Ketamine modulates hippocampal neurochemistry and functional connectivity: a combined magnetic resonance spectroscopy and resting-state fMRI study in healthy volunteers.

A growing body of evidence suggests glutamate excess in schizophrenia and that N-methyl-d-aspartate receptor (NMDAR) hypofunction on γ-aminobutyric acid (GABA) interneurons disinhibiting pyramidal cells may be relevant to this hyperglutamatergic state. To better understand how NMDAR hypofunction affects the brain, we used magnetic resonance spectroscopy and resting-state functional magnetic resonance imaging (MRI) to study the effects of ketamine on hippocampal neurometabolite levels and functional connectivity in 15 healthy human subjects. We observed a ketamine-induced increase in hippocampal Glx (glutamate+glutamine; F=3.76; P=0.04), a decrease in fronto-temporal (t=4.92, PFDR<0.05, kE=2198, x=-30, y=52, z=14) and temporo-parietal functional connectivity (t=5.07, PFDR<0.05, kE=6094, x=-28, y=-36, z=-2), and a possible link between connectivity changes and elevated Glx. Our data empirically support that hippocampal glutamatergic elevation and resting-state network alterations may arise from NMDAR hypofunction and establish a proof of principle whereby experimental modelling of a disorder can help mechanistically integrate distinct neuroimaging abnormalities in schizophrenia.

[The immune system and Alzheimer's disease]. / Het immuunsysteem en de ziekte van Alzheimer.

BACKGROUND: It has still not been established unequivocally whether vascular risk factors and inflammatory reactions, determined by heredity, are a cause or a result of Alzheimer's disease AIM: If the offspring of parents with AD have more risk factors and more frequent and severe inflammatory reactions than the offspring of parents without AD , this argues strongly in favor of a causal relationship between vascular risk factors, a pro-inflammatory cytokine response and AD. AIM: To determine whether the offspring of parents with ad have more risk factors and more frequent and severe inflammatory reactions than the offspring of parents without ad. method Vascular risk-factors, pro-inflammatory cytokines and the apoe genotype were determined in 206 offspring of parents with ad and in 200 offspring of parents without AD. RESULTS: Offspring of parents with ad carried more apoe epsilon4 than offspring of parents without ad (47% vs 21%). Middle-aged offspring of parents with a history of ad also had higher blood pressure and a greater atherosclerotic burden than the offspring of parents without AD. Also their response to the pro-inflammatory cytokine was significantly higher. CONCLUSION: Hypertension and an inherited pro-inflammatory cytokine profile in middle age are early risk factors that contribute to the development of ad in old age. Offspring with a parental history of AD should therefore be offered screening and treatment for hypertension and have their blood pressure checked so that the development of AD in old age can be prevented.

Menopause impacts the relation of plasma adiponectin levels with the metabolic syndrome.

OBJECTIVE: Plasma adiponectin is negatively correlated with metabolic syndrome (MetS) components obesity and insulin sensitivity. Here, we set out to evaluate the effect of menopause on the association of plasma adiponectin with MetS. DESIGN: Data on plasma adiponectin and MetS were available from 2256 individuals participating in the Erasmus Rucphen Family study. Odds ratios for MetS were calculated by logistic regression analysis using plasma adiponectin quartiles. The discriminative accuracy of plasma adiponectin for MetS was determined by calculating the area under the curve (AUC) of receiver operator. Analyses were performed in women and men, pre- and postmenopausal women and younger and older men. RESULTS: Virtually all determinants of MetS differed significantly between groups. Low plasma adiponectin showed the highest risk for MetS in postmenopausal women (odds ratio = 18.6, 95% CI = 7.9-44.0). We observed a high discriminative accuracy of age and plasma adiponectin for MetS not only in postmenopausal women (AUC = 0.76) but also in other subgroups (AUC from 0.67 to 0.87). However, in all groups, the discriminative accuracy of age and body mass index (BMI) for MetS was similar to the discriminative accuracy of age and plasma adiponectin. CONCLUSIONS: Low plasma levels of adiponectin are associated with increased prevalence of MetS, especially in postmenopausal women. Age and BMI have similar discriminatory accuracies for presence of MetS when compared with age and plasma adiponectin. Thus, we conclude that the association of plasma adiponectin with MetS is significantly affected by menopause but challenge the additional value of adiponectin for the discriminatory accuracy for presence of MetS.

