OBJECTIVE To assess the short- and long-term effects of addition of exercise to a very low calorie diet (VLCD) on low-grade inflammation in obese patients with type 2 diabetes mellitus (T2DM).... Show moreOBJECTIVE To assess the short- and long-term effects of addition of exercise to a very low calorie diet (VLCD) on low-grade inflammation in obese patients with type 2 diabetes mellitus (T2DM). METHODS Twenty seven obese, insulin-dependent T2DM patients followed a 4-month VLCD with (n=13) or without (n=14) exercise and were followed up to 18 months. Anthropometric measurements, metabolic and inflammatory parameters were assessed before, directly after the intervention and at 6 and 18 months follow-up. The same measurements were performed only once in 56 healthy lean and 56 healthy obese controls. RESULTS At baseline hsCRP, IL10 and IL8 were significantly elevated in obese T2DM compared to lean healthy controls. After 4 months, despite substantial weight loss (-25.4 ± 1.3 kg), neither the VLCD nor VLCD+exercise had an effect on plasma cytokines. At 6 months, in the weight-stabilizing period, measures of low-grade inflammation had decreased substantially and equally in both intervention groups. Despite subsequent weight regain, beneficial effect was sustained up to 18 months in both groups, except for IL1 and hsCRP which had returned to baseline in the VLCD-only group. CONCLUSION Our findings suggest that severe caloric restriction increases cytokine production by adipose tissue macrophages and that the beneficial effects of weight loss become apparent only in the eucaloric state. Show less
Wang, Y.A.; Snel, M.; Jonker, J.T.; Hammer, S.; Lamb, H.J.; Roos, A. de; ... ; Rensen, P.C.N. 2011
High fat feeding induces a variety of obese and lean phenotypes in inbred rodents. Compared to Diet Resistant (DR) rodents, Diet Induced Obese (DIO) rodents are insulin resistant and have a reduced... Show moreHigh fat feeding induces a variety of obese and lean phenotypes in inbred rodents. Compared to Diet Resistant (DR) rodents, Diet Induced Obese (DIO) rodents are insulin resistant and have a reduced dopamine receptor D2 (DRD2) mediated tone. We hypothesized that this differing dopaminergic tone contributes to the distinct metabolic profiles of these animals. C57Bl6 mice were classified as DIO or DR based on their weight gain during 10 weeks of high fat feeding. Subsequently DIO mice were treated with the DRD2 agonist bromocriptine and DR mice with the DRD2 antagonist haloperidol for 2 weeks. Compared to DR mice, the bodyweight of DIO mice was higher and their insulin sensitivity decreased. Haloperidol treatment reduced the voluntary activity and energy expenditure of DR mice and induced insulin resistance in these mice. Conversely, bromocriptine treatment tended to reduce bodyweight and voluntary activity, and reinforce insulin action in DIO mice. These results show that DRD2 activation partly redirects high fat diet induced metabolic anomalies in obesity-prone mice. Conversely, blocking DRD2 induces an adverse metabolic profile in mice that are inherently resistant to the deleterious effects of high fat food. This suggests that dopaminergic neurotransmission is involved in the control of metabolic phenotype. Show less
Schroijen, M.A.; Dekkers, O.M.; Grootendorst, D.C.; Noordzij, M.; Romijn, J.A.; Krediet, R.T.; ... ; NECOSAD Study Grp 2011
Objective: Arthropathy is an invalidating complication of acromegaly. Although acromegalic arthropathy shares features with primary osteoarthritis, joint spaces are widened rather than narrowed in... Show moreObjective: Arthropathy is an invalidating complication of acromegaly. Although acromegalic arthropathy shares features with primary osteoarthritis, joint spaces are widened rather than narrowed in patients with long term cure of acromegaly. The late effects of acromegaly on hand joints have not been characterized. Therefore the objective of the current study was to assess joint space widths of hand joints in patients with long-term control of acromegaly and to identify factors associated with joint space width.Design: Cross-sectional studyMethods: Cross-sectional study in 89 patients(age 58±12yr, 49% women) with long-term controlled acromegaly and 471 controls without hand symptoms(age 46±12yr, 42% women). Radiological joint space widths of individual hand joints were measured by automated image analysis.Results: Patients had wider mean joint spaces than controls: MCP-joints were ~24%, PIP-joints ~21%, and DIP-joints ~20% wider (patients vs controls; p<0.001 for all joints). Mean joint space width exceeded the 95th percentile of the values obtained in controls in 64% of patients. Higher IGF-1 and GH concentrations at diagnosis were associated with larger joint space widths (adjusted ß for pretreatment GH in tertiles:0.09(95%CI 0.03-1.84) and for IGF-1 in tertiles 0.14(95%CI 0.05-0.23) at the MCP-joints in acromegalic patients. In male, but not in female, patients increased joint space widths were associated with more self-reported pain(p=0.02).Conclusions: Using a new semi-automated image analysis of hand radiographs, acromegalic patients with long-term disease control appeared to have increased joint spaces of all hand joints. Joint space widths were positively related to disease activity at diagnosis, but not to duration of follow-up, suggesting irreversible cartilage hypertrophy. Irreversible cartilage hypertrophy may partly explain persisting hand complaints, despite long-term disease control. Show less
