Acute Hyperkalemia Induced by Hyperglycemia: Hormonal Mechanisms STANLEY GOLDFARB, M.D., MALCOLM COXf M.D.f IRWIN SINGER, M.D., F.A.C.P., and MARTIN GOLDBERG, M.D., F.A.C.P., Philadelphia, Pennsylvania
Two insulin-requiring diabetics with isolated hyporeninemic hypoaldosteronism spontaneously developed hyperkalemia that was aggravated whenever blood glucose concentration rose. Acute glucose infusions raised the serum potassium concentration in these patients with combined insulin and aldosterone deficiency but lowered, or did not change, the serum potassium concentration in normal subjects and in patients with either aldosterone or insulin deficiency alone. The paradoxical hyperkalemic response to glucose in patients with combined hormonal deficiency was blunted by prior administration of deoxycorticosterone acetate and abolished by prior administration of insulin. Our studies emphasize the crucial roles played by insulin and aldosterone in regulating the serum potassium concentration in man, and the need to avoid hyperglycemia in patients with combined insulin and aldosterone deficiency.
RECENT REPORTS in the literature suggest that the serum potassium concentration is controlled by an intricate hormonal system (1-7). Insulin and aldosterone seem to exert both acute and chronic influences on the serum potassium concentration through elaborate positive and negative feedback control systems. Secretion of each of these hormones may play an important role in defending against a rise in the extracellular fluid potassium level in the presence of hyperkalemic stimuli, such as a high potassium intake or potassium-sparing diuretic administration. We recently encountered two patients with combined deficiency of insulin and aldosterone who demonstrated important aspects of the hormonal control system concerned with the regulation of the serum potassium concentration. In addition to baseline hyperkalemia, presumably a function of hypoaldosteronism (8-10), these two persons also manifested acute increases in serum potassium levels in response to hyperglycemia, a seldom considered acute hyperkalemic stress (11). Each patient showed a strong, positive, direct correlation between the level of blood glucose and the serum potassium concentration, irrespective of whether hyperglycemia occurred spontaneously or as a result of intravenous glucose infusion. This unusual phenomenon seemed to occur only when combined insulin • From the Renal-Electrolyte Section, Departments of Medicine, Veterans Administration Hospital and the Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.
and aldosterone deficiency was present and was markedly altered when either hormone was replaced. One of the two persons (Patient 2) has been the subject of a recent, single case report ( 1 2 ) . In order to elucidate the mechanism of glucose-induced hyperkalemia and to evaluate various aspects of the aldosterone-insulin-potassium homeostatic system, we compared the physiologic responses of these two patients with combined aldosterone and insulin deficiency to two patients with aldosterone deficiency alone, one patient with insulin deficiency alone, and two normal persons. Patients and Methods
Group I included two persons with combined aldosterone and insulin deficiency. Both patients were ketosis-prone, insulinrequiring diabetics with hyporeninemic hypoaldosteronism; both had unexplained hyperkalemia in the absence of acidemia, excessive potassium intake, potassium-sparing diuretic therapy, or severe renal insufficiency (serum creatinine level, < 4.0 mg/dl). In each of these patients, a rise in blood glucose, either through lability of their diabetes mellitus or after intravenous glucose infusion, resulted in an acute rise in the serum potassium concentration. In Patient 2, the injudicious administration of intravenous glucose for suspected hypoglycemia raised the level of blood glucose to > 1500 mg/dl and serum potassium to > 8.5 meq/litre and resulted in ventricular tachycardia. Group II included two persons with isolated aldosterone deficiency. These two patients with hyporeninemic hypoaldosteronism also had unexplained hyperkalemia in the absence of known hyperkalemic stimuli. Both patients, however, had normal carbohydrate metabolism. Group III consisted of an insulin-requiring diabetic whose renin-angiotensin-aldosterone axis was found to be normal. Finally, group IV consisted of two normal volunteers (see Table 1 for patient characteristics). Persons in groups I-III were admitted to the Clinical Research Center of the Hospital of the University of Pennsylvania and were studied under metabolic balance conditions (12). All subjects except Patient 4 (group II) were studied on a 10 meq/day sodium and 60 meq/day potassium diet. (Because of marked hyperkalemia and a tendency toward acidosis in Patient 4, his diet was supplemented with sodium bicarbonate tablets to provide an additional 30 meq of sodium per day.) Twenty-four hour urinary aldosterone excretion was measured at the end of a 7-day low sodium diet. At the same time, plasma renin activity and aldosterone concentration, taken both supine and after 3 hours upright, were measured. Adrenal glucocorticoid function was determined by a standard corticotropin stimulation test (13). All patients received an acute intravenous infusion of 0.5 to 1 g/kg of glucose (dextrose 50 g/dl solution) for 5 minutes after an overnight fast. (Regular insulin was withheld from the diabetic patients during these infusions.) Serum glucose levels, serum potassium concentration, and venous C0 2 content
426
Downloaded From: https://annals.org/ by a Glasgow Univ Library User on 08/03/2018
Annals of Internal Medicine 84:426-432. 1976
Table 1 . Patient Characteristics
Group*
Patient
Age
Serum Creatinine
Highest Serum Potassium Level Observed
1
yrs 54
mg/dl 3.5
2
48
3 4
m IV
I
II
Baseline Serum pH
Other Major Diseases
meq/litre 7.2
7.37
1.4
6.2
7.42
82 51
1.9 2.1
6.9 6.0
7.41 7.41
Diabetic nephropathy and retinopathy ASCVDj, hypertension ASCVD Hypertension
5
52
1.9
5.2
7.49
ASCVD
6 7
31 31
1.1 1.0
4.1 4.2
*•.
• .•
Therapy
Insulin Digoxin, insulin NaHCOa, hydralazine, methyldopa Digoxin, quinidine
. ..
* Group I: combined aldosterone and insulin deficiency; II: isolated aldosterone deficiency; III: isolated insulin deficiency; IV: normal subjects, t ASCVD = atherosclerotic cardiovascular disease.
were monitored every 15 minutes for the first hour and then every 30 minutes for the second hour; plasma insulin levels were similarly measured in Patient 4 and the normal subjects. In order to evaluate the role of aldosterone or insulin deficiency, or both, in producing glucose-induced hyperkalemia, the following studies were done after either mineralocorticoid or insulin replacement. In both patients in group I, the glucose infusion protocol was repeated after 5 to 7 days of treatment with desoxycorticosterone acetate (DOCA) in oil, 10 mg intramuscularly twice a day. In one of the subjects with combined aldosterone and insulin deficiency (Patient 1), the glucose infusion was also done beginning 30 minutes after the administration of 20 U of crystalline insulin subcutaneously. In all subjects, except for Patient 3 (group II), a time control was done to evaluate the spontaneous variation in serum potassium under conditions similar to those of the glucose infusions but without glucose. In the two control patients (group IV), adequacy of the renin-angiotensin-aldosterone system was ascertained by determination of 24-hour urinary aldosterone excretion, supine plasma renin activity, and supine plasma aldosterone concentration after a 48-hour, 20 meq/day sodium diet following 40 mg of furosemide by mouth (14). Intravenous glucose infusion was then done as described above. Multiple simultaneous measurements of serum glucose, serum potassium, and venous COz content were done on each patient in the fasting state, as well as in the late afternoon and evening hours, during balance periods when neither DOCA nor diuretic therapy was being administered. Diabetic patients were given insulin in doses found to prevent severe hyperglycemia ( > 400 mg/dl). Other medications, including digoxin, ferrous sulfate, and pancreatic enzyme preparations, were administered to each patient as clinically indicated. Patient 4 (group II) had severe hypertension requiring methyldopa therapy, but no other patients received drugs known to suppress renin secretion. Balance studies and urinary and serum determinations of sodium, potassium, creatinine, and glucose concentrations and venous C0 2 content were done as previously reported (15). Plasma and urinary aldosterone were measured by radioimmunoassay (13, 16). Plasma insulin was measured by the Phadebas® insulin test (Pharmacia Fine Chemicals, Piscataway, New Jersey). Plasma renin activity was measured as angiotensin I generation (17). Results MEASUREMENTS OF PLASMA RENIN ACTIVITY AND ADRENAL CORTICAL FUNCTION
In all patients, adequacy of the low sodium intake as a
