Salcaprozate-based ionic liquids for GLP-1 gastric delivery: A mechanistic understanding of in vivo performance.

Oral delivery of peptides requires formulations with high concentrations of permeation enhancer (PE) to promote absorption, and often necessitates fasting time between dosing and food ingestion. Improved formulations promoting a more rapid absorption would increase convenience of use but requires a faster onset of action. We have developed a salcaprozate-based ionic liquid (IL) formulation, namely choline salcaprozate (CHONAC), for oral delivery of a glucagon-like peptide-1 (GLP-1) analogue via gastric absorption.

Improved leptin sensitivity and increased soluble leptin receptor concentrations may underlie the additive effects of combining PYY [, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ] and exendin-4 on body weight lowering in diet-induced obese mice.

Objective: Co-treatment with long acting PYY and the GLP-1 receptor agonists has potential as an efficient obesity treatment. This study investigates whether the mechanisms behind additive reduction of food intake and weight loss depends on complementary effects in brain areas regulating food intake and if restoration of leptin sensitivity is involved.

Methods: Diet-induced obese (DIO) mice were co-treated with PYY(3-36) and exendin-4 (Ex4, GLP-1R agonist) for 14 days using minipumps.

GDF15 promotes weight loss by enhancing energy expenditure in muscle.

Caloric restriction that promotes weight loss is an effective strategy for treating non-alcoholic fatty liver disease and improving insulin sensitivity in people with type 2 diabetes. Despite its effectiveness, in most individuals, weight loss is usually not maintained partly due to physiological adaptations that suppress energy expenditure, a process known as adaptive thermogenesis, the mechanistic underpinnings of which are unclear. Treatment of rodents fed a high-fat diet with recombinant growth differentiating factor 15 (GDF15) reduces obesity and improves glycaemic control through glial-cell-derived neurotrophic factor family receptor α-like (GFRAL)-dependent suppression of food intake.

Standard procedures for blood withdrawal in conscious male rats induce stress and profoundly affect glucose tolerance and secretion of glucoregulatory hormones.

Objective: A fundamental difference between physiological and pharmacological studies in rats and humans is that withdrawal of blood from conscious rats necessitates restraint which inevitably inflicts a higher level of stress. We investigated the impact of handling on acute glucose regulation and secretion of glucoregulatory hormones in rats.

Methods: Fasted male Sprague Dawley rats (375-400 g, n = 11) were given an oral glucose tolerance test (OGTT) by gavage (2 g/kg).

Housing-temperature reveals energy intake counter-balances energy expenditure in normal-weight, but not diet-induced obese, male mice.

Most metabolic studies on mice are performed at room temperature, although under these conditions mice, unlike humans, spend considerable energy to maintain core temperature. Here, we characterize the impact of housing temperature on energy expenditure (EE), energy homeostasis and plasma concentrations of appetite- and glucoregulatory hormones in normal-weight and diet-induced obese (DIO) C57BL/6J mice fed chow or 45% high-fat-diet, respectively. Mice were housed for 33 days at 22, 25, 27.

Targeting the Gut in Obesity: Signals from the Inner Surface.

Obesity is caused by prolonged energy surplus. Current anti-obesity medications are mostly centralized around the energy input part of the energy balance equation by increasing satiety and reducing appetite. Our gastrointestinal tract is a key organ for regulation of food intake and supplies a tremendous number of circulating signals that modulate the activity of appetite-regulating areas of the brain by either direct interaction or through the vagus nerve.

Plasma GDF15 levels are similar between subjects after bariatric surgery and matched controls and are unaffected by meals.

Growth differentiating factor 15 (GDF15) is expressed in the intestine and is one of the most recently identified satiety peptides. The mechanisms controlling its secretion are unclear. The present study investigated whether plasma GDF15 concentrations are meal-related and if potential responses depend on macronutrient type or are affected by previous bariatric surgery.

Acute ketosis inhibits appetite and decreases plasma concentrations of acyl ghrelin in healthy young men.

Aim: To investigate the acute effect of ketone ester (KE) ingestion on appetite and plasma concentrations of acyl ghrelin (AG), unacylated ghrelin (UAG) and glucagon-like peptide-1 (GLP-1) secretion, and to compare responses with those elicited by isocaloric glucose (GLU) administration.

Methods: We examined 10 healthy young men on three separate occasions using a placebo (PBO)-controlled crossover design. A KE versus taste-matched isovolumetric and isocaloric 50% GLU and taste-matched isovolumetric PBO vehicle was orally administered.

Amino acids differ in their capacity to stimulate GLP-1 release from the perfused rat small intestine and stimulate secretion by different sensing mechanisms.

The aim of this study was to explore individual amino acid-stimulated GLP-1 responses and the underlying stimulatory mechanisms, as well as to identify the amino acid-sensing receptors involved in amino acid-stimulated GLP-1 release. Experiments were primarily based on isolated perfused rat small intestines, which have intact epithelial polarization allowing discrimination between luminal and basolateral mechanisms as well as quantitative studies of intestinal absorption and hormone secretion. Expression analysis of amino acid sensors on isolated murine GLP-1 secreting L-cells was assessed by qPCR.

Responses of gut and pancreatic hormones, bile acids, and fibroblast growth factor-21 differ to glucose, protein, and fat ingestion after gastric bypass surgery.

