Showing papers by "Cees J. Tack published in 2014"

IL-37 protects against obesity-induced inflammation and insulin resistance

Abstract: Cytokines of the IL-1 family are important modulators of obesity-induced inflammation and the development of systemic insulin resistance. Here we show that IL-1 family member IL-37, recently characterized as an anti-inflammatory cytokine, ameliorates obesity-induced inflammation and insulin resistance. Mice transgenic for human IL-37 (IL-37tg) exhibit reduced numbers of adipose tissue macrophages, increased circulating levels of adiponectin and preserved glucose tolerance and insulin sensitivity after 16 weeks of HFD. In vitro treatment of adipocytes with recombinant IL-37 reduces adipogenesis and activates AMPK signalling. In humans, elevated steady-state IL-37 adipose tissue mRNA levels are positively correlated with insulin sensitivity and a lower inflammatory status of the adipose tissue. These findings reveal IL-37 as an important anti-inflammatory modulator during obesity-induced inflammation and insulin resistance in both mice and humans, and suggest that IL-37 is a potential target for the treatment of obesity-induced insulin resistance and type 2 diabetes.

Non-invasive quantification of the beta cell mass by SPECT with 111In-labelled exendin

Abstract: A reliable method for in vivo quantification of pancreatic beta cell mass (BCM) could lead to further insight into the pathophysiology of diabetes. The glucagon-like peptide 1 receptor, abundantly expressed on beta cells, may be a suitable target for imaging. We investigated the potential of radiotracer imaging with the GLP-1 analogue exendin labelled with indium-111 for determination of BCM in vivo in a rodent model of beta cell loss and in patients with type 1 diabetes and healthy individuals. The targeting of 111In-labelled exendin was examined in a rat model of alloxan-induced beta cell loss. Rats were injected with 15 MBq 111In-labelled exendin and single photon emission computed tomography (SPECT) acquisition was performed 1 h post injection, followed by dissection, biodistribution and ex vivo autoradiography studies of pancreatic sections. BCM was determined by morphometric analysis after staining with an anti-insulin antibody. For clinical evaluation SPECT was acquired 4, 24 and 48 h after injection of 150 MBq 111In-labelled exendin in five patients with type 1 diabetes and five healthy individuals. The tracer uptake was determined by quantitative analysis of the SPECT images. In rats, 111In-labelled exendin specifically targets the beta cells and pancreatic uptake is highly correlated with BCM. In humans, the pancreas was visible in SPECT images and the pancreatic uptake showed high interindividual variation with a substantially lower uptake in patients with type 1 diabetes. These studies indicate that 111In-labelled exendin may be suitable for non-invasive quantification of BCM. Trial registration ClinicalTrials.gov NCT01825148, EudraCT: 2012-000619-10

Chronic fatigue in type 1 diabetes: highly prevalent but not explained by hyperglycemia or glucose variability

Abstract: OBJECTIVE Fatigue is a classical symptom of hyperglycemia, but the relationship between chronic fatigue and diabetes has not been systematically studied. We investigated prevalence, impact, and potential determinants of chronic fatigue in patients with type 1 diabetes mellitus (T1DM). RESEARCH DESIGN AND METHODS Out of 324 randomly selected T1DM outpatients, 214 participated in this cross-sectional observational study. Participants were compared with age- and sex-matched population-based controls. Chronic fatigue, functional impairments, current health status, comorbidity, diabetes-related factors, and fatigue-related cognitions and behaviors were assessed with questionnaires, and HbA1c values and comorbidity were assessed with medical records. Sixty-six patients underwent continuous glucose monitoring combined with an electronic fatigue diary for 5 days. Acute fatigue and four glucose parameters were determined: mean, variability, and relative time spent in hypoglycemia and hyperglycemia. RESULTS T1DM patients were significantly more often chronically fatigued (40%; 95% CI 34–47%) compared with matched controls (7%; 95% CI 3–10%; P < 0.001). Chronically fatigued patients had significantly more functional impairments. Fatigue was the most troublesome symptom. Age, depression, pain, sleeping problems, low self-efficacy concerning fatigue, and physical inactivity were significantly associated with chronic fatigue. Chronically fatigued patients spent slightly less time in hypoglycemia (proportion 0.07 ± 0.06 vs. 0.12 ± 0.10; P = 0.025). Glucose parameters were not related to acute fatigue. CONCLUSIONS Chronic fatigue is highly prevalent and clinically relevant in T1DM. Its significant relationship with cognitive behavioral variables and weak association with blood glucose levels suggests that behavioral interventions could be helpful in managing chronic fatigue in T1DM.

