P7S Medical Review: Spring 1997, Vol.4, No.1
*On Diabetic Acidosis:A Detailed Study of Electrolyte Balances Following the Withdrawal and Reestablishment of Insulin Therapy

*This is an excerpt of the original article which appeared in The Journal of Clinical Investigation, vol. XII, pp. 297-326. Reproduced by copyright permission of The American Society for Clinical Investigation.

In 1923, Gamble, Ross and Tisdall (1) made an important advance in the field of metabolic research by developing a method for the comprehensive analysis of the excretion of body electrolytes and water. They applied this method to the study of the acidosis occurring in starving epileptic children and were able to demonstrate the fundamental significance of mass movements of inorganic base and tissue fluids in this condition. With the addition of the measurement of electrolyte intake, this procedure has since been utilized in a number of similar problems. More recently Gamble et al. (2), Folling (3), and others have made studies of the acidosis resulting from the ingestion of CaCl₂ and NH₄Cl. Under these circumstances, also, many alterations were noted, identical with those occurring in the acidosis of starvation.

The state of diabetic acidosis, which presents a more complex picture than do these other types of acidosis, has been described by many observers and a number of its physiological and chemical disturbances are well known. However, there has been no analysis which has successfully differentiated the phenomena due to a disturbance of carbohydrate metabolism from those due to ketogenic acidosis. When patients present themselves for treatment, the acidosis is usually so far advanced that there is little, if any, opportunity to follow the chain of events leading up to it. Furthermore, the need for therapy in these patients is so urgent that it is impossible to institute the procedures required for a complete balance study. Consequently, only fragmentary information has been gained about the response of the body to the appearance of acidosis or the process of recovery from it. For these reasons, we have studied in two cases of diabetes mellitus² the nature and order of changes in water and electrolyte balances resulting from the abrupt withdrawal of insulin and also the steps taking place in recovery, when insulin is again instituted.

This patient was a white boy of nineteen who developed diabetes at the age of twelve and who had been cared for in the wards and diabetic clinic of the Presbyterian Hospital since the onset of his disease. His diabetes was always severe, he had been through two serious attacks of acidosis, and required between 60 and 80 units of insulin daily in order to remain approximately sugar-free. In spite of this he was a well developed, active, normal youth. He was admitted to the Research Service on January 2, 1931 for this study. Nothing abnormal was found on physical examination. His blood pressure was 119/70. Routine blood counts were normal. His urine, except for the presence of glucose, was normal. His basal metabolic rate was ±0 per cent and his fasting respiratory quotient was 0.76.

The patient remained in bed except for four hours a day, when he was allowed to sit in a chair. He was given a diet containing 125 grams of carbohydrate, 75 grams of protein and 140 grams of fat, with a constant fluid intake. During the course of the experiment he ate identical meals each day. Every five days, when a fresh supply of food was procured, an analysis of a duplicate day's diet was made for water, total nitrogen, calcium, total inorganic base, potassium, phosphorus and chloride. Sodium and magnesium were determined together, by difference. Complete twenty-four hour urine specimens were analyzed daily for NH3, Ca, K, total inorganic base, Cl, P, inorganic SO4, total nitrogen, creatinine, ketones and sugar. The pH and titratable acid were also determined daily. All stools were saved, were collected in three-day, four-day or five-day specimens, and these were analyzed for Ca, K, total inorganic base, P, Cl and total N. The patient received 45 units of insulin before breakfast, 35 units before supper and 10 units at midnight and remained essentially sugar-free.

The period of insulin withdrawl. At the end of [a 10 day] foreperiod, insulin administration was terminated abruptly. Except for this change, the regime was carried on as before. On the first day the patient complained of slight dryness of the mouth. This symptom became progressively worse. After two days, he complained of weakness of his legs, slight nausea and he appeared apathetic. At the beginning of the fourth day without insulin, the symptoms were about the same but towards the end of this day he became obviously ill. Nausea was extreme; and the patient rapidly developed epigastric pain, headache, restlessness and prostration. By midnight of this day, after the patient had vomited three times, his clinical picture became too grave to warrant further delay in restorative therapy. Consequently, he was given an infusion of 1000 cc. of physiological NaCl solution and received 40 units of insulin, followed by 10 units every hour for the next 17 hours. During the period of increasing acidosis, the patient forced himself to eat all his meals. The vomitus on the fourth day was collected and analyzed and appropriate corrections were made in the tables. Corrections were also made for the infusion.

