Abstract
Aims
To examine whether all-cause mortality is independently associated with serum bicarbonate concentration below the laboratory reference interval in a representative, well-characterised community-based cohort of people with type 2 diabetes.
Methods
1478 FDS2 participants with type 2 diabetes (mean age 65.8 years, 51.6% males, median diabetes duration 9.0 years) from the longitudinal, observational Fremantle Diabetes Study Phase II (FDS2) were followed from study entry to death or end-2016. Independent associates of a low baseline serum bicarbonate (< 22 mmol/L) were determined using multiple logistic regression. The role of important covariates in influencing the association between bicarbonate and mortality was assessed by a stepwise Cox regression approach.
Results
A low serum bicarbonate was associated with increased all-cause mortality in unadjusted analysis (hazard ratio (HR) 1.90 (95% confidence limits (CL) 1.39, 2.60 per mmol/L). Mortality remained significantly associated with low serum bicarbonate (HR 1.40 (95% CL 1.01, 1.94) per mmol/L) in a Cox regression model with adjustment for factors associated with mortality but not low serum bicarbonate, but inclusion of estimated glomerular filtration rate categories rendered the association non-significant (HR 1.16 (95% CL 0.83, 1.63) per mmol/L).
Conclusions
A low serum bicarbonate is not an independent prognostic marker in people with type 2 diabetes but it may be a manifestation of the pathway between the development of impaired renal function and death.
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Introduction
The serum bicarbonate concentration is a commonly measured surrogate marker of acid–base status in hospitalised and community-based patients. It is well recognised that both metabolic and respiratory acid–base derangements can affect the serum bicarbonate concentration and this complicates its clinical interpretation. Nevertheless, recent studies have identified serum bicarbonate as a marker of mortality risk that is independent of other predictive variables. There is evidence that a low serum bicarbonate concentration is independently associated with all-cause mortality in representative community-based individuals [1,2,3,4] regardless of whether the cause is a metabolic acidosis or compensated respiratory alkalosis [3]. In the case of patients with chronic kidney disease (CKD) or hypertension, a low serum bicarbonate was an independent risk factor for mortality in some [5,6,7] but not all [8,9,10] studies.
Whether a low serum bicarbonate is an independent mortality risk factor among people with type 2 diabetes is uncertain. Type 2 diabetes is associated with an increased risk of CKD [11] and pulmonary dysfunction [12, 13], and relatively frequent use of diuretic and anti-hypertensive medications [14], factors that can have a complex influence on acid–base status. While most studies in the general population and in people with CKD suggest a significant link between a low serum bicarbonate and death [1,2,3,4,5,6,7], there is no such independent association in people with diabetic nephropathy [15], type 2 diabetes and CKD [6], or diabetes from the community [16], even if a positive association was reported in the subset of people with diabetes in another community-based cohort [1].
Apparent discrepancies between studies and across patient groups may reflect differences in selection criteria, sample sizes and thus statistical power, and/or availability of clinically important covariates which may include the existence of other, more potent, mortality risk factors in people with diabetes. The aim of the present study was, therefore, to examine whether all-cause mortality is independently associated with serum bicarbonate concentration below the reference interval in a representative, well-characterised cohort of people with type 2 diabetes from the Fremantle Diabetes Study Phase II (FDS2). We also aimed to determine whether there are covariates of serum bicarbonate that modulate its relationship with mortality and help explain inconsistencies between previous published studies.
Materials and methods
Participants
The Fremantle Diabetes Study Phase II (FDS2) is a prospective observational study of diabetes in a postcode-defined urban population of approximately 153,000 people living in and around the port city of Fremantle in Western Australia (WA) [17]. Of 4639 people identified as living with diabetes between 2008 and 2011, 1668 (36.0%) were recruited together with 64 participants of the Fremantle Diabetes Study Phase I who had moved out of the study area. Altogether, 1482 (85.6%) had type 2 diabetes based on demographic, anthropometric, clinical and laboratory features [18]. The present study included 1478 (99.7%) of the 1482 FDS2 participants with type 2 diabetes who had a valid measurement of the serum bicarbonate concentration at baseline.
