Copyright ©2014 Baishideng Publishing Group Inc. All rights reserved.
World J Clin Cases. Oct 16, 2014; 2(10): 488-496
Published online Oct 16, 2014. doi: 10.12998/wjcc.v2.i10.488
Diabetes mellitus and electrolyte disorders
George Liamis, Evangelos Liberopoulos, Fotios Barkas, Moses Elisaf
George Liamis, Evangelos Liberopoulos, Fotios Barkas, Moses Elisaf, Department of Internal Medicine, School of Medicine, University of Ioannina, Stavrou Niarchou Avenue, 45110 Ioannina, Greece
Author contributions: Liamis G, Liberopoulos E, Barkas F and Elisaf M contributed to this paper.
Correspondence to: George Liamis, MD, PhD, Assistant Professor of Internal Medicine, Department of Internal Medicine, School of Medicine, University of Ioannina, Stavrou Niarchou Avenue, 45110 Ioannina, Greece.
Telephone: +30-26-51007509 Fax: +30-26-51007016
Received: December 25, 2013
Revised: July 24, 2014
Accepted: September 23, 2014
Published online: October 16, 2014


Diabetic patients frequently develop a constellation of electrolyte disorders. These disturbances are particularly common in decompensated diabetics, especially in the context of diabetic ketoacidosis or nonketotic hyperglycemic hyperosmolar syndrome. These patients are markedly potassium-, magnesium- and phosphate-depleted. Diabetes mellitus (DM) is linked to both hypo- and hyper-natremia reflecting the coexistence of hyperglycemia-related mechanisms, which tend to change serum sodium to opposite directions. The most important causal factor of chronic hyperkalemia in diabetic individuals is the syndrome of hyporeninemic hypoaldosteronism. Impaired renal function, potassium-sparing drugs, hypertonicity and insulin deficiency are also involved in the development of hyperkalemia. This article provides an overview of the electrolyte disturbances occurring in DM and describes the underlying mechanisms. This insight should pave the way for pathophysiology-directed therapy, thus contributing to the avoidance of the several deleterious effects associated with electrolyte disorders and their treatment.

Key Words: Glucose, Osmotic diuresis, Hyponatremia, Hyperkalemia, Hypomagnesemia

Core tip: Diabetic patients frequently develop a constellation of electrolyte disorders. These patients are often potassium-, magnesium- and phosphate-depleted, especially in the context of diabetic ketoacidosis or nonketotic hyperglycemic hyperosmolar syndrome. Diabetes is linked to both hypo- and hyper-natremia, as well as to chronic hyperkalemia which may be due to hyporeninemic hypoaldosteronism. This article provides an overview of the electrolyte disturbances occurring in diabetes and describes the underlying mechanisms. This insight should pave the way for pathophysiology-directed therapy, thus contributing to the avoidance of the several deleterious effects associated with electrolyte disorders and their treatment.


Electrolyte disorders are common in clinical practice. They are mainly encountered in hospital populations occurring in a broad spectrum of patients (from asymptomatic to critically ill) and being associated with increased morbidity and mortality[1-3]. The disturbances of electrolyte homeostasis are also frequently observed in community subjects. Community-acquired electrolyte disorders, even chronic and mild, are related to poor prognosis[3]. Electrolyte disorders are usually multifactorial in nature. Various pathophysiological factors, such as nutritional status, gastrointestinal absorption capacity, coexistent acid-base abnormalities, pharmacological agents, other comorbid diseases (mainly renal disease) or acute illness, alone or in combination, play a key role.

Diabetes mellitus (DM) is included among the diseases with increased frequency of electrolyte abnormalities given that the aforementioned factors (especially impaired renal function, malabsorption syndromes, acid-base disorders and multidrug regimens) are often present in diabetics[4].

This article provides an overview of the electrolyte disturbances occurring in DM and describes possible underlying mechanisms (Table 1). This insight should pave the way for pathophysiology-directed therapy, possibly contributing to the avoidance of several deleterious effects associated with electrolyte disorders and their treatment.

Table 1 Principal causes of electrolyte disorders in diabetic patients.
Sodium disorders1
Pseudohyponatremia (marked hyperlipidemia)
Hyperglycemia (hypertonicity)-induced movement of water out of the cells (dilutional hyponatremia)
Osmotic diuresis-induced hypovolemic hyponatremia
Drug-induced hyponatremia: hypoglycemic agents (chlorpropamide, tolbutamide, insulin) or other medications (e.g., diuretics, amitriptyline)
Pseudonormonatremia (marked hyperlipidemia, severe hypoproteinemia)
Pseudohypernatremia (severe hypoproteinemia)
Loss of water in excess of sodium and potassium (osmotic dieresis), if this water loss is replaced insufficiently
Potassium disorders
Shift hypokalemia: insulin administration
Gastrointestinal loss of K+: malabsorption syndromes (diabetic-induced motility disorders, bacterial overgrowth, chronic diarrheal states)
Renal loss of K+: osmotic diuresis, hypomagnesemia, diuretics (thiazides, thiazide-like agents, furosemide)
Shift hyperkalemia: acidosis, insulin deficiency, hypertonicity, rhabdomyolysis, drugs (e.g., beta blockers)
Reduced glomerular filtration of K+: acute and chronic kidney disease
Reduced tubular secretion of K+: hyporeninemic hypoaldosteronism, drugs (angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, renin inhibitors, beta blockers, potassium-sparing diuretics)
Magnesium disorders
Pseudohypomagnesemia: hypoalbuminemia
Shift hypomagnesemia: insulin administration
Poor dietary Mg2+ intake
Gastrointestinal Mg2+ losses: diarrhea as a result of diabetic autonomic neuropathy
Increased renal Mg2+ losses due to osmotic diuresis, glomerular hyperfiltration, diuretic administration
Recurrent metabolic acidosis
Calcium disorders
Pseudohypοcalcemia: hypoalbuminemia2
Acute renal failure due to accompanying hyperphosphatemia
Advanced chronic renal insufficiency due to hyperphosphatemia and low levels of vitamin D
Nephrotic syndrome: loss of 25-hydroxyvitamin D3 and its binding protein in the urine
Vitamin D deficiency
Drug-mediated: loop diuretics
Concurrent hyperparathyroidism
Thiazide therapy
Phosphorus disorders
Osmotic diuresis
Drugs: thiazides, loop diuretics, insulin
Malabsorption syndromes
Primary hyperthyroidism
Vitamin D deficiency

