SUBJECTS AND METHODS
Ten NIDDM patients taking only oral hypoglycemic agents or controlled on diets and four nondiabetic control subjects participated in this study after informed consent. Besides diabetes mellitus, these patients had no evidence of other diseases including hypertension, renal insufficiency or proteinuria by history, physical examination, or laboratory testing. Oral hypoglycemic agents were withheld 3 days before the day of study, and otherwise, receiving their usual diets, all fasted overnight. The subjects remained supine from 10 AM to the end of the study at 1 PM. Starting at 11AM after a baseline period of 1 hr, they drank 100 g of glucose in 200 ml water and were observed for the next 2 h. Venous blood, taken via an indwelling catheter in antecubital vein containing heparin on line to prevent clotting and avoiding hemolysis in procedure of serum preparation right after collection of blood with extreme care if indicated, at 0 just before oral intake of glucose, 30, 60, 90, 120 min, was analyzed for serum potassium, sodium, and venous pH (by automated multiple analysis system using ion selective electrodes and glucose oxidase method, Nova profile 5), serum creatinine (by automated bichromatic analysis system, Hitachi 736–20), and serum osmolality by freezing point depression (Model 3D II, Advanced Instruments, INC., Massachusetts, U.S.A). Serum aldosterone level of all prepared and stored serums at −20°C was measured by radioimmunoassay (Kit from Abbott laboratory) at same time. Nondiabetic control subjects were designated as group 1. Diabetic subjects were divided in two groups according to mean values of changes of serum potassium levels from baselines throughout the study for 2 hours after oral glucose loading, i.e., group 2 and 3 with increases and decreases of it respectively. Differences between groups were evaluated using Student’s t tests. Results were expressed as mean±SE or mean±SD as appropriate.
DISCUSSION
When normal subjects are given hypertonic glucose acutely, an early transfer of potassium to the extracellular fluid, due to hypertonicity
1–4), occurs, but a concomitant increase in insulin secretion facilitating the intracellular movement of both glucose and potassium produces the decrease in serum potassium frequently leading to hypokalemia as the net result
5–11). Similarly, in this present study, after acute oral glucose loading, four control subjects were followed by a gradual decrease in changes of mean values of serum potassium with the fall of a mean value of 0.36 mEq/L at 120 minutes and reached the hypokalemic range (serum potassium concentration < 3.5 mEq/L) in three of four control subjects (
Fig. 1). However, in diabetic subjects, since the report of Goldfarb et al.
6,7) in 1975 and 1976 describing two patients with diabetes mellitus and selective hypoaldosteronism, in addition to baseline hyperkalemia showing acute increases in serum potassium levels in response to hyperglycemia after intravenous administration of glucose, several studies confirmed this so called paradoxical increase in serum potassium concentration after oral or intravenous glucose loading
8–11). The two patients in the study of Goldfarb et al.
6) and many patients in the study of Perez et al.
8) observed this paradoxical increase in diabetic subjects with baseline hyperkalemia, some degree of renal insufficiency and with combined insulin and aldosterone deficiency. In the normal subjects and in two patients with either aldosterone or insulin deficiency alone in the report of Goldfarb et al.
6), the serum potassium levels were lowered or not changed. But, in 1978, Viberti
9) found that this paradoxical increase in serum potassium by 0.2 to 1.0 mEq/L (mean, 0.6 mEq/L) in eight diabetics with normal potassium levels, normal renal function and without “clinically overt” hypoaldosteronism, though aldosterone levels were not measured in this study. Also, in 1978, Ammon et al.
10) reported a diabetic patient, who exhibited glucose induced paradoxical increase despite normal plasma and urinary aldosterone levels, and in 1981, Nicolis et al.
11) observed four insulin deprived patients with diabetes mellitus and normal potassium and aldosterone levels, who became paradoxically hyperkalemic after 100 g of oral glucose loading with a rise of blood potassium concentrations averaging 1.3 mEq/L (range, 0.7 to 1.8 mEq/I) greater than those observed by Perez et al. and Viberti
8,9). As described in these previous studies, the underlying mechanisms whereby these paradoxical increases of potassium concentrations in diabetic subjects and complex roles of lack of insulin, presence or absence of aldosterone, and other contributing factors such as baseline potassium level, renal insufficiency and previous potassium balance were not well defined so far.
As reported, most of these previous study subjects were insulin deprived (Insulin dependent diabetes mellitus, IDDM, Type 1 DM) or at least insulin requiring patients
6–11). There is a paucity in the study of potassium derangements following the acute glucose loading in subjects of noninsulin dependent diabetes mellitus (NIDDM, Type 2 DM). However, many other frequent studies revealing subjects at a risk of hyperkalemia out of proportion to the degree of renal impairments with a propensity toward underlying selective hypoaldosteronism were commonly associated with noninsulin dependent diabetic patients, (type 2 DM) as well as insulin dependent diabetes mellitus, (type 1 DM)
12–14).
This study was aimed to see the prevalence of paradoxical increases of serum potassium concentrations in oral hypoglycemic agents or diet controlled noninsulin dependent diabetes mellitus (NIDDM) following acute oral glucose load as well as the presence or absence of hypoaldosteronism, changes of serum aldosterone levels, other factors such as pH and the contribution of them toward the possible changes of serum potassium after oral glucose loading.
