NN1213 - A Potent, Long-Acting, and Selective Analog of Human Amylin.

Amylin, a member of the calcitonin family, acts via amylin receptors in the hindbrain and hypothalamus to suppress appetite. Native ligands of these receptors are peptides with short half-lives. Conjugating fatty acids to these peptides can increase their half-lives.

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NN1177 is a glucagon/glucagon-like peptide 1 receptor co-agonist investigated for chronic weight management and treatment of non-alcoholic steatohepatitis. Here, we show concentration-dependent down-regulation of cytochrome P450 enzymes using freshly isolated human hepatocytes treated with this linear 29-amino acid peptide. Notably, reductions in CYP3A4 mRNA expression (57.

Development of Cagrilintide, a Long-Acting Amylin Analogue.

A hallmark of the pancreatic hormone amylin is its high propensity toward the formation of amyloid fibrils, which makes it a challenging drug design effort. The amylin analogue pramlintide is commercially available for diabetes treatment as an adjunct to insulin therapy but requires three daily injections due to its short half-life. We report here the development of the stable, lipidated long-acting amylin analogue cagrilintide () and some of the structure-activity efforts that led to the selection of this analogue for clinical development with obesity as an indication.

Oral semaglutide improves postprandial glucose and lipid metabolism, and delays gastric emptying, in subjects with type 2 diabetes.

Aim: To assess the effects of oral semaglutide on postprandial glucose and lipid metabolism, and gastric emptying, in subjects with type 2 diabetes (T2D).

Materials And Methods: In this randomized, double-blind, single-centre, crossover trial, subjects with T2D received once-daily oral semaglutide (escalated to 14 mg) followed by placebo, or vice versa, over two consecutive 12-week periods. Glucose and lipid metabolism, and gastric emptying (paracetamol absorption) were assessed before and after two types of standardized meals (standard and/or fat-rich) at the end of each treatment period.

Effects of oral semaglutide on energy intake, food preference, appetite, control of eating and body weight in subjects with type 2 diabetes.

Aim: To evaluate the effect of oral semaglutide on energy intake and appetite in subjects with type 2 diabetes (T2D).

Materials And Methods: In this randomized, double-blind, placebo-controlled, two-period cross-over trial, 15 subjects with T2D received 12 weeks of treatment with once-daily oral semaglutide (4-week dose escalation from 3 to 7 to 14 mg) followed by placebo, or vice versa. Energy intake was measured during an ad libitum lunch, evening meal and snack box after a standard breakfast.

Effects of semaglutide on beta cell function and glycaemic control in participants with type 2 diabetes: a randomised, double-blind, placebo-controlled trial.

Aims/hypothesis: Semaglutide is a glucagon-like peptide-1 analogue in development for the treatment of type 2 diabetes. Its effects on first- and second-phase insulin secretion and other measures of beta cell function and glycaemic control were assessed.

Methods: In this single-centre, double-blind, placebo-controlled, parallel-group trial, conducted at the Profil Institut für Stoffwechselforschung, Germany, 75 adult (aged 18-64 years) participants with type 2 diabetes (eligibility: HbA of 6.

The role of the area postrema in the anorectic effects of amylin and salmon calcitonin: behavioral and neuronal phenotyping.

Amylin reduces meal size by activating noradrenergic neurons in the area postrema (AP). Neurons in the AP also mediate the eating-inhibitory effects of salmon calcitonin (sCT), a potent amylin agonist, but the phenotypes of the neurons mediating its effect are unknown. Here we investigated whether sCT activates similar neuronal populations to amylin, and if its anorectic properties also depend on AP function.

Novel α-MSH analog causes weight loss in obese rats and minipigs and improves insulin sensitivity.

Obesity is a major burden to people and to health care systems around the world. The aim of the study was to characterize the effect of a novel selective α-MSH analog on obesity and insulin sensitivity. The subchronic effects of the selective MC4-R peptide agonist MC4-NN1-0182 were investigated in diet-induced obese (DIO) rats and DIO minipigs by assessing the effects on food intake, energy consumption, and body weight.

Strategies to reduce treatment costs of peristomal skin complications.

Peristomal skin complications (PSCs) are common and troublesome and the consequences are substantial both for the patient and from a health-economic viewpoint. The purpose of this article is to demonstrate that early detection and treatment of PSCs, combined with the use of a correctly fitted and appropriate pouching system, can reduce treatment costs-in the UK, it is estimated to save £28.1m annually.

Recombinant adiponectin does not lower plasma glucose in animal models of type 2 diabetes.

