Determinants of intra-individual variation of glucoregulation in diabetes mellitus type 1

Type 1 diabetes mellitus (DM1) is caused by a loss of β-cell mass, due to an
auto-immune process which leads to absolute insulin deficiency. The Diabetes
Control and Complications Trial (DCCT) proved that there is a curvilinear
relation between the degree of glycaemic control, maintained over the long term
and the onset or progression of microvascular and macrovascular complications.
However, in patients with DM1, glucoregulation can not be normalized despite
intensive insulin therapy and/or lifestyle adaptions. There are unexpected
variations in glucoregulation in these patients on a day to day basis. We
hypothesize that these intra-individual variations in glucoregulation in DM1
are caused to a large extend by variations in physiological determinants of
glucoregulation.
In healthy individuals, plasma glucose homeostasis results from a tightly
controlled balance between glucose production and glucose utilization, in which
variations in insulin secretion play a key role. Normal glucose regulation
shows a 24h circadian rhythmicity with variations in glucose tolerance.
However, these variations normally do not affect plasma glucose levels, due to
concomitant variations in insulin secretion. In contrast, DM1 patients can not
compensate these variations in glucose tolerance by subtle changes in
endogenous insulin secretion.
Increasing evidence exists for an important role of sleep in diurnal variations
in glucose metabolism. Recently, attention has been focussed on the
pathophysiological effects of sleep loss on glucose metabolism and endocrine
function. Decreased quality of sleep and sleep loss impair glucose tolerance
and insulin sensitivity, even in healthy individuals. We postulate that
disturbed sleep duration and/or quality could be one of these important
physiological determinants which can disturb glucoregulation in DM1.
This study is aimed to elucidate the effects of disturbed sleep on
intra-individual variations on glucose regulation at basal conditions and
during hyperinsulinemic euglycaemic clamp studies before and after sleep
deprivation.

Objective:
1. To determine intra-individual variations of post absorptive glucose
metabolism in patients with DM1 and healthy individuals.
2. To determine the effect of short sleep deprivation on glucoregulation in
patients with DM1 and healthy individuals.

The study is a prospective, intervention study.

normal sleep vs short sleep (9.45 vs 5 uur)

Burden:
Subjects will spent 3 nights in our resaerch center, of which 2 nights with
normal sleep and 1 night with short sleep. No adverse events are expected from
this. Subsequently, will be in our hospital for half a day and for 2 whole
days. During these study days, subjects will lie in bed and blood will be drawn
from an infusion. In total, during this whole study period of 10 weeks, 501 ml
bloodwill be drawn from each subject.
Basal experiment: infusion of labeled glucose which is not radioactive en
therefore no adverse effects are expected
Hyperinsulinaemic euglyceamic clamp: infusion of insulin and labeld glucose.
Blood glucose measurements will be made at regular time intervals to adjust
glucose infusion and prevent hypoglycemia.