ORIGINAL ARTICLE

Korean J Intern Med 2015;30:648-656 http://dx.doi.org/10.3904/kjim.2015.30.5.648

Blood disturbances during severe in Korean patients with type 2 diabetes

Mi Yeon Kang

Department of Internal Medicine, Background/Aims: To investigate abnormalities in electrolyte levels during Saint Carollo Hospital, Suncheon, severe hypoglycemia in Korean patients with type 2 diabetes mellitus (T2DM) in a Korea clinical setting. Methods: Blood electrolyte levels in adult T2DM patients during severe hypo- glycemia were collected from January 1, 2008 to December 31, 2012. Patients who maintained normal and levels were utilized in the study. Severe hypoglycemia was defined as a condition requiring medical assistance, such as administering carbohydrates when serum levels less than 70 mg/dL were observed, in conjunction with other symptoms of hypoglycemia. Results: A total of 1,068 patients who visited the emergency room with severe hypoglycemia were screened, of which 219 patients were included in this study. The incidence of abnormal levels for any electrolyte was 47%. Hypokalemia (< 3.5 mmol/L) was the most common type of electrolyte disturbance observed at 21.9%. A decrease in serum potassium levels was associated with decreases in blood glu- cose levels (r = 0.151, p = 0.025). During severe hypoglycemia, median blood glucose Received : November 21, 2014 Revised : December 26, 2014 levels, incidence of tachycardia (> 100 beats per minute) and severe hypertension (≥ Accepted : April 5, 2015 180/120 mmHg) were 30 mg/dL (range, 14 to 62) and 35 mg/dL (range, 10 to 69; p = 0.04), 18.8% and 7.2% (p = 0.02), and 20.8% and 10.2% (p = 0.05) in the hypokalemia Correspondence to and normokalemia groups, respectively. Mi Yeon Kang, M.D. Department of Internal Medicine, Conclusions: During severe hypoglycemia, hypokalemia occurred in 21.9% of Saint Carollo Hospital, 221 T2DM patients and was associated with tachycardia and severe hypertension. Sungwang-ro, Suncheon 57931, Therefore, the results suggest that severe hypoglycemia may increase cardiovas- Korea Tel: +82-61-720-2428 cular events in T2DM. Fax: +82-61-720-6000 E-mail: [email protected] Keywords: Severe hypoglycemia; ; Hypokalemia; Diabetes mellitus, type 2

INTRODUCTION and is associated with increased risks of vascular events and death [3,4]. A plausible mechanism of increased Although previous studies have demonstrated that inten- cardiovascular mortality during severe hypoglycemia sive glycemic control in diabetes mellitus is important might be associated with fatal arrhythmias induced to prevent micro- and macrovascular complications during hypoglycemia [5]. Several experimental studies [1,2], the risk of hypoglycemia should not be overlooked. have observed relationships between hypokalemia and Severe hypoglycemia can cause serious conditions such prolonged corrected QT (QTc) interval, which causes as loss of consciousness, seizures, and encephalopathy fatal cardiac arrhythmias and sudden death [6-8]. It has

Copyright © 2015 The Korean Association of Internal Medicine pISSN 1226-3303 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ eISSN 2005-6648 by-nc/3.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited. http://www.kjim.org Kang MY. Electrolytes during severe hypoglycemia

