Dietary sodium and potassium intake in people with diabetes: are guidelines being met?

OBJECTIVE: Despite public health bodies advocating for lowering dietary sodium and increasing potassium intake to improve cardiovascular outcomes, people with diabetes are not meeting these targets. We hypothesize that (i) both at an individual level and within the cohort, there will be a low adherence to the guidelines and (ii) sodium and potassium intake will remain stable over time. METHODS: We conducted this prospective study in a cohort of 904 participants with diabetes who provided 24-h urine collections from 2009 to 2015. Dietary sodium and potassium intake were estimated from 24-h urinary sodium (uNa) and potassium (uK) measurements. Additional data were collected for: 24-h urinary volume (uVol), creatinine (uCr),; serum creatinine, urea, estimated glomerular filtration rate (eGFR), glycated haemoglobin (HbA1c), fasting glucose, lipids); clinical characteristics (age, blood pressure (BP), body mass index (BMI) and duration of diabetes). Adherence to recommended dietary sodium (uNa < 2300 mg/24 h (100mmol/24 h)) and potassium (uK > 4680 mg/24 h(120 mmol/24)) intake were the main outcome measures. RESULTS: Participants (n = 904) completed 3689 urine collections (average four collections/participant). The mean ± SD (mmol/24 h) for uNa was 181 ± 73 and uK was 76 ± 25. After correcting uNa for uCr, 7% and 5% of participants met dietary sodium and potassium guidelines respectively. Males were less likely to meet sodium guidelines (OR 0.40, p < 0.001) but were more likely to meet potassium guidelines (OR 6.13, p < 0.001). Longer duration of diabetes was associated with higher adherence to sodium and potassium guidelines (OR 1.04, p < 0.001 and OR 0.96, p = 0.006 respectively). Increasing age was significantly associated with adherence to potassium guidelines (OR 0.97, p = 0.007). CONCLUSIONS: People with diabetes do not follow current dietary sodium and potassium guidelines and are less likely to change their dietary intake of sodium and potassium over time.

Effect of Salt Supplementation on Sympathetic Activity and Endothelial Function in Salt-Sensitive Type 2 Diabetes.

CONTEXT: Lower sodium intake is paradoxically associated with higher mortality in type 2 diabetes (T2D). OBJECTIVE: To determine whether sympathetic nervous system (SNS) activation and endothelial dysfunction contribute to these observations, we examined the effect of salt supplementation on these systems in people with T2D with habitual low sodium. We hypothesized that salt supplementation would lower SNS activity and improve endothelial function compared to placebo. DESIGN: We conducted a randomized, double-blinded, placebo-controlled crossover trial. SETTING: The study took place in a tertiary referral diabetes outpatient clinic. PARTICIPANTS: Twenty-two people with T2D with habitual low sodium intake (24-hour urine sodium <150 mmol/24h) were included. INTERVENTION: Salt supplementation (100 mmol NaCl/24h) or placebo for 3 weeks was administered. MAIN OUTCOME MEASURES: The primary outcome of SNS activity and endothelial function was assessed as follows: Microneurography assessed muscle sympathetic nerve activity (MSNA), pulse amplitude tonometry assessed endothelial function via reactive hyperemic index (RHI), and arterial stiffness was assessed via augmentation index (AI). Secondary outcomes included cardiac baroreflex, serum aldosterone, ambulatory blood pressure monitoring (ABPM), heart rate variability (HRV), and salt sensitivity. RESULTS: Compared to placebo, salt supplementation increased MSNA (burst frequency P = .047, burst incidence P = .016); however, RHI (P = .24), AI (P = .201), ABPM (systolic P = .09, diastolic P = .14), and HRV were unaffected. Salt supplementation improved baroreflex (slope P = .026) and lowered aldosterone (P = .004), and in salt-resistant individuals there was a trend toward improved RHI (P = .07). CONCLUSIONS: In people with T2D and low habitual sodium intake, salt supplementation increased SNS activity without altering endothelial function or blood pressure but improved baroreflex function, a predictor of cardiac mortality. Salt-resistant individuals trended toward improved endothelial function with salt supplementation.

Effect of angiotensin II receptor blocker and salt supplementation on short-term blood pressure variability in type 2 diabetes.

