Showing papers by "Cees J. Tack published in 2017"
TL;DR: The results reveal that activation of SUCNR1 in macrophages is important for both infiltration and inflammation of adipose tissue in obesity, and suggest that S UCNR1 is a promising therapeutic target in obesity-induced type 2 diabetes.
Abstract: Aims/hypothesis
Obesity induces macrophages to drive inflammation in adipose tissue, a crucial step towards the development of type 2 diabetes. The tricarboxylic acid (TCA) cycle intermediate succinate is released from cells under metabolic stress and has recently emerged as a metabolic signal induced by proinflammatory stimuli. We therefore investigated whether succinate receptor 1 (SUCNR1) could play a role in the development of adipose tissue inflammation and type 2 diabetes.
106 citations
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
TL;DR: Plasma triglycerides and glucose levels are major determinants of the plasma Mg2+ concentration, whereas only a minor part of hypomagnesemia can be explained by drug intake, excluding polypharmacy as a major cause for hypomAGnesemia in type 2 diabetes.
Abstract: BACKGROUND: Hypomagnesemia (plasma magnesium (Mg2+) concentration <0.7 mmol/L) has been described in patients with type 2 diabetes. Polypharmacy is inevitable when treating a complex disease such as type 2 diabetes and could explain disturbances in the plasma Mg2+ concentration. In this study, we aimed to establish the extent of hypomagnesemia in a cohort of type 2 diabetes patients and to identify the determinants of plasma Mg2+ levels. METHODS: Patient data and samples of 395 type 2 diabetes patients were investigated. Plasma Mg2+ concentrations were measured using a spectrophotometric assay. Using Pearson correlation analyses, variables were correlated to plasma Mg2+ levels. After excluding confounding variables, all parameters correlating (P < 0.1) with plasma Mg2+ were included in a stepwise backward regression model. RESULTS: The mean plasma Mg2+ concentration in this cohort was 0.74 +/- 0.10 mmol/L. In total, 121 patients (30.6%) suffered from hypomagnesemia. Both plasma triglyceride (r = -0.273, P < 0.001) and actual glucose levels (r = -0.231, P < 0.001) negatively correlated with the plasma Mg2+ concentration. Patients using metformin (n = 251, 62%), proton pump inhibitors (n = 179, 45%) or beta-adrenergic receptor agonists (n = 31, 8%) displayed reduced plasma Mg2+ levels. Insulin use (n = 299, 76%) positively correlated with plasma Mg2+ levels. The model predicted (R2) 20% of all variance in the plasma Mg2+ concentration. CONCLUSIONS: Hypomagnesemia is highly prevalent in type 2 diabetes patients. Plasma triglycerides and glucose levels are major determinants of the plasma Mg2+ concentration, whereas only a minor part (<10%) of hypomagnesemia can be explained by drug intake, excluding polypharmacy as a major cause for hypomagnesemia in type 2 diabetes.
62 citations
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
TL;DR: Although the findings need to be confirmed in larger and longer-term studies, they suggest that CBT can effectively reduce fatigue severity and functional impairment in type 1 diabetes.
31 citations
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
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
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
TL;DR: Pain was highly prevalent in fatigued patients with type 1 diabetes, although pain impact and severity were relatively low, and the location of some pain symptoms was similar to the location in the general population.
11 citations
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
TL;DR: The hypothesis that initiation of insulin therapy would be associated with an increase in sedentary behavior and lower low, moderate, and vigorous-intensity physical activity, which would subsequently relate to weight gain was examined.
Abstract: The insulin therapy–mediated weight gain in patients with type 2 diabetes (T2D) may relate to altered physical activity patterns (1). In this study, we examined the hypothesis that initiation of insulin therapy would be associated with an increase in sedentary behavior (i.e., sitting time) and lower low-, moderate-, and vigorous-intensity physical activity, which would subsequently relate to weight gain.
We included 40 T2D patients who started insulin therapy and followed these patients for a period of 12 months. Patients were randomly selected from one university hospital, three nonuniversity teaching hospitals, and four primary care practices. The decision to start insulin treatment was at the discretion of the responsible physician and was always based on failure of glycemic control while on oral glucose-lowering agents and diet. Measurements were performed before and 6 months and 12 months after initiation of insulin therapy. We examined body weight, waist-to-hip circumference, fasting glucose, and HbA1c using standardized procedures. Free-living daytime physical activity was objectively measured (SenseWear Pro3 Armband, BodyMedia, Pittsburgh, PA) (2). We examined 1 ) time (hours/day) spent in sitting ( 3.0 METs); 2 ) steps per day; and 3 ) sit-to-stand maneuvers (transition from …
TL;DR: Bioequivalence analysis showed that daclatasvir does not influence the pharmacokinetics of metformin in healthy subjects and Pharmacodynamic parameters were also comparable between treatments.
Abstract: AIM
The aim of this study was to evaluate the effect of the proposed organic cation transporter (OCT) inhibitor daclatasvir on the pharmacokinetics and pharmacodynamics of the OCT substrate metformin.