stimulus to aldosterone secretion was manifested by at least a 1.5 kg weight loss, except for Patient 4. In his case, a rise in blood urea nitrogen level from 35 to 59 mg/dl, with no change in serum creatinine, and a continued negative sodium balance during reduced sodium intake implied an adequate stimulus of extracellular fluid volume depletion. In the two normal persons (group IV), acute sodium depletion elevated mean supine plasma renin activity to 2.38 ± 0.21 ng/ml • 2 h, mean supine plasma aldosterone concentration to 30.4 ± 10.8 ng/dl, and mean 24-hour urinary aldosterone excretion to 68.5 ± 10.4 /xg. In contrast, for groups I and II, mean supine plasma renin activity was 0.86 ± 0.36 ng/ml • 2 h, the mean supine plasma aldosterone concentration was 5.3 ± 2.4 ng/dl, and the mean 24-hour urinary aldosterone excretion was 4.1 ± 2.0 /xg. The patient in group III had a supine plasma renin activity of 2.39 mg/ml • 2 h, a supine plasma aldosterone concentration of 32.5 ng/dl, and a 24-hour urinary aldosterone excretion of 60 /xg. In all persons in groups I-III, Cortisol reserve, as tested by synthetic corticotropin infusion (250 /xg), was normal (plasma Cortisol rose from a mean of 12.2 ± 0.6 to a mean of 24.3 ± 1.2 /xg/dl) (13). These studies demonstrate the syndrome of hyporeninemic hypoaldosteronism in groups I and II and normal juxtaglomerular and adrenal cortical function in groups III and IV (Table 2 ) . CORRELATION BETWEEN SPONTANEOUS VARIATIONS IN SERUM POTASSIUM AND SERUM GLUCOSE CONCENTRATIONS
The simultaneous measurement of serum glucose and serum potassium on many occasions during the balance periods produced a strong positive correlation in the two patients with combined aldosterone and insulin deficiency (group I), as shown for Patient 1 in Figure 1. The corresponding regression line for Patient 2 is serum K+ concentration = 4.85 + 0.002 X serum glucose concentration; r=0.64, P < 0.01. If this line is extrapolated to a serum glucose concentration of 1500 mg/dl, it would Goldfarb et a/. • Hyperkalemia and Hyperglycemia
Downloaded From: https://annals.org/ by a Glasgow Univ Library User on 08/03/2018
427
Table 2. Laboratory Values
Group
Patient
Plasma Renin
Plasma Cortisol Precorticotropin
Postcorticotropin
Supine
ng/ml -2h 1.15 1.48 0.19 0.28 1.73 1.80 0.36 1.01 2.39 4.75 2.58 . .. 2.17
iig/dl
I II III IV
1 2 3 4 5 6 7
13.4 11.2 13.0 12.6 10.6
22.4 22.0 27.0 25.8 26.6
correspond to a serum potassium of approximately 8.5 meq/litre; these values were observed in this patient who had combined aldosterone and insulin deficiency and who developed a hyperkalemic ventricular arrhythmia. There was no significant correlation between serum potassium and venous COz content (P > 0.5); acid-base status was stable in these patients. These measurements confirmed our initial clinical impression of a glucose-potassium relation and suggested a unique glucose-related hyperkalemic abnormality in these persons. However, our diabetic patient with normal mineralocorticoid function (group III) had no significant relation between serum glucose and serum potassium despite intermittent hyperglycemia (P > 0.2). This observation suggested that insulin deficiency alone was not responsible for glucose-induced hyperkalemia. Because our patients with hypoaldosteronism alone (group II) did not have spontaneous hyperglycemia, these observations could not provide pertinent data on the role of aldosterone deficiency per se in producing glucoseinduced hyperkalemia. To study that possible role, acute elevation of serum glucose by hypertonic glucose infusion was necessary.
Upright
Plasma Aldosterone Supine
Upright
24-Hour Urinary Aldosterone
ng/dl 4.1
11.8
. ..
. ..
1.9 10.0 32.5 19.6 41.1
11.2 11.6 95.4
ug/day 1.1 5.1 1.6 8.4 60.0 58.1 78.9
EFFECT OF INTRAVENOUS GLUCOSE INFUSION ON SERUM POTASSIUM CONCENTRATION
To test the hypothesis that combined aldosterone and insulin deficiency was responsible for the observed relation between serum glucose and potassium, all patients underwent glucose infusion. In Figure 2, the effect of glucose infusion on serum potassium concentration is shown for each person in each of the four groups. The points to the left in each panel indicate the preinfusion serum potassium concentration, while the points to the right show the serum potassium concentration 1 hour after infusion. The mean serum glucose level during intravenous glucose infusion was higher in the diabetic than in the nondiabetic patients with hypoaldosteronism (group I = 424 ± 45 mg/dl; group II = 260 ± 25 mg/dl). However, there was no significant difference in the mean level of blood glucose reached in the diabetic patients with or without hypoaldosteronism (group I = 424 ± 45 mg/dl; group III = 487 ± 14 mg/dl). Thus, the absolute level of hyperglycemia was not in itself a determinant of the rise in serum potassium concentration produced in the patients with combined insulin and aldosterone deficiency. Venous C0 2 content was also monitored in each patient,
Figure 1 . Correlation between serum potassium and blood glucose concentrations in a subject (Patient 1) with combined aldosterone and insulin deficiency. 428
April 1976 • Annals of Internal Medicine • Volume 84 • Number 4
Downloaded From: https://annals.org/ by a Glasgow Univ Library User on 08/03/2018
and no change in C0 2 content of more than 1 mmol/litre was found in any patient, except for Patient 3 in group II. In this person, venous C0 2 content fell from 25 to 21 mmol/litre, but serum potassium concentration also fell during the infusion. In the normal subjects (group IV), as seen in the upper left panel of Figure 2, acute hyperglycemia led to a significant fall in serum potassium. Recent reports in the literature would suggest that such a fall is the result of glucose-induced secretion of insulin, a major hormonal stimulus to acute cellular potassium uptake (1-5). Insulin levels rose in these two persons, in response to hypertonic glucose infusion, from 11.0 to 66.0 fiU/ml and from 14.0 to 105.0 //.U/ml, respectively. The effects of intravenous glucose infusion on serum potassium concentration in patients with isolated hypoaldosteronism (group II) are shown in the upper right panel of Figure 2. The fall in serum potassium level in these persons was quite similar to that in the normal subjects, as was the degree of insulin secretion. In Patient 4, plasma insulin level rose from 3.4 to 45.0 /xU/ml in response to hypertonic glucose infusion. Thus, hypoaldosteronism alone will not result in glucose-induced hyperkalemia; in these patients, the hyperinsulinemia produced by glucose infusion caused an acute fall in the serum potassium concentration. As seen in the lower left panel of Figure 2, insulin deficiency alone will not produce this paradoxical phenomenon either. In the diabetic patient (group III), acute hyperglycemia resulted in no change in serum potassium level compared with time control studies. As seen in the lower right panel of Figure 2, the infusion of hypertonic glucose in the two patients with combined aldosterone and insulin deficiency (group I) produced a marked rise in serum potassium concentration (from 5.0 to 5.7 meq/litre in one patient and from 5.5 to 6.3 meq/litre in the other). These elevations were significantly greater than the minimal variation that occurred in the time control determinations (P < 0.05). Thus, glucose-induced hyperkalemia is the result of combined aldosterone and insulin deficiency.
Figure 2. Serum potassium concentration before and after glucose infusion. The points to the left in each panel indicate the preinfusion serum potassium concentration, and the points to the right indicate the serum potassium concentration 1 hour after glucose infusion.
tion of the insulin component of the combined deficiency state allowed serum potassium concentration to fall from 5.7 meq/litre to 5.1 meq/litre during the glucose infusion. Thus, while mineralocorticoid administration has a protective effect against glucose-induced hyperkalemia in the combined deficiency state, insulin alone will produce prompt reversion to a normal response. Discussion
EFFECT OF DOCA ON SERUM POTASSIUM RESPONSE TO GLUCOSE INFUSION
In both patients in group I, the administration of DOCA for 5 to 7 days markedly altered the acute response to glucose infusion (Figure 3, left and middle panels). In each patient, hyperglycemia of a similar degree to that previously produced resulted in no significant change in serum potassium concentration. These patients then most closely followed the pattern seen in Patient 5, with insulin deficiency alone. Mineralocorticoid deficiency thus seems to play a key role in the production of glucose-induced hyperkalemia when insulin deficiency is also present. EFFECT OF INSULIN ON SERUM POTASSIUM RESPONSE TO GLUCOSE INFUSION
In Patient 1 (group I), glucose infusion was done 30 minutes after the administration of 20 units of crystalline insulin subcutaneously (Figure 3, right panel). The correc-
The mechanisms of the control of the serum potassium concentration during hyperkalemic stress have recently been investigated extensively. Acute hyperkalemia produced by intravenous potassium infusion has been shown to result in a marked hyperinsulinemia, which in turn directly stimulates cellular potassium uptake (1-5, 18, 19). Thus, insulin has been viewed as the hormone responsible for preventing life-threatening hyperkalemia during acute increases in extracellular potassium concentration. Aldosterone has been classically viewed as the hormone important in regulating total body potassium content and has been thought to exert its effect by modulating renal potassium excretion (6, 7). Recently, several authors have presented evidence that aldosterone may also play an important extrarenal role in regulating serum potassium concentration and may function to condition experimental animals to tolerate acute, exogenous potassium loads (2022). Goldfarb et a/. • Hyperkalemia and HvDerglycemia
Downloaded From: https://annals.org/ by a Glasgow Univ Library User on 08/03/2018
429
Figure 3. Effects of desoxycorticosterone acetate (DOCA) (left and middle panels) and insulin (right panel) on serum potassium response to glucose infusion (plotted similarly to Figure 2).