Low innate production of interleukin-1beta and interleukin-6 is associated with the absence of osteoarthritis in old age.

OBJECTIVE: We investigated whether innate differences in cytokine response were associated with the absence of osteoarthritis (OA) in old age. DESIGN: In 82 participants from a cross-sectional birth cohort, radiographs of hands, hips and knees were taken at the age of 90 years. OA was defined as a Kellgren-Lawrence score of at least two. "Free from OA" was defined at patient level as absence of hip and knee OA, and presence of OA in maximally two hand joints. The innate cytokine response was determined in whole-blood samples upon stimulation with lipopolysaccharide. Logistic regression analyses were used to investigate associations between absence of OA in relation to tertiles of interleukin (IL)-1beta, IL-6, tumor necrosis factor (TNF)-alpha, IL-1 receptor antagonist (RA) and IL-10. Adjustments were made for gender and body mass index. RESULTS: Sixteen percent of the participants were "free from OA". Subjects in the lowest tertile of Il-1beta production had a 11-fold increased chance to be free of OA [odds ratio (OR) 11.3, confidence intervals (CI) 95% 1.1-115.9], subjects in the lowest tertile of IL-6 production had an almost 7-fold increased chance to be free of OA (OR 6.7, 95% CI 1.1-41.2). Absence of hand OA was associated with low innate production of IL-6 and IL-1RA, absence of hip OA was associated with low innate IL-1beta production. No associations were found for TNF-alpha and IL-10. CONCLUSIONS: Low innate capacity to produce the pro-inflammatory cytokines IL-1beta and IL-6 is associated with the absence of OA in old age.

Growth hormone and ghrelin secretion are associated with clinical severity in Huntington's disease.

BACKGROUND AND PURPOSE: Huntington's disease (HD) is a fatal hereditary neurodegenerative disorder caused by an increased CAG repeat size in the huntingtin gene. Apart from neurological impairment, the disease is also accompanied by progressive weight loss, abnormalities in glucose homeostasis and a higher prevalence of diabetes mellitus, which may partly be caused by disturbed growth hormone (GH) and ghrelin secretion. Therefore, we aimed to perform a detailed analysis of GH and ghrelin secretion in HD patients in relation to clinical signs and symptoms. METHODS: In nine early-stage, medication-free HD patients and nine age-, gender- and body mass index-matched controls, we measured serum GH levels every 10 min for 24 h and assessed ghrelin response to food intake. Multi-parameter auto-deconvolution and approximate entropy analysis were applied to quantify basal, pulsatile, and total GH secretion rates as well as the regularity of GH secretion. RESULTS: We found no significant differences in GH and ghrelin secretion characteristics between HD patients and controls (total GH secretion: 137 +/- 36 vs. 181 +/- 43 mU/l/24 h, respectively; P = 0.439). However, in HD patients, both GH secretion and its irregularity as well as the degree of postprandial ghrelin suppression significantly increased with worsening motor and functional impairment (all P < 0.05). Moreover, postprandial ghrelin suppression also increased with decreasing body weight and higher CAG repeat number (both P < 0.05). CONCLUSIONS: These findings suggest changes in the regulation of GH and ghrelin secretion dynamics in early stage HD patients that could become more prominent in the later stages of the disease.

Performance of the whole-blood stimulation assay for assessing innate immune activation under field conditions.

Innate propensity of immune activation is reflected in production of pro- and anti-inflammatory cytokines upon stimulation of Toll-like receptors (TLR) in whole-blood stimulation assays. The validity of the whole-blood stimulation assay under field conditions has not been evaluated extensively. Here, we have determined correlation of individually repeated whole-blood stimulation assays in a field-study in Ghana and compared it with that of two Dutch populations performed under optimal conditions. We also examined cytokine production to various TLR-agonists in order to create an assay that would mimic general innate immune responses. Under field conditions repeated assessments of lipopolysaccharide-induced Tumor Necrosis Factor-alpha (TNFalpha) production were poorly correlated (r=0.15, p=0.087). Correlation was relatively high for production of Interleukin-10 (IL10) (r=0.48, p<0.001) and comparable to that observed in the Dutch population under optimal conditions. Combined stimulation with lipopolysaccharide and zymosan resulted in cytokine production profiles that were similar to that attained after stimulation with a mixed culture of bacteria. Here, we conclude that variation of a whole-blood assay performed in field setting is large in general but that production of IL10 seems to better reflect an innate pro- or anti-inflammatory tendency whereas production of TNFalpha may predominantly reflect recent immunological challenges. Furthermore, simultaneous stimulation of several Toll-like receptors may mimic general innate immune activation.

