Effects of hydration on plasma copeptin, glycemia and gluco-regulatory hormones: a water intervention in humans
European Journal of Nutrition
https://doi.org/10.1007/s00394
Effects of hydration on plasma copeptin, glycemia and gluco- regulatory hormones: a water intervention in humans
Sofia Enhörning 0 1 2 4 5 6 7 8
Irina Tasevska 0 1 2 4 5 6 7 8
Ronan Roussel 0 1 2 4 5 6 7 8
Nadine Bouby 0 1 2 4 5 6 7 8
Margaretha Persson 0 1 2 4 5 6 7 8
Philippe Burri 0 1 2 4 5 6 7 8
Lise Bankir 0 1 2 4 5 6 7 8
Olle Melander 0 1 2 4 5 6 7 8
0 Department of Internal Medicine, Skåne University Hospital, Lund University , Malmö , Sweden
1 Department of Anesthesiology, Skåne University Hospital, Lund University , Malmö , Sweden
2 Department of Endocrinology, Skåne University Hospital, Lund University , Malmö , Sweden
3 Sofia Enhörning
4 Department of Clinical Sciences, Clinical Research Center, Skåne University Hospital , Jan Waldenströms gata 35, 91:12, 205 02 Malmö , Sweden
5 University Pierre et Marie Curie, Centre de Recherche des Cordeliers , Paris , France
6 Assistance Publique Hôpitaux de Paris, Hôpital Bichat, DHU FIRE , Paris , France
7 INSERM, Unit 1138, Centre de Recherche des Cordeliers , Paris , France
8 Department of Clinical Sciences, Lund University , Malmö , Sweden
Purpose High plasma copeptin, a marker of vasopressin, predicts diabetes mellitus. We tested if copeptin could be suppressed by increased water intake in healthy individuals, and if a water-induced change in copeptin was accompanied by altered concentrations of glucose, insulin or glucagon. Methods Thirty-nine healthy individuals underwent, in random order, 1 week of high water intake (3 L/day on top of habitual intake) and 1 week of normal (habitual) fluid intake (control). Fasting plasma concentrations of copeptin, glucose, insulin and glucagon were compared between the ends of both periods. Furthermore, acute copeptin kinetics were mapped for 4 h after ingestion of 1 L of water. Results After acute intake of 1 L water, copeptin was significantly reduced within 30 min, and reached maximum reduction within 90 min with on average 39% reduction (95% confidence interval (95 CI) 34-45) (p< 0.001) and remained low the entire test period (4 h). One week of increased water intake led to a 15% reduction (95 CI 5-25) (p = 0.003) of copeptin compared to control week. The greatest reduction occurred among subjects with habitually high copeptin and concentrated urine (“water-responders”). Water-responders had significant water-induced reduction of glucagon, but glucose and insulin were unaffected. Conclusions Both acute and 1 week extra water intake potently reduced copeptin concentration. In those with the greatest decline (water-responders), who are typically low drinkers with high baseline copeptin, water induced a reduction in fasting glucagon. Long-term trials assessing the effect of water on glucometabolic traits should focus on low-water drinkers with high copeptin concentration.
Vasopressin; Glucagon; Insulin; OGTT; Water
-
Université Paris Diderot, Sorbonne Paris Cité, UFR de
Médecine, Paris, France
Introduction
Vasopressin (VP) is released from the posterior pituitary
gland mainly in conditions of increased plasma osmolality
or hypovolemia. Apart from maintaining plasma
osmolality by mediating water reabsorption in conditions of low
water intake, VP has many other physiological functions.
VP stimulates hepatic glycogenolysis and gluconeogenesis
by acting on VP receptor 1a [
1, 2
] and release of either
insulin or glucagon from the pancreas, depending on the
current plasma glucose concentration, through VP
receptor 1b (V1bR) [3]. Furthermore, VP plays a role in the
hypothalamic–pituitary–adrenal axis by mediating
adrenocorticotropic hormone release from the anterior pituitary
[
4, 5
]. Thus, VP may influence glucose homeostasis in
many ways [6].
Usual concentrations of VP are very low and the peptide
is short lived in plasma. The sensitivity of most VP assays
is too low to detect the hormone in the low
physiological range [
7
]. An assay has been developed to indirectly
evaluate VP concentration by measurement of copeptin,
the C-terminal cleavage product of the VP precursor
protein. Copeptin is very stable in vitro and released in a
1:1 ratio with VP [
8–10
]. We previously showed that
fasting plasma concentration of VP, measured as copeptin,
strongly predicts new-onset type 2 diabetes [
11
], a finding
later replicated in other large prospective population-based
studies [
12, 13
]. Furthermore, we showed that subjects
with high copeptin concentration have an increased risk
of all components of the metabolic syndrome [
11, 14, 15
]
as well as cardiovascular disease and premature mortality,
both in diabetics and non-diabetics [
16–18
].