been well described that a decrease in serum potassium and with symptoms of hypoglycemia [13]. during insulin induced hypoglycemia is caused both by Patients’ characteristics including age, gender, height, insulin and adrenaline [9,10]. weight, the duration of diabetes and hypertension, glu- Furthermore, a relationship between insulin induced cose lowering agents, anti-hypertensive medications, hypoglycemia and hypokalemia during hypoglycemia in smoking history, alcohol consumption, the inducing diabetes has been reported. Recently, one study reported factor for hypoglycemia, co-morbidities (coronary artery alterations of all electrolytes during insulin induced hy- disease and cerebral vascular disease) and vital signs ob- poglycemia in patients with type 1 diabetes. This study tained upon hospital arrival were examined for this study. suggested hypoglycemia causes increases in serum sodi- The vital signs were monitored hourly for all patients and um and chloride levels and decreases in serum potassium were checked more frequently for patients whose vital levels [11]. signs remained unstable. We also assessed hemoglobin However, one study reported altered serum sodium and A1c (HbA1c), plasma C-peptide levels, blood glucose lev- chloride levels during severe hypoglycemia in diabetes els, plasma insulin levels, and serum chemistry profiles rare, whereas alterations of all electrolyte levels during obtained during severe hypoglycemia before carohydrates severe , such as diabetic ketoacidosis and were administered. a hyperglycemic hyperosmolar state, have been well es- Normal ranges for the analyzed electrolyte groups (Or- tablished [12]. Incidences of hypokalemia during severe tho Clinical Diagnostics, Raritan, NJ, USA) are as follows: hypoglycemia in patients with type 2 diabetes appear to sodium (Na) 135 to 148 mmol/L, chloride (Cl) 95 to 110 be lacking in the documents. mmol/L, potassium (K) 3.5 to 5.3 mmol/L. Levels below The aim of this study was to evaluate abnormalities in the normal range are defined as hypo- and levels above blood electrolyte levels and to assess individuals’ vital the normal range are defined as hyper-. signs during severe hypoglycemia in Korean patients The patients’ blood pressure, heart rate, respiratory with type 2 diabetes in real-life conditions. rate, and body temperature were monitored both during the severe hypoglycemic stage and the recovery stage. The recovery stage was defined as the patients’ condition upon METHODS recovery from severe hypoglycemia and being discharged from the emergency room. These individuals were not Research design and methods treated with antihypertensive or vasopressor drugs during Medical records for adult type 2 diabetic patients who this period. Tachycardia was defined as a heart rate of > experienced hypoglycemia and were treated with glucose 100 beats per minute. Severe hypertension is a systolic were collected from the Emergency Department in the blood pressure of ≥ 180 mmHg or a diastolic blood pres- Saint Carollo Hospital from 1 January, 2008 to 31 De- sure of ≥ 120 mmHg [14]. The patient’s body temperature cember, 2012. The criteria for patient inclusion were the was measured via tympanic membrane and hypothermia diagnosis of type 2 diabetic mellitus and a serum glucose was defined by a body temperature of < 35°C [15]. level < 70 mg/dL. Serum electrolyte, creatinine, blood urea nitrogen (BUN) and glucose levels were recorded prior to Statistical analysis the administration of carbohydrates by the Emergency The data were analyzed using the SPSS version 13.0 Department. The exclusion criteria included patients (SPSS Inc., Chicago, IL, USA). Normally distributed data under 20 years old, patients with abnormal serum creat- are presented as the mean ± standard deviation and inine or BUN levels, and patients with alternative causes non-normally distributed data are presented as the me- of electrolyte disturbances or vital signs’ changes such dian range. Continuous variables were compared using as severe diarrhea, chronic alcoholism, liver cirrhosis, a Mann-Whitney U test or paired t test. Categorical vari- malignancy, infection, and adrenal insufficiency. Severe ables were compared using chi-square tests. Correlations hypoglycemia was defined as a condition requiring active were evaluated using Pearson correlation coefficient or medical assistance, such as administering carbohydrate Spearman rank correlation coefficient. Thep value < 0.05 when the serum glucose level was less than 70 mg/dL, was considered statistically significant.

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RESULTS 0.57) (Table 1). The majority of patients treated with oral glucose-lowering agents were also taking sulfonylureas Of the 1,068 patients who visited the emergency room (88.3%). with severe hypoglycemia and were screened, 219 patients The occurrence of normal levels for the electrolytes— were analyzed for this study, 90 of whom were male. serum potassium, sodium, and chloride—was 53% (116/219 The mean patient age was 71.0 ± 10.7 years. The median patients). Of the 47% of patients with electrolyte distur- duration of diabetes was 10 years (range, 0.08 to 40). The bances, 39.7% (87/219 patients) of patients were abnormal median duration of hypertension was 7 years (range, 0.33 in one electrolyte level and 7.3% (16/219 patients) in two to 40) and 66.2% of the subjects had a medical history of electrolyte levels. A disturbance in all three electrolyte hypertension. The mean HbA1c levels were 6.6% ± 1.7%, levels was not observed. The most common type of elec- while the median blood glucose levels were 34 mg/dL trolyte disturbance present during severe hypoglycemia (range, 6 to 69). Treatments for type 2 diabetes including was pure hypokalemia at 18.7% (41/219 patients) (Fig. 1). oral glucose-lowering agents alone, insulin therapy alone The median serum potassium levels during severe and a combination of both therapies were 79.0%, 12.1%, hypoglycemia were 3.92 mmol/L (range, 2.61 to 5.86). Se- and 8.9%, respectively. The treatment methods for type rum potassium and blood glucose levels were positively 2 diabetes were not significantly different for those with correlated during severe hypoglycemia (r = 0.151, p = 0.025) hypokalemia (hypo-K) and normokalemia (normo-K; p = (Fig. 2A) and also showed significant correlation when ad-

