Diurnal rhythm in endogenous glucose production is a major contributor to fasting hyperglycaemia in type 2 diabetes. Suprachiasmatic deficit or limit cycle behaviour?

Abstract

Aims/hypothesis: An increase in endogenous glucose production (EGP) is a major contributor to fasting morning hyperglycaemia in type 2 diabetes. This increase is dissipated with fasting, later in the day. To understand its origin, EGP, gluconeogenesis and hormones that regulate metabolism were measured over 24 h. We hypothesised that EGP, and therefore glycaemia, would demonstrate a centrally mediated circadian rhythm in type 2 diabetes.

Subjects and methods: Seven subjects with type 2 diabetes and six age- and BMI-matched control subjects, fasting after breakfast (08.00 h), underwent a further 24-h fast, with the infusion of [U-(13)C]glucose and [3-(14)C]lactate, starting at 14.00 h. The MCR and production of total and gluconeogenic glucose were determined from the tracer concentrations using compartmental analysis.

Results: MCR was near constant: 1.73+/-0.10 in control and 1.40+/-0.14 ml kg(-1) min(-1) in diabetic subjects (p=0.04). EGP in diabetes rose gradually overnight from 8.2+/-0.7 to 11.3+/-0.5 micromol kg(-1) min(-1) at 06.00 h (p<0.05). Glucose utilisation lagged EGP, rising from 8.5+/-0.6 to 10.5+/-0.4 micromol kg(-1) min(-1) (p<0.05), inducing a fall in glycaemia from a peak of 8.0+/-0.5 mmol/l to 6.3+/-0.4 mmol/l (p<0.05). Cortisol and melatonin showed diurnal variations, whereas insulin, glucagon and leptin did not. Melatonin was most closely related to EGP, but its secretion was attenuated in diabetes (p<0.05).

Conclusions/interpretation: In type 2 diabetes, EGP and gluconeogenesis display diurnal rhythms that drive the fasting hyperglycaemia and are absent in healthy control subjects. The rise in EGP may be related to a deficit in suprachiasmatic nucleus activity in diabetes, or result from non-linear behaviour plus a transition from a normal steady state to a limit cycle pattern in diabetes, or both.