OBJECTIVE Head and neck paragangliomas (HNPGL) are associated with mutations in genes encoding subunits of succinate dehydrogenase (SDH). The aim of this study was to evaluate SDH mutations, family... Show moreOBJECTIVE Head and neck paragangliomas (HNPGL) are associated with mutations in genes encoding subunits of succinate dehydrogenase (SDH). The aim of this study was to evaluate SDH mutations, family history and phenotypes of patients with HNPGL in the Netherlands. DESIGN We evaluated the clinical data and the mutation status of 236 patients referred between 1950 and 2009 to Leiden University Medical Center. RESULTS The large majority of the patients carried mutations in SDHD (83%), and the p.Asp92Tyr Dutch founder mutation in SDHD alone accounted for 72% of all patients with HNPGL. A mutation in SDHAF2 was found in 4%, mutations in SDHB in 3% and a mutation in SDHC was identified in a single patient (0·4%). Over 80% of patients presented with positive family history, of whom 99·5% carried a mutation in an SDH gene. SDH mutations were also found in 56% of isolated patients, chiefly in SDHD (46%), but also in SDHB (8%) and SDHC (2%). The clinical parameters of these different subgroups are discussed: including the age at diagnosis, associated pheochromocytomas, tumour multifocality and malignancy rate. CONCLUSION The majority of Dutch patients with HNPGL present with a positive family history, in contrast to other European countries. The clinical characteristics of patients with HNPGL are chiefly determined by founder mutations in SDHD, the major causative gene in both familial and isolated patients with HNPGL. The high frequency of founder mutations in SDHD suggests a higher absolute prevalence of paraganglioma syndrome in the Netherlands. Show less
Insulin signaling in the central nervous system (CNS) is required for the inhibitory effect of insulin on glucose production. Our aim was to determine whether the CNS is also involved in the... Show moreInsulin signaling in the central nervous system (CNS) is required for the inhibitory effect of insulin on glucose production. Our aim was to determine whether the CNS is also involved in the stimulatory effect of circulating insulin on the tissue-specific retention of fatty acid (FA) from plasma. In wild-type mice, hyperinsulinemic-euglycemic clamp conditions stimulated the retention of both plasma triglyceride-derived FA and plasma albumin-bound FA in the various white adipose tissues (WAT) but not in other tissues, including brown adipose tissue (BAT). Intracerebroventricular (ICV) administration of insulin induced a similar pattern of tissue-specific FA partitioning. This effect of ICV insulin administration was not associated with activation of the insulin signaling pathway in adipose tissue. ICV administration of tolbutamide, a K-ATP channel blocker, considerably reduced (during hyperinsulinemic-euglycemic clamp conditions) and even completely blocked (during ICV administration of insulin) WAT-specific retention of FA from plasma. This central effect of insulin was absent in CD36-deficient mice, indicating that CD36 is the predominant FA transporter in insulin-stimulated FA retention by WAT. In diet-induced insulin-resistant mice, these stimulating effects of insulin (circulating or ICV administered) on FA retention in WAT were lost. In conclusion, in insulin-sensitive mice, circulating insulin stimulates tissue-specific partitioning of plasma-derived FA in WAT in part through activation of K ATP channels in the CNS. Apparently, circulating insulin stimulates fatty acid uptake in WAT but not in BAT, directly and indirectly through the CNS.-Coomans, C. P., J. J. Geerling, B. Guigas, A. M. van den Hoek, E. T. Parlevliet, D. M. Ouwens, H. Pijl, P. J. Voshol, P. C. N. Rensen, L. M. Havekes, and J. A. Romijn. Circulating insulin stimulates fatty acid retention in white adipose tissue via K-ATP channel activation in the central nervous system only in insulin-sensitive mice. J. Lipid Res. 2011. 52: 1712-1722. Show less
Chen, W.J.Y.; Greulich, S.; Rijzewijk, L.J.; Jonker, J.T.; Meer, R.W. van der; Lamb, H.J.; ... ; Diamant, M. 2011
CONTEXT Cranial radiotherapy is an important cause of hypopituitarism. The prevalence of hypopituitarism varies considerably between studies. OBJECTIVE We conducted a systematic review and meta... Show moreCONTEXT Cranial radiotherapy is an important cause of hypopituitarism. The prevalence of hypopituitarism varies considerably between studies. OBJECTIVE We conducted a systematic review and meta-analysis of reported prevalences of hypopituitarism in adults radiated for nonpituitary tumors. DATA SOURCES We searched PubMed, EMBASE, Web of Science, and the Cochrane Library to identify potentially relevant studies. STUDY SELECTION Studies were eligible for inclusion with the following criteria: 1) cranial radiotherapy for nonpituitary tumors and/or total body irradiation for hematological malignancies; 2) adult population (>18 yr old); and 3) report on endocrine evaluation. DATA EXTRACTION Data review was done by two independent reviewers. Besides extraction of baseline and treatment characteristics, also endocrine tests, definitions, and cutoff values used to define pituitary insufficiency were extracted. RESULTS Eighteen studies with a total of 813 patients were included. These included 608 patients treated for nasopharyngeal cancer (75%) and 205 for intracerebral tumors. The total radiation dose ranged from 14 to 83 and 40 to 97 Gy for nasopharyngeal and intracerebral tumors, respectively. The point prevalence of any degree of hypopituitarism was 0.66 [95% confidence interval (CI), 0.55-0.76]. The prevalence of GH deficiency was 0.45 (95% CI, 0.33-0.57); of LH and FSH, 0.3 (95% CI, 0.23-0.37); of TSH, 0.25 (95% CI, 0.16-0.37); and of ACTH, 0.22 (95% CI, 0.15-0.3), respectively. The prevalence of hyperprolactinemia was 0.34 (95% CI, 0.15-0.6). There were no differences between the effects of radiotherapy for nasopharyngeal vs. for intracerebral tumors. CONCLUSION Hypopituitarism is prevalent in adult patients after cranial radiotherapy for nonpituitary tumors. Therefore, all patients treated by cranial radiotherapy should have structured periodical assessment of pituitary functions. Show less
