the blood glucose with conventional doses of insulin. When chronic intake of carbohydrate exceeds 400 to 500 gm, it is virtually impossible to reduce blood sugar with exogenous insulin. 3. Immunologic insulin resistance is a condition characterized by high titers of insulin antibody, usually of the IgG class, to beef insulin ..:. Treatment consists of the use of an insulin with a structure more like human insulin. Davidson and DeBra Hi recommend the use of sulfated beef insulin, which in their hands is highly efficacious. This insulin, which is not available in the United States, may be indicated for that small minority of patients with immunologic insulin resistance to insulin Ca small group in itself) who do not respond to pork insulin and in whom steroids are contraindicated. Because the insulin antibodies bind exogenous insulin, imparting a repository effect, most patients with insulin resistance can be managed satisfactorily with two doses daily of pork Regular insulin. A few patients require steroids, in which case prednisone, 60 to 80 mg per day for 10 days, usually results in a dramatic reduction in insulin requirements. Two new types of insulin resistance have' r~cently been elucidated. One is associated with marked destructiop of insulin at the injection site"J and the other with impairment of the action of insulin on fat cell receptors." Fortunately, patients with increased destruction' of insulin at the injection site are exceedingly rare. The diagnosis and treatment of the former condition requires the use of intravenous insulin. Patients with receptor problems must be treated with high doses of Regular Insulin. Fortunately, in both types of insulin resistance the resistance tends to fluctuate so that patients can be controlled for varying intervals with conventional doses of insulin.

ACKNOWI,EDGME:-ns

The authors wish to express their appreciation to the following individuals for the submission of data and review of this manuscript: Ronald E. Chance, Ph.D., Jaime A. Davidson, M.D., Robert L. Nelson, M.D., Mary A. Root, Ph.D., and Samuel M. Wentworth, M.D.

REFERENCES 1. Alberti, K. G. M. M.: Low-dose insulin in the treatment of diabetic ketoacidosis, Arch.

Intern. Med., 137:1367,1977.

':'Some commercial laboratories report antibody titers to beef and to pork insulin, and in these reports the pork titer is frequently elevated, suggesting that the patient is resistant to pork insulin also. In our experience, since the elevated pork tit er probably represents in vitro cross reaction between the patient's antibody to beef insulin and to pork insulin, it does not necessarily predict that immunologic resistance to pork insulin is present clinically.