DM is a well-known cause of dysnatremias via several underlying mechanisms[3,5]. Glucose is an osmotically active substance. Hyperglycemia increases serum osmolality, resulting in movement of water out of the cells and subsequently in a reduction of serum sodium levels ([Na+]) by dilution. Therefore, in hyperglycemic patients, the corrected [Na+] should be taken into account, which is calculated by adding to measured [Na+] 1.6 mmol/L for every 100 mg/dL (5.55 mmol/L) increment of serum glucose above normal; a correction factor by 2.4 mmol/L is used when serum glucose concentrations are higher than 400 mg/dL (22.2 mmol/L)[6,7]. It is worth mentioning that the corrected [Na+] after adjustment for the dilutional effect of hyperglycemia should be considered as a useful tool for the monitoring of treatment in hyperglycemic states[8]. Uncontrolled DM can also induce hypovolemic-hyponatremia due to osmotic diuresis. Moreover, in diabetic ketoacidosis ketone bodies (b-hydroxybutyrate and acetoacetate) obligate urinary electrolyte losses and aggravate the renal sodium wasting[7,9]. It should be emphasized, however, that hypotonic renal losses (loss of water in excess of sodium and potassium) due to osmotic diuresis can lead to hypernatremia if this water loss is replaced insufficiently. In a study in 113 hypernatremic patients hospitalized in an internal medicine clinic, poorly controlled DM was implicated in the development of hypernatremia in one third of cases (34.5%)[5]. Consequently, in patients with uncontrolled DM serum concentration of [Na+] is variable, reflecting the balance between the hyperglycemia-induced water movement out of the cells that lowers [Na+], and the glucosuria-induced osmotic diuresis, which tends to raise [Na+].

Drug-induced hyponatremia due to hypoglycemic agents (chlorpropamide, tolbutamide, insulin) or other medications (e.g., diuretics, amitriptyline for the treatment of diabetic neuropathy) should be considered in every diabetic patient with low [Na+][10,11]. Chlorpropamide, which is now rarely used in the treatment of patients with DM, can induce hyponatremia in approximately 4% to 6% by potentiating the effect of antidiuretic hormone. Elderly patients concomitantly using diuretics have greater risk of developing hyponatremia[12,13]. Tolbutamide can lead to hyponatremia by decreasing renal free water clearance[13]. Noteworthy, despite fluid retention being a common adverse effect of thiazolidinediones (pioglitazone and rosiglitazone), hyponatremia related to these drugs was reported only once[14]. There is experimental evidence that glucagon-like peptide 1 receptor agonists influence water and electrolyte balance[15]. However, to the best of our knowledge, dysnatremias (or other electrolyte disorders) related to these drugs have not reported in humans. Moreover, the new class of oral antidiabetic agents known as sodium-glucose cotransporter type 2 (SGLT2) inhibitors does not appear to be associated with electrolyte abnormalities in early clinical studies[16,17].

It has been reported that DM per se (independently of drugs or hyperglycemia) is associated with hyponatremia[11]. Recently, in a study in 5179 community subjects aged 55 years or more DM was associated with hyponatremia (OR = 1.98; 95%CI: 1.47-2.68), with the serum glucose levels being too low to fully explain the degree of hyponatremia[3]. Altered vasopressin metabolism, interaction between insulin and vasopressin, both of which act in the renal collecting duct, and the reabsorption of more hypotonic fluid due to slower stomach emptying have been proposed as possible underlying mechanisms of this association[18-20]. Although rare, the inverse etiological relation between hyponatremia and DM also exists. In fact, brain edema in the setting of untreated symptomatic hyponatremia may induce cerebral herniation and infarction of pituitary and hypothalamus, leading to central DM and insipidus[21].

DM is also associated with an artificially decreased or elevated serum sodium value, that is different compared with the actual systemic level. In normal subjects, serum is composed of water (approximately 93%), with fats and proteins accounting for the remaining 7%. Sodium is located in the serum water phase only. A reduction in serum water fraction (< 80%) may occur in patients with marked hyperlipidemia as with lactescent serum in uncontrolled DM. In these settings, the serum sodium concentration, measured per liter of serum, not serum water, is artificially reduced (pseudohyponatremia). The presence of normal serum sodium levels in a patient with hyperlipidemia should also raise the suspicion that hypernatremia may be present (pseudonormonatremia). The opposite phenomenon of pseudohypernatremia and pseudonormonatremia may also occur as a result of severe hypoproteinemia, not infrequently observed in diabetics with nephrotic or malabsorption syndromes. In lipemic or hypoproteinemic samples the direct ion-selective electrodes (ISE) method for the measurement of serum sodium should be used, since the indirect ISE is prone to spurious dysnatremias[22].

It is known that rapid correction of serum sodium may be followed by development of central demyelinating lesions, particularly in the pons (a disorder called central pontinemyelinolysis orosmotic demyelination) with major disability or even fatal outcome[2]. Diabetics may have an increased risk for the osmotic demyelination syndrome (ODS) during correction of hyponatremia since risk factors for this disorder (thiazide diuretics, malnutrition, hypokalemia, and hypoxia)[23] are not infrequently present in such patients. Hypokalemia is also associated with a poor outcome in patients who develop the syndrome[24].

It should be emphasized that ODS is mainly observed during overly rapid correction of chronic hyponatremia. However, in diabetic patients hypernatremia and hypokalemia (in the absence of hyponatremia or hyperosmolality) are rarely associated with ODS. The mechanism by which these electrolyte disorders may cause ODS in the diabetic state is not yet known[25,26].

It has been suggested that in cases of nonketotic hyperglycemic hyperosmolar syndrome (HHS) altered mental status is predicted best by [Na+]; serum glucose concentration alone is considered a poor indicator. In fact, there is evidence that hyperglycemic patients with hypertonicity are symptomatic only if hypernatremia is present[5,27]. On the contrary, neurological symptoms may be absent in the context of severe gradually developing hyperglycemia[27,28]. This could be attributed to the capacity of the brain tissue to restore intracellular water by accumulating electrolytes and the so-called idiogenic osmoles. Furthermore, the brain cells are relatively permeable to glucose even in the absence of insulin[28,29]. Therefore, hyperglycemia by itself does not create severe hypertonicity in central nervous system (CNS)[28]. On the other hand, hypernatremia induces severe cellular dehydration in CNS cells. This state is associated with a rather slow compensatory accumulation of brain osmolar content[28].