While the clinical syndromes of hypoaldosteronism (either isolated or as a part of generalized adrenocortical insufficiency) and hypoinsulinism are well recognized, the consequences of the combined deficiency of aldosterone and insulin on potassium homeostasis have not been systematically examined. We recently proposed that glucose-induced hyperkalemia might be a manifestation of combined aldosterone and insulin deficiency. In our study, we have presented data that clearly support the concept that hyperglycemia may lead to hyperkalemia and have shown the interrelation between aldosterone and insulin deficiences in producing this clinical disorder. The concept of potassium as an insulin secretogogue and insulin as a hypokalemic hormone derives from the observations of Farber and colleagues (23), as well as more recent studies of others (1-5). These workers have presented evidence that the pancreatic islet cells release both insulin and glucagon in response to potassium infusions. Insulin directly stimulates net cellular potassium uptake into muscle and liver irrespective of the level of plasma glucose (24-26), while glucagon prevents the hypoglycemia that would otherwise result from the hyperinsulinemia (1). The evidence that insulin deficiency may lead to hyperkalemia is much less direct and exists in a number of clinical observations. First, diabetic patients are prone to hyperkalemia during the use of triamterene and amiloride, two agents known to impair renal potassium excretion and possibly transcellular potassium flux as well (27, 28). Secondly, there seems to be an increased occurrence of the syndrome of hyperkalemia hyperchloremic acidosis in diabetic patients with mild renal insufficiency (29). Finally, many patients who reportedly had hyperkalemia in conjunction with isolated hyporeninemic hypoaldosteronism have been diabetics (8-10, 30). Each of these observations suggests that when renal potassium excretion is impaired, the insulin system may assume increased significance as a modulator of serum potassium concentration. In our diabetic patients with hypoaldosteronism, the occurrence of abnormal adrenal mineralocorticoid function combined with deficiency of insulin resulted in an impaired 430
response to a hyperkalemic stress and an inability to maintain potassium homeostasis. Although perhaps not generally appreciated, there is some evidence that acute hyperglycemia may be an important hyperkalemic stress. Seldin and Tarail (11) observed an apparent redistribution of potassium from the intracellular to the extracellular space after hypertonic glucose infusions in man. They attributed this phenomenon to transcellular movements of potassium, in concert with movements of intracellular water, in response to the hypertonicity of the extracellular fluid. Makoff and associates (31) expanded on these findings and produced hyperkalemia in animals during hypertonic mannitol infusions. Recent evidence from studies of isolated rat muscle by Adler, Anderson, and Zelt (32) further suggest that extracellular hypertonicity leads to a fall in intracellular potassium content. Other mechanisms may be responsible for glucose-induced hyperkalemia besides osmotically induced transcellular potassium shifts. Since glycogen is rich in potassium, glycogenolytic hormones could simultaneously release large amounts of potassium and elevate the plasma glucose concentration. Although there is no direct evidence to support such a hypothesis, glucagon does enhance potassium efflux from the isolated, perfused rat liver and may have a similar effect in these patients (33-35). The possibility that the mechanism of hyperkalemia during spontaneous hyperglycemia is identical to that during infusion hyperglycemia cannot be excluded. Thus, hypertonic glucose infusion in a person without the modulating influence of aldosterone (to condition the subject to tolerate hyperkalemia) and without insulin (to stimulate rapid cellular uptake of potassium) could lead to clinically significant hyperkalemia. The studies in patients with hyporeninemic hypoaldosteronism alone (group II) show that mineralocorticoid deficiency by itself will not result in glucose-induced hyperkalemia. In Patient 4, a normal insulin response to hyperglycemia was documented and was the probable mechanism of the observed fall in serum potassium concentration. Furthermore, the deficiency of insulin alone, as observed in Patient 5 (group III), will not result in glucose-induced hyperkalemia. In this patient, normal mineralocorticoid function was protective against
April 1976 • Annals of Internal Medicine • Volume 84 • Number 4
Downloaded From: https://annals.org/ by a Glasgow Univ Library User on 08/03/2018
the hyperkalemic stress. These findings confirm those of Farber and colleagues (23), who studied the effects of hyperglycemia in insulin-requiring diabetics; as in our patient, hyperglycemia did not alter serum potassium concentration in these persons. The results of the experiments in which hormonal deficits were corrected further support the hypothesis that combined insulin and aldosterone deficiency causes glucoseinduced hyperkalemia. In our two patients with combined hormonal deficiency (group I), the chronic administration of DOCA produced a response to hypertonic glucose that was identical to that seen in the patient with insulin deficiency alone. In these persons, there is neither a rise nor a significant fall in serum potassium level after hypertonic glucose infusion. Thus, mineralocorticoid action apparently prevents glucose-induced hyperkalemia in insulin-deficient persons. The precise nature of this protective effect cannot be ascertained from these studies. However, Patient 1 remained in positive potassium balance during mineralocorticoid therapy, while Patient 2 was in a cumulative negative potassium balance of only 20 meq when the protective effect of DOCA was demonstrated. These data suggest that the mode of action of mineralocorticoids is primarily extrarenal in producing this effect (20-22). Finally, the acute administration of crystalline insulin before hypertonic glucose infusion in Patient 1 produced a "normal" hypokalemic response. This finding supports the contention that insulin secretion is primarily responsible for the hypokalemic effect of intravenous glucose infusions. Our studies provide evidence that the combination of hypoaldosteronism and hypoinsulinism leads to a unique, identifiable abnormality in potassium metabolism, namely, glucose-induced hyperkalemia. In view of the near catastrophic response to an infusion of hypertonic glucose in our initial patient, this phenomenon is of clinical importance. Further, these studies suggest the possibility of a singular susceptibility to acute hyperkalemia in diabetic persons whenever renal or extrarenal potassium handling is impaired, such as with the use of potassium-sparing diuretics (27, 28), with the use of succinylcholine (36), during acute muscle breakdown (37), or during the injudicious administration of hypertonic glucose solutions. ACKNOWLEDGMENTS: The authors thank Miss Cordelia Shute and the nursing staff of the Clinical Research Center of the Hospital of the University of Pennsylvania; Dr. Karl Engleman for advice and for measurement of plasma renin activity; Dr. John Hansell for determination of plasma insulin; Dr. Gordon Williams for assays of plasma and urinary aldosterone; Mr. A. B. Kelley for technical assistance; Mr. Craig Schneider for preparing the figures; and Ms. Adair Ruff for secretarial assistance. Grant support: By U.S. Public Health Service Training Grant #AM 05634-05; Veterans Administration Renal Training Program #204; U.S. Public Health Service Research Grants AMHL 17344-04 and HL 00340-25; U.S. Public Health Service CRC Grant #RR 00040; and the Philadelphia Veterans Administration Hospital (103.14M). A preliminary report of this paper was presented before the Annual Meeting of the American College of Physicians, San Francisco, California, April 1975. Received 16 September 1975; revision accepted 13 January 1976. • Requests for reprints should be addressed to Stanley Goldfarb, M.D., Hospital of the University of Pennsylvania, 860 Gates Pavilion, Philadelphia, PA 19104.
