Plasma Hypertonicity Research Articles

Therapeutic hypernatremia management during continuous renal replacement therapy with elevated intracranial pressures and respiratory failure.

Cerebral edema and elevated intracranial pressure (ICP) are common complications of acute brain injury. Hypertonic solutions are routinely used in acute brain injury as effective osmotic agents to lower ICP by increasing the extracellular fluid tonicity. Acute kidney injury in a patient with traumatic brain injury and elevated ICP requiring renal replacement therapy represents a significant therapeutic challenge due to an increased risk of cerebral edema associated with intermittent conventional hemodialysis. Therefore, continuous renal replacement therapy (CRRT) has emerged as the preferred modality of therapy in this patient population. We present our current treatment approach, with demonstrative case vignette illustrations, utilizing hypertonic saline protocols (3% sodium-chloride or, with coexisting severe combined metabolic and respiratory acidosis, with 4.2% sodium-bicarbonate) in conjunction with the CRRT platform, to induce controlled hypernatremia of approximately 155mEq/L in hemodynamically unstable patients with acute kidney injury and elevated ICP due to acute brain injury. Rationale, mechanism of activation, benefits and potential pitfalls of the therapy are reviewed. The impact of hypertonic citrate solution during regional citrate anticoagulation is specificallydiscussed. Maintaining plasma hypertonicity in the setting of increased ICP and acute kidney injury could prevent the worsening of ICP during renal replacement therapy by minimizing the osmotic gradient across the blood-brain barrier and maximizing cardiovascular stability.

Hypertonic saline infusion affects glycemic responses following glucose load in healthy men

Low water intake and plasma hypertonicity have been independently associated with hyperglycemia and incidence of diabetes mellitus in epidemiological studies. Recent data also suggest that reducing water intake deteriorates glucose regulation in patients with type 2 diabetes. To date, it is unclear whether plasma hypertonicity would also impact glycemic control in subjects with normal glycemic and insulinemic function.OBJECTIVETo assess the effect of hypertonic saline infusion on glycemic responses to an oral glucose tolerance test (OGTT) in healthy adult men.METHODS30 healthy, non‐smoking adult men (36.6±7.0 y, 83.9±12.8 kg, body mass index 27.0±3.4 kg·m−2, HbA1c 5.2±0.3%, HOMA‐IR 1.59±0.97) were recruited for this study. Each subject underwent two experimental trials, consisting of a 2‐h intravenous infusion of saline (ISO: 0.9% NaCl and HYPER: 3.0% NaCl) at an infusion rate of 0.1 ml·kg·min−1, followed by a 4‐h oral OGTT. Blood samples were taken at 30 min intervals throughout the infusion period and during the OGTT. Plasma osmolality (POsm), glucose (Glu), angiotensin II (AngII), renin, and aldosterone (Ald) were measured and plasma volume (PV) was calculated using hematocrit and hemoglobin based on the Dill & Costill equation.RESULTSPOsm at baseline was similar between conditions (287±3 and 286±3 mmol·kg−1 in HYPER and ISO, respectively). Following the 2‐h infusion, POsm was significantly higher in the HYPER condition than the ISO condition (305‐±3 vs. 288±3 mmol·kg−1; P < 0.0001), with greater PV expansion (20.1±6.9 vs. 10.9±3.2%, P < 0.0001). In the HYPER condition, POsm remained above baseline throughout the OGTT (296±3 mmol·kg−1 at OGTT4‐h; P < 0.0001). During the OGTT, Glu in the HYPER trial was higher than in the ISO trial at 60 min (HYPER: 157±24; ISO: 145±29 mg·dL−1; P < 0.018) and 90 min (HYPER: 139±33; ISO 128±29 mg·dL−1; P < 0.038). The renin‐angiotensin‐aldosterone system was suppressed as indicated by decreased plasma values of AngII, renin, and Ald, probably due to PV expansion in both trials.CONCLUSIONPlasma hypertonicity induced by hypertonic saline infusion unfavorably affected glycemic response to an OGTT in healthy adult men.Support or Funding InformationThis research was supported by Danone ResearchThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

High sodium continuous veno-venous hemodialysis with regional citrate anticoagulation and online dialysate generation in patients with acute liver failure and cerebral edema.

