Impact of High Sugar Intake on KRAS-Mediated Pancreatic Carcinogenesis in Diabetes Mellitus

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies worldwide, with a five-year survival rate below 12%, largely attributable to the absence of effective early detection strategies and the near-universal resistance to conventional systemic therapies. Activating mutations in the KRAS proto-oncogene—particularly KRASᴳ¹²ᴰ and KRASᴳ¹²ᵝ—are detected in over 90% of PDAC cases and represent the earliest and most defining molecular events in pancreatic carcinogenesis. Concurrently, diabetes mellitus (DM) and high dietary sugar intake have emerged as significant risk factors for PDAC, with diabetic patients carrying approximately two to three times the risk of developing PDAC compared to non-diabetic individuals. Crucially, recent mechanistic evidence has established a direct molecular link between high-glucose environments and the preferential induction of de novo KRAS mutations in pancreatic cells. In high-glucose conditions, cellular O-linked N-acetylglucosamine (O-GlcNAc) modification is dramatically elevated due to upregulation of the hexosamine biosynthesis pathway (HBP). This O-GlcNAcylation specifically targets ribonucleotide reductase subunit 1 (RRM1/RNR), impairing its enzymatic activity, depleting deoxynucleotide triphosphate (dNTP) pools, and inducing genomic instability that preferentially generates KRASᴳ¹²ᴰ mutations in pancreatic cells. Once established, oncogenic KRAS drives comprehensive metabolic reprogramming including enhanced aerobic glycolysis (Warburg effect), activation of the HBP and pentose phosphate pathway (PPP), glutamine scavenging, and lipid biogenesis—all of which are further amplified by the hyperglycemic milieu of DM. Hyperinsulinemia, a hallmark of type 2 DM, independently accelerates pancreatic intraepithelial neoplasia (PanIN) progression through insulin receptor–mediated activation of PI3K/AKT and RAF/MEK/ERK cascades in acinar cells. High fructose intake, increasingly prevalent through consumption of high-fructose corn syrup and sucrose-rich diets, amplifies KRAS-MAPK signaling through ketohexokinase C (KHK-C) and mTORC1 co-activation. This review provides a comprehensive synthesis of the epidemiological, molecular, and preclinical evidence linking high sugar intake and DM to KRAS-mediated pancreatic carcinogenesis, examines the downstream oncogenic signaling networks, the consequent desmoplastic tumor microenvironment, and explores the translational implications for prevention and targeted therapy.