Glucagonlike Peptide-1 Receptor Imaging in Individuals with Type 2 Diabetes.

The glucagonlike peptide-1 receptor (GLP1R) is a gut hormone receptor, intricately linked to regulation of blood glucose homeostasis via several mechanisms. It is an established and emergent drug target in metabolic disease. The PET radioligand Ga-DO3A-VS-exendin4 (Ga-exendin4) has the potential to enable longitudinal studies of GLP1R in the human pancreas.

Drug Occupancy Assessment at the Glucose-Dependent Insulinotropic Polypeptide Receptor by Positron Emission Tomography.

Targeting of the glucose-dependent insulinotropic polypeptide receptor (GIPR) is an emerging strategy in antidiabetic drug development. The aim of this study was to develop a positron emission tomography (PET) radioligand for the GIPR to enable the assessment of target distribution and drug target engagement in vivo. The GIPR-selective peptide S02-GIP was radiolabeled with Ga.

The Novel Phosphate and Bile Acid Sequestrant Polymer SAR442357 Delays Disease Progression in a Rat Model of Diabetic Nephropathy.

As a gut-restricted, nonabsorbed therapy, polymeric bile acid sequestrants (BAS) play an important role in managing hyperlipidemia and hyperglycemia. Similarly, nonabsorbable sequestrants of dietary phosphate have been used for the management of hyperphosphatemia in end-stage renal disease. To evaluate the potential utility of such polymer sequestrants to treat type 2 diabetes (T2D) and its associated renal and cardiovascular complications, we synthesized a novel polymeric sequestrant, SAR442357, possessing optimized bile acid (BA) and phosphate sequestration characteristics.

Gut Mucosal Gene Expression and Metabolic Changes After Roux-en-Y Gastric Bypass Surgery.

Objective: Changes in the secretion of gut-derived peptide hormones have been associated with the metabolic benefits of Roux-en-Y gastric bypass (RYGB) surgery. In this study, the effects of RYGB on anthropometrics, postprandial plasma hormone responses, and mRNA expression in small intestinal mucosa biopsy specimens before and after RYGB were evaluated.

Methods: In a cross-sectional study, 20 individuals with obesity undergoing RYGB underwent mixed meal tests and upper enteroscopy with retrieval of small intestinal mucosa biopsy specimens 3 months before and after surgery.

Imaging of the Glucagon Receptor in Subjects with Type 2 Diabetes.

Despite the importance of the glucagon receptor (GCGR) in disease and in pharmaceutical drug development, there is a lack of specific and sensitive biomarkers of its activation in humans. The PET radioligand Ga-DO3A-VS-Tuna-2 (Ga-Tuna-2) was developed to yield a noninvasive imaging marker for GCGR target distribution and drug target engagement in humans. The biodistribution and dosimetry of Ga-Tuna-2 was assessed by PET/CT in 13 individuals with type 2 diabetes as part of a clinical study assessing the occupancy of the dual GCGR/glucagon like peptide-1 receptor agonist SAR425899.

Assessment of glucagon receptor occupancy by Positron Emission Tomography in non-human primates.

The glucagon receptor (GCGR) is an emerging target in anti-diabetic therapy. Reliable biomarkers for in vivo activity on the GCGR, in the setting of dual glucagon-like peptide 1/glucagon (GLP-1/GCG) receptor agonism, are currently unavailable. Here, we investigated [Ga]Ga-DO3A-S01-GCG as a biomarker for GCGR occupancy in liver, the tissue with highest GCGR expression, in non-human primates (NHP) by PET.

Investigating Intestinal Glucagon After Roux-en-Y Gastric Bypass Surgery.

Context: After Roux-en-Y gastric bypass (RYGB) surgery, postprandial plasma glucagon concentrations have been reported to increase. This occurs despite concomitant improved glucose tolerance and increased circulating plasma concentrations of insulin and the glucagon-inhibiting hormone glucagon-like peptide 1 (GLP-1).

Objective: To investigate whether RYGB-induced hyperglucagonemia may be derived from the gut.

Hepatic transcriptomic signatures of statin treatment are associated with impaired glucose homeostasis in severely obese patients.

Background: Clinical data identified an association between the use of HMG-CoA reductase inhibitors (statins) and incident diabetes in patients with underlying diabetes risk factors such as obesity, hypertension and dyslipidemia. The molecular mechanisms however are unknown.

Methods: An observational cross-sectional study included 910 severely obese patients, mean (SD) body mass index (BMI) 46.

First-in-class positron emission tomography tracer for the glucagon receptor.

Unlabelled: The glucagon receptor (GCGR) is emerging as an important target in anti-diabetic therapy, especially as part of the pharmacology of dual glucagon-like peptide-1/glucagon (GLP-1/GCG) receptor agonists. However, currently, there are no suitable biomarkers that reliably demonstrate GCG receptor target engagement.