METHODS
This was an open-label, two-period, randomized, crossover trial in 20 healthy subjects. Treatment A consisted of metformin and treatment B consisted of metformin + daclatasvir. Pharmacokinetic curves were recorded at steady state. Geometric mean ratios (GMRs) with 90% confidence intervals (CIs) were calculated for metformin area under the concentration-time curve from 0 to 12 hours (AUC0–12), maximum plasma concentration (Cmax) and final plasma concentration (Clast). An oral glucose tolerance test was performed, measuring insulin, glucose and lactate levels.
RESULTS
The GMRs (90% CI) of metformin AUC0–12, Cmax and Clast (B versus A) were 109% (102–116%), 108% (101–116%) and 112% (103–122%). The GM AUC0–2 for insulin, glucose and lactate during treatment A and B were 84 and 90 h.mE/L, 13.6 and 13.4 h.mmol/L and 3.4 and 3.5 h.mmol/L, respectively.
CONCLUSIONS
Bioequivalence analysis showed that daclatasvir does not influence the pharmacokinetics of metformin in healthy subjects. Pharmacodynamic parameters were also comparable between treatments.
TL;DR: To assess the impact of a multifaceted strategy to improve perioperative diabetes care throughout the hospital care pathway, a large number of patients with type 2 diabetes are referred to the hospital for treatment.
Abstract: Aims
To assess the impact of a multifaceted strategy to improve perioperative diabetes care throughout the hospital care pathway.
Methods
We conducted a controlled before-and-after study in six hospitals. The purpose of the strategy was to target four predominant barriers that obstruct optimal care delivery. We provided feedback on baseline indicator performance, developed a multidisciplinary protocol and patient information, and provided professional education. After a 6-month intervention, we determined the performance changes against three outcome indicators and nine process indicators using data on 811 patients with diabetes who underwent major surgery. The progress of the interventions was monitored closely.
Results
Two process indicators improved significantly in the intervention hospitals: the proportion of patients for whom glycaemic control had been evaluated preoperatively increased by 9% (P < 0.002) and the proportion of patients with blood glucose measurements within 1 h after surgery increased by 29% (P < 0.0001). Four other process indicators and all three outcome indicators improved more in the intervention hospitals than in the control hospitals, but the differences were not statistically significant. These included the proportion of patients with all glucose values at 6–10 mmol/l (+3%) and the proportion of patients with hyperglycaemia (−8%). The implementation of the multidisciplinary protocol was still ongoing after the 6-month intervention period.
Conclusions
The multifaceted improvement strategy had a limited impact on the quality of perioperative diabetes care. This study demonstrates the complexity of improving perioperative diabetes care throughout the multiprofessional hospital care pathway.
TL;DR: The results suggest that perioperative diabetes care is reactive rather than proactive, and that current emphasis of professionals is on treating instead of preventing postoperative hyperglycemia.
Abstract: As perioperative hyperglycemia is associated with poor postoperative patient outcomes, clinical guidelines provide recommendations for optimal perioperative glucose control. It is unclear to what extent recommended glucose levels are met in daily practice, and little is known about factors that influence these levels. We describe blood glucose levels throughout the hospital care pathway in 375 non-critically ill patients with diabetes who underwent major surgery (abdominal, cardiac, or orthopedic) in 6 hospitals, examine determinants of these levels including adherence to 9 quality indicators for optimal perioperative diabetes care, and perform qualitative interviews to identify barriers for optimal care. Virtually all patients (95%) experienced at least one hyperglycemic value (>10 mmol/l); 9% had at least one value
TL;DR: The cross‐sectional association between individual and partner’s level of occupation on HbA1c levels in people with Type 2 diabetes in the Netherlands is examined.
Abstract: Aims: Individual indicators of socio-economic status have been associated with glycaemic control in people with Type 2 diabetes, but little is known about the association between partner’s socio-economic status and HbA1c levels. We therefore examined the cross-sectional association between individual and partner’s level of occupation on HbA1c levels in people with Type 2 diabetes in the Netherlands. Methods: We included people with Type 2 diabetes with a partner who were treated in primary, secondary and tertiary care in the Diabetes Pearl cohort. Occupational level was classified according to International Standard Classification of Occupations (ISCO)-08 skill levels. Linear regression analyses were performed stratified for sex, and corrected for age, recruitment centre and diabetes medication. Results: In total, 3257 participants (59.8% men, mean 62.2±9.4 years) were included. For men, having a partner with an intermediate level of occupation was associated with lower HbA1c levels [e.g. ISCO level 3: –2 mmol/mol (95% CI –4;–1) or -0.2% (95% CI –0.4;–0.1)], compared with having a partner of the highest occupational level (ISCO level 4). In women, having an unemployed partner was associated with higher HbA1c levels [14 mmol/mol (95% CI 6; 22) or 1.3% (95% CI 0.6; 2.0)], compared with having a partner of the highest occupational level. Conclusions: Partner's occupational status provided additional information on the association between socio-economic status and HbA1c levels in people with Type 2 diabetes. Women seemed to benefit from a partner with a higher occupational status, while men seemed to benefit from a partner with a lower status. Because of the cross-sectional nature of the present study, more research is necessary to explore this association.