The development of hypernatremia is associated with endocrine dysfunction. There is some evidence in animals and man that hypernatremia and hyperosmolarity are associated with impairment of both insulin-mediated glucose metabolism and glucagon-dependent glucose release[30-33]. Thus, hypernatremia and hyperosmolarity should be considered as contributing factors to the occurrence of hyperglycemia in critically ill patients[34]. Moreover, hypernatremia is implicated in the profound inhibition of gonadotrophin release in postmenopausal diabetic women with HHS. Although the underlying mechanisms remain unknown, it appears that hypernatremia induces a decrease in gonadotrophin-releasing hormone expression in GT1-7 neurons[35].

Rhabdomyolysis, though uncommon, has been described in the diabetic state[36]. It appears that high serum sodium and glucose levels represent the most important determinants for the occurrence of this complication[37].


The causes of hypokalemia in diabetics include: (1) redistribution of potassium [K+] from the extracellular to the intracellular fluid compartment (shift hypokalemia due to insulin administration); (2) gastrointestinal loss of K+ due to malabsorption syndromes (diabetic-induced motility disorders, bacterial overgrowth, chronic diarrheal states); and (3) renal loss of K+ (due to osmotic diuresis and/or coexistent hypomagnesemia). Hypomagnesemia can cause hypokalemia possibly because a low intracellular magnesium [Mg2+] concentration activates the renal outer medullary K+ channel to secrete more K+[38].

Exogenous insulin can induce mild hypokalemia because it promotes the entry of K+ into skeletal muscles and hepatic cells by increasing the activity of the Na+-K+-ATPase pump[39]. The increased secretion of epinephrine due to insulin-induced hypoglycemia may also play a contributory role[40]. The major setting in which insulin administration leads to hypokalemia is during the treatment of severe hyperglycemia. The majority of patients with diabetic ketoacidosis (DKA) and HHS are markedly K+-depleted. The average K+ deficit is 3-5 mEq/kg, but it can exceed 10 mEq/kg in some cases[41,42]. A number of factors contribute to the DKA- and HHS-associated potassium depletion, including vomiting, increased renal losses due to the osmotic diuresis and ketoacid anion excretion, and the loss of K+ from the cells due to glycogenolysis and proteolysis[41,43]. On admission, however, the serum K+ levels are usually normal, or, in about one-third of patients, increased despite the K+ depletion[41,43]. It is thought that hyperosmolality and insulin deficiency are primarily responsible for the relative rise in the serum potassium concentration in this setting. As mentioned, hyperglycemia increases serum osmolality resulting in movement of water out of cells. The loss of intracellular water leads to an increased intracellular K+ concentration, favoring a gradient for K+ to move out of the cells. Simultaneously, the friction forces between solvent (water) and solute can result in K+ being carried along with water through the water pores in the cell membrane[43]. In contrast, acidemia probably does not play a major role given that organic acids are much less likely to influence the internal K+ distribution[44]. Insulin therapy lowers K+ concentration driving K+ into cells (both directly and indirectly by reversing hyperglycemia). Therefore, insulin therapy may cause severe hypokalemia, particularly in patients with a normal or low serum K+ concentration at presentation. Insulin administration in patients with massive K+ deficits who are hypokalemic prior to therapy should be delayed until the serum K+ is above 3.3 mEq/L to avoid possible arrhythmias, cardiac arrest and respiratory muscle weakness[42,45,46]. It is obvious that the risk of hypokalemia-related complications is particularly higher in diabetic subjects who have hypertension, myocardial infarction/ischemia, or heart failure as comorbidities. In addition, since diabetics are frequently on diuretics, diuretic-associated hypokalemia (as well as hypomagnesemia and hypophosphatemia) should be taken into account in this setting.

Hypokalemia is associated with impaired insulin secretion and decreased peripheral glucose utilization resulting in carbohydrate intolerance and hyperglycemia[47]. This is particularly problematic in diabetic patients causing a vicious circle where low serum K+ levels lead to poorly controlled DM and vice versa.


The incidence of hyperkalemia is higher in diabetic patients than in the general population[48,49]. Redistribution of potassium from the intracellular to the extracellular compartment (shift hyperkalemia) can induce hyperkalemia with no net total body K+ increase. Examples of shift hyperkalemia in DM include acidosis (for each 0.1 fall in pH, potassium increases by approximately 0.4 mmol/L), insulin deficiency, hypertonicity, cell lysis (rhabdomyolysis), and drugs (e.g., beta blockers). Reduced glomerular filtration of K+ (due to acute kidney injury and chronic kidney disease) and many drugs that interfere with K+ excretion are associated with hyperkalemia. These include angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, renin inhibitors, beta blockers and potassium-sparing diuretics. Of note, the typical healthy diabetic diet is often rich in K+ and low in sodium contributing to the occurrence of hyperkalemia in susceptible individuals[48,49]. Nevertheless, the most common causal factor of chronic hyperkalemia in diabetics is the reduced tubular secretion of K+ due to the syndrome of hyporeninemic hypoaldosteronism[50]. This syndrome is characterized by mild to moderate renal insufficiency and patients typically present with asymptomatic hyperkalemia. The development of overt hyperkalemia is most common in patients with other risk factors that further impair the efficiency of potassium excretion, such as renal insufficiency, volume depletion, or the use of medications that interfere with potassium handling (see above).

