Reduced insulinotropic effects of glucagonlike peptide I-(7-36)-amide and gastric inhibitory polypeptide in isolated perfused diabetic rat pancreas

Suzuki, S.; Kawai, K.; Ohashi, S.; Mukai, H.; Murayama, Y.; Yamashita, K.

doi:10.2337/diabetes.39.11.1320

Cited by 19 publications

(10 citation statements)

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“…sulin and somatostatin release. This concept is supported by ~he recent finding that GLP-I(7-36) amide does not suppress glucagon secretion in perfused pancreata frown streptozotocin-treated rats which had a 50% reduced insulin release during stimulation with GLP-l(7-36)amide or GIP compared to non-diabetic controls [29]. In addition, such paracrin¢ mechanisms seem to be involved in the reported inhibitory action of GLP-I (7-37) on glucagon gene transcription in isolated rat islets [26] and the hamster glucagonorna cell line iNR.i(39 [:30i.…”

Section: Discussionsupporting

confidence: 70%

Functional receptors for the insulinotropic hormone glucagon‐like peptide‐I(7–37) on a somatostatin secreting cell line

Fehmann

Habener

1991

FEBS Letters

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Glucagon‐like peptide‐I (7–37) [(GLP‐I(7–37)] is an instestinal peptide hormone that has potent insulinotropic activities in vivo in response to oral nutrients. In the isolated perfused pancreas, and in vitro in cultured B cells, GLP‐I(7–37) receptor binding and GLP‐I(7–37)‐induced cAMP generation and harmone secretion was studied using cell lines producing insulin/B cell (βTC‐1), glucagon/A cell (INR1G9) and somatostatin/D cell (RIN 1027‐B2). [125I]GLP‐I(7–37) bound specifically to both B and D cells but not to A cells. GLP‐I(7–37) induced cAMP‐formation in B and D cells with a maximum response at 10 nmol/l(B cells) or at 100 nmol/l (D cells). Insulin secretion from perifused B cells was stimulated by GLP‐I(7–37) (maximum at 10 nmol/l) and 10 nmol/l GLP‐I(7–37) released somatostatin from perifused D cells, GLP‐I(7–37) did not influence cAMP or glucagon secretion from A cells. These data indicate that pancreatic B and D cells, but not the A cells are influenced directly by GLP‐I(7–37) via binding to specific receptors. Our findings support a model of physiologic regulation of insulin secretion whereby GLP‐I(7–37) released from the intestine in response to oral nutrients potently stimulates insulin secretion via an endocrine mechanism that in turn may be dampened by a feed‐back suppression by the release of somatostatin. In addition, suppression of the secretion of glucagon, a hormone whose actions are counter‐regulatory to those of insulin, may occur by paracrine mechanisms involving GLP‐I(7–37)‐mediated stimulation of both insulin and somatostatin secretion.

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Section: Discussionsupporting

confidence: 70%

Functional receptors for the insulinotropic hormone glucagon‐like peptide‐I(7–37) on a somatostatin secreting cell line

Fehmann

Habener

1991

FEBS Letters

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“…Preliminary results suggest that GLP-1 in pharmacological doses can stimulate insulin secretion in type-2 diabetic patients (22). In streptozotocin-diabetic rats, on the other hand, the insulinotropic effectiveness of both GIP and GLP-1 [7-36 amide] was reduced (23).…”

Section: Introductionmentioning

confidence: 96%

“…In the isolated perfused pancreas of the rat, pig, or dog, GLP-1 [7-36 amide] or suppressed pancreatic glucagon concentrations (23)(24)(25)(26). Except for preliminary data ( 10,27), the conditions under which glucagon secretion is regulated by GLP-1 [7-36 amide] in normal humans and type-2 diabetic patients have not been defined.…”

Section: Introductionmentioning

confidence: 99%

Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus.

Nauck

Heimesaat²,

Ørskov³

et al. 1993

J. Clin. Invest.

1,518

1,158

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In type-2 diabetes, the overall incretin effect is reduced. 17-36 amidel dose-dependently augmented insulin secretion (insulin, C-peptide) in both groups (P < 0.05). With GIP, the maximum effect in type-2 diabetic patients was significantly lower (by 54%; P < 0.05) than in normal subjects. With GLP-1 17-36 amidel type-2 diabetic patients reached 71% of the increments in C-peptide of normal subjects (difference not significant). Glucagon was lowered during hyperglycemic clamps in normal subjects, but not in type-2 diabetic patients, and further by GLP-1 17-36 amidel in both groups (P < 0.05), but not by GIP. In conclusion, in mild type-2 diabetes, GLP-1 17-36 amidel, in contrast to GIP, retains much of its insulinotropic activity. It also lowers glucagon concentrations. (J. Clin. Invest. 1993. 91:301-307.) Key words: enteroinsular axis* gastric inhibitory peptide -glucagon-like peptide 1 17-36 amidel * hyperglycemic clamp * incretin hormones -pancreatic glucagon