Table 1. Summary of patients' information collected during a severe hypoglycemic event Variable Total Hypokalemia Normokalemia p value No. of individuals 219 48 167 4 Age, yr 71.0 ± 10.7 69.4 ± 11.1 71.4 ± 10.6 71.3 ± 11.8 0.13 Sex, male:female 90:129 20:28 69:98 1:3 0.97 Duration of diabetes, yr 10 (0.08–40.0) 10 (0.083–40.0) 10 (0.16–40) 10 (3–20) 0.06 Hypertension 145 (66.2) 34 (70.8) 108 (64.7) 3 (75.0) 0.43 Duration, yr 7 (0.33–40) 10 (0.33–40) 10 (1–40) 8 (8–10) 0.87 ARB/ACE inhibitors 50 11 39 0 0.49 Diuretics 22 5 17 0 0.80 β-Blockers 13 6 6 1 0.07 channel blockers 36 10 25 1 0.69 Treatment of diabetes 214 47 163 4 0.57 OHA alone 169 (79.0) 35 (74.5) 131 (80.4) 3 (75.0) Insulin alone 26 (12.1) 6 (12.8) 19 (11.7) 1 (25.0) Combination 19 (8.9) 6 (12.8) 13 (8.0) 0 HbA1c, % 6.6 ± 1.7 6.9 ± 1.9 6.5 ± 1.7 5.7 ± 0.0 0.49 Blood glucose, mg/dL 34 (6–69) 30 (14–62) 35 (10–69) 46 (6–65) 0.04 Serum sodium, mmol/L 141.5 ± 4.8 141.8 ± 3.7 141.4 ± 5.1 139.2 ± 3.9 0.78 Serum chloride, mmol/L 103.5 ± 5.1 102.6 ± 4.7 103.8 ± 5.3 102.6 ± 3.8 0.12 Serum potassium, mmol/L 4.0 ± 0.6 3.2 ± 0.2 4.1 ± 0.4 5.7 ± 0.2 < 0.01 Values are presented as number, mean ± SD, median (interquartile range), or number (%). A p value indicates comparison of participant characteristics between hypokalemia and normokalemia groups. Vital signs and laboratory data during severe hy- poglycemia were measured upon hospital arrival. ARB, angiotensin II receptor blockers; ACE, angiotensin-converting enzyme; OHA, oral hypoglycemic agent; HbA1c, hemoglo- bin A1c.

650 www.kjim.org http://dx.doi.org/10.3904/kjim.2015.30.5.648 Kang MY. Electrolytes during severe hypoglycemia

(%) Pure electrolyte disturbnace 60 Mixed electrolyte disturbance (%) 25

50 Hypo- 20 Hyper- 40 15 30

10 20

5 10

0 0 Potassium Sodium Chloride Normal Abnormal A B Figure 1. (A) The incidence of normal and abnormal blood electrolytes during severe hypoglycemia. (B) In pure electrolyte dis- turbances, the incidence of each electrolyte disturbance. The normal ranges for each electrolyte are defined as follows: sodium 135 to 148 mmol/L, chloride 95 to 110 mmol/L, potassium 3.5 to 5.3 mmol/L. Levels below the normal range are defined as hypo- and levels above the normal range are defined as hyper-. A pure electrolyte disturbance was defined as an abnormal level in the one electrolyte and a mixed electrolyte disturbance was defined as two or three electrolyte levels being abnormal.