Of note, dapagliflozin (a SGLT2 inhibitor) may be protective from the development of hyperkalemia in patients with moderate renal impairment due to osmotic diuresis[17]. However, the administration of SGLT2 inhibitors in hypovolemic patients may cause elevated serum creatinine levels and decreases in glomerular filtration rate due to deterioration of intravascular volume contraction. Indeed, worsening renal function and hyperkalemia may occur in patients on canagliflozin, particularly those predisposed to hyperkalemia due to impaired renal function, medications or other medical conditions[51]. Hyporeninemic hypoaldosteronism is more frequently observed in diabetic and elderly patients as well as in those with chronic renal impairment. Diabetic nephropathy accounts for 43%-63% of cases comprising the most common cause of hyporeninemic hypoaldosteronism[33,50,52]. Normal ageing, especially after the sixth decade, is associated with a decline in renin production. Moreover, elderly patients may have decreased renal function even without significant elevations in serum creatinine levels [< 1.2 mg/dL (106 μmol/L)]. Consequently, diabetics (especially the elderly) on medications known to interfere with K+ homeostasis are at increased risk for hyperkalemia[33,53]. In such cases, close K+ monitoring is fully warranted[54]. Clinicians must also be alert that hyperkalemia in patients with type 1 DM may be due to concurrent adrenal insufficiency in the setting of autoimmune polyglandular syndrome[55].


Hypomagnesemia is a frequent electrolyte disorder in diabetic patients[56]. Recently, DM was identified as an independent risk factor for hypomagnesemia in community subjects aged 55 years or more (OR = 3.32; 95%CI: 2.00-5.50)[3]. In a recent prospective study in hypomagnesemic patients (either on admission or during hospitalization in an internal medicine clinic) DM was evident in a considerable proportion (40%), mainly as a contributing factor. Osmotic diuresis accompanied by inappropriate magnesiuria was the prominent underlying mechanism of hypomagnesemia in these diabetic patients[57]. Except for glucosuria, several other possible explanations for hypomagnesemia in DM have been reported. These include poor dietary intake, glomerular hyperfiltration, altered insulin metabolism, diuretic administration and recurrent metabolic acidosis[56]. Increased gastrointestinal Mg2+ losses due to diarrhea as a result of diabetic autonomic neuropathy can also cause low serum Mg2+ levels. Of note, a case of symptomatic hypomagnesemia [serum Mg2+ concentration 0.66 mEq/L (0.33 mmol/L), reference range 1.42-1.84 mEq/L (0.71-0.94 mmol/L)] was attributed to metformin-induced diarrhea[58]. Furthermore, insulin promotes net shift of Mg2+ from extracellular to intracellular space and can contribute to hypomagnesemia[59,60]. The increased secretion of epinephrine due to insulin-induced hypoglycemia may also play a role. The risk of hypomagnesemia related to insulin therapy is increased in poorly controlled diabetic patients given that hyperglycemia induces increased renal Mg2+ loss via osmotic diuresis. Hypokalemia, hypophosphatemia as well as acidosis-related urinary Mg2+ losses contribute to the high incidence of hypomagnesemia in the setting of diabetic ketoacidosis[61,62]. It should be noted that hypoalbuminemia is associated with spurious hypomagnesemia. In hypoalbuminemic states (serum albumin < 4 g/dL) the corrected serum Mg2+ should be calculated using the formula: corrected Mg2+ (mEq/L) = measured Mg2+(mEq/L) + 0.01 × (40 - albumin in g/L)[63].

Mg2+ is essential for life being involved in numerous enzymatic reactions, including ATP use, cell membrane, ion channels and mitochondrial function, as well as protein synthesis. The most clinically significant consequences of hypomagnesemia are ascribed to alterations in the function of excitable membranes in nerve, muscle, and the cardiac conducting system. Moreover, low serum Mg2+ levels can secondarily induce hypokalemia, hypocalcemia, and hypophosphatemia, potentially causing further derangements in neuromuscular and cardiovascular physiology. Hypomagnesemia has been implicated in various long-term complications of DM, such as hypertension, increased carotid wall thickness, coronary artery disease, dyslipidemia, diabetic retinopathy, neuropathy, ischemic stroke, and foot ulcerations[56]. Hypomagnesemia has also been linked to diabetic nephropathy (from microalbuminuria to advanced renal disease)[64-66]. It has been proposed that hypomagnesemia is a predictor of end-stage renal disease in patients with diabetic nephropathy[66]. In addition, magnesium deficit is associated with carbohydrate intolerance and insulin resistance, thus inducing or worsening existing DM[67,68]. On the contrary, increased dietary Mg2+ intake has been associated with a reduced risk of type 2 DM[69].


Patients with DM have an increased risk for development of acute renal failure due to volume depletion, sepsis, rhabdomyolysis and drugs (e.g., radiographic contrast media). In this setting severe hyperphosphatemia may occur when phosphorus cannot be excreted by the malfunctioning kidney either with or without increased cell catabolism, thus resulting in hypocalcemia. Advanced chronic renal insufficiency may be associated with hypocalcemia due to accompanying hyperphosphatemia and low levels of vitamin D. Patients with nephrotic syndrome may exhibit hypocalcemia, even if the glomerular filtration rate is well preserved. This is attributed to the loss of 25-hydroxyvitamin D3 and its binding protein in the urine. Hypomagnesemia is another potential cause of hypocalcemia in diabetics. Mg2+ depletion leads to hypocalcemia mainly because of impaired release of parathyroid hormone (PTH) or skeletal and renal tubule resistance to the action of PTH[1]. Vitamin D deficiency and furosemide administration may also play a role in the occurrence of hypocalcemia[70]. There is evidence that diabetic patients are relatively hypoparathyroid[71]. In fact, a mild shift downwards in the set-point for PTH secretion in patients with insulin-dependent DM as well as a diminished parathyroid gland responsiveness to hypocalcemia in uremic diabetic patients have been reported[72,73].

Hypoalbuminemia is associated with pseudohypocalcemia defined as a reduction of total serum calcium concentration in the presence of normal ionized serum calcium levels. In hypoalbuminemic states, one of the commonly used formulas to correct total calcium levels is by adding 0.8 mg/dL (0.2 mmol/L) to measured calcium values for every 1 g/dL decrease in serum albumin from normal value (assumed to be 4 g/dL). Given that the accuracy of this method is poor (particularly among critically ill and geriatric patients), the biologically active ionized calcium concentration should be measured when possible[1,74].