Postprandial gut hormone responses change after Roux-en-Y gastric bypass (RYGB), and we investigated the impact of glucose, protein, and fat (with and without pancreas lipase inhibition) on plasma responses of gut and pancreas hormones, bile acids, and fibroblast growth factor 21 (FGF-21) after RYGB and in nonoperated control subjects. In a randomized, crossover study 10 RYGB operated and 8 healthy weight-matched control subjects were administered 4 different 4-h isocaloric (200 kcal) liquid meal tests containing >90 energy (E)% of either glucose, protein (whey protein), or fat (butter with and without orlistat). The primary outcome was glucagon-like peptide-1 (GLP-1) secretion (area under the curve above baseline).

Bile acids drive colonic secretion of glucagon-like-peptide 1 and peptide-YY in rodents.

A large number of glucagon-like-peptide-1 (GLP-1)- and peptide-YY (PYY)-producing L cells are located in the colon, but little is known about their contribution to whole body metabolism. Since bile acids (BAs) increase GLP-1 and PYY release, and since BAs spill over from the ileum to the colon, we decided to investigate the ability of BAs to stimulate colonic GLP-1 and PYY secretion. Using isolated perfused rat/mouse colon as well as stimulation of the rat colon in vivo, we demonstrate that BAs significantly enhance secretion of GLP-1 and PYY from the colon with average increases of 3.

Abscisic acid stimulates the release of insulin and of GLP-1 in the rat perfused pancreas and intestine.

Aims: Previous results indicate that nanomolar concentrations of abscisic acid (ABA) stimulate insulin release from β-pancreatic cells in vitro and that oral ABA at 50 mg/kg increases plasma GLP-1 in the fasted rat. The aim of this study was to test the effect of ABA on the perfused rat pancreas and intestine, to verify the insulin- and incretin-releasing actions of ABA in controlled physiological models.

Materials And Methods: Rat pancreas and small intestine were perfused with solutions containing ABA at high-micromolar concentrations, or control secretagogues.

Neuromedin U Does Not Act as a Decretin in Rats.

Studies on isolated pancreatic islets suggest that neuromedin U (NMU), a brain and gastrointestinal peptide, acts as a decretin hormone, inhibiting glucose-stimulated insulin secretion. We investigated whether this effect could be reproduced in vivo and in isolated perfused rat pancreas. Unlike the incretin hormone, glucagon-like peptide 1 (GLP-1), intravenous NMU administration had no effects on blood glucose and plasma insulin and glucagon in vivo.

Peptide production and secretion in GLUTag, NCI-H716, and STC-1 cells: a comparison to native L-cells.

GLUTag, NCI-H716, and STC-1 are cell lines that are widely used to study mechanisms underlying secretion of glucagon-like peptide-1 (GLP-1), but the extent to which they resemble native L-cells is unknown. We used validated immunoassays for 14 different hormones to analyze peptide content (lysis samples; n = 9 from different passage numbers) or peptide secretion in response to buffer (baseline), and after stimulation with 50 mM KCl or 10 mM glucose + 10 µM forskolin/3-isobutyl-1-methylxanthine (n = 6 also different passage numbers). All cell lines produced and processed proglucagon into GLP-1, GLP-2, glicentin, and oxyntomodulin in a pattern (prohormone convertase (PC)1/3 dependent) similar to that described for human gut.

Glucose stimulates neurotensin secretion from the rat small intestine by mechanisms involving SGLT1 and GLUT2, leading to cell depolarization and calcium influx.

Neurotensin (NT) is a neurohormone produced in the central nervous system and in the gut epithelium by the enteroendocrine N cell. NT may play a role in appetite regulation and may have potential in obesity treatment. Glucose ingestion stimulates NT secretion in healthy young humans, but the mechanisms involved are not well understood.

Measurement of the incretin hormones: glucagon-like peptide-1 and glucose-dependent insulinotropic peptide.

The two incretin hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), are secreted from the gastrointestinal tract in response to meals and contribute to the regulation of glucose homeostasis by increasing insulin secretion. Assessment of plasma concentrations of GLP-1 and GIP is often an important endpoint in both clinical and preclinical studies and, therefore, accurate measurement of these hormones is important. Here, we provide an overview of current approaches for the measurement of the incretin hormones, with particular focus on immunological methods.

GLP-1 amidation efficiency along the length of the intestine in mice, rats and pigs and in GLP-1 secreting cell lines.

XXX: Measurements of plasma concentrations of the incretin hormone GLP-1 are complex because of extensive molecular heterogeneity. This is partly due to a varying and incompletely known degree of C-terminal amidation. Given that virtually all GLP-1 assays rely on a C-terminal antibody, it is essential to know whether or not the molecule one wants to measure is amidated.

Targeting the intestinal L-cell for obesity and type 2 diabetes treatment.

Degradation-resistant glucagon-like peptide-1 (GLP-1) mimetics and GLP-1 enhancers (inhibitors of dipeptidyl peptidase-4, the enzyme which degrades and inactivates GLP-1) have been used for treatment of type 2 diabetes mellitus since 2005-2006. Cutting-edge research is now focusing on uncovering the secretory mechanisms of the GLP-1-producing cells (L-cells) with the purpose of developing agonists that enhance endogenous hormone secretion. Since GLP-1 co-localizes with other anorectic peptides, cholecystokinin, oxyntomodulin/glicentin and peptide YY, L-cell targeting might cause release of several hormones at the same time, providing additive effects on appetite and glucose regulation.