Oral glutamine increases circulating glucagon-like peptide 1, glucagon, and insulin concentrations in lean, obese, and type 2 diabetic subjects.

Background: Incretin hormones, such as glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), play an important role in meal-related insulin secretion. We previously demonstrated that glutamine is a potent stimulus of GLP-1 secretion in vitro.

Objective: Our objective was to determine whether glutamine increases circulating GLP-1 and GIP concentrations in vivo and, if so, whether this is associated with an increase in plasma insulin.

Glucose sensing in L cells: a primary cell study.

Glucagon-like peptide-1 (GLP-1) is an enteric hormone that stimulates insulin secretion and improves glycaemia in type 2 diabetes. Although GLP-1-based treatments are clinically available, alternative strategies to increase endogenous GLP-1 release from L cells are hampered by our limited physiological understanding of this cell type. By generating transgenic mice with L cell-specific expression of a fluorescent protein, we studied the characteristics of primary L cells by electrophysiology, fluorescence calcium imaging, and expression analysis and show that single L cells are electrically excitable and glucose responsive.

Nutritional regulation of glucagon-like peptide-1 secretion.

Glucagon-like peptide-1 (GLP-1), released from L-cells in the intestinal epithelium, plays an important role in postprandial glucose homeostasis and appetite control. Following the recent therapeutic successes of antidiabetic drugs aimed at either mimicking GLP-1 or preventing its degradation, attention is now turning towards the L-cell, and addressing whether it would be both possible and beneficial to stimulate the endogenous release of GLP-1 in vivo. Understanding the mechanisms underlying GLP-1 release from L-cells is key to this type of approach, and the use of cell line models has led to the identification of a variety of pathways that may underlie the physiological responses of L-cells to food ingestion.

Dissociation between sensing and metabolism of glucose in sugar sensing neurones.

Some of the neurones controlling sleep, appetite and hormone release act as specialized detectors of ambient glucose. Their sugar sensing is conventionally thought to involve glucokinase-dependent metabolism of glucose to ATP, which then alters membrane excitability by modulating ATP-dependent channels or transporters, such as ATP-inhibited K(+) channels (K(ATP)). However, recent studies also provide examples of both glucose-excited (GE) and glucose-inhibited (GI) neurones that sense glucose independently of such metabolic pathways.

Extrahepatic cholestasis increases liver stiffness (FibroScan) irrespective of fibrosis.

Unlabelled: Transient elastography (FibroScan [FS]) is a novel non-invasive tool to assess liver fibrosis/cirrhosis. However, it remains to be determined if other liver diseases such as extrahepatic cholestasis interfere with fibrosis assessment because liver stiffness is indirectly measured by the propagation velocity of an ultrasound wave within the liver. In this study, we measured liver stiffness immediately before endoscopic retrograde cholangiopancreatography and 3 to 12 days after successful biliary drainage in patients with extrahepatic cholestasis mostly due to neoplastic invasion of the biliary tree.

Calcium elevation in mouse pancreatic beta cells evoked by extracellular human islet amyloid polypeptide involves activation of the mechanosensitive ion channel TRPV4.

Aims/hypothesis: To investigate the mechanism by which human islet amyloid polypeptide (hIAPP) fibril formation results in calcium influx across the plasma membrane of pancreatic beta cells, and its association with apoptosis.

Methods: Cytoplasmic intracellular calcium concentrations ([Ca(2+)](i)) were monitored for 2 h as the 340/380 nm fluorescence ratio in fura-2 loaded cells of the MIN6 mouse pancreatic beta cell line. Cell morphology was evaluated by transmission electron microscopy, and viability by FACS.

No differences in mortality between users of pancreatic-specific and non-pancreatic-specific sulphonylureas: a cohort analysis.

To assess whether users of pancreatic-specific sulphonylureas are at reduced risk of mortality and cardiovascular mortality compared with users of non-specific sulphonylureas, we conducted a cohort study in the population of Tayside, Scotland. We identified 3331 patients with type 2 diabetes who were newly treated with sulphonylureas between 1994 and 2001 and categorized them into those treated with only pancreatic-specific sulphonylureas and those treated with only non-specific sulphonylureas. The risks of mortality and cardiovascular mortality were compared in a survival analysis.

[Sonographic course of alcoholic fatty liver by interobserver and digital evaluation of liver echogenicity].

Background: The reversibility of alcoholic fatty liver is well-known. The present study aims to investigate whether sonographic controls can document this reversibility under abstinence therapy with respect to inter-observer variability.

