Kidney /nternaiional, Vol. 11(1977), pp. 443—452

Role of glucoregulatory hormones in potassium homeostasis JAMES P. KNOCHEL Department of Internal Medicine, University of Texas, Southwestern Medical School, Dallas, Texas

An incompletely defined interregulatory balance exists between potassium, insulin, and aldosterone. That potassium administration enhances and hypo-

tance. Therapeutically, it is a powerful tool for treatment of acute hyperkalemia. On the other hand, its action can produce disastrous cardiac arrhythmias in

kalemia depresses aldoterone production is well

a patient receiving digitalis if he should become

known. It is not as well known that the same relationship exists between potassium and insulin. In a normal subject, acute hyperkalemia stimulates release of insulin from the pancreas. Potassium deficiency, on

acutely hypokalemic.

the other hand, may depress production of insulin. Both insulin and aldosterone, under appropriate conditions, may indirectly promote transfer of potassium ions from extracellular to intracellular fluid. In contrast, deficiency of either insulin or aldosterone, and

expecially both, may favor development of hyperkalemia. Pharmacologically, glucagon, epinephrine, norepi-

nephrine, and somatotropin may also influence transfer of potassium between extracellular and intra-

When potassium ions are transported from the

extracellular fluid with glucose, their destiny inside the cell is largely unknown. Harrop and Benedict proposed that potassium is incorporated as a salt of a phosphorylated carbohydrate [3]. Definitive in forma-

tion on this possibility is not available. It has also been proposed that potassium is deposited as a complex of glycogen, since during glycogenesis, it can be shown that an approximately fixed quantity of potassium is incorporated into tissue for each unit mass of glycogen synthesized [4]. There is no positive evidence, however, to support the notion that a potassium-glycogen complex exists. Based upon electrical

cellular fluid. Their precise physiological roles in

phenomena, we would favor the view that in-

potassium homeostasis, however, are much less evident than that for insulin and aldosterone. It is the intention of this brief review to point out the salient effects and mechanisms whereby the foregoing substances affect potassium homeostasis and to

tracellular potassium for the most part exists as a free ion in solution [5, 6]. Efjct of insulin on sodium and potassium transport.

In vitro studies have shown that insulin stimulates effiux of sodium from human lymphocytes [7], rat brain [8], uterus [9], and skeletal muscle of the frog [10] and rat [II, 12]. It also favors retention of both

point out physiologically important interrelationships wherever possible. Hypokalemia induced by hyperglycemia or insulin administration. It has been recognized for many years that administration of glucose may be associated with

sodium and potassium by the kidney [13]. In association with increased sodium efflux from these tissues, insulin increases oxygen consumption [14, 15] and lactate production by skeletal muscle, thus suggesting utilization of energy for sodium transport. Studies by Andres et al [16] and Zierler [17] have

a decline in the concentration of potassium in both serum and urine [1, 2]. It is now clear that hyperglycemia induced by administration of glucose in-

shown that insulin-mediated potassium transfer in muscle occurs independently of glucose. Using the

duces release of insulin from the beta cells of the pan-

creas. Insulin, released by the stimulus of hyperglycemia, or following its injection, promotes transfer of potassium ions into several tissues, those of most importance being the liver and skeletal muscle. The capacity of insulin to promote transfer of po-

isolated extensor digitorum longus muscle of the rat,

tassium into cells has considerable practical impor-

rose before there was a detectable increase of tissue potassium content. Furthermore, the final value of

they demonstrated that insulin produced a loss of sodium and net accumulation of potassium. The measured intracellular electronegativity, however, the negative potential surpassed that which could have accounted for the measured rise of intracellular

© 1977. by the International Society of Nephrology.

