Erythropoietin during hypoglycaemia in type 1 diabetes: Relation to basal renin-angiotensin system activity and cognitive function☆
Introduction
Preservation of cognitive function during hypoglycaemic episodes is crucial for patients with insulin-treated diabetes in order to avoid severe hypoglycaemic events and accidents. The understanding of cerebral metabolic adaptation to hypoglycaemia and clarification of endogenous defence mechanisms are therefore important. A putative mechanism may involve erythropoietin (EPO), since a neuroprotective role has emerged for EPO in conditions with impaired substrate supply [1]. EPO is produced in the brain along with its own receptor, especially in response to intracerebral metabolic stress such as acute brain hypoxia [2], [3]. Also brain capillary endothelial cells express EPO receptor mRNA [4]. A number of in vitro studies suggest that EPO in a paracrine brain-specific system may preserve cognitive function during hypoglycaemia [5], [6], [7]. EPO may also ameliorate the blood brain barrier (BBB) dysfunction during hypoglycaemia [8], since EPO has been shown to prevent BBB damage induced by ischemia [9]. However, knowledge of EPO responses and effect during insulin-induced hypoglycaemia in man does not exist.
Data from our group suggest that high activity in the renin-angiotensin system (RAS) is associated with poorer cognitive function among healthy adults during hypoglycaemia [10]. In accordance, several independent studies have reported a positive correlation between serum angiotensin converting enzyme (ACE) activity or RAS activity and risk of severe hypoglycaemia in type 1 diabetes [11], [12], [13], [14]. The physiological pathways involved are not known, but EPO may be involved, since angiotensin II stimulates production of EPO [15], [16], [17].
The aim of this study was to assess plasma EPO levels during hypoglycaemia in patients with type 1 diabetes and to explore the influence of basal RAS activity. Furthermore, we assessed a possible relation between EPO and cognitive function during hypoglycaemia.
Section snippets
Subjects
Nine subjects with high RAS activity and nine subjects with low RAS activity were selected from a group of 260 outpatients with type 1 diabetes. Selection according to RAS groups was based on three factors, all independently contributing to risk of hypoglycaemia: serum ACE activity [11], [12], [13], [14], plasma concentration of angiotensinogen [18], and the angiotensin II receptor subtype 2 genotype 1675 polymorphism [18]. The two non-genetic factors are both stable during hypoglycaemia [10].
Design
The study was a single-blinded, controlled, cross-over study. Hypoglycaemia was induced by a standardized intravenous insulin-infusion. Each subject was studied at two occasions separated by at least 4 weeks, during hypoglycaemia and at maintained baseline glycaemia (control study).
Week before experiment
The subjects were instructed to live and eat as normal as possible, and to avoid any rigorous exercise and alcohol or psychoactive drugs in the week before the experiment.
Day before experiment
In the evening before the experiment the
Day of hypoglycaemia
Nadir plasma glucose was 2.2 (0.3) mmol/l and mean plasma glucose in the stimulus period was 2.5 (0.32 SD) mmol/l (mean (SD)) (n = 18). The hypoglycaemic stimulus was similar in both groups. In high RAS group nadir plasma glucose was 2.2 (0.4) mmol/l and in low RAS group nadir plasma glucose was 2.3 (0.3) mmol/l (mean (SD); p = 0.41) (Fig. 1). The standard deviation of the plasma glucose values measured during hypoglycaemia was calculated for each participant. The mean value was 0.37 (0.16) mmol/l (mean
Discussion
This study demonstrates an increase in plasma EPO concentrations during mild hypoglycaemia in patients with type 1 diabetes, but only in subjects with high RAS activity. The approximate 20% increment is remarkable as acute hypoxia has been reported to increase plasma EPO in healthy humans by around 30% [27]. To our knowledge, hypoglycaemia has not earlier been found to stimulate EPO release in man. The finding is in accordance with studies showing that hypoglycaemia stimulates production of
Conflict of interest
None.
Acknowledgements
We thank research nurses Pernille Banck, Tove Larsen and Margrethe Larsen, Endocrinology Section, Department of Cardiology and Endocrinology, Hillerød Hospital, for skilful technical assistance during the experiments. Also thanks to associate professor Lene Theil Skovgaard, Department of Biostatistics, University of Copenhagen for guiding.
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2015, Journal of Diabetes and its ComplicationsCitation Excerpt :These studies have shown an increased prevalence of anemia in patients with diabetes, even in the absence of kidney disease (McGill & Bell, 2006; Thomas, 2006), possibly indicative of erythropoietin deficiency or ineffectiveness. In type 1 diabetes, hypoglycemia has been shown to trigger a rise in erythropoietin (Kristensen, Høi-Hansen, Olsen, Pedersen-Bjergaard, & Thorsteinsson, 2009) through a response influenced by basal renin–angiotensin-system activity, though measurement of erythropoietin levels does not predict future risk of severe hypoglycemia (Kristensen, Pedersen-Bjergaard, Schalkwijk, Olsen, & Thorsteinsson, 2010). In addition, in patients with type 1 diabetes and hypoglycemia unawareness, treatment with exogenous erythropoietin improves cognitive function during hypoglycemia (Kristensen et al., 2013).
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The study was funded by grants from The EFSD/JDRF/Novo Nordisk Programme for Research in Type 1 Diabetes, The Foundation of Harald Jensen and wife, The Foundation of Olga Bryde Nielsen, The Foundation of Region 3, The Research Foundation of Frederiksborg County (Hillerød Hospital), and The Tvergaard Foundation.