New developments in the incretin concept

Creutzfeldt, W.; Ebert, R.

doi:10.1007/bf00281990

Cited by 281 publications

(138 citation statements)

References 99 publications

(69 reference statements)

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“…These results provided further experimental evidence for the postulated role of the enteroinsular axis in glucose homeostasis [15]. They also established the essential role of incretins [16], or substances secreted in the gut in response to nutrients, in the regulation of secretions of the pancreatic islet hormones. Administration of GLP-I(7-37) and GLP-I(7 36)amide together with a meal in patients with Type II diabetes mellitus (NIDDM) eliminated the postpandrial rise in blood glucose [11,12].…”

Section: Introductionsupporting

confidence: 57%

Tissue‐specific expression of the human receptor for glucagon‐like peptide‐I: brain, heart and pancreatic forms have the same deduced amino acid sequences

Yang¹,

Mojsov²

1995

FEBS Letters

394

248

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Glucagon-like peptide-I(GLP-I), encoded by the glucagon gene and released from the gut in response to nutrients, is a potent stimulator of glucose-induced insulin secretion. In human subjects GLP-I exerts its physiological effect as an incretin. The incretin effect of GLP-I is preserved in patients with Type II diabetes mellitus (NIDDM), suggesting that GLP-I receptor agonist can be used therapeutically in this group of patients. In these studies we addressed the question of whether GLP-I has broader actions in human physiology. To investigate this issue we examined the tissue distribution of GLP-I receptor using RNAse protection assay in order to avoid the cross-reactivities with structurally related receptors and to increase the sensitivity of detection. The riboprobe was synthesized from the human pancreatic GLP-I receptor cDNA and used in hybridization experiments with total RNA isolated from different human tissues. In addition to the pancreas, we found expression of GLP-I receptor mRNA in lung, brain, kidney, stomach and heart. Peripheral tissues which are the major sites of glucose turnover, such as liver, skeletal muscle and adipose did not express the pancreatic form of the GLP-I receptor. We also cloned and sequenced GLP-I receptor cDNA from human brain and heart. The deduced amino acid sequences are the same as the sequence found in the pancreas. These results indicate that GLP-I might have effects beyond the pancreas, including the cardiovascular and central nervous systems where a receptor with the same ligand binding specificity is found.

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Section: Introductionsupporting

confidence: 57%

Tissue‐specific expression of the human receptor for glucagon‐like peptide‐I: brain, heart and pancreatic forms have the same deduced amino acid sequences

Yang¹,

Mojsov²

1995

FEBS Letters

394

248

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“…The term "incretin" refers to a gut hormone that is released by oral glucose and that potentiates glucose-stimulated insulin secretion (6). However, the term may be more general and apply to a gut factor stimulating the endocrine pancreas, even Fig.…”

Section: Discussionmentioning

confidence: 99%

Incretin and islet hormonal responses to fat and protein ingestion in healthy men

Carr

Larsen²,

Winzell

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

166

129

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and glucose-dependent insulinotropic polypeptide (GIP) regulate islet function after carbohydrate ingestion. Whether incretin hormones are of importance for islet function after ingestion of noncarbohydrate macronutrients is not known. This study therefore examined integrated incretin and islet hormone responses to ingestion of pure fat (oleic acid; 0.88 g/kg) or protein (milk and egg protein; 2 g/kg) over 5 h in healthy men, aged 20 -25 yr (n ϭ 12); plain water ingestion served as control. Both intact (active) and total GLP-1 and GIP levels were determined as was plasma activity of dipeptidyl peptidase-4 (DPP-4). Following water ingestion, glucose, insulin, glucagon, GLP-1, and GIP levels and DPP-4 activity were stable during the 5-h study period. Both fat and protein ingestion increased insulin, glucagon, GIP, and GLP-1 levels without affecting glucose levels or DPP-4 activity. The GLP-1 responses were similar after protein and fat, whereas the early (30 min) GIP response was higher after protein than after fat ingestion (P Ͻ 0.001). This was associated with sevenfold higher insulin and glucagon responses compared with fat ingestion (both P Ͻ 0.001). After protein, the early GIP, but not GLP-1, responses correlated to insulin (r 2 ϭ 0.86; P ϭ 0.0001) but not glucagon responses. In contrast, after fat ingestion, GLP-1 and GIP did not correlate to islet hormones. We conclude that, whereas protein and fat release both incretin and islet hormones, the early GIP secretion after protein ingestion may be of primary importance to islet hormone secretion.insulin; glucagon; glucagon-like peptide-1; glucose-dependent insulinotropic polypeptide; incretins; man THE INTEGRATED ENDOCRINE RESPONSES TO FOOD INGESTION are dependent on both the size and the composition of a meal and include the postprandial release of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) and the islet hormones insulin and glucagon (3,5,21,32). Most studies have focused on responses to an oral glucose tolerance test, after which levels of GIP, GLP-1, and insulin rise, whereas glucagon levels are suppressed (4,18,20, 24). It is also known that fat and protein ingestion stimulate GLP-