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Showing papers by "Bastiaan E. de Galan published in 2017"


Journal ArticleDOI
TL;DR: The International Hypoglycaemia Study Group recommends that the frequency of detection of a glucose concentration <3.0 mmol/l (<54 mg/dl), which it considers to be clinically significant biochemical hypoglycaemic, be included in reports of clinical trials of glucoselowering drugs evaluated for the treatment of diabetes mellitus.
Abstract: Position Statement The International Hypoglycaemia Study Group recommends that the frequency of detection of a glucose concentration <3.0 mmol/l (<54 mg/dl), which it considers to be clinically significant biochemical hypoglycaemia, be included in reports of clinical trials of glucose-lowering drugs evaluated for the treatment of diabetes mellitus.

321 citations


Journal ArticleDOI
01 Apr 2017-Diabetes
TL;DR: Ex vivo ex vivo stimulations of peripheral blood mononuclear cells and monocytes obtained during hyperinsulinemic-euglycemic-hypoglycemic clamps concluded that hypoglycemia promotes mobilization of specific leukocyte subsets from the marginal pool and induces proinflammatory functional changes in immune cells.
Abstract: Severe hypoglycemic events have been associated with increased cardiovascular mortality in patients with diabetes, which may be explained by hypoglycemia-induced inflammation. We used ex vivo stimulations of peripheral blood mononuclear cells (PBMCs) and monocytes obtained during hyperinsulinemic-euglycemic (5.0 mmol/L)-hypoglycemic (2.6 mmol/L) clamps in 11 healthy participants, 10 patients with type 1 diabetes and normal awareness of hypoglycemia (NAH), and 10 patients with type 1 diabetes and impaired awareness (IAH) to test whether the composition and inflammatory function of immune cells adapt to a more proinflammatory state after hypoglycemia. Hypoglycemia increased leukocyte numbers in healthy control participants and patients with NAH but not in patients with IAH. Leukocytosis strongly correlated with the adrenaline response to hypoglycemia. Ex vivo, PBMCs and monocytes displayed a more robust cytokine response to microbial stimulation after hypoglycemia compared with euglycemia, although it was less pronounced in patients with IAH. Of note, hypoglycemia increased the expression of markers of demargination and inflammation in PBMCs. We conclude that hypoglycemia promotes mobilization of specific leukocyte subsets from the marginal pool and induces proinflammatory functional changes in immune cells. Inflammatory responses were less pronounced in IAH, indicating that counterregulatory hormone responses are key modulators of hypoglycemia-induced proinflammatory effects. Hypoglycemia-induced proinflammatory changes may promote a sustained inflammatory state.

62 citations


Journal ArticleDOI
01 Jul 2017-Diabetes
TL;DR: It is demonstrated that a single HIIT session rapidly reduces awareness of subsequent hypoglycemia in patients with type 1 diabetes and NAH, but does not in patientswith IAH, and attenuates hypoglyCEmia-induced cognitive dysfunction.
Abstract: High-intensity interval training (HIIT) gains increasing popularity in patients with diabetes. HIIT acutely increases plasma lactate levels. This may be important, since administration of lactate during hypoglycemia suppresses symptoms and counterregulation, whilst preserving cognitive function. We tested the hypothesis that HIIT acutely reduces awareness of hypoglycemia and attenuates hypoglycemia-induced cognitive dysfunction. In a randomized crossover trial, patients with type 1 diabetes and normal awareness of hypoglycemia (NAH), patients with impaired awareness of hypoglycemia (IAH), and healthy participants (n=10 per group) underwent a hyperinsulinemic-hypoglycemic (2.6 mmol/L) clamp, either after a HIIT session or after seated rest. Compared to rest, HIIT reduced symptoms of hypoglycemia in patients with NAH, but not in healthy participants or patients with IAH. HIIT attenuated hypoglycemia-induced cognitive dysfunction, which was mainly driven by changes in the NAH subgroup. HIIT suppressed cortisol and growth hormone responses, but not catecholamine responses to hypoglycemia. The present findings demonstrate that a single HIIT session rapidly reduces awareness of subsequent hypoglycemia in patients with type 1 diabetes and NAH, but not in patients with IAH, and attenuates hypoglycemia-induced cognitive dysfunction. The role of exercise-induced lactate in mediating these effects, potentially serving as an alternative fuel for the brain, should be further explored.

33 citations


Journal ArticleDOI
TL;DR: Investigation of the effect of hypoglycemia on both global and regional cerebral blood flow in type 1 diabetes patients with impaired awareness of hypglycemia and healthy controls suggests that changes in cerebralBlood flow during hypoglyCEmia contribute to impairedawareness of hyp glucosecemia.
Abstract: It is unclear whether cerebral blood flow responses to hypoglycemia are altered in people with type 1 diabetes and impaired awareness of hypoglycemia. The aim of this study was to investigate the effect of hypoglycemia on both global and regional cerebral blood flow in type 1 diabetes patients with impaired awareness of hypoglycemia, type 1 diabetes patients with normal awareness of hypoglycemia and healthy controls ( n = 7 per group). The subjects underwent a hyperinsulinemic euglycemic-hypoglycemic glucose clamp in a 3 T MR system. Global and regional changes in cerebral blood flow were determined by arterial spin labeling magnetic resonance imaging, at the end of both glycemic phases. Hypoglycemia generated typical symptoms in patients with type 1 diabetes and normal awareness of hypoglycemia and healthy controls, but not in patients with impaired awareness of hypoglycemia. Conversely, hypoglycemia increased global cerebral blood flow in patients with impaired awareness of hypoglycemia, which was not observed in the other two groups. Regionally, hypoglycemia caused a redistribution of cerebral blood flow towards the thalamus of both patients with normal awareness of hypoglycemia and healthy controls, consistent with activation of brain regions associated with the autonomic response to hypoglycemia. No such redistribution was found in the patients with impaired awareness of hypoglycemia. An increase in global cerebral blood flow may enhance nutrient supply to the brain, hence suppressing symptomatic awareness of hypoglycemia. Altogether these results suggest that changes in cerebral blood flow during hypoglycemia contribute to impaired awareness of hypoglycemia.