Clinical methods
Participants had comprehensive face-to-face assessments at baseline and biennially, interspersed with biennial postal questionnaires [17]. At each visit, demographic and clinical information was documented, physical examinations and associated investigations were carried out, and fasting blood and urine samples for biochemical tests were obtained. A body shape index (ABSI) was calculated as a more robust index of visceral obesity as a predictor of death [19]. Micro- and macrovascular complications of diabetes at study entry were identified using standard criteria [17, 20], including distal symmetric polyneuropathy (a score of > 2/8 on the clinical portion of the Michigan Neuropathy Screening Instrument [21]), retinopathy from graded fundus photographs, nephropathy (first-morning urinary albumin:creatinine ratio > 3.0 mg/mmol), renal impairment by estimated glomerular filtration rate (eGFR) determined using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation [22], coronary heart disease (CHD) (self-reported history of myocardial infarction, angina and/or revascularisation, or prior hospitalisations for these events), cerebrovascular disease (self-reported stroke/transient ischaemic attack or prior hospitalisations for these events) and peripheral arterial disease (ankle:brachial index ≤ 0.90 on either leg or diabetes-related amputation). The Charlson Comorbidity Index was calculated as a measure of chronic disease effects after excluding diabetes and diabetes-related conditions [23].
The Hospital Morbidity Data Collection (HMDC) contains information regarding all public/private hospitalisations in WA since 1970 while the Death Registrations contains information on all deaths in WA [24]. The FDS2 has been linked through the WA Data Linkage System (WADLS) to these databases, as approved by the WA Department of Health Human Research Ethics Committee, to provide validated data on incident events to end-2016.
Biochemical assays
Morning fasting venous blood samples were collected from each patient, centrifuged promptly and analysed for standard biochemical parameters in a single nationally accredited laboratory. Spot first-morning urine samples were also collected. The homeostasis model assessment (HOMA) was used to estimate steady state beta cell function (%B) and sensitivity (%S) as percentages of a normal reference population, and insulin resistance (IR) which is the reciprocal of %S (100/%S) [25]. Serum bicarbonate was measured by the phosphoenolpyruvate carboxylase method using an Integra 800 analyser (Roche Diagnostics Australia, Castle Hill, NSW, Australia) and then an Abbott Architect ci8200 analyser (Abbott Diagnostics, Macquarie Park, NSW, Australia). Between-run imprecision (expressed as coefficient of variation) was 5.5% at 13.5 mmol/L and 3.5% at 29.6 mmol/L. The reference interval in this laboratory is 22–32 mmol/L. For the purposes of the present study, a low serum bicarbonate was defined as < 22 mmol/L. Serum potassium, creatinine, glucose, cholesterol, triglycerides and HDL-cholesterol, as well as urine albumin and creatinine, were measured by standard methods on the Integra 800 and Architect ci8200 analysers. Glycated haemoglobin was estimated by immunoassay on the Roche Integra 800 analyser throughout the study.
Data analysis
The computer package IBM SPSS Statistics 25 (IBM Corporation, Armonk, NY, USA) was used for statistical analysis. Data are presented as percentages, mean ± SD, geometric mean (SD range), or, in the case of variables which did not conform to a normal or log-normal distribution, median and [inter-quartile range]. For independent samples, two-way comparisons for proportions were by Fisher’s exact test, for normally distributed variables by Student’s t-test, and for non-normally distributed variables by Mann–Whitney U-test. Multiple logistic regression using backward stepwise conditional modelling (P < 0.05 for entry, P ≥ 0.05 for removal), with all clinically plausible variables at P < 0.20 in bivariable analyses considered for entry, identified independent associates of baseline serum bicarbonate < 22 mmol/L. Cox regression was used to determine independent predictors of all-cause mortality using backward stepwise conditional modelling (P < 0.05 for entry, P ≥ 0.05 for removal) with all clinically plausible variables at P < 0.20 in bivariable analyses considered for entry.