Liraglutide reverses pronounced insulin-associated weight gain, improves glycaemic control and decreases insulin dose in patients with type 2 diabetes: a 26 week, randomised clinical trial (ELEGANT).

Abstract: The best treatment strategy for a patient with type 2 diabetes who shows pronounced weight gain after the introduction of insulin treatment is unclear. We determined whether addition of a glucagon-like peptide-1 (GLP-1) analogue could reverse pronounced insulin-associated weight gain while maintaining glycaemic control, and compared this with the most practised strategy, continuation and intensification of standard insulin therapy. In a 26-week, randomised controlled trial (ELEGANT), conducted in the outpatient departments of one academic and one large non-academic teaching hospital in the Netherlands, adult patients with type 2 diabetes with ≥4% weight gain during short-term (≤16 months) insulin therapy received either open-label addition of liraglutide 1.8 mg/day (n = 26) or continued standard therapy (n = 24). A computer-generated random number list was used to allocate treatments. Participants were evaluated every 4–6 weeks for weight, glycaemic control and adverse events. The primary endpoint was between-group weight difference after 26 weeks of treatment (intention to treat). Of 50 randomised patients (mean age 58 years, BMI 33 kg/m2, HbA1c 7.4% [57 mmol/mol]), 47 (94%) completed the study; all patients were analysed. Body weight decreased by 4.5 kg with liraglutide and increased by 0.9 kg with standard therapy (mean difference −5.2 kg [95% CI −6.7, −3.6 kg]; p < 0.001). The respective changes in HbA1c were −0.77% (−8.4 mmol/mol) and +0.01% (+0.1 mmol/mol) (difference −0.74% [−8.1 mmol/mol]) ([95% CI −1.08%, −0.41%] [−11.8, −4.5 mmol/mol]; p < 0.001); respective changes in insulin dose were −29 U/day and +5 U/day (difference −33 U/day [95% CI −41, −25 U/day]; p < 0.001). In five patients (19%), insulin could be completely discontinued. Liraglutide was well tolerated; no severe adverse events or severe hypoglycaemia occurred. In patients with pronounced insulin-associated weight gain, addition of liraglutide to their treatment regimen reverses weight, decreases insulin dose and improves glycaemic control, and hence seems a valuable therapeutic option compared with continuation of standard insulin treatment. Trial registration ClinicalTrials.gov NCT01392898 Funding The study was funded by Novo Nordisk.

Diabetes-specific emotional distress in people with Type 2 diabetes: a comparison between primary and secondary care

Abstract: AIMS: To compare levels of diabetes distress in people with Type 2 diabetes treated in primary and secondary care and to examine demographic and clinical correlates that may explain potential differences in levels of distress between care settings. METHODS: People with Type 2 diabetes from 24 primary care practices (n = 774) and three secondary care clinics (n = 526) completed the Problem Areas In Diabetes questionnaire. Data on HbA1c levels and diabetes complications were derived from medical charts. Hierarchical ordinal regression analysis was used to investigate which correlates could explain the potential differences in level of diabetes distress between care settings. RESULTS: Diabetes distress levels and the prevalence of elevated diabetes distress were considerably lower in the participants treated in primary care (mean (sd) total diabetes distress score 8 (11); 4% of participants with a Problem Areas In Diabetes score >/= 40) than in secondary care (mean (sd) total diabetes distress score 23 (21); 19% of participants with a Problem Areas In Diabetes score >/= 40, P < 0.001). In addition to care setting, the following variables were also independently related to diabetes distress: younger age, ethnic minority status, using insulin, having a higher HbA1c level, having a higher BMI and the presence of neuropathy. Other diabetes complications were not independently associated with diabetes distress. CONCLUSIONS: In primary care, lower levels of diabetes distress were reported than in secondary care. The difference in diabetes distress between care settings can be largely, but not fully, explained by specific demographic and clinical characteristics. These results need to be interpreted with caution as they are based on two separate studies, but do call into question the need to screen for diabetes distress in people with Type 2 diabetes in primary care.