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potassium concentration [18]. Zierler concluded that insulin hyperpolarized the muscle membrane by some

unexplained mechanism, that potassium transport followed in its wake and was consequently deetrogenic. More recent studies have confirmed earlier obser-

vations that insulin-stimulated sodium efflux from frog muscle occurs independently of glucose transport [19, 201. Moore, using sodium-loaded frog skeletal muscle, showed that insulin treatment stimulated sodium etliux, decreased intracellular water content, and increased intracellular potassium concentration [10]. Gavryck, Moore, and Thompson, studying isolated sarcolemmal membranes from the frog, obtained evidence that insulin increases the activity of a magnesium-dependent, sodium-potassiumadenosine triphosphatase (Na-K-ATPase) [8]. This

effect was quantitatively dependent upon sodium concentration in the incubating medium. It could be

inhibited by either blocking the action of Na-KATPase with ouahain, or by eliminating potassium from the incubating medium. Large concentrations of insulin could overcome ouabain inhibition. When the concentrations of potassium and sodium were raised sufficiently so that activity of the pump was maximally stimulated, insulin had no additional stim-

ulatory effect. At lower concentrations of sodium, however, the increased ATPase activity mediated by insulin was readily detectable. Kipnis and Parrish [12] suggested that transport of sodium and amino acids mediated by insulin might be closely related. They found that insulin-stimulated

transport of c-aminoisobutyric acid in the rat diaphragm was virtually abolished if sodium transport were inhibited or if sodium were excluded from the incubating solution. There also exists a very interesting association between potassium and glycogen in skeletal muscle. A normal quantity of potassium in muscle is necessary for glycogen synthesis. Ouabain, an inhibitor of NaK-ATPase, also inhibits activation of glycogen synthetase by insulin [21, 221. In potassium deficiency, both storage and synthesis of glycogen are seriously impaired [23]. As will be subsequently discussed, potassium deficiency decreases the capacity to produce

insulin. In patients with insulin-deficient diabetes mellitus, glycogen synthetase activity and glyeogen content of muscle are also significantly less than normal. Both abnormalities return to normal after treatment with insulin [24]. In potassium deficient skeletal

letal muscle could be the result of impaired transport which, in turn, might result from insulin deficiency. Adrenergic receptor function and serum potassium concentration. Substantial evidence indicates that acute stimulation of alpha-adrenergic receptors may result in hyperkalemia. In contrast, acute stimulation of heta-adrenergic receptors may cause hypokalemia. Infusion of either epinephrine or norepinephrine i.v. may cause acute transient hyperkalemia. Although infusion of either substance may depress plasma insulin [26], the hyperkalemic response to these catecholamines occurs very rapidly and consequently is probably not the result of an acute insulin lack. Craig and Mendell [27] showed that hyperkalemia

induced by epinephrine is mediated by potassium released from the liver. During epinephrine infusion, potassium and glucose concentration rose in hepatic venous blood but not in carotid arterial blood. The a/pha-adrenergic blocker dibenamine prevented the hyperkalemic response to epinephrine. Therefore, it seems likely that hyperkalemia immediately after epinephrine infusion results from a/pha-adrenergic stim-

ulation. Hyperglycemia induced by epinephrine is followed by hypokalemia. Although the acute and transient hyperkalemia induced by epinephrine does not occur if an animal is pretreated with dibenzyline, dibenamine, or phentolamine, the latter drugs do not inhibit hyperglycemia [28]. Vick, Todd, and Leudke [291 examined the rela-

tionships between potassium transfers in liver and skeletal muscle during epinephrine-induced hypokalemia. During iv. infusion of epinephrine, they showed that the hypokalernia could be reversed by propranolol. Their studies also indicated that uptake of potassium under the influence of epinephrine occurred in both liver and skeletal muscle and that these effects were mediated through beta-adrenergic receptors.

Lum and Lockwood [30, 31] showed that both nicotine and epinephrine exert a protective effect against the hyperkalemia produced by infusion of potassium chloride. The protection by both of these agents is abolished by propranolol. Their data clearly supported earlier evidence that heta-adrenergic stimulation leads to uptake of potassium ions by skeletal muscle cells. Of great importance, the beta-adrenergic stimulation produced by epinephrine and its action to protect against cardiotoxic hyperkalemia persists in the pancreatectomized animal. That this eliminates

muscle, the concentration of sodium is abnormally elevated and the resting membrane potential abnormally low [251. It seems conceivable that at least

insulin as a mediator of hypokalemia induced by epinephrine was predictable since epinephrine infusion has been shown to inhibit release of insulin [26]. The beta-adrenergic stimulator isoproterenol

some of the abnormalities in potassium-deficient ske-

also provides protection against hyperkalemia.