To understand the relationship between a low serum bicarbonate and all-cause mortality, (1) unadjusted Cox regression was first performed with low serum bicarbonate as the exposure and all-cause mortality as the outcome (model 1); (2) adjustment was then made for age and sex (model 2); (3) further adjustment was made for those variables independently associated with all-cause mortality but not low serum bicarbonate (model 3); (4) non-significant variables in model 3 were removed using backward conditional modelling (P < 0.05 for entry, P ≥ 0.05 for removal; model 4); (5) heart rate, which was significantly associated with both low serum bicarbonate and all-cause mortality, was added to model 4 (model 5); (6) eGFR categories < 60 ml/min/1.73m2, which were significantly associated with both low serum bicarbonate and all-cause mortality, were added to model 4 (model 6).
Results
Baseline characteristics
The serum bicarbonate concentration was available for 1478 of the 1482 participants with type 2 diabetes in the FDS2 cohort (99.7%; mean age 65.8 ± 11.6 years, 51.6% males, median diabetes duration 9.0 [3.0–15.9] years). Their mean serum bicarbonate was 24 ± 2 mmol/L. The demographic, clinical and biochemical characteristics of patients with serum bicarbonate < 22 mmol/L and ≥ 22 mmol/L are summarised in Table 1. Participants with a low serum bicarbonate were more likely to be Australian Aboriginal and less likely to be Anglo-Celt, were younger at diagnosis of diabetes, had longer diabetes duration, higher fasting glucose and HbA1c, more intensive blood glucose-lowering treatment, greater obesity, higher heart rate, serum potassium, serum triglycerides, urinary albumin:creatinine ratio and prevalence of CHD and cerebrovascular disease, lower diastolic blood pressure, serum HDL-cholesterol and eGFR, and more comorbidities. Independent associates of a low serum bicarbonate concentration in the whole cohort are shown in Table 2. Factors that were independently associated with a low serum bicarbonate were heart rate, serum potassium, eGFR < 60 mL/min/1.73m2 and history of CHD, while age at diabetes diagnosis, being on insulin therapy and HDL-cholesterol were negatively associated.
Serum bicarbonate and all-cause mortality
During a total of 9834 person-years (6.7 ± 1.7 years) of follow-up to end-December 2016, 272 (18.4%) of the cohort died. Baseline associates of all-cause mortality are shown in Table 3. Serum bicarbonate was negatively associated with all-cause mortality; 17.3% of those who died during follow-up had a low serum bicarbonate compared with 9.2% of survivors (P < 0.001). The most parsimonious Cox model of time to all-cause mortality included age, sex, marital status, ethnic background, current smoking, obesity, heart rate, estimated glomerular filtration rate categories < 60 mL/min/1.73m2, distal symmetric polyneuropathy, peripheral arterial disease and comorbidities (Table 4, Model 7).
In unadjusted Cox regression, participants with a low serum bicarbonate were nearly twice as likely to die (HR (95% CI): 1.90 (1.39, 2.60), P < 0.001; Table 4, Model 1). In multivariable Cox regression models, the association of low serum bicarbonate with mortality remained significant after adjustment for age and sex (1.73 (1.27, 2.38), P < 0.001; Table 4, Model 2). When variables independently associated with mortality but not with low serum bicarbonate were entered and non-significant variables removed, the association of a low serum bicarbonate with mortality was attenuated but remained statistically significant (1.40 (1.01, 1.94), P = 0.044; Table 4, Model 4). Further separate adjustment for heart rate and low eGFR categories rendered the association of a low serum bicarbonate with mortality non-significant (P = 0.058 and 0.397, respectively; Table 4, Models 5 and 6), although the change in risk when heart rate was added was small.
Discussion
The present study shows that a baseline serum bicarbonate concentration < 22 mmol/L in community-based people with type 2 diabetes was a significant predictor of subsequent all-cause mortality in statistical models incorporating limited adjustment for confounding variables. However, this association was non-significant in fully adjusted models that included impaired renal function. These observations suggest that a low serum bicarbonate may a manifestation of the causal pathway between renal impairment and death, but that it is not an independent risk factor for mortality in type 2 diabetes.
There appears to be a distinction between the consistent finding that a low serum bicarbonate is associated with the risk of death in representative general population samples after adjustment for relevant covariates including eGFR [1,2,3,4] and the inconsistent but largely negative results in studies of people with CKD [5,6,7,8, 10] or diabetes [1, 6, 16]. In the present study, we developed models which adjusted for increasing numbers of clinically relevant covariates and, in accord with post hoc analyses of two large two angiotensin II receptor blocking agent trials in people with diabetic nephropathy [15], found that eGFR abrogated the relationship between serum bicarbonate and death.