References 1. SANTUSANIO F, FALOONA GF, KNOCHEL JP, et al: Evidence for
a role of endogenous insulin and glucagon in the regulation of potassium homeostasis. J Lab Clin Med 81:809-817, 1973 2. HIATT N, DAVIDSON MB, BONO VIES G, et al: Role of insulin in
the transfer of infused potassium to tissue. Horm Metab Res 5:84-88, 1973 3. HIATT N, YAMAKAWA T, DAVIDSON MB: Necessity for insulin in
transfer of excess infused K to intracellular fluid. Metabolism 23:43-49, 1974 4. PETTIT GW, VICK RL: Contribution of pancreatic insulin to extrarenal potassium homeostasis: a 2-compartment model. Am J Physiol 226:319-324, 1974 5. PETTIT GW, VICK RL, SWANDER AM: Plasma K+ and insulin:
changes during KC1 infusion in normal and nephrectomized dogs. Am J Physiol 228:107-109, 1975 6. KNOCHEL JP, WHITE MG: The role of aldosterone in renal physiology. Arch Intern Med 131:876-884, 1973 7. CANNON PJ, AMES RP, LARAGH JH: Relation between potassium
balance and aldosterone secretion in normal subjects and in patients with hypertensive or renal tubular disease. / Clin Invest 45:865-879, 1966 8. SCHAMBELAN M, STOCKIGT JR, BIGLIERI EG:
Isolated hypo-
aldosteronism in adults—a renin-deficiency syndrome. N Engl J Med 287:573-578, 1972 9. PEREZ G, SIEGEL L, SCHREINER GE: Selective hypoaldosteronism
with hyperkalemia. Ann Intern Med 76:757-763, 1972 10. WEIDMANN P, REINHART R, MAXWELL MH, et al: Syndrome of
hyporeninemic hypoaldosteronism and hyperkalemia in renal disease. / Clin Endocrinol Metab 36:965-977, 1973 11. SELDIN DW, TARAIL R: Effect of hypertonic solutions on metabolism and excretion of electrolytes. / Clin Invest 159:160-74, 1949 12. GOLDFARB S, STRUNK B, SINGER I, et al: Paradoxical glucose
induced hyperkalemia: combined aldosterone and insulin deficiencies. Am J Med 59:744-750, 1975 13. DLUHY RG, HIMATHONGKAM T, GREENFIELD M: Rapid ACTH
test with plasma aldosterone levels. Improved diagnostic discrimination. Ann Intern Med 80:693-696, 1974 14. WALLACH L, NYARAI I, DAWSON KG:
Stimulated
renin: a
screening test for hypertension. Ann Intern Med 82:27-34, 1975 15. RASTEGAR A, AGUS ZS, CONNOR TB, et al: Renal handling of
calcium and phosphorus during mineralocorticoid escape in man. Kidney lnt 2:279-286, 1972 16. LANGAN J, JACKSON R, ADLEN EV, et al: A simple radioim-
munoassay for urinary aldosterone. / Clin Endocrinol Metab 38:189-193, 1974 17. GIESE J, JORGENSON M, NIELSON MD, et al: Plasma renin
concentration measured by use of radioimmunoassay for angiotensin I. Scand J Clin Lab Invest 26:355-367, 1970 18. KUZUYA T, KAJINUMA H, IDE T: Effect of intrapancreatic in-
jection of potassium and calcium on insulin and glucagon secretion in dogs. Diabetes 23:55-60,1974 19. HENQUIN JC, LAMBERT AE: Cationic environment and dynamics of insulin secretion. II. Effect of a high concentration of potassium. Diabetes 23:933-942, 1974 20. ALEXANDER EA, LEVINSKY NG: An extrarenal mechanism of
potassium adaptation. J Clin Invest 47:740-748, 1968 21. ADLER S: An extrarenal action of aldosterone on mammalian skeletal muscle. Am J Physiol 218: 616-621, 1970 22. DAWBORN JK WATSON L: Effect of prolonged administration of aldosterone on potassium and magnesium metabolism in the rabbit. Med J Aust 2:304-307, 1968 23. FARBER SJ, PELLEGRINO ED, CONAN NJ, et al: Observations on
the plasma potassium level of man. Am J Med Sci 221:678687, 1951 24. ZIERLER KL: Effect of insulin on potassium efflux from rat muscle in the presence and absence of glucose. Am J Physiol 198:1066-1070, 1960 25. BURTON SD, ISHIDA T: Effect of insulin on potassium and glucose movement in perfused rat liver. Am J Physiol 209:11451161, 1965 26. KESTENS PJ, HAXHE JJ, LAMBOTTE L, et al: The effect of in-
sulin on the uptake of potassium and phosphate by the isolated perfused canine liver. Metabolism 12:941-950, 1963 27. MCNAY JL, ORAN E: Possible predisposition of diabetic patients to hyperkalemia following administration of the potassiumretaining diuretic, Amiloride (MK870). Metabolism 19:58-70, 1970 28. WALKER BR, CAPUZZI DM, ALEXANDER F, et al: Hyperkalemia
after triamterene in diabetic patients. Clin Pharmacol Ther 13: 643-651, 1972 Goldfarb et a/. • Hyperkalemia and Hyperglycemia
Downloaded From: https://annals.org/ by a Glasgow Univ Library User on 08/03/2018
431
29. CARROL HJ,
FARBER SJ:
Hyperkalemia
and
Res 17:539-564, 1961
hyperchloremic
acidosis in chronic pyelonephritis. Metabolism 13:808-817, 1964
34. GLINSMAN WH, MORTIMORE GE: Influence of glucagon and
3', 5'-AMP on insulin responsiveness of the perfused rat liver. Am J Physiol 215:553-559, 1968
30. WEIDMANN P, MAXWELL MH, ROWE P, et al: Role of the renin-
angiotensin-aldosterone system in the regulation of plasma potassium in chronic renal disease. Nephron 15:35-49, 1975 31. MAKOFF DL, D A SILVA J A, ROSENBAUM BJ, et al: Hypertonic
expansion: acid-base and electrolyte changes. Am J Physiol 218:1201-1207, 1970 32. ADLER S, ANDERSON B, ZELT B: Effect of osmolarity of intra-
cellular pH of rat diaphragm muscle. Am J Physiol 228:725729, 1975 33. MILLER LL: Some direct actions of insulin, glucagon and hydrocortisone on the isolated perfused rat liver. Recent Prog Horm
35. BURTON SD, MONDON CE, ISHIDA T: Dissociation of potassium
and glucose efflux in isolated perfused rat liver. Am J Physiol 212:261-266, 1967 36. COOPERMAN L: Succinylcholine-induced hyperkalemia in neuromuscular disease. JAMA 213:1867-1871, 1970 37. GROSSMAN RA, HAMILTON RW, MORSE BM, et al: Nontrau-
matic rhabdomyolysis and acute renal failure. N Engl J Med 291:807-811, 1974
Historic Documents in American Medicine
The Battle Against Illness Occurring without our anticipation or consent, [disease] produces an unexpected suspension of all the pursuits of business; exhausts the proceeds of those which had been made efficient; precludes the consummation of others; and restrains us from engaging in new ones, till the "golden moments of opportunity" have perhapsfleetedaway for ever. On our social plans and pleasures it exerts an influence equally unpropitious. A sick man is no longer a sociable, but a selfish being. He sinks to the state of a dependent on the community, and asks nothing from it, but sympathy and assistance;—and these afford him no other enjoyment than what arises from the removal of pain, or the dissipation of irksomeness. Their effects are negative, rather than positive. He wants the power to be an actor in the busy and bustling operations of society; and cannot even be a spectator of scenes in which he once performed a conspicuous part, and from which, in health, he unceasingly derived entertainment and happiness. Finally, disease is a foe which invades us in as many forms as Proteus could assume. It is the great enemy of all enterprise and improvement: the sedative which paralyzes every faculty and passion: the poison which deranges every mental operation: the opposing power of patriotism, philanthropy and ambition—relaxing the arm of industry, subverting the schemes of benevolence, and extinguishing the lights of genius, to lead him captive through the mazes of error and dullness. It may be likened to the dark cloud which intercepts the sun beams till the germinating corn perishes in the earth; or the baleful mist that spreads mildew over the ripening harvest;—nay, its ravages are terrible as the volcano which breaks up the foundations of a country; prostrating as the tempest that lays waste its cultivated surface; overwhelming as the inundation which buries up its monuments, and "completes the work of devastation and ruin." The struggle of the medical profession with this fell power, can only be compared to the holy but interminable contest of truth with error and falsehood; or the glorious warfare that liberty maintains against the black empire of despotism:—the magazines of science supply the shield and armour, philanthropy inspires the heroism, and the life of man is the prize of victory. DANIEL DRAKE
An Inaugural Discourse on Medical Education; Delivered at the Opening of the Medical College of Ohio, in Cincinnati, November 11th, 1820 Cincinnati, Ohio, Looker, Palmer and Reynolds, Printers, 1820, as it appears in Physician to the West: Selected Writings of Daniel Drake on Science and Society Edited with introductions by Henry D. Shapiro and Zane L. Miller Lexington, Kentucky; The University Press of Kentucky, 1970, pp. 151-167
432
Apr//1976 • Annals of Internal Medicine • Volume 84 • Number 4
Downloaded From: https://annals.org/ by a Glasgow Univ Library User on 08/03/2018
Two insulin-requiring diabetics with isolated hyporeninemic hypoaldosteronism spontaneously developed hyperkalemia that was aggravated whenever blood glucose concentration rose. Acute glucose infusions raised the serum potassium concentration in these patients with combined insulin and aldosterone deficiency but lowered, or did not change, the serum potassium concentration in normal subjects and in patients with either aldosterone or insulin deficiency alone. The paradoxical hyperkalemic response to glucose in patients with combined hormonal deficiency was blunted by prior administration of deoxycorticosterone acetate and abolished by prior administration of insulin. Our studies emphasize the crucial roles played by insulin and aldosterone in regulating the serum potassium concentration in man, and the need to avoid hyperglycemia in patients with combined insulin and aldosterone deficiency.
