It is often useful for the physician to classify diabetes as stable or unstable. Maturity-onset diabetes is usually stable, and its management is not difficult, provided the patient is interested and cooperative. Tendency to obesity, relative insensitivity to insulin, and absence of ketosis are characteristic of such patients. Relative insensitivity to insulin does not imply unresponsiveness, but rather that the blood sugar is not overly labile and does not fall sharply in response to exercise or injected insulin. Many patients with such insensitivity to insulin are adequately managed on diet, alone or in combination with the oral hypoglycemic agents. When the latter fail, usually a single morning dose of long-acting insulin is satisfactory in controlling glycosuria and hyperglycemia during a 24-hour interval. Occasionally a small dose of crystalline insulin given in the same injection will be needed to control glycosuria between breakfast and lunch

Gardner, Clay T., Jr.

VCU Scholars Compass

Problems in the Insulin Dependent Diabetic CLAY T. GARDNER, JR. Departments of Medicine and Radiology, Medical College of Virginia, Richmond It is often useful for the phy-sician to classify diabetes as stable or unstable. Maturity-onset diabetes is usually stable, and its manage-ment is not difficult, provided the patient is interested and cooperative. Tendency to obesity, relative in-sensitivity to insulin, and absence of ketosis are characteristic of such patients. Relative insensitivity to in-sulin does not imply unresponsive-ness, but rather that the blood sugar is not overly labile and does not fall sharply in response to exercise or injected insulin. Many patients with such insensitivity to insulin are adequately managed on diet, alone or in combination with the oral hy-poglycemic agents. When the latter fail , usually a single morning dose of long-acting insulin is satisfactory in controlling glycosuria and hy-perglycemia during a 24-hour in-terval. Occasionally a small dose of crystalline insulin given in the same injection will be needed to control glycosuria between breakfast and lunch. UNSTABLE DIABETES Unstable or "brittle" diabetes usually is associated with the growth-onset type, although it may be present in many patients whose diabetes appeared after the age of 40. "Brittle" diabetics are insulin dependent and prone to ketosis. They are usually of average or be-low average weight and often are emotionally labile. Marked fluctua-tions in blood glucose following ex-ercise or ingestion of food , as well as during infections, may lead to periods of marked hyperglycemia or 28 hypoglycemia. These rapid and of-ten unpredictable shifts in blood glucose are disturbing to the pa-tient and his family and frustrating to the physician. In considering the causes of un-stable diabetes one must differen-tiate between primary instability and transient conditions which may influence diabetes unfavorably and cause temporary instability. Stable diabetes may be aggravated by a number of conditions such as infec-tion, thyrotoxicosis, and physical or emotional stress. If treatment is poorly planned or carried out, er-ratic behavior of the blood glucose may result from giving excessively large doses of insulin, or from giv-ing it at the wrong time of day. Re-bound hyperglycemia and occa-sionally ketosis may result from excessive insulin administration and may, in some instances, be re-sponsible for periods of instability in an otherwise stable diabetic (Somogyi, 1960). Primary instability characterizes the "very brittle patient." The basic cause is complete or nearly com-plete lack of endogenous insulin production. This condition usually manifests itself during the growth years ; after diabetes has been pres-ent five years or more, little or no insulin can be found in the blood. Examination of pancreatic tissue from a patient with this type of di-abetes reveals little or no insulin. This fact accounts for unrespon-siveness to the sulfonylurea com-pounds wl1ose major action de-pends upon the ability of the pancreas to1 produce and release in-sulin. The "brittle" diabetic is there-fore totally dependent on exogenous insulin. Normal homeostatic mech-anisms concerned with the release of pancreatic insulin in response to metabolic needs are no longer pres-ent. The physician then faces a dif-ficult task in attempting to supply insulin by injection, in an effort to prevent glycosuria and to maintain the blood glucose at a normal level throughout each 