Even though a causal relationship between high VP
concentration and risk of diabetes, cardiovascular disease
and mortality remains to be proven, there is a growing
body of epidemiological and experimental data
supporting causality, which in turn has led to increased interest
in reducing VP secretion with either pharmacological or
non-pharmacological tools. In healthy humans, variation
of water intake, even within the normal range, is the most
well-established factor controlling release of VP, with low
water intake increasing and high water intake decreasing
VP secretion, all to keep plasma osmolality constant [
19
].
Previous experiments have shown that median plasma
copeptin values decreased from 3.3 to 2.0 pmol/L within
120 min after an acute water load (20 mL/kg body weight)
in young healthy subjects [
9
]. However, the effect of
increased water intake on glucose metabolism and
diabetes development has not been studied in humans neither in
short-term nor in long-term studies. We recently showed in
obese Zucker rats that glucose tolerance deteriorated when
they were chronically exposed to high VP. Conversely,
when endogenous VP was reduced by an enhanced water
intake, their insulin resistance and hepatic fat
accumulation were markedly ameliorated [
20
]. Previous trials and
observational studies in humans have demonstrated that
high water intake may promote better glucose control,
weight loss and decreased cardiovascular risk [
21–23
].
Furthermore, evidence from humans and animals suggests
a protective effect of increased hydration/decreased VP on
kidney function [
24–26
].
The first aim of this study was to test if it is possible to
reduce plasma copeptin concentration in healthy individuals,
both acutely and within 1 week, by increasing water intake.
The second aim was to test if a water-induced reduction in
plasma copeptin is accompanied by altered plasma
concentrations of glucose, insulin or glucagon, either in the fasted
state or during an oral glucose tolerance test (OGTT).
Subjects and methods
Study population
Fifty-five healthy subjects aged 20–70 years were recruited
via advertisement in local newspaper or through telephone
contacts with individuals that have participated in two
population-based cohort studies in Malmö [
11, 27
]. Thirty-nine
subjects (71%) completed the study, and 37 subjects had
complete data on plasma copeptin concentrations. The
participants were exposed to two different intervention
procedures in randomized order: water load (acutely and during
1 week), or no change from usual fluid intake (as a time
control).
Study protocol
Each subject underwent two different experimental periods
in random order: 1 week with 3 L increased water
ingestion per day in addition to each subject’s own food and fluid
intake (water week = HWI-Wk), and 1 week on their usual
fluid intake (control week= CONT-Wk). Each subject thus
served as its own control. During HWI-Wk, the participants
were instructed to increase their daily intake of water with
3L and were provided with two bottles (1.5 L each) of still
water per day (10 mg/L sodium).
In addition, on day 1 (the first out of seven intervention
days), subjects acutely ingested either 1 L of still bottled
water (on the HWI-Wk) or only 10 mL of water (on the
CONT-Wk) during a maximum time period of 20 min. To
map the acute effect of water on copeptin, blood for copeptin
measurement was sampled every 30 min for 4 h after the
intake of water. For this reason, day 1 of the HWI-Wk then
continued with the rest of the daily (3 L) water intake, that
is, subjects had to consume 2 additional liters of water on
top of their usual food and fluid intakes.
The intervention weeks were separated by 3 weeks of
each subject’s usual fluid intake as a wash-out period. The
complete study protocol is shown in Fig. 2.
Laboratory measurements
Copeptin was measured in our lab at baseline in fasting
plasma samples stored at − 80 °C using an ultrasensitive
assay on KRYPTOR Compact Plus analyzers and a
commercial sandwich immunoluminometric assay (ThermoFisher
Scientific, B.R.A.H.M.S Biomarkers) as previously
described [
8, 28
]. All other laboratory analyses were
performed using certified methods at the University Hospital’s
central clinical lab. Procedure for OGTTs: after an overnight
fast (no meals or drinks after 10PM the evening before)
subjects ingested 75 g of glucose over a maximum period of
3 min, starting sometime between 7:30 and 9:00 AM,
followed by blood sampling for glucose measurement at 30, 60
and 120 min. Twenty-four hour urine collections followed
procedures developed at the Department of Endocrinology,
Skåne University Hospital, and consisted of a
comprehensible written instruction aimed at ensuring accurate and
complete collection of urine.