High blood pressure variability (BPV) has been associated with increased cardiovascular (CV) risk. The effect of dietary salt and renin-angiotensin-aldosterone system (RAAS) activity on short-term BPV in type 2 diabetes mellitus (T2DM) is not well characterised. We aimed to determine the effect of dietary salt (sodium chloride, NaCl) supplementation on 24-h mean arterial BPV (24hBPV) during angiotensin II receptor blocker (telmisartan) use and to evaluate the effects of age, sex, plasma renin activity (PRA) and serum aldosterone on 24hBPV. In a randomised, double-blind, crossover study, patients with T2DM (n = 28), treated with telmisartan received NaCl (100 mmol/24 h) or placebo capsules during 2 weeks of telmisartan. Following a 6-week washout, the protocol was repeated in reverse. 24hBPV was evaluated as a co-efficient of variation [CV (%) = mean/standard deviation] × 100). Twenty-four hour urinary sodium excretion, ambulatory BP and biochemical tests were performed at each phase. Results were analysed using a linear mixed model to generate predicted values for 24hBPV. Predicted 24hBPV was higher with telmisartan vs baseline (p = 0.01), with a trend towards reduced 24hBPV with salt (p = 0.052). Predicted 24hBPV was lower in females (p = 0.017), increasing age (p = 0.001) and increasing PRA (p = 0.011). In patients with T2DM, predicted 24hBPV increased from baseline with telmisartan, but there was no additional increase in predicted 24hBPV with salt supplementation. This suggests that in the short-term, salt supplementation has no apparent deleterious effects on 24hBPV. Long-term studies are required to evaluate the effect of 24hBPV on CV outcomes in patients with T2DM.

Feasibility of using a transition diabetes team to commence injectable therapies postdischarge from a tertiary hospital: a pilot, randomised controlled trial.

OBJECTIVES: This study aimed to investigate if the use of a transition team was feasible for patients with diabetes being discharged from hospital on injectable diabetes therapies. DESIGN: Pilot, randomised controlled trial. SETTING: The trial was conducted between 2014 and 2016 conjointly by a tertiary referral hospital and a community healthcare provider. PARTICIPANTS: Hospital inpatients (n=105) on new injectable diabetes therapies were randomised 1:1 to transition team or standard care. The transition team received in-home diabetes education 24-48 hours postdischarge, with endocrinologist review 2-4 weeks and 16 weeks postdischarge. MAIN OUTCOME MEASURES: The primary outcome was feasibility, defined by percentage of patients successfully receiving the intervention. Secondary outcomes included safety, defined by hospital readmission and emergency department presentations within 16 weeks postrandomisation, and treatment satisfaction, measured using Diabetes Treatment Satisfaction Questionnaire (DTSQ). Exploratory outcomes included length of stay (LOS) and change in haemoglobin A1c (HbA1c) throughout the study. RESULTS: The intervention was deemed feasible (85% (95% CI 73% to 94%)). No difference in safety between groups was detected. No difference in change in HbA1c between groups was detected (standard care median HbA1c -1.5% (IQR -3.7% to -0.2%) vs transition team median HbA1c -1.9% (IQR -3.8% to -0.2%), p=0.83). There was a trend towards reduced LOS in the transition team group (per protocol, standard care median LOS 8 (IQR 5.5-12); transition team median LOS 6 (IQR 3-12), p=0.06). There was a significant improvement in patient satisfaction in the transition team (standard care median 10.5 (IQR 8.5-16); transition team DTSQ change version median 15 (IQR 10-17.5), p=0.047), although interpretability is limited by missing data. CONCLUSION: This study demonstrated that the use of a novel transition diabetes team is a feasible alternative model of care.

Comparison of endothelial function and sympathetic nervous system activity along the glucose continuum in individuals with differing metabolic risk profiles and low dietary sodium intake.