A possible explanation for these different observations is that, in people from the general population who do not have CKD or diabetes, a chronic low grade metabolic acidosis, for which a low serum bicarbonate is a surrogate, has pathophysiological consequences including accelerated renal damage [26], protein catabolism [27], systemic inflammation [28] and activation of the renin-angiotensin system [29]. These effects are amplified and swamped by the dominant adverse metabolic consequences of CKD, which is also associated with exacerbation of major conventional cardiovascular disease risk factors including hypertension and dyslipidaemia [30]. This is likely to be the case in diabetes as well, although there is some evidence that that a low serum bicarbonate in an individual with diabetes is not as strongly associated with kidney disease progression and mortality as in people with CKD but without diabetes [31]. Nevertheless, there was an independent graded positive association between baseline eGFR and a low serum bicarbonate in our participants even if the cross-sectional nature of the analysis does not allow distinguishing cause from consequence.
There were other significant independent associates of a serum bicarbonate < 22 mmol/L in the present study. The association with a younger age at diagnosis likely reflects the effect of accelerated cellular ageing in diabetes [32] which could exacerbate the age-related increase in the serum bicarbonate [33]. The inverse association between insulin therapy and a low serum bicarbonate can be explained by its known effect of inhibiting adipocyte lipolysis and thereby reducing serum free fatty acid and ketoacid concentrations [34]. Evidence from in vitro to in vivo studies suggests that acidosis may cause decreased cardiomyocyte contractility and a reflex increased heart rate [35,36,37], consistent with the positive association between low serum bicarbonate and heart rate in the present and previous [1, 16] studies. An increase in heart rate is also a known risk factor for cardiovascular disease and death in general populations studies, as demonstrated in a recent meta-analysis showing an increase in risk for all-cause mortality of 17% per 10 beats/minute increase [38] compared with a similar 29% per 10 beats/minute increased risk among our participants. Interestingly, no other studies of the association of serum bicarbonate with mortality have included heart rate as a covariate. An association between serum potassium and a low serum bicarbonate is well recognised, including in older people with renal impairment [39], as is an inverse association between serum HDL-cholesterol and a low serum bicarbonate [9] and between CHD and a low serum bicarbonate [16].
Our study had some limitations. We used the serum bicarbonate as a surrogate measure of metabolic acidosis even though respiratory alkalosis is a possible cause of low bicarbonate. In common with most relevant studies to date, we did not have measures of blood pH or pCO2 so cannot make the distinction between these states but our results with respect to associations of a low serum bicarbonate with factor such as renal impairment, hyperkalaemia and increased heart rate are consistent with the published evidence. We did not have enough incident cases of CHD or incident heart failure to make meaningful analyses of the relationship between bicarbonate and these outcomes. On the other hand, the present study is one of few of the association of bicarbonate and mortality to be carried out in a representative community-based cohort of people with type 2 diabetes, with extensive clinical and biochemical characterisation of the participants. Model adjustment utilised the most parsimonious approach, thus reducing the risk of over-adjustment.
The clinical implications of our findings are that a low serum bicarbonate, measured as part of routine care, is a crude mortality risk factor that may indicate need for intensified cardiometabolic management in people with type 2 diabetes. In most, similar information will be obtained from the eGFR as calculated from serum creatinine measurement. However, in some groups of people, particularly frail elderly patients and those who have suffered significant limb amputations in whom eGFR may be overestimated by serum creatinine, a serum bicarbonate may be complementary or even better marker of mortality risk.
In conclusion, in our community-based cohort of people with type 2 diabetes, a serum bicarbonate below the laboratory reference interval was bivariately significantly associated with all-cause mortality, but adjustment for important confounders including renal dysfunction abrogated this association. Our results are consistent with serum bicarbonate being one manifestation of the pathway from impaired renal function to death in people with type 2 diabetes. A low serum bicarbonate in a patient being cared for in the community may be a valid marker of increased risk of death, especially in patients with complications of advanced diabetes such as sarcopenia or amputation in whom the calculated eGFR may be less reliable.