6 160 120

110 5 150

100 4 140 90 K (mmol/L) CI (mmol/L) 3 (mmol/L) Na 130 80 r = 0.151, p = 0.025 r = –0.005, p = 0.938 r = –0.111, p = 0.102 2 120 70 0 10 20 30 40 50 60 70 80 0 10 20 30 40 50 60 70 80 0 10 20 30 40 50 60 70 80

Glucose (mg/dL) Glucose (mg/dL) Glucose (mg/dL)

A

160 155 120 155 150 115 150 110 145 105 145 140 100 140 95 135 135 90 CI (mmol/L) Na (mmol/L) Na (mmol/L) Na 130 130 85 80 125 125 r = –0.075, p = 0.270 r = 0.60, p = 0.000 75 r = 0.071, p = 0.296 120 120 70 2 2.5 3 3.5 4 4.5 5 5.5 6 75 80 85 90 95 100 105 110 115 120 2 2.5 3 3.5 4 4.5 5 5.5 6 B K (mmol/L) CI (mmol/L) K (mmol/L)

Figure 2. (A) Correlation between the blood glucose and each electrolyte during severe hypoglycemia. (B) Correlation between the blood electrolyte levels during severe hypoglycemia.

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(%) (%) (%)

100 100 100

80 80 80

60 60 60

40 40 40

20 20 20 76.3 21.9 84.9 84.5 1.8 11.0 4.1 4.1 11.4 0 0 0 n = 48 n = 167 n = 4 n = 24 n = 186 n = 9 n = 9 n = 185 n = 25 Potassium Sodium Chloride

Hypokalemia Normokalemia Hyponatremia Normonatremia Hypochloremia Normochloremia Hyperkalemia Hypernatremia A B C

Figure 3. The incidence of each electrolyte during severe hypoglycemia. (A) Potassium, (B) sodium, and (C) chloride are shown.

= 0.04). The prevalence of preexisting hypertension, the 6 r = 0.175, p = 0.009 duration of hypertension and the use of antihypertensive agents were not significantly different between the hy-

5 po-K and normo-K groups. The patients’ age and serum potassium levels during hypoglycemia were positively correlated (r = 0.175, p = 0.009) (Fig. 4). However, no signif- 4 icant difference in patient age was observed between the hypo-K and normo-K groups (69.4 ± 11.1 years vs. 71.4 ±

K (mmol/L) 3 10.6 years, p = 0.13). Furthermore, there were no significant differences in HbA1c, serum sodium and serum chloride levels between the hypo-K and normo-K groups (Table 1). 2 The median sodium and chloride levels during severe 20 30 40 50 60 70 80 90 100 hypoglycemia upon emergency room arrival were 142.3 Age (yr) mmol/L (range, 124.9 to 150.5) and 103.2 mmol/L (range, Figure 4. Correlation between patient age and serum potas- 80.1 to 116.0), respectively. No correlation between blood sium levels during severe hypoglycemia. glucose levels and both serum sodium (r = –0.005, p = 0.938) and serum chloride levels (r = –0.111, p = 0.102) was observed. However, serum sodium levels and chloride justed by age (r = 0.167, p = 0.013). However, no correlations levels were highly correlated (r = 0.60, p = 0.000) (Fig. 2). between serum potassium and sodium levels (r = –0.075, p The presence of hyponatremia (n = 24), normonatremia = 0.270) or serum potassium and chloride levels (r = 0.071, (n = 186), and hypernatremia (n = 9) were 11.0%, 84.9%, p = 0.296) were observed during a hypoglycemic event (Fig. and 4.1%, respectively (Fig. 3B). The incidences of hypo- 2B). The incidences of hypo-K (n = 48), normo-K (n = 167), chloremia (n = 9), normochloremia (n = 185), and hyper- and hyperkalemia (hyper-K, n = 4) were 21.9%, 76.3%, and chloremia (n = 25) were 4.1%, 84.5%, and 11.4%, respectively 1.8 %, respectively (Fig. 3A). In the hypo-K and normo-K (Fig. 3C). No additional clinical parameters or subgroups groups, the median blood glucose levels were 30 mg/dL were classified by the serum sodium and chloride levels. (range, 14 to 62) and 35 mg/dL (range, 10 to 69), respec- Heart rate, systolic, and diastolic blood pressure were tively. Blood glucose levels were significantly lower in the significantly different during the severe hypoglycemia hypo-K group when compared to the normo-K group (p stage, as compared to the recovery stage (Table 2). How-