RECENT REPORTS in the literature suggest that the serum potassium concentration is controlled by an intricate hormonal system (1-7). Insulin and aldosterone seem to exert both acute and chronic influences on the serum potassium concentration through elaborate positive and negative feedback control systems. Secretion of each of these hormones may play an important role in defending against a rise in the extracellular fluid potassium level in the presence of hyperkalemic stimuli, such as a high potassium intake or potassium-sparing diuretic administration. We recently encountered two patients with combined deficiency of insulin and aldosterone who demonstrated important aspects of the hormonal control system concerned with the regulation of the serum potassium concentration. In addition to baseline hyperkalemia, presumably a function of hypoaldosteronism (8-10), these two persons also manifested acute increases in serum potassium levels in response to hyperglycemia, a seldom considered acute hyperkalemic stress (11). Each patient showed a strong, positive, direct correlation between the level of blood glucose and the serum potassium concentration, irrespective of whether hyperglycemia occurred spontaneously or as a result of intravenous glucose infusion. This unusual phenomenon seemed to occur only when combined insulin • From the Renal-Electrolyte Section, Departments of Medicine, Veterans Administration Hospital and the Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.
and aldosterone deficiency was present and was markedly altered when either hormone was replaced. One of the two persons (Patient 2) has been the subject of a recent, single case report ( 1 2 ) . In order to elucidate the mechanism of glucose-induced hyperkalemia and to evaluate various aspects of the aldosterone-insulin-potassium homeostatic system, we compared the physiologic responses of these two patients with combined aldosterone and insulin deficiency to two patients with aldosterone deficiency alone, one patient with insulin deficiency alone, and two normal persons. Patients and Methods
Group I included two persons with combined aldosterone and insulin deficiency. Both patients were ketosis-prone, insulinrequiring diabetics with hyporeninemic hypoaldosteronism; both had unexplained hyperkalemia in the absence of acidemia, excessive potassium intake, potassium-sparing diuretic therapy, or severe renal insufficiency (serum creatinine level, < 4.0 mg/dl). In each of these patients, a rise in blood glucose, either through lability of their diabetes mellitus or after intravenous glucose infusion, resulted in an acute rise in the serum potassium concentration. In Patient 2, the injudicious administration of intravenous glucose for suspected hypoglycemia raised the level of blood glucose to > 1500 mg/dl and serum potassium to > 8.5 meq/litre and resulted in ventricular tachycardia. Group II included two persons with isolated aldosterone deficiency. These two patients with hyporeninemic hypoaldosteronism also had unexplained hyperkalemia in the absence of known hyperkalemic stimuli. Both patients, however, had normal carbohydrate metabolism. Group III consisted of an insulin-requiring diabetic whose renin-angiotensin-aldosterone axis was found to be normal. Finally, group IV consisted of two normal volunteers (see Table 1 for patient characteristics). Persons in groups I-III were admitted to the Clinical Research Center of the Hospital of the University of Pennsylvania and were studied under metabolic balance conditions (12). All subjects except Patient 4 (group II) were studied on a 10 meq/day sodium and 60 meq/day potassium diet. (Because of marked hyperkalemia and a tendency toward acidosis in Patient 4, his diet was supplemented with sodium bicarbonate tablets to provide an additional 30 meq of sodium per day.) Twenty-four hour urinary aldosterone excretion was measured at the end of a 7-day low sodium diet. At the same time, plasma renin activity and aldosterone concentration, taken both supine and after 3 hours upright, were measured. Adrenal glucocorticoid function was determined by a standard corticotropin stimulation test (13). All patients received an acute intravenous infusion of 0.5 to 1 g/kg of glucose (dextrose 50 g/dl solution) for 5 minutes after an overnight fast. (Regular insulin was withheld from the diabetic patients during these infusions.) Serum glucose levels, serum potassium concentration, and venous C0 2 content
426
Downloaded From: https://annals.org/ by a Glasgow Univ Library User on 08/03/2018
Annals of Internal Medicine 84:426-432. 1976
Table 1 . Patient Characteristics
Group*
Patient
Age
Serum Creatinine
Highest Serum Potassium Level Observed
1
yrs 54
mg/dl 3.5
2
48
3 4
m IV
I
II
Baseline Serum pH
Other Major Diseases
meq/litre 7.2
7.37
1.4
6.2
7.42
82 51
1.9 2.1
6.9 6.0
7.41 7.41
Diabetic nephropathy and retinopathy ASCVDj, hypertension ASCVD Hypertension
5
52
1.9
5.2
7.49
ASCVD
6 7
31 31
1.1 1.0
4.1 4.2
*•.
• .•
Therapy
Insulin Digoxin, insulin NaHCOa, hydralazine, methyldopa Digoxin, quinidine
. ..
* Group I: combined aldosterone and insulin deficiency; II: isolated aldosterone deficiency; III: isolated insulin deficiency; IV: normal subjects, t ASCVD = atherosclerotic cardiovascular disease.
were monitored every 15 minutes for the first hour and then every 30 minutes for the second hour; plasma insulin levels were similarly measured in Patient 4 and the normal subjects. In order to evaluate the role of aldosterone or insulin deficiency, or both, in producing glucose-induced hyperkalemia, the following studies were done after either mineralocorticoid or insulin replacement. In both patients in group I, the glucose infusion protocol was repeated after 5 to 7 days of treatment with desoxycorticosterone acetate (DOCA) in oil, 10 mg intramuscularly twice a day. In one of the subjects with combined aldosterone and insulin deficiency (Patient 1), the glucose infusion was also done beginning 30 minutes after the administration of 20 U of crystalline insulin subcutaneously. In all subjects, except for Patient 3 (group II), a time control was done to evaluate the spontaneous variation in serum potassium under conditions similar to those of the glucose infusions but without glucose. In the two control patients (group IV), adequacy of the renin-angiotensin-aldosterone system was ascertained by determination of 24-hour urinary aldosterone excretion, supine plasma renin activity, and supine plasma aldosterone concentration after a 48-hour, 20 meq/day sodium diet following 40 mg of furosemide by mouth (14). Intravenous glucose infusion was then done as described above. Multiple simultaneous measurements of serum glucose, serum potassium, and venous COz content were done on each patient in the fasting state, as well as in the late afternoon and evening hours, during balance periods when neither DOCA nor diuretic therapy was being administered. Diabetic patients were given insulin in doses found to prevent severe hyperglycemia ( > 400 mg/dl). Other medications, including digoxin, ferrous sulfate, and pancreatic enzyme preparations, were administered to each patient as clinically indicated. Patient 4 (group II) had severe hypertension requiring methyldopa therapy, but no other patients received drugs known to suppress renin secretion. Balance studies and urinary and serum determinations of sodium, potassium, creatinine, and glucose concentrations and venous C0 2 content were done as previously reported (15). Plasma and urinary aldosterone were measured by radioimmunoassay (13, 16). Plasma insulin was measured by the Phadebas® insulin test (Pharmacia Fine Chemicals, Piscataway, New Jersey). Plasma renin activity was measured as angiotensin I generation (17). Results MEASUREMENTS OF PLASMA RENIN ACTIVITY AND ADRENAL CORTICAL FUNCTION
In all patients, adequacy of the low sodium intake as a
stimulus to aldosterone secretion was manifested by at least a 1.5 kg weight loss, except for Patient 4. In his case, a rise in blood urea nitrogen level from 35 to 59 mg/dl, with no change in serum creatinine, and a continued negative sodium balance during reduced sodium intake implied an adequate stimulus of extracellular fluid volume depletion. In the two normal persons (group IV), acute sodium depletion elevated mean supine plasma renin activity to 2.38 ± 0.21 ng/ml • 2 h, mean supine plasma aldosterone concentration to 30.4 ± 10.8 ng/dl, and mean 24-hour urinary aldosterone excretion to 68.5 ± 10.4 /xg. In contrast, for groups I and II, mean supine plasma renin activity was 0.86 ± 0.36 ng/ml • 2 h, the mean supine plasma aldosterone concentration was 5.3 ± 2.4 ng/dl, and the mean 24-hour urinary aldosterone excretion was 4.1 ± 2.0 /xg. The patient in group III had a supine plasma renin activity of 2.39 mg/ml • 2 h, a supine plasma aldosterone concentration of 32.5 ng/dl, and a 24-hour urinary aldosterone excretion of 60 /xg. In all persons in groups I-III, Cortisol reserve, as tested by synthetic corticotropin infusion (250 /xg), was normal (plasma Cortisol rose from a mean of 12.2 ± 0.6 to a mean of 24.3 ± 1.2 /xg/dl) (13). These studies demonstrate the syndrome of hyporeninemic hypoaldosteronism in groups I and II and normal juxtaglomerular and adrenal cortical function in groups III and IV (Table 2 ) . CORRELATION BETWEEN SPONTANEOUS VARIATIONS IN SERUM POTASSIUM AND SERUM GLUCOSE CONCENTRATIONS
