Understanding Artificial Pancreas Systems: Results from a 24-Month Trial

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EPO treatment reduced reaction time prolongation during hypoglycemia by 66 milliseconds compared to placebo (p=0.02), representing a 35% smaller increase from baseline. This improvement was seen in 9 of 11 participants. However, the benefit was limited to this one complex attention task and did not extend to simpler cognitive tests, suggesting mixed overall cognitive protection.

EPO treatment was associated with 4.7 fewer errors during hypoglycemia compared to placebo (p=0.01), representing a 44% reduction in error increment from baseline. Nine of 11 participants had fewer errors after EPO treatment. The benefit was specific to the complex attention task and not seen in other cognitive measures.

EPO treatment showed a small, non-significant reduction in reaction time prolongation (−21 msec, p=0.58) on this simpler reaction time test during hypoglycemia. The lack of statistical significance suggests EPO's neuroprotective effects may be limited to more complex cognitive tasks requiring sustained attention.

EPO treatment showed a non-significant trend toward less impairment on the trail making test during hypoglycemia (−14% difference, p=0.42). This test measures attention and executive function, but the lack of statistical significance indicates no clear benefit from EPO on this measure.

EPO treatment did not significantly improve performance on any of the three Stroop test components (word, color, word/color) during hypoglycemia (p-values 0.39-0.53). The Stroop test measures selective attention and cognitive flexibility, suggesting EPO's benefits may not extend to these specific cognitive domains.

EPO treatment did not significantly change autonomic symptoms, neuroglycopenic symptoms, or symptoms of cognitive dysfunction during hypoglycemia (all p>0.18). This indicates EPO does not improve subjective awareness of hypoglycemia or reduce symptom burden, despite objective improvements in one cognitive test.

EEG frequency slowing during hypoglycemia was not affected by EPO treatment (p=0.87). Both placebo and EPO groups showed similar reductions in dominant frequency from baseline to hypoglycemia, suggesting EPO does not prevent the electrophysiological changes associated with hypoglycemia.

EPO treatment did not alter the hormonal counter-regulatory response to hypoglycemia. Concentrations of adrenaline, glucagon, cortisol, and growth hormone during hypoglycemia were similar between EPO and placebo days (all p>0.31). This indicates EPO's cognitive effects are not mediated through changes in hormonal defense mechanisms against hypoglycemia.

Single intravenous dose of 40,000 IU erythropoietin (Eprex) administered 6 days before experimental hypoglycemia

EPO treatment improved performance on a complex reaction time task requiring sustained attention during hypoglycemia, with 66 milliseconds faster responses and nearly 5 fewer errors

Nine out of 11 participants showed better performance after EPO compared to placebo on this specific test

EPO did not improve simpler cognitive tests, EEG activity, hypoglycemia awareness symptoms, or hormonal counter-regulation

This proof-of-concept study suggests erythropoietin has selective neuroprotective effects during hypoglycemia, specifically preserving function in brain regions responsible for sustained attention and working memory. The lack of effect on simpler cognitive tasks, symptoms, or hormonal responses suggests EPO's benefit is limited to complex executive functions requiring sustained mental effort. While the 66-millisecond improvement may seem small, it could be clinically meaningful in situations requiring rapid decision-making, such as driving. However, the very small sample size and narrow benefit profile mean these findings need replication in larger trials before clinical significance can be determined.

Single intravenous dose of 40,000 IU erythropoietin (Eprex, 1 mL) administered six days before experimental hypoglycemia testing. Control group received 1 mL isotonic saline placebo. The six-day interval was chosen based on prior research showing cognitive benefits of EPO in healthy subjects at seven days post-administration. Participants were instructed to avoid rigorous exercise, alcohol, and psychoactive drugs for one week before testing. Continuous glucose monitoring with hypoglycemia alarms was used to prevent antecedent hypoglycemia before experimental sessions.

Kristensen PL, Pedersen-Bjergaard U, Kjær TW, et al. Influence of Erythropoietin on Cognitive Performance during Experimental Hypoglycemia in Patients with Type 1 Diabetes Mellitus: A Randomized Cross-Over Trial. PLoS ONE. 2013;8(4):e59672. doi:10.1371/journal.pone.0059672

EPO treatment significantly improved performance on the RT2 test, a complex 1-back reaction time task assessing sustained attention and working memory. Compared to placebo, EPO-treated participants had 66 milliseconds less reaction time prolongation (p=0.02) and 4.7 fewer errors (p=0.01) during hypoglycemia—representing a 35% reduction in reaction time worsening and 44% reduction in error increment. Nine of 11 subjects performed better after EPO treatment on this test. However, EPO showed no significant benefit on simpler reaction time tests (RT1), trail making test, or Stroop color-word tests (p-values 0.39-0.80). EEG frequency slowing during hypoglycemia was not affected by EPO treatment. Hypoglycemia symptom scores (autonomic, neuroglycopenic, and cognitive dysfunction symptoms) and counter-regulatory hormone responses (adrenaline, glucagon, cortisol, growth hormone) were similar between EPO and placebo days. No adverse effects were observed.

