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1.  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.
The incidence of severe hypoglycemia in type 1 diabetes has not decreased over the past decades. New treatment modalities minimizing the risk of hypoglycemic episodes and attenuating hypoglycemic cognitive dysfunction are needed. We studied if treatment with the neuroprotective hormone erythropoietin (EPO) enhances cognitive function during hypoglycemia.
Materials and Methods
Eleven patients with type 1 diabetes, hypoglycemia unawareness and recurrent severe hypoglycemia completed the study. In a double-blind, randomized, balanced, cross-over study using clamped hypoglycemia they were treated with 40,000 IU of EPO or placebo administered intravenously six days before the two experiments. Cognitive function (primary endpoint), hypoglycemic symptoms, and counter-regulatory hormonal response were recorded.
Compared with placebo, EPO treatment was associated with a significant reduction in errors in the most complex reaction time task (−4.7 (−8.1 to −1.3), p = 0.01) and a less reaction time prolongation (−66 (−117 to −16) msec, p = 0.02). EPO treatment did not change performance in other measures of cognition. Hypoglycemic symptoms, EEG-changes, and counter-regulatory hormone concentrations did not differ between EPO and placebo treatment.
In patients with type 1 diabetes and hypoglycemia unawareness, treatment with EPO is associated with a beneficial effect on cognitive function in a complex reaction time task assessing sustained attention/working memory. Hypoglycemic symptoms and hormonal responses were not changed by EPO treatment.
Trial Registration NCT00615368
PMCID: PMC3618268  PMID: 23577069
2.  A prospective randomised cross-over study of the effect of insulin analogues and human insulin on the frequency of severe hypoglycaemia in patients with type 1 diabetes and recurrent hypoglycaemia (the HypoAna trial): study rationale and design 
Severe hypoglycaemia still represents a significant problem in insulin-treated diabetes. Most patients do not experience severe hypoglycaemia often. However, 20% of patients with type 1 diabetes experience recurrent severe hypoglycaemia corresponding to at least two episodes per year. The effect of insulin analogues on glycaemic control has been documented in large trials, while their effect on the frequency of severe hypoglycaemia is less clear, especially in patients with recurrent severe hypoglycaemia. The HypoAna Trial is designed to investigate whether short-acting and long-acting insulin analogues in comparison with human insulin are superior in reducing the occurrence of severe hypoglycaemic episodes in patients with recurrent hypoglycaemia. This paper reports the study design of the HypoAna Trial.
The study is a Danish two-year investigator-initiated, prospective, randomised, open, blinded endpoint (PROBE), multicentre, cross-over trial investigating the effect of insulin analogues versus human insulin on the frequency of severe hypoglycaemia in subjects with type 1 diabetes. Patients are randomised to treatment with basal-bolus therapy with insulin detemir / insulin aspart or human NPH insulin / human regular insulin in random order. The major inclusion criterion is history of two or more episodes of severe hypoglycaemia in the preceding year.
In contrast to almost all other studies in this field the HypoAna Trial includes only patients with major problems with hypoglycaemia. The HypoAna Trial will elucidate whether basal-bolus regimen with short-acting and long-acting insulin analogues in comparison with human insulin are superior in reducing occurrence of severe hypoglycaemic episodes in hypoglycaemia prone patients with type 1 diabetes. NCT00346996.
PMCID: PMC3433358  PMID: 22727048
Type 1 diabetes; Severe hypoglycaemia; Human insulin; Insulin analogues; PROBE
3.  Association of IGF1 with glycemic control and occurrence of severe hypoglycemia in patients with type 1 diabetes mellitus 
Endocrine Connections  2012;1(1):31-36.
GH is implicated in the counter-regulatory response to hypoglycemia. We tested whether IGF1 levels are associated with occurrence of severe hypoglycemic events in patients with type 1 diabetes and whether the IGF1 concentration is influenced by glycemic control.
A total of 228 outpatients with type 1 diabetes were included in a post hoc analysis of a 1-year observational study on severe hypoglycemia. Serum total IGF1 was measured at entry into the study. The occurrence of severe episodes of hypoglycemia, mild symptomatic, and biochemical as well as hypoglycemia awareness status was assessed. Also patients were included in a multiple regression analysis to investigate the role of HbA1c in the IGF1 concentration.
IGF1 levels were associated with neither severe hypoglycemia in the entire cohort (P=0.30) nor in any gender nor when confining the analysis to those with long-standing diabetes (>20 years) (n=112, P=0.68) and those with both long-standing diabetes and undetectable C-peptide (n=51, P=0.067). Levels of IGF1 were associated with neither mild symptomatic hypoglycemia (P=0.24) nor biochemical hypoglycemia (0.089) nor hypoglycemia awareness (P=0.16). At a multiple regression analysis, HbA1c was negatively associated with IGF1 (P=0.001).
In type 1 diabetes, circulating IGF1 levels are negatively associated with glycemic control. However, IGF1 levels were not associated with occurrence of hypoglycemia or hypoglycemia awareness in these patients.
PMCID: PMC3682234  PMID: 23781301
type 1 diabetes; IGF1; hypoglycemia; HbA1c
4.  Pregnancy-Induced Rise in Serum C-Peptide Concentrations in Women With Type 1 Diabetes 
Diabetes Care  2009;32(6):1052-1057.
The purpose of this study was to investigate whether pregnancy induces increased insulin production as a marker of improved β-cell function in women with long-term type 1 diabetes.
This was a prospective study of 90 consecutive pregnant women with type 1 diabetes. At 8, 14, 21, 27, and 33 weeks blood samples were drawn for measurements of A1C, C-peptide, and serum glucose. C-peptide (detection limit: 6 pmol/l) was considered stimulated at a corresponding serum glucose concentration ≥5.0 mmol/l. GAD antibody concentration was determined at 8 and 33 weeks in 35 women.
C-peptide concentrations gradually increased throughout pregnancy regardless of serum glucose concentrations in the 90 women with a median duration of diabetes of 17 years (range 1–36 years). Among 35 women with paired recordings of stimulated C-peptide, C-peptide production was detectable in 15 (43%) at 8 weeks and in 34 (97%) at 33 weeks (P < 0.0001), and median C-peptide gradually increased from 6 to 11 pmol/l (P = 0.0004) with a median change of 50% (range −50 to 3,271%) during pregnancy. GAD antibodies were present in 77% with no change from 8 to 33 weeks (P = 0.85). Multivariate regression analysis revealed a positive association between the absolute increase in C-peptide concentrations during pregnancy and decreased A1C from 8 to 33 weeks (P = 0.003).
A pregnancy-induced increase in C-peptide concentrations in women with long-term type 1 diabetes was demonstrated, even in women with undetectable C-peptide concentrations in early pregnancy. This increase is suggestive of improved β-cell function and was associated with improvement in glycemic control during pregnancy.
PMCID: PMC2681014  PMID: 19244092

Results 1-4 (4)