24-hour period. As Dr. Alexander Marble para-phrased this problem, "One strives to mimic nature, and, of course, succeeds only imperfectly." MANAGEMENT OF PRIMARY INSTABILITY In the management of the un-stable or "brittle" diabetic, those conditions which aggravate dia-betes should be sought and treated. One should carefully avoid over-dosage of insulin. This is extremely important since it is hypoglycemia, not diabetes itself, that most often incapacitates the diabetic in his job and in many other social situa-tions. Management is based on an attempt to secure uniformity of the controllable factors which influence blood glucose. These include diet, insulin, and physical activity. The diet should be reasonably constant from day to day in conjunction with a relatively fixed , daily insulin dose. Physical activity lowers the requirement for injected insulin, and strenuous or unusual exercise may precipitate hypoglycemic epi-sodes; in such circumstances addi-tional food may be taken. If un-usual physical activity is antici-MCV QUARTERLY 2(1): 28-31 , 1966 pated, an appropriate decrease may be made in the dose of insulin. The "brittle" diabetic invariably requires daily injections of insulin. There are various insulin programs, most of which include giving the major portion of the day's insulin in the form of a long-acting insulin, either NPH or Lente insulin, as an "anchor" dose before breakfast. If one has been careful to keep uni-form the patient's daily diet, ex-ercise, and insulin dose, this single morning dose may be all that is needed to maintain blood glucose within the normal range during a 24-hour period. Unfortunately, this is most often not the case in the unstable diabetic. Lack of uniform-ity, either in diet or exercise, while receiving a relatively fixed dose of daily insulin accounts for many of the wide swings in blood glucose following insulin injection. In either stable or unstable dia-betes, despite satisfactory control in the afternoon and evening fol-lowing a single morning dose of long-acting insulin, the fasting blood sugar may be high the fol-lowing morning. One may effec-tively control this by a split dose of long-acting insulin, employing a smaller increment, usually 5 to 10 units, at bedtime. If the tests at supper are poor, then giving this smaller increment before supper along with a small dose of regular insulin may bring about satisfac-tory control. If either the single morning dose or split dose brings about satisfactory control before breakfast and supper, yet fails to control hyperglycemia and gly-cosuria before lunch, then a small dose of crystalline insulin may be given along with the pre-breakfast injection of longer-acting insulin. Adjustments in insulin dosage are usually made in 3 to 5 unit increments, allowing two to three days between successive changes. Ordinarily, changes in insulin dose are not made frequently, and cer-tainly not on the basis of a single test, but rather according to the general trend of tests at a given C. T. GARDNER, JR. time of day. The patient should keep a record of urine tests so the degree of control at any given time of day can be easily ascertained. Phenformin (DBI) has been recommended as an additional sup-plement to insulin in "brittle" pa-tients in an attempt to lessen fluct-uations in the blood sugar. This was tried without much success in approximately 20 juvenile patients over a two-year period at the MCV diabetic clinic. The insulin dose was significantly decreased, yet these patients remained just as "brittle" while on phenformin (DBI). Causes of Primary Instability Although the basic cause of pri-mary instability seems to be nearly total lack of endogenous insulin production, the factors contributing to the "brittle" state are poorly un-derstood. The rebound phenome-non following excessive insulin dos-age (Somogyi, 1960) all too often is not corrected simply by reducing insulin dosage. In many instances this may result in an increasing fre-quency of periods of ketosis. The capricious response of such patients to insulin therapy might arise from alterations in the han-dling and disposal of insulin in the body. Prout and Katims (1959) advanced the hypothesis that some type of plasma binding of insulin with erratic release of free insulin might result in a variable clinical response to the same dose of in-sulin. Lennon and others ( 1960) have demonstrated in vivo that such plasma binding is reflected in prolonged plasma disappearance of }181-labeled insulin. Although al-tered degradation of insulin by im-paired renal or hepatic function may play an important role, the influence of previous insulin ther-apy appears to be a major factor in this altered handling of exog-enous insulin. This suggests that binding of insulin by insulin-neu-tralizing antibodies may be an im-portant cause. 