[The relationship of mental health providers with health insurers; an exploration]. / De ggz in relatie tot zorgverzekeraars; een verkenning.

BACKGROUND: In 2020, Zorgverzekeraars Nederland (ZN), the umbrella organization of nine health insurers in The Netherlands. presented a vision of the future of mental health care in the Netherlands in ‘De GGZ in 2025. Vergezicht op de geestelijke gezondheidszorg’ (‘Outlook on mental health care’). This document can be seen as marking the fact that key stakeholders share a common vision on the future of the GGZ in the Netherlands. Contracting care is often difficult. The tension between providing quality and sufficient care and available funding leads to friction. Congruence in vision, goals and practices are important conditions for adequate relationship building. Does the vision document contribute to this? AIM: To discuss the experiences of mental health care administrators and health insurers in contracting and collaboration. METHOD: Conducting interviews with both directors of mental health institutions and the strategic (policy) advisors of health insurers. In the approach we used the salience model. RESULTS: The relationship between mental health care administrators and health insurers is perceived to be distrustful and complex, and has deteriorated slightly in 2021 compared to 2019. Perceived power, legitimacy and urgency affect the relationship. Almost all health insurers are characterized as dominant stakeholders based on the salience model. Both parties are open to improving the relationship, which requires more transparency and mutual understanding. CONCLUSION: With the supported content of the vision document, there is to some extent shared governance. The change steps (shared innovation) considered desirable will be promoted by partly granting the intended benefits to each other (shared savings).

Hepatic ChREBP orchestrates intrahepatic carbohydrate metabolism to limit hepatic glucose 6-phosphate and glycogen accumulation in a mouse model for acute Glycogen Storage Disease type Ib.

OBJECTIVE: Carbohydrate Response Element Binding Protein (ChREBP) is a glucose 6-phosphate (G6P)-sensitive transcription factor that acts as a metabolic switch to maintain intracellular glucose and phosphate homeostasis. Hepatic ChREBP is well-known for its regulatory role in glycolysis, the pentose phosphate pathway, and de novo lipogenesis. The physiological role of ChREBP in hepatic glycogen metabolism and blood glucose regulation has not been assessed in detail, and ChREBP's contribution to carbohydrate flux adaptations in hepatic Glycogen Storage Disease type 1 (GSD I) requires further investigation. METHODS: The current study aimed to investigate the role of ChREBP as a regulator of glycogen metabolism in response to hepatic G6P accumulation, using a model for acute hepatic GSD type Ib. The immediate biochemical and regulatory responses to hepatic G6P accumulation were evaluated upon G6P transporter inhibition by the chlorogenic acid S4048 in mice that were either treated with a short hairpin RNA (shRNA) directed against ChREBP (shChREBP) or a scrambled shRNA (shSCR). Complementary stable isotope experiments were performed to quantify hepatic carbohydrate fluxes in vivo. RESULTS: ShChREBP treatment normalized the S4048-mediated induction of hepatic ChREBP target genes to levels observed in vehicle- and shSCR-treated controls. In parallel, hepatic shChREBP treatment in S4048-infused mice resulted in a more pronounced accumulation of hepatic glycogen and further reduction of blood glucose levels compared to shSCR treatment. Hepatic ChREBP knockdown modestly increased glucokinase (GCK) flux in S4048-treated mice while it enhanced UDP-glucose turnover as well as glycogen synthase and phosphorylase fluxes. Hepatic GCK mRNA and protein levels were induced by shChREBP treatment in both vehicle- and S4048-treated mice, while glycogen synthase 2 (GYS2) and glycogen phosphorylase (PYGL) mRNA and protein levels were reduced. Finally, knockdown of hepatic ChREBP expression reduced starch domain binding protein 1 (STBD1) mRNA and protein levels while it inhibited acid alpha-glucosidase (GAA) activity, suggesting reduced capacity for lysosomal glycogen breakdown. CONCLUSIONS: Our data show that ChREBP activation controls hepatic glycogen and blood glucose levels in acute hepatic GSD Ib through concomitant regulation of glucose phosphorylation, glycogenesis, and glycogenolysis. ChREBP-mediated control of GCK enzyme levels aligns with corresponding adaptations in GCK flux. In contrast, ChREBP activation in response to acute hepatic GSD Ib exerts opposite effects on GYS2/PYGL enzyme levels and their corresponding fluxes, indicating that GYS2/PYGL expression levels are not limiting to their respective fluxes under these conditions.

