Simultaneous liver-pancreas transplantation for cystic fibrosis-related liver disease: a multicenter experience.

BACKGROUND: Diabetes is associated with increased morbidity and mortality in patients with cystic fibrosis (CF). While liver transplantation is well established for CF-related liver disease (CFLD), the role of simultaneous liver-pancreas transplantation is less understood. METHODS: We polled 81 pediatric transplantation centers to identify and characterize subjects who had undergone simultaneous liver-pancreas transplantation and obtain opinions about this procedure in CFLD. RESULTS: Fifty (61.7%) polled transplant centers responded and 94% reported that they would consider simultaneous liver-pancreas transplantation for CFLD and diabetes. A total of 8 patients with simultaneous liver-pancreas transplantation were identified with median follow up of 38 months. All patients had pre-existing diabetes. Exocrine and endocrine pancreatic function was initially restored in all patients with later functional loss in one patient. Body mass index Z-score increased between one year pre-transplantation and one year post-transplantation (P=0.029). CONCLUSIONS: Patients with CFLD undergoing initial assessment for liver transplantation may benefit from consideration of simultaneous liver-pancreas transplantation.

Acute cannabinoid receptor type 1 (CB1R) modulation influences insulin sensitivity by an effect outside the central nervous system in mice.

AIMS/HYPOTHESIS: Modulation of central nervous system (CNS) and extra-CNS cannabinoid receptor type 1 (CB1R) affects metabolic conditions, independently of weight loss. Here we examined the relative contributions of acute CNS and extra-CNS CB1R modulation on insulin sensitivity using pharmacological gain- and loss-of-function of CB1R in mice. METHODS: We assessed the effects of acute modulation of CB1R on insulin sensitivity and tissue glucose uptake by administering a CB1R agonist (HU210) and antagonist (AM251) (vs vehicle) i.v. in wild-type mice. In addition, we administered a CB1R agonist (vs vehicle) systemically (i.v.) to Cb1r (also known as Cnr1) knockout (Cb1r (-/-)) mice or intracerebroventricularly (i.c.v.) in wild-type mice to elucidate the peripheral vs CNS-mediated regulatory effect of CB1R on insulin sensitivity. RESULTS: HU210 induced significant insulin resistance in wild-type mice with a reduction of whole-body glucose disappearance rate and muscle Akt phosphorylation, as well as of glucose uptake by skeletal muscle, but not by adipose tissue, changes that were prevented by pretreatment with AM251. HU210 did not affect insulin sensitivity in Cb1r (-/-) mice, suggesting that the observed effects were mediated through CB1R. HU210 administered i.c.v. did not induce insulin resistance, suggesting that acute stimulation of CNS CB1R was not required for this effect. CONCLUSIONS/INTERPRETATION: Skeletal muscle insulin sensitivity is affected by acute CB1R modulation. These changes are mediated by extra-CNS CB1R, probably by the receptors in skeletal muscle tissue.

Introduction of bubble CPAP in a teaching hospital in Malawi.

BACKGROUND: Continuous positive airway pressure (CPAP) is relatively inexpensive and can be easily taught; it therefore has the potential to be the optimal respiratory support device for neonates in developing countries. OBJECTIVE: The possibility of implementing bubble CPAP in a teaching hospital with a large neonatology unit but very limited resources was investigated. METHODS: A CPAP system was developed consisting of a compressor, oxygen concentrator, water bottle to control the pressure and binasal prongs. Neonates with birthweights between 1 and 2·5 kg with persistent respiratory distress 4 hours after birth were eligible for bubble CPAP. RESULTS: In the 7-week introduction period from 11 March until 27 April 2008, 11 neonates were treated with CPAP. Five of these neonates met the inclusion criteria and six neonates did not meet these criteria. Of the five neonates who received CPAP and met the inclusion criteria, three survived. The six infants who did not meet the inclusion criteria included three preterm infants with apnoea (all died), two with birthweights <1 kg (both died) and a firstborn twin (1.2 kg) who survived. No major complications of CPAP occurred. Bubble CPAP could be used independently by nurses after a short training period. CONCLUSION: Successful long-term implementation of CPAP depends on the availability of sufficient trained nursing staff.

Adiponectin levels correlate with the severity of hypertriglyceridaemia in glycogen storage disease Ia.

Glycogen storage disease type Ia (GSD Ia) is characterized by severe hypercholesterolaemia and hypertriglyceridaemia. Little is known about the aetiology of the hyperlipidaemia in GSD Ia. Adipokines play an important regulatory role in lipid metabolism. We investigated whether adipokine concentrations were correlated with the degree of hyperlipidaemia in GSD Ia patients. Six patients with GSD Ia were studied in semi-fasted conditions. Adiponectin, but not leptin, correlated (r(2) = -0.79, p = 0.02) with plasma triglyceride concentrations in the GSD Ia patients. Leptin correlated well with BMI (r(2) = 0.59, p < 0.01). However, neither body mass index (BMI) nor homeostasis model assessment (HOMA), as a marker of insulin sensitivity, correlated with triglyceride concentrations. Although a small number of patients were studied, these results indicate that adiponectin concentrations are correlated with the degree of hypertriglyceridaemia in GSD Ia. Pharmacological treatment aimed at increasing adiponectin levels might improve the metabolic status of these patients.

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.