OBJECTIVE: Low sodium intake may trigger sympathetic nervous system (SNS) activation and endothelial dysfunction. Studies have not explored these associations along the glucose continuum. Accordingly, we compared endothelial function and SNS activity in individuals with low sodium intake and differing categories of metabolic risk along the glucose continuum. We hypothesized that low sodium intake is associated with (1) impairment of endothelial function and (2) higher SNS activity in individuals with higher metabolic risk. RESEARCH DESIGN AND METHODS: In this prospective observational study, participants (n=54) with low sodium intake (single 24 hours urine sodium excretion <150 mmol/24 hours) were categorized based on oral glucose tolerance testing as: normal glucose tolerance (NGT, n=10), impaired glucose tolerance (IGT, n=15), treatment naive type 2 diabetes (T2D-) (n=12) or treated type 2 diabetes (T2D+) (n=17). We assessed endothelial function using pulse amplitude tonometry (PAT) derived reactive hyperemic index and PAT ratio; arterial stiffness via augmentation index; muscle sympathetic nerve activity (MSNA) using microneurography; cardiac baroreflex; heart rate; blood pressure; glycosylated hemoglobin A1c (HbA1c) and lipid profile. RESULTS: Mean (SD) sodium excretion was 110.6 (26) mmol/24 hours. Compared with NGT, IGT and T2D-, the T2D+ group had lower MSNA (p=0.005), PAT ratio (p=0.04) and baroreflex sensitivity (p=0.0002) and an augmented heart rate (p=0.02). The T2D+ group had appropriate mean (SD) glycemic (HbA1c 7.2 (1.72)%), total cholesterol (4.2 (1.0) mmol/L), low-density lipoprotein (2.2 (1.0) mmol/L) and blood pressure (systolic 136 (13), diastolic 78 (12)) (mm Hg) control. CONCLUSIONS: Individuals with T2D+ have impaired endothelial and baroreflex function, despite low sodium intake, appropriately managed cardiometabolic risk factors and lower SNS activity, compared with others along the glucose continuum. Whether low sodium intake is associated with modulation of the sympathovascular profile in T2D requires further investigation.

Sodium Intake, Circulating Microvesicles and Cardiovascular Outcomes in Type 2 Diabetes.

There is ongoing debate surrounding the complex relationship between dietary sodium intake and cardiovascular morbidity and mortality. The existing literature consists largely of observational studies that have demonstrated positive, negative, U-/J-shaped or unclear associations between sodium intake and cardiovascular outcomes. Our group and others have previously demonstrated an inverse relationship between dietary sodium intake and cardiovascular outcomes in people with type 2 diabetes. Increased activity of the renin-angiotensin-aldosterone system and sympathetic nervous system is postulated to contribute to these paradoxical findings through endothelial dysfunction, a precursor to the development of cardiovascular disease. Microvesicles are submicron (0.1 - 1.0µm) vesicles that form during cellular activation, injury or death with endothelial microvesicles being recognized markers of endothelial dysfunction. They are pathologically elevated in a variety of vascular-related conditions including type 2 diabetes. Lower habitual sodium intake in type 2 diabetes has been associated with higher pro-coagulant platelet microvesicles levels but not with endothelial microvesicles. Research utilizing endothelial microvesicles to evaluate the mechanistic relationship between dietary sodium intake and adverse cardiovascular outcomes in type 2 diabetes remains scarce.

The relationship between habitual dietary sodium intake and RAAS blockade on circulating microparticle levels in type two diabetes.

OBJECTIVE: Low sodium intake is paradoxically associated with adverse cardiovascular outcomes in individuals with type 2 diabetes mellitus (T2D), possibly from renin-angiotensin-aldosterone system (RAAS) activation, leading to endothelial dysfunction. In the present study, we investigated the associations between habitual sodium intake and RAAS blockade on endothelial function by measuring circulating microparticles (MPs) in individuals with T2D. METHODS: We conducted a prospective, cross-sectional study in 74 individuals with T2D. Habitual dietary sodium intake was estimated by using the mean of three corrected 24-h urine sodium excretion measurements (24hUNa). MP subtypes in platelet-free plasma were quantitated using flow cytometry. RESULTS: No associations between 24hUNa with levels of endothelial MPs were observed. Instead, a trend toward higher diabetes related CD36+/CD235a+ MP levels was associated with lower 24hUNa (rho = -0.23, P=0.05). When stratified according to tertiles of 24hUNa, platelet-derived CD42b+/CD41+ and CD42+/CD41+/Annexin V+ MPs were higher in the lowest tertile (24hUNa < 157 mmol/24 h) (P=0.02 respectively). Despite RAAS blockade being associated with lower levels of most MP subsets, it was not associated with lower MPs, in the setting of low sodium intake. CONCLUSION: Lower sodium intake is associated with higher circulating procoagulant MPs, but not with evidence of endothelial dysfunction in individuals with T2D.