Acute liver failure is associated with a high mortality rate. Induction of plasma hypertonicity with mannitol or hypertonic saline remains the cornerstone in the management of resultant cerebral edema. Significant disadvantages of this approach include poor or unpredictable control of serum sodium concentration and volume expansion, among others. We used high sodium continuous veno-venous hemodialysis with regional citrate anticoagulation and online dialysate generation to accurately control the serum sodium in eleven patients with acute liver failure, renal failure, and cerebral edema. We used a Fresenius 2008 K/K2 machine in hemodialysis mode to deliver a blood flow of 60 ml/minute and dialysate flow of 400 ml/minute. Our previously published protocol results in complete removal of infused citrate by the dialyzer. On-line clearance calculations were used to model the time required to reach the target serum sodium. All patients achieved serum sodium within 2 mEq/L of target without fluctuations or rebound. Nine patients survived without requiring liver transplantation and two died despite reaching the prescribed serum sodium target. We did not encounter any citrate toxicity. We describe a novel approach for delivering continuous osmotherapy to patients with acute liver failure, renal failure, and cerebral edema. In comparison to standard therapy, the described modality enables precise titration of serum sodium without undesirable fluctuations in extracellular fluid volume. A particular advantage is zero delivery of citrate to this vulnerable group of patients with acute liver failure.

Activation of ENaC by AVP contributes to the urinary concentrating mechanism and dilution of plasma.

Arginine vasopressin (AVP) activates the epithelial Na(+) channel (ENaC). The physiological significance of this activation is unknown. The present study tested if activation of ENaC contributes to AVP-sensitive urinary concentration. Consumption of a 3% NaCl solution induced hypernatremia and plasma hypertonicity in mice. Plasma AVP concentration and urine osmolality increased in hypernatremic mice in an attempt to compensate for increases in plasma tonicity. ENaC activity was elevated in mice that consumed 3% NaCl solution compared with mice that consumed a diet enriched in Na(+) with ad libitum tap water; the latter diet does not cause hypernatremia. To determine whether the increase in ENaC activity in mice that consumed 3% NaCl solution served to compensate for hypernatremia, mice were treated with the ENaC inhibitor benzamil. Coadministration of benzamil with 3% NaCl solution decreased urinary osmolality and increased urine flow so that urinary Na(+) excretion increased with no effect on urinary Na(+) concentration. This decrease in urinary concentration further increased plasma Na(+) concentration, osmolality, and AVP concentration in these already hypernatremic mice. Benzamil similarly compromised urinary concentration in water-deprived mice and in mice treated with desmopressin. These results demonstrate that stimulation of ENaC by AVP plays a critical role in water homeostasis by facilitating urinary concentration, which can compensate for hypernatremia or exacerbate hyponatremia. The present findings are consistent with ENaC in addition to serving as a final effector of the renin-angiotensin-aldosterone system and blood pressure homeostasis, also playing a key role in water homeostasis by regulating urine concentration and dilution of plasma.

Unique Interweaved Microtubule Scaffold Mediates Osmosensory Transduction via Physical Interaction with TRPV1

The electrical activity of mammalian osmosensory neurons (ONs) is increased by plasma hypertonicity to command thirst, antidiuretic hormone release, and increased sympathetic tone during dehydration. Osmosensory transduction is a mechanical process whereby decreases in cell volume cause the activation of transient receptor potential vanilloid type-1 (TRPV1) channels to induce depolarization and increase spiking activity in ONs. However, it is not known how cell shrinking is mechanically coupled to channel activation. Using superresolution imaging, we found that ONs are endowed with a uniquely interweaved scaffold of microtubules throughout their somata. Microtubules physically interact with the C terminus of TRPV1 at the cell surface and provide a pushing force that drives channels activation during shrinking. Moreover, we found that changes in the density of these interactions can bidirectionally modulate osmosensory gain. Microtubules are thus an essential component of the vital neuronal mechanotransduction apparatus that allows the brain to monitor and correct body hydration.