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2. Alberti, K. G. M. M., Hockaday, T. D. R., and Turner, R. C.: Small doses of intramuscular insulin in the treatment of diabetic "coma." Lancet, 1 :515-522,1973. 3. Albisser, A. M., Leibel, B. S., Ewart. T. G., et al.: An artificial endocrine pancreas. Diabetes, 23:389-396,1974. 4. Albisser, A. M., Leibel, B. S., Ewart, T. G., et al.: Clinical control of diabetes by the artifical pancreas, Diabetes, 23 :397-404, 1974. 5. Bar, R. S., and Roth, J.: Insulin receptor status in disease states of man. Arch. Intern. Med., 137:474, 1977. 6. Berson, S. A., Yalow, R. S., Bauman, A., et al.: Insulin I'Cl' Metabolism in human subjects: Demonstration of insulin binding globulin in circulation of insulin treated subjects. J. Clin. Invest., 35:170-1~O, 1956. 7. Bressler, R., Galloway, J. A.: Insulin treatment of diabetes mellitus. MED. CLIN. N. AMER., 55:861-876,1971. 8. Bucholtz, H. K.: Insulin allergy: An approach to therapy. Southern Med. J., 69: 11181120, 1976. 9. Cahill, G. F., Etzwiler, D. D., and Freinkel, N.: Blood glucose control in daibetes (organization section). Diabetes, 25 :237-239, 1976. 10. Chance, R. E., Root, M. A., and Galloway, J. A.: The immunogenicity of insulin preparations. Acta Endocrinol., 83: 185-196 (S-205), 1976. 11. Chick, W. L., Perna, J. J., Lauris, V., et al.: Artificial pancreas using living beta cells: Effects on glucose homeostasis in diabetic rats. Science, 197 :780-782, 1977. 12. Clements, R. S., Jr., and Reynertson, R.: Myoinositol metabolism in diabetes mellitus. Effect of insulin treatment. Diabetes, 26:215-221,1977. 13. Control of diabetes and insulin antibodies. Brit. Med. J., 1 :(Feb. 28):484, 1976. 14. Cockel, R., and Mann, S.: Insulin allergy treated by low-dosage hydrocortisone. Brit. Med., J., 3 :722, 1967. 15. Corcoran, A. C.: Note on rapid desensitization in a case of hypersensitiveness to insulin. Amer. J. Med. Sci., 196:359,1938. 16. Davidson, J. K., and DeBra, D. W.: Immunologic insulin resistance. Diabetes, accepted for publication. 17. Davidson, J. A., Galloway, J. A., Petersen, B. H., et al.: The use of purified insulins in insulin allergy. Presented at the 34th Annual Meeting of the American Diabetes Association, Atlanta, June 1974. 18. Dixon, K., Exon, P. D., and Malins, J. M.: Insulin antibodies and control of diabetes. Quart. J. Med., 44:543-553,1975. 19. Engerman, R., Bloodworth, J. M. B., Jr., and Nelson, S.: Relationship of microvascular disease in diabetes to metabolic control. Diabetes, 26: 760-769, 1977. 20. Field, J. B.: Chronic insulin resistance. Acta Diabet. Lat., 7:220-241,1970. 21. Fisher, J. N., Shahshahani, N., and Kitabchi, A. E.: Diabetic ketoacidosis: Low dose insulin therapy by various routes. New Engl. J. Med., 297:238-241,1977. 22. Galloway, J. A.: Diabetes mellitus. Indianapolis, Indiana, Eli Lilly and Co., S. O. Waife, ed., 7th ed., 1969. 23. Galloway, J. A., and Shuman, C. R: Diabetes and surgery. A Study of 667 Cases. Amer. J. Med., 34:177-191,1963. 24. Galloway, J A., and Shuman, C. R.: Profile, specific methods of management, and response of diabetic patients to anesthesia and surgery. Internat. Anesthesiol. Clin., 5:437-466, 1967. 25. Galloway, J. A., Root, M. A., Chance, R. E., et al.: New forms of insulin. Reprinted from Kryston, L. J., and Shaw, R. A., eds.: Endocrinology and Diabetes. New York, Grune and Stratton, 1975, pp. 329-342. 26. Galloway, J A., Root, M. A., Rathmacher, R. P., et al.: A comparison of acid regular and neutral regular insulin. Diabetes, 22:471-479,1973. 27. Genuth, S. M.: Constant intravenous insulin infusion in diabetic ketoacidosis. J.A.M.A., 223:1348-1351, 1973. 28. Ginsberg, S., Block, M. B., Mako, M. E., et a!.: Serum insulin levels following administration of exogenous insulin. J. Clin. Endocrinol. Metab., 36:1175-1179,1973. 29. Goldman, R. A., Lewis, A. E., and Rose, L. I.: Anaphylactoid reaction to single component pork insulin. J.A.M.A., 236:1148-1149,1976. 30. Gough, D. A., Aisenberg, S., Colton, C. K., et al.: The status of electrochemical sensors for in vivo glucose monitoring. Proceedings of a Workshop-Conference held in Freiburg (Germany), 1976, pp. 10-22. 31. Guerra, S. M. 0., and Kitabchi, A. E.: Comparison of the effectiveness of various routes of insulin injection: insulin levels and glucose response in normal subjects. J. Clin. Endocrinol. Metab., 42:869-874, 1976. 32. Hallas-Moller, K.: The Lente insulins. Diabetes, 5 :7,1956. 33. Hannan, T. J., and Stathers, G. M.: Constant low-dose insulin infusion in severe diabetes mellitus. Med. J. Austral., page 11-13 (January 3-10), 1976.

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