Increased hepatic glucagon sensitivity in totally pancreatectomised patients.

OBJECTIVE: The metabolic phenotype of totally pancreatectomised patients includes hyperaminoacidaemia and predisposition to hypoglycaemia and hepatic lipid accumulation. We aimed to investigate whether the loss of pancreatic glucagon may be responsible for these changes. METHODS: Nine middle-aged, normal-weight totally pancreatectomised patients, nine patients with type 1 diabetes (C-peptide negative), and nine matched controls underwent two separate experimental days, each involving a 150-min intravenous infusion of glucagon (4 ng/kg/min) or placebo (saline) under fasting conditions while any basal insulin treatment was continued. RESULTS: Glucagon infusion increased plasma glucagon to similar high physiological levels in all groups. The infusion increased hepatic glucose production and decreased plasma concentration of most amino acids in all groups, with more pronounced effects in the totally pancreatectomised patients compared with the other groups. Glucagon infusion diminished fatty acid re-esterification and tended to decrease plasma concentrations of fatty acids in the totally pancreatectomised patients but not in the type 1 diabetes patients. CONCLUSION: Totally pancreatectomised patients were characterised by increased sensitivity to exogenous glucagon at the level of hepatic glucose, amino acid, and lipid metabolism, suggesting that the metabolic disturbances characterising these patients may be rooted in perturbed hepatic processes normally controlled by pancreatic glucagon.

Sources of drug information.

Modern healthcare requires clinicians to navigate through complex drug treatments. This review offers an overview of sources of drug information which can be used for general medication prescription and for challenging patient populations. Key considerations for pregnant or breastfeeding patients, those with renal impairment, and those with liver dysfunction are discussed. We also touch on adverse drug reactions and drug interactions. Finally, information about services from independent regional drug information centers, that can be used by clinicians, are provided.

Hyperglucagonaemia and amino acid alterations in individuals with type 2 diabetes and non-alcoholic fatty liver disease.

Aims: Hyperglucagonaemia contributes to the pathophysiology in type 2 diabetes (T2D), but the mechanisms behind the inappropriate glucagon secretion are not fully understood. Glucagon and amino acids are regulated in a feedback loop referred to as the liver-α cell axis. Individuals with non-alcoholic fatty liver disease (NAFLD) appear to be glucagon resistant, disrupting the liver-α cell axis resulting in hyperglucagonaemia and hyperaminoacidaemia. We investigated the associations between circulating glucagon, amino acids, and liver fat content in a cohort of individuals with T2D. Methods: We included 110 individuals with T2D in this cross-sectional study. Liver fat content was quantified using 1H magnetic resonance spectroscopy (MRS). Associations between liver fat content and plasma glucagon and amino acids, respectively, were estimated in multivariate linear regression analyses. Results: Individuals with NAFLD (n = 52) had higher plasma glucagon concentrations than individuals without NAFLD (n = 58). The positive association between plasma glucagon concentrations and liver fat content was confirmed in the multivariable regression analyses. Plasma concentrations of isoleucine and glutamate were increased, and glycine and serine concentrations were decreased in individuals with NAFLD. Concentrations of other amino acids were similar between individuals with and without NAFLD, and no clear association was seen between liver fat content and amino acids in the regression analyses. Conclusion: MRS-diagnosed NAFLD in T2D is associated with hyperglucagonaemia and elevated plasma concentrations of isoleucine and glutamate and low plasma concentrations of glycine and serine. Whether NAFLD and glucagon resistance per se induce these changes remains to be elucidated.

Bile acid diarrhoea.

Bile acid diarrhoea is a socially debilitating disease caused by irritation of the colonic mucosa due to a spillover of bile acids from the small intestine into the colon. Studies estimate a prevalence of 1-2% of the adult population, but many patients never seek help or are misdiagnosed. Bile acid diarrhoea is treated with bile acid sequestrants, however, new research shows superior effect on reported symptoms with the glucagon-like peptide 1 receptor agonist liraglutide.

Identification of bile acid-CoA:amino acid N-acyltransferase as the hepatic N-acyl taurine synthase for polyunsaturated fatty acids.

N-acyl taurines (NATs) are bioactive lipids with emerging roles in glucose homeostasis and lipid metabolism. The acyl chains of hepatic and biliary NATs are enriched in polyunsaturated fatty acids (PUFAs). Dietary supplementation with a class of PUFAs, the omega-3 fatty acids, increases their cognate NATs in mice and humans. However, the synthesis pathway of the PUFA-containing NATs remains undiscovered. Here, we report that human livers synthesize NATs and that the acyl-chain preference is similar in murine liver homogenates. In the mouse, we found that hepatic NAT synthase activity localizes to the peroxisome and depends upon an active-site cysteine. Using unbiased metabolomics and proteomics, we identified bile acid-CoA:amino acid N-acyltransferase (BAAT) as the likely hepatic NAT synthase in vitro. Subsequently, we confirmed that BAAT knockout livers lack up to 90% of NAT synthase activity and that biliary PUFA-containing NATs are significantly reduced compared with wildtype. In conclusion, we identified the in vivo PUFA-NAT synthase in the murine liver and expanded the known substrates of the bile acid-conjugating enzyme, BAAT, beyond classic bile acids to the synthesis of a novel class of bioactive lipids.

Cardiometabolic effects of antidiabetic drugs in non-alcoholic fatty liver disease.

