Title : From historically used plants to novel peptides for the treatment of type-2 diabetes and alzheimer’s disease

Several plants and plant-derived bioactive substances show significant promise in the prevention and management of type 2 diabetes (T2DM) and Alzheimer's disease (AD). They often act on shared pathways like insulin signaling, oxidative stress, and neuroinflammation. Natural compounds, especially polyphenols and plant-derived bioactive peptides (PDPs), have been the focus of worldwide research.

Examples of key plants and phytochemicals comprise i) bitter melon (Momordica charantia), rich in steroidal saponins and polypeptide-p, improving glucose tolerance and insulin sensitivity; ii) turmeric (Curcuma longa) containing curcumin, which is effective in improving insulin sensitivity, reducing neuroinflammation, and lowering amyloid-beta accumulation; iii) cinnamon (Cinnamomum zeylanicum) with a polymer known as methylhydroxychalcone (MHCP) and cinnamaldehyde; iv) fenugreek (Trigonella foenum-graecum) of which the seeds contain 4hydroxyisoleucine and galactomannans, increasing insulin secretion and improving peripheral glucose uptake; v) ginseng (Panax ginseng) with the family of ginsenosides that are effective in controlling blood sugar and improving cognitive function by reducing neurotoxicity and enhancing synaptic plasticity; vi) green tea (Camellia sinensis), rich in EGCG (epigallocatechin gallate), which enhances insulin sensitivity and protects neurons; vii) walnut (Juglans regia) with walnutderived peptides (e.g., YVLLPSPK, PPKNW) that reduce amyloid-beta aggregation, improve gut health, and alleviate memory impairment; viii) garlic and onion (Allium species) containing sulfur compounds (like allicin) that are claimed to enhance insulin sensitivity.

A number of innovative peptides and therapies have become available or are in advanced development. Peptides for the treatment of T2DM include i) GLP-1 Receptor Agonists (GLP-1 RAs) like semaglutide and liraglutide. While primarily approved for T2DM and obesity, they show neuroprotective effects in clinical trials. Recent studies indicate a reduction in dementia risk for T2DM patients using these drugs, a very interesting observation that may help us to unravel their mechanism of action and the role of fibril and/or plaque formation; ii) tirzepatide (Mounjaro), a dual GLP-1/GIP receptor agonist currently available for T2DM that also offers potential for neuroprotection; iii) DA4-JC, a novel dual GLP-1/GIP agonist that has effectively reduced cognitive decline and amyloid deposits in animal models; iv) intranasal insulin where the unique delivery route bypasses systemic risks (like hypoglycemia) and targets the brain directly to restore insulin signaling, which may improve working memory in AD patients; v) there are also peptides specifically targeting protein aggregation in AD (RI-AG03, a "retro-inverse" peptide that blocks the aggregation of the tau protein; ISAD1, a peptide that refolds tau proteins into non-toxic forms; AAC2, a peptide that improves glucose uptake in brain tissue via the insulin-independent GLUT1 transporter, which could be effective against insulin resistance; PEPITEM, a naturally occurring peptide currently being studied to reverse the inflammation associated with obesity and T2DM).

Evidence has grown demonstrating that people with T2DM have a significantly higher risk of developing AD, often driven by shared mechanisms like insulin resistance, chronic inflammation, high blood sugar and plaque formation of peptides. This connection is now considered a significant global public health problem due to the aging population and the concurrent epidemics of obesity and diabetes.

Jan Tytgat is full professor and head of Toxicology & Pharmacology at the Universiteit of Leuven (KU Leuven, Belgium). He obtained a Master’s degree in Pharmaceutical Sciences and went on to obtain a PhD in physiology at KU Leuven. From 1990-1992 he attended Harvard Medical School in Boston (USA) for postdoctoral training. He is the author of more than 380 scientific publications ((ORCID: 0000-0003-1778-6022; h-index 61) and several books. He holds a patent for the treatment of intoxication caused by Cnidaria. He has received several awards, including the international Redi Award from the International Society on Toxinology (IST) (2024).