Very small study (only 11 participants) limits confidence in findings

Benefit seen in only one specific cognitive test; other tests showed no improvement

Current form of EPO cannot be used routinely due to blood clot and blood pressure risks

Optimal timing and dose of EPO for hypoglycemia protection is unknown

In 11 people with type 1 diabetes prone to severe low blood sugar, a single high dose of erythropoietin improved performance on a complex attention task during experimentally induced hypoglycemia, but didn't affect other cognitive tests or hypoglycemia symptoms.

This was a very small study with only 11 participants, making it difficult to detect modest effects and limiting how broadly the findings can be applied. The timing and dose of EPO (40,000 IU given six days before hypoglycemia) were chosen based on limited prior research in healthy people, not specifically tested for diabetes or hypoglycemia settings, so the optimal regimen is unknown. The benefit was seen in only one type of cognitive test (complex reaction time), while other tests showed no improvement, suggesting the effect is narrow and may not translate to overall brain protection. Mean blood sugar during hypoglycemia was slightly higher on the EPO day (2.2 vs 2.0 mmol/L), which could have influenced results despite statistical adjustment. The participants all had long-standing diabetes and hypoglycemia unawareness, so results may not apply to people with different diabetes characteristics. Most importantly, this form of EPO cannot be used routinely in diabetes because it increases red blood cell production, raising risks of blood clots and high blood pressure—the findings are mainly useful for guiding development of safer, non-blood-forming EPO variants. The short washout period (6 weeks) and small sample size also make it harder to completely rule out carryover effects in this crossover design.

Reaction time in complex attention task ↓ (66 milliseconds faster)

Errors in complex attention task ↓ (4.7 fewer errors)

The ADA's comprehensive annual clinical practice guidelines address severe hypoglycemia as a critical barrier to achieving glycemic targets in type 1 diabetes. The guidelines emphasize the importance of hypoglycemia prevention strategies, patient education about recognizing and treating low blood sugar, and the need for individualized glucose targets that balance glycemic control with hypoglycemia risk.

American Diabetes Association Standards of Care in Diabetes—2024

This comprehensive review examines the epidemiology and clinical consequences of hypoglycemia in diabetes, including its effects on cognitive function, cardiovascular events, and mortality. The review discusses mechanisms of hypoglycemia-induced brain dysfunction and summarizes evidence on strategies to minimize hypoglycemia risk while maintaining glycemic control.

Hypoglycaemia, cardiovascular disease, and mortality in diabetes: epidemiology, pathogenesis, and management

The NIDDK provides patient and clinician education about hypoglycemia in diabetes, explaining how low blood sugar affects brain function and cognition. Resources describe symptoms of hypoglycemia, risks of severe episodes, and evidence-based prevention and treatment strategies for people with diabetes using insulin or other glucose-lowering medications.

This review examines erythropoietin's neuroprotective properties beyond its hematopoietic effects, including its ability to cross the blood-brain barrier at high doses and protect neurons during metabolic stress such as hypoxia and ischemia. The review discusses potential mechanisms including anti-apoptotic effects, reduction of inflammation, and promotion of neurogenesis.

Erythropoietin: Emerging Role in Stroke Protection

Double-blind, randomized, balanced crossover trial. Eleven adults with type 1 diabetes, hypoglycemia unawareness, and recurrent severe hypoglycemia received 40,000 IU intravenous EPO or placebo six days before experimental hypoglycemia sessions (at least 6 weeks apart). Hypoglycemia was induced using insulin and glucose clamps targeting plasma glucose of 2.0-2.2 mmol/L. Cognitive function was assessed using computerized reaction time tests (CalCAP RT1 and RT2), trail making test, and Stroop test at baseline, during hypoglycemia, and during recovery. Hypoglycemia symptoms, EEG, and counter-regulatory hormones were also measured.

Erythropoietin may improve some cognitive tasks during low blood sugar in type 1 diabetes

This small study tested whether erythropoietin (EPO), a hormone known to protect brain cells, could help preserve mental function during low blood sugar episodes in people with type 1 diabetes. Eleven participants received either EPO or placebo before undergoing controlled hypoglycemia. EPO improved performance on one specific attention task but didn't help with other mental tests or reduce symptoms.

The benefit was seen in only one out of multiple cognitive tests, and the study was very small with just 11 participants. Regular EPO treatment is not safe for people with diabetes because it increases red blood cell production, raising risks of blood clots, stroke, and high blood pressure. The findings are mainly useful for developing safer, modified versions of EPO that protect brain cells without affecting blood cells. The study used experimental hypoglycemia in a controlled setting, which may differ from real-world low blood sugar episodes. Most participants had decades of diabetes and impaired hypoglycemia awareness, so results may not apply to people with different diabetes characteristics or those who can still sense their low blood sugar.

Whether erythropoietin improves cognitive function during low blood sugar in type 1 diabetes patients

Adults with type 1 diabetes who experience hypoglycemia unawareness and recurrent severe hypoglycemia (2 or more episodes per year). Study participants had long-standing diabetes (median 29 years duration), used insulin therapy, and had HbA1c levels around 7.6%. Results may be most relevant for individuals at high risk of severe hypoglycemia where cognitive protection during episodes could be clinically meaningful.

Erythropoietin may improve some cognitive tasks during low blood sugar in type 1 diabetes

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