652 www.kjim.org http://dx.doi.org/10.3904/kjim.2015.30.5.648 Kang MY. Electrolytes during severe hypoglycemia

Table 2. A comparison of blood pressure and heart rate between the severe hypoglycemic stage and the recovery stage Variable Hypoglycemia (n = 219) Recovered stage (n = 213) p value Heart rate, beats/min 81.3 ± 14.1 77.3 ± 12.8 0.000 Tachycardiaa 21 (9.6) 10 (4.7) 0.049 Systolic blood pressure, mmHg 146.6 ± 25.5 135.5 ± 19.3 0.000 Diastolic blood pressure, mmHg 84.6 ± 13.2 80.4 ± 12.0 0.000 Severe hypertensionb 29 (13.2) 4 (1.9) 0.000 Values are presented as means ± SD or number (%). aTachycardia was defined as a heart rate of > 100 beats per minute. bSevere hypertension was defined as a systolic blood pressure of ≥ 180 mmHg or a diastolic blood pressure of ≥ 120 mmHg.

ever, during severe hypoglycemia, heart rate, systolic, and disturbances, with pure hypokalemia being the most diastolic blood pressure were not significantly different common type. Furthermore, a positive relationship among the electrolyte subgroups (Table 3), nor did these between a decrease in serum potassium and a decrease parameters differ significantly when examining blood in plasma glucose was observed, and hypokalemia was glucose levels. associated with tachycardia and severe hypertension. The incidences of tachycardia and severe hypertension Therefore, this study suggests that hypokalemia asso- during severe hypoglycemia were significantly higher ciated with hypoglycemia may be associated with the than those of the recovery stage (9.6% vs. 4.7%, p = 0.049) increased risks of cardiovascular events in type 2 diabetes (13.2% vs. 1.9%, p = 0.000) (Table 2). In the hypo-K and during severe hypoglycemia. normo-K groups, the incidences of tachycardia during Previous epidemiological studies have shown that severe hypoglycemia were 18.8% and 7.2%, respectively. the incidence of severe hypoglycemia due to efforts to The presence of tachycardia was significantly higher in intensively control glucose has increased [16,17]. Severe the hypo-K group than in the normo-K group during hypoglycemia could lead to arrhythmias, cardiovascular severe hypoglycemia (p = 0.02). Although the incidence events, dementia, and death [18,19]. It is well accepted that of severe hypertension during severe hypoglycemia did the prolongation of QTc intervals related to ventricular not significantly differ between the hypo-K and normo-K arrhythmias and sudden death is induced by severe hypo- groups (p = 0.05), the incidence of severe hypertension of glycemia in patients with both type 1 and type 2 diabetes the hypo-K group was twice that of the normo-K group [20]. Although hypoglycemia itself without hypokalemia (20.8% vs. 10.2%). However, for the serum electrolyte sub- might cause the prolongation of QTc interval in patients groups, sodium, and chloride, the incidences of tachycar- with type 2 diabetes [21], hypoglycemia with hypokalemia dia and severe hypertension during severe hypoglycemia could augment the prolongation of the QTc interval were not significantly different (Table 3). [6,20]. Moreover, hypokalemia-associated with hypogly- No significant differences in body temperature between cemia is known to be associated with hyperinsulinemia the severe hypoglycemic stage and the recovery stage were and the increased secretion of catecholamines [20,22]. observed (36.14°C ± 0.25°C vs. 36.14°C ± 0.26°C, p = 0.87), One previous study reported that during severe hy- and no cases of hypothermia were recorded. poglycemia, the incidence of hypokalemia was 42.4% and 36.3% in type 1 and type 2 diabetes, respectively [19]. They suggested hypokalemia shows another threat asso- DISCUSSION ciated with severe hypoglycemia [19]. The present study demonstrated the incidence of hypokalemia was 21.9% This study is the first to examine electrolyte profiles in type 2 diabetes during severe hypoglycemia and also during severe hypoglycemia in patients with type 2 dia- found that serum potassium and blood glucose levels betes in clinical practice. The results demonstrated that were positively correlated during severe hypoglycemia. In 47% of patients with severe hypoglycemia had electrolyte the present study, the presence of hypokalemia was lower