Effects of aspirin on serum C-reactive protein and interleukin-6 levels in patients with type 2 diabetes without cardiovascular disease: a randomized placebo-controlled crossover trial.

AIM: Low-grade inflammation plays a pivotal role in atherogenesis in type 2 diabetes. Next to its antithrombotic effects, several lines of evidence demonstrate anti-inflammatory properties of aspirin. We determined the effects of aspirin on inflammation - represented by C-reactive protein (CRP) and interleukin-6 (IL-6) - in type 2 diabetic subjects without cardiovascular disease and assessed differential effects of aspirin 300 mg compared with 100 mg. METHODS: A randomized, placebo-controlled, double-blind, crossover trial was performed in 40 type 2 diabetic patients. In two periods of 6 weeks, patients used 100 or 300 mg aspirin and placebo. Plasma CRP and IL-6 levels were measured before and after both periods. RESULTS: Use of aspirin resulted in a CRP reduction of 1.23 +/- 1.02 mg/l (mean +/- s.e.m.), whereas use of placebo resulted in a mean increase of 0.04 +/- 1.32 mg/l (P = 0.366). Aspirin reduced IL-6 with 0.7 +/- 0.5 pg/ml, whereas use of placebo resulted in a mean increase of 0.2 +/- 0.8 pg/ml (P = 0.302). There were no significant differences in effects on CRP and IL-6 between 100 and 300 mg aspirin. CONCLUSIONS: Our results indicate that a 6-week course of aspirin does not improve low-grade inflammation in patients with type 2 diabetes without cardiovascular disease, although a modest effect could not be excluded. No significant differential effects between aspirin 100 and 300 mg were found.

Plasma arginine vasopressin and atrial natriuretic peptide concentration in patients with hyponatremia at diagnosis and following treatment.

BACKGROUND: Much evidence for arginine vasopressin (AVP) and atrial natriuretic peptide (ANP) in the pathogenesis of hyponatremia in humans is based on single measurements. To study the roles of AVP and ANP in the pathogenesis and recovery of hyponatremia, sequential measurements of ANP and AVP were taken during treatment in a group of hyponatremic patients with different etiologies. METHODS: Consecutive adult patients with hyponatremia (serum Na <130 mmol/l) and healthy controls were studied. Volume status was determined by clinical and laboratory criteria. Plasma AVP and ANP, fractional sodium excretion, and urine osmolality were determined daily until serum Na was above 135 mmol/l or for at most 7 days. RESULTS: A total of 16 controls and 40 hyponatremic patients (12 normovolemic, 9 hypervolemic, and 19 hypovolemic) were studied. Patients' plasma AVP on the first day [1.0 (0.3-2.3) ng/l] and on the last day [1.1 (0.3-2.5) ng/l] of the study did not differ from that of controls [0.7 (0.5-1.0) ng/l]. Serum sodium concentration increased significantly in patients between the first and the last day. Patients had significantly lower ANP concentrations, both on the first day [25 (15-46) ng/l] and on the last day [29 (17-46) ng/l], than controls [41 (28-51) ng/l]. Plasma AVP was elevated relative to serum osmolality on the first day and to a lesser extent on the last day of the study. CONCLUSIONS: AVP is inappropriately high in a majority of hyponatremic patients. Plasma AVP and ANP concentrations do not change during treatment in hyponatremic patients despite a significant increase in serum osmolality. A low ANP concentration in clinically normovolemic and hypovolemic patients indicates volume depletion, which may lead to baroreceptor-stimulated AVP secretion.

GH deficiency in patients irradiated for acromegaly: significance of GH stimulatory tests in relation to the 24 h GH secretion.

