Abstract:
Epidemiological evidence strongly links Type 1 and Type 2 Diabetes Mellitus with an elevated risk of Alzheimer’s Disease (AD), a relationship so robust that AD is increasingly characterized as "Type 3 Diabetes." While central insulin resistance is a recognized driver of neurodegeneration, the specific contribution of C-peptide deficiency to AD pathogenesis has remained largely unexplored. This presentation introduces a novel, integrated neuroendocrine model demonstrating that C-peptide is not merely a byproduct of insulin biosynthesis, but a critical neuroprotective hormone. We present a "pincer movement" therapeutic strategy, validated by AI-driven molecular modeling, that leverages a coformulation of insulin and C-peptide to simultaneously inhibit Amyloid-Beta (Aβ) production and drive its immune-mediated clearance. First, we elucidate the neuronal pathway wherein C-peptide functions as an essential ligand for the G-protein coupled receptor GPR146. In the absence of C-peptide, dysregulated signaling compromises neuronal metabolic integrity. We demonstrate that C-peptide binding promotes GPR146 internalization, leading to the downstream upregulation of Sirtuin 1 (SIRT1). SIRT1 acts as a pivotal molecular switch in Amyloid Precursor Protein (APP) processing: it suppresses Beta-site APP Cleaving Enzyme 1 (BACE1), thereby inhibiting the amyloidogenic pathway that generates toxic Aβ peptides. Concurrently, SIRT1 upregulates ADAM10 (α-secretase), promoting the non-amyloidogenic pathway and effectively halting the generation of new neurotoxic plaques. Second, we describe a distinct, non-overlapping neuro-immune pathway governing Aβ clearance. We have previously established that C-peptide deficiency drives chronic hypercortisolemia via the constitutive activation of the SREBP2-cholesterol axis. Here, we present evidence that this elevated cortisol suppresses the expression of Adhesion G ProteinCoupled Receptor G1 (ADGRG1/GPR56) on microglia, the brain’s resident immune cells. The restoration of physiological C-peptide levels normalizes systemic cortisol, preserving ADGRG1 expression. Signaling through ADGRG1 activates the transcription factor MYC, which drives a transcriptomic program that enhances microglial phagocytosis and the lysosomal degradation of existing Aβ plaques. By targeting the GPR146-SIRT1 axis to stop plaque formation and the Cortisol-ADGRG1-MYC axis to clear existing aggregates, this dual-mechanism therapy offers a comprehensive approach superior to single-target interventions. Furthermore, we highlight that the insulinomimetic activity of C-peptide activates the PI3K/AKT pathway, which reduces Tau hyperphosphorylation, further mitigating neurofibrillary tangle formation. These findings position the restoration of insulin:C-peptide coordination as a promising disease-modifying intervention for diabetic-associated neurodegeneration.