29 PROBLEMS IN THE INSULIN DEPENDENT DIABETIC Differences in responsiveness of muscle and adipose tissue to free and complexed insulin may be im-portant. Plasma-bound insulin may be free to act on adipose tissue, while only free insulin acts on mus-cle. Perhaps the insulin !ability might result from the gradual satu-ration of plasma-binding sites with complexed insulin free to act only on adipose tissue. At a certain level of dosage, saturation of the bind-ing sites occurs, and free insulin is then available to act on the mass of muscle tissue, thus precipitating hypoglycemia. Bolinger ( 1964) demonstrated markedly delayed disappearance times of regular insulin in "brittle" diabetics. The characteristics of regular insulin in these subjects ap-proached that of long-acting insulin. He postulated that regulatory dif-ficulties should be exaggerated by the use of long-acting insulin, in that the slow release rate of insulin from injection sites approached the rate of degradation, thus permitting erratic , filling of the plasma-binding sites. He found that in general the longer the disappearance time of insulin, the greater the proportion of regular insulin required for good regulation. INSULIN RESISTANCE Another problem in insulin-requiring diabetics is the patient whose insulin dose increases stead-ily. Insulin resistance has been arbi-trarily defined as existing when the daily insulin requirement exceeds 200 units. However, some degree of resistance occurs in any individ-ual requiring over 30 to 40 units daily, since this amount provides adequate replacement therapy in depancreatized human subjects. Many factors can increase the re-quirement for insulin in human dia-betics and should be considered whenever insulin dosage has to be raised progressively. Insulin resist-ance resulting from any of these . known factors is usually secondary to such factors as obesity, keto~ 30 acidosis, infection, stress, puberty, pregnancy, and a number of endo-crine disturbances, notably thyro-toxicosis. "Primary" or chronic insulin re-sistance is distinguished by the ab-sence of any of the factors known to aggravate diabetes. In most cases it can be attributed to the develop-ment by the patient of y-globulin antibodies to exogenous insulin and primarily against the bovine insulin component in most commercial preparations which are usually mix-tures of 70% bovine and 30% pork insulin (Berson and Yalow, 1958; Berson et al., 1956; Field et al., 1961). In some cases of apparently pri-mary resistance, anti-insulin anti-bodies cannot be demonstrated, and high levels of active plasma insulin seem to be physiologically ineffec-tive (Field, 1960). Tissue unre-sponsiveness to insulin has been postulated to explain such cases. It is also theoretically possible that primary insulin resistance could re-sult from excessive amounts of binding substances found in associ-ation with serum albumin or the y- or fl-globulins. Primary insulin resistance may occur in either sex, at any age, and in either stable or unstable diabetes ( Smelo, 1948). Some authors think it occurs more commonly where in-sulin has been given intermittently (Calvin and Moloney, 1959). The onset is unpredictable and may ter-minate in a few weeks or persist for several years ( Smelo, 1948) . This fact makes evaluation of any therapeutic program difficult. Sus-ceptibility to keto-acidosis is about the same as before the onset. Con-trol of the diabetes is usually pos-sible if enough insulin is given, and prognosis is good for ultimate sub-sidence of the resistance (Smelo, 1948). TREATMENT OF INSULIN RESISTA~CE I The first important measure is to give large enough doses of ordinary commercial insulin. In most cases there is a level which will ulti-mately overcome the resistance, with subsequent improvement in insulin sensitivity ( Smelo, 1948). Success may depend on willingness to administer very large doses of insulin, and on the realization that subsequent increases in dosage must be made by geometric progression. With our knowledge of insulin-neutralizing antibodies, a rational treatment can be based on meas-ures which influence antibody syn-thesis. Adrenal cortical steroids have