Main outcome measures
On day 1 of the HWI-Wk, plasma copeptin concentrations
were measured at 30-min intervals during 4 h after ingestion
of 1L water to map copeptin changes after an acute water
load.
Absolute differences (“∆values”) between habitual values
(mean value of variables measured on days 8 and 9 during
CONT-Wk) and post-intervention values (mean value of
variables measured on days 8 and 9 during HWI-Wk) were
calculated for fasting plasma copeptin, glucose, insulin and
glucagon and osmolality. Furthermore, ∆values between
habitual (day 9 of CONT-Wk) and post-intervention (day 9
of HWI-Wk) 120-min values during an OGTT were
calculated for glucose, insulin and glucagon. Finally, based on the
24 h urine collections returned on day 9, ∆ values between
habitual (CONT-Wk) and post-intervention (HWI-Wk) urine
osmolality and urine volume were calculated.
Statistics
Significance of differences between end of HWI-Wk and
end of CONT-Wk, as well as differences in copeptin at
different times after acute water load compared to time
0 min (pre-water load), was tested using paired t test or
Wilcoxon signed rank test, depending on normality.
Subjects were a posteriori divided into “water-responders” and
“non-water-responders” according to the amplitude of the
copeptin decline (∆copeptin) between the CONT-Wk and
the HWI-Wk. Water-responders were defined as subjects in
the top tertile of the copeptin decline. Significance of
differences between these two subgroups was tested using
independent sample t test or Mann–Whitney U test depending on
normality. We used linear regression analysis of crude and
serum albumin-corrected residuals between water-induced
changes (end of HWI-Wk vs end of CONT-Wk) of copeptin
vs changes of glucose, insulin and glucagon during the same
time period.
SPSS statistical software version 23 (SPSS Inc., Chicago,
Ill., USA) was used for all analyses. A two-sided p value of
< 0.05 was considered statistically significant.
Results
The 37 participants had a median age of 53 year
(interquartile range 37–68). Nine were men and mean body mass index
was 25.2 kg/m2 (SD 4.4).
Acute and 1‑week effect of increased water intake on copeptin
After a rapid oral water load of 1 L, plasma copeptin was
significantly reduced within 30 min, and reached maximum
reduction within 90 min with on the average 39%
reduction (95 CI 34–45; p < 0.001). This significant reduction of
copeptin was sustained over the entire duration of the test
(4 h) (Fig. 1).
One week of increased water intake was accompanied
by a 15% reduction (95 CI 5–25; p = 0.003) of copeptin at
the end of the HWI-Wk compared to that at the end of the
CONT-Wk (Table 1).
The amplitude of copeptin reduction at the end of
HWIWk vs after CONT-Wk was strongly and positively
correlated with higher habitual copeptin (r = 0.63, p < 0.001),
higher habitual urine osmolality (r = 0.62, p < 0.001) and
lower habitual urine volume (r = − 0.52, p = 0.001), i.e.,
indices of lower water intake during the habitual
(CONTWk) state. Water-responders, i.e., subjects belonging to the
top tertile of water-induced copeptin reduction (n = 12),
had an average copeptin reduction of 41% (95 CI 34–49;
p < 0.001), whereas the remaining subjects
(non-waterresponders, n = 25) showed a non-significant reduction of
copeptin of 2.7% (95 CI − 8.3 to 14; p = 0.61) (Table 2).
In line with the continuous correlation analyses, the main
characteristics separating water-responders from
non-waterresponders were that water-responders had habitually higher
copeptin, higher urine osmolality and lower urine volume,
i.e., indices of being less hydrated (Table 2; Fig. 3a, b).
Fig. 1 Effect of acute water
load on plasma copeptin.
Plasma copeptin concentration
[expressed as mean (95 CI)]
measured minutes after 1 L
water intake (n = 39). At 0 min,
median (IQ) copeptin value
is 5.05 (3.53–6.44) pmol/L,
whereas it decreases to 2.77
(2.28–3.57) pmol/L at 90 min.