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than that of the aforementioned study, most likely due 0.42 0.35 0.30 0.62 0.83 value to a lower number of patients treated with insulin ther- p apy (21.0% vs. 51.0%). Additionally, hypothermia was not observed in this study while the previous study reported the incidence of hypothermia as 22.6%. Therefore it is

25 speculated that hypokalemia might be associated with 3 (12.0) 1 (4.0) 83.6 ± 11.5 79.0 ± 14.7

142.0 ± 24.0 relative hyperinsulinemia and hypothermia during severe

Hyperchloremia hypoglycemia. Lower doses of thiazide or thiazide-like diuretics can cause a significant decrease in serum potassium levels [23]. Conversely, angiotensin II receptor blockers and (9.7) (13.5)

± 13.7 ± 25.3 ± 13.5 185 angiotensin-converting enzyme inhibitors can induce 25 18 Chloride (normal range, 95–110 mmol/L) 81.5

84.6 hyperkalemia [24]. Several experimental studies have 146.9 Normochloremia demonstrated that the β-adrenoreceptor blockade at- tenuates the decrease in serum potassium during in- 120 mmHg. 120 0.32 0.77 0.26 0.92 0.41

value sulin-induced hypoglycemia [9,10]. However, this study ≥ p could not find any antihypertensive agents associated with hypokalemia during severe hypoglycemia due to multidrug regimens and limited data. 186 (10.2) (14.5) ± 14.6 ± 25.8 ± 13.5

Only one previous experimental study has reported

27 19 that insulin-induced hypoglycemia provokes increases 81.7 84.8 147.3 Normonatremia in serum sodium and serum chloride levels, but de- creases serum potassium levels during hypoglycemia. They suggested these changes in blood electrolyte levels ± 12.2 (8.3) ± 25.9 ± 12.5 (8.3) 24

2 2 during hypoglycemia could be explained by the effect

79.1 + + 84.6

Sodium (normal range, 135–148 mmol/L) of insulin and catecholamines on the Na /K pump [11]. 140.8 Hyponatremia It was this study that first described the disturbance of serum sodium and serum chloride levels during severe 180 mmHg or a diastolic blood pressure of 0.20 0.02 0.67 0.89 0.05 value ≥

p hypoglycemia in a clinical setting. However, contrary to our expectations, this study demonstrated that serum potassium levels were not associated with serum sodium

± 13.6 and serum chloride levels during severe hypoglycemia. ± 24.0 ± 13.0 (7.2) (10.2) 167

17 12 Additionally, this study suggested that the serum sodium 80.8 84.6 146.5

Normokalemia and serum chloride disturbances during severe hypo- glycemia may not negatively affect heart rates and blood pressure. However, this could not be confirmed as the ± 16.0 ± 29.7 ± 14.3 reported change of serum sodium and serum chloride 48 (18.8) (20.8)

9

10 levels with or without the change of serum potassium 84.0 84.6 146.3 Hypokalemia Potassium (normal range, 3.5–5.3 mmol/L) levels during severe hypoglycemia could not be located. Several studies have reported that sympathoadrenal

b activation response to hypoglycemia resulted in increases in heart rates and blood pressure [19,25,26]. Similarly, this

a study also observed significant increases in heart rates and blood pressure during severe hypoglycemia, as com- pared to the recovery stage. Incidences of tachycardia and severe hypertension were significantly different during Severe hypertension was defined as a systolicblood pressureof Variable Number Hear rate, beats/min Tachycardia mmHg SBP, mmHg DBP, hypertensionSevere Tachycardia was defined heartas a 100rateof > beats per minute. Table 3.Table The comparisons of blood pressure and heart rate between each subgroup of electrolytes analyzed during a severe hypoglycemic event Values are presented as means ± SD or number (%). systolicSBP, blood pressure; diastolic DBP, blood pressure. a b

