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Repunte-Canonigo V.,Scripps Research Institute | Berton F.,Scripps Research Institute | Berton F.,University of Pisa | Cottone P.,Scripps Research Institute | And 6 more authors.
Brain Research | Year: 2010

The anterior cingulate cortex (ACC) has been implicated in alcohol and drug addiction. We recently identified the small G protein K-ras as an alcohol-regulated gene in the ACC by gene expression analysis. We show here that the adiponectin receptor 2 (AdipoR2) was differentially regulated by alcohol in the ACC in a K-ras-dependent manner. Additionally, withdrawal-associated increased drinking was attenuated in AdipoR2 null mice. Intracellular recordings revealed that adiponectin increased the excitability of ACC neurons and that this effect was more pronounced during alcohol withdrawal, suggesting that AdipoR2 signaling may contribute to increased ACC activity. Altogether, the data implicate K-ras-regulated pathways involving AdipoR2 in the cellular and behavioral actions of alcohol that may contribute to overactivity of the ACC during withdrawal and excessive alcohol drinking. © 2010 Elsevier B.V.

Pottegard A.,University of Southern Denmark | Bjerregaard B.K.,Statens Serum Institute | Larsen M.D.,University of Southern Denmark | Larsen K.S.,University of Southern Denmark | And 3 more authors.
European Journal of Clinical Pharmacology | Year: 2014

Purpose: The purpose of this study was to characterise the utilization of the glucagon-like peptide-1 (GLP-1) analogues exenatide and liraglutide in Denmark. Methods: From the Danish National Prescription Registry, we extracted all prescriptions for either liraglutide or exenatide twice-daily in the period 1 April 2007 to 31 December 2012. Using descriptive statistics, we calculated incidence rates, prevalence proportions, daily consumption, and concomitant drug use. For a subset of users we included data from other registries and characterised the baseline characteristics of incident users of GLP-1 analogues. Results: We identified 21,561 and 2,354 users of liraglutide and exenatide respectively. From market entry in 2009 liraglutide showed an increasing prevalence reaching 2.4 per thousand inhabitants in 2012. Exenatide ranged between 0.01 and 0.25 per thousand inhabitants from 2007 to 2012. Treatment intensity showed geographical variation ranging from 1.84per thousand inhabitants to 3.22 per thousand inhabitants for liraglutide. Average doses were 1.34 mg/day (liraglutide) and 16.4 μg/day (exenatide). Treatment initiation was most often performed by a hospital physician and was not associated with any changes in concomitant treatment with antihypertensives, cholesterol-lowering drugs or anticoagulants. Of liraglutide and exenatide users, 38 % and 43 % also used insulin. Low kidney function (eGFR < 30 ml/min) was found in 10.1 % and 9.0 % of users of liraglutide and exenatide respectively. Conclusions: The preferred GLP-1 analogue in Denmark is liraglutide. Certain aspects of the utilization of GLP-1 analogues, such as large regional differences and concomitant use of GLP-1 analogues and insulin, warrant further investigation. © 2013 Springer-Verlag Berlin Heidelberg.

Ostoft S.H.,Diabetes Research Division | Ostoft S.H.,Copenhagen University | Ostoft S.H.,Novo Nordisk AS | Bagger J.I.,Diabetes Research Division | And 11 more authors.
Diabetes | Year: 2014

Maturity-onset diabetes of the young (MODY) is a clinically and genetically heterogeneous subgroup of non-autoimmune diabetes, constituting 1-2% of all diabetes. Because little is known about incretin function in patients with MODY, we studied the incretin effect and hormone responses to oral and intravenous glucose loads in patients with glucokinase (GCK)-diabetes (MODY2) and hepatocyte nuclear factor 1a (HNF1A)-diabetes (MODY3), respectively, and in matched healthy control subjects. Both MODY groups exhibited glucose intolerance after oral glucose (most pronounced in patients with HNF1A-diabetes), but only patients with HNF1A-diabetes had impaired incretin effect and inappropriate glucagon responses to OGTT. Both groups of patients with diabetes showed normal suppression of glucagon in response to intravenous glucose. Thus, HNF1A-diabetes, similar to type 2 diabetes, is characterized by an impaired incretin effect and inappropriate glucagon responses, whereas incretin effect and gluca-gon response to oral glucose remain unaffected in GCK-diabetes, reflecting important pathogenetic differences between the two MODY forms. © 2014 by the American Diabetes Association.

