Galparan: A Powerful Insulin-Releasing Chimeric Peptide Acting at a Novel Site

Abstract Galparan is a 27-amino acid long chimeric peptide, GWTLNSAGYLLGP-INLKALAALAKKIL amide, consisting of galanin-(1–13) linked to mastoparan amide via a peptide bond to provide the mastoparan and galanin effector parts of the molecules. Galparan (10μ m) powerfully stimulates insulin secretion from isolated rat pancreatic islets in a reversible and dose-dependent manner; the stimulation is 26-fold at 3.3 mm glucose and 6-fold at 16.7 mm glucose. Galparan also enhances insulin secretion to a similar extent from islets of diabetic GK rats. The stimulatory effect of galparan on insulin release is not directly dependent on extracellular Ca2+, nor can it be explained only by changes in free cytosolic Ca2+ concentrations. Furthermore, galparan is effective in evoking insulin release in B cells depolarized by 25 mm KCl when ATP-sensitive K+ channels are kept open by diazoxide. Thus, galparan, like mastoparan, stimulates exocytosis of insulin at a distal site in the stimulus-secretion coupling of the B cell. This distal site is not identical to that used by mastoparan, as pertussis toxin pretreatment does not influence the insulinogenic effect of galparan. In conclusion, galparan evokes a large and reversible insulin secretion, acting at a yet unknown distal site and also promoting exocytosis in depolarized B cells from normal rats as well as diabetic GK rats

Alpha-cells of the endocrine pancreas: 35 years of research but the enigma remains

Glucagon, a hormone secreted from the alpha-cells of the endocrine pancreas, is critical for blood glucose homeostasis. It is the major counterpart to insulin and is released during hypoglycemia to induce hepatic glucose output. The control of glucagon secretion is multifactorial and involves direct effects of nutrients on alpha-cell stimulus-secretion coupling as well as paracrine regulation by insulin and zinc and other factors secreted from neighboring beta- and delta-cells within the islet of Langerhans. Glucagon secretion is also regulated by circulating hormones and the autonomic nervous system. In this review, we describe the components of the alpha-cell stimulus secretion coupling and how nutrient metabolism in the alpha-cell leads to changes in glucagon secretion. The islet cell composition and organization are described in different species and serve as a basis for understanding how the numerous paracrine, hormonal, and nervous signals fine-tune glucagon secretion under different physiological conditions. We also highlight the pathophysiology of the alpha-cell and how hyperglucagonemia represents an important component of the metabolic abnormalities associated with diabetes mellitus. Therapeutic inhibition of glucagon action in patients with type 2 diabetes remains an exciting prospect