Showing papers by "Bastiaan E. de Galan published in 2019"

Early Detection of Hypoglycemia in Type 1 Diabetes Using Heart Rate Variability Measured by a Wearable Device

Abstract: OBJECTIVE Changes in heart rate variability (HRV) occur at the initiation of hypoglycemia due to sympathetic nervous system activity. We investigated the use of HRV detection by a wearable device as an early alert for hypoglycemia. RESEARCH DESIGN AND METHODS This proof-of-principle study included 23 patients with type 1 diabetes (14 women, mean age 42 ± 11 years). Patients wore a VitalConnect HealthPatch for 5 days. Hypoglycemia was defined as glucose ≤70 mg/dL (≤3.9 mmol/L) by fingerstick measurement. HRV was analyzed in standardized periods before the hypoglycemic event. RESULTS Sixty-six hypoglycemic events were recorded. Hypoglycemia caused a typical HRV pattern in 36 (55%) of the hypoglycemic events. Eighteen events (27%) showed an atypical pattern. Ten events were unclassified (15%), and two did not display a change in HRV (3%). CONCLUSIONS Hypoglycemia causes early changes in HRV that can be detected by a wearable device. Measuring real-time HRV seems promising for early hypoglycemia detection.

Effect of lactate administration on brain lactate levels during hypoglycemia in patients with type 1 diabetes.

Abstract: Administration of lactate during hypoglycemia suppresses symptoms and counterregulatory responses, as seen in patients with type 1 diabetes and impaired awareness of hypoglycemia (IAH), presumably ...

Elevated brain glutamate levels in type 1 diabetes: correlations with glycaemic control and age of disease onset but not with hypoglycaemia awareness status.

Abstract: Chronic hyperglycaemia in type 1 diabetes affects the structure and functioning of the brain, but the impact of recurrent hypoglycaemia is unclear. Changes in the neurochemical profile have been linked to loss of neuronal function. We therefore aimed to investigate the impact of type 1 diabetes and burden of hypoglycaemia on brain metabolite levels, in which we assumed the burden to be high in individuals with impaired awareness of hypoglycaemia (IAH) and low in those with normal awareness of hypoglycaemia (NAH). We investigated 13 non-diabetic control participants, 18 individuals with type 1 diabetes and NAH and 13 individuals with type 1 diabetes and IAH. Brain metabolite levels were determined by analysing previously obtained 1H magnetic resonance spectroscopy data, measured under hyperinsulinaemic–euglycaemic conditions. Brain glutamate levels were higher in participants with diabetes, both with NAH (+15%, p = 0.013) and with IAH (+19%, p = 0.003), compared with control participants. Cerebral glutamate levels correlated with HbA1c levels (r = 0.40; p = 0.03) and correlated inversely (r = −0.36; p = 0.04) with the age at diagnosis of diabetes. Other metabolite levels did not differ between groups, apart from an increase in aspartate in IAH. In conclusion, brain glutamate levels are elevated in people with type 1 diabetes and correlate with glycaemic control and age of disease diagnosis, but not with burden of hypoglycaemia as reflected by IAH. This suggests a potential role for glutamate as an early marker of hyperglycaemia-induced cerebral complications of type 1 diabetes. ClinicalTrials.gov NCT03286816; NCT02146404; NCT02308293

Effect of Dapagliflozin Treatment on the Expression of Renal Sodium Transporters/Channels on High-Fat Diet Diabetic Mice.

Abstract: BACKGROUND: Inhibition of the Na+/glucose co-transporter 2 is a new therapeutic strategy for diabetes. It is unclear how proximal loss of Na+ (and glucose) affects the subsequent Na+ transporters in the proximal tubule (PT), thick ascending limb of loop of Henle (TAL), distal convoluted tubule (DCT) and collecting duct (CD). METHODS: Mice on a high fat diet were administered 3 doses streptozotocin 6 days prior to oral dapagliflozin administration or vehicle for 18 days. A control group of lean mice were also included. Body weight and glucose were recorded at regular intervals during treatment. Renal Na+ transporters expression in nephron segments were analyzed by RT-qPCR and Western blot. RESULTS: Dapagliflozin treatment resulted in a significant reduction in body weight and blood glucose compared to vehicle-treated controls. mRNA results showed that Na+-hydrogen antiporter 3 (NHE3), Na+/phosphate cotransporter (NaPi-2a) and epithelial Na+ channel expression was increased, Ncx1, ENaCbeta and ENaCgamma expression declined (p all < 0.05), respectively, in dapagliflozin-treated mice when compared with saline vehicle mice. Na-K-2Cl cotransporters and Na-Cl cotransporter mRNA expression was not affected by dapagliflozin treatment. Na+/K+-ATPase (Atp1b1) expression was also increased significantly by dapagliflozin treatment, but it did not affect Atp1a1 and glucose transporter 2 expression. Western blot analysis showed that NaPi-2a, NHE3 and ATP1b1 expression was upregulated in dapagliflozin-treated diabetic mice when compared with saline vehicle mice (p < 0.05). CONCLUSION: Our findings suggest that dapagliflozin treatment augments compensatory changes in the renal PT in diabetic mice.