Data availability
Restrictions apply to the availability of data generated or analysed during this study to preserve patient confidentiality or because they were used under license. The corresponding author will on request detail the restrictions and any conditions under which access to some data may be provided.
References
Al-Kindi SG, Sarode A, Zullo M, Rajagopalan S, Rahman M, Hostetter T et al (2020) Serum bicarbonate concentration and cause-specific mortality: the national health and nutrition examination survey 1999–2010. Mayo Clin Proc 95(1):113–123. https://doi.org/10.1016/j.mayocp.2019.05.036
Park M, Jung SJ, Yoon S, Yun JM, Yoon HJ (2015) Association between the markers of metabolic acid load and higher all-cause and cardiovascular mortality in a general population with preserved renal function. Hypertens Res 38(6):433–438. https://doi.org/10.1038/hr.2015.23
Raphael KL, Murphy RA, Shlipak MG, Satterfield S, Huston HK, Sebastian A et al (2016) Bicarbonate concentration, acid-base status, and mortality in the health, aging, and body composition study. Clin J Am Soc Nephrol 11(2):308–316. https://doi.org/10.2215/CJN.06200615
Raphael KL, Zhang Y, Wei G, Greene T, Cheung AK, Beddhu S (2013) Serum bicarbonate and mortality in adults in NHANES III. Nephrol Dial Transpl 28(5):1207–1213. https://doi.org/10.1093/ndt/gfs609
Kovesdy CP, Anderson JE, Kalantar-Zadeh K (2009) Association of serum bicarbonate levels with mortality in patients with non-dialysis-dependent CKD. Nephrol Dial Transpl 24(4):1232–1237. https://doi.org/10.1093/ndt/gfn633
Navaneethan SD, Schold JD, Arrigain S, Jolly SE, Wehbe E, Raina R et al (2011) Serum bicarbonate and mortality in stage 3 and stage 4 chronic kidney disease. Clin J Am Soc Nephrol 6(10):2395–2402. https://doi.org/10.2215/CJN.03730411
Tangri N, Reaven NL, Funk SE, Ferguson TW, Collister D, Mathur V (2021) Metabolic acidosis is associated with increased risk of adverse kidney outcomes and mortality in patients with non-dialysis dependent chronic kidney disease: an observational cohort study. BMC Nephrol 22(1):185. https://doi.org/10.1186/s12882-021-02385-z
Dobre M, Yang W, Chen J, Drawz P, Hamm LL, Horwitz E et al (2013) Association of serum bicarbonate with risk of renal and cardiovascular outcomes in CKD: a report from the chronic renal insufficiency cohort (CRIC) study. Am J Kidney Dis 62(4):670–678. https://doi.org/10.1053/j.ajkd.2013.01.017
Dobre M, Pajewski NM, Beddhu S, Chonchol M, Hostetter TH, Li P et al (2020) Serum bicarbonate and cardiovascular events in hypertensive adults: results from the systolic blood pressure intervention trial. Nephrol Dial Transpl 35(8):1377–1384. https://doi.org/10.1093/ndt/gfz149
Dobre M, Yang W, Pan Q, Appel L, Bellovich K, Chen J et al (2015) Persistent high serum bicarbonate and the risk of heart failure in patients with chronic kidney disease (CKD): A report from the Chronic Renal Insufficiency Cohort (CRIC) study. J Am Heart Assoc 4(4):e001599. https://doi.org/10.1161/JAHA.114.001599
