Primary Objective: Gain insight in the course of plasma phosphate and its (de-)regulators during DKA. Secondary Objective(s): Address the potential association and role of hypophosphatemia in oxidative stress / mitochondrial dysfunction / tissue…
ID
Source
Brief title
Condition
- Diabetic complications
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary outcome is the association between FGF23 and phosphate during treatment
for DKA corrected for follow-up time. Time course analyses will be performed to
gain insight in the sequence of events and potential causal relationships.
Furthermore, consequences of hypophosphatemia in cellular energy state will be
addressed.
Secondary outcome
Secondary outcomes include markers of oxidative stress, mitochondrial
dysfunction and cellular senescence.
Background summary
Diabetic ketoacidosis (DKA) is a life-threatening complication of type 1
diabetes mellitus (T1DM). Despite advanced treatments, the current mortality of
DKA is approximately 10-14%. DKA is characterized by hyperglycemia (defined as
glucose >15mmol/L) and metabolic acidosis (defined as pH <7.30). The mainstay
of DKA treatment consists of insulin therapy (often intravenous) and
intravenous fluid therapy administration.
During treatment for DKA the incidence of hypophosphatemia is estimated 74-90%.
Although its etiology and clinical relevance are unclear, it is theoretically
hypothesized that hypophosphatemia in DKA is the effect of transcellular shifts
and osmotic diuresis. Consequences of severe hypophosphatemia include skeletal
muscle weakness, cardiomyopathy, respiratory failure and seizures. Previous
studies found the degree of acidosis at presentation to be the main determinant
of developing hypophosphatemia during DKA. (1,2) However, these studies
conducted were limited by the retrospective design and lack of information on
regulators of phosphate metabolism that are not routinely measured in clinical
practice. In stable outpatients, fibroblast growth factor 23 (FGF23),
parathyroid hormone (PTH), calcitriol and calcium are important regulators of
serum phosphate. We expect that the balance between these regulators will be
disrupted during hypophosphatemia in DKA (FGF23 increased, PTH increased and
calcitriol decreased). In addition, as deregulators in phosphate metabolism may
subsequently promote oxidative stress and mitochondrial dysfunction leading to
cell damage and accelerated cellular aging (3,4); oxidative stress, ageing,
cellular senescence and mitochondrial dysfunction will also be assessed.
In this study we aim to investigate the role of phosphate(regulators) over time
during DKA. Time course analysis will provide more insight into the sequencing
of events and possible causal relationships, and will also provide clinical
relevance in determining optimal timing for measuring phosphate and its
regulators during DKA. Together, this provides a better understanding of
phosphate regulation and its consequences.
1. van der Vaart A, Waanders F, van Beek AP, Vriesendorp TM, Wolffenbutel
BHR, van Dijk PR. Incidence and determinants of hypophosphatemia in diabetic
ketoacidosis: an observational study. BMJ open diabetes Res care. 2021
Feb;9(1).
2. Shen T, Braude S. Changes in Serum phosphate during treatment of diabetic
ketoacidosis: Predictive significance of severity of acidosis on presentation.
Intern Med J. 2012;42(12):1347-50.
3. Peng A, Wu T, Zeng C, Rakheja D, Zhu J, Ye T, et al. Adverse effects of
simulated hyper- and hypo-phosphatemia on endothelial cell function and
viability. PLoS One. 2011;6(8).
4. Rains JL, Jain SK. Oxidative stress, insulin signaling, and diabetes. Vol.
50, Free Radical Biology and Medicine. 2011;50(5): 567-575.
Study objective
Primary Objective: Gain insight in the course of plasma phosphate and its
(de-)regulators during DKA.
Secondary Objective(s): Address the potential association and role of
hypophosphatemia in oxidative stress / mitochondrial dysfunction / tissue
damage during DKA.
Study design
This investigator-initiated study is designed as a prospective cohort study.
Sample collection at admission to the emergency department is already done
with Acutelines (METC no. NCT04615065). After admission at the ED, samples will
be collected at the nursing ward and patients will be followed up one month
after discharge from the hospital. Inclusion and study procedures will take
place at the Department of Acute Medicine of the University Medical Center
Groningen (UMCG), the Netherlands. Study measurements will be performed in
hospital (baseline and after 4, 12, 16, 20, 24 and 48 hours of admission) and
30 days after discharge. Overall, we anticipate a total study duration of one
month for each participant.
Study burden and risks
Participants already donated blood during their stay in the hospital for the
Acutelines study. Urine and blood samples are taken during the study
simultaneously with venous blood samples during routine care (90 mL blood and
48 mL urine in total). Patients will be approached one month after discharge
for repeated measurements.
Hanzeplein 1
Groningen 9713GZ
NL
Hanzeplein 1
Groningen 9713GZ
NL
Listed location countries
Age
Inclusion criteria
- Age 18 to 75 years
- T1DM, diagnosed prior to admission (the T1DM diagnosis should be based upon
the presence of (i) hyperglycemia (fasting glucose levels >7.0 mmol/L or random
glucose levels >11.1 mmol/L), (ii) c-peptide levels of less than 0.2 nmol/L and
(iii) presence of auto-immunity (anti-GAD, anti-islet auto-antibodies and/or
zinc receptors))
- DKA defined as
• Blood glucose levels >15mmol/L
• Presence of urine ketones
• pH levels <7.30 kPa
- Dutch writing and speaking proficiency
- Ability to provide oral and written informed consent.
- Included in Acutelines, where blood sample was drawn upon ED admission
Exclusion criteria
- Pregnancy (actual or planned)
- Known underlying condition in which phosphate metabolism is altered,
including hyperparathyroidism, vitamin D deficiency, Fanconi syndrome,
chronic diarrhoea, and use of medication with hypophosphatemia as a
side-effect, such a
pamidronic acid or ferric carboxymaltose
- Inability or unwillingness to meet the protocol requirements
- Any severe or uncontrolled medical or psychological condition which, in the
opinion of the investigator, would compromise the ability to meet protocol
requirements
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL79086.042.21 |