Methods: 59 male patients with alcohol dependency were examined by ultrasound at the beginning and the end of a long-term in-patient withdrawal therapy.

Cyclic AMP triggers glucagon-like peptide-1 secretion from the GLUTag enteroendocrine cell line.

Aims/hypothesis: To investigate the pathways by which cyclic AMP (cAMP) stimulates glucagon-like peptide-1 (GLP-1) secretion, using the GLUTag enteroendocrine cell line.

Materials And Methods: GLP-1 release from GLUTag cells was measured in response to agents that increase cAMP, and single cells were studied by fluorescence calcium imaging and electrophysiology to evaluate the underlying pathways.

Results: Pituitary adenylate cyclase-activating polypeptide increased cAMP levels and stimulated GLP-1 release from GLUTag cells.

An SCN9A channelopathy causes congenital inability to experience pain.

The complete inability to sense pain in an otherwise healthy individual is a very rare phenotype. In three consanguineous families from northern Pakistan, we mapped the condition as an autosomal-recessive trait to chromosome 2q24.3.

Sodium-coupled glucose cotransporters contribute to hypothalamic glucose sensing.

Specialized neurons within the hypothalamus have the ability to sense and respond to changes in ambient glucose concentrations. We investigated the mechanisms underlying glucose-triggered activity in glucose-excited neurons, using primary cultures of rat hypothalamic neurons monitored by fluorescence calcium imaging. We found that 35% (738 of 2,139) of the neurons were excited by increasing glucose from 3 to 15 mmol/l, but only 9% (6 of 64) of these glucose-excited neurons were activated by tolbutamide, suggesting the involvement of a ATP-sensitive K(+) channel-independent mechanism.

Mucolipin-1 is a lysosomal membrane protein required for intracellular lactosylceramide traffic.

Mucolipin-1 is a membrane protein encoded by the gene MCOLN1, mutations in which result in the lysosomal storage disorder mucolipidosis type IV (MLIV). Efficient lysosomal targeting of mucolipin-1 requires di-leucine motifs in both the N-terminal and the C-terminal cytosolic tails. We have shown that aberrant lactosylceramide trafficking in MLIV cells may be rescued by wild-type mucolipin-1 expression but not by mucolipin-1 mistargeted to the plasma membrane or by lysosome-localized mucolipin-1 mutated in its predicted ion pore-selectivity region.

[Diagnostics for diseases of the gallbladder and biliary tract from the viewpoint of the internist and surgeon. Demands made on radiological diagnostics].

Jaundice and colic pain of the right upper quadrant are the main symptoms of biliary diseases. Gallstone-related diseases often lead to hospital admission. The evaluation of a patient with biliary symptoms requires a combination of history taking, physical examination, laboratory analysis, and imaging modalities.

The neurotransmitters glycine and GABA stimulate glucagon-like peptide-1 release from the GLUTag cell line.

The incretin hormone, glucagon-like peptide-1 (GLP-1) is released from intestinal L-cells following food ingestion. Its secretion is triggered by a range of nutrients, including fats, carbohydrates and proteins. We reported previously that Na(+)-dependent glutamine uptake triggered electrical activity and GLP-1 release from the L-cell model line GLUTag.

Relapsing diabetes can result from moderately activating mutations in KCNJ11.

Neonatal diabetes can either remit and hence be transient or else may be permanent. These two phenotypes were considered to be genetically distinct. Abnormalities of 6q24 are the commonest cause of transient neonatal diabetes (TNDM).

Characterization and functional role of voltage gated cation conductances in the glucagon-like peptide-1 secreting GLUTag cell line.

Glucagon-like peptide-1 (GLP-1) is released from intestinal L-cells in response to nutrient ingestion. It is currently under therapeutic evaluation because it enhances insulin secretion in type 2 diabetes. Previous studies using the GLP-1 secreting cell line GLUTag have shown that the cells are electrically active, and that the action potential frequency is regulated by nutrients.

Glutamine potently stimulates glucagon-like peptide-1 secretion from GLUTag cells.

Aims/hypothesis: Glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) are secreted from enteroendocrine L cells in response to nutrient ingestion. As glutamine is an important metabolic fuel for the gut, the aim of this study was to investigate the effect of glutamine on the GLP-1-secreting cell line, GLUTag.

Methods: GLP-1 release was measured following incubation of GLUTag cells under a range of conditions.