Effect of the GLP-1 Receptor Agonist Exenatide on Impaired Awareness of Hypoglycemia in Type 1 Diabetes: A Randomized Controlled Trial

Abstract: Context Impaired awareness of hypoglycemia (IAH), resulting from habituation to recurrent hypoglycemia, can be reversed by strict avoidance of hypoglycemia. Adjunctive treatment with glucagon-like peptide-1 (GLP-1) receptor agonists may reduce glucose variability, hence lower the risk of hypoglycemia and improve awareness. The aim of our study was to investigate the effect of exenatide on awareness of hypoglycemia in people with type 1 diabetes and IAH. Methods This was a randomized double-blind, placebo-controlled cross-over trial. Ten patients with type 1 diabetes and IAH were included (age 38.5±4.4 years, 40% males, HbA1c 7.2±0.4 % (55.2±4.8 mmol/mol)). Patients were treated with exenatide 5µg twice daily (first 2 weeks), followed by 10µg twice daily (remaining 4 weeks) or matching placebo, with a 4-week washout period. Patients wore blinded glucose sensors in the final weeks and modified hyperinsulinemic normoglycemic-hypoglycemic glucose clamps (nadir 2.5 mmol/l) were performed at the end of each treatment period. Results Treatment with exenatide caused body weight to fall as compared to placebo (-3.9±0.9 vs. 0.6±1.2 kg, p=0.047). Exenatide did not change mean 24-hour glucose levels (8.3±0.4 vs. 8.5±0.3 mmol/l, exenatide vs. placebo, p=0.64), median (interquartile range) percentage of time spent in hypoglycemia (15.5 [4.5, 25.5] vs. 7.8 [4.4, 17.1]%, p=0.11) and frequency of hypoglycemia (15.8±3.7 vs. 12.1±3.5, p=0.19). Symptom scores in response to clamped hypoglycemia were similar between exenatide (median change 1.0 [-1.5, 7.0]) and placebo (4.5 [1.5, 5.8], p=0.08). Conclusions Six weeks treatment with exenatide did not improve awareness of hypoglycemia in patients with type 1 diabetes and IAH.

SUGAR-DIP trial: oral medication strategy versus insulin for diabetes in pregnancy, study protocol for a multicentre, open-label, non-inferiority, randomised controlled trial.

Abstract: Introduction In women with gestational diabetes mellitus (GDM) requiring pharmacotherapy, insulin was the established first-line treatment. More recently, oral glucose lowering drugs (OGLDs) have gained popularity as a patient-friendly, less expensive and safe alternative. Monotherapy with metformin or glibenclamide (glyburide) is incorporated in several international guidelines. In women who do not reach sufficient glucose control with OGLD monotherapy, usually insulin is added, either with or without continuation of OGLDs. No reliable data from clinical trials, however, are available on the effectiveness of a treatment strategy using all three agents, metformin, glibenclamide and insulin, in a stepwise approach, compared with insulin-only therapy for improving pregnancy outcomes. In this trial, we aim to assess the clinical effectiveness, cost-effectiveness and patient experience of a stepwise combined OGLD treatment protocol, compared with conventional insulin-based therapy for GDM. Methods The SUGAR-DIP trial is an open-label, multicentre randomised controlled non-inferiority trial. Participants are women with GDM who do not reach target glycaemic control with modification of diet, between 16 and 34 weeks of gestation. Participants will be randomised to either treatment with OGLDs, starting with metformin and supplemented as needed with glibenclamide, or randomised to treatment with insulin. In women who do not reach target glycaemic control with combined metformin and glibenclamide, glibenclamide will be substituted with insulin, while continuing metformin. The primary outcome will be the incidence of large-for-gestational-age infants (birth weight >90th percentile). Secondary outcome measures are maternal diabetes-related endpoints, obstetric complications, neonatal complications and cost-effectiveness analysis. Outcomes will be analysed according to the intention-to-treat principle. Ethics and dissemination The study protocol was approved by the Ethics Committee of the Utrecht University Medical Centre. Approval by the boards of management for all participating hospitals will be obtained. Trial results will be submitted for publication in peer-reviewed journals.

Clinical impact of artifactual hypoglycaemia and its diagnosis at the bedside.