Seizure as the first presentation of diabetes mellitus

Seizure as the first presentation of diabetes mellitus

Indirect Effects of Elevated Body Mass Index on Memory Performance Through Altered Cerebral Metabolite Concentrations

Elevated body mass index (BMI) at midlife is associated with increased risk of cognitive decline in later life. The goal of the current study was to assess mechanisms of early brain vulnerability by examining if higher BMI at midlife affects current cognitive performance through alterations in cerebral neurochemistry. Fifty-five participants, aged 40 to 60 years, underwent neuropsychological testing, health screen, and proton magnetic resonance spectroscopy examining N-acetylaspartate, creatine (Cr), myo-inositol (mI), choline, and glutamate concentrations in occipitoparietal gray matter. Concentrations of N-acetylaspartate, choline, mI, and glutamate were calculated as a ratio over Cr and examined in relation to BMI using multivariate regression analyses. Structural equation modeling was used to determine if BMI had an indirect effect on cognition through cerebral metabolite levels. Higher BMI was associated with elevations in mI/Cr (F(5,45) = 3.843, p = .006, β = 0.444, p = .002), independent of age, sex, fasting glucose levels, and systolic blood pressure. Moreover, a χ(2) difference test of the direct and indirect structural equation models revealed that BMI had an indirect effect on global cognitive performance (Δχ(2) = 19.939, df = 2, p < .001). Subsequent follow-up analyses revealed that this effect was specific to memory (Δχ(2) = 22.027, df = 2, p < .001). Higher BMI was associated with elevations in mI/Cr concentrations in the occipitoparietal gray matter and indirectly related to poorer memory performance through mI/Cr levels, potentially implicating plasma hypertonicity and neuroinflammation as mechanisms underlying obesity-related brain vulnerability.

Clinical review: Practical approach to hyponatraemia and hypernatraemia in critically ill patients

Disturbances in sodium concentration are common in the critically ill patient and associated with increased mortality. The key principle in treatment and prevention is that plasma [Na+] (P-[Na+]) is determined by external water and cation balances. P-[Na+] determines plasma tonicity. An important exception is hyperglycaemia, where P-[Na+] may be reduced despite plasma hypertonicity. The patient is first treated to secure airway, breathing and circulation to diminish secondary organ damage. Symptoms are critical when handling a patient with hyponatraemia. Severe symptoms are treated with 2 ml/kg 3% NaCl bolus infusions irrespective of the supposed duration of hyponatraemia. The goal is to reduce cerebral symptoms. The bolus therapy ensures an immediate and controllable rise in P-[Na+]. A maximum of three boluses are given (increases P-[Na+] about 6 mmol/l). In all patients with hyponatraemia, correction above 10 mmol/l/day must be avoided to reduce the risk of osmotic demyelination. Practical measures for handling a rapid rise in P-[Na+] are discussed. The risk of overcorrection is associated with the mechanisms that cause hyponatraemia. Traditional classifications according to volume status are notoriously difficult to handle in clinical practice. Moreover, multiple combined mechanisms are common. More than one mechanism must therefore be considered for safe and lasting correction. Hypernatraemia is less common than hyponatraemia, but implies that the patient is more ill and has a worse prognosis. A practical approach includes treatment of the underlying diseases and restoration of the distorted water and salt balances. Multiple combined mechanisms are common and must be searched for. Importantly, hypernatraemia is not only a matter of water deficit, and treatment of the critically ill patient with an accumulated fluid balance of 20 litres and corresponding weight gain should not comprise more water, but measures to invoke a negative cation balance. Reduction of hypernatraemia/hypertonicity is critical, but should not exceed 12 mmol/l/day in order to reduce the risk of rebounding brain oedema.

Plasma hypertonicity in children.

The plasma hypertonicity is a severe and quite frequent disorder in children. The most frequent causes are hypernatremia related conditions, even though other causes of hyperosmolarity, such as hyperglycaemia and exogenous solutes accumulation also occur. The management and treatment of this condition is delicate and requires a thorough understanding of the underlying hydro electrolytic disorder. The authors perform a theoretical review of plasma hypertonicity in children, focusing on the three most frequent associated conditions: hypernatremic dehydration, salt poisoning and hyperosmolar coma.