Recovery period. Within eighteen hours after insulin was again administered, the patient became symptom-free. The changes in the electrolyte balances were striking and in general were the reverse of those resulting from insulin withdrawal. At the end of five days, equilibrium in the body was nearly reestablished at the level of the control period.

This patient was a white man of 25, who developed diabetes mellitus at the age of 24. He had been in the hospital at 20 for the repair of a hernia and again at 21 for excision of a thyroglossal cyst. The onset of his diabetes was complicated by mild hyperthyroidism and a basal metabolic rate of +27. With rest and regulation of diabetes this promptly subsided and a few weeks later the basal metabolic rate was +8.

The period of insulin withdrawal. There was little symptomatic response in this patient to the withdrawal of insulin; he complained of thirst on the second day but this manifestation subsided and no subjective evidence of ketosis appeared. No vomiting occurred and no infusions were necessary; the patient consumed his diet without difficulty. Glycosuria appeared on the first day, and maintained a relatively constant level of 125 grams a day after the first day. This may be compared with an intake of 186 grams of carbohydrate ingested as such, and 54 grams available from the protein of the diet. Although no significant quantity of ketone bodies appeared in the urine for several days, organic acids increased definitely in the first twenty-four hours of this period.

This study of the quantitative changes resulting from the abrupt withdrawal of insulin in the patients suffering from diabetes of varying degrees of severity has yielded considerable data concerning some of the disturbances in electrolyte physiology occurring during the development of diabetic acidosis. In one of the patients presented above, W. O'C., the withdrawal of insulin was associated with the development of marked and persistent glycosuria and very mild ketosis, but without the development of acidosis. In the other patient, T.M., severe acidosis developed within four days. In many respects the analytical data show striking similarities in the reactions of these two patients, and it has consequently been possible to segregate those changes associated with the development of severe glycosuria alone from those due to the combined effects of glycosuria and ketogenic acidosis.

Responses of water and electrolytes to disturbances of carbohydrate metabolism. Polyuria has always been recognized as a concomitant phenomenon of marked glycosuria. It is apparent from work reported in this paper that sudden interference with carbohydrate metabolism not only causes a greatly increased water excretion, but also brings about an equally pronounced excretion of the electrolytes normally present in intra- and extracellular fluids. The abrupt return to normal carbohydrate metabolism, as a result of insulin therapy, is accompanied by the reverse effect, namely, marked retention of water and electrolytes, particularly Na, K and Cl. This movement of water and electrolytes is, in most respects, similar to that observed in fasting infants (1), in CaCl2 and NH4Cl acidosis (2) (3), in cardiac diuresis (12) and in spontaneous diuresis in nutritional edema (13). Furthermore, as was pointed out in the preceding section, the effect of these changes in electrolyte and water excretion on the electrolyte pattern of the blood serum is qualitatively similar to that observed in diuresis in cardiac and nutritional edema. Thus it is apparent that these changes comprise a general type of response not necessarily dependent upon disturbances of carbohydrate metabolism.

Alterations in water balance associated with the sudden breakdown of normal carbohydrate metabolism have been ascribed to a hypothetical relationship between water and glycogen storage. This point of view has been challenged recently by Bridge and Bridges (14) who have been unable to confirm the original observations upon which this hypothesis was founded. The changes in water and electrolyte balances described in our studies are of an order of magnitude far greater than could be explained on this basis. Even on the unjustified assumption of complete deglycogenation of the patients and on the further assumption that four grams of water are lost with each gram of glycogen, it would not be possible to account for more than half of the observed water loss. Furthermore, an analysis of the electrolyte excretion showed an output of sodium sufficiently great to make it certain that the amount of extracellular water lost from the body was no less striking than that of water lost from within the cells. Since glycogen storage is entirely an intracellular phenomenon, it may be inferred that all water released by glycogen breakdown should have the electrolyte structure of intracellular fluid.

These facts might, however, be harmonized in the following manner: Let it be supposed that with glycogen loss there occurs a considerable loss of intracellular fluid, and with the latter fluid, its proper content of potassium. It is well known that potassium salts exert a strong diuretic effect, both with respect to the extracellular and intracellular fluid. If, then, the endogenous potassium, released by glycogen breakdown, exerts a similar diuretic effect, this might account for the great excretion of water and electrolytes, both intra- and extracellular, which we have found to occur.

