Editor’s note : Most researchers endeavor to translate their basic findings into the clinic. While we have successfully cured diseases in mice, our struggle to generate similar positive results in humans continues. Preclinical animal models are poor predictors of successful clinical trials, as they often do not encompass the physiologically relevant features of the disease. Shreyas Jadhav explores this conundrum further by shining the spotlight on an article published in Nature Scientific Reports that highlights the differences between mice and human gene expression profiles in Type 2 diabetes and their impact on translation studies. Ultimately, a thorough understanding of the differences between mice and humans can save time and money to avoid failure in clinical trials. – Radhika Raheja
Almost 90% of diabetes cases are type 2 diabetes, which is characterized by the inability of the body to properly utilize released insulin or due to impaired insulin secretion from the islets. Since insulin regulates glucose levels in the blood, inadequate amounts of insulin in turn results in a buildup of glucose levels, which consequently affects normal physiology. Insulin release from islet cells is regulated by a complex mechanism involving neurotransmitters and hormones. G-Protein Coupled Receptors (GPCRs) are being pursued as potential therapeutic targets for developing pharmaceuticals to treat diabetes due to their role in insulin release by beta cells. In a recently published report in the journal Nature Scientific Reports, researchers have analyzed the GPCR expression profiles in mouse and human islet cells and made some interesting observations in the differences in their expression profiles and their subsequent impact on clinical translation.
Specifically, they compared the GPCR expression profile by qPCR in two laboratory mouse strains (outbred ICR and inbred C57B/6) and human islet cells and reported some interesting findings. Of the 341 GPCR mRNAs analyzed in mice, 183 GPCR mRNAs were expressed above the cut off limit. Not surprising, there was a strong correlation between the GPCR expression profiles of the two mouse strains. They observed strain specific expression profile wherein 12 GPCRs were expressed solely by the C57 mouse islets and 17 additional GPCRs were exclusive to the ICR mouse islets. Finally, out of the ten most abundantly expressed GPCRs, eight were common to both strains (Calcrl, Cckar, Ffar1, Galr1, Glp1r, Gpr158, Gpr56 and Gprc5c). Of the ten most abundantly expressed mouse GPCRs, only three were commonly expressed between mouse and human islets (GPR56, GLP-1 and FFAR1). Interestingly, GLP-1, the most well characterized islet GPCR was present in both mouse and human islets. Indeed GLP-1 receptor is a target for type 2 diabetes and there are currently at least five FDA approved compounds in the market.
The authors further highlighted the significance of these observed differences in the GPCR expression profiles between human and mice by demonstrating functional relevance. Given that the A3 (ADORA3) receptor is expressed only in mice and not in human islets, the A3 agonist MRS 5698 was able to inhibit glucose induced insulin secretion from mouse islets and had no effect on human islets. Also, since the galanin receptors were highly expressed in mouse islets and not as much in human islets, activation of these receptors inhibited insulin secretion in mice whereas their activation in human islets had no effect. Finally, the Gi coupled sst1 (SSTR1) receptor mRNA which showed high expression level in human islets, inhibited insulin secretion in response to the agonist CH 275. The same agonist failed to show a similar response in mouse islets.
While the majority of our current understanding of the disease mechanisms arises from research in rodent models of diabetes (as shown by the identification of the GLP-1 receptor to develop therapeutics), there exist significant differences in the expression profiles of genes between mice and humans. These differences, unequivocally, will have to be taken into account while establishing procedures to develop therapeutics. Despite the ongoing research efforts to understand the molecular mechanisms underlying the cause of diabetes, definitive treatment strategies remain largely elusive. This, in part, is due to the complex nature of the disorder and the lack of good disease models.
Given that the ultimate goal is to develop pharmaceuticals that will successfully treat humans, there is a need to overcome the limitations posed by rodent models by at least understanding the similarities and differences between specific human and rodent cells in terms of their expression profiles. This paper represents a step in that direction.
Indeed, this scenario is not exclusive to diabetes and extends to other conditions as well, mainly neurodegenerative disorders where we do not have mouse models that mimic the human condition. This certainly poses a challenge in developing therapeutics that can be used to treat patients. While we have to assess strategies to humanize mouse models, iPS cells (including patient derived iPSC’s) could potentially be employed to understand disease mechanisms and as a drug screening platform.
Article in spotlight
Stefan Amisten, Patricio Atanes, Ross Hawkes, Inmaculada Ruz-Maldonado, Bo Liu, Fariborz Parandeh, Min Zhao, Guo Cai Huang, Albert Salehi and Shanta J. Persaud. A comparative analysis of human and mouse islet G-protein coupled receptor expression. Nature Scientific Reports 7, 46600 (2017)
Amisten, S., Salehi, A., Rorsman, P., Jones, P. M. & Persaud, S. J. An atlas and functional analysis of G-protein coupled receptors in human islets of Langerhans. Pharmacology & therapeutics 139, 359–391 (2013).
Lalita Prasad-Reddy, Diana Issacs. A clinical review of GLP-1 receptor agonists: efficacy and safety in diabetes and beyond. Drugs in Context, 4: 212283 (2015)
Aileen JF King. The use of animal models in diabetes research. British Journal of Pharmacology 166, 877-894 (2012)
Sarah Crunkhorn. Human iPSC-derived b-like cells rescue diabetic mice. Nature Reviews Drug Discivery 15, 382-383 (2016)
Monica J. Justice, and Paraminder Dhillon Dis. Model. Mech. 2016;9:101-103
About the author
Shreyas Jadhav completed his PhD from the Indian Institute of Technology, Kanpur, India, where he studied the role of mRNA translation in the C.elegans model. During his postdoctoral research at Harvard Medical School (Boston Children’s Hospital and Brigham and Women’s Hospital) and Tufts University, his research focused on applying Molecular and Cellular biology techniques to understanding kidney disease mechanisms, including fibrosis. He is interested in communicating research to a broad audience within the scientific community.
About the editor
Radhika Raheja completed her PhD from Cornell University and is currently a Postdoctoral fellow at the Brigham and Women’s Hospital. Her research interests have centered around oncology and neuroimmunology. Among other things, she is striving to effectively communicate scientific discoveries to the community.
About the illustrator
Vinita Bharat Ph.D., is currently a postdoctoral research fellow at European Neuroscience Institute, Göttingen, Germany and had been an International Max Planck Research School (IMPRS) student here. Her research area focuses on cellular and molecular neuroscience. Other than enjoying ‘being a scientist’, she has also been working on science education. Presenting science in easy and fun way is what she loves doing through her platform “Fuzzy Synapse” (one can find fuzzy synapse on Facebook, Instagram and Twitter). She is a fun, enthusiastic and curious person, passionate about traveling, loves celebrations and bringing smiles around her.