Arsenic inhibits SGK1 activation of CFTR Cl − channels in the gill of killifish, Fundulus heteroclitus

Seawater acclimation in killifish, Fundulus heteroclitus, is mediated in part by a rapid (1 h) translocation of CFTR Cl − channels from an intracellular pool to the plasma membrane in gill and increased CFTR-mediated Cl − secretion. This effect is mediated by serum and glucocorticoid-inducible kinase 1 (SGK1), which is stimulated by plasma hypertonicity rather than cortisol. Since arsenic exposure prevents acclimation to seawater by decreasing CFTR protein levels we tested the hypothesis that arsenic (as sodium arsenite) blocks acclimation to seawater by down regulating SGK1 expression. Freshwater adapted killifish were exposed to arsenic (48 h) and transferred to seawater containing arsenic, and SGK and CFTR expression were measured. Arsenic reduced the seawater induced increase in SGK1 mRNA and protein abundance, and reduced both the total amount of CFTR and the amount of CFTR in the plasma membrane. The decrease in membrane CFTR reduced Cl − secretion. Arsenic also increased the amount of ubiquitinated CFTR and its degradation by the lysosome. Thus, we propose a model whereby arsenic reduces the ability of killifish to acclimate to seawater by blocking the seawater induced increase in SGK1, which results in increased ubiquitination and degradation of CFTR.

CENTRAL OSMOREGULATORY INFLUENCES ON THERMOREGULATION

1. Many mammals maintain a constant core body temperature in the face of a heat load by using evaporative cooling responses, such as sweating, panting and spreading of saliva. These cooling mechanisms incur a body fluid deficit if the fluid lost as sweat, saliva or respiratory moisture is not replaced by the ingestion of water; body fluid hypertonicity and hypovolaemia result. 2. Evidence in several mammals shows that, as they become dehydrated, evaporative cooling mechanisms such as sweating and panting are inhibited so that further fluid loss from the body is reduced. As a result, core temperature in the dehydrated animal is maintained at a higher than normal level. 3. Increasing the osmotic pressure of plasma has an inhibitory effect on panting and sweating in mammals. It has been proposed that osmoreceptors mediate these inhibitory influences of plasma hypertonicity on sweating and panting. 4. The suppression of panting in dehydrated sheep is mediated by cerebral osmoreceptors that are probably located in the lamina terminalis. We speculate that osmoreceptors in the lamina terminalis may also influence thermoregulatory sweating. 5. When dehydrated animals drink water, sweating and panting resume rapidly before water has been absorbed from the gut. It is likely that the act of drinking initiates a reflex that can override the osmoreceptor inhibition of panting, resulting in core temperature falling back quickly to a normal level.

FOREBRAIN OSMOTIC REGULATION OF THE SYMPATHETIC NERVOUS SYSTEM

1. Accumulating evidence in both humans and animals indicates that acute increases in plasma osmolality elevate sympathetic nerve activity (SNA). In addition, plasma hyperosmolality (or hypernatraemia) can produce sustained increases in SNA and arterial blood pressure (ABP) through stimulation of forebrain osmoreceptors. 2. Although an abundance of information exists regarding the osmoregulatory circuits for thirst and secretion of antidiuretic hormone, much less is known about those pathways and synaptic mechanisms linking osmotic perturbations and SNA. To date, the available evidence suggests that osmosensitive sites within the forebrain lamina terminalis, such as the organum vasculosum of the lamina terminalis, are key elements that link plasma hypertonicity to elevated SNA. 3. The major efferent target of osmosensitive regions in the forebrain lamina terminalis is the hypothalamic paraventricular nucleus (PVH). Evidence from a number of studies indicates that the PVH contributes to both acute and chronic osmotically driven increases in SNA. In turn, PVH neurons increase SNA through a direct vasopressinergic spinal pathway and/or a glutamatergic pathway to bulbospinal sympathetic neurons of the rostral ventrolateral medulla. 4. Future studies are needed to: (i) define the contribution of various osmosensitive regions of the forebrain lamina terminalis to acute and chronic osmotically driven increases in SNA; (ii) identify the cellular mechanisms and neural circuitry linking plasma osmolality and SNA; and (iii) define whether such mechanisms contribute to elevated SNA in salt-sensitive hypertension.

Enhanced nephrogenesis in offspring of water-restricted rat dams

Maternal water restriction (WR) may induce offspring plasma hypertonicity and enhanced vasopressin secretory responses. We determined effects of pregnancy WR on offspring body composition, renal morphology, and blood pressure. Pregnant Sprague Dawley rats (n = 21) were randomized to WR, pair-fed (PF), and control from embryo day (e) 10 to e21. Offspring body and organ weights and glomerular number and size were measured at birth and at 21 days of age. At 6 and 9 weeks, offspring blood pressure was determined. At 21 days of age, WR offspring glomerular number was increased (17%; P < .05), whereas PF glomerular number was lower (4%), compared with controls. Systolic blood pressures were elevated in both WR and PF at both 6 and 9 weeks. Pregnancy WR stimulates offspring nephrogenesis, suggesting an adaptive response to future dehydration. Programmed hypertension in WR and PF groups likely occurs via different mechanisms.