Glucoregulatory hormones in potassium homeosiasis

In contrast to the effects of epinephrine, norepinephrine induces a more modest increase of blood glucose and does not cause hypokalemia [31]. These effects correspond to the predominant alpha-adrenergic effect of norepinephrine. The foregoing evidence has several implications. First, certain adrenergic agents possessing beta-ad-

renergic receptor-stimulating properties might be

useful in the treatment of acute hyperkalemia. Such treatment has been successfully used in patients with hyperkalemic familial periodic paralysis [32]. Second, agents tending to block potassium uptake by skeletal muscle cells, such as propranolol, could well be useful in managing certain hypokalemic states in which potassium movement into muscle is accelerated, such as periodic paralysis. Accordingly, three patients with

445

renergic blocker dibenamine, one cannot conclude that glucagon is a specific a-adrenergic agonist. The cited studies were done in intact animals. Therefore,

it is possible that glucagon might have facilitated release of catecholamines which, in turn, caused the hyperkalemia. That glucagon induces release of catecholamines has been demonstrated [361. Effct of glucagon on electrolyte excretion. When glucagon is administered in quantities sufficient to

induce abnormally elevated concentrations in plasma, the excretion of sodium, potassium, calcium, phosphorus, and magnesium may abruptly increase

hypokalemic periodic paralysis associated with thyrotoxicosis improved after propranolol treatment [331. Third, certain patients receiving propranolol or other beta-blockers could conceivably develop dangerous hyperkalemia during at least five conditions: insulin deficiency, renal failure, exercise, administration of potassium chloride, and while simultaneously ingesting drugs, such as sprionolactone, which inter-

fere with the action of aldosterone. Indeed, in patients with uncomplicated essential hypertension, treatment with beta-blockers has resulted in slight

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elevation of serum potassium concentration [34, 351. Frank hyperkalemia as a result of such therapy, however, has apparently not been reported.

Glucagon. In a pattern quite similar to that observed during infusion of epinephrine, administration of glucagon in pharmacologic doses may be followed

by acute hyperglycemia and hyperkalemia [28]. Glucagon has a potent glycogenolytic effect in the liver but not in skeletal muscle [36]. Several very interesting observations have been made concerning the effect of glucagon. In Figure 1, it is shown that these hyperglycemic and hyperkalemic responses may be dissociated by repeated injection. In this study, cats were injected with glucagon, 50sg/kg of body wt, i.v., every 30 mm. As the liver became depleted of glycogen, the hyperglycemic response became correspondingly less. Nevertheless, the hyperkalemic response persisted. This suggests that hyperkalemia after glucagon, although it is of hepatic origin [38], is

120

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probably not the direct result of glycogenolysis.

Moreover, dibenamine inhibits the hyperkalemic effect of glucagon but does not alter its capacity to split

glycogen. Fasting for a sufficient period of time to deplete hepatic glycogen eliminates the hyper-

Glucagon

Fig. I. Glucagon, 50 jig/kg, administered every 30 mm, hyperkalenjia occurring aJmer each dose. The hyperglycemic response pro-

glycemic effect of glucagon but not the hyperkalemic

gressively fell. These findings suggest that the hyperkalemic and

effect [28]. Although glucagon-mediated release of potassium from the liver is inhibited by the a-ad-

produced through the courtesy of ELLIS S. BECKSTT SB, macol Exp Ther 142:3 18, 1963.)

hyperglycemic responses to glucagon are independent. (Re-

J

Phar-

446

Knochel

[371. Although the glomerular filtration rate may also

tassium chloride, maximum hyperkalemia was

rise, the rise is not sufficient to account for the increase in electrolyte excretion. Furthermore, the ef-

slightly but significantly less when potassium intake

fect on electrolyte excretion is independent of hyper-

glycemia or glycosuria [381. Its effect is felt to be primarily on the tubule itself [39]. The propensity of glucagon to increase electrolyte excretion into the urine could have clinical relevance when it is used in the treatment of congestive heart failure [40]. Observations published in abstract form [41] have shown that administration of I to 16 mg of glucagon per hour for one to two days was associated with modest hypokalemia. This did not occur if p0tassium supplements were given.