The incidence of DM in primary hyperparathyroidism and that of primary hyperparathyroidism in DM is approximately 8% and 1%, respectively. Both values are about three-fold higher than that anticipated in the general population[75]. Hyperparathyroidism is related to long-term insulin resistance and relative insulin insufficiency, leading to overt DM or deterioration of glycemic control of established DM[75,76]. It is thought that an elevated intracellular free calcium concentration (by decreasing normal insulin-stimulated glucose transport) increases the requirement for insulin, resulting in hyperparathyroidism-mediated insulin resistance[75]. Diabetic patients should be evaluated for hypercalcemia given that untreated hyperparathyroidism is linked to hypertension[75,77]. The detection of high serum calcium levels in a patient with type 1 DM should raise the suspicion that autoimmune hyperparathyroidism associated with anti-calcium-sensing receptor autoantibodies may be present[78]. Recently, a case of severe hypercalcemia [15 mg/dL (3.75 mmol/L)] in DKA was reported[79]. Dehydration might represent the most important causative factor for the occurrence of hypercalcemia in this case. A decreased bone formation due to metabolic acidosis and an increased bone mineral dissolution and resorption due to severe insulin deficiency and metabolic acidosis may also play a role[80]. Hyperglycemia-mediated inhibition of bone mineralization, insulin growth factor-1 deficiency, hypophosphatemia and immobilization are also included among the potential contributory factors of hypercalcemia in DKA[79,81,82]. Also, diabetic patients on thiazide diuretics are more prone to exhibit hypercalcemia.


Diabetic patients have underlying conditions that predispose to the development of hypophosphatemia. These include primary hyperthyroidism, vitamin D deficiency, malabsorption, and the use of diuretics (thiazides and furosemide)[83]. It is known that increased insulin levels promote the transport of both glucose and phosphate into the skeletal muscle and liver cells. However, in normal subjects the administration of insulin leads only to a slight decrement of serum phosphate levels. The risk of severe hypophosphatemia is increased in cases of underlying phosphate depletion[62,84]. Decompensated DM with ketoacidosisis associated with excessive phosphate loss due to osmotic diuresis. Despite phosphate depletion, the serum phosphate concentration at presentation is usually normal or even high because both insulin deficiency and metabolic acidosis cause a shift of phosphate out of cells[85]. Administration of insulin and fluids, and correction of ketoacidosis may reveal phosphate deficiency and cause a sharp decrease in plasma phosphate concentration due to intracellular shift[83].

In a study of 69 patient with DKA, the incidence of hyperphosphatemia was 94.7% at presentation. The mean serum phosphate concentration fell from 9.2 mg/dL (3 mmol/L) to 2.8 mg/dL (0.9 mmol/L) 12 h after initiating treatment, while some patients exhibited values as low as 1.0 mg/dL (0.32 mmol/L)[85].

The routine administration of phosphate during treatment of DKA and HHS is not recommended since randomized trials failed to show any clinical benefit from phosphate administration[42,83,86,87]. What is more, correction of hypophosphatemia may have adverse effects, such as hypocalcemia and hypomagnesemia[42,83,88]. Careful phosphate replacement is required in patients with severe hypophosphatemia of less than 1.0 mg/dL (0.32 mmol/L) and in patients who develop cardiac dysfunction, hemolytic anemia, or respiratory depression[42,89,90].


Electrolyte abnormalities are common in diabetic patients and may be associated with increased morbidity and mortality. These disturbances are particularly common in decompensated DM, in the elderly as well as in the presence of renal impairment. Patients with DM may receive complex drug regimens some of which may be associated with electrolyte disorders. Discontinuation of these medications, when possible, as well as strict control of glycemia are of paramount importance to prevent electrolyte abnormalities in diabetic patients. The successful management of these disorders can best be accomplished by elucidating the underlying pathophysiologic mechanisms.


P- Reviewer: Gillessen A, Haidara M, Swierczynski JT, Tziomalos K S- Editor: Ji FF L- Editor: A E- Editor: Liu SQ