Acute sub-diaphragmatic anterior vagus nerve stimulation increases peripheral glucose uptake in anaesthetized rats.

The sub-diaphragmatic vagus innervates various organs involved in the control of glucose homeostasis including the liver, pancreas and the intestines. In the current study, we investigated the effect of acute electrical stimulation of the anterior trunk of the sub-diaphragmatic vagus on glucose fluxes in anaesthetized adult male rats. After overnight fast, rats underwent either vagus nerve stimulation (VNS+, n = 11; rectangular pulses at 5 Hz, 1.5 mA, 1 msec pulse width) or sham stimulation (VNS-; n = 11) for 120 min under isoflurane anesthesia. Before stimulation, the rats received an i.v. bolus of 1 mL/kg of a sterilized aqueous solution containing 125 mg/mL of D-[6,6-2H2] glucose. Endogenous glucose production (EGP) and glucose clearance rate (GCR) were calculated by kinetic analysis from the wash-out of injected D-[6,6-2H2]glucose from the circulation. VNS+ resulted in lower glucose levels compared to the VNS- group (p < 0.05), with similar insulin levels. EGP was similar in both groups, but the GCR was higher in the VNS+ group compared to the VNS- group (p < 0.001). Circulating levels of the sympathetic transmitter norepinephrine were reduced by VNS+ relative to VNS- treatment (p < 0.01). It is concluded that acute anterior sub-diaphragmatic VNS causes stimulation of peripheral glucose uptake, while plasma insulin levels remained similar, and this is associated with lower activity of the sympathetic nervous system.

Health care reform and financial crisis in the Netherlands: consequences for the financial arena of health care organizations.

Over the past decade, many health care systems across the Global North have implemented elements of market mechanisms while also dealing with the consequences of the financial crisis. Although effects of these two developments have been researched separately, their combined impact on the governance of health care organizations has received less attention. The aim of this study is to understand how health care reforms and the financial crisis together shaped new roles and interactions within health care. The Netherlands - where dynamics between health care organizations and their financial stakeholders (i.e., banks and health insurers) were particularly impacted - provides an illustrative case. Through semi-structured interviews, additional document analysis and insights from institutional change theory, we show how banks intensified relationship management, increased demands on loan applications and shifted financial risks onto health care organizations, while health insurers tightened up their monitoring and accountability practices towards health care organizations. In return, health care organizations were urged to rearrange their operations and become more risk-minded. They became increasingly dependent on banks and health insurers for their existence. Moreover, with this study, we show how institutional arenas come about through both the long-term efforts of institutional agents and unpredictable implications of economic and societal crises.

Power, legitimacy and urgency: Unravelling the relationship between Dutch healthcare organisations and their financial stakeholders.

Healthcare organisations rely on their financial stakeholders for capital to invest in state-of-the-art buildings, equipment, innovation and the delivery of healthcare services. Nevertheless, relations between healthcare organisations and their financial stakeholders have not been well studied. Here, we studied the relations between Dutch healthcare organisations and two of their main financial stakeholders (banks and health insurers) against the backdrop of system reforms and the financial crisis. We conducted a survey of healthcare executives to evaluate their relations with banks and health insurers in terms of power, legitimacy and urgency. These three attributes are based on the salience model of Mitchel, Agle and Wood (1997). We further tested for differences in power, legitimacy and urgency across organisational sector and size. The results showed that healthcare organisations value banks as legitimate stakeholders with a well-demarcated influence and a clear-cut function. The relationship with health insurers is more complex. Healthcare organisations experience considerable influence from health insurers but question the legitimacy of their claims. Since health insurers play a crucial role in the Dutch healthcare system, these findings question the workability of the relationship between healthcare organisations and health insurers and the position of health insurers in the overall healthcare sector. Our results are relevant to countries with public-private health systems and contribute to the development of the salience model by showing the individual value of stakeholder attributes and the relevance of context.