was 200 mEq/day than when it was 40 mhq/day. While receiving a 40 mEq potassium intake, insulin rose and plasma glucose fell when hyperkalemia (6.0

mEq/liter) was induced. In contrast, when dietary potassium intake was 200 mEq, hyperkalemia (5.6 mEq/liter) did not induce a change in either plasma glucose or insulin. As discussed in the previous section of this review, under conditions of acute hyperkalemia, increased

insulin most likely promotes transfer of potassium ions into several tissues, the most important being skeletal muscle and liver. The foregoing evidence sug-

Endocrine response to hyperkalernia. Experimen-

gests that insulin plays a role in the immediate de-

tally, acute hyperkalemia produced by infusion of

fense against hyperkalemia. In experimental animals,

potassium chloride induces a catharsis of several hor-

tolerance to hyperkalemia is severely impaired by pancreatectomy or by administration of alloxan [42,

mones from their sites of storage. These include insulin [42, 43], glucagon [42], aldosterone [44], growth hormone [45], and catecholarnines [46]. In vitro hyperkalernia may also promote release of luteinizing hormone [451 and thyrotropin [481. Insulin, aldosterone, growth hormone, and epinephrine possess the capacity, at least indirectly, to transfer potassium ions from the extracellular to the intracellular fluid. Except for insulin and aldosterone, sufficient information is not currently available to permit assessment of other hormones as to their physiologic roles in protection against hyperkalemia. Grodksy and his coworkers were the first to observe that increased potassium concentration in vitro caused release of insulin [49, 50]. This effect is observed even in the absence of glucose. It has also been

shown that extracellular sodium and an intact sodium pump are prerequisites for kaliogenic insulin release [51]. Using pen fused isolated rat islets, Lam-

bert, Henquin, and Malvaux [52] showed that ouabain interfered with glucogenic as well as kaliogenic insulin secretion. Subsequent in vivo studies in experimental animals [42, 43] and human volunteers [45] showed that hyperkalemia also elicits increased insulin secretion in man. In the dog, elevation of serum potassium by as little as 0.2 to 0.3 mEq/liter is sufficient to induce insulin release [42, 53]. Dluhy, Axelrod, and Williams [45] studied ten human volunteers whose sodium intakes were either 10 5) or 200 mEq/day (N = 5). They mEq/day (N infused 75 mEq of potassium chloride over 120 mm when dietary potassium intake was 40 mEq/day and again when it was 200 mEq/day. Sodium intake had no apparent effect. (This is a surprising observation: in the rat, sodium restriction induces at least partial potassium adaptation [59]). Studies were conducted when balance was achieved. During infusion of po-

54, 55]. The capacity to dissipate acute hyperkalemia

in the insulin-deficient animal, however, can be restored by insulin [54]. Hyperkalemia induced by infusion of potassium salts is spontaneously corrected by excretion of potassium into the urine, as well as temporary transfer of potassium from extracellular to intracellular fluid. Repeated bouts of hyperkalemia or steadily increasing potassium in the diet leads to a state of potassium adaptation [56—581. In this acquired state, acute loads

of potassium, which previously would have been fatal, can be safely administered without harmful effects. Strong evidence indicates that increased aldosterone production is at least one of the factors

involved in potassium adaptation [59]. A state of potassium adaptation may well exist in advanced renal failure [60]. Most patients with chronic renal failure overproduce aldosterone [61]. They have the capacity to excrete more potassium per unit of gb-

merular filtration rate than normal subjects [60]. They also tend to develop acute hyperkalemia during administration of drugs interfering with the action of aldosterone, such as spironolactone [62, 63]. The latter response underscores the importance of aldoste-

rone production in chronic renal failure. In studies of potassium-adapted rats, we found that plasma immunoreactive insulin concentration was the same as that in control animals [64]. This and

the finding by Dluhy and his associates [451 on human subjects ingesting a diet containing 200 mEq of potassium does not mitigate the role of insulin in the

defense against hyperkalemia in the potassiumadapted state. Although highly speculative, a process

can be envisioned in which insulin is required to facilitate adaptation of mechanisms to forestall hyperkalemia, perhaps specific potassium transport sys-