1.  Liamis G, Milionis HJ, Elisaf M. A review of drug-induced hypocalcemia. J Bone Miner Metab. 2009;27:635-642.  [PubMed]  [DOI]
2.  Liamis G, Kalogirou M, Saugos V, Elisaf M. Therapeutic approach in patients with dysnatraemias. Nephrol Dial Transplant. 2006;21:1564-1569.  [PubMed]  [DOI]
3.  Liamis G, Rodenburg EM, Hofman A, Zietse R, Stricker BH, Hoorn EJ. Electrolyte disorders in community subjects: prevalence and risk factors. Am J Med. 2013;126:256-263.  [PubMed]  [DOI]
4.  Elisaf MS, Tsatsoulis AA, Katopodis KP, Siamopoulos KC. Acid-base and electrolyte disturbances in patients with diabetic ketoacidosis. Diabetes Res Clin Pract. 1996;34:23-27.  [PubMed]  [DOI]
5.  Liamis G, Tsimihodimos V, Doumas M, Spyrou A, Bairaktari E, Elisaf M. Clinical and laboratory characteristics of hypernatraemia in an internal medicine clinic. Nephrol Dial Transplant. 2008;23:136-143.  [PubMed]  [DOI]
6.  Hillier TA, Abbott RD, Barrett EJ. Hyponatremia: evaluating the correction factor for hyperglycemia. Am J Med. 1999;106:399-403.  [PubMed]  [DOI]
7.  Liamis G, Milionis HJ, Elisaf M. Hyponatremia in patients with infectious diseases. J Infect. 2011;63:327-335.  [PubMed]  [DOI]
8.  Liamis G, Gianoutsos C, Elisaf MS. Hyperosmolar nonketotic syndrome with hypernatremia: how can we monitor treatment? Diabetes Metab. 2000;26:403-405.  [PubMed]  [DOI]
9.  Chiasson JL, Aris-Jilwan N, Bélanger R, Bertrand S, Beauregard H, Ekoé JM, Fournier H, Havrankova J. Diagnosis and treatment of diabetic ketoacidosis and the hyperglycemic hyperosmolar state. CMAJ. 2003;168:859-866.  [PubMed]  [DOI]
10.  Liamis G, Milionis H, Elisaf M. A review of drug-induced hyponatremia. Am J Kidney Dis. 2008;52:144-153.  [PubMed]  [DOI]
11.  Beukhof CM, Hoorn EJ, Lindemans J, Zietse R. Novel risk factors for hospital-acquired hyponatraemia: a matched case-control study. Clin Endocrinol (Oxf). 2007;66:367-372.  [PubMed]  [DOI]
12.  Kadowaki T, Hagura R, Kajinuma H, Kuzuya N, Yoshida S. Chlorpropamide-induced hyponatremia: incidence and risk factors. Diabetes Care. 1983;6:468-471.  [PubMed]  [DOI]
13.  Moses AM, Howanitz J, Miller M. Diuretic action of three sulfonylurea drugs. Ann Intern Med. 1973;78:541-544.  [PubMed]  [DOI]
14.  Berker D, Aydin Y, Arduç A, Ustün I, Ergün B, Guler S. Severe hyponatremia due to rosiglitazone use in an elderly woman with diabetes mellitus: a rare cause of syndrome of inappropriate antidiuretic hormone secretion. Endocr Pract. 2008;14:1017-1019.  [PubMed]  [DOI]
15.  Filippatos TD, Elisaf MS. Effects of glucagon-like peptide-1 receptor agonists on renal function. World J Diabetes. 2013;4:190-201.  [PubMed]  [DOI]
16.  Shah NK, Deeb WE, Choksi R, Epstein BJ. Dapagliflozin: a novel sodium-glucose cotransporter type 2 inhibitor for the treatment of type 2 diabetes mellitus. Pharmacotherapy. 2012;32:80-94.  [PubMed]  [DOI]
17.  Kohan DE, Fioretto P, Tang W, List JF. Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int. 2014;85:962-971.  [PubMed]  [DOI]
18.  Bankir L, Bardoux P, Ahloulay M. Vasopressin and diabetes mellitus. Nephron. 2001;87:8-18.  [PubMed]  [DOI]
19.  Bustamante M, Hasler U, Kotova O, Chibalin AV, Mordasini D, Rousselot M, Vandewalle A, Martin PY, Féraille E. Insulin potentiates AVP-induced AQP2 expression in cultured renal collecting duct principal cells. Am J Physiol Renal Physiol. 2005;288:F334-F344.  [PubMed]  [DOI]
20.  Davis FB, Davis PJ. Water metabolism in diabetes mellitus. Am J Med. 1981;70:210-214.  [PubMed]  [DOI]
21.  Fraser CL, Arieff AI. Fatal central diabetes mellitus and insipidus resulting from untreated hyponatremia: a new syndrome. Ann Intern Med. 1990;112:113-119.  [PubMed]  [DOI]
22.  Liamis G, Liberopoulos E, Barkas F, Elisaf M. Spurious electrolyte disorders: a diagnostic challenge for clinicians. Am J Nephrol. 2013;38:50-57.  [PubMed]  [DOI]
23.  Lauriat SM, Berl T. The hyponatremic patient: practical focus on therapy. J Am Soc Nephrol. 1997;8:1599-1607.  [PubMed]  [DOI]
24.  Kallakatta RN, Radhakrishnan A, Fayaz RK, Unnikrishnan JP, Kesavadas C, Sarma SP. Clinical and functional outcome and factors predicting prognosis in osmotic demyelination syndrome (central pontine and/or extrapontine myelinolysis) in 25 patients. J Neurol Neurosurg Psychiatry. 2011;82:326-331.  [PubMed]  [DOI]
25.  Hegazi MO, Mashankar A. Central pontine myelinolysis in the hyperosmolar hyperglycaemic state. Med Princ Pract. 2013;22:96-99.  [PubMed]  [DOI]
26.  Shintani M, Yamashita M, Nakano A, Aotani D, Maeda K, Yamamoto T, Nishimura H. Central pontine and extrapontine myelinolysis associated with type 2 diabetic patient with hypokalemia. Diabetes Res Clin Pract. 2005;68:75-80.  [PubMed]  [DOI]
27.  Popli S, Leehey DJ, Daugirdas JT, Bansal VK, Ho DS, Hano JE, Ing TS. Asymptomatic, nonketotic, severe hyperglycemia with hyponatremia. Arch Intern Med. 1990;150:1962-1964.  [PubMed]  [DOI]
28.  Milionis HJ, Liamis G, Elisaf MS. Appropriate treatment of hypernatraemia in diabetic hyperglycaemic hyperosmolar syndrome. J Intern Med. 2001;249:273-276.  [PubMed]  [DOI]
29.  Lund-Andersen H. Transport of glucose from blood to brain. Physiol Rev. 1979;59:305-352.  [PubMed]  [DOI]
30.  Komjati M, Kastner G, Waldhäusl W, Bratusch-Marrain P. Detrimental effect of hyperosmolality on insulin-stimulated glucose metabolism in adipose and muscle tissue in vitro. Biochem Med Metab Biol. 1988;39:312-318.  [PubMed]  [DOI]