Angiotensin mediated programmed hypertension in maternally dehydrated and nutrient restricted offspring

Maternal water restriction (WR) and associated dehydration-anorexia causes IUGR and programmed offspring hypernatremia and systemic hypertension. Maternal nutrient restriction (NR) also results in IUGR and programmed offspring hypertension, though not plasma hypertonicity. The renin-angiotensin system (RAS) is central to both blood pressure homeostasis and osmoregulation, and angiotensin II (AngII) is the primary RAS effector hormone secreted. We hypothesized that alterations in central and peripheral AngII contributes to programmed hypertension and/or osmoregulation.

The altered fluid distribution in obesity may reflect plasma hypertonicity

This study explored whether the increased extracellular relative to intracellular fluid (ECF/ICF) ratio in obesity might reflect osmotic effects of elevated plasma solute concentrations. Cross-sectional, epidemiological survey. The present analysis used nationally representative data from the Third National Health and Nutrition Examination Survey on community-dwelling adults (aged 40-59 years) in the US without evidence of glucose dysregulation or chronic disease (n=1285). Body mass index (BMI) was estimated from measured height and weight. Total body reactance, an index of body fluid distribution, was determined by bioelectrical impedance analysis. Plasma tonicity (the cumulative index of osmotically effective plasma solute) was estimated from plasma glucose, sodium and potassium. Sex-specific relative odds of lower reactance (<or=50 Omega/m for women, <or=40 Omega/m for men) and plasma hypertonicity (tonicity >or=295 mmol/l) associated with overweight (25<or=BMI <30) and obesity (BMI>or=30) were estimated using logistic regression models that controlled for sociodemographic variables, smoking, leisure-time physical activity, total energy intake, serum creatinine, plasma insulin and glucose. Multinomial logistic regression models tested for associations between weight status and specific serum solute. Independent of covariates, in men and women, overweight and obesity were associated with increased odds of lower reactance and hypertonicity. Overweight and obese individuals with lower reactance had significantly higher serum sodium than normal weight individuals. Elevated plasma solute concentrations are associated with obesity in free-living adults. Physicians and researchers should be alert to a possible link between hypertonicity and obesity. Grants from the NIH, Nestle Waters.

A proposed method for assessing plasma hypertonicity in vivo

Indices of plasma hypertonicity, elevated plasma concentrations of solutes that draw fluid out of cells by osmosis, are needed to pursue hypertonicity as a possible risk factor for obesity and chronic disease. This paper proposes a new index that may be more sensitive to mild hypertonicity in vivo at a point in time than traditional measures. The index compares mean corpuscular volume (MCV) estimates from diluted (in solution by automated cell counter) and nondiluted blood (calculated from manual hematocrit, MCV=Hct/RBC*10(6)). A larger Auto vs Manual MCV (>2 fl) in vitro indicates hypertonicity in vivo if the cell counter diluent is isotonic with the threshold for plasma vasopressin (PVP) release and PVP is detectable in plasma (>0.5 pg/ml). To evaluate this principle of concept, hypertonicity was induced by 24-h fluid restriction after a 20 ml/kg water load in four healthy men (20-46 years). Unlike serum and urine indices, the MCV difference-&-PVP index detected hypertonicity in all participants.

Plasma Hypertonicity: Another Marker of Frailty?

Plasma Hypertonicity: Another Marker of Frailty?

Gender Specificity of Programmed Plasma Hypertonicity and Hemoconcentration in Adult Offspring of Water-Restricted Rat Dams