Responses of water and electrolytes to ketogenic acidosis. Odin (15) observed that the withdrawal of insulin from diabetic patients resulted in augmented excretion of inorganic base and that this was later followed by an increase in the rate of ammonia excretion. This author interpreted his results as indicating a mobilization of inorganic base dependent upon the formation of ketone acids. From the foregoing discussion and the analytical data presented in this paper, it becomes obvious that the initial loss of inorganic base in the acute diabetic state is not primarily dependent upon the development of ketosis but accompanies the sudden appearance of marked glycosuria. It may be recalled that in the patient, W. O'C., who developed an insignificant ketosis, the peak of base excretion and loss of body water appeared within the first forty-eight hours of insulin withdrawal and thereafter the rate of excretion fell to a lower level which was, however, higher than that of the foreperiod. In contrast to this chain of events, the patient T.M., who developed a severe and rapidly increasing ketosis, showed a secondary rise in the excretion of inorganic base surpassing the highest level reached with the initial disturbance of carbohydrate metabolism. It is thus apparent that the excretion of ketones in large amounts greatly augments the loss of sodium and potassium and water which accompanies the development of glycosuria, and that the loss of potassium was greater in relation to the loss of sodium in the patient who developed acidosis.

It is evident that such rapid loss of sodium and potassium, if continued, would soon bring about a depletion of base in the body sufficient to cause dehydration of the tissues, and also a decrease in blood volume with the state of shock as an end result. This point of view is confirmed by the well-defined concentration of the blood in the patient T.M. which occurred when the clinical and chemical manifestations of acidosis became acute.

Implications referable to electrolyte balance studies in general. In the course of this work several observations were made that were not directly relevant to the problem of diabetic acidosis. As has been pointed out in the discussion above, particularly as regards chloride metabolism, it is obvious that one must be guarded in drawing conclusions concerning the total metabolism of an ion from the changes that take place in its concentration in the blood serum. It is quite possible for the serum level to be higher following a period of actual negative balance. In making such balance studies we, as well as others, have found that practically all the essential changes occur in the urinary constituents. Stool analyses contributed nothing to the knowledge of mechanisms by which the human body adjusts to the type of stress occurring in our patients.

We have repeatedly called attention to the difficulty of interpreting electrolyte balance studies in the absence of data on skin excretion. To ignore skin loss is obviously absurd and the assumption of constant skin excretion has no sound support. Moreover, there is no reason for believing that the distribution of base in sweat is similar to that of the blood or urine. Swanson and Iob have shown that infants on a diet of cow's milk excrete through the skin more base than chlorine and much more K than Na. Water excretion through the skin changed tremendously (cf. above) under the conditions of our experiments and probably not in any consistent quantitative relationship to the mineral loss by the same route. Hence, detailed inferences as to cell or tissue space storage of electrolytes and water derived from comparisons of water and food intake with urine and stool are not satisfactory at present.

1. The effects of the withdrawal and reestablishment of insulin therapy in two diabetic subjects have been studied intensively by means of relatively complete electrolyte balances.

2. In the analysis of these experiments it has been possible to segregate the disturbances due to extensive alteration of carbohydrate metabolism alone, from those dependent upon ketogenic acidosis.

3. The effects of insulin withdrawal upon the two subjects, one of whom developed a ketogenic acidosis, and the other a glycosuria with minimal ketosis, may be summarized as follows:

(a) During the first forty-eight hours, accompanying the initial glycosuria, and before the development of acidosis, both patients showed essentially the same response, namely a loss of both intra- and extracellular body water, together with their constituent electrolytes.

(b) In the patient with simple glycosuria, during the days succeeding withdrawal of insulin, the water and electrolyte excretion continued at a level above that of the foreperiod, though less than during the first forty-eight hours. Glucose, water and electrolyte excretion proceeded at an approximately constant rate, at this new level.

(c) The other patient (T.M.) also began on his second day of insulin withdrawal to decrease his water and electrolyte output. Then, however, with the progressive development of ketogenic acidosis, there occurred a second rise in water and electrolyte excretion. This was qualitatively similar to that of the first two days. It continued progressively until terminated by restoration of insulin therapy.

(d) During recovery, following readministration of insulin, the responses of both patients were the same, there was retention of intracellular and extracellular water and their constituent electrolytes. Glycosuria and ketonuria subsided promptly.

(e) In both patients the level of ammonia excretion remained above that of the foreperiod for three to four days after the termination of ketosis.

(f) In both patients there appeared to be a decrease in water loss through the skin during the "acidosis" and recovery periods as compared with the foreperiod.

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