31.  Komjati M, Kastner G, Waldhäusl W, Bratusch-Marrain P. Effect of hyperosmolality on basal and hormone-stimulated hepatic glucose metabolism in vitro. Eur J Clin Invest. 1989;19:128-134.  [PubMed]  [DOI]
32.  Bratusch-Marrain PR, DeFronzo RA. Impairment of insulin-mediated glucose metabolism by hyperosmolality in man. Diabetes. 1983;32:1028-1034.  [PubMed]  [DOI]
33.  Liamis G, Milionis H, Elisaf M. Blood pressure drug therapy and electrolyte disturbances. Int J Clin Pract. 2008;62:1572-1580.  [PubMed]  [DOI]
34.  Lindner G, Funk GC. Hypernatremia in critically ill patients. J Crit Care. 2013;28:216.e11-216.e20.  [PubMed]  [DOI]
35.  Lado-Abeal J, Lorenzo-Solar M, Lago-Lestón R, Palos-Paz F, Domingez-Gerpe L. Hyperglycaemic hyperosmolar nonketotic state as a cause of low gonadotrophin levels in postmenopausal diabetic women: a role for severe hypernatraemia. J Neuroendocrinol. 2007;19:983-987.  [PubMed]  [DOI]
36.  Lord GM, Scott J, Pusey CD, Rees AJ, Walport MJ, Davies KA, Bulpitt C, Bloom SR, Muntoni FM. Diabetes and rhabdomyolysis. A rare complication of a common disease. BMJ. 1993;307:1126-1128.  [PubMed]  [DOI]
37.  Singhal PC, Abramovici M, Ayer S, Desroches L. Determinants of rhabdomyolysis in the diabetic state. Am J Nephrol. 1991;11:447-450.  [PubMed]  [DOI]
38.  Yang L, Frindt G, Palmer LG. Magnesium modulates ROMK channel-mediated potassium secretion. J Am Soc Nephrol. 2010;21:2109-2116.  [PubMed]  [DOI]
39.  Minaker KL, Rowe JW. Potassium homeostasis during hyperinsulinemia: effect of insulin level, beta-blockade, and age. Am J Physiol. 1982;242:E373-E377.  [PubMed]  [DOI]
40.  Petersen KG, Schlüter KJ, Kerp L. Regulation of serum potassium during insulin-induced hypoglycemia. Diabetes. 1982;31:615-617.  [PubMed]  [DOI]
41.  Kreisberg RA. Diabetic ketoacidosis: new concepts and trends in pathogenesis and treatment. Ann Intern Med. 1978;88:681-695.  [PubMed]  [DOI]
42.  Kitabchi AE, Umpierrez GE, Murphy MB, Kreisberg RA. Hyperglycemic crises in adult patients with diabetes: a consensus statement from the American Diabetes Association. Diabetes Care. 2006;29:2739-2748.  [PubMed]  [DOI]
43.  Adrogué HJ, Lederer ED, Suki WN, Eknoyan G. Determinants of plasma potassium levels in diabetic ketoacidosis. Medicine (Baltimore). 1986;65:163-172.  [PubMed]  [DOI]
44.  Adrogué HJ, Madias NE. Changes in plasma potassium concentration during acute acid-base disturbances. Am J Med. 1981;71:456-467.  [PubMed]  [DOI]
45.  Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult patients with diabetes. Diabetes Care. 2009;32:1335-1343.  [PubMed]  [DOI]
46.  Beigelman PM. Potassium in severe diabetic ketoacidosis. Am J Med. 1973;54:419-420.  [PubMed]  [DOI]
47.  Wilcox CS. Metabolic and adverse effects of diuretics. Semin Nephrol. 1999;19:557-568.  [PubMed]  [DOI]
48.  Palmer BF. Managing hyperkalemia caused by inhibitors of the renin-angiotensin-aldosterone system. N Engl J Med. 2004;351:585-592.  [PubMed]  [DOI]
49.  Uribarri J, Oh MS, Carroll HJ. Hyperkalemia in diabetes mellitus. J Diabet Complications. 1990;4:3-7.  [PubMed]  [DOI]
50.  DeFronzo RA. Hyperkalemia and hyporeninemic hypoaldosteronism. Kidney Int. 1980;17:118-134.  [PubMed]  [DOI]
51.  Cada DJ, Ingram KT, Levien TL, Baker DE. Canagliflozin. Hosp Pharm. 2013;48:855-867.  [PubMed]  [DOI]
52.  Arruda JA, Batlle DC, Sehy JT, Roseman MK, Baronowski RL, Kurtzman NA. Hyperkalemia and renal insufficiency: role of selective aldosterone deficiency and tubular unresponsiveness to aldosterone. Am J Nephrol. 1981;1:160-167.  [PubMed]  [DOI]
53.  Oxlund CS, Henriksen JE, Tarnow L, Schousboe K, Gram J, Jacobsen IA. Low dose spironolactone reduces blood pressure in patients with resistant hypertension and type 2 diabetes mellitus: a double blind randomized clinical trial. J Hypertens. 2013;31:2094-2102.  [PubMed]  [DOI]
54.  Raebel MA, Ross C, Xu S, Roblin DW, Cheetham C, Blanchette CM, Saylor G, Smith DH. Diabetes and drug-associated hyperkalemia: effect of potassium monitoring. J Gen Intern Med. 2010;25:326-333.  [PubMed]  [DOI]
55.  Van den Driessche A, Eenkhoorn V, Van Gaal L, De Block C. Type 1 diabetes and autoimmune polyglandular syndrome: a clinical review. Neth J Med. 2009;67:376-387.  [PubMed]  [DOI]
56.  Pham PC, Pham PM, Pham SV, Miller JM, Pham PT. Hypomagnesemia in patients with type 2 diabetes. Clin J Am Soc Nephrol. 2007;2:366-373.  [PubMed]  [DOI]
57.  Liamis G, Liberopoulos E, Alexandridis G, Elisaf M. Hypomagnesemia in a department of internal medicine. Magnes Res. 2012;25:149-158.  [PubMed]  [DOI]
58.  Svare A. A patient presenting with symptomatic hypomagnesemia caused by metformin-induced diarrhoea: a case report. Cases J. 2009;2:156.  [PubMed]  [DOI]
59.  Paolisso G, Sgambato S, Passariello N, Giugliano D, Scheen A, D’Onofrio F, Lefèbvre PJ. Insulin induces opposite changes in plasma and erythrocyte magnesium concentrations in normal man. Diabetologia. 1986;29:644-647.  [PubMed]  [DOI]
60.  Matsumura M, Nakashima A, Tofuku Y. Electrolyte disorders following massive insulin overdose in a patient with type 2 diabetes. Intern Med. 2000;39:55-57.  [PubMed]  [DOI]