BACKGROUND: Radiotherapy for pituitary adenomas frequently leads to GH deficiency (GHD). The characteristics of GH secretion in GHD induced by postoperative radiotherapy for acromegaly are not known. HYPOTHESIS: In the long term, stimulated and spontaneous GH release is not different between patients with GHD treated by postoperative radiotherapy for acromegaly or for other pituitary adenomas. DESIGN/SUBJECTS: We compared the characteristics of basal and stimulated GH secretion in patients with GHD, who had previously received adjunct radiotherapy after surgery for GH-producing adenomas (n=10) vs for other pituitary adenomas (n=10). All patients had a maximal GH concentration by insulin tolerance test (ITT) of 3 microg/l or less, compatible with severe GHD. Mean time after radiation was 17 and 18.7 years, respectively. Stimulated GH release was also evaluated by infusion of growth hormone-releasing hormone (GHRH), GHRH-arginine and arginine, and spontaneous GH by 10 min blood sampling for 24 h. Pulse analyses were performed by Cluster and approximate entropy. OUTCOMES: There were no differences between both patient groups in stimulated GH concentrations in any test. Spontaneous GH secretion was not different between both patient groups, including basal GH release, pulsatility and regularity. Pulsatile secretion was lost in two acromegalic and three non-acromegalic patients. Insulin-like growth factor-I (IGF-I) was below -2 s.d. score in nine patients in each group. CONCLUSION: Acromegalic patients treated by surgery and postoperative radiotherapy with an impaired response to the ITT do not differ, in the long term, in GH secretory characteristics from patients treated similarly for other pituitary tumors with an impaired response to the ITT. The ITT (or the GHRH-arginine test) is therefore reliable in establishing the diagnosis of GHD in patients treated for acromegaly by surgery and radiotherapy.

[Thyroid function, activities of daily living and survival in extreme old age: the 'Leiden 85-plus Study']. / Schildklierfunctie, dagelijks functioneren en overleving van de oudste ouderen; de 'Leiden 85-plus Studie'.

OBJECTIVE: To determine the relationship between differences in thyroid function, changes in the activities of daily living and survival in the extremely-old segment of the general population in order to see whether screening for and treatment of subclinical thyroid-function disorders in the elderly will have a positive effect. DESIGN: Prospective observational population study among 85-year-olds. METHOD: As part of the 'Leiden 85-plus Study', all persons were followed who had their 85th birthday during the period from 1 September 1997 to 31 August 1999 (average length of time followed: 3.7 years; SD: 1.4). There were 558 participants. The thyroid function of these subjects was determined and the limitations in the activities of daily living, depressive symptoms, cognitive function and mortality were recorded annually. RESULTS: At the age of 85, there was no relation between the serum levels of thyroid-stimulating hormone (TSH) or free thyroxine (FT4) and limitations in the activities of daily living, the occurrence of depressive symptoms and cognitive deterioration. Neither was any relationship found during the period of follow-up. A higher TSH-level was associated with a lower mortality, even after correction for the differences in performance and health during the base measurement (mortality risk: 0.77 per SD-increase in TSH; 95% CI: 0.63-0.94). The mortality risk per SD-increase in FT4 was 1.16 (95% CI: 1.04-1.30). CONCLUSION: From the age of 85, there was no relationship between thyroid function and limitations in the activities of daily living, the occurrence of depressive symptoms or a deterioration in cognitive functions. Moreover, elderly persons with a less active thyroid gland lived longer. This raises the question whether the screening for and treatment of subclinical thyroid-function disorders in persons of extreme old age, as recommended, will have any positive effects.

In vivo insulin responsiveness for glucose uptake and production at eu- and hyperglycemic levels in normal and diabetic rats.