Aims/hypothesis: Several studies have shown that adiponectin can lower blood glucose in diabetic mice. The aim of this study was to establish an effective adiponectin production process and to evaluate the anti-diabetic potential of the different adiponectin forms in diabetic mice and sand rats.

Methods: Human high molecular weight, mouse low molecular weight and mouse plus human globular adiponectin forms were expressed and purified from mammalian cells or yeast.

Identification and in vivo and in vitro characterization of long acting and melanocortin 4 receptor (MC4-R) selective α-melanocyte-stimulating hormone (α-MSH) analogues.

We report in vitro and in vivo data of new α-melanocyte-stimulating hormone (α-MSH) analogues which are N-terminal modified with a long chain fatty acid derivative. While keeping the pharmacophoric motif (d-Phe-Arg-Trp) fixed, we tried to improve selectivity and physicochemical parameters like solubility and stability of these analogues by replacing amino acids further away from the motif. Receptor specific changes in binding affinity to the melanocortin receptors were observed between the acetyl derivatives and the fatty acid analogues.

Ferret islet amyloid polypeptide (IAPP): characterization of in vitro and in vivo amyloidogenicity.

Diabetes in the domestic ferret (Mustela putorius furo) has previously been described and the purpose of this study was to evaluate if the ferret could serve as a model for the study of β-cell degeneration associated with formation of islet amyloid. The nucleotide and amino acid sequence of ferret islet amyloid polypeptide (IAPP) 1-37 was identified and the synthesized peptide was studied with regards to in vitro amyloidogenicity and potential cellular toxicity in a comparative approach to human, cat and the nonamyloidogenic rat IAPP. Ferret IAPP forms amyloid-like fibrils, but with a longer lag phase than human and cat IAPP and the aggregation process was shown to reduce cell viability of cultured β-cells, but with less potency than these two amyloidogenic counterparts.

Psychoanalytic reflections through the prism of September 11, 2001.

An important area for psychoanalytic study is the significance for intrapsychic life of important events taking place in the community of which analyst and analysand are a part. September 11, 2001 provides a vantage point for examination of questions that arise from looking at the interrelationship between current environment and intrapsychic life. Two cases are presented as a focus for discussing the interaction of the memorialized past and occurrences in present reality, the significance for an analysis of analyst and patient sharing the same experience, instigations to progress that a current event may provide and the ways in which communal experience influences intrapsychic life.

Aggression in cataract-bearing alpha-1,3-galactosyltransferase knockout mice.

The Galalpha1-3Galbeta1-4GlcNAc epitope is the key antigen in the hyperacute rejection of pig-to-man xenotransplantation. In the alpha-1,3-galactosyltransferase knockout (alpha-1,3GT-KO) mouse - a model for xenograft donor pigs - a targeted mutation of the alpha-1,3 galactosyltransferase gene (Ggta1) has been constructed. These mice are depleted of the carbohydrate antigen and besides the mice are also known to develop cortical cataracts.

Glucose intolerance in a xenotransplantation model: studies in alpha-gal knockout mice.

Xenotransplantation holds the promise of replacing failing human organs with organs of animal origin. Transplantation of pancreatic islets from pigs to humans might restore glucose homeostasis and offer diabetic patients considerable improvement in their quality of life. The alpha-gal epitope, present in all mammals except humans, apes and Old World monkeys, is a decisive obstruction to successful xenotransplantation of vascularized organs as the reaction of alpha-gal-bearing endothelia with natural alpha-gal antibodies in the human blood mediates hyperacute rejection of the xenograft.

The resistance of delayed xenograft rejection to alpha(1,3)-galactosyltransferase gene inactivation and CD4 depletion in a mouse-to-rat model.

Critical to the prevention of xenograft loss is the prevention of delayed xenograft rejection (DXR), due to its resistance to conventional immunosuppression. The role of the carbohydrate galactose-alpha1,3-galactose (alpha1,3Gal) has been a matter of great debate and it has been proposed that the reaction between alpha1,3Gal epitopes on donor endothelial cells and recipient anti-alpha1,3Gal antibodies (Abs) may damage the graft during DXR. Recipient anti-alpha1,3Gal Abs are produced by CD4-dependent B cells.

In her mother's voice: reflections on "femininity" and the superego.

For some female analysands the anxiety generated by superego conflict stimulated by aggressive and creative wishes may be warded off by invoking representations of the archaic all-powerful, limit-setting mother. To understand this clinical phenomenon in terms of a specific kind of female superego vulnerability is to miss the possibility that the fantasy of being mother's good little girl may be employed in the service of concealing the analysand's wishes and capacity for creative and destructive power. In the analytic hour we see transformed aspects of the analysand's past that are useful to the mind in its current operations.