The simultaneous measurement of serum glucose and serum potassium on many occasions during the balance periods produced a strong positive correlation in the two patients with combined aldosterone and insulin deficiency (group I), as shown for Patient 1 in Figure 1. The corresponding regression line for Patient 2 is serum K+ concentration = 4.85 + 0.002 X serum glucose concentration; r=0.64, P < 0.01. If this line is extrapolated to a serum glucose concentration of 1500 mg/dl, it would Goldfarb et a/. • Hyperkalemia and Hyperglycemia
Downloaded From: https://annals.org/ by a Glasgow Univ Library User on 08/03/2018
427
Table 2. Laboratory Values
Group
Patient
Plasma Renin
Plasma Cortisol Precorticotropin
Postcorticotropin
Supine
ng/ml -2h 1.15 1.48 0.19 0.28 1.73 1.80 0.36 1.01 2.39 4.75 2.58 . .. 2.17
iig/dl
I II III IV
1 2 3 4 5 6 7
13.4 11.2 13.0 12.6 10.6
22.4 22.0 27.0 25.8 26.6
correspond to a serum potassium of approximately 8.5 meq/litre; these values were observed in this patient who had combined aldosterone and insulin deficiency and who developed a hyperkalemic ventricular arrhythmia. There was no significant correlation between serum potassium and venous COz content (P > 0.5); acid-base status was stable in these patients. These measurements confirmed our initial clinical impression of a glucose-potassium relation and suggested a unique glucose-related hyperkalemic abnormality in these persons. However, our diabetic patient with normal mineralocorticoid function (group III) had no significant relation between serum glucose and serum potassium despite intermittent hyperglycemia (P > 0.2). This observation suggested that insulin deficiency alone was not responsible for glucose-induced hyperkalemia. Because our patients with hypoaldosteronism alone (group II) did not have spontaneous hyperglycemia, these observations could not provide pertinent data on the role of aldosterone deficiency per se in producing glucoseinduced hyperkalemia. To study that possible role, acute elevation of serum glucose by hypertonic glucose infusion was necessary.
Upright
Plasma Aldosterone Supine
Upright
24-Hour Urinary Aldosterone
ng/dl 4.1
11.8
. ..
. ..
1.9 10.0 32.5 19.6 41.1
11.2 11.6 95.4
ug/day 1.1 5.1 1.6 8.4 60.0 58.1 78.9
EFFECT OF INTRAVENOUS GLUCOSE INFUSION ON SERUM POTASSIUM CONCENTRATION
To test the hypothesis that combined aldosterone and insulin deficiency was responsible for the observed relation between serum glucose and potassium, all patients underwent glucose infusion. In Figure 2, the effect of glucose infusion on serum potassium concentration is shown for each person in each of the four groups. The points to the left in each panel indicate the preinfusion serum potassium concentration, while the points to the right show the serum potassium concentration 1 hour after infusion. The mean serum glucose level during intravenous glucose infusion was higher in the diabetic than in the nondiabetic patients with hypoaldosteronism (group I = 424 ± 45 mg/dl; group II = 260 ± 25 mg/dl). However, there was no significant difference in the mean level of blood glucose reached in the diabetic patients with or without hypoaldosteronism (group I = 424 ± 45 mg/dl; group III = 487 ± 14 mg/dl). Thus, the absolute level of hyperglycemia was not in itself a determinant of the rise in serum potassium concentration produced in the patients with combined insulin and aldosterone deficiency. Venous C0 2 content was also monitored in each patient,
Figure 1 . Correlation between serum potassium and blood glucose concentrations in a subject (Patient 1) with combined aldosterone and insulin deficiency. 428
April 1976 • Annals of Internal Medicine • Volume 84 • Number 4
Downloaded From: https://annals.org/ by a Glasgow Univ Library User on 08/03/2018
and no change in C0 2 content of more than 1 mmol/litre was found in any patient, except for Patient 3 in group II. In this person, venous C0 2 content fell from 25 to 21 mmol/litre, but serum potassium concentration also fell during the infusion. In the normal subjects (group IV), as seen in the upper left panel of Figure 2, acute hyperglycemia led to a significant fall in serum potassium. Recent reports in the literature would suggest that such a fall is the result of glucose-induced secretion of insulin, a major hormonal stimulus to acute cellular potassium uptake (1-5). Insulin levels rose in these two persons, in response to hypertonic glucose infusion, from 11.0 to 66.0 fiU/ml and from 14.0 to 105.0 //.U/ml, respectively. The effects of intravenous glucose infusion on serum potassium concentration in patients with isolated hypoaldosteronism (group II) are shown in the upper right panel of Figure 2. The fall in serum potassium level in these persons was quite similar to that in the normal subjects, as was the degree of insulin secretion. In Patient 4, plasma insulin level rose from 3.4 to 45.0 /xU/ml in response to hypertonic glucose infusion. Thus, hypoaldosteronism alone will not result in glucose-induced hyperkalemia; in these patients, the hyperinsulinemia produced by glucose infusion caused an acute fall in the serum potassium concentration. As seen in the lower left panel of Figure 2, insulin deficiency alone will not produce this paradoxical phenomenon either. In the diabetic patient (group III), acute hyperglycemia resulted in no change in serum potassium level compared with time control studies. As seen in the lower right panel of Figure 2, the infusion of hypertonic glucose in the two patients with combined aldosterone and insulin deficiency (group I) produced a marked rise in serum potassium concentration (from 5.0 to 5.7 meq/litre in one patient and from 5.5 to 6.3 meq/litre in the other). These elevations were significantly greater than the minimal variation that occurred in the time control determinations (P < 0.05). Thus, glucose-induced hyperkalemia is the result of combined aldosterone and insulin deficiency.
Figure 2. Serum potassium concentration before and after glucose infusion. The points to the left in each panel indicate the preinfusion serum potassium concentration, and the points to the right indicate the serum potassium concentration 1 hour after glucose infusion.
tion of the insulin component of the combined deficiency state allowed serum potassium concentration to fall from 5.7 meq/litre to 5.1 meq/litre during the glucose infusion. Thus, while mineralocorticoid administration has a protective effect against glucose-induced hyperkalemia in the combined deficiency state, insulin alone will produce prompt reversion to a normal response. Discussion
EFFECT OF DOCA ON SERUM POTASSIUM RESPONSE TO GLUCOSE INFUSION
In both patients in group I, the administration of DOCA for 5 to 7 days markedly altered the acute response to glucose infusion (Figure 3, left and middle panels). In each patient, hyperglycemia of a similar degree to that previously produced resulted in no significant change in serum potassium concentration. These patients then most closely followed the pattern seen in Patient 5, with insulin deficiency alone. Mineralocorticoid deficiency thus seems to play a key role in the production of glucose-induced hyperkalemia when insulin deficiency is also present. EFFECT OF INSULIN ON SERUM POTASSIUM RESPONSE TO GLUCOSE INFUSION
In Patient 1 (group I), glucose infusion was done 30 minutes after the administration of 20 units of crystalline insulin subcutaneously (Figure 3, right panel). The correc-
The mechanisms of the control of the serum potassium concentration during hyperkalemic stress have recently been investigated extensively. Acute hyperkalemia produced by intravenous potassium infusion has been shown to result in a marked hyperinsulinemia, which in turn directly stimulates cellular potassium uptake (1-5, 18, 19). Thus, insulin has been viewed as the hormone responsible for preventing life-threatening hyperkalemia during acute increases in extracellular potassium concentration. Aldosterone has been classically viewed as the hormone important in regulating total body potassium content and has been thought to exert its effect by modulating renal potassium excretion (6, 7). Recently, several authors have presented evidence that aldosterone may also play an important extrarenal role in regulating serum potassium concentration and may function to condition experimental animals to tolerate acute, exogenous potassium loads (2022). Goldfarb et a/. • Hyperkalemia and HvDerglycemia
Downloaded From: https://annals.org/ by a Glasgow Univ Library User on 08/03/2018
429
Figure 3. Effects of desoxycorticosterone acetate (DOCA) (left and middle panels) and insulin (right panel) on serum potassium response to glucose infusion (plotted similarly to Figure 2).
