Impact of Anticholinergics On Insulin Response To Oral Glucose Load In Patients With Impaired Glucose Tolerance

Several animal based in-vitro (Bergman et.al., 1973) and in-vivo studies (Bloom et al., 1981; Ahren et al., 1986) have indicated a stimulatory role for acetylcholine (ACh) on insulin secretion. Vagal stimulation has been demonstrated in rats to enhance the insulinotropic action and its effect is antagonized by anticholinergics (Kaneto et al., 1968). Additionally, a cholinergic basis has been extrapolated to spontaneous and meal induced insulin release in rats (Strubbe et al., 1989). It may therefore be hypothesized that the parasympathetic nervous system (PNS) is responsible for an increase in the preabsorptive insulin response to oral glucose load or meals and/or acting via an ‘incretin’-mediated mechanism or by regulating gastric emptying and hence absorption. Apart from in-vitro studies (Malaisse et al., 1967), human studies on the impact of cholinergics in patients with impaired glucose tolerance (IGTT) are limited. Moreover, in humans, the data regarding the impact of cholinergics on insulin appears contradictory. Tappy et al. (1986) have demonstrated that in obese humans, atropine reduced the basal levels of insulin without effecting beta cell responsiveness to a hyperglycemic clamp. Coiro et al. (1986) reported that in humans, muscarinic antagonists (atropine, pirenzepine) were able to modify basal insulin release but unable to impact upon meal induced insulin release.

Accordingly, in this study we propose to evaluate in patients with impaired glucose tolerance (IGTT), the effect of hyoscine, a competitive muscarinic antagonist with regard to:

1. glucose responses to an oral glucose load

2. monitor concomitant changes in insulin levels.

The role of Ach in regulating gastric motility is well-known (Cooke AR. et al., 1976), but the gastric emptying rate was not evaluated in this study. The level of PNS activity in preabsorptive ± postprandial insulin release and cholinergic signaling within islets could also represent a potential therapeutic target in patients with IGTT, highlighting its relevance in future drug development.

Scheme:

Subjects = T2DM : Healthy - 10:6 (n=16)

Day 1

Screening : Glycemic status Baseline plasma glucose (PG); Serum Insulin obtained

OGTT (75 g PO; t= 0 min) Serial sampling for PG, serum insulin (At t=0 min, and then every 30 min up to 120 min)

Day 4

OGTT (75 g PO; t= 0 min) plus Hyoscine (20 mg; PO; single dose, t= 0min)

Serial sampling for PG, serum insulin (At t= 0 min, and then every 30 min up to 120 min)

PG & Insulin vs time curve plots Comparison & Analysis of data sets.