Diurnal Cycling of Insulin Sensitivity in Type 2 Diabetes: Evidence for Deviation From Physiology at an Early Stage

The aim of this study was to establish the contribution of insulin resistance to the morning (a.m.) versus afternoon (p.m.) lower glucose tolerance of people with type 2 diabetes (T2D). Eleven subjects with T2D (mean [SD] diabetes duration 0.79 [0.23] years, BMI 28.3 [1.8] kg/m(2), A1C 6.6% [0.26%] [48.9 (2.9) mmol/mol]), treatment lifestyle modification only) and 11 matched control subjects without diabetes were monitored between 5:00 and 8:00 a.m. and p.m. (in random order) on one occasion (study 1), and on a subsequent occasion, they underwent an isoglycemic clamp (a.m. and p.m., both between 5:00 and 8:00, insulin infusion rate 10 mU/m(2)/min) (study 2). In study 1, plasma glucose, insulin, C-peptide, and glucagon were higher and insulin clearance lower in subjects with T2D a.m. versus p.m. and versus control subjects (P < 0.05), whereas free fatty acid, glycerol, and beta-hydroxybutyrate were lower a.m. versus p.m. However, in study 2 at identical hyperinsulinemia a.m. and p.m. (similar to 150 pmol/L), glucose R-a and glycerol R-a were both less suppressed a.m. versus p.m. (P < 0.05) in subjects with T2D. In contrast, in control subjects, glucose R-a was more suppressed a.m. versus p.m. Leucine turnover was no different a.m. versus p.m. In conclusion, in subjects with T2D, insulin sensitivity for glucose (liver) and lipid metabolism has diurnal cycles (nadir a.m.) opposite that of control subjects without diabetes already at an early stage, suggesting a marker of T2D.