UNLABELLED: Whole body glucose uptake (BGU) and hepatic glucose production (HGP) at maximal plasma insulin concentrations (+/- 5000 microU/ml) were determined by eu- (EC) (6 mM) and hyperglycemic (HC) (20 mM) clamps (120 min), combined with [3-3H]glucose infusion, in normal and streptozotocin-treated (65 mg/kg) 3-day diabetic, conscious rats. In normal rats, during EC, BGU was 12.4 +/- 0.4 mg/min and during HC, when urinary glucose loss was 0.54 +/- 0.09 mg/min, BGU was 25.5 +/- 1.6 mg/min. However, throughout the final 60 min of HC, glucose infusion rate (GIR) was not constant but a linear decline in time (r = -0.99) of 17%, P less than 0.0001, was observed indicating a hyperglycemia-induced desensitization process. In diabetic rats, during EC, BGU was 7.7 +/- 0.3 mg/min and during HC, BGU was 15.5 +/- 1.4 mg/min. Throughout the final 60 min of HC, GIR was constant, suggesting that the hyperglycemia-induced desensitization process was already completed. In normal and diabetic rats, HGP was similar: during EC 0.2 +/- 0.5 mg/min and 0.1 +/- 0.5 mg/min, and during HC 0.4 +/- 0.4 mg/min and 0.5 +/- 0.6 mg/min, respectively. In vitro adipocyte and muscle insulin receptor studies showed normal to increased receptor number and increased receptor autophosphorylation in diabetic compared to normal rats. IN CONCLUSION: (i) 3-day diabetic rats show, at maximal plasma insulin concentrations, insulin resistance to BGU, but not to HGP. The resistance to BGU is equally present (reduction of 38%) at eu- and hyperglycemic levels as compared to normal rats. (ii) 3-day diabetic rats reveal no defect in adipocyte and muscle insulin receptor function. These data indicate that the diabetes induced insulin resistance for BGU is at the post-receptor level and due to a decreased maximal capacity (Vmax) for glucose uptake, with no change in affinity, or Km.

Irregular and frequent cortisol secretory episodes with preserved diurnal rhythmicity in primary adrenal Cushing's syndrome.

To evaluate the pathophysiology of altered cortisol secretion in patients with primary adrenal hypercortisolism, cortisol secretion was investigated in 12 patients, seven with a unilateral adenoma and five with ACTH-independent macronodular adrenal hyperplasia compared with age- and gender-matched controls and with patients with pituitary-dependent hypercortisolism. Pulsatile secretion was increased 2-fold (P = 0.04), attributable to increased event frequency (P = 0.002). All patients showed a significant diurnal rhythm with a delay in phase shift of 3 h (P = 0.01). Approximate entropy ratio, a feedback-sensitive measure, was increased compared with controls (P = 0.00003) but similar to that of pituitary-dependent hypercortisolism (P = 0.77), denoting loss of autoregulation. Cortisol burst-mass tended to be smaller in patients with ACTH-independent macronodular adrenal hyperplasia than in unilateral adenoma (P = 0.06). In conclusion, increased cortisol secretion in patients with primary adrenal Cushing's syndrome is caused by amplified pulsatile secretion via event frequency modulation. We speculate that partial preservation of secretory regularity and diurnal rhythmicity point to incomplete autonomy of these tumors.

Reversible diastolic dysfunction after long-term exogenous subclinical hyperthyroidism: a randomized, placebo-controlled study.

BACKGROUND: Subclinical hyperthyroidism has been reported to affect systolic and diastolic cardiac function. However, the reversibility of these effects is not well established. OBJECTIVE: Our objective was to investigate the presence and reversibility of cardiac abnormalities in patients with long-term exogenous subclinical hyperthyroidism. DESIGN: We conducted a prospective, single-blinded, placebo-controlled randomized trial of 6 months duration with two parallel groups. SETTING: The study occurred at the Leiden University Medical Center, a tertiary referral center for thyroid carcinoma. PATIENTS: As a model for subclinical hyperthyroidism, 25 patients with a history of differentiated thyroid carcinoma with more than 10 yr of TSH suppressive therapy with L-T4 were studied. INTERVENTIONS: L-T4 dose was replaced by study medication containing L-T4 or placebo. Medication was titrated in a single-blinded fashion to establish continuation of TSH suppression (low-TSH group) or euthyroidism (euthyroid group). MEASUREMENTS: We assessed serum levels of free T4 and TSH and used echo Doppler cardiography including tissue Doppler to establish left ventricular (LV) dimensions and function as well as diastolic function. Baseline echocardiography data were compared with 24 controls. RESULTS: There were no differences in baseline cardiac parameters and TSH levels between the two groups. Although mean LV mass index was increased as compared with 24 controls, only four patients had LV hypertrophy at baseline. This was not improved by restoration of euthyroidism. At baseline, diastolic function was impaired in all patients as indicated by abnormal values for the peak flow of the early filling phase (E, 55.3 +/- 9.5 mm/sec), the ratio of E and the peak flow of the atrial filling phase (E/A ratio, 0.87 +/- 0.13), the early diastolic velocity obtained by tissue Doppler (E', 5.7 +/- 1.3 cm/sec), and the peak atrial filling velocity obtained by tissue Doppler (A', 6.8 +/- 1.4 cm/sec), prolonged E deceleration time (234 +/- 34 msec), and isovolumetric relaxation time (121 +/- 15 msec). After 6 months, significant improvements were observed in the euthyroid group in the E/A ratio (+41%; P < 0.001), E deceleration time (-18%; P = 0.006), isovolumetric relaxation time (-25%; P < 0.001), E' (+31%; P < 0.001), and the E'/A' ratio (+40%; P < 0.001). CONCLUSIONS: We conclude that prolonged subclinical hyperthyroidism is accompanied by diastolic dysfunction that is at least partly reversible after restoration of euthyroidism. Because isolated diastolic dysfunction may be associated with increased mortality, this finding is of clinical significance.

