Targeting GPCRs and their Ligands in the Gut Establishing Glucose Homeostasis and Appetite Regulation

Editors

Aylin Carla Hanyaloglu

Imperial College London

Caroline Gorvin

University of Birmingham

Alejandra Tomas

Imperial College London

Impact

Original Research

12 July 2022

Noninvasive Evaluation of GIP Effects on β-Cell Mass Under High-Fat Diet

Sakura Kiyobayashi

, 10 more and

Nobuya Inagaki

3,384 views

2 citations

Original Research

30 June 2022

Analysis of Intestinal Short-Chain Fatty Acid Metabolism Profile After Probiotics and GLP-1 Treatment for Type 2 Diabetes Mellitus

Qiuxia Min

, 6 more and

Ning Xu

5,421 views

8 citations

Original Research

29 April 2022

Conversion of Gastrointestinal Somatostatin-Expressing D Cells Into Insulin-Producing Beta-Like Cells Upon Pax4 Misexpression

Anna Garrido-Utrilla

, 7 more and

Patrick Collombat

3,938 views

5 citations

Review

25 April 2022

Is Glucagon Receptor Activation the Thermogenic Solution for Treating Obesity?

Ellen Conceição-Furber

, 2 more and

Ricardo J. Samms

A major challenge of obesity therapy is to sustain clinically relevant weight loss over time. Achieving this goal likely requires both reducing daily caloric intake and increasing caloric expenditure. Over the past decade, advances in pharmaceutical engineering of ligands targeting G protein-coupled receptors have led to the development of highly effective anorectic agents. These include mono-agonists of the GLP-1R and dual GIPR/GLP-1R co-agonists that have demonstrated substantial weight loss in experimental models and in humans. By contrast, currently, there are no medicines available that effectively augment metabolic rate to promote weight loss. Here, we present evidence indicating that activation of the GCGR may provide a solution to this unmet therapeutic need. In adult humans, GCGR agonism increases energy expenditure to a magnitude sufficient for inducing a negative energy balance. In preclinical studies, the glucagon-GCGR system affects key metabolically relevant organs (including the liver and white and brown adipose tissue) to boost whole-body thermogenic capacity and protect from obesity. Further, activation of the GCGR has been shown to augment both the magnitude and duration of weight loss that is achieved by either selective GLP-1R or dual GIPR/GLP-1R agonism in rodents. Based on the accumulation of such findings, we propose that the thermogenic activity of GCGR agonism will also complement other anti-obesity agents that lower body weight by suppressing appetite.

8,589 views

20 citations

(A, B) Representative pictures of pancreatic islets stained with insulin antibody. (C) Relative pancreatic islets area. (D) Insulin-stained area related to total pancreatic islets area. (E) C-peptide (solid bars) and glucose (dotted bars) levels in serum. (F) Ex vivo insulin secretion from incubated pancreatic islets. Original magnification x20 (A, B) Data are mean ± SEM of 5 mice/group (A–D) and 21-23 mice/group (E). Data represent the mean ± SEM from 3-5 independent experiments (F). ****p < 0.001 vs. CNT mice.

Original Research

25 February 2022

PTEN Deletion in Adult Mice Induces Hypoinsulinemia With Concomitant Low Glucose Levels

Maria Crespo-Masip

, 6 more and

José Manuel Valdivielso

3,144 views

3 citations

Original Research

10 January 2022

Gut Microbial Signatures for Glycemic Responses of GLP-1 Receptor Agonists in Type 2 Diabetic Patients: A Pilot Study

Chih-Yiu Tsai

, 6 more and

Chi-Neu Tsai

Backgrounds: Glucagon-like peptide-1 receptor agonist (GLP-1 RA) is probably one of more effective antidiabetic agents in treatment of type 2 diabetes mellitus (T2D). However, the heterogenicity in responses to GLP-1 RA may be potentially related to gut microbiota, although no human evidence has been published. This pilot study aims to identify microbial signatures associated with glycemic responses to GLP-1 RA.

Materials and Methods: Microbial compositions of 52 patients with T2D receiving GLP-1 RA were determined by 16S rRNA amplicon sequencing. Bacterial biodiversity was compared between responders versus non-responders. Pearson’s correlation and random forest tree algorithm were used to identify microbial features of glycemic responses in T2D patients and multivariable linear regression models were used to validate clinical relevance.

Results: Beta diversity significantly differed between GLP-1 RA responders (n = 34) and non-responders (n = 18) (ADONIS, P = 0.004). The top 17 features associated with glycohemoglobin reduction had a 0.96 diagnostic ability, based on area under the ROC curve: Bacteroides dorei and Roseburia inulinivorans, the two microbes having immunomodulation effects, along with Lachnoclostridium sp. and Butyricicoccus sp., were positively correlated with glycemic reduction; Prevotella copri, the microbe related to insulin resistance, together with Ruminococcaceae sp., Bacteroidales sp., Eubacterium coprostanoligenes sp., Dialister succinatiphilus, Alistipes obesi, Mitsuokella spp., Butyricimonas virosa, Moryella sp., and Lactobacillus mucosae had negative correlation. Furthermore, Bacteroides dorei, Lachnoclostridium sp. and Mitsuokella multacida were significant after adjusting for baseline glycohemoglobin and C-peptide concentrations, two clinical confounders.

Conclusions: Unique gut microbial signatures are associated with glycemic responses to GLP-RA treatment and reflect degrees of dysbiosis in T2D patients.

10,130 views

49 citations