27 citations


Journal ArticleDOI
01 Dec 2017-Diabetes
TL;DR: The concept of enhanced lactate transport as well as increased lactate oxidation in patients with type 1 diabetes and IAH is supported.
Abstract: Since altered brain lactate handling has been implicated in the development of impaired awareness of hypoglycemia (IAH) in type 1 diabetes, the capacity to transport lactate into the brain during hypoglycemia may be relevant in its pathogenesis High-intensity interval training (HIIT) increases plasma lactate levels We compared the effect of HIIT-induced hyperlacticacidemia on brain lactate during hypoglycemia between 1) patients with type 1 diabetes and IAH, 2) patients with type 1 diabetes and normal awareness of hypoglycemia, and 3) healthy participants without diabetes (n = 6 per group) All participants underwent a hypoglycemic (28 mmol/L) clamp after performing a bout of HIIT on a cycle ergometer Before HIIT (baseline) and during hypoglycemia, brain lactate levels were determined continuously with J-difference-editing 1H-MRS, and time curves were analyzed using nonlinear mixed-effects modeling At the beginning of hypoglycemia (after HIIT), brain lactate levels were elevated in all groups but most pronounced in patients with IAH During hypoglycemia, brain lactate decreased ∼30% below baseline in patients with IAH but returned to baseline levels and remained there in the other two groups Our results support the concept of enhanced lactate transport as well as increased lactate oxidation in patients with type 1 diabetes and IAH

18 citations


Journal ArticleDOI
TL;DR: Using a jet injector for insulin administration was associated with slightly altered variability in pharmacokinetic endpoints, but with about similar variability in Pharmacodynamic endpoints compared to conventional administration.
Abstract: Background:Jet injection has been shown to accelerate the absorption and action of rapid-acting insulin. In this study, we compared the variability of absorption characteristics between jet injection and conventional administration of the rapid-acting insulin analogue aspart.Methods:A total of 30 healthy volunteers were enrolled in this randomized controlled blinded parallel study. On two test days, they received insulin aspart (0.2 units/kg body weight), either by jet injection or conventional pen, followed by a 6-hour euglycemic glucose clamp. Plasma glucose and insulin levels and glucose infusion rates were measured every 5 to 10 minutes to calculate the variability in pharmacological endpoints.Results:Jet injection advanced the times until maximal insulin concentration (T-INSmax) and glucose infusion rate (T-GIRmax) by ~40% (both P < .01). The difference between the two test days for these endpoints did not differ between jet injection and conventional administration (T-INSmax: 7.3 ± 1.9 vs 22.3 ± 6.3...

12 citations


Journal ArticleDOI
TL;DR: Genotypes at two variants of ADRB2 are associated with IAH, comparable with the risk of classical risk factors for IAH.
Abstract: OBJECTIVE: It is likely that impaired awareness of hypoglycemia (IAH) and severe hypoglycemia are in part determined by genetic factors. The aim of this study was to investigate candidate genes for associations with IAH and severe hypoglycemia in a cohort of patients with type 1 diabetes. PARTICIPANTS AND METHODS: Consecutive patients with type 1 diabetes were genotyped for single-nucleotide polymorphisms in or near the genes for the beta1 and beta2 adrenergic receptor (ADRB1, ADRB2), SORCS1, and BNC2, and for the insertion/deletion polymorphism in the ACE gene. IAH and severe hypoglycemia were assessed using a validated questionnaire. RESULTS: Of 486 patients, 32.5% were classified as having IAH. The Arg16Gly polymorphism of ADRB2 was associated with IAH (odds ratio: 1.49, 95% confidence interval: 1.01-2.20, P=0.046) Gly16 (GG) versus carriers of the A allele. In a haplotype analysis, the association was the highest in patients with GG at position 16 and heterozygous at position 27 (odds ratio: 2.19, 95% confidence interval: 1.33-3.61, P=0.03). There were no associations between IAH and other genes, and none of the studied genes was associated with severe hypoglycemia. CONCLUSION: Genotypes at two variants of ADRB2 are associated with IAH. This association is comparable with the risk of classical risk factors for IAH.

10 citations


Journal ArticleDOI
TL;DR: This model demystifies the metabolic 'black box' by enabling in silico simulations and fitting of individual responses to clinical data and can be accurately adjusted to match the individual requirements of characterized diabetic patients without the physical burden of treatment.

2 citations