In vivo relationship between insulin clearance and action in healthy subjects and IDDM patients.

The relationship between plasma clearance rate of insulin (PCR) and insulin-stimulated glucose disposal was investigated in 15 healthy subjects and 30 insulin-dependent diabetes mellitus (IDDM) patients with the sequential euglycemic (5 mM) clamp technique (insulin infusion rates of 0.5, 1, 2, and 5 mU.kg-1.min-1 in 2-h steps). In IDDM patients, insulin-stimulated glucose disposal was decreased at low insulinemia (steps 1-3), whereas at maximal insulinemia (step 4), insulin action was normal. In the healthy subjects, strong positive correlations were found for PCR versus steady-state glucose infusion rate (SSGIR): r = 0.71 (P less than 0.005), 0.72 (P less than 0.005), 0.72 (P less than 0.005), and 0.78 (P less than 0.001) for steps 1-4, respectively. In contrast, in the IDDM patients, no relationship was observed: r = 0.01, -0.03, 0.06, and 0.01 (NS) for steps 1-4, respectively. In univariate analyses of PCR, no differences were found between patient subgroups with values for percentage of tracer binding below or above 5% or insulin-antibody-binding capacities and equilibrium constants below or above the median. In multiple regression models, adjusting for insulin antibodies, preceding glycemic control (HbA1 or fructosamine), and duration of IDDM, correlations for PCR versus SSGIR remained nonsignificant. In conclusion, insulin action is correlated to insulin clearance in healthy subjects, suggesting a functional relationship from an in vivo perspective. No such relationship was present in patients with IDDM, even after adjusting for insulin antibodies, preceding glycemic control, and duration of IDDM.

The effects of duct obliteration and of autotransplantation on the endocrine function of canine pancreatic segments.

This study in dogs addresses itself to the endocrine function of the duct-obliterated left pancreatic lobe (body and tail), which is the portion of the pancreas used for segmental transplantation. The endocrine function was determined with intravenous (i.v.) glucose tolerance tests and expressed in K-values and insulin-response curves. Duct obliteration of the nontransplanted left lobe was associated with normal K-values in the presence of the unmodified right lobe, but with reduced K-values in its absence. Removal of the left lobe while leaving the right lobe untouched was not associated with reduced K-values, but duct obliteration of the whole pancreas was. When the duct-obliterated left lobe was transplanted onto the iliac vessels (segmental autografts), K-values were reduced when compared with the unmodified situation, but were significantly higher than with nontransplanted, duct-obliterated left lobes. Insulin-response curves of nontransplanted, duct-obliterated segments differed both qualitatively and quantitatively from the unmodified situation, but insulin-response curves of duct-obliterated segmental autografts showed only qualitative differences with the unmodified situation. It is concluded that duct obliteration rather than the absence of the right lobe is the predominant cause of reduced glucose tolerance with duct-obliterated left pancreatic lobes. It is suggested that duct obliteration affects the endocrine pancreas both in a qualitative and quantitative fashion. The qualitative effect is similarly demonstrable with segmental autografts and nontransplanted segments, but the quantitative effect is largely dissolved with autografting by virtue of caval as opposed to portal venous drainage.

Crossover study on effects of duct obliteration, celiac denervation, and autotransplantation on glucose- and meal-stimulated insulin, glucagon, and pancreatic polypeptide levels.

