Pituitary Adenylate Cyclase-Activating Polypeptide Stimulates Insulin and Glucagon Secretion in Humans

Abstract

Pituitary adenylate cyclase-activating polypeptide (PACAP) has been localized to pancreatic nerves and demonstrated to stimulate insulin and glucagon secretion in experimental animals. This study examined the occurrence and possible function of PACAP in the human pancreas. The content of PACAP27 was 0.44 +/- 0.04 pmol/g tissue, and that of PACAP38 was 29.6 +/- 6.4 pmol/g tissue in extracted human pancreas (n = 4). Furthermore, in a homogeneous group of seven healthy postmenopausal women, all aged 57 yr, iv infusion of synthetic human PACAP27 (3 pmol/kg.min for 75 min) increased basal levels of insulin, C peptide, and glucagon without significantly influencing basal glucose after 14 min. At 15 min, glucose was administered rapidly (0.3 g/kg, iv). The peak insulin after bolus glucose was 797 +/- 232 pmol/L during PACAP27 infusion vs. 559 +/- 164 pmol/L during saline infusion (P = 0.018). Also, the peak in C peptide after glucose was potentiated by PACAP27 (P = 0.018). In contrast, hepatic extraction, calculated as the C peptide/insulin molar ratio, was not significantly affected by PACAP27, and neither the glucose elimination rate nor reduction of serum insulin after the glucose-induced peak was changed by PACAP27. We conclude that PACAP occurs in human pancreas and stimulates insulin and glucagon secretion in humans. This suggests that PACAP is involved in the regulation of islet function in humans.

The Cephalic Insulin Response to Meal Ingestion in Humans Is Dependent on Both Cholinergic and Noncholinergic Mechanisms and Is Important for Postprandial Glycemia

“…In any case, our study suggests that the neural cephalic phase insulin response to meal ingestion is attributable to both cholinergic and noncholinergic mechanisms. The nature of these noncholinergic autonomic mechanisms has not been established, but most likely includes noncholinergic neurotransmitters in the parasympathetic nerves, such as VIP, PACAP, and GRP (2,(11)(12)(13)(14). Results of recent animal studies also support the suggestion that these neuropeptides might be involved in the postprandial neurally mediated insulin secretion (15)(16)(17).…”

“…For example, islet parasympathetic nerves harbor several neuropeptides in addition to acetylcholine, such as vasoactive intestinal polypeptide (VIP), pituitary adenylate cyclaseϪactivating polypeptide (PACAP), and gastrin-releasing polypeptide (GRP) (2). These neuropeptides are released after vagal nerve activation of the pancreas (11)(12)(13) and stimulate insulin secretion (2,14). Prevention of their effects inhibits the insulin response to oral administration of glucose in mice (15)(16)(17).…”

Alpha cell function in health and disease: influence of glucagon-like peptide-1

“…Although other non-glucose secretagogues, such as isoproterenol, are also used in provocative tests of beta cell function [26], bolus administration of isoproterenol is less effective than arginine in stimulation of acute glucagon release in humans [27]. Acute insulin-induced hypoglycaemia has also been used to assess alpha cell [9] NEFA [8] Parasympathetic nerves [10] Ketones [7] Adrenaline (epinephrine) [112] Insulin [113] Oxytocin [114] Somatostatin [115] Vasopressin [116] Secretin [117] GIP [118] GLP-1 [54] PACAP [119] Carbohydrate meal [18] GRP [120] CCK [121] VIP [122] Protein meal [18] Stress [20] Hypoglycaemia [3] GRP gastrin-releasing peptide; PACAP pituitary adenylate cyclaseactivating polypeptide; VIP vasoactive intestinal polypeptide function in humans [28], although arginine stimulation tests clearly pose less risk and are more routinely employed.…”

A Potent and Highly Selective VPAC2 Agonist Enhances Glucose-Induced Insulin Release and Glucose Disposal

“…On the other hand, the expression pattern of VPAC1, coupled with the glycogenolytic activity of PACAP, suggests that activation of this receptor contributes to the increase in hepatic glucose production (10 -12). The administration of PACAP27 to either mice (13) or humans (14) has been reported to increase plasma insulin levels without affecting plasma glucose levels. Because PACAP27 activates both VPAC1 and VPAC2, the increase in glucose production may have offset the increase in insulin secretion.…”