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severe hypoglycemia, as compared to the recovery stage. Group. The effect of intensive treatment of diabetes on This study is the first to demonstrate that the incidences the development and progression of long-term compli- of tachycardia and severe hypertension were higher in the cations in insulin-dependent diabetes mellitus. N Engl J hypo-K group than in the normo-K group during severe Med 1993;329:977-986. hypoglycemia. This further supports the theory that 2. UK Prospective Diabetes Study (UKPDS) Group. Intensive adrenalin release during hypoglycemia drives potassium blood-glucose control with sulphonylureas or insulin into the cell as suggested in previous studies [22,27]. compared with conventional treatment and risk of com- A few limitations were observed with this study. First- plications in patients with type 2 diabetes (UKPDS 33). ly, due to a limited sample size, the association between Lancet 1998;352:837-853. electrolyte disturbances and insulin and C-peptide levels 3. Oyer DS. The science of hypoglycemia in patients with could not be examined. Secondly, records of counter-reg- diabetes. Curr Diabetes Rev 2013;9:195-208. ulatory hormones responding to hypoglycemia could 4. Zoungas S, Patel A, Chalmers J, et al. Severe hypoglyce- not be located; however, they are checked routinely in a mia and risks of vascular events and death. N Engl J Med clinical setting. This study provides important clinical 2010;363:1410-1418. information about severe hypoglycemia; however, fur- 5. Chow E, Bernjak A, Williams S, et al. Risk of cardiac ar- ther studies involving larger sample sizes from multiple rhythmias during hypoglycemia in patients with type 2 centers are needed to confirm these results. diabetes and cardiovascular risk. Diabetes 2014;63:1738- In summary, this study showed that electrolyte distur- 1747. bances occurred in type 2 diabetes patients with severe 6. Marques JL, George E, Peacey SR, et al. Altered ventricular hypoglycemia, and hypokalemia was the most common repolarization during hypoglycaemia in patients with di- type. Furthermore, hypokalemia-associated with hypo- abetes. Diabet Med 1997;14:648-654. glycemia provoked tachycardia and severe hypertension 7. Landstedt-Hallin L, Englund A, Adamson U, Lins PE. In- during severe hypoglycemia. creased QT dispersion during hypoglycaemia in patients with type 2 diabetes mellitus. J Intern Med 1999;246:299- 307. KEY MESSAGE 8. Heller SR. Abnormalities of the electrocardiogram during 1. A total of 47% of type 2 diabetic patients with se- hypoglycaemia: the cause of the dead in bed syndrome? vere hypoglycemia exhibited electrolyte distur- Int J Clin Pract Suppl 2002;(129):27-32. bances, with pure hypokalemia being the most 9. Petersen KG, Schluter KJ, Kerp L. Regulation of serum common type. potassium during insulin-induced hypoglycemia. Diabe- 2. A positive relationship between a decrease in tes 1982;31:615-617. serum potassium and a decrease in plasma glu- 10. Fisher BM, Thomson I, Hepburn DA, Frier BM. Effects cose during severe hypoglycemia was observed. of adrenergic blockade on serum potassium changes in 3. Hypokalemia-associated with hypoglycemia was response to acute insulin-induced hypoglycemia in non- associated with tachycardia and severe hyper- diabetic humans. Diabetes Care 1991;14:548-552. tension during severe hypoglycemia. 11. Caduff A, Lutz HU, Heinemann L, Di Benedetto G, Ta- lary MS, Theander S. Dynamics of blood electrolytes in repeated hyper- and/or hypoglycaemic events in patients Conflict of interest with type 1 diabetes. Diabetologia 2011;54:2678-2689. No potential conflict of interest relevant to this article 12. Kitabchi AE, Nyenwe EA. Hyperglycemic crises in dia- was reported. betes mellitus: diabetic ketoacidosis and hyperglycemic hyperosmolar state. Endocrinol Metab Clin North Am 2006;35:725-751. REFERENCES 13. Workgroup on Hypoglycemia, American Diabetes Associ- ation. Defining and reporting hypoglycemia in diabetes: 1. The Diabetes Control and Complications Trial Research a report from the American Diabetes Association Work-

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