Tuttle KR, Jones CR, Daratha KB, Koyama AK, Nicholas SB, Alicic RZ et al (2022) Incidence of chronic kidney disease among adults with diabetes, 2015–2020. N Engl J Med 387(15):1430–1431. https://doi.org/10.1056/NEJMc2207018
Davis TM, Knuiman M, Kendall P, Vu H, Davis WA (2000) Reduced pulmonary function and its associations in type 2 diabetes: the fremantle diabetes study. Diabetes Res Clin Pract 50(2):153–159
Davis WA, Knuiman M, Kendall P, Grange V, Davis TM, Fremantle DS (2004) Glycemic exposure is associated with reduced pulmonary function in type 2 diabetes: the fremantle diabetes study. Diabetes Care 27(3):752–757. https://doi.org/10.2337/diacare.27.3.752
Lastra G, Syed S, Kurukulasuriya LR, Manrique C, Sowers JR (2014) Type 2 diabetes mellitus and hypertension: an update. Endocrinol Metab Clin North Am 43(1):103–122. https://doi.org/10.1016/j.ecl.2013.09.005
Schutte E, Lambers Heerspink HJ, Lutgers HL, Bakker SJ, Vart P, Wolffenbuttel BH et al (2015) Serum bicarbonate and kidney disease progression and cardiovascular outcome in patients with diabetic nephropathy: a post hoc analysis of the RENAAL (reduction of end points in non-insulin-dependent diabetes with the angiotensin II Antagonist Losartan) study and IDNT (irbesartan diabetic nephropathy trial). Am J Kidney Dis 66(3):450–458. https://doi.org/10.1053/j.ajkd.2015.03.032
Chubb SA, Davis WA, Peters KE, Davis TM (2016) Serum bicarbonate concentration and the risk of cardiovascular disease and death in type 2 diabetes: the fremantle diabetes study. Cardiovasc Diabetol 15(1):143. https://doi.org/10.1186/s12933-016-0462-x
Davis TM, Bruce DG, Davis WA (2013) Cohort profile: the fremantle diabetes study. Int J Epidemiol 42(2):412–421. https://doi.org/10.1093/ije/dys065
Davis WA, Peters KE, Makepeace A, Griffiths S, Bundell C, Grant SFA et al (2018) Prevalence of diabetes in Australia: insights from the Fremantle Diabetes Study Phase II. Intern Med J 48(7):803–809. https://doi.org/10.1111/imj.13792
Krakauer NY, Krakauer JC (2012) A new body shape index predicts mortality hazard independently of body mass index. PLoS ONE 7(7):e39504. https://doi.org/10.1371/journal.pone.0039504
Norman PE, Davis WA, Bruce DG, Davis TM (2006) Peripheral arterial disease and risk of cardiac death in type 2 diabetes: the fremantle diabetes study. Diabetes Care 29(3):575–580
Feldman EL, Stevens MJ, Thomas PK, Brown MB, Canal N, Greene DA (1994) A practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy. Diabetes Care 17(11):1281–1289
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI et al (2009) A new equation to estimate glomerular filtration rate. Ann Intern Med 150(9):604–612
Charlson ME, Pompei P, Ales KL, MacKenzie CR (1987) A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 40(5):373–383
Holman CD, Bass AJ, Rosman DL, Smith MB, Semmens JB, Glasson EJ et al (2008) A decade of data linkage in Western Australia: strategic design, applications and benefits of the WA data linkage system. Aust Health Rev 32(4):766–777
Oxford University, Diabetes Trails Unit: HOMA2 Calculator. https://www.dtu.ox.ac.uk/homacalculator/ (2014). Accessed April 2023.