*p < 0.001
P-copeptin (pmol/L)
U-osmolality (mosm/kg H2O)
U-volume (mL/24 h)
Osmolar excretion rate (mosm/24 h)
P-osmolality (mosm/kg H2O)
P-urea (mmol/L)b
P-sodium (mmol/L)b
P-potassium (mmol/L)b
P-creatinine (µmol/L)b
End of control week End of water week
Data are expressed as median (interquartile range) if nothing else is specified
Fasting values if nothing else is specified
aΔchange = end of control week − end of water week
bData are expressed as mean (SD)
Effects of 1 week of increased water intake on plasma glucose, insulin and glucagon concentrations
Overall, there were no significant differences in glucose,
insulin or glucagon concentrations at the end of
HWIWk as compared to end of CONT-Wk (Table 3), nor was
there any significant correlation between ∆copeptin and
0 min ∆glucose (r = − 0.08, p = 0.6), 120 min∆ glucose
(r = 0.02, p = 0.9), 0 min ∆insulin (r = − 0.15, p = 0.39)
or 120 min ∆ insulin (r = − 0.16, p = 0.36). Results were
similar after correction for change of water-induced plasma
albumin as a proxy for water-induced plasma dilution.
However, greater water-induced reduction of copeptin
significantly associated with reduction of glucagon
(∆glucagon) both at 0 and 120 min of an OGTT when going from
habitual water intake to high water intake [crude
correlations between ∆copeptin and 0 min ∆glucagon (r = 0.37,
p = 0.03), and 120 min post-OGTT ∆glucagon (r = 0.39,
p = 0.02), respectively]. To make sure that water-induced
Data are expressed as median (interquartile range) if nothing else is specified
Fasting values if nothing else is specified
aNon-water responder refers to subjects with the lowest water-induced copeptin reduction, i.e., first and second tertile of Δ-copeptin
(corresponding to a copeptin reduction of ≤ 2 pmol/L)
bWater responder refers to subjects with the highest water-induced copeptin reduction, i.e., third tertile of Δ-copeptin (corresponding to a
copeptin reduction of > 2 pmol/L)
cData are expressed as mean (95 CI)
dData are expressed as mean (SD)
eIndependent sample T test
Data are expressed as median (interquartile range) if nothing else is specified
Fasting values if nothing else is specified
aΔchange = end of control week − end of water week
bData are expressed as mean (SD)
cDuring an oral glucose tolerance test (OGTT)
Δchangea, b
reductions of glucagon were not simply a result of volume
expansion, we corrected these correlations for water-induced
change of plasma albumin concentration. The correlations
remained significant (p = 0.01 for water-induced glucagon
reduction at 0 min and p = 0.02 at 120 min of the OGTT). In
concert with this, the water-induced change of both fasting
and 120 min glucagon differed significantly between
waterresponders and non-water-responders (Fig. 3a, b). Moreover,
in water-responders, high water intake was accompanied by
a significant decrease of glucagon under fasting conditions
(p = 0.04) and a borderline significant glucagon decrease at
120 min of an OGTT (p = 0.07), whereas this was not the
case among non-water-responders (Fig. 2a, b).
Habitual glucometabolic parameters did not differ
significantly between water-responders and non-water-responders
(Supplemental table 1).
HWI-Wk: 3L extra water/day
CONT-Wk: habitual water intake
Ini al
examina on
with medical
history and
clinical
examina on
random order
over-night fas ng
blood sampling.
Acute water inges on:
1L (HWI-WK) or 10 ml
(CONT-Wk) of water
during a maximum of
20min, and copep n
measurements every
30 min for 4h.
The last interven on day (both during
HWIWK and CONT-Wk): Over night fas ng blood
sampling for measurement of copep n,
osmolality, insulin, glucagon, glucose,
electrolytes, urea and crea nine. A 24h urine
collec on was ini ated.
Safety & compliance check: blood
sampling for electrolytes, urea and
osmolality measurements
Day
0
1
2
3
4
5
6
7
8
Final examina on: clinical
examina on, return of the 24h urine
collec on (for measurement of
electrolytes, osmolality and
crea nine), over-night fas ng blood
sampling (plasma copep n,
osmolality, insulin, glucagon,
glucose, crea nine) and an OGTT
with 120min measurement of
glucagon and 30, 60 and 120min
measurement of insulin and
glucose.
3weeks wash out
Next
interven on
end of HWI-Wk and end of CONT-Wk. Water-responders refer to
subjects with the highest water-induced copeptin reduction, i.e.,
third tertile of Δcopeptin (corresponding to a copeptin reduction of
> 2 pmol/L)
Discussion
The key finding of the present study is that in 37 healthy
volunteers there is a significant reduction of copeptin
after an increased water intake for 1 week, as compared
with habitual water intake. However, the effect varies
substantially between individuals. The one-third showing
the largest copeptin reduction (water-responders) were
characterized by indices of relatively low habitual water
intake, as compared to non-water-responders. One week
of increased hydration does not alter glycemia, insulin or
glucagon concentrations in the whole group. However, in
water-responders it leads to a significant reduction of
fasting glucagon concentration.