Constitutive Ras activity induces hippocampal hypertrophy and remodeling of pyramidal neurons in synRas mice.

The small G protein Ras, which is involved critically in neurotrophic signal transduction, has been implicated in neuronal plasticity of both the developing and the adult nervous systems. In the present study, the cumulative effects of constitutive Ras activity from early in postnatal development into the adult upon the morphology of hippocampal pyramidal neurons were investigated in synRas mice overexpressing Val12-Ha-Ras postmitotically under the control of the rat synapsin I promoter. In synRas mice, stereologic investigations revealed hypertrophy of the hippocampus associated with an increase in perikaryal size of pyramidal neurons within the CA2/CA3 region and the gyrus dentatus.

Haemodynamic effects of dopexamine on postprandial splanchnic hyperaemia.

Background: The synthetic beta(2)-adrenergic and dopaminergic agonist dopexamine is supposed to prevent splanchnic hypoperfusion in critically ill patients, thus potentially interacting with haemodynamic effects of early enteral nutrition. However, precise mechanism of action and interaction with postprandial splanchnic hyperaemia of the drug are largely unknown, even in healthy subjects.

Materials And Methods: Twelve healthy volunteers received dopexamine 1 microg x kg(-1) min(-1) and dopexamine and placebo (NaCl 0.

A novel missense mutation in AE1 causing autosomal dominant distal renal tubular acidosis retains normal transport function but is mistargeted in polarized epithelial cells.

Mutations in SLC4A1, encoding the chloride-bicarbonate exchanger AE1, cause distal renal tubular acidosis (dRTA), a disease of defective urinary acidification by the distal nephron. In this study we report a novel missense mutation, G609R, causing dominant dRTA in affected members of a large Caucasian pedigree who all exhibited metabolic acidosis with alkaline urine, prominent nephrocalcinosis, and progressive renal impairment. To investigate the potential disease mechanism, the consequent effects of this mutation were determined.

Sulphonylurea action revisited: the post-cloning era.

Hypoglycaemic agents such as sulphonylureas and the newer group of "glinides" stimulate insulin secretion by closing ATP-sensitive potassium (K(ATP)) channels in pancreatic beta cells, but have varying cross-reactivity with related channels in extrapancreatic tissues such as heart, vascular smooth and skeletal muscle. Experiments on the structure-function relationships of recombinant K(ATP) channels and the phenotypes of mice deficient in different K(ATP) channel subunits have provided important insights into the mechanisms underlying sulphonylurea selectivity, and the potential consequences of K(ATP) channel blockade outside the pancreatic beta cell. The different pharmacological properties of K(ATP) channels from beta cells compared with those from cardiac, smooth and skeletal muscle, are accounted for by the expression of alternative types of sulphonylurea receptor, with non-identical drug binding sites.

A novel glucose-sensing mechanism contributing to glucagon-like peptide-1 secretion from the GLUTag cell line.

Glucagon-like peptide 1 (GLP-1) secretion from intestinal L-cells is triggered by luminal nutrients. We reported previously that glucose-triggered GLP-1 release from the L-cell model GLUTag involves closure of ATP-sensitive K+ (K(ATP)) channels. We show here that GLP-1 secretion and electrical activity of GLUTag cells is triggered not only by metabolizable sugars (glucose or fructose) but also by the nonmetabolizable monosaccharide methyl-alpha-glucopyranoside.

Characterisation of new KATP-channel mutations associated with congenital hyperinsulinism in the Finnish population.

Aims/hypothesis: ATP-sensitive potassium (K(ATP)) channels are crucial for the regulation of insulin secretion from pancreatic beta cells and mutations in either the Kir6.2 or SUR1 subunit of this channel can cause congenital hyperinsulinism (CHI). The aim of this study was to analyse the functional consequences of four CHI mutations (A1457T, V1550D and L1551V in SUR1, and K67N in Kir6.

Differential selectivity of insulin secretagogues: mechanisms, clinical implications, and drug interactions.

The sulphonylurea receptor (SUR) subunits of K(ATP) channels are the targets for several classes of therapeutic drugs. Sulphonylureas close K(ATP) channels in pancreatic beta-cells and are used to stimulate insulin release in type 2 diabetes, whereas the K(ATP) channel opener nicorandil acts as an antianginal agent by opening K(ATP) channels in cardiac and vascular smooth muscle. The predominant type of SUR varies between tissues: SUR1 in beta-cells, SUR2A in cardiac muscle, and SUR2B in smooth muscle.