Evaluation of pressure-controlled mammography compression paddles with respect to force-controlled compression paddles in clinical practice.

OBJECTIVES: To reduce pain and discomfort associated with breast compression in mammography, a pressure-controlled compression paddle was recently introduced. The objective was to evaluate the pressure-controlled paddle by comparing it to the standard force-controlled paddle. METHODS: Differences of compressed breast thickness (CBT), compression force, compression pressure, and average glandular dose (AGD) between annual follow-up full-field digital mammography exams of 3188 patients were retrospectively examined. Two groups were compared: (1) force-force group (FF-group), both examinations were performed with the force-controlled paddle, and (2) force-pressure group (FP-group), only the follow-up examination was performed with the pressure-controlled paddle. In an additional group of patients, pain scores on a scale of 0 (no pain at all) to 10 (worst pain imaginable) were evaluated prospectively (n = 343) who were randomly assigned to either paddle. RESULTS: Median differences between follow-up exams in CBT, compression force, compression pressure, and AGD were for the FF- and FP-group respectively - 1.0 vs 0.0 mm (p < 0.001); 0.0 vs - 1.0 daN (p = 0.002); - 1.0 vs - 0.5 kPa (p = 0.005); and 0.05 vs - 0.02 mGy (p < 0.001). These differences were, although statistically significant, clinically non-relevant (defined as ΔCBT > ± 2 mm; Δforce > ± 2 daN; Δpressure > ± 1 kPa and ΔAGD > ± 0.1 mGy). The subanalysis dividing CBT into five categories revealed similar results. The median [interquartile range] pain scores were 6 [3, 7] and 5 [3, 7] for the force-controlled and pressure-controlled paddle, respectively, which was not significantly different (p = 0.113). CONCLUSIONS: We observed no clinically relevant differences in CBT, compression force, compression pressure, AGD, or pain score between the force- and pressure-controlled paddle. As such, we found no basis for preferring one paddle over the other. KEY POINTS: • The pressure-controlled paddle did not show any clinically relevant changes in breast compression parameters compared to the force-controlled paddle. • The pressure-controlled paddle did not lead to significant reduction in pain scores indicated by the patients compared to the force-controlled paddle. • A large variation in compression force and compression pressure was observed in mammography exams for the both the force- and pressure-controlled compression paddle.

Optimizing VAP scars after childhood cancer treatment: a pilot study.

PURPOSE: Majority of pediatric cancer patients are treated with chemotherapy using Venous Access Ports (VAP). However, after surgical removal of the VAP prominent scars often remain and standard care is lacking. METHODS: Patients (N = 20) who were willing to participate were included prior to surgical removal of their VAP. All patients were off therapy at time of VAP removal. Patients had the option to either choose from Dermatix®, meridian color therapy (MCT), or no additional treatment (NAT). Assessment of scars was done prior to and 3, 6, and 12 months after surgical VAP removal using Patient and Observer Scar Assessment Scales (POSAS) questionnaires. To identify whether Dermatix® or MCT is associated with better scar healing than without additional treatment, Mann-Whitney U tests were used. RESULTS: After 12 months of follow-up, both patients and dermatologists noted VAP scars had healed better after MCT compared to those without treatment (P = 0.010 for both POSAS patient and POSAS observer). No significant differences were observed between VAP scars after Dermatix® use and those with no treatment. CONCLUSIONS: Scar healing after MCT significantly improved, whereas Dermatix® treatment showed no significant differences compared to NAT. To translate this to daily care, a larger prospective study is needed to validate these findings.