In segmental-pancreas transplantation the body and tail of the pancreas are used. In an experimental study in dogs, the effects of sequentially conducted removal of the right pancreatic lobe (pancreatic head), duct obliteration, celiac denervation, and autotransplantation were studied according to a crossover design. Two groups of dogs were studied. In both groups the right lobe of the pancreas was removed at primary operation, and the duct of the transected left lobe (body and tail) was injected with fibrin sealant. The left lobe was completely freed from surrounding tissue (celiac denervation) in group 1 (n = 9), and the innervation of the left lobe was left intact in group 2 (n = 8). At 12 wk, two dogs in group 1 and four dogs in group 2 underwent successful autotransplantation of the left lobe. Pancreatic hormone secretion was stimulated by intravenous glucose injection and test-meal administration before primary operation and at 11 and 18 wk thereafter. The combination of removal of the right lobe and duct obliteration led to a decrease in glucose tolerance at both stimulation tests and a decrease in peripheral insulin release after intravenous glucose injection. At test-meal administration, no change in insulin and glucagon levels was demonstrated. If celiac denervation was added, similar results were obtained based on the understanding that the peripheral insulin release after the test meal was significantly elevated. Meal-stimulated pancreatic polypeptide response was abolished in both groups. Removal of the right lobe leads to parasympathic denervation of the left lobe, and celiac denervation mainly interferes with alpha-adrenergic innervation.(ABSTRACT TRUNCATED AT 250 WORDS)

Contribution of partial pancreatectomy, systemic hormone delivery, and duct obliteration to glucose regulation in canine pancreas. Importance in pancreas transplantation.

Our aim was to isolate and determine the contribution of partial pancreatectomy, systemic delivery of pancreatic hormones, and duct obliteration to glucose regulation after segmental pancreas transplantation in dogs. Fasting, postprandial, and intravenous glucose-stimulated glucose, insulin, glucagon, pancreatic polypeptide (PP), and cholecystokinin (CCK) and intravenous bombesin-stimulated PP levels were studied in beagles at three successive intervals in a crossover design. The first was 6 wk after partial (approximately 70%) pancreatectomy with intact regular enteric exocrine drainage from the duodenal pancreatic remnant, the next was 2 wk after venous transposition with systemic delivery of pancreatic hormones, and the third was 6 wk after in situ duct obliteration of the remnant. With partial pancreatectomy, K values were modestly diminished (30%), and a concomitant reduction of second-phase intravenous glucose-stimulated insulin release was observed. Other parameters were not significantly affected. Venous transposition doubled peripheral plasma levels of insulin under all conditions. Fasting glucose, PP, and CCK levels decreased slightly. Other parameters were not affected. Duct obliteration of the systemic draining pancreatic remnants seriously impaired glucose sensitivity, resulting in a 50% reduction of K values and fasting and sustained postprandial hyperglycemia (approximately 8 mM) and a 70-50% reduction (acute and overall responses, respectively) of intravenous glucose-stimulated insulin. Fasting hormone and postprandial insulin, glucagon, and CCK levels were not affected. The postprandial PP response was severely reduced, and bombesin-stimulated PP release was abolished by duct obliteration. We conclude that histological changes associated with duct obliteration are the major determinants of glucose regulation in segmental pancreas transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased prevalence of catecholamine excess and phaeochromocytomas in a well-defined Dutch population with SDHD-linked head and neck paragangliomas.

OBJECTIVE: The aim of this study was to identify the prevalence of catecholamine excess and phaeochromocytomas in a well-defined population of people with hereditary head and neck paragangliomas. METHODS: We studied in a prospective follow-up protocol all consecutive patients referred to the Department of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands with documented head and neck paragangliomas and either a positive family history for paragangliomas or a proven SDHD gene mutation. Initial analysis included medical history, physical examination and the measurement of excretion of catecholamines in two 24-h urine collections. In the case of documented catecholamine excess iodinated meta-iodobenzylguanidine (123I-MIBG) scintigraphy and magnetic resonance imaging were done. RESULTS: Between 1988 and 2003, 40 consecutive patients (20 male and 20 female) with documented head and neck paragangliomas were screened. Biochemical screening revealed urinary catecholamine excess in 15 patients (37.5%). In nine of these 15 patients a lesion was found by 123I-MIBG scintigraphy. Exact localization by magnetic resonance imaging revealed phaeochromocytomas in seven of the 15 patients. One of the nine patients had an extra-adrenal paraganglioma. Histopathological examination in a subset of tumors displayed loss of heterozygosity of the wild-type SDHD allele in all cases. CONCLUSIONS: The prevalence of catecholamine excess (37.5%) and phaeochromocytomas (20.0%) is high in patients with familial head and neck paragangliomas. Therefore, patients with hereditary head and neck paragangliomas require lifelong follow up by biochemical testing for catecholamine excess.