Glucoregulatory hormones in potassium homeostasis

tems. Once developed, acute elevations of insulin in

response to mild hyperkalemia may no longer be required. Although equally speculative, it is possible that the molecular species of insulin could be altered in the potassium-adapted state in an opposite manner to that shown to occur in potassium deficiency [65]. Under such conditions, plasma concentration per se

would not necessarily reflect activity. At any rate, there is overwhelming evidence that either experimental or clinical insulin deficiency interfers with potassium tolerance. Hyperkalemia in diabetes mel/itus. Since induction

of only slight hyperkalemia in a normal subject is apparently counteracted by release of insulin, one would predict that patients with insulin deficiency

under the same conditions might become more hyperkalemic or at least display more prolonged hyperkalemia. As indicated earlier, the ability to counteract hyperkalemia is not only dependent upon insulin secretion but also upon an intact adrenal cortex, specifically requiring the ability to produce aldosterone. Since the onset of aldosterone action is delayed, neither its production nor its effect would appear to be emergency physiological mechanisms by

which acute hyperkalemia in a nonpotassium-

447

tonicity incident to infusion of hypertonic mannitol or sodium chloride. The effect of glucose was not examined. That such a response to hypertonicity may have clinical relevance has recently been pointed out by Goldfarb and his coworkers [68, 69]. Studying patients with diabetes mellitus associated with hyporeninemic hypoaldosteronim, they showed that acute

hyperglycemia could induce dangerous levels of hyperkalemia. The latter did not occur under con-

ditions of optimum treatment with insulin and mineralocorticoid.

More recently, evidence has been obtained by Perez and his associates [70] showing that patients with diabetes mellitus, and especially those who have been previously hyperkalemic in association with moderately advanced renal failure, display an elevated serum potassium concentration during hyper-

glycemia induced by ingesting 100 g of glucose during a glucose tolerance test. This response stands in sharp contrast to the slight decline of serum potas-

sium induced by oral ingestion of glucose in this quantity by a normal person. The role of glucagon in acute hyperkalemia. Studies

adapted subject is counterbalanced. Nevertheless,

conducted on dogs in this laboratory suggest that glucagon may play an important role in the defense

adrenal insufficiency is associated with intolerance to potassium, and the physiologic process of potassium adaptation apparently cannot develop in the absence of aldosterone production. The practical corollary of

against acute hyperkalemia [42]. Figure 2 illustrates that hyperkalemia in the dog is promptly followed by release of insulin from the pancreas. There is a simultaneous increase of glucagon secretion. It was our

this phenomenon is the propensity toward acute hyperkalemia in patients with diabetes mellitus after administration of drugs which interfere with the action of aldosterone, such as triamterene [66]. Acute hyperkalemia sufficient to alter the electro-

cardiogram may also occur with hypertonicity of plasma under certain conditions. Potassium concentration in intracellular water is very high compared to its concentration in extracellular water. A sudden increase in osmotic activity outside a cell may in turn induce an osmotic flow of water. Such a rapid flow of water through cellular pores could be accompanied

by a flux of potassium ions (solvent drag). Under normal conditions, such acute hyperkalemia would be met by a rapid release of insulin, which in turn

mg/lOG ml 100

80

pg/mi 150 125

would promote transport of potassium ions back into

100

the cell. Therefore, in normal subjects, significant hyperkalemia as a result of acute hyperglycemia would probably not occur. On the other hand, in

75 50

patients with insulin deficiency, it is not at all surpris-

—20—10 0 10 20 30 45

60 70

90

120

Time, mm

ing that hyperkalemia would occur in the event of acute hyperglycemia. Moreno, Murphy, and Goldsmith [67] showed that mild hyperkalemia could be

tration remains normal. (Reproduced through the courtesy of

similarly induced in normal subjects by sudden hyper-

SANTENSANIO

Fig. 2. In/usion o/ poiassiu,n chloride (KCI) into normal dogs resulting in release of both insulin and glucagon. Plasma glucose concen-

et al, J Lab ('un Med 8 1:809, 1973.)