An acute water load results in a potent approximately 40%
reduction of copeptin, which is sustained at least over 4 h.
We and others previously established that VP, as
measured by copeptin, is an independent risk factor for diabetes,
the metabolic syndrome, chronic kidney disease,
cardiovascular disease and premature death in the population [
11,
15–17, 29, 30
]. It is well known that certain diseases such as
heart failure, acute myocardial infarction, hemorrhage and
sepsis result in marked elevation of copeptin [
31–34
], but,
in the general population, the most likely cause of having
elevated copeptin is a low water intake. Given the
multiple reports on an independent relationship between high
copeptin and risk of cardiometabolic diseases, the potential
of using increased hydration as a preventive tool for these
diseases has acquired increasing interest. Importantly, in
animal models, beneficial effects on metabolism have been
demonstrated through VP reduction achieved by increased
hydration, whereas elevation of VP deteriorated glucose
tolerance, pointing at a likely causal relationship [
20
].
Furthermore, genetic variation in the human VP gene was recently
associated with both elevated copeptin and increased risk
of hyperglycemia, providing additional support of
causality between elevated copeptin and metabolic disease [
35
].
If causal, this relationship would open the possibility of a
metabolic intervention based on water intake. However, it
is not known to what extent an increased water intake is
instrumental in decreasing VP secretion. The first aim of this
study was, therefore, to test if, and to what extent, copeptin
can be reduced in healthy humans by increased water intake
acutely and over 1 week.
The acute effect of a large oral water load on copeptin
has been previously demonstrated once in younger subjects
[
9
]. What is new and important from a therapeutic point of
view is that the copeptin reduction was sustained throughout
the 4 h of the test and, judging from the curve shape,
probably lasted even longer (Fig. 1). This suggests that water
does not have to be continuously ingested to achieve
sustained reduction of copeptin, but that the same amount can
be drunk during a short period of time (> 20 min) with a
sustained effect over at least 4 h. When investigating the
effect of increased water intake on copeptin over 1 week, we
compared copeptin after HWI-Wk to that after CONT-Wk.
Although the subjects were instructed to ingest 3 L of water
on top of habitual intake, the difference in urine volume
after the two respective weeks suggests that the achieved
difference in water intake was close to 2 L per day (Table 1).
Thus, it seems likely that when adding 3 L of water, the
habitual intake decreases.
The 15% average reduction of copeptin was largely driven
by the water-responders, who had an average copeptin
reduction of 41%, compared to virtually no reduction at all in
non-water-responders (Table 2). To characterize the
waterresponders, i.e., individuals who would benefit the most
from increased water used therapeutically to decrease VP,
we compared measures of hydration during habitual water
intake (end of CONT-Wk) between water-responders and
non-water-responders (Table 2). This comparison showed
that water-responders are characterized by higher copeptin,
higher urine osmolality and lower urine volume, i.e., indices
of relatively lower water intake. This suggests that any
intervention study aiming at lowering VP by increasing water
intake should focus on subjects with high copeptin and low
water intake.
As high copeptin has been repeatedly shown to be a
strong independent risk factor for diabetes, the second aim
of our study was to investigate if a reduction of copeptin by
increased water intake for 1 week may influence glycemia,
insulin or glucagon concentrations. We did not find any
difference in these metabolic indices at the end of the HWI-Wk
compared to the end of the CONT-Wk. It is possible that
1 week is too short to lead to metabolic alterations reflected
by these measures, or that the study was underpowered to
detect an existing effect. One additional explanation for the
overall neutral effects on these metabolic factors could be
that metabolic alterations are only seen in subjects whose
copeptin is in fact reduced by increased water intake, i.e.,
in water-responders. Interestingly, whereas glycemia and
insulin were not altered by hydration in water-responders,
fasting glucagon was significantly reduced, and glucagon
post-oral glucose challenge was borderline significantly
reduced (Fig. 3a, b). Although this finding needs replication,
it suggests that just 1 week of increased hydration in subjects
with habitual low water intake leads to a marked reduction
of VP which is paralleled by a reduction of glucagon. High
glucagon secretion is an important risk factor for impaired
glucose tolerance and type 2 diabetes [
36
]. Type 2 diabetes
is associated with elevated glucagon concentration
throughout the day [
37
], and both type 2 diabetes and impaired
glucose tolerance are associated with impaired suppression of
glucagon secretion [
38, 39
]. Furthermore, elevated glucagon
secretion is manifest long before the onset of impaired
glucose tolerance [39]. VP stimulates glucagon secretion by
activation of V1bR in α-cells of pancreatic islets [
3
] which
is concordant with our finding that fasting glucagon
concentration was reduced upon water-induced suppression of
VP (copeptin). In addition, we recently showed in rodents
that during conditions of high VP, selective
pharmacological blockade of V1bR with SR149415 resulted in reduction
of plasma glucagon [
40
]. Taken together, our finding that
water-induced decrease of copeptin in water-responders is
associated with fasting glucagon reduction encourages
longterm studies of anti-diabetic effects of water
supplementation in subjects with low water intake.