NGS panel analysis in 24 ectopia lentis patients; a clinically relevant test with a high diagnostic yield.

BACKGROUND: Several genetic causes of ectopia lentis (EL), with or without systemic features, are known. The differentiation between syndromic and isolated EL is crucial for further treatment, surveillance and counseling of patients and their relatives. Next generation sequencing (NGS) is a powerful tool enabling the simultaneous, highly-sensitive analysis of multiple target genes. OBJECTIVE: The aim of this study was to evaluate the diagnostic yield of our NGS panel in EL patients. Furthermore, we provide an overview of currently described mutations in ADAMTSL4, the main gene involved in isolated EL. METHODS: A NGS gene panel was analysed in 24 patients with EL. RESULTS: A genetic diagnosis was confirmed in 16 patients (67%). Of these, four (25%) had a heterozygous FBN1 mutation, 12 (75%) were homozygous or compound heterozygous for ADAMTSL4 mutations. The known European ADAMTSL4 founder mutation c.767_786del was most frequently detected. CONCLUSION: The diagnostic yield of our NGS panel was high. Causative mutations were exclusively identified in ADAMTSL4 and FBN1. With this approach the risk of misdiagnosis or delayed diagnosis can be reduced. The value and clinical implications of establishing a genetic diagnosis in patients with EL is corroborated by the description of two patients with an unexpected underlying genetic condition.

Short-Course Radiotherapy Followed by Neoadjuvant Bevacizumab, Capecitabine, and Oxaliplatin and Subsequent Radical Treatment in Primary Stage IV Rectal Cancer: Long-Term Results of a Phase II Study.

BACKGROUND: In a Dutch phase II trial conducted between 2006 and 2010, short-course radiotherapy followed by systemic therapy with capecitabine, oxaliplatin, and bevacizumab as neoadjuvant treatment and subsequent radical surgical treatment of primary tumor and metastatic sites was evaluated. In this study, we report the long-term results after a minimum follow-up of 6 years. METHODS: Patients with histologically confirmed rectal adenocarcinoma with potentially resectable or ablatable metastases in liver or lungs were eligible. Follow-up data were collected for all patients enrolled in the trial. Overall and recurrence-free survival were calculated using the Kaplan-Meier method. RESULTS: Follow-up data were available for all 50 patients. After a median follow-up time of 8.1 years (range 6.0-9.8), 16 patients (32.0%) were still alive and 14 (28%) were disease-free. The median overall survival was 3.8 years (range 0.5-9.4). From the 36 patients who received radical treatment, two (5.6%) had a local recurrence and 29 (80.6%) had a distant recurrence. CONCLUSIONS: Long-term survival can be achieved in patients with primary metastatic rectal cancer after neoadjuvant radio- and chemotherapy. Despite a high number of recurrences, 32% of patients were alive after a median follow-up time of 8.1 years.

Maternal-fetal cholesterol transport in the second half of mouse pregnancy does not involve LDL receptor-related protein 2.

AIM: LDL receptor-related protein type 2 (LRP2) is highly expressed on both yolk sac and placenta. Mutations in the corresponding gene are associated with severe birth defects in humans, known as Donnai-Barrow syndrome. We here characterized the contribution of LRP2 and maternal plasma cholesterol availability to maternal-fetal cholesterol transport and fetal cholesterol levels in utero in mice. METHODS: Lrp2+/- mice were mated heterozygously to yield fetuses of all three genotypes. Half of the dams received a 0.5% probucol-enriched diet during gestation to decrease maternal HDL cholesterol. At E13.5, the dams received an injection of D7-labelled cholesterol and were provided with 1-13 C acetate-supplemented drinking water. At E16.5, fetal tissues were collected and maternal cholesterol transport and fetal synthesis quantified by isotope enrichments in fetal tissues by GC-MS. RESULTS: The Lrp2 genotype did not influence maternal-fetal cholesterol transport and fetal cholesterol. However, lowering of maternal plasma cholesterol levels by probucol significantly reduced maternal-fetal cholesterol transport. In the fetal liver, this was associated with increased cholesterol synthesis rates. No indications were found for an interaction between the Lrp2 genotype and maternal probucol treatment. CONCLUSION: Maternal-fetal cholesterol transport and endogenous fetal cholesterol synthesis depend on maternal cholesterol concentrations but do not involve LRP2 in the second half of murine pregnancy. Our results suggest that the mouse fetus can compensate for decreased maternal cholesterol levels. It remains a relevant question how the delicate system of cholesterol transport and synthesis is regulated in the human fetus and placenta.