Knochel

448

from the beta cell, such is not the case [72]. We have examined the relationship of serum potassium, immunoreactive insulin, immunoreactive glucagon, and glucose during exhaustive exercise in dogs (Fig. 4). During exercise there was a slow but progressive increase in the concentration of potassium. Despite hyperkalemia, insulin concentration fell. Glucose increased despite the likelihood that its utilization was greater. Glucagon showed a pronounced rise and was probably at least partially responsible for the rise in blood glucose concentration. Of interest, when the

mg/tOO ml 250

225 200 175 150

pg/mi

exercise was stopped there was a sudden, sharp rise of

400

insulin. The reason why insulin levels in plasma do not rise during exercise, despite hyperkalemia, is not completely clear. However, it seems possible that alpha-adrenergic stimulation mediated by release of

300 200 100

Time, mm

Fig. 3, Infusion of potassium chloride (KCI) into dogs viih experimental diahejes Ine//itus induced by alloxan, requiringlesspota,ssiutn to induce the same level of hj'perkalemia as observed in the normal

dog. In these dogs, glucagon rose during hyperkalernia and was associated with progressive hyperglycemia. Insulin did not increase. (Reproduced through the courtesy of SANTENSANIO et a!, .1 Lab C/in Med 8 1:809, 1973.)

catecholamines during intense exercise could possibly prevent insulin release as well as stimulate release of glucagon [26]. If the metabolic effect and secretion of

catecholamines were immediately dissipated upon completion of exercise, then one could postulate that the insulin rebound is kaliogenic. Insulin, in turn, would dissipate the hyperkalemia by promoting potassium transport into cells. We have interpreted the foregoing alterations of

contention that glucagon probably induces glyco-

insulin and glucagon during exercise to be protective in nature [72]. The rise of glucagon and the decline of

genolysis in the liver and thereby prevents acute hypoglycemia which would otherwise occur in the

glucose for the brain. In support of this notion, it was

wake of insulin secretion. In support, Figure 3 shows that plasma glucose rises during acute hyperkalemia in the animal made insulin-deficient by previous ad-

insulin would help provide an adequate supply of also shown that infusion of glucose in small quan-

ministration of alloxan. In the alloxan-treated animals, much less potassium chloride was required to

6

produce a similar degree of hyperkalemia than in

5

normal dogs. Potassium, insulin, and glucagon during exercise. It seems appropriate at this point to interject some observations made on the behavior of insulin and glucagon and their relationship to serum potassium during exhaustive physical exercise. Severe exercise is asso-

3

ciated with release of potassium ions from contracting muscle cells in sufficient quantity to produce acute hyperkalemia. This is usually not severe. During such exercise in the untrained subject, however, potassium concentration in plasma may on occasion

become sufficiently elevated to produce electrocardiographic evidence of hyperkalemia [71]. Based

upon this observation, it has been suggested that hyperkalemia-mediated arrhyth niias might be implicated in the occasional sudden death associated with massive exertion in the untrained subject. Although one might expect that acute hyperkalemia during exercise would be met by a release of insulin

—20 Mart

end

31)

60

Time, mm

Fig. 4. Glucagon and glucose rising during exhaustive exercise, se-

rum poassiuu,. Insulin declines to low levels. Upon cessation of exercise, insulin rises sharply, potassium and glucagon fall.

