Hidehiko Itoh

Glucagonostatic and insulinotropic action of glucagonlike peptide I-(7-36)-amide

We examined the effect of glucagonlike peptides (GLPs), which are cleaved from preproglucagon in the enteroglucagon cells, on rat endocrine pancreas with the isolated perfused system. GLP-I-(7–36)-amide, a truncated form of full-sequence GLP-I-(1–37), showed a potent inhibitory effect on glucagon secretion. This inhibitory effect of GLP-I-(7–36)-amide was demonstrated at concentrations of 0.25, 2.5, and 25 nM in 11.2 and 2.8 mM glucose. In contrast, insulin release was significantly stimulated by GLP-I-(7–36)-amide at its concentration from 0.025 to 25 nM in a high glucose concentration, whereas in a low glucose concentration, the stimulation was seen only at the highest concentration (25 nM). Neither GLP-I-(1–37) nor GLP-II showed any effect on glucagon and insulin release. Although several gastrointestinal hormones have been nominated as incretins, none of them may suppress the glucagon secretion. A truncated form of GLP-I, GLP-I-(7–36)-amide thus seems to be a unique incretin that exerts glucagonostatic action.

Trophic effect of glucagon-(1-21)-peptide on the isolated rat ileal mucosal cells.

The trophic effect of glucagon-(1-21)-peptide on rat ileal epithelial cells was studied in vitro. Glucagon-(1-21)-peptide stimulated [3H]thymidine incorporation of mucosal cells significantly in a dose-dependent manner. Then glucagon-related peptides which have common sequences with glucagon-(1-21)-peptide were also tested. The biological potencies to augment [3H]-thymidine uptake were closely related with their amino-acid residues of N-terminal region. The result suggests that the N-terminal amino-acid sequence of glucagon molecule plays an important role in intestinal cell growth.

Glucagonlike peptide-1 (7–36)amide suppresses glucagon secretion and decreases cyclic AMP concentration in cultured in-R1-G9 cells

We previously reported that GLP-1(7-36)amide had glucagonostatic action as well as insulinotropic action in the perfused rat pancreas. In this study, we examined the effect of GLP-1(7-36)amide on glucagon secretion and cAMP concentration in glucagon-secreting cell line, In-R1-G9. GLP-1(7-36)amide (1nM) significantly suppressed glucagon secretion and decreased cAMP concentration in the cells. GLP-1(1-37) did not affect glucagon secretion. It is suggested that inhibitory effect of GLP-1(7-36)amide on glucagon secretion is at least partly mediated by adenylate cyclase system.

Inhibition of pentagastrin-stimulated gastric acid secretion by intraileal administration of bile and elevation of plasma concentrations of gut glucagon-like immunoreactivity in anesthetized dogs

The effects of intraileal administration of bile on gastric acid secretion stimulated by a submaximal dose of intravenous pentagastrin infusion and on plasma concentrations of gut glucagon-like immunoreactivity (gut GLI) were studied in anesthetized dogs. Gastric acid secretion was measured for a 2-h period at 15-min intervals before and after intraluminal instillation of test solutions. 100 ml of canine bladder bile diluted to 10% in saline evoked a significant inhibition (20%) of gastric acid secretion. The inhibition of gastric acid secretion was accompanied by an elevation of plasma concentration of gut GLI, whereas saline instillation (in controls) caused no responses. Although the inhibition of gastric acid secretion and the elevation of plasma gut GLI are parallel phenomena, gut GLI can be reasonably postulated as one of the candidate mediators of bile-induced inhibition of gastric acid secretion, since its structurally related peptides, pancreatic glucagon, glicentin and oxyntomodulin have been reported as inhibitors of gastric acid secretion.

Effect of glucagon-(1-21)-peptide on secretin-stimulated pancreatic exocrine secretion in anesthetized dogs

The effects of glucagon-(1-21)-peptide on pancreatic exocrine secretion and plasma glucose levels were studied and compared with those of native glucagon in anesthetized dogs. Intravenous bolus administration of 1 nmol or 10 nmol/kg of glucagon-(1-21)-peptide evoked a significant inhibition of secretin-stimulated pancreatic juice secretion and protein output in a dose-dependent manner, as equimolar doses of glucagon did. Native glucagon induced an immediate and transient increase in pancreatic juice volume, which was followed by a significant inhibition. However, glucagon-(1-21)-peptide showed only the inhibitory action. Glucagon-(1-21)-peptide had no effect on plasma glucose levels even when a dose of 10 nmol/kg was given. The results suggest that the N-terminal amino-acid residues of glucagon play an important role in the inhibition of pancreatic exocrine secretion.

Presence of glucagon-(1–21)-like immunoreactive substance in the dog small intestinal mucosa

By using an antiserum (K291) specifically directed to the C-terminal of glucagon-(1-21)-peptide, we demonstrated the presence of glucagon-(1-21)-like immunoreactivity (G21-IR) in the dog intestine. G21-IR was found to be widely distributed throughout the small intestine and colon in parallel with the distribution of glucagon-like immunoreactivity (GLI), measured by N-terminal glucagon antiserum (OAL196). The subsequent analyses by gel filtration and three HPLC columns (reverse phase, ion exchange and further reverse phase columns) showed that G21-IR consisted of three main peaks, and the smallest molecular form of G21-IR is identical to glucagon-(1-21)-peptide.