We studied the impact of maternal water-restriction during rat pregnancy on newborn plasma composition, and determined the persistence of plasma composition alterations in adult offspring. Maternal dams were water-restricted from 10 days of pregnancy until term (21 days) and throughout lactation to increase plasma sodium levels by approximately 6 mEq/L. At 21 days of age, offspring were weaned, and subsequently maintained on ad libitum food and water until 12 weeks of age. Daily water and food intake was monitored. Blood samples and organs were collected from 1-day- and 12-week-old offspring. Hematocrit, plasma osmolality, sodium, and arginine vasopressin (AVP) levels were analyzed. Because water-restriction led to concomitant reduction in maternal food intake (ie, dehydration anorexia), henceforth these dams and their offspring are referred to as "water-deprived/food-reduced" rats. Water-deprived/food-reduced dams had significantly increased plasma sodium levels, reduced food intake, and lower body weight gain during pregnancy and lactation as compared to control dams. One-day-old newborns of water-deprived/food-reduced dams weighed 17% less and had increased plasma sodium levels, osmolality, and hematocrit. At 12 weeks of age, males exhibited 11% and females 19% reduction in body weight from controls. Notably, male offspring of water-deprived/food-reduced dams showed significantly elevated plasma sodium levels, osmolality, and hematocrit. Additionally, males demonstrated reduced adrenal growth and decreased water intake. Conversely, the female offspring had similar plasma osmolality with decreased sodium levels, though a persistently elevated hematocrit. No differences were evident in plasma AVP levels. Maternal water deprivation/food reduction is associated with increased newborn plasma osmolality and sodium levels and long-term physiologic changes in the offspring. The gender-specificity of programmed hyperosmolality, though not hemoconcentration, implicates differing pathways/mechanisms for these phenotypic alterations. The contributions of pregnancy hypertonicity versus nutrient restriction in the mechanism for programmed offspring phenotype remain to be elucidated.

High Prevalence of Plasma Hypertonicity among Community-Dwelling Older Adults: Results from NHANES III

Objective Recent data suggest that as many as 50% of older adults may have hypertonic plasma, an indicator of cell dehydration that predicts a range of adverse outcomes. To determine if a prevalence of this magnitude could be real, this study used nationally representative data to estimate the prevalence of hypertonicity, and to test for biologically plausible associations between hypertonicity, older age, glucose dysregulation, hemoconcentration, reduced bioelectrical impedance, and water intake. Design Cross-sectional. Subjects Community-dwelling adults (aged 20 to 90 years) who gave blood as part of the Third National Health and Nutrition Examination Survey (N=14,855). Statistical Analyses Plasma tonicity was estimated from glucose, sodium, and potassium values. The weighted prevalences of mild (295 to 300 mmol/L) and overt hypertonicity (≥300 mmol/L) were estimated by age, sex, race/ethnicity, fasting, and glycemic status. Hyper- and normotonic (285 to 295 mmol/L) groups were compared with respect to elevated blood chemistry values, bioelectrical impedance analysis parameters, as well as total water intake (grams, % Adequate Intake, and grams per kilogram body weight), using multivariable models that adjusted for age, sex, race/ethnicity, and survey design. Results Mild and overt hypertonicity were observed in 40% and 20% of the sample, respectively. Hypertonicity was positively associated with older age, Hispanic and African-American race, impaired glucose tolerance, diabetes, and hemoconcentration, and inversely associated with bioelectrical impedance analysis parameters. Hypertonicity was associated with greater total water intake in younger adults, but decreased intake in older adults. Conclusions Clinicians and researchers should be alert to hypertonicity and its causes in older adults.

Hypertonic hyperglycemia progresses to diabetes faster than normotonic

To explore whether elevated plasma glucose might progress to diabetes via a mechanism that involves plasma hypertonicity, we evaluated the independent and joint effects of these variables on diabetes risk. Community-dwelling older adults (70+years), who reported no previous diagnosis of diabetes and had glucose levels below 200 mg/dl in the 1992 Duke EPESE survey, were re-interviewed in 1996 for diabetes status (n = 979). Plasma tonicity at baseline was estimated from serum glucose, sodium, and potassium measures. In logistic regression models that controlled for glucose, as well as age, sex, race, weight status, activity level, serum creatinine, history of heart disease, stroke and cancer, plasma hypertonicity (> or = 300 mOsm/l) was independently associated with increased odds of developing diabetes (OR = 2.0, 95% CI: 0.9-4.2). Hypertonicity magnified the effects of elevated glucose (> or = 125 mg/dl), such that individuals with both exposures were over four times more likely to develop diabetes than those with elevated glucose only (OR = 4.9, 95%CI: 1.7-14.3), adjusting for all covariates. When tonicity was replaced by its determinant variables, glucose, sodium and potassium, in the multivariable models, independent effects of sodium were also observed. Further work is needed to pursue plasma hypertonicity as a factor in the progression of elevated plasma glucose to diabetes.