While the clinical syndromes of hypoaldosteronism (either isolated or as a part of generalized adrenocortical insufficiency) and hypoinsulinism are well recognized, the consequences of the combined deficiency of aldosterone and insulin on potassium homeostasis have not been systematically examined. We recently proposed that glucose-induced hyperkalemia might be a manifestation of combined aldosterone and insulin deficiency. In our study, we have presented data that clearly support the concept that hyperglycemia may lead to hyperkalemia and have shown the interrelation between aldosterone and insulin deficiences in producing this clinical disorder. The concept of potassium as an insulin secretogogue and insulin as a hypokalemic hormone derives from the observations of Farber and colleagues (23), as well as more recent studies of others (1-5). These workers have presented evidence that the pancreatic islet cells release both insulin and glucagon in response to potassium infusions. Insulin directly stimulates net cellular potassium uptake into muscle and liver irrespective of the level of plasma glucose (24-26), while glucagon prevents the hypoglycemia that would otherwise result from the hyperinsulinemia (1). The evidence that insulin deficiency may lead to hyperkalemia is much less direct and exists in a number of clinical observations. First, diabetic patients are prone to hyperkalemia during the use of triamterene and amiloride, two agents known to impair renal potassium excretion and possibly transcellular potassium flux as well (27, 28). Secondly, there seems to be an increased occurrence of the syndrome of hyperkalemia hyperchloremic acidosis in diabetic patients with mild renal insufficiency (29). Finally, many patients who reportedly had hyperkalemia in conjunction with isolated hyporeninemic hypoaldosteronism have been diabetics (8-10, 30). Each of these observations suggests that when renal potassium excretion is impaired, the insulin system may assume increased significance as a modulator of serum potassium concentration. In our diabetic patients with hypoaldosteronism, the occurrence of abnormal adrenal mineralocorticoid function combined with deficiency of insulin resulted in an impaired 430
response to a hyperkalemic stress and an inability to maintain potassium homeostasis. Although perhaps not generally appreciated, there is some evidence that acute hyperglycemia may be an important hyperkalemic stress. Seldin and Tarail (11) observed an apparent redistribution of potassium from the intracellular to the extracellular space after hypertonic glucose infusions in man. They attributed this phenomenon to transcellular movements of potassium, in concert with movements of intracellular water, in response to the hypertonicity of the extracellular fluid. Makoff and associates (31) expanded on these findings and produced hyperkalemia in animals during hypertonic mannitol infusions. Recent evidence from studies of isolated rat muscle by Adler, Anderson, and Zelt (32) further suggest that extracellular hypertonicity leads to a fall in intracellular potassium content. Other mechanisms may be responsible for glucose-induced hyperkalemia besides osmotically induced transcellular potassium shifts. Since glycogen is rich in potassium, glycogenolytic hormones could simultaneously release large amounts of potassium and elevate the plasma glucose concentration. Although there is no direct evidence to support such a hypothesis, glucagon does enhance potassium efflux from the isolated, perfused rat liver and may have a similar effect in these patients (33-35). The possibility that the mechanism of hyperkalemia during spontaneous hyperglycemia is identical to that during infusion hyperglycemia cannot be excluded. Thus, hypertonic glucose infusion in a person without the modulating influence of aldosterone (to condition the subject to tolerate hyperkalemia) and without insulin (to stimulate rapid cellular uptake of potassium) could lead to clinically significant hyperkalemia. The studies in patients with hyporeninemic hypoaldosteronism alone (group II) show that mineralocorticoid deficiency by itself will not result in glucose-induced hyperkalemia. In Patient 4, a normal insulin response to hyperglycemia was documented and was the probable mechanism of the observed fall in serum potassium concentration. Furthermore, the deficiency of insulin alone, as observed in Patient 5 (group III), will not result in glucose-induced hyperkalemia. In this patient, normal mineralocorticoid function was protective against
April 1976 • Annals of Internal Medicine • Volume 84 • Number 4
Downloaded From: https://annals.org/ by a Glasgow Univ Library User on 08/03/2018
the hyperkalemic stress. These findings confirm those of Farber and colleagues (23), who studied the effects of hyperglycemia in insulin-requiring diabetics; as in our patient, hyperglycemia did not alter serum potassium concentration in these persons. The results of the experiments in which hormonal deficits were corrected further support the hypothesis that combined insulin and aldosterone deficiency causes glucoseinduced hyperkalemia. In our two patients with combined hormonal deficiency (group I), the chronic administration of DOCA produced a response to hypertonic glucose that was identical to that seen in the patient with insulin deficiency alone. In these persons, there is neither a rise nor a significant fall in serum potassium level after hypertonic glucose infusion. Thus, mineralocorticoid action apparently prevents glucose-induced hyperkalemia in insulin-deficient persons. The precise nature of this protective effect cannot be ascertained from these studies. However, Patient 1 remained in positive potassium balance during mineralocorticoid therapy, while Patient 2 was in a cumulative negative potassium balance of only 20 meq when the protective effect of DOCA was demonstrated. These data suggest that the mode of action of mineralocorticoids is primarily extrarenal in producing this effect (20-22). Finally, the acute administration of crystalline insulin before hypertonic glucose infusion in Patient 1 produced a "normal" hypokalemic response. This finding supports the contention that insulin secretion is primarily responsible for the hypokalemic effect of intravenous glucose infusions. Our studies provide evidence that the combination of hypoaldosteronism and hypoinsulinism leads to a unique, identifiable abnormality in potassium metabolism, namely, glucose-induced hyperkalemia. In view of the near catastrophic response to an infusion of hypertonic glucose in our initial patient, this phenomenon is of clinical importance. Further, these studies suggest the possibility of a singular susceptibility to acute hyperkalemia in diabetic persons whenever renal or extrarenal potassium handling is impaired, such as with the use of potassium-sparing diuretics (27, 28), with the use of succinylcholine (36), during acute muscle breakdown (37), or during the injudicious administration of hypertonic glucose solutions. ACKNOWLEDGMENTS: The authors thank Miss Cordelia Shute and the nursing staff of the Clinical Research Center of the Hospital of the University of Pennsylvania; Dr. Karl Engleman for advice and for measurement of plasma renin activity; Dr. John Hansell for determination of plasma insulin; Dr. Gordon Williams for assays of plasma and urinary aldosterone; Mr. A. B. Kelley for technical assistance; Mr. Craig Schneider for preparing the figures; and Ms. Adair Ruff for secretarial assistance. Grant support: By U.S. Public Health Service Training Grant #AM 05634-05; Veterans Administration Renal Training Program #204; U.S. Public Health Service Research Grants AMHL 17344-04 and HL 00340-25; U.S. Public Health Service CRC Grant #RR 00040; and the Philadelphia Veterans Administration Hospital (103.14M). A preliminary report of this paper was presented before the Annual Meeting of the American College of Physicians, San Francisco, California, April 1975. Received 16 September 1975; revision accepted 13 January 1976. • Requests for reprints should be addressed to Stanley Goldfarb, M.D., Hospital of the University of Pennsylvania, 860 Gates Pavilion, Philadelphia, PA 19104.