61.  Bauza J, Ortiz J, Dahan M, Justiniano M, Saenz R, Vélez M. Reliability of serum magnesium values during diabetic ketoacidosis in children. Bol Asoc Med P R. 1998;90:108-112.  [PubMed]  [DOI]
62.  Liamis G, Milionis HJ, Elisaf M. Medication-induced hypophosphatemia: a review. QJM. 2010;103:449-459.  [PubMed]  [DOI]
63.  Kroll MH, Elin RJ. Relationships between magnesium and protein concentrations in serum. Clin Chem. 1985;31:244-246.  [PubMed]  [DOI]
64.  Corsonello A, Ientile R, Buemi M, Cucinotta D, Mauro VN, Macaione S, Corica F. Serum ionized magnesium levels in type 2 diabetic patients with microalbuminuria or clinical proteinuria. Am J Nephrol. 2000;20:187-192.  [PubMed]  [DOI]
65.  Pham PC, Pham PM, Pham PA, Pham SV, Pham HV, Miller JM, Yanagawa N, Pham PT. Lower serum magnesium levels are associated with more rapid decline of renal function in patients with diabetes mellitus type 2. Clin Nephrol. 2005;63:429-436.  [PubMed]  [DOI]
66.  Sakaguchi Y, Shoji T, Hayashi T, Suzuki A, Shimizu M, Mitsumoto K, Kawabata H, Niihata K, Okada N, Isaka Y. Hypomagnesemia in type 2 diabetic nephropathy: a novel predictor of end-stage renal disease. Diabetes Care. 2012;35:1591-1597.  [PubMed]  [DOI]
67.  Weisinger JR, Bellorín-Font E. Magnesium and phosphorus. Lancet. 1998;352:391-396.  [PubMed]  [DOI]
68.  Barbagallo M, Dominguez LJ. Magnesium metabolism in type 2 diabetes mellitus, metabolic syndrome and insulin resistance. Arch Biochem Biophys. 2007;458:40-47.  [PubMed]  [DOI]
69.  Dong JY, Xun P, He K, Qin LQ. Magnesium intake and risk of type 2 diabetes: meta-analysis of prospective cohort studies. Diabetes Care. 2011;34:2116-2122.  [PubMed]  [DOI]
70.  Takiishi T, Gysemans C, Bouillon R, Mathieu C. Vitamin D and diabetes. Endocrinol Metab Clin North Am. 2010;39:419-446, table of contents.  [PubMed]  [DOI]
71.  McNair P, Christensen MS, Madsbad S, Christiansen C, Transbøl I. Hypoparathyroidism in diabetes mellitus. Acta Endocrinol (Copenh). 1981;96:81-86.  [PubMed]  [DOI]
72.  Schwarz P, Sørensen HA, Momsen G, Friis T, Transbøl I, McNair P. Hypocalcemia and parathyroid hormone responsiveness in diabetes mellitus: a tri-sodium-citrate clamp study. Acta Endocrinol (Copenh). 1992;126:260-263.  [PubMed]  [DOI]
73.  Heidbreder E, Götz R, Schafferhans K, Heidland A. Diminished parathyroid gland responsiveness to hypocalcemia in diabetic patients with uremia. Nephron. 1986;42:285-289.  [PubMed]  [DOI]
74.  Byrnes MC, Huynh K, Helmer SD, Stevens C, Dort JM, Smith RS. A comparison of corrected serum calcium levels to ionized calcium levels among critically ill surgical patients. Am J Surg. 2005;189:310-314.  [PubMed]  [DOI]
75.  Taylor WH, Khaleeli AA. Coincident diabetes mellitus and primary hyperparathyroidism. Diabetes Metab Res Rev. 2005;17:175-180.  [PubMed]  [DOI]
76.  Procopio M, Borretta G. Derangement of glucose metabolism in hyperparathyroidism. J Endocrinol Invest. 2003;26:1136-1142.  [PubMed]  [DOI]
77.  Gulcelik NE, Bozkurt F, Tezel GG, Kaynaroglu V, Erbas T. Normal parathyroid hormone levels in a diabetic patient with parathyroid adenoma. Endocrine. 2009;35:147-150.  [PubMed]  [DOI]
78.  Pelletier-Morel L, Fabien N, Mouhoub Y, Boitard C, Larger E. Hyperparathyroidism in a patient with autoimmune polyglandular syndrome. Intern Med. 2008;47:1911-1915.  [PubMed]  [DOI]
79.  Makaya T, Chatterjee S, Arundel P, Bevan C, Wright NP. Severe hypercalcemia in diabetic ketoacidosis: a case report. Diabetes Care. 2013;36:e44.  [PubMed]  [DOI]
80.  Topaloglu AK, Yildizdas D, Yilmaz HL, Mungan NO, Yuksel B, Ozer G. Bone calcium changes during diabetic ketoacidosis: a comparison with lactic acidosis due to volume depletion. Bone. 2005;37:122-127.  [PubMed]  [DOI]
81.  Balint E, Szabo P, Marshall CF, Sprague SM. Glucose-induced inhibition of in vitro bone mineralization. Bone. 2001;28:21-28.  [PubMed]  [DOI]
82.  Bereket A, Wilson TA, Kolasa AJ, Fan J, Lang CH. Regulation of the insulin-like growth factor system by acute acidosis. Endocrinology. 1996;137:2238-2245.  [PubMed]  [DOI]
83.  Fisher JN, Kitabchi AE. A randomized study of phosphate therapy in the treatment of diabetic ketoacidosis. J Clin Endocrinol Metab. 1983;57:177-180.  [PubMed]  [DOI]
84.  Moe SM. Disorders involving calcium, phosphorus, and magnesium. Prim Care. 2008;35:215-237, v-vi.  [PubMed]  [DOI]
85.  Kebler R, McDonald FD, Cadnapaphornchai P. Dynamic changes in serum phosphorus levels in diabetic ketoacidosis. Am J Med. 1985;79:571-576.  [PubMed]  [DOI]
86.  Keller U, Berger W. Prevention of hypophosphatemia by phosphate infusion during treatment of diabetic ketoacidosis and hyperosmolar coma. Diabetes. 1980;29:87-95.  [PubMed]  [DOI]
87.  Wilson HK, Keuer SP, Lea AS, Boyd AE, Eknoyan G. Phosphate therapy in diabetic ketoacidosis. Arch Intern Med. 1982;142:517-520.  [PubMed]  [DOI]
88.  Winter RJ, Harris CJ, Phillips LS, Green OC. Diabetic ketoacidosis. Induction of hypocalcemia and hypomagnesemia by phosphate therapy. Am J Med. 1979;67:897-900.  [PubMed]  [DOI]
89.  Kreisberg RA. Phosphorus deficiency and hypophosphatemia. Hosp Pract. 1977;12:121-128.  [PubMed]  [DOI]
90.  Evans KJ, Thompson J, Spratt SE, Lien LF, Vorderstrasse A. The implementation and evaluation of an evidence-based protocol to treat diabetic ketoacidosis: a quality improvement study. Adv Emerg Nurs J. 2014;36:189-198.  [PubMed]  [DOI]