Enhancement and extinction effects in surface-enhanced stimulated Raman spectroscopy.

We address the optical physics of surface-enhanced stimulated Raman spectroscopy (SESRS) from the microscopic to macroscopic scales to provide experimental design criteria in colloidal-suspension SESRS. The nanoparticles that provide local field enhancement also extinguish the Raman signal. We compute the total Raman signal detected from a suspension of Raman-active molecules and nanoparticles due to the cumulative effects of enhancement and extinction and find optimum operating parameters for pump frequency and nanoparticle concentration.

Gluteal blood flow and oxygenation during electrical stimulation-induced muscle activation versus pressure relief movements in wheelchair users with a spinal cord injury.

BACKGROUND: Prolonged high ischial tuberosities pressure (IT pressure), decreased regional blood flow (BF) and oxygenation (%SO2) are risk factors for developing pressure ulcers (PUs) in patients with spinal cord injury (SCI). Electrical stimulation (ES)-induced gluteal and hamstring muscle activation may improve pressure distribution by changing the shape of the buttocks while sitting and also increase BF and %SO2. OBJECTIVE: To compare acute effects of ES-induced gluteal and hamstring muscle activation with pressure relief movements (PRMs) on IT pressure, BF and %SO2. PARTICIPANTS AND METHODS: Twelve men with SCI performed PRMs - push-ups, bending forward and leaning sideward - and received surface ES (87±19 mA) to the gluteal and hamstring muscles while sitting in their wheelchair. Ischial tuberosities pressure was measured using a pressure mapping system; (sub)cutaneous BF and %SO2 were measured using reflection spectroscopy and laser Doppler, respectively. RESULTS: Compared with rest (156±26 mm Hg), IT pressure was significantly lower during all other conditions (push-ups 19±44; bending forward 56±33; leaning sideward 44±38; ES 67±45 mm Hg). For the whole group, all PRMs significantly augmented BF (+39 to -96%) and %SO2 (+6.0 to -7.9%-point), whereas ES-induced muscle activation did only for peak BF. In all, 63% of the participants showed an increased BF (average 52%) with ES. CONCLUSION: PRMs acutely reduced IT pressure and improved oxygenation and BF in SCI. The currently used ES method cannot replace PRMs, but it may be used additionally. ES-induced muscle activation is not as effective for acute pressure relief, but the frequency of stimulation is much higher than the performance of PRMs and can therefore be more effective in the long term.

The intensity of chair-assisted exercises in cognitively healthy older adults.

INTRODUCTION: The American College of Sports Medicine prescribes regular performance of at least moderate-intensity physical activity for healthy aging. This study examined whether 1 session of 30 min of chair-assisted exercises for the elderly meets this intensity criterion. METHOD: This cross-sectional study included 47 cognitively healthy volunteers (mean age 84 years). During the performance of 30 min of chair-assisted exercises the authors determined oxygen uptake (VO2), carbon dioxide production, heart rate (HR), and rating of perceived exertion (RPE). These measures were expressed as a percentage of the estimated maximal VO2 (VO2max) and the estimated maximal HR (HRmax) and estimated as metabolic equivalent units (METs). RESULTS: Participants performed chair-assisted exercises at 61.0% ± 14.7% of VO2max, 67.6% ± 11.3% HRmax, 3.9 ± 0.9 METs, and 13.1 ± 2.1 RPE. CONCLUSIONS: The intensity of these chair-assisted exercises is at least moderate for older adults, which is necessary for healthy aging.