References 1. SANTUSANIO F, FALOONA GF, KNOCHEL JP, et al: Evidence for
a role of endogenous insulin and glucagon in the regulation of potassium homeostasis. J Lab Clin Med 81:809-817, 1973 2. HIATT N, DAVIDSON MB, BONO VIES G, et al: Role of insulin in
the transfer of infused potassium to tissue. Horm Metab Res 5:84-88, 1973 3. HIATT N, YAMAKAWA T, DAVIDSON MB: Necessity for insulin in
transfer of excess infused K to intracellular fluid. Metabolism 23:43-49, 1974 4. PETTIT GW, VICK RL: Contribution of pancreatic insulin to extrarenal potassium homeostasis: a 2-compartment model. Am J Physiol 226:319-324, 1974 5. PETTIT GW, VICK RL, SWANDER AM: Plasma K+ and insulin:
changes during KC1 infusion in normal and nephrectomized dogs. Am J Physiol 228:107-109, 1975 6. KNOCHEL JP, WHITE MG: The role of aldosterone in renal physiology. Arch Intern Med 131:876-884, 1973 7. CANNON PJ, AMES RP, LARAGH JH: Relation between potassium
balance and aldosterone secretion in normal subjects and in patients with hypertensive or renal tubular disease. / Clin Invest 45:865-879, 1966 8. SCHAMBELAN M, STOCKIGT JR, BIGLIERI EG:
Isolated hypo-
aldosteronism in adults—a renin-deficiency syndrome. N Engl J Med 287:573-578, 1972 9. PEREZ G, SIEGEL L, SCHREINER GE: Selective hypoaldosteronism
with hyperkalemia. Ann Intern Med 76:757-763, 1972 10. WEIDMANN P, REINHART R, MAXWELL MH, et al: Syndrome of
hyporeninemic hypoaldosteronism and hyperkalemia in renal disease. / Clin Endocrinol Metab 36:965-977, 1973 11. SELDIN DW, TARAIL R: Effect of hypertonic solutions on metabolism and excretion of electrolytes. / Clin Invest 159:160-74, 1949 12. GOLDFARB S, STRUNK B, SINGER I, et al: Paradoxical glucose
induced hyperkalemia: combined aldosterone and insulin deficiencies. Am J Med 59:744-750, 1975 13. DLUHY RG, HIMATHONGKAM T, GREENFIELD M: Rapid ACTH
test with plasma aldosterone levels. Improved diagnostic discrimination. Ann Intern Med 80:693-696, 1974 14. WALLACH L, NYARAI I, DAWSON KG:
Stimulated
renin: a
screening test for hypertension. Ann Intern Med 82:27-34, 1975 15. RASTEGAR A, AGUS ZS, CONNOR TB, et al: Renal handling of
calcium and phosphorus during mineralocorticoid escape in man. Kidney lnt 2:279-286, 1972 16. LANGAN J, JACKSON R, ADLEN EV, et al: A simple radioim-
munoassay for urinary aldosterone. / Clin Endocrinol Metab 38:189-193, 1974 17. GIESE J, JORGENSON M, NIELSON MD, et al: Plasma renin
concentration measured by use of radioimmunoassay for angiotensin I. Scand J Clin Lab Invest 26:355-367, 1970 18. KUZUYA T, KAJINUMA H, IDE T: Effect of intrapancreatic in-
jection of potassium and calcium on insulin and glucagon secretion in dogs. Diabetes 23:55-60,1974 19. HENQUIN JC, LAMBERT AE: Cationic environment and dynamics of insulin secretion. II. Effect of a high concentration of potassium. Diabetes 23:933-942, 1974 20. ALEXANDER EA, LEVINSKY NG: An extrarenal mechanism of
potassium adaptation. J Clin Invest 47:740-748, 1968 21. ADLER S: An extrarenal action of aldosterone on mammalian skeletal muscle. Am J Physiol 218: 616-621, 1970 22. DAWBORN JK WATSON L: Effect of prolonged administration of aldosterone on potassium and magnesium metabolism in the rabbit. Med J Aust 2:304-307, 1968 23. FARBER SJ, PELLEGRINO ED, CONAN NJ, et al: Observations on
the plasma potassium level of man. Am J Med Sci 221:678687, 1951 24. ZIERLER KL: Effect of insulin on potassium efflux from rat muscle in the presence and absence of glucose. Am J Physiol 198:1066-1070, 1960 25. BURTON SD, ISHIDA T: Effect of insulin on potassium and glucose movement in perfused rat liver. Am J Physiol 209:11451161, 1965 26. KESTENS PJ, HAXHE JJ, LAMBOTTE L, et al: The effect of in-
sulin on the uptake of potassium and phosphate by the isolated perfused canine liver. Metabolism 12:941-950, 1963 27. MCNAY JL, ORAN E: Possible predisposition of diabetic patients to hyperkalemia following administration of the potassiumretaining diuretic, Amiloride (MK870). Metabolism 19:58-70, 1970 28. WALKER BR, CAPUZZI DM, ALEXANDER F, et al: Hyperkalemia
after triamterene in diabetic patients. Clin Pharmacol Ther 13: 643-651, 1972 Goldfarb et a/. • Hyperkalemia and Hyperglycemia
Downloaded From: https://annals.org/ by a Glasgow Univ Library User on 08/03/2018
431
29. CARROL HJ,
FARBER SJ:
Hyperkalemia
and
Res 17:539-564, 1961
hyperchloremic
acidosis in chronic pyelonephritis. Metabolism 13:808-817, 1964
34. GLINSMAN WH, MORTIMORE GE: Influence of glucagon and
3', 5'-AMP on insulin responsiveness of the perfused rat liver. Am J Physiol 215:553-559, 1968
30. WEIDMANN P, MAXWELL MH, ROWE P, et al: Role of the renin-
angiotensin-aldosterone system in the regulation of plasma potassium in chronic renal disease. Nephron 15:35-49, 1975 31. MAKOFF DL, D A SILVA J A, ROSENBAUM BJ, et al: Hypertonic
expansion: acid-base and electrolyte changes. Am J Physiol 218:1201-1207, 1970 32. ADLER S, ANDERSON B, ZELT B: Effect of osmolarity of intra-
cellular pH of rat diaphragm muscle. Am J Physiol 228:725729, 1975 33. MILLER LL: Some direct actions of insulin, glucagon and hydrocortisone on the isolated perfused rat liver. Recent Prog Horm
35. BURTON SD, MONDON CE, ISHIDA T: Dissociation of potassium
and glucose efflux in isolated perfused rat liver. Am J Physiol 212:261-266, 1967 36. COOPERMAN L: Succinylcholine-induced hyperkalemia in neuromuscular disease. JAMA 213:1867-1871, 1970 37. GROSSMAN RA, HAMILTON RW, MORSE BM, et al: Nontrau-
matic rhabdomyolysis and acute renal failure. N Engl J Med 291:807-811, 1974
Historic Documents in American Medicine
The Battle Against Illness Occurring without our anticipation or consent, [disease] produces an unexpected suspension of all the pursuits of business; exhausts the proceeds of those which had been made efficient; precludes the consummation of others; and restrains us from engaging in new ones, till the "golden moments of opportunity" have perhapsfleetedaway for ever. On our social plans and pleasures it exerts an influence equally unpropitious. A sick man is no longer a sociable, but a selfish being. He sinks to the state of a dependent on the community, and asks nothing from it, but sympathy and assistance;—and these afford him no other enjoyment than what arises from the removal of pain, or the dissipation of irksomeness. Their effects are negative, rather than positive. He wants the power to be an actor in the busy and bustling operations of society; and cannot even be a spectator of scenes in which he once performed a conspicuous part, and from which, in health, he unceasingly derived entertainment and happiness. Finally, disease is a foe which invades us in as many forms as Proteus could assume. It is the great enemy of all enterprise and improvement: the sedative which paralyzes every faculty and passion: the poison which deranges every mental operation: the opposing power of patriotism, philanthropy and ambition—relaxing the arm of industry, subverting the schemes of benevolence, and extinguishing the lights of genius, to lead him captive through the mazes of error and dullness. It may be likened to the dark cloud which intercepts the sun beams till the germinating corn perishes in the earth; or the baleful mist that spreads mildew over the ripening harvest;—nay, its ravages are terrible as the volcano which breaks up the foundations of a country; prostrating as the tempest that lays waste its cultivated surface; overwhelming as the inundation which buries up its monuments, and "completes the work of devastation and ruin." The struggle of the medical profession with this fell power, can only be compared to the holy but interminable contest of truth with error and falsehood; or the glorious warfare that liberty maintains against the black empire of despotism:—the magazines of science supply the shield and armour, philanthropy inspires the heroism, and the life of man is the prize of victory. DANIEL DRAKE
An Inaugural Discourse on Medical Education; Delivered at the Opening of the Medical College of Ohio, in Cincinnati, November 11th, 1820 Cincinnati, Ohio, Looker, Palmer and Reynolds, Printers, 1820, as it appears in Physician to the West: Selected Writings of Daniel Drake on Science and Society Edited with introductions by Henry D. Shapiro and Zane L. Miller Lexington, Kentucky; The University Press of Kentucky, 1970, pp. 151-167
432
Apr//1976 • Annals of Internal Medicine • Volume 84 • Number 4
Downloaded From: https://annals.org/ by a Glasgow Univ Library User on 08/03/2018
