Paradigm Shifts in Nocturnal Glucose Control in Type 2 Diabetes

Abstract

Abstract Context A better understanding of nocturnal regulation of glucose homeostasis will provide the framework for designing rational therapeutic strategies to improve the management of overnight glucose in patients with type 2 diabetes (T2D). Objective To establish the nocturnal pattern and regulation of glucose production (EGP) in humans and to determine whether the pattern is dysregulated in people with T2D. Design Subjects were infused with [3-3H] glucose overnight. Arterial blood samples were drawn for hormones and analytes to estimate EGP throughout the night. Deuterium-labeled water was provided to measure gluconeogenesis (GNG) using the hexamethylenetetramine method of Landau. Setting Mayo Clinic Clinical Research Trials Unit, Rochester, MN, USA. Participants and Interventions A total of 43 subjects [23 subjects with T2D and 20 nondiabetic (ND) subjects comparable for age and body mass index] were included in this study. Main Outcome(s) Measure(s) Glucose and EGP. Results Plasma glucose, C-peptide, and glucagon concentrations were higher throughout the night, whereas insulin concentrations were higher in subjects with T2D vs ND subjects at 1:00 and 4:00 am but similar at 7:00 am. EGP was higher in the subjects with T2D than in the ND subjects throughout the night (P < 0.001). Glycogenolysis (GGL) fell and GNG rose, resulting in significantly higher (P < 0.001) rates of GNG at 4:00 and 7:00 am and significantly (P < 0.001) higher rates of GGL at 1:00, 4:00, and 7:00 am in T2D as compared with ND. Conclusions These data imply that optimal therapies for T2D for nocturnal/fasting glucose control should target not only the absolute rates of EGP but also the contributing pathways of GGL and GNG sequentially.