Evaluation of short-course radiotherapy followed by neoadjuvant bevacizumab, capecitabine, and oxaliplatin and subsequent radical surgical treatment in primary stage IV rectal cancer.

BACKGROUND: To evaluate the efficacy and tolerability of preoperative short-course radiotherapy followed by capecitabine and oxaliplatin treatment in combination with bevacizumab and subsequent radical surgical treatment of all tumor sites in patients with stage IV rectal cancer. PATIENTS AND METHODS: Adults with primary metastasized rectal cancer were enrolled. They received radiotherapy (5 × 5 Gy) followed by bevacizumab (7.5 mg/kg, day 1) and oxaliplatin (130 mg/m(2), day 1) intravenously and capecitabine (1000 mg/m(2) twice daily orally, days 1-14) for up to six cycles. Surgery was carried out 6-8 weeks after the last bevacizumab dose. The percentage of radical surgical treatment, 2-year survival and recurrence rates, and treatment-related toxicity was evaluated. RESULTS: Of 50 included patients, 42 (84%) had liver metastases, 5 (10%) lung metastases, and 3 (6%) both liver and lung metastases. Radical surgical treatment was possible in 36 (72%) patients. The 2-year overall survival rate was 80% [95% confidence interval (CI) 66.3%-90.0%]. The 2-year recurrence rate was 64% (95% CI 49.8%-84.5%). Toxic effects were tolerable. No treatment-related deaths occurred. CONCLUSIONS: Radical surgical treatment of all tumor sites carried out after short-course radiotherapy, and bevacizumab-capecitabine-oxaliplatin combination therapy is a feasible and potentially curative approach in primary metastasized rectal cancer.

A novel approach to monitor glucose metabolism using stable isotopically labelled glucose in longitudinal studies in mice.

The aetiology of insulin resistance is still an enigma. Mouse models are frequently employed to study the underlying pathology. The most commonly used methods to monitor insulin resistance are the HOMA-IR, glucose or insulin tolerance tests and the hyperinsulinemic euglycaemic clamp (HIEC). Unfortunately, these tests disturb steady state glucose metabolism. Here we describe a method in which blood glucose kinetics can be determined in fasted mice without noticeably perturbing glucose homeostasis. The method involves an intraperitoneal injection of a trace amount of [6,6-(2)H2]glucose and can be performed repeatedly in individual mice. The validity and performance of this novel method was tested in mice fed on chow or high-fat diet for a period of five weeks. After administering the mice with [6,6-(2)H2]glucose, decay of the glucose label was followed in small volumes of blood collected by tail tip bleeding during a 90-minute period. The total amount of blood collected was less than 120 µL. This novel approach confirmed in detail the well-known increase in insulin resistance induced by a high-fat diet. The mice showed reduced glucose clearance rate, and reduced hepatic and peripheral insulin sensitivity. To compensate for this insulin resistance, ß-cell function was slightly increased. We conclude that this refinement of existing methods enables detailed information of glucose homeostasis in mice. Insulin resistance can be accurately determined while mechanistic insight is obtained in underlying pathology. In addition, this novel approach reduces the number of mice needed for longitudinal studies of insulin sensitivity and glucose metabolism.

Plasmon switching: observation of dynamic surface plasmon steering by selective mode excitation in a sub-wavelength slit.

We report a plasmon steering method that enables us to dynamically control the direction of surface plasmons generated by a two-mode slit in a thin metal film. By varying the phase between different coherent beams that are incident on the slit, individual waveguide modes are excited. Different linear combinations of the two modes lead to different diffracted fields at the exit of the slit. As a result, the direction in which surface plasmons are launched can be controlled. Experiments confirm that it is possible to distribute an approximately constant surface plasmon intensity in any desired proportion over the two launching directions. We also find that the anti-symmetric mode generates surface plasmons more efficiently than the fundamental symmetric mode.