Methods: Two potent GCG receptor peptide agonists, S01-GCG and S02-GCG, were labeled with positron emission tomography (PET) radionuclide gallium-68.

The role of C16:0 ceramide in the development of obesity and type 2 diabetes: CerS6 inhibition as a novel therapeutic approach.

Objective: Ectopic fat deposition is associated with increased tissue production of ceramides. Recent genetic mouse studies suggest that specific sphingolipid C16:0 ceramide produced by ceramide synthase 6 (CerS6) plays an important role in the development of insulin resistance. However, the therapeutic potential of CerS6 inhibition not been demonstrated.

A novel dual glucagon-like peptide and glucagon receptor agonist SAR425899: Results of randomized, placebo-controlled first-in-human and first-in-patient trials.

Aims: To evaluate the safety, pharmacokinetics and pharmacodynamics of SAR425899, a novel polypeptide, active as an agonist at both the glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCR), in healthy volunteers and in overweight/obese patients with type 2 diabetes (T2D).

Methods: Subcutaneous administrations of SAR425899 were tested in two randomized, placebo-controlled, double-blind clinical trials. In the first trial, healthy overweight volunteers (body mass index [BMI] 25-30 kg/m ; n = 32) received single-ascending doses (0.

Team Players or Opponents: Coadministration of Selective Glucagon and GLP-1 Receptor Agonists in Obese Diabetic Monkeys.

We assessed the therapeutic contribution of the individual components of glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR) agonists alone and in combination upon energy homeostasis and glycemic control in diet-induced obese, diabetic nonhuman primates. The pharmacological active dose ranges of selective agonists were established through a dose-finding study, followed by a 6-week chronic study. Repeated subcutaneous administration of a selective GCGR agonist (30 µg/kg once daily) did not affect food intake or body weight, whereas the selective GLP-1R agonist (3 µg/kg once daily) alone decreased energy intake by 18% and body weight by 3.

Running on mixed fuel-dual agonistic approach of GLP-1 and GCG receptors leads to beneficial impact on body weight and blood glucose control: A comparative study between mice and non-human primates.

Aim: We performed acute and chronic studies in healthy and diet-induced obese animals using mouse-specific or monkey-specific dual GLP-1R/GCGR agonists to investigate their effects on food intake, body weight, blood glucose control and insulin secretion. The selective GLP-1R agonist liraglutide was used as comparator.

Methods: The mouse-specific dual agonist and liraglutide were tested in lean wild type, GLP-1R knockout and diet-induced obese mice at different doses.

Guanylin and uroguanylin mRNA expression is increased following Roux-en-Y gastric bypass, but guanylins do not play a significant role in body weight regulation and glycemic control.

Aim: To determine whether intestinal expression of guanylate cyclase activator 2A (GUCA2A) and guanylate cyclase activator 2B (GUCA2B) genes is regulated in obese humans following Roux-en-Y gastric bypass (RYGB), and to evaluate the corresponding guanylin (GN) and uroguanylin (UGN) peptides for potentially contributing to the beneficial metabolic effects of RYGB.

Methods: Enteroendocrine cells were harvested peri- and post-RYGB, and GUCA2A/GUCA2B mRNA expression was compared. GN, UGN and their prohormones (proGN, proUGN) were administered subcutaneously in normal-weight mice to evaluate effects on food intake and glucose regulation.

On ceramides, other sphingolipids and impaired glucose homeostasis.

In most people with type 2 diabetes, progression from obesity to diabetes is accompanied by elevated tissue exposures to a variety of lipids. Among these lipid species, ceramides and more complex sphingolipids have gained recent attention as being pathophysiologically relevant for the development of insulin resistance and impaired glycemic control. Upon excess intake of saturated fat, ceramides accumulate in insulin sensitive tissues either as a consequence of de novo synthesis or through mobilization from complex sphingolipids.

Expression of the fatty acid receptor GPR120 in the gut of diet-induced-obese rats and its role in GLP-1 secretion.

Stimulation of the G protein coupled receptor GPR120 has been shown to have anti-inflammatory and insulin-sensitizing effects, to promote glucagon like peptide-1 (GLP-1) secretion, and to play a key role in sensing dietary fat and control energy balance. In a search for differentially expressed genes potentially involved in food intake and body-weight regulation we identified GPR120 to be differentially regulated in the intestine of selectively bred diet induced obese (DIO) and diet resistant (DR) rats. Subsequently we investigated the effect of GPR120 receptor stimulation with the long chain fatty acid alpha linolenic acid (ALA) on GLP-1 secretion in rats.

Mice with a targeted deletion of the type 2 deiodinase are insulin resistant and susceptible to diet induced obesity.

