Acute cholinergic muscarinic blockade with pirenzepine (PIR) induces dose-related reductions in plasma glucose (PG) and plasma insulin (PI) after mixed meals in normal individuals and in type 2 diabetic and polycystic ovary syndrome patients (1–2). Altogether, 24 patients with type 2 diabetes (12 male and 12 female) with a fasting plasma glucose ≥10 mmol/l were studied for the effects of PIR (50 mg b.i.d.) given for 2 weeks on fasting and postprandial plasma glucose and insulin concentrations. Patients on ACE inhibitors or thiazide diuretics were excluded.
Oral hypoglycemics were stopped at least 2 weeks before treating the patients with either PIR or placebo in a randomized, cross-over, double-blind fashion with a 2-week washout period between the two treatment arms. At the beginning (day 1) and end (day 14) of each treatment period, blood was sampled over 12 h, during which time the patients received three standard meals. The scheduling for blood sampling, meals, and PIR administration is illustrated in Fig. 1. The primary outcome measure for the study was the difference between PIR- and placebo-treated fasting plasma glucose on day 14 of the study. Statistical analysis was performed using the paired Student’s t test.
There was a significant reduction in the fasting PG levels on day 14 (PIR) compared with day 14 (placebo) (mean reduction ± SD, 1.2 ± 1.6 mmol/l, 95% CI 0.5–1.9, P = 0.002 by paired Student’s t test) (Fig. 1). There were trends for reduction in the glucose area under the curve and highest postprandial peaks for day 14 (PIR) compared with day 14 (placebo), but the results did not reach statistical significance. There was no significant difference in fasting plasma insulin levels.
The mechanism through which PIR produces its effect on PG is unknown. Possible hypotheses are the obliteration of an increased hypothalamic cholinergic tone responsible for increased 24-h growth hormone (GH) secretion, particularly suppression of nocturnal GH secretion, which we and others (3,4) have previously demonstrated. Another possibility is the effect of PIR on gastrointestinal hormones through its anticholinergic effect, which may affect PG levels indirectly (5).
In conclusion, PIR caused a statistically significant reduction in fasting PG levels compared with placebo after 2 weeks of therapy, but there was no corresponding increase in insulin levels. PIR may be an effective drug in the treatment of type 2 diabetes.
Day curve of plasma glucose (A) and insulin (B) concentrations after 14 days of PIR (50 mg b.i.d.) (•) and placebo (○). The vertical continuous lines represent the time when pirenzepine was administered and the interrupted lines represent the times at which breakfast, lunch, and dinner were given.
Day curve of plasma glucose (A) and insulin (B) concentrations after 14 days of PIR (50 mg b.i.d.) (•) and placebo (○). The vertical continuous lines represent the time when pirenzepine was administered and the interrupted lines represent the times at which breakfast, lunch, and dinner were given.
Article Information
This study was supported by a grant from Boehringer Ingelheim.
We are indebted to Drs. Mary Lewis and Mark Lewis for their assistance with the insulin assay and Liz Gardner for her assistance with statistical analysis.
References
Address correspondence to Dr. Basil G. Issa, MD, FRCP, MRCP(I), Diabetes Centre, North Manchester General Hospital, Delaunays Road, Crumpsall, Manchester M8 5RB U.K. E-mail: [email protected].