Lactose maldigestion during methotrexate-induced gastrointestinal mucositis in a rat model.

Patients with chemotherapy-induced gastrointestinal mucositis suffer from anorexia, diarrhea, and stomach pain, often causing weight loss and malnutrition. When the intestinal function during mucositis would be known, a rational feeding strategy might improve the nutritional state, accelerate recuperation, and increase survival of mucositis patients. We developed a methotrexate (MTX)-induced mucositis rat model to study nutrient digestion and absorption. To determine lactose digestion and absorption of its derivative glucose during mucositis, we injected Wistar rats intravenously with MTX (60 mg/kg) or 0.9% NaCl (controls). Four days later, we orally administered trace amounts of [1-(13)C]lactose and [U-(13)C]glucose and quantified the appearance of labeled glucose in the blood for 3 h. Finally, we determined plasma citrulline level and harvested the small intestine to assess histology, myeloperoxidase level, glycohydrolase activity, immunohistochemical protein, and mRNA expression. MTX-treated rats showed profound villus atrophy and epithelial damage. During the experimental period, the absorption of lactose-derived [1-(13)C]glucose was 4.2-fold decreased in MTX-treated rats compared with controls (P < 0.01). Lactose-derived [1-(13)C]glucose absorption correlated strongly with villus length (rho = 0.86, P < 0.001) and with plasma citrulline level (rho = 0.81, P < 0.001). MTX treatment decreased jejunal lactase activity (19.5-fold, P < 0.01) and immunohistochemical protein and mRNA expression (39.7-fold, P < 0.01) compared with controls. Interestingly, MTX treatment did not affect the absorption of [U-(13)C]glucose during the experimental period. We conclude that lactose digestion is severely decreased during mucositis while glucose absorption is still intact, when supplied in trace amounts. Plasma citrulline level might be a useful objective, noninvasive marker for lactose maldigestion during mucositis in clinic.

Soraphen, an inhibitor of the acetyl-CoA carboxylase system, improves peripheral insulin sensitivity in mice fed a high-fat diet.

AIM: Inhibition of the acetyl-CoA carboxylase (ACC) system, consisting of the isozymes ACC1 and ACC2, may be beneficial for treatment of insulin resistance and/or obesity by interfering with de novo lipogenesis and beta-oxidation. We have evaluated effects of pharmacological inhibition of ACC by soraphen (SP) on high fat (HF) diet-induced insulin resistance in mice. METHOD: Male C57Bl6/J mice were fed control chow, a HF diet or a HF diet supplemented with SP (50 or 100 mg/kg/day). RESULTS: Body weight gain and total body fat content of SP-treated animals were significantly reduced compared with HF-fed mice. Fractional synthesis of palmitate was significantly reduced in mice treated with SP, indicative for ACC1 inhibition. Plasma beta-hydroxybutyrate levels were significantly elevated by SP, reflecting simultaneous inhibition of ACC2 activity. Mice treated with SP showed improved peripheral insulin sensitivity, as assessed by hyperinsulinaemic euglycaemic clamps. CONCLUSION: Pharmacological inhibition of the ACC system is of potential use for treatment of key components of the metabolic syndrome.

Enhanced glucose cycling and suppressed de novo synthesis of glucose-6-phosphate result in a net unchanged hepatic glucose output in ob/ob mice.