The interleukin-1 receptor antagonist anakinra improves first-phase insulin secretion and insulinogenic index in subjects with impaired glucose tolerance

Abstract: Inflammation at the level of the β cell appears to be involved in progressive β-cell dysfunction in type 2 diabetes. We assessed the effect of blocking interleukin-1 (IL-1) by anakinra [recombinant human interleukin-1 receptor antagonist (IL-1Ra)] on β-cell function. Sixteen participants with impaired glucose tolerance were treated with 150 mg anakinra daily for 4 weeks in a double blind, randomized, placebo-controlled cross-over study with a wash-out period of 4 weeks. At the end of each treatment period, oral glucose tolerance tests (OGTTs) and hyperglycaemic clamps were performed. First-phase insulin secretion improved after anakinra treatment compared with placebo, 148 ± 20 versus 123 ± 14 mU/l, respectively (p = 0.03), and the insulinogenic index was higher after anakinra treatment. These results support the concept of involvement of IL-1β in the (progressive) decrease of insulin secretion capacity associated with type 2 diabetes.

Diabetes-Related Distress, Insulin Dose, and Age Contribute to Insulin-Associated Weight Gain in Patients With Type 2 Diabetes: Results of a Prospective Study

Abstract: OBJECTIVE The determinants of insulin-associated weight gain in type 2 diabetes mellitus (T2DM) are partly unknown. Therefore, we conducted a prospective study to identify predictors of insulin-associated weight gain. RESEARCH DESIGN AND METHODS In patients with T2DM, we assessed physical activity by accelerometry and measured diabetes-related distress by questionnaires before and 6 and 12 months after starting insulin therapy. Glycemic control (HbA 1c ) and insulin dose were monitored. RESULTS After 12 months of insulin therapy, mean body weight had increased by 3.0 ± 2.5 kg ( P 1c was correlated with insulin-associated weight gain. With the use of a multiple linear regression model, a cluster of variables was identified that significantly related to weight gain. Diabetes-related distress, initial insulin dose, and the increase of insulin dose during the course of the study as well as age appeared to be important predictors of weight gain after initiation of insulin therapy. Physical activity (measured as MET) decreased from 1.40 ± 0.04 at baseline to 1.32 ± 0.04 MET ( P CONCLUSIONS Diabetes-related distress, initial and titration of insulin dose, and age all significantly predict insulin-associated weight gain. After the initiation of insulin therapy, physical activity decreased significantly, but this did not determine weight gain over the first 12 months. Our study findings may have clinical implications.

Physical activity at altitude: challenges for people with diabetes: a review.

Abstract: BACKGROUND A growing number of subjects with diabetes take part in physical activities at altitude such as skiing, climbing, and trekking. Exercise under conditions of hypobaric hypoxia poses some unique challenges on subjects with diabetes, and the presence of diabetes can complicate safe and successful participation in mountain activities. Among others, altitude can alter glucoregulation. Furthermore, cold temperatures and altitude can complicate accurate reading of glucose monitoring equipment and storage of insulin. These factors potentially lead to dangerous hyperglycemia or hypoglycemia. Over the last years, more information has become available on this subject. PURPOSE To provide an up-to-date overview of the pathophysiological changes during physical activity at altitude and the potential problems related to diabetes, including the use of (continuous) blood glucose monitors and insulin pumps. To propose practical recommendations for preparations and travel to altitude for subjects with diabetes. DATA SOURCES AND SYNTHESIS We researched PubMed, medical textbooks, and related Internet sites, and extracted human studies and data based on relevance for diabetes, exercise, and altitude. LIMITATIONS Given the paucity of controlled trials regarding diabetes and altitude, we composed a narrative review and filled in areas lacking diabetes-specific studies with data obtained from nondiabetic subjects. CONCLUSIONS Subjects with diabetes can take part in activities at high, and even extreme, altitude. However, careful assessment of diabetes-related complications, optimal preparation, and adequate knowledge of glycemic regulation at altitude and altitude-related complications is needed.