Strategies for enumeration of circulating microvesicles on a conventional flow cytometer: Counting beads and scatter parameters.

Enumeration of circulating microvesicles (MVs) by conventional flow cytometry is accomplished by the addition of a known amount of counting beads and calculated from the formula: MV/µl = (MV count/bead count) × final bead concentration. We sought to optimize each variable in the equation by determining the best parameters for detecting 'MV count' and examining the effects of different bead preparations and concentrations on the final calculation. Three commercially available bead preparations (TruCount, Flow-Count and CountBright) were tested, and MV detection on a BD FACSCanto was optimized for gating by either forward scatter (FSC) or side scatter (SSC); the results were compared by calculating different subsets of MV on a series of 74 typical patient plasma samples. The relationship between the number of beads added to each test and the number of beads counted by flow cytometry remained linear over a wide range of bead concentrations (R2 ≥ 0.997). However, TruCount beads produced the most consistent (concentration variation = 3.8%) calculated numbers of plasma CD41+/Annexin V+ MV, which were significantly higher from that calculated using either Flow-Count or CountBright (p < 0.001). The FACSCanto was able to resolve 0.5 µm beads by FSC and 0.16 µm beads by SSC, but there were significantly more background events using SSC compared with FSC (3113 vs. 470; p = 0.008). In general, sample analysis by SSC resulted in significantly higher numbers of MV (p < 0.0001) but was well correlated with enumeration by FSC for all MV subtypes (ρ = 0.62-0.89, p < 0.0001). We conclude that all counting beads provided linear results at concentrations ranging from 6 beads/µl to 100 beads/µl, but TruCount was the most consistent. Using SSC to gate MV events produced high background which negatively affected counting bead enumeration and overall MV calculations. Strategies to reduce SSC background should be employed in order to reliably use this technique.

Relationship between urinary sodium-to-potassium ratio and ambulatory blood pressure in patients with diabetes mellitus.

Previous studies investigating the relationship between sodium intake and blood pressure have mostly relied on dietary recall and clinic blood pressure measurement. In this cross-sectional study, we aimed to investigate the relationship between 24 hour urinary sodium and potassium excretion, and their ratio, with 24 hour ambulatory blood pressure parameters including nocturnal blood pressure dipping in patients with type 1 and 2 diabetes. We report that in 116 patients with diabetes, systolic blood pressure was significantly predicted by the time of day, age, the interaction between dipping status with time, and 24 hour urinary sodium-to-potassium ratio (R2  = 0.83) with a relative contribution of 53%, 21%, 20% and 6%, respectively. However, there was no interaction between urinary sodium-to-potassium ratio and dipping status.

Sodium and Its Role in Cardiovascular Disease - The Debate Continues.

Guidelines have recommended significant reductions in dietary sodium intake to improve cardiovascular health. However, these dietary sodium intake recommendations have been questioned as emerging evidence has shown that there is a higher risk of cardiovascular disease with a low sodium diet, including in individuals with type 2 diabetes. This may be related to the other pleotropic effects of dietary sodium intake. Therefore, despite recent review of dietary sodium intake guidelines by multiple organizations, including the dietary guidelines for Americans, American Diabetes Association, and American Heart Association, concerns about the impact of the degree of sodium restriction on cardiovascular health continue to be raised. This literature review examines the effects of dietary sodium intake on factors contributing to cardiovascular health, including left ventricular hypertrophy, heart rate, albuminuria, rennin-angiotensin-aldosterone system activation, serum lipids, insulin sensitivity, sympathetic nervous system activation, endothelial function, and immune function. In the last part of this review, the association between dietary sodium intake and cardiovascular outcomes, especially in individuals with diabetes, is explored. Given the increased risk of cardiovascular disease in individuals with diabetes and the increasing incidence of diabetes worldwide, this review is important in summarizing the recent evidence regarding the effects of dietary sodium intake on cardiovascular health, especially in this population.

Bowel perforation complicating an ACTH-secreting phaeochromocytoma.