The relative contribution of insulin secretory capacity, insulin action, and incretins to metabolic control after islet transplantation in dogs.

Adequate metabolic control is central to the concept of islet transplantation, but has received limited attention. We studied metabolic control in 8 dogs at 6-9 months after intrasplenic autografting of approximately 25% of the normal mass islets--as compared to 30 controls. A similar posttransplant reduction to approximately 25% of the insulin secretory capacity as assessed by intravenous arginine stimulation during 35 mM glucose clamps, mirrored the reduction of the islet mass. Postprandially, in contrast, the insulin response had increased to 140% in the islet recipients--with a concomitant rise of glycemia to approximately 8.5 mM. Posttransplant, the insulin secretory capacity correlated both with the index of insulin action (which averaged 55% of the normal value) as assessed by euglycemic hyperinsulinemic clamps, and--inverse--with the postprandial glucose excursions. Because insulin action did not correlate with postprandial glucose, the insulin secretory capacity appears to be the primary determinant of the impaired glucose tolerance. Marked postprandial hyperglucagonemia, and a virtually absent pancreatic polypeptide response in the grafted animals, may also have contributed to the impaired glucose tolerance. Posttransplant, infusion of a physiological dose of the gut hormone glucagon-like peptide-1 during 8.5 mM glucose clamps--mimicking the postprandial glycemia--potentiated glucose-stimulated insulin 175%. Thus, after transplantation of a suboptimal islet mass, postprandial glucose excursions are restrained by hyperglycemic potentiation of the entero-insular axis, which may account for the difference in the insulin response to the intravenous and oral challenges. Because, the insulin secretory capacity reflects the islet mass and appears to be the major determinant of glucoregulation, transplantation of a larger islet mass may allow near-normal glycemic control.

Increased insulin action and clearance in hyperthyroid newly diagnosed IDDM patient. Restoration to normal with antithyroid treatment.

In a patient with hyperthyroidism and newly diagnosed insulin-dependent diabetes mellitus (IDDM), insulin action and clearance were studied before the initiation of antithyroid treatment and at 3-mo intervals for 1 yr thereafter. The sequential euglycemic clamp technique (5 mM) was used with insulin infusion rates of 0.5, 1.0, 2.0, and 5.0 mU.kg-1.min-1 in four steps of 2 h. The data were compared with nine control subjects and nine newly diagnosed euthyroid IDDM patients treated with insulin for 0.5 mo. Insulin sensitivity was increased in the patients (ED50 40 vs. 52 mU/L, range 43-70, in controls and 70 mU/L, range 59-120, in IDDM subjects). Insulin responsiveness was markedly elevated; the steady-state glucose infusion rate (SSGIR) of step 4 was 104 vs. 64 mumol.kg-1.min-1 (range 50-79) in controls and 61 mumol.kg-1.min-1 (range 47-69) in IDDM subjects. Insulin clearance was elevated in all steps (1-3, 20-23 vs. 9-15 ml.kg-1.min-1; 4, 18 vs. 6-12 ml.kg-1.min-1 in control and IDDM subjects). Parallel to the normalization of thyroid metabolism, insulin action (ED50 60 mU/L, SSGIR in step 4, 51 mumol.kg-1.min-1) and insulin clearance (steps 1-3, 11-14 ml.kg-1.min-1; step 4, 7 ml.kg-1.min-1) returned to the normal range in 6 mo. Both remained within the normal range until 12 mo. In the patient with newly diagnosed IDDM, the initial marked increases of insulin action and clearance were due to coexistent hyperthyroidism. With the amelioration of the hyperthyroid state, both processes became normal. The parallelism between insulin action and clearance suggests a functional relationship.