Dietary lipids do not contribute to the higher hepatic triglyceride levels of fructose- compared to glucose-fed mice

Abstract: Fructose consumption has been associated with the surge in obesity and dyslipidemia. This may be mediated by the fructose effects on hepatic lipids and ATP levels. Fructose metabolism provides carbons for de novo lipogenesis (DNL) and stimulates enterocyte secretion of apoB48. Thus, fructose-induced hepatic triglyceride (HTG) accumulation can be attributed to both DNL stimulation and dietary lipid absorption. The aim of this study was to assess the effects of fructose diet on HTG and ATP content and the contributions of dietary lipids and DNL to HTG. Measurements were performed in vivo in mice by magnetic resonance imaging (MRI) and novel magnetic resonance spectroscopy (MRS) approaches. Abdominal adipose tissue volume and intramyocellular lipid levels were comparable between 8-wk fructose- and glucose-fed mice. HTG levels were ∼1.5-fold higher in fructose-fed than in glucose-fed mice (P<0.05). Metabolic flux analysis by (13)C and (2)H MRS showed that this was not due to dietary lipid absorption, but due to DNL stimulation. The contribution of oral lipids to HTG was, after 5 h, 1.60 ± 0.23% for fructose and 2.16 ± 0.35% for glucose diets (P=0.26), whereas that of DNL was higher in fructose than in glucose diets (2.55±0.51 vs.1.13±0.24%, P=0.01). Hepatic energy status, assessed by (31)P MRS, was similar for fructose- and glucose-fed mice. Fructose-induced HTG accumulation is better explained by DNL and not by dietary lipid uptake, while not compromising ATP homeostasis.

Mannose-Binding Lectin is required for the effective clearance of apoptotic cells by adipose tissue macrophages during obesity

Abstract: Obesity is accompanied by the presence of chronic low-grade inflammation manifested by infiltration of macrophages into adipose tissue. Mannose-binding lectin (MBL), a soluble mediator of innate immunity, promotes phagocytosis and alters macrophage function. To assess the function of MBL in the development of obesity, we studied wild-type and MBL(-/-) mice rendered obese using a high-fat diet (HFD). Whereas no gross morphological differences were observed in liver, an HFD provoked distinct changes in the adipose tissue morphology of MBL(-/-) mice. In parallel with increased adipocyte size, MBL(-/-) mice displayed an increased influx of macrophages into adipose tissue. Macrophages were polarized toward an alternatively activated phenotype known to modulate apoptotic cell clearance. MBL deficiency also significantly increased the number of apoptotic cells in adipose tissue. Consistent with these observations, recombinant MBL enhanced phagocytic capacity of the stromal vascular fraction isolated from adipose tissue and modulated uptake of apoptotic adipocytes by macrophages. Despite changes in macrophage abundance and polarity, the absence of MBL did not affect systemic insulin resistance. Finally, in humans, lower levels of circulating MBL were accompanied by enhanced macrophage influx in subcutaneous adipose tissue. We propose a novel role for MBL in the recognition and clearance of apoptotic adipocytes during obesity.

Physical fitness can partly explain the metabolically healthy obese phenotype in women.

Abstract: To investigate whether physical fitness and/or fat distribution and inflammation profile may explain why approximately 30% of the women with obesity are protected against obesity-related disorders. 10 metabolically healthy obese women and 10 age- and weight-matched women with the metabolic syndrome were enrolled. Physical fitness (VO 2max ), daily physical activity levels (METs, steps per day), insulin sensitivity (clamp), body fat distribution (DXA scan) and, inflammation markers and adipokines were determined. The metabolically healthy obese women had a 17% higher VO 2max (25.1±3.9 vs. 21.5±3.1 ml ∙ min −1 ∙ kg −1 , p=0.04) and tended to take more steps per day (7 388±1 440 vs. 5 927±1 301, p=0.06) than women with the metabolic syndrome. Despite equivalent levels of fat mass, metabolically healthy obese women had significantly lower circulating TNF-α levels compared to women with the metabolic syndrome (3.55±3.83 vs. 0.43±0.97 ng/ml, p=0.03). No differences were seen in insulin sensitivity, adipokines, and inflammatory markers between both groups. Metabolically healthy obese women have a higher cardio-respiratory fitness and lower TNF-α levels, which may partly explain why these women are protected from the detrimental effects of obesity compared to obese women with the metabolic syndrome.