Petersen A.B.,Bispebjerg Hospital | Christensen M.,Bispebjerg Hospital | Christensen M.,Diabetes Research Division
Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy | Year: 2013

The glucagon-like peptide (GLP)-1 receptor agonist lixisenatide (Lyxumia®) was approved for marketing by the European Medicines Agency in February 2013 and has been evaluated in a clinical study program called GetGoal. Lixisenatide activates the GLP-1 receptor and thereby exercises the range of physiological effects generated by GLP-1, which consist of increased insulin secretion, inhibition of glucagon secretion, and decreased gastrointestinal motility alongside the promotion of satiety. In the GetGoal study program, lixisenatide demonstrated significant reductions in glycated hemoglobin (HbA1c), and fasting and postprandial plasma glucose compared with placebo. The effect on glycemia was evident, with both monotherapy and in combination with insulin and various oral antidiabetic agents. Furthermore, a general trend towards reduced bodyweight was reported. In head-to-head trials with the other GLP-1 receptor agonists (exenatide and liraglutide) on the market, lixisenatide demonstrated a superior effect with respect to reduction in postprandial plasma glucose and had a tendency towards fewer adverse events. However, lixisenatide seemed to be less efficient or at best, equivalent to exenatide and liraglutide in reducing HbA1c, fasting plasma glucose, and bodyweight. The combination of a substantial effect on postprandial plasma glucose and a labeling with once daily administration separates lixisenatide from the other GLP-1 receptor agonists. The combination of basal insulin, having a lowering effect on fasting plasma glucose, and lixisenatide, curtailing the postprandial glucose excursions, makes sense from a clinical point of view. Not surprisingly, lixisenatide is undergoing clinical development as a combination product with insulin glargine (Lantus®). At present the main place in therapy of lixisenatide seems to be in combination with basal insulin. A large multicenter study will determine the future potential of lixisenatide in preventing cardiovascular events and mortality, in patients with type 2 diabetes and recent acute coronary syndrome. © 2013 Petersen and Christensen, publisher and licensee Dove Medical Press Ltd.

Sonne D.P.,Diabetes Research Division | Hansen M.,Diabetes Research Division | Knop F.K.,Diabetes Research Division
European Journal of Endocrinology | Year: 2014

Bile acid sequestrants have been used for decades for the treatment of hypercholesterolaemia. Sequestering of bile acids in the intestinal lumen interrupts enterohepatic recirculation of bile acids, which initiate feedback mechanisms on the conversion of cholesterol into bile acids in the liver, thereby lowering cholesterol concentrations in the circulation. In the early 1990s, it was observed that bile acid sequestrants improved glycaemic control in patients with type 2 diabetes. Subsequently, several studies confirmed the finding and recently - despite elusive mechanisms of action - bile acid sequestrants have been approved in the USA for the treatment of type 2 diabetes. Nowadays, bile acids are no longer labelled as simple detergents necessary for lipid digestion and absorption, but are increasingly recognised as metabolic regulators. They are potent hormones, work as signalling molecules on nuclear receptors and G protein-coupled receptors and trigger a myriad of signalling pathways in many target organs. The most described and well-known receptors activated by bile acids are the farnesoid X receptor (nuclear receptor) and the G protein-coupled cell membrane receptor TGR5. Besides controlling bile acid metabolism, these receptors are implicated in lipid, glucose and energy metabolism. Interestingly, activation of TGR5 on enteroendocrine L cells has been suggested to affect secretion of incretin hormones, particularly glucagon-like peptide 1 (GLP1 (GCG)). This review discusses the role of bile acid sequestrants in the treatment of type 2 diabetes, the possible mechanism of action and the role of bile acid-induced secretion of GLP1 via activation of TGR5. © 2014 European Society of Endocrinology.

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