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“…Several reports have shown that both GIP and GLP-1 are equipotent in stimulating insulin secretion [11,12] whereas others have suggested that GLP-1 possesses greater insulinotropic activity [13,14]. The interpretation that GLP-1 is the more important incretin hormone stems very largely from studies using exendin amide, a GLP-1-like peptide isolated from the venom of Heloderma suspectum [15].…”

Section: Electrospray Ionization-mass Spectrometry (Esi-ms)mentioning

confidence: 99%

Effects of the novel (Pro3)GIP antagonist and exendin(9–39)amide on GIP- and GLP-1-induced cyclic AMP generation, insulin secretion and postprandial insulin release in obese diabetic (ob/ob) mice: evidence that GIP is the major physiological incretin

et al. 2003

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Aims/hypothesis. This study examined the biological effects of the GIP receptor antagonist, (Pro 3 )GIP and the GLP-1 receptor antagonist, exendin(9-39)amide. Methods Cyclic AMP production was assessed in Chinese hamster lung fibroblasts transfected with human GIP or GLP-1 receptors, respectively. In vitro insulin release studies were assessed in BRIN-BD11 cells while in vivo insulinotropic and glycaemic responses were measured in obese diabetic (ob/ob) mice. Results. In GIP receptor-transfected fibroblasts, (Pro 3 )-GIP or exendin(9-39)amide inhibited GIP-stimulated cyclic AMP production with maximal inhibition of 70.0±3.5% and 73.5±3.2% at 10 −6 mol/l, respectively. In GLP-1 receptor-transfected fibroblasts, exendin-(9-39)amide inhibited GLP-1-stimulated cyclic AMP production with maximal inhibition of 60±0.7% at 10 −6 mol/l, whereas (Pro 3 )GIP had no effect. (Pro 3 )-GIP specifically inhibited GIP-stimulated insulin release (86%; p<0.001) from clonal BRIN-BD11 cells, but had no effect on GLP-1-stimulated insulin release. In contrast, exendin(9-39)amide inhibited both GIP and GLP-1-stimulated insulin release (57% and 44%, respectively; p<0.001). Administration of (Pro 3 )GIP, exendin(9-39)amide or a combination of both peptides (25 nmol/kg body weight, i.p.) to fasted (ob/ob) mice decreased the plasma insulin responses by 42%, 54% and 49%, respectively (p<0.01 to p<0.001). The hyperinsulinaemia of non-fasted (ob/ob) mice was decreased by 19%, 27% and 18% (p<0.05 to p<0.01) by injection of (Pro 3 )GIP, exendin(9-39)amide or combined peptides but accompanying changes of plasma glucose were small. Conclusions/interpretation. These data show that (Pro 3 )GIP is a specific GIP receptor antagonist. Furthermore, feeding studies in one commonly used animal model of obesity and diabetes, (ob/ob) mice, suggest that GIP is the major physiological component of the enteroinsular axis, contributing approximately 80% to incretin-induced insulin release. [Diabetologia (2003) 46:222-230] Keywords Enteroinsular axis, GIP receptor antagonist, glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, insulin release. The insulin secretory activity of pancreatic beta cells can be modulated in both a positive or negative manner by several peptide hormones and neurotransmitters [1,2,3]. The two intestinal hormones, glucosedependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1-(7-36)amide (GLP-1) have long been recognised as potent stimulators of insulin secretion under physiological conditions, and for that reason they are considered important incretin hormones [4,5,6]. The effects of both GIP and GLP-1 are glucose-dependent, providing a safeguard against potentially hazardous hypoglycaemic episodes, and as a

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Reduced insulinotropic effects of glucagonlike peptide I-(7-36)-amide and gastric inhibitory polypeptide in isolated perfused diabetic rat pancreas

Cited by 19 publications

References 0 publications

Functional receptors for the insulinotropic hormone glucagon‐like peptide‐I(7–37) on a somatostatin secreting cell line

Functional receptors for the insulinotropic hormone glucagon‐like peptide‐I(7–37) on a somatostatin secreting cell line

Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus.

Effects of the novel (Pro3)GIP antagonist and exendin(9–39)amide on GIP- and GLP-1-induced cyclic AMP generation, insulin secretion and postprandial insulin release in obese diabetic (ob/ob) mice: evidence that GIP is the major physiological incretin

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