MAP3K8 (TPL2/COT) Affects Obesity-Induced Adipose Tissue Inflammation without Systemic Effects in Humans and in Mice

Abstract: Chronic low-grade inflammation in adipose tissue often accompanies obesity, leading to insulin resistance and increasing the risk for metabolic diseases. MAP3K8 (TPL2/COT) is an important signal transductor and activator of pro-inflammatory pathways that has been linked to obesity-induced adipose tissue inflammation. We used human adipose tissue biopsies to study the relationship of MAP3K8 expression with markers of obesity and expression of pro-inflammatory cytokines (IL-1β, IL-6 and IL-8). Moreover, we evaluated obesity-induced adipose tissue inflammation and insulin resistance in mice lacking MAP3K8 and WT mice on a high-fat diet (HFD) for 16 weeks. Individuals with a BMI >30 displayed a higher mRNA expression of MAP3K8 in adipose tissue compared to individuals with a normal BMI. Additionally, high mRNA expression levels of IL-1β, IL-6 and IL-8, but not TNF -α, in human adipose tissue were associated with higher expression of MAP3K8. Moreover, high plasma SAA and CRP did not associate with increased MAP3K8 expression in adipose tissue. Similarly, no association was found for MAP3K8 expression with plasma insulin or glucose levels. Mice lacking MAP3K8 had similar bodyweight gain as WT mice, yet displayed lower mRNA expression levels of IL-1β, IL-6 and CXCL1 in adipose tissue in response to the HFD as compared to WT animals. However, MAP3K8 deficient mice were not protected against HFD-induced adipose tissue macrophage infiltration or the development of insulin resistance. Together, the data in both human and mouse show that MAP3K8 is involved in local adipose tissue inflammation, specifically for IL-1β and its responsive cytokines IL-6 and IL-8, but does not seem to have systemic effects on insulin resistance.

Life-long physical activity restores metabolic and cardiovascular function in type 2 diabetes

Abstract: Short-to-moderate duration exercise training improves fitness and lowers cardiovascular risk in type 2 diabetes (T2DM). However, the impact of long-term compliance to an active lifestyle of T2DM patients on cardiovascular risk factors has never been studied but could provide information on the maximal achievable health effect of physical activity in T2DM. This study examined the impact of a life-long active lifestyle by comparing physical fitness, cardiovascular risk and vascular function between long-term physically active T2DM patients versus sedentary T2DM patients and controls. Fitness, HOMA-IR, brachial artery flow-mediated dilation (FMD) and lifetime risk for cardiovascular disease were assessed in 15 exercising T2DM patients, 12 age-, sex- and weight-matched sedentary T2DM patients and 9 sedentary men free of established cardiovascular and metabolic disease as controls. Long-term regular exercise was defined as self-reported participation of >2.5 h of (predominantly) endurance exercise per week, which was performed for 18–47 years. Sedentary T2DM patients showed lower fitness (21.8 ± 2.3, 32.6 ± 6.0 and 31.1 ± 3.2 ml O2/kg/min), higher HOMA-IR (8.3 ± 5.0, 2.0 ± 1.8 and 1.1 ± 0.5 100/%S) and higher lifetime risk scores (17.3 ± 5.4, 9.3 ± 5.0 and 8.9 ± 3.9 %) compared to active peers and controls, respectively. Brachial artery FMD was lower in sedentary T2DM patients compared with active peers, but not in controls (3.3 ± 1.2, 5.2 ± 2.1 and 3.8 ± 1.2 %). Life-long active T2DM patients have superior fitness levels, HOMA-IR, cardiovascular risk and FMD compared to sedentary peers, whilst no differences were found when compared to controls. This study provides evidence that a life-long active lifestyle, even in T2DM, may be able to effectively normalize cardiovascular risk.

ChronicFatigueinType1Diabetes: HighlyPrevalentbutNotExplained by Hyperglycemia or Glucose Variability

Abstract: 47%) compared with matched controls (7%; 95% CI 3–10%;P,0.001). Chronically fatigued patients had significantly more functional impairments. Fatigue was the most troublesome symptom. Age, depression, pain, sleeping problems, low selfefficacy concerning fatigue, and physical inactivity were significantly associated with chronic fatigue. Chronically fatigued patients spent slightly less time in hypoglycemia (proportion 0.07 6 0.06 vs. 0.12 6 0.10; P = 0.025). Glucose parameters were not related to acute fatigue.

Beta2-adrenoceptor stimulation has no effect on skeletal muscle glucose uptake.

Abstract: Introduction Blockade of the β-adrenergic receptor induces insulin resistance and chronic β-adrenoceptor stimulation improves insulin sensitivity in animals. We tested whether acute β2-adrenoceptor stimulation increased insulin-induced glucose uptake in human forearm skeletal muscle.