ACTH-secreting phaeochromocytoma (ASP) is a rare cause of ACTH-dependent Cushing's syndrome (CS). We report the case of a 63-year-old female presenting with CS secondary to an ASP complicated by bowel perforation. This case report highlights ASP as an uncommon but important cause of ectopic ACTH secretion (EAS). There have been 29 cases of ASP, all of which were unilateral and benign, but associated with significant complications. Patients presenting with ASP have the potential for cure with unilateral adrenalectomy. Given this promising prognosis if recognised, ASP should be considered in the diagnostic workup of ACTH-dependent CS. As this case demonstrates, gastrointestinal complications can arise from severe hypercortisolaemia associated with CS. Early medical and surgical intervention is imperative as mortality approaches 50% once bowel perforation occurs. LEARNING POINTS: Consider phaeochromocytoma in the diagnostic workup of ACTH-dependent CS; screen with plasma metanephrines or urinary catecholamines.Serial screening may be required if ACTH-secreting phaeochromocytoma is suspected, as absolute levels can be misleading.Early catecholamine receptor blockade and adrenal synthesis blockade may avoid the need for rescue bilateral adrenalectomy in ACTH-secreting phaeochromocytoma.Consider early medical or surgical management when gastrointestinal features are present in patients with CS, as bowel perforation due to severe hypercortisolaemia can occur and is associated with significant mortality.

Short-term dietary salt supplementation blunts telmisartan induced increases in plasma renin activity in hypertensive patients with type 2 diabetes mellitus.

Current guidelines recommend low dietary salt intake (LDS) in patients with diabetes to reduce blood pressure (BP). However, low salt intake has been associated with higher mortality rates in people with diabetes. Our aim is to examine the effect of angiotensin II receptor blocker (ARB), telmisartan, with and without dietary sodium chloride (NaCl) supplementation, on BP [mean arterial pressure (MAP)], plasma renin activity (PRA), serum aldosterone level and estimated glomerular filtration rate (eGFR) in hypertensive patients with type 2 diabetes. In a randomized, double-blind, placebo-controlled study (RCT), 28 patients with type 2 diabetes, treated with telmisartan (40 mg daily), received 2 weeks of placebo or NaCl capsules (100 mmol/24 h). Following a 6-week washout, the protocol was repeated in reverse. Twenty-four-hour urinary sodium excretion (24hUNa), ambulatory BP (ABP) monitoring and blood tests were performed before and after each study phase. The telmisartan-associated increase in PRA was blunted by approximately 50% during salt supplementation compared with placebo; median PRA was 2.3 µg/l/h with placebo compared with 1.7 µg/l/h with salt (P<0.001). A trend towards blunting of ARB induced increases in serum aldosterone was also demonstrated. Salt supplementation significantly reduced the MAP lowering effects of telmisartan (P<0.05). The present study demonstrates that salt supplementation blunts the telmisartan induced increase in PRA in patients with type 2 diabetes.

Relationship between urinary sodium excretion and serum aldosterone in patients with diabetes in the presence and absence of modifiers of the renin-angiotensin-aldosterone system.

Although low dietary salt intake has beneficial effects on BP (blood pressure), low 24hUNa (24 h urinary sodium excretion), the most accurate estimate of dietary salt intake, is associated with increased mortality in people with diabetes. In the non-diabetic population, low salt intake is associated with increased RAAS (renin-angiotensin-aldosterone system) activity. In this cross-sectional study, we examined the relationship between 24hUNa, PRA (plasma renin activity), serum aldosterone and BNP (brain natriuretic peptide) in patients with diabetes. Clinical characteristics, 24hUNa, PRA, serum aldosterone and BNP were recorded in 222 consecutive patients (77% with Type 2 diabetes) attending a diabetes clinic at a tertiary hospital. The relationship between 24hUNa, serum aldosterone, PRA, BNP, urinary potassium excretion, serum potassium, serum sodium, eGFR (estimated glomerular filtration rate), urinary albumin excretion and HbA1c (glycated haemoglobin) was examined by a multivariable regression model. Levels of 24hUNa significantly predicted serum aldosterone in a linear fashion (R²=0.20, P=0.002). In the subgroup of patients (n=46) not taking RAAS-modifying agents, this relationship was also observed (R²=0.10, P=0.03), and the effect of 24hUNa on serum aldosterone was found to be more pronounced than in the whole cohort (coefficient=-0.0014, compared with -0.0008). There was no demonstrable relationship between 24hUNa and PRA or BNP. Low 24hUNa is associated with increased serum aldosterone in people with diabetes, in the presence and absence of RAAS-modifying agents. This raises the possibility that stimulation of the RAAS may be a mechanism that contributes to adverse outcomes observed in patients with low 24hUNa.