Glucoregulatory hormones in potassium homeostasis

449

Rapoport and Hurd [78] studied the effect of

tities (15 mg/mm/kg of body wt), started before and continued throughout exercise, prevented glucagon release. Furthermore, in other animals fasted for a sufficiently long time to deplete liver glycogen, comparable exercise was associated with release of glucagon and maintenance of blood glucose at a satisfactory level. Such avoidance of hypoglycemia during

glucose intolerance. Seven developed glucose intoler-

exercise despite the absence of liver glycogen indicates that glucose had to be derived by gluconeogenesis. It is possible that glucagon mediated this

subjects whose glucose intolerance became abnormal showed a greater decline of serum potassium. Their average values for serum potassium before and after

process. The possibility that exercise-induced hyperkalemia might be the cause of glucagon release during

thiazides were 4.6 mEq/liter and 3.4 mEq/liter, respectively. In those who demonstrated no abnor-

such exercise has not been conclusively demon-

mality, comparable values were 4.7 mEq/liter and 4.2 m Eq/liter. Conn [791 examined patients with primary aldoste-

strated. Decreased insulin production and abnormal carbohydrate metabolism in potassium deficiency. That potassium deficiency leads to a derangement of carbohy-

drate metabolism in man was first published by McQuarrie, Zierler, and Johnson in 1937 [73, 741. They described a patient with a "hypercorticoadrenal syndrome" who displayed atypical diabetes mellitus, hypertension, hypernatremia, hypokalemia, and evidence that increased dietary sodium chloride worsened the diabetes. This patient clearly resembles primary aldosteronism, as described later by Conn, Knopf, and Nesbit [75]. Following the introduction and clinical use of the benzothiadiazine diuretics, several observers noted that some patients became frankly diabetic. Shapiro,

Benedek, and Small [76] examined the effect of chiorothiazide in IS hypertensive patients with

chlorothiazide treatment in 15 patients who had either a family history of diabetes or confirmed mild

ance after receiving thiazides for one week. Potassium chloride supplements corrected the glucose in-

tolerance even if thiazides were continued. The

ronism before and after administration of supplemental potassium or after operative correction. He was the first to show clearly that glucose intolerance was associated with subnormal insulin production

and that both were corrected by either potassium supplementation or surgical correction of the aldoste-

ronism. His studies also showed that serum potassium concentration did not reliably reflect total body potassium stores.

Based upon the material presented [76—79], it would appear that clinically important carbohydrate intolerance associated with diuretic therapy is most apt to occur in patients who already have either frank diabetes or at least the preclinical disease. Perhaps related to insulin deficiency, their serum potassium

concentration may not become frankly low, and

slightly abnormal glucose tolerance tests. Fifteen normal subjects were used as controls. Both groups re-

therefore, potassium deficiency may not be suspected. Although never examined, my own observations sug-

ceived large doses of chiorothiazide for one to two weeks. In each of the hypertensive patients, glucose intolerance became more pronounced after thiazides. Five of the 15 developed symptomatic diabetes meltitus. In contrast, there was no change in the normal subjects. The hypertenisve patients also displayed a lesser decline of blood sugar in response to i.v. tolbutamide after thiazide administration. Since serum potassium declined less than 0.5 mEq/liter, the authors did not ascribe deterioration of glucose tolerance to potassium deficiency. Sagild, Andersen, and Andreasen examined the ef-

gest that patients with diabetes mellitus and glycosuria, who have associated hypertension in contrast

fect of experimental potassium deficiency on glucose utilization in five normal subjects [771. In each, the rate of glucose utilization decreased. Despite potassium deficits ranging from 200 to 500 mEq, however, serum potassium remained normal in two and fell to

to uncomplicated hypertensives, are much more likely in incur potassium deficiency as a result of diuretic therapy. If volume contraction secondary to

diuretics increases production of aldosterone, enhanced delivery of sodium to the distal nephron in the wake of the osmotic diuresis associated with glycosuria could conceivably enhance the rate of potassium loss. Furthermore, if significant potassium deficiency should occur in such patients, especially those with adult onset diabetes, it seems possible that their already marginal insulin production would become further depressed.

3.0 mEq or less in three of the five subjects. Such evidence supports the notion that the total deficit of potassium is not necessarily reflected by frank hypo-

An additional factor that could impair carbohydrate utilization in potassium deficiency is production of an abnormal molecular species of insulin. Thus, Gorden, Sherman, and Simopoulos [65] have shown that the poorly-active, pro-insulin fraction of total insulin released from the pancreas is increased

kalemia.

in potassium deficiency.