AIMS/HYPOTHESIS: Leptin-deficient ob/ob mice are hyperinsulinaemic and hyperglycaemic; however, the cause of hyperglycaemia remains largely unknown. METHODS: Glucose metabolism in vivo in 9-h fasted ob/ob mice and lean littermates was studied by infusing [U-(13)C]-glucose, [2-(13)C]-glycerol, [1-(2)H]-galactose and paracetamol for 6 h, applying mass isotopomer distribution analysis on blood glucose and urinary paracetamol-glucuronide. RESULTS: When expressed on the basis of body weight, endogenous glucose production (109+/-23 vs 152+/-27 micromol.kg(-1).min(-1), obese versus lean mice, p<0.01) and de novo synthesis of glucose-6-phosphate (122+/-13 vs 160+/-6 micromol.kg(-1).min(-1), obese versus lean mice, p<0.001) were lower in ob/ob mice than in lean littermates. In contrast, glucose cycling was greatly increased in obese mice (56+/-13 vs 26+/-4 micromol.kg(-1).min(-1), obese versus lean mice, p<0.001). As a result, total hepatic glucose output remained unaffected (165+/-31 vs 178+/-28 micromol.kg(-1).min(-1), obese vs lean mice, NS). The metabolic clearance rate of glucose was significantly lower in obese mice (8+/-2 vs 18+/-2 ml.kg(-1).min(-1), obese versus lean mice, p<0.001). Hepatic mRNA levels of genes encoding for glucokinase and pyruvate kinase were markedly increased in ob/ob mice. CONCLUSIONS/INTERPRETATION: Unaffected total hepatic glucose output in the presence of hyperinsulinaemia reflects hepatic insulin resistance in ob/ob mice, which is associated with markedly increased rates of glucose cycling. Hyperglycaemia in ob/ob mice primarily results from a decreased metabolic clearance rate of glucose.

Acute inhibition of hepatic glucose-6-phosphatase does not affect gluconeogenesis but directs gluconeogenic flux toward glycogen in fasted rats. A pharmacological study with the chlorogenic acid derivative S4048.

Effects of acute inhibition of glucose-6-phosphatase activity by the chlorogenic acid derivative S4048 on hepatic carbohydrate fluxes were examined in isolated rat hepatocytes and in vivo in rats. Fluxes were calculated using tracer dilution techniques and mass isotopomer distribution analysis in plasma glucose and urinary paracetamol-glucuronide after infusion of [U-(13)C]glucose, [2-(13)C]glycerol, [1-(2)H]galactose, and paracetamol. In hepatocytes, glucose-6-phosphate (Glc-6-P) content, net glycogen synthesis, and lactate production from glucose and dihydroxyacetone increased strongly in the presence of S4048 (10 microm). In livers of S4048-treated rats (0.5 mg kg(-1)min(-)); 8 h) Glc-6-P content increased strongly (+440%), and massive glycogen accumulation (+1260%) was observed in periportal areas. Total glucose production was diminished by 50%. The gluconeogenic flux to Glc-6-P was unaffected (i.e. 33.3 +/- 2.0 versus 33.2 +/- 2.9 micromol kg(-1)min(-1)in control and S4048-treated rats, respectively). Newly synthesized Glc-6-P was redistributed from glucose production (62 +/- 1 versus 38 +/- 1%; p < 0.001) to glycogen synthesis (35 +/- 5% versus 65 +/- 5%; p < 0.005) by S4048. This was associated with a strong inhibition (-82%) of the flux through glucokinase and an increase (+83%) of the flux through glycogen synthase, while the flux through glycogen phosphorylase remained unaffected. In livers from S4048-treated rats, mRNA levels of genes encoding Glc-6-P hydrolase (approximately 9-fold), Glc-6-P translocase (approximately 4-fold), glycogen synthase (approximately 7-fold) and L-type pyruvate kinase (approximately 4-fold) were increased, whereas glucokinase expression was almost abolished. In accordance with unaltered gluconeogenic flux, expression of the gene encoding phosphoenolpyruvate carboxykinase was unaffected in the S4048-treated rats. Thus, acute inhibition of glucose-6-phosphatase activity by S4048 elicited 1) a repartitioning of newly synthesized Glc-6-P from glucose production into glycogen synthesis without affecting the gluconeogenic flux to Glc-6-P and 2) a cellular response aimed at maintaining cellular Glc-6-P homeostasis.