Wesson DE, Simoni J (2009) Increased tissue acid mediates a progressive decline in the glomerular filtration rate of animals with reduced nephron mass. Kidney Int 75(9):929–935. https://doi.org/10.1038/ki.2009.6
May RC, Kelly RA, Mitch WE (1987) Mechanisms for defects in muscle protein metabolism in rats with chronic uremia. Influence of metabolic acidosis. J Clin Investig 79(4):1099–1103. https://doi.org/10.1172/JCI112924
Bellocq A, Suberville S, Philippe C, Bertrand F, Perez J, Fouqueray B et al (1998) Low environmental pH is responsible for the induction of nitric-oxide synthase in macrophages. Evidence for involvement of nuclear factor-kappaB activation. J Biol Chem 273(9):5086–5092. https://doi.org/10.1074/jbc.273.9.5086
Ng HY, Chen HC, Tsai YC, Yang YK, Lee CT (2011) Activation of intrarenal renin-angiotensin system during metabolic acidosis. Am J Nephrol 34(1):55–63. https://doi.org/10.1159/000328742
Palsson R, Patel UD (2014) Cardiovascular complications of diabetic kidney disease. Adv Chronic Kidney Dis 21(3):273–280. https://doi.org/10.1053/j.ackd.2014.03.003
Khairallah P, Scialla JJ (2017) Role of acid-base homeostasis in diabetic kidney disease. Curr Diab Rep 17(4):28. https://doi.org/10.1007/s11892-017-0855-6
Burton DGA, Faragher RGA (2018) Obesity and type-2 diabetes as inducers of premature cellular senescence and ageing. Biogerontology 19(6):447–459. https://doi.org/10.1007/s10522-018-9763-7
Amodu A, Abramowitz MK (2013) Dietary acid, age, and serum bicarbonate levels among adults in the United States. Clin J Am Soc Nephrol 8(12):2034–2042. https://doi.org/10.2215/CJN.03600413
Szabo Z, Arnqvist H, Hakanson E, Jorfeldt L, Svedjeholm R (2001) Effects of high-dose glucose-insulin-potassium on myocardial metabolism after coronary surgery in patients with Type II diabetes. Clin Sci (Lond) 101(1):37–43
Orchard CH, Kentish JC (1990) Effects of changes of pH on the contractile function of cardiac muscle. Am J Physiol 258(6 Pt 1):C967–C981. https://doi.org/10.1152/ajpcell.1990.258.6.C967
Stengl M, Ledvinova L, Chvojka J, Benes J, Jarkovska D, Holas J et al (2013) Effects of clinically relevant acute hypercapnic and metabolic acidosis on the cardiovascular system: an experimental porcine study. Crit Care 17(6):R303. https://doi.org/10.1186/cc13173
Weber T, Tschernich H, Sitzwohl C, Ullrich R, Germann P, Zimpfer M et al (2000) Tromethamine buffer modifies the depressant effect of permissive hypercapnia on myocardial contractility in patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 162(4 Pt 1):1361–1365. https://doi.org/10.1164/ajrccm.162.4.9808092
Aune D, Sen A, o’Hartaigh B, Janszky I, Romundstad PR, Tonstad S et al (2017) (2017) Resting heart rate and the risk of cardiovascular disease, total cancer, and all-cause mortality—a systematic review and dose-response meta-analysis of prospective studies. Nutr Metab Cardiovasc Dis 27(6):504–517. https://doi.org/10.1016/j.numecd.2017.04.004
Kanda E, Ai M, Yoshida M, Kuriyama R, Shiigai T (2013) High serum bicarbonate level within the normal range prevents the progression of chronic kidney disease in elderly chronic kidney disease patients. BMC Nephrol 14:4. https://doi.org/10.1186/1471-2369-14-4
Acknowledgements
We are grateful to FDS2 participants and FDS staff for help with collecting and recording clinical information. We thank the Biochemistry Department at Fremantle Hospital and Health Service for performing laboratory tests. The authors wish to thank the staff from the Department of Health WA’s Data Linkage Services, the Hospital Morbidity Data Collection and the Western Australian Registry of Births, Deaths and Marriages.
Funding
Open Access funding enabled and organized by CAUL and its Member Institutions. FDS2 was supported by the National Health and Medical Research Council (Project Grants 513781 and 1042231). TMED is supported by a Medical Research Future Fund Practitioner Fellowship (1154192). These funding bodies had no involvement in the study design, data collection, analysis and interpretation of results or writing this manuscript.
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SAPC was responsible for all biochemical analyses and produced the first draft of the manuscript. WAD performed all statistical analyses and reviewed and edited the manuscript. TMED is principal investigator of the FDS, conceived the present sub-study and produced the final version of the manuscript.
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The FDS2 was approved by the South Metropolitan Area Health Service Human Research Ethics Committee, all participants gave written informed consent, and the study was performed in accordance with ethical standards specified in the Declaration of Helsinki.
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Chubb, S.A.P., Davis, W.A. & Davis, T.M.E. Serum bicarbonate concentration and the risk of death in type 2 diabetes: the Fremantle Diabetes Study Phase II. Acta Diabetol 60, 1333–1342 (2023). https://doi.org/10.1007/s00592-023-02130-y
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DOI: https://doi.org/10.1007/s00592-023-02130-y