450

Knochel

Studies from this laboratory [6, 801 have shown

9. LOSTROH AJ, KRAHL ME: Insulin action: Accumulation in

that some patients with end-stage renal disease,

vitro of Mg2il and K in rat uterus; ion pump activity.

whose serum potassium concentration is clearly nor-

mal, may display moderate total body potassium deficits. Each of these patients showed impaired abil-

ity to utilize glucose. Each showed an abnormally elevated glucagon [8 1]. Conventional hemodialysis for several weeks restored glucose utilization to nor-

mal. Of interest, glucagon remained elevated and there was no apparent alteration of total insulin activity in plasma. Muscle and total body potassium content, however, rose after dialysis. Although the rise of body potassium may have facilitated improvement in glucose utilization, it is impossible to positively assign the improvement to this change. Thus, recent studies have shown that the molecular species of both insulin [82] and glucagon [83] in patients with renal failure may be abnormal. Such information obscures interpretation as to whether or not deficiency of "normal" insulin results in a higher set for serum potassium concentration in renal failure as it apparently does in patients with diabetes mellitus. That Westervelt observed a normal movement of potassium in response to insulin in patients with

renal failure [84] suggests that a true insulin deficiency may exist. Obviously, a considerable amount of work needs to be done on this important derangemen t.

Biochim Biophys Ac/a 291:260—268, 1973

10. MOORE RD: Effect of insulin upon the sodium pump in frog skeletal muscle. J Phy.siol 232:23—45. 1973 II. BRODAL BP, JEBENS E, O V. IVERSFN OJ: Effect of insulin on

(Na, K )-activated adenosine triphosphatase activity in rat muscle sarcoleinma. Nature 249:41—43, 1974 12. KIPNIS DM, PARRISH JE: Role of Na and K on sugar (2deoxyglucose) and amino acid (a-aminoisobutyric acid) transport in striated muscle. Fed Proc 24:1051-1059, 1965 13. NIZET A, LFBFBVRF P. CRABBE 0: Control by insulin of sodium, potassium and water excretion by the isolated dog kidney. Arch Gen Phvsiol 323:11—20, 1971 14. MANERY iF, GIiURLEY DRH, FISHER KU: The potassium uptake and rate of oxygen consumption of isolated frog skel-

etal muscle in the presence of insulin and lactate. Can J Bio'hem Physiol 34:893—902, 1956

IS. SMIIIIE LB, MANERY iF: Effect of external potassium concen-

trations, insulin and lactate on frog muscle potassium and respiratory rate. Aol J Physiol 198:67—77, 1960 6. ANDRE5 R, BAITZAN MA, CADER G, ZIPRI,i:R KL: Effect of

insulin on carbohydrate metabolism and on potassium in the forearm of man. 2 C/in Invest 41:108—115, 1962 17. ZIERI.ER KL: Hyperpolarization of muscle by insulin in a glucose-free environment. Am 2 Phy,siol 197:524—526. 1959 IS. HODGKiN Al, KATZ B: The effect of sodium ions on the

electrical activity of the giant axon of the squid. J Phy.sio/ 108:37—77, 1949

19. CREE5E R: Sodium fluxes in diaphragm muscle and the effects of insulin and serum proteins. 2 Phy.siol 197:225—2778. 1958 20. MOORE RD: The ionic effects of insulin. Abs Biophy.s Soc USA PA 12, 1965 21. BI.AIT LM, MCVERRY PH, KIMM KH: Regulation of hepatic

glycogen synthetase of Rana catesbeiana: Inhibition of the Reprint requests to Dr. 2. P. Knochel, Department of Internal Medicine, flniversijr of Texas, Southwestern Medical School, Dallas, lxas 75235, U.S.A References

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3. HARROP GA, BENEDICT EM: The participation of inorganic substances in carbohydrate metabolism. 2 Biol Chem 59:683, 1924

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