Background: The type 2 iodothyronine deiodinase (D2) converts the pro-hormone thyroxine into T3 within target tissues. D2 is essential for a full thermogenic response of brown adipose tissue (BAT), and mice with a disrupted Dio2 gene (D2KO) have an impaired response to cold. BAT is also activated by overfeeding.

FGF21 reloaded: challenges of a rapidly growing field.

Fibroblast growth factor 21 (FGF21) is a pleiotropic hormone-like protein and a major metabolic regulator. However, several key aspects of FGF21 biology remain poorly understood. Indeed, the list of controversies in the FGF21 field spans a variety of topics, from basic matters such as the anatomic distribution of FGF21 expression and the molecular composition of the FGF21 receptor, to the ultimate question of therapeutic relevance of FGF21-dependent pathways in humans.

Stereological assessment of pancreatic beta-cell mass development in male Zucker Diabetic Fatty (ZDF) rats: correlation with pancreatic beta-cell function.

The present study was initiated to improve our understanding of pancreatic beta-cell dynamics in male Zucker Diabetic Fatty (ZDF) rats and hence provide a framework for future diabetes studies in this animal model. Male ZDF rats from 6, 8, 10, 12, 14, 16, 20 and 26 weeks of age were subjected to an oral glucose tolerance test (OGTT). The animals were then euthanized and pancreases were removed for morphometric analyses of pancreatic beta-cell mass.

Preproglucagon derived peptides GLP-1, GLP-2 and oxyntomodulin in the CNS: role of peripherally secreted and centrally produced peptides.

The scientific understanding of preproglucagon derived peptides has provided people with type 2 diabetes with two novel classes of glucose lowering agents, the dipeptidyl peptidase IV (DPP-IV) inhibitors and GLP-1 receptor agonists. For the scientists, the novel GLP-1 agonists, and DPP-IV inhibitors have evolved as useful tools to understand the role of the preproglucagon derived peptides in normal physiology and disease. However, the overwhelming interest attracted by GLP-1 analogues as potent incretins has somewhat clouded the efforts to understand the importance of preproglucagon derived peptides in other physiological contexts.

Long-term characterization of the diet-induced obese and diet-resistant rat model: a polygenetic rat model mimicking the human obesity syndrome.

The availability of useful animal models reflecting the human obesity syndrome is crucial in the search for novel compounds for the pharmacological treatment of obesity. In the current study, we have performed an extensive characterization of the obesity syndrome in a polygenetic animal model, namely the selectively bred diet-induced obese (DIO) and diet-resistant (DR) rat strains. We show that they constitute useful models of the human obesity syndrome.

The novel triple monoamine reuptake inhibitor tesofensine induces sustained weight loss and improves glycemic control in the diet-induced obese rat: comparison to sibutramine and rimonabant.

Tesofensine, a novel triple monoamine reuptake inhibitor, produces a significant weight loss in humans. The present study aimed at characterizing the weight-reducing effects of tesofensine in a rat model of diet-induced obesity. Sibutramine and rimonabant were used as reference comparators.

ADD1/SREBP1c activates the PGC1-alpha promoter in brown adipocytes.

Cold adaptation elicits a paradoxical simultaneous induction of fatty acid synthesis and beta-oxidation in brown adipose tissue. We show here that cold exposure coordinately induced liver X receptor alpha (LXRalpha), adipocyte determination and differentiation-dependent factor 1 (ADD1)/sterol regulatory element-binding protein-1c (SREBP1c) and peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC1alpha) in brown and inguinal white adipose tissues, but not in epididymal white adipose tissue. Using in vitro models of white and brown adipocytes we demonstrate that beta-adrenergic stimulation induced expression of LXRalpha, ADD1/SREBP1c and PGC1alpha in cells with a brown-like adipose phenotype.

The imprinted gene neuronatin is regulated by metabolic status and associated with obesity.

Using restriction fragment differential display (RFDD) technology, we have identified the imprinted gene neuronatin (Nnat) as a hypothalamic target under the influence of leptin. Nnat mRNA expression is decreased in several key appetite regulatory hypothalamic nuclei in rodents with impaired leptin signaling and during fasting conditions. Furthermore, peripheral administration of leptin to ob/ob mice normalizes hypothalamic Nnat expression.

Characterization of beta-cell mass and insulin resistance in diet-induced obese and diet-resistant rats.

The selectively bred diet-induced obese (DIO) and diet-resistant (DR) rats represent a polygenetic animal model mimicking most clinical variables characterizing the human metabolic syndrome. When fed a high-energy (HE) diet DIO rats develop visceral obesity, dyslipidemia, hyperinsulinemia, and insulin resistance but never frank diabetes. To improve our understanding of the underlying cause for the deteriorating glucose and insulin parameters, we have investigated possible adaptive responses in DIO and DR rats at the level of the insulin-producing beta-cells.