Cholinergic blockade with pirenzepine induces dose‐related reduction in glucose and insulin responses to a mixed meal in normal subjects and non‐insulin dependent diabetics

Bevan, John S.; Ara, Jamal; Page, M. D.; Scanlon, M. F.; Peters, John R.

doi:10.1111/j.1365-2265.1991.tb03501.x

Cited by 15 publications

(15 citation statements)

References 19 publications

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“…Furthermore, it has been proposed that insulin resistance in patients with non-insulin-dependent diabetes and hepatic diseases may be accounted for by hepatic parasympathetic neuropathy (Lautt, 1979). In contrast, it has been reported that cholinergic blockade with pirenzepine produced an improvement of glu-cose tolerance in normal human and noninsulin dependent diabetics (Bevan et at., 1991). The main objective of this study was to investigate the influence of muscarinic cholinergic blockade on insulin sensitivity, and to assess possible alterations in the endogenous pancreatic hormones produced by this blockade.…”

Section: Introductionmentioning

confidence: 99%

Induction of insulin resistance by cholinergic blockade with atropine in the cat

Xie

Lautt

1995

Journal of Autonomic Pharmacology

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1. Insulin sensitivity was quantified using a modified euglycaemic technique after hepatic cholinergic blockade with atropine and compared with that after surgical denervation. 2. Intraportal administration of atropine produced dose-dependent inhibition of insulin sensitivity in glucose metabolism. ED50 of atropine was 0.99 mg kg-1 (1 mg = 1.5 microM) with maximum inhibition of 40.3 +/- 11.6%. 3. Atropine (3 mg kg-1) reduced insulin sensitivity by a similar amount (33.6 +/- 3.4%) to that produced by hepatic surgical denervation (37.8 +/- 9.8%). Doses greater than 3 mg kg-1 failed to further alter the insulin resistance produced by surgical denervation or atropine (3 mg kg-1) administration, suggesting that activation of hepatic parasympathetic nerves is necessary to fully express the insulin effect. 4. Atropine reduced insulin sensitivity without changes in plasma concentrations of glucagon or insulin. The temporal response to insulin in this euglycaemic study was not changed after atropine administration or after surgical hepatic denervation. 5. It is suggested that hepatic parasympathetic nerves show a synergistic effect with insulin. Disease states that result in hepatic parasympathetic neuropathy would be expected to produce an insulin resistant liver. 6. The modified euglycaemic clamp method for assessing insulin responses was shown to be reproducible up to four times in the same animal and was sufficiently sensitive and quantitative to be able to generate a dose-response curve in each animal for atropine-induced insulin resistance.

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Section: Introductionmentioning

confidence: 99%

Induction of insulin resistance by cholinergic blockade with atropine in the cat

Xie

Lautt

1995

Journal of Autonomic Pharmacology

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“…Somatostatin reduces insulin but decreases glucose tolerance in patients with PCOS (Prelevic et al, 1990). In contrast, pirenzepine (PIR), a muscarinic cholinergic antagonist, reduces both insulin and glucose responses to food in normal individuals and patients with non-insulin dependent diabetes mellitus (Page et al, 1989;Bevan et al, 1991). We have therefore studied the dose related actions of PIR on insulin and glucose in response to food in obese clinically hyperandrogenic women with PCOS.…”

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confidence: 99%

Acute cholinergic blockade with low dose pirenzepine reduces the insulin and glucose responses to a mixed meal in obese women with the polycystic ovary syndrome

Premawardhana

Ismail

Riad-Fahmy

et al. 1994

Clinical Endocrinology

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Acute cholinergic muscarinic blockade with pirenzepine significantly reduces meal stimulated plasma insulin and plasma glucose concentrations in clinically hyperandrogenic women with polycystic ovary syndrome. The ability of pirenzepine to reduce plasma insulin without worsening glycaemia is a particular advantage and may be therapeutically relevant. Further studies are under way to assess the usefulness of pirenzepine in long-term suppression of plasma insulin in this group of patients.

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“…We anticipated that muscarinic blockade would have at least a modest effect on gastric emptying based on previously published studies (8,33). Indeed, because of the importance of vagal innervation in the control of gastric motility, blockade of either muscarinic or nicotinic signaling is expected to retard gastric emptying and therefore the delivery of nutrients to the absorptive surface of the small intestine.…”

Section: Discussionmentioning

confidence: 99%

Activation of the Parasympathetic Nervous System Is Necessary for Normal Meal-Induced Insulin Secretion in Rhesus Macaques1

D’Alessio

Kieffer

Taborsky

et al. 2001

The Journal of Clinical Endocrinology &Amp; Metabolism

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Meal-induced insulin secretion is thought to be regulated primarily by absorbed nutrients and incretin hormones released from the gastrointestinal tract. In addition, the parasympathetic nervous system (PNS) is known to mediate preabsorptive, or cephalic phase, insulin secretion. Despite evidence that the PNS remains activated during the absorptive phase of the meal, its role in mediating postprandial insulin secretion has not been established. To study the role of the PNS in absorptive phase insulin release, we measured plasma concentrations of glucose as well as islet hormones and incretins in six healthy rhesus monkeys before and for 60 min after meals while they were infused with saline (control), atropine (muscarinic blockade), or trimethaphan (nicotinic blockade). During the infusion of saline, plasma levels of glucose, pancreatic polypeptide (PP), insulin, glucose-dependent insulinotropic polypeptide, and glucagon-like peptide-1 increased promptly after meal ingestion and remained elevated throughout the 60 min of the study. The PP response was nearly abolished in animals treated with trimethaphan, indicating functional blockade of PNS input to the islet, and in contrast to the control study, there were minimal changes in plasma concentrations of glucose, incretin hormones, and insulin. Because trimethaphan inhibited glycemic and incretin stimuli in addition to blocking PNS input to the islet, it was not possible to discern the relative roles of these factors in the stimulation of insulin secretion. Atropine also significantly decreased PNS transmission to the islet, as reflected by PP levels similar to those observed with trimethaphan. Unlike the trimethaphan study, plasma glucose levels rose normally during atropine treatment and were similar to those in the control study over the course of the experiments (114 +/- 22 and 132 +/- 23 mmol/L.60 min, respectively). In addition, the rise in plasma glucagon-like peptide-1 following the meal was not suppressed by atropine, and the glucose-dependent insulinotropic polypeptide responses were only modestly decreased. Despite the significant increases in circulating glucose and incretins, plasma insulin levels were greatly attenuated by atropine, so that the 60 min responses were more comparable to those during trimethaphan treatment than to those in the control study (atropine, 3,576 +/- 1,284; trimethaphan, 4,128 +/- 2,616; control, 15,834 +/- 5,586 pmol/L.60 min; P: < 0.05). Thus, muscarinic blockade markedly suppressed the meal-induced insulin response despite normal postprandial glycemia and significant elevations of incretins. These results indicate that activation of the PNS during the absorptive phase of meals contributes significantly to the postprandial insulin secretory response.

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Cholinergic blockade with pirenzepine induces dose‐related reduction in glucose and insulin responses to a mixed meal in normal subjects and non‐insulin dependent diabetics

Cited by 15 publications

References 19 publications

Induction of insulin resistance by cholinergic blockade with atropine in the cat

Induction of insulin resistance by cholinergic blockade with atropine in the cat

Acute cholinergic blockade with low dose pirenzepine reduces the insulin and glucose responses to a mixed meal in obese women with the polycystic ovary syndrome

Activation of the Parasympathetic Nervous System Is Necessary for Normal Meal-Induced Insulin Secretion in Rhesus Macaques1

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