The results of these studies showed that, in noninsulin dependent diabetics who are in two physiologic defects, i.e, abnormal insulin secretion and resistance to insulin action in target tissues
15), the rise in blood glucose after oral glucose administration leading to hyperosmolality elicited heterogeneous responses with changes in mean values of serum potassium with gradual paradoxical increases up to about 0.44 mEq/L at 120 minutes in six diabetic subjects of ten diabetic patients. In the remaining 4 patients, with similar decreases up to about 0.34 mEq/L in changes of mean values of serum potassium levels was like that seen in four nondiabetic control subjects. Three of four nondiabetic subjects and two of four diabetic patients with these similar decreases in serum potassium became hypokalemic (serum potassium concentration<3.5 mEq/L), whereas no patient of six diabetic patients with paradoxical increases of serum potassium developed hyperkalemia (serum potassium concentration>5.0mEq/L) (
Fig. 1). These findings, compared to higher incidence of hyperkalemia of previous studies of mostly insulin requiring patients, would be related to relative lack of baseline hyperkalemia in our study subjects. Baseline serum potassium levels showed a significant difference (3.7±0.1 vs 3.9±0.1 mEq/L, p<0.05) as well as baseline serum osmolality (288±2 vs 301±1 mOsm/Kg water, p<0.05) between these two diabetic subgroups (
Table 2). The reasons for these heterogeneous responses for ten NIDDM patients are unclear yet. But, in view of significant correlation between both mean values of changes of serum osmolality and those of serum potassium changes (
Fig. 4), as well as between mean values of increments in serum glucose and those in serum osmolar changes (
Fig. 3) in all diabetic subjects and nondiabetic control subjects, and equal significant difference of baseline serum potassium and baseline serum osmolality, diverse hyperosmolality related to various degree of abnormal insulin secretion and end organ resistance to the effects of insulin in noninsulin dependent diabetics would be at least in part the likely answers for it. In more recent studies, hyperosmolality induced with hypertonic saline caused hyperkalemia equally in diabetic and in diabetic patients
16), and in the patients with renal failure acute increase in blood osmolality by hypertonic NaCl was a cause of hyperkalemia independent of insulin levels
17). This suggests that hyperosmolality may cause increased blood potassium levels even when insulin levels are normal. Therefore, the role of insulin regulating potassium metabolism in humans is complex and incompletely known.
All ten diabetic subjects, in whom heterogeneous response in serum potassium levels developed when they were fed glucose, had normal baseline serum levels of aldosterone and potassium. The paradoxical rises and falls in serum potassium concentrations in both ten diabetics and four control subjects parallels the rises and falls of changes in mean values of serum aldosterone levels (
Fig. 5). Our findings support that aldosterone deficiency is not a prerequisite for hyperkalemic effects of hypertonicity in diabetics
9–11,16), and aldosterone responds promptly to even minor changes in blood potassium concentration (0.2 to 0.3 mEq/L) as a potent and directly acting aldosterone secretogogue independent of changes in extracellular fluid volume and the renin-angiotensin system
18,19), but they indicate that this response is not immediately effective in returning plasma potassium level toward normal.
This conclusion agrees with the well-known time delay intervening between the administration of aldosterone and the onset of a kaliuretic response
20). However, in this study, since blood insulin levels were not measured, the influence of mineralocorticoid replacements were not evaluated, and NIDDM patients with hypoaldosteronism were not included for oral glucose loading, still the complex hormonal, especially insulin and aldosterone, roles in derangements of serum potassium in NIDDM patients after oral glucose loading remains to be solved and needs more study. But, we can only speculate on the importance of these two factors in our present study.
In addition to two hormones-Insulin and aldosterone, and the degree of hypertonicity, other factors such as blood pH
21,22) and beta adrenergic receptors
23,24) may contribute to potassium derangements by the influences on transcellular movement of potassium. Metabolic acidosis and inhibition of beta adrenergic receptor with medication were known as factors to develop hyperkalemia. But, the subjects in our study had no medications of beta blockers or beta stimulators and no evidence of clinically overt autonomic neuropathy. In venous pH, the subgroup of diabetic subjects with decrease in serum potassium after glucose load was significantly more acidemic with higher baseline serum potassium level compared to the other subgroup of diabetics with paradoxical increase in serum potassium after it (3.9±0.1 vs 3.7±0.1 mEq/L in serum potassium levels, 7.37±0.01 vs 7.40±0.01 in venous pH, p<0.05) (
Table 2). However, there was no uniform parallel changes in venous pH on time course following the changes of serum potassium after oral glucose loading in diabetic and control subgroups (
Fig. 6).
In conclusion, the heterogeneous serum potassium changes after acute oral glucose loading were observed in noninsulin dependent diabetes mellitus (NIDDM) patients. More than half of these NIDDM patients (six of ten) showed the paradoxical increases in serum potassium levels in the presence of baseline normokalemia, normal renal function and normal aldosterone levels. These abnormalities may predispose to unexpected acute aggravation of hyperkalemia, particularly in the setting of baseline hyperkalemia already challenged by severe acidosis, impaired renal function, severe hyperglycemia, or with potassium salts or potassium-sparing diuretics. The mechanism of this heterogeneity of serum potassium changes in NIDDM would be related to in part various degree of abnormal insulin secretion and end organ resistance in insulin effects, but it remains for more study including further clarification of complex roles of both insulin and aldosterone in addition to other factors, such as hypertonicity, blood pH and beta adrenergic receptors.