BACKGROUND: Higher gluconeogenesis (GNG) contributes to higher nocturnal endogenous glucose production (EGP) in type 2 diabetes (T2D). Studies using 13C Magnetic Resonance Spectroscopy (MRS) have confirmed lower hepatic glycogen content in T2D than in subjects without diabetes (ND). OBJECTIVE: We determined the role of glycogen loading vs non-glycogen loading on contribution of GNG to nocturnal EGP in T2D. METHODS: 14 T2D and 15 matched ND subjects were studied on two occasions, with glycogen loaded (GL: 60% carbohydrate) vs non-glycogen loaded (NGL: 40% carbohydrate) isocaloric meals for 3 days, in random order in the overnight state. [6,6-2H2] Glucose was infused to measure EGP, deuterium labelled water was used to measure GNG and 13C MRS scans were performed in fed and fasted state to measure hepatic glycogen content. RESULTS: Hepatic glycogen content and nocturnal EGP were higher (p<
0.05) in GL vs NGL in both cohorts. % GNG to EGP averaged ∼50% in ND throughout the night after both meals. In contrast, % GNG to nocturnal EGP in T2D was lower with GL vs NGL and matched the pattern observed in ND with GL lowering overnight rates of GNG in T2D. CONCLUSION: Selective targeting of GNG at night with appropriate medications could reduce nocturnal and early morning fasting hyperglycemia and hepatic insulin resistance in people with T2D.