Abstract: SIR, The term artifactual hypoglycaemia has been proposed for the discrepancy between low capillary and normal plasma glucose levels, and has been described in various conditions, including RP [1]. Early recognition is challenging, but is important to prevent anxiety and unnecessary treatment and diagnostic tests. We present a case of artifactual hypoglycaemia in a patient with SSc and propose a quick method for its diagnosis. A 57-year-old man was referred from another hospital because of recurrent, asymptomatic hypoglycaemia. His medical history included SSc and RP, treated with lowdose prednisolone, and aortic valve stenosis with intestinal angiodysplasia for which somatostatin had been recently started. Subsequent monitoring of capillary glucose by finger-stick measurements revealed glucose levels ranging between 2.3 and 7.7 mmol/l, with 15% of these below 3.5 mmol/l. Screening diagnostic analysis for insulinoma, performed before the patient was referred, was reportedly negative. Somatostatin, which was thought to have caused the low glucose levels, had been discontinued, the dose of prednisolone was increased (from 5 to 10 mg daily) and continuous feeding over a nasogastric tube had been initiated. However, none of these interventions had led to a clear, sustainable glucose-increasing effect (Fig. 1), although his body weight had increased by 4 kg. The patient had become increasingly anxious about the apparent treatment resistance of his hypoglycaemia. The patient occasionally reported non-specific symptoms like blurred vision and tremor that were unrelated to the capillary glucose level and did not respond to ingestion of dextrose. We concluded that the criteria of Whipple’s triad for hypoglycaemia were not met [2] and suspected a measurement artefact. Because his sclerosis-affected skin hindered venous access, we performed simultaneous measurements on the patient’s earlobe when finger-stick measurement suggested hypoglycaemia. These measurements revealed glucose levels to be 2.8 mmol/l higher in earlobe capillary blood, with none of them being in the hypoglycaemic range. Screening for diabetes in people at elevated risk is routine practice at all levels of clinical care across medical specialties. Hypoglycaemia in such a patient not treated with glucose-lowering agents should raise the health care provider’s suspicion of artifactual hypoglycaemia, especially when the event is based on capillary blood glucose, measured by finger-stick. Unawareness of this phenomenon may lead to unnecessary diagnostic and therapeutic interventions, as exemplified in our patient. Artifactual hypoglycaemia, previously referred to as pseudo-hypoglycaemia, has been described in patients with RP, circulatory shock, peripheral arterial disease, Eisenmenger syndrome, acrocyanosis or hypothermia [1]. It has been ascribed to reduced perfusion of the peripheral microcirculation with decelerated glucose transit and increased glucose uptake into the surrounding tissue [3]. Additionally, the term has also been used to describe falsely low plasma glucose values resulting from increased glycolysis by leukocytes, e.g. in chronic myeloid leukaemia [1, 3]. Diagnosis of artifactual hypoglycaemia relies on simultaneous glucose measurements in capillary blood and a venous specimen [1]. Because venous access can be difficult in patients with SSc because of their fibrotized skin and stiffened veins, we chose the earlobe as alternative site for glucose measurement. Earlobe measurements reflect also capillary blood glucose; however, the earlobe remains unaffected by SSc, because it lacks connective tissue [4, 5]. In addition, it allows for diagnosis at the bedside with the same glucose metre, thus circumventing any differences in accuracy with laboratory methods. Our case has potential clinical consequences for patients with SSc and RP at risk for or having been diagnosed with diabetes. Indeed, artifactual normal or lower than expected finger-stick glucose values in these patients may give false assumptions of the level of glucose control in people with (coexistent) diabetes or even refute its diagnosis, potentially withholding patients from appropriate treatment. This phenomenon must be particularly considered if there is a discrepancy between the haemoglobin A1c level and glucose values measured by fingerstick. Whenever frequent glucose monitoring is required, e.g. with insulin treatment, switching from finger-stick to earlobe capillary glucose measurement may be considered. This case illustrates the importance of awareness of artifactual hypoglycaemia, not only to avoid unnecessary work-up and therapy, but also to prevent anxiety associated with the belief of having a medical condition that appears unsolvable. We suggest performing simultaneous glucose measurements on the patient’s earlobe and finger-stick whenever this phenomenon is likely to occur, not only in patients with supposedly hypoglycaemia, but also in case of lower than expected glucose levels in patients with (poorly controlled) diabetes mellitus.

PET imaging during hypoglycaemia to study adipose tissue metabolism.

Abstract: BACKGROUND: Disturbances in adipose tissue glucose uptake may play a role in the pathogenesis of type 2 diabetes, yet its examination by 2-deoxy-2-[(18) F]fluorodeoxyglucose ([(18) F]FDG) PET/CT is challenged by relatively low uptake kinetics. We tested the hypothesis that performing [(18) F]FDG PET/CT during a hypoglycaemic clamp would improve adipose tissue tracer uptake to allow specific comparison of adipose tissue glucose handling between people with or without type 2 diabetes. DESIGN: We enrolled participants with or without diabetes who were at least overweight, to undergo a hyperinsulinaemic hypoglycaemic clamp or a hyperinsulinaemic euglycaemic clamp (n = 5 per group). Tracer uptake was quantified using [(18) F]FDG PET/CT. RESULTS: Hypoglycaemic clamping increased [(18) F]FDG uptake in visceral adipose tissue of healthy participants (P = 0.002). During hypoglycaemia, glucose uptake in visceral adipose tissue of type 2 diabetic participants was lower as compared to healthy participants (P < 0.0005). No significant differences were observed in skeletal muscle, liver or pancreas. CONCLUSIONS: The present findings indicate that [(18) F]FDG PET/CT during a hypoglycaemic clamp provides a promising new research tool to evaluate adipose tissue glucose metabolism. Using this method, we observed a specific impairment in visceral adipose tissue [(18) F]FDG uptake in type 2 diabetes, suggesting a previously underestimated role for adipose tissue glucose handling in type 2 diabetes.