Pancreatic islet cell response to multiple stimuli in long standing diabetes mellitus type 1

Type 1 diabetes mellitus (T1D) is an autoimmune disease in which pancreatic *-
cells are destroyed and endogenous insulin production is lost. Moreover in the
period around diagnosis there is a clear functional *-cell function deficit
including disturbed proinsulin cleavage.1 There is mounting evidence that some
*-cells still survive in a significant portion of patients with long standing
T1D. In patients with the diagnosis of T1D for 4-67 years, *-cells are detected
in 88% of subjects histologically and stimulated C-peptide concentrations
could be detected with an ultrasensitive assay in 73% of patients with T1D and
a median disease duration of thirty years.2;3 Studies have shown that this
residual *-cell function is associated with improved glycaemic regulation,
lower risk of complications and fewer hypoglycaemic events.4;5 There is little
known about the function of these residual *-cells in regard to the secretion
insulin to various stimuli and the efficiency of proinsulin cleavage in
long-standing T1D. Furthermore, cumulative *-cell stimulation might be a useful
clinical marker for *-cell mass, which now can only be assessed post-mortem.
Elucidating this differential and cumulative *-cell response to various stimuli
can lead to better pathophysiological understanding and novel treatment
insights.

Besides the obvious *-cell deficit in type 1 diabetes, hyperglucagonaemia after
meals and lack of glucagon secretion during hypoglycaemia are observed.6;7
Since little is known about the *-cell function regarding the response to the
various *-cell stimuli and the precise role of the *-cells in the
pathophysiology of T1D remains unclear, glucagon concentration will also be
assessed.

Primary objective:
- To determine the residual *-cell function by measuring thedifferential
response of *-cells measured by C-peptide and proinsulin secretion to various
stimuli in patients with long-standing type 1 diabetes mellitus.

Secondary objectives:
- To determine the residual *-cell function by measuring the response of alpha
cells measured by glucagon to various stimuli in patients with long-standing
type 1 diabetes mellitus.
- To determine how the various stimuli relate to the more commonly used mixed
meal tolerance test (MMTT)

This is a prospective, single-centre, non-therapeutic intervention study

The patients will visit our research unit twice. The first visit consists of a
mixed meal test with a standardised liquid meal followed by an 5g arginine
bolus. On the second visit they will receive a euglycaemic clamp set at 5
mmol/L after which a 5g arginine bolus is given. This is followed by a
hyperglycaemic clamp set at 14 mmol/L after which another bolus of arginine is
given. For the last step patients receive a continuous infusion of
glucagon-like peptide 1 (GLP-1) followed again by a bolus of arginine.

Burden:
The study participants are asked to visit twice after an overnight fast and
remain recumbent each visit for 2-5 hours. Two venous catheters will be placed
to draw a total of 150 ml blood . Arginine was well-tolerated in previous
studies with flushing and oral paraesthesia as most common complaints, and some
patients experienced mild nausea.8 The most reported adverse effect of GLP-1
are gastro-intestinal symptoms,9;10 although this is uncommon with the dose
that is administered intravenously in this study.11-13 In a previous study some
mild hypoglycaemic symptoms occurred after the GLP-1 infusion was stopped but
this could be abolished by a meal and by infusing glucose thirty minutes
longer.14

Risks:
An anaphylactic reaction to arginine has been described once.15 Since GLP-1 is
a physiological peptide it is tolerated well, some gastro-intestinal symptoms
have been described although this is uncommon after intravenous
administration.9;10

Benefit:
More insight in the pathophysiology of type 1 diabetes, possible therapeutic
approaches to stimulate remaining *-cells and a clinically applicable marker of
total *-cell mass.