PURPOSE: Non-alcoholic fatty liver disease (NAFLD) affects about 25% of the population worldwide. NAFLD may be viewed as the hepatological manifestation of metabolic syndrome. Patients with metabolic syndrome due to diabetes or obesity have an increased risk of cardiovascular disease. This narrative review describes cardiometabolic effects of antidiabetic drugs in NAFLD. METHODS: We conducted a systematic search in PubMed and manually scanned bibliographies in trial databases and reference lists in relevant articles. RESULTS: Heart disease is the leading cause of death in NAFLD. Conversely, NAFLD is an independent cardiovascular risk factor in patients suffering from metabolic syndrome. NAFLD is associated with markers of atherosclerosis, and patients have increased risk of ischaemic heart disease. Additionally, patients with NAFLD have increased risk of cardiac dysfunction and heart failure. There are no randomized controlled trials showing clear effects of medical treatment on clinical outcomes in patients with NAFLD. However, based on evidence from small trials and extrapolation from trials evaluating patients with type 2 diabetes, some antidiabetic drugs may be beneficial on cardiovascular function in patients with NAFLD. CONCLUSION: At present, there is promising evidence of a potential effect of antidiabetic drugs for patients with NAFLD. Future studies should address the treatment of NAFLD and the liver-related consequences but also aim at improving the cardiometabolic outcomes.

The Scandinavian baltic pancreatic club (SBPC) database: design, rationale and characterisation of the study cohort.

OBJECTIVES: Chronic pancreatitis (CP) is a multifaceted disease associated with several risk factors and a complex clinical presentation. We established the Scandinavian Baltic Pancreatic Club (SBPC) Database to characterise and study the natural history of CP in a Northern European cohort. Here, we describe the design of the database and characteristics of the study cohort. METHODS: Nine centres from six different countries in the Scandinavian-Baltic region joined the database. Patients with definitive or probable CP (M-ANNHEIM diagnostic criteria) were included. Standardised case report forms were used to collect several assessment variables including disease aetiology, duration of CP, preceding acute pancreatitis, as well as symptoms, complications, and treatments. The clinical stage of CP was characterised according to M-ANNNHEIM. Yearly follow-up is planned for all patients. RESULTS: The study cohort comprised of 910 patients (608 men: 302 women; median age 58 (IQR: 48-67) years with definite 848 (93%) or probable CP 62 (7%). Nicotine (70%) and alcohol (59%) were the most frequent aetiologies and seen in combination in 44% of patients. A history of recurrent acute pancreatitis was seen in 49% prior to the development of CP. Pain (69%) and exocrine pancreatic insufficiency (68%) were the most common complications followed by diabetes (43%). Most patients (30%) were classified as clinical stage II (symptomatic CP with exocrine or endocrine insufficiency). Less than 10% of the patients had undergone pancreatic surgery. CONCLUSION: The SBPC database provides a mean for future prospective, observational studies of CP in the Northern European continent.

Asthma in ear, nose, and throat primary care patients with chronic rhinosinusitis with nasal polyps.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common inflammatory disorder associated with asthma. This association is well described in patients with CRSwNP undergoing endoscopic sinus surgery (ESS); however, some patients are never referred for surgery, and the frequency of asthma in this group is largely unknown. OBJECTIVE: To determine the frequency of asthma in patients with CRSwNP treated in a primary care (PC) setting who have never been referred for surgery and to compare this with ESS patients. METHODS: Fifty-seven patients with CRSwNP who had never undergone ESS were prospectively recruited from nine PC ear, nose, and throat clinics in the Copenhagen area. CRSwNP was diagnosed according to the European Position Paper on Chronic Rhinosinusitis and Nasal Polyps; severity was assessed by using a visual analog scale. Allergy, lung function, and asthma tests (reversibility to ß2-agonist, peak expiratory flow variability, and mannitol challenge) were performed. Findings were compared with our previously published data from patients with CRSwNP referred for surgery. RESULTS: Asthma was diagnosed in 25 patients (44%) based on respiratory symptoms and a positive asthma test; of these, 12 (48%) had undiagnosed asthma prior to study onset. Furthermore, when using the same methods, we found a lower frequency of asthma in PC patients compared with ESS patients (44% versus 65%, p = 0.04). CONCLUSION: A high prevalence of asthma in PC patients with CRSwNP was found. Frequently, asthma was undiagnosed. However, asthma was significantly less prevalent in PC patients compared with patients referred for ESS. The frequent concomitance of asthma, i.e., united airways disease, in PC patients calls for closer collaboration between ear, nose, and throat specialists, and asthma specialists.

Management of chronic rhinosinusitis with nasal polyps and coexisting asthma: A systematic review.

BACKGROUND: Chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) and asthma are strongly associated, and patients suffering from both diseases are often difficult to treat. However, no guidelines about the management of patients with CRS and coexisting asthma exist. OBJECTIVE: The purpose of this systematic review was to evaluate the management of CRSwNP and coexisting asthma. METHODS: We systematically searched electronic databases and included clinical trials in which the clinical outcomes after medical or surgical treatment of patients with CRSwNP and asthma were assessed. The strength of the evidence for each outcome was graded on the basis of study quality and consistency in findings. RESULTS: We included seven trials in which the effect of montelukast, omalizumab, erythromycin, and functional endoscopic sinus surgery (FESS) were studied in 317 adults with CRSwNP and asthma. All the interventions improved the majority of subjective and objective nasal outcomes significantly. However, few studies found significant effects on pulmonary function tests. The strength of the evidence was low overall. CONCLUSION: Both FESS and medical interventions with systemic anti-inflammatory drugs improved nasal outcomes, although their efficacy in relation to the lower airways remains unclear. A low number of studies met inclusion criteria for this systematic review, which emphasizes the need for high-quality trials to explore the treatment of patients with CRSwNP and coexisting asthma.