**Background:** Type 2 diabetes mellitus (T2DM) affects an estimated 537 million adults globally as of 2021, with projections rising to 783 million by 2045. Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by brain atrophy, amyloid-beta plaques, and neurofibrillary tangles, affecting approximately 5.8 million Americans in 2020. Emerging evidence suggests a strong biochemical link between T2DM and AD, with AD increasingly referred to as 'type 3 diabetes' due to shared features of impaired insulin signaling, insulin resistance, chronic inflammation, and oxidative stress. Current pharmacological treatments for T2DM have adverse effects, and no treatment effectively prevents or reverses AD progression. Up to 30% of diabetes patients use complementary and alternative medicine. Momordica charantia (bitter melon) has been used traditionally in Asia, South America, India, and East Africa for its glucose-lowering effects.
**Methods:** This is a narrative review synthesizing preclinical (cell and animal model) studies on the bioactive compounds of M. charantia and their mechanisms of action relevant to T2DM and AD. The review covers the pathophysiology of both diseases, their common molecular links, and the phytochemistry of M. charantia including polysaccharides, proteins/peptides (polypeptide-p, peroxidase), saponins/terpenoids (charantin), and flavonoids/phenolic compounds (quercetin, rutin, kaempferol, isorhamnetin).
**Key Results:** The review reports that M. charantia polysaccharides exhibit antioxidant, α-amylase inhibition, and ACE inhibition functions, and a water-soluble polysaccharide (MBP) demonstrated significant hypoglycemic effects. Polypeptide-p acts as an insulin-like hypoglycemic protein; when injected subcutaneously, it mimics human insulin by binding to insulin receptors. Charantin, a cucurbitane-type triterpenoid, showed hypoglycemic activity and was suggested to be potentially more effective than tolbutamide. Quercetin increased glucose uptake via GLUT4 translocation through AMPK pathway activation, preserved β-cell function against H2O2-induced oxidative damage in INS-1 cells, and reduced extracellular β-amyloidosis in triple transgenic AD mice after 3-month treatment. Rutin improved glucose tolerance, reduced serum glucose, improved lipid profile (LDL, VLDL, triglycerides), and prevented Aβ25-35 fibril formation in APPswe cells. Kaempferol improved AMPK activation, reduced apoptosis via caspase 3 suppression, and increased insulin secretion. Isorhamnetin (10 mg/kg or 20 mg/kg orally for 10 days) reduced oxidative stress and hyperglycemia in STZ-diabetic mice. The review notes that M. charantia contains approximately 20.1% monounsaturated fatty acids and 64.3% polyunsaturated fatty acids of total fatty acid content.
**Clinical Implications:** The authors emphasize that despite extensive preclinical evidence, very few clinical human studies with adequate design quality have been published. Most research has produced controversial results due to variations in experimental design, dosage, and types of bioactive compounds examined. The possible complications from long-term consumption in humans have not been extensively explored. The review advocates for carefully designed clinical trials with adequate sample size and statistical power to establish safety and efficacy. M. charantia is noted to be not safe for children or pregnant/breastfeeding women, and patients should consult healthcare providers before use due to risk of hypoglycemia when combined with conventional diabetes medications. The authors conclude that M. charantia represents a cost-effective, safe option with few side effects, but remains in initial processing stages for clinical application.