We previously showed that the risk of future diabetes
development among normoglycemic subjects was 3.5-fold
higher in the top quartile compared to the bottom quartile of
fasting plasma copeptin concentration after adjustment for
known diabetes risk factors. The top quartile corresponded
to copeptin of > 6.1 pmol/L in females and > 10.7 pmol/L in
males [
11
]. In the current study population, a similar
proportion of subjects (23%) had habitual fasting plasma copeptin
concentration above these thresholds, denoting high
diabetes risk, and 89% of these high-diabetes-risk subjects were
water-responders. We, therefore, suggest that approximately
25% of the population would represent an ideal target group
for studying the effects of water supplementation on diabetes
risk, as these subjects, apart from having a high diabetes
risk, are, to the great majority, water-responders with low
habitual water intake.
Limitations
We did not control the participants’ food intake in the
current study. Osmolar excretion was significantly higher at the
end of HWI-Wk than at the end of CONT-Wk (Table 1).
This difference obviously results from a greater food intake
during increased hydration. We previously observed that
rats tend to eat more when hydration is increased [
24, 41
].
It is likely that in the present study, copeptin concentration
could have been reduced even more during HWI-Wk if food
intake had not increased, because increased protein intake
is known to increase VP secretion. However, the habitual
osmolar excretion rate was similar in water-responders and
non-water-responders (Table 2) and there was no
significant difference in ∆osmolar excretion
(CONT-Wk − HWIWk) between water-responders and non-water-responders
(p = 1.0). Thus, the better glucagon-lowering effect observed
in water-responders (Fig. 3a, b) cannot result from
differences in the amount of ingested food. Furthermore, we did
not monitor the participants’ actual water intake with
questionnaires or diaries in the current study. Instead, we used
measures of urinary volume as a proxy for water intake.
Finally, the choice to set the increased water ingestion to 3 L
per day was arbitrary.
Conclusion
High water intake acutely leads to a potent and sustained
reduction of plasma copeptin. Over 1 week, the copeptin
lowering effect of increased water intake is on the average
more modest. However, in subjects with habitually high
copeptin and signs of low water intake (i.e.,
water-responders), the reduction in copeptin is about 40%. Furthermore,
water-responders exhibit reduced concentrations of
glucagon. Our results indicate that water-responders, who have
both greater diabetes risk and markedly reduced copeptin
after high water intake, represent an ideal target segment
of the healthy population for a long duration randomized
controlled trial testing the effects of hydration on
cardiometabolic outcomes.
Acknowledgements We are grateful to the volunteers participating in
this study. This study was supported by grants from Knut and Alice
Wallenberg Foundation, Göran Gustafsson Foundation, the Swedish
Heart- and Lung Foundation, the Swedish Research Council, the
European Research Council (StG282255) the Novo Nordisk Foundation,
Region Skåne, Skåne University Hospital, ALF-funds and the H4H
Kidney Health Foundation.
Compliance with ethical standards
Conflict of interest Melander has received a research grant and
consultancy fee from Danone Research. Roussel has received a research grant
and consultancy fee from Danone Research. Bankir is an occasional
consultant for Danone Research. The authors report no other conflicts
of interest in this work.
Informed consent This study in humans has been approved by the
ethics committee of Lund University and has, therefore, been performed
in accordance with the ethical standards laid down in the 1964
Declaration of Helsinki and its later amendments. All participants provided
written informed consent prior to their inclusion in the study.
Open Access This article is distributed under the terms of the Creative
Commons Attribution 4.0 International License
(http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided you give appropriate
credit to the original author(s) and the source, provide a link to the
Creative Commons license, and indicate if changes were made.
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