been used successfully (Field, 1962; Oakly et al., 1959), al-though the mechanism of their beneficial effect is uncertain. Their action may be mediated through an effect either on inhibition of ant\-body synthesis, or by influencing the rate of dissociation of the antigen-antibody complex. Less antigenic types of insulin other than commercial beef-pork insulin have been used successfully. Since the major antigenic property of this mixture can be attributed to beef insulin, whose molecular struc-ture differs considerably from hu-man insulin (Harris et al., 1956; Berson and Yalow, 1959), pure pork insulin has been used success-fully in a number of cases (Gold-man and Kaye, 1962; Feldman et al., 1963). The molecular simi-larity of pork and human insulin probably accounts for its weaker antigenic properties (Harris et al., 1956; Berson and Yalow, 1959) . The human insulin molecule con-sists of two long amino acid chains designated A and B chains joined by disulfide bridges (Harris et al., 1956) . Pork insulin differs only by the terminal amino acid on the long B chain. Other more antigenic insulins such as beef insulin differ by additional changes in the se-quence of the important amino acid triplet at the 8, 9, and 10 positions enclosed within the disulfide bridge on the shorter A chain. Although not generally useful, the sulfonylurea drugs have helped in a few selected cases of mild insu-lin resistance. These patients have usually been mild, maturity-onset diabetics whose insulin doses have had to be increased gradually over a period of one to two years. Vary-ing the insulin dose has usually made little or no difference in the ultimate control of their diabetes. Since antibodies against commercial insulin of animal origin do not sig-nificantly neutralize endogenous in-sulin, stimulation of pancreatic in-sulin by these agents may bring about secretion of enough non-antigenic endogenous insulin to control the diabetes. REFERENCES BERSON, S. A., AND R. S. YALOW. In-sulin antagonists, insulin anti-bodies and insulin resistance. Am. J. Med. 25: 155-159, 1958. BERSON, S. A., AND R. S. YALOW. Species-specificity of human anti-beef, pork insulin serum. J. Clin. Invest. 38: 2017-2025, 1959. BERSON, S. A., R. S. YALOW, A. BAU-MAN, M. A. ROTHSCHILD, AND K. NEWERLY. Insulin-1131 metabo-lism in human subjects : demon-stration of insulin binding globu-lin in the circulation of insulin treated subjects. J. Clin. Invest. 35: 170-190, 19 56. BOLINGER, R. E., J. H. MORRIS, F. G. McKNIGHT, AND D. A. DIEDERICH. Disappearance of P31-labeled in-sulin from plasma as a guide to management of diabetes. New Eng.J.Med.270: 767-770, 1964. CALVIN, E., AND P. J. MOLONEY. Re-sistance to insulin due to neutral-izing antibodies. J. Clin. En-docrinol. Metab. 19: 1055-1068, 1959. FELDMAN, R., G. M. GRODSKY, F. W. KOHOUT, AND N. B. MCWILLIAMS. Immunologic studies in a diabetic subject resistant to bovine in-sulin but sensitive to porcine in-sulin. Am. J. Med. 35: 411-417, 1963. FIELD, J. B. Effect of humoral and tissue factors on insulin action. Diabetes 9: 245-249, 1960. FIELD, J. B. Studies on steroid treat-ment of chronic insulin resist-ance. Diabetes 11: 165-170, 1962. C. T. GARDNER, JR. FIELD, J. B., P. JOHNSON, AND B. HER-RING. Insulin-resistant diabetes as-sociated with increased endoge-nous plasma insulin followed by complete remission. J. Clin. In-vest. 40: 1672-1683, 1961. GOLDMAN, A. S., AND R. KAYE. In-sulin resistance in a diabetic child: report of a case success-fully treated with pork insulin. Diabetes 11: 122-125, 1962. HARRIS, J. I., F. SANGER, AND M. A. NAUGHTON. Species differences in insulin. Arch. Biochem. Biophys. 65: 427-438, 1956. LENNON, E. J., N . H. ENGBRING, AND w. w. ENGSTROM. In vivo studies of insulin transporting antibody. Clin. Res. 8: 242, 1960. MARBLE, A. Insulin in the treatment of diabetes. J. Lancet 83: 340-346, 1963. 0AKLY, W., J. B. FIELD, G. E. Sow-TON, AND B. RIGBY. Action of prednisone in insulin-resistant diabetes. Brit. Med. J. 1: 1601-1606, 1959. PROUT, T. E., AND R. B. KATIMS. Effect of insulin-binding serum globulin on insulin requirement. Diabetes 8: 425-431, 1959. SMELO, L. S. Insulin resistance. Proc. Am. Diabet. Assoc. 8: 77, 1948. SOMOGYI, M. Exacerbation of diabetes by excess insulin action. Diabetes 9: 328-330, 1960. 31 

Problems in the Insulin Dependent Diabetic

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Problems in the Insulin Dependent Diabetic

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