Title : AI receptor binding studies reveal GPR146 conformational states across diabetic phenotypes: Analysis of C-peptide and insulin interactions in cholesterol metabolism, cortisol regulation, and the vitamin D-renin-angiotensin axis
Abstract:
Recent advances in artificial intelligence (AI) have enabled deeper insights into peptide-receptor interactions relevant to diabetes management. In a collaborative study between utR Biotech and Innoplexus, AI-based molecular modelling was employed to investigate the binding profiles of insulin, C-peptide, and cholesin across key metabolic receptors. This presentation will discuss comprehensive receptor binding studies that reveal distinct GPR146 conformational states in type 2 diabetics, type 1 diabetics, and normal individuals, elucidating how these states regulate cholesterol and lipid metabolism through differential receptor dynamics.
The analysis confirmed that both insulin and C-peptide bind to the insulin receptor, with C-peptide demonstrating a notably stronger binding affinity. Both peptides also interact with GPR146 at distinct sites, while cholesin exhibits weaker binding and partial overlap with the C-peptide binding domain. Notably, GPR146 exists in five distinct conformational states. When C-peptide binds to GPR146, it induces receptor internalization, thereby reducing the total cellular signalling network of GPR146. This internalization naturally downregulates cholesterol and lipid synthesis and lowers cortisol levels, helping to prevent the onset of metabolic dysfunction.
Pathway analysis revealed that insulin inhibits adenylyl cyclase, promoting lipid and cholesterol synthesis and elevating systemic cortisol levels. Cortisol, in turn, binds to the glucocorticoid receptor, upregulating 2,204 genes and downregulating 1,846, including approximately 40 genes implicated in diabetes-related comorbidities. Cortisol signalling also interferes with vitamin D synthesis, disrupting regulatory systems including the renin-angiotensin axis, sirtuin pathways, Wnt/β-catenin signalling, and nitric oxide production. Importantly, vitamin D synthesis participates in direct regulation of the renin-angiotensin system, affecting key components including renin, angiotensinogen, ACE, ACE2, and angiotensin receptor expression patterns.
The dynamic equilibrium of this system is highly dependent on the half-lives of insulin and C-peptide. The use of long-acting insulin analogues disrupts this balance by interfering with GPR146 internalization, potentially perpetuating comorbidities associated with diabetes. Additionally, C-peptide binds to the elastin receptor, which is implicated in upregulating AT2R expression—shifting the renin-angiotensin system toward an anti-inflammatory state.
These findings support the therapeutic potential of co-administering insulin and C-peptide in a 1:1 ratio to restore physiological signaling, reduce metabolic stress, and improve long-term outcomes in insulin-dependent diabetes. A brief overview of receptor binding studies and downstream signaling pathways will be presented, with particular emphasis on GPR146 conformational variations across diabetic phenotypes and their impact on cholesterol metabolism, cortisol synthesis regulation, and renin-angiotensin system components.
