Breaking Stereotypes: Diabetes Research, GLP-1, and the Roadmap for Preclinical Studies

On November 14th, World Diabetes Day serves as a global call to action to confront the complexities of diabetes, a condition that often grapples with various stereotypes and misconceptions. It's a common misbelief that only overweight individuals are at risk of diabetes or that young people need not be concerned about it. There are also misconceptions about dietary restrictions, with some assuming that people with diabetes can't enjoy fruits or can indulge in unhealthy eating as long as they take blood sugar-lowering medications. In this article, we aim to dispel these stereotypes and shed light on the importance of diabetes research, as we work together to better understand and manage this prevalent health condition.

Let's address these common misconceptions and delve into current trends in diabetes research and treatments.

GLP-1: A Potential Game-Changer in Diabetes Treatment

A great portion of diabetes research focuses on a particular gene, GLP-1, which inevitably leads us to glucagon-like peptide-1 (GLP-1) medications. Leading up to this year's Nobel Prize announcement, many industry experts anticipated that GLP-1 drugs might revolutionize the landscape of diabetes and obesity treatment. While it didn't secure the Nobel Prize, the transformative potential of GLP-1 drugs in metabolic and cardiovascular disease research remains promising.

The Star Target: GLP-1R

GLP-1, a hormone secreted by intestinal L cells, binds to the glucagon-like peptide 1 receptor (GLP-1R) protein. GLP-1R is encoded by the GLP-1R gene and is widely expressed in tissues such as the brain, small intestine, heart, and lungs. It plays a crucial role in insulin secretion signal transduction cascades in response to GLP-1 and GLP-1 analogs. Additionally, data from animal models indicate that it has neuroprotective effects ^[1-2].

GLP-1R Gene Polymorphism and its Relevance to Diabetes Research:

The polymorphism of the GLP-1R gene is closely associated with diabetes, and the GLP-1R protein is an important drug target for the treatment of type 2 diabetes and stroke. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are innovative antidiabetic drugs  that work by activating GLP-1R to enhance insulin secretion, suppress glucagon secretion, delay gastric emptying, and reduce food intake through central appetite suppression. This leads to the reduction of blood sugar and weight loss effects ^[3].

Introducing the B6-hGLP-1R Mouse Model

The B6-hGLP-1R strain (Product Number: C001421) is a genetically humanized Glp1r mouse model developed by Cyagen. This model involves the insertion of the genetic sequence encoding the core transmembrane domain and the larger extracellular domain of the human GLP1R protein into the mouse Glp1r gene sequence. While expressing the critical functional regions of the human GLP-1R protein, it retains the signal peptide and 3'UTR region of the mouse Glp1r gene. Homozygotes of this strain are viable and fertile.

This model aids research on the pathogenic mechanisms of metabolic diseases like obesity and type 2 diabetes, screening for and developing GLP-1RA drugs, and studying the neuroprotective effects of these drugs in neurological diseases. 

In addition to the B6-hGLP-1R model, Cyagen also offers other genetically edited models such as B6-ob/ob (Lep KO), induction models for type 1 and type 2 diabetes, and custom in vitro/in vivo research models by request.

B6-hGLP-1R Model Validation Data

To substantiate the reliability and efficacy of our humanized GLP-1 Receptor (B6-hGLP-1R) mouse model, we present comprehensive validation data across three key aspects: pancreatic tissue immunohistochemistry (IHC), pancreatic tissue immunofluorescence (IF), and efficacy validation of GLP-1R agonists.

By meticulously examining these aspects, we aim to provide a transparent and thorough assessment of the B6-hGLP-1R mouse model's suitability for research in metabolic diseases, drug development, and neuroprotective studies. This validation data serves as a testament to the model's reliability and relevance in advancing scientific understanding and innovation in the field.

⮚ Pancreatic Tissue Immunohistochemistry (IHC) Staining

Figure 1. Distribution of human GLP-1R protein in pancreatic tissues of 6-week-old wild-type (C57BL/6N) and B6-hGLP-1R homozygous (HO) mice.

Immunohistochemistry (IHC) staining was conducted to examine the distribution of GLP-1R protein in pancreatic tissues of wild-type and B6-hGLP-1R mice. The results revealed a significant expression of GLP-1R protein in the pancreatic islets of B6-hGLP-1R mice*. This IHC staining provides a visual representation of the presence and localization of GLP-1R in the pancreas.

*The GLP-1R antibody used for detection is a cross-reactive antibody that recognizes both human and mouse sources.

⮚ Pancreatic Tissue Immunofluorescence (IF) Staining

Figure 2. Distribution of human GLP-1R protein in pancreatic tissues of 6-week-old wild-type (C57BL/6N) and B6-hGLP-1R homozygous (HO) mice.

In Figure 2, we delve deeper into the distribution of human GLP-1R protein in pancreatic tissues, using Immunofluorescence (IF) staining. IF staining was employed to examine the distribution of GLP-1R protein in pancreatic tissues of (C57BL/6N) and B6-hGLP-1R homozygous mice (HO) at 6 weeks. The IF staining results revealed a significant expression of GLP-1R protein in the pancreatic islets of B6-hGLP-1R mice*.

*The GLP-1R antibody used for detection is a cross-reactive antibody that recognizes both human and mouse sources.

⮚ Efficacy Validation of GLP-1R Agonist PF-06882961

Figure 3. GLP-1R agonist PF-06882961 significantly reduces blood glucose levels in B6-hGLP-1R mice under both normal diet (CD) and high-fat diet (HFD) conditions.

Demonstrating a significant reduction in blood sugar levels, Figure 3 portrays the impact of the GLP-1R agonist PF-06882961 under both normal diet (CD) and high-fat diet (HFD) conditions in B6-hGLP-1R mice. This result suggests the model's responsiveness to pharmacological intervention, showcasing its potential for studying antidiabetic compounds.

⮚ Efficacy Validation of GLP-1R Agonist Semaglutide

Figure 4. GLP-1R agonist Semaglutide significantly reduces blood glucose levels and body weight in B6-hGLP-1R mice under high-fat diet (HFD) conditions.

Figure 4 delves into the efficacy of Semaglutide, another GLP-1R agonist, exhibiting a noteworthy reduction in blood sugar levels and body weight in B6-hGLP-1R mice subjected to a high-fat diet (HFD). These findings not only emphasize the model's relevance in studying metabolic disorders but also highlight its suitability for investigating weight management, a crucial aspect in diabetes research.

By elucidating the positive outcomes of these agonist validations, our B6-hGLP-1R mouse model demonstrates promise as a robust tool for diabetes research. The model's responsiveness to GLP-1R agonists positions it as a valuable platform for screening and evaluating potential antidiabetic drugs. These results not only contribute to the understanding of the model's physiological relevance but also open avenues for innovative drug development and targeted therapeutic interventions in the realm of diabetes and metabolic disorders.

Recommendation of Metabolism and Cardiovascular Models

In the field of metabolism and cardiovascular disease research, Cyagen is customer-centric and collaborates extensively with pharmaceutical companies, biotechnology firms, and university research departments worldwide. We have established various disease models related to obesity, diabetes, atherosclerosis, and more. These include multiple types of metabolism and cardiovascular-related models, such as Ldlr KO (em), Uox-KO (Prolonged), and Apoe KO, which contribute to advancing new drug research and development.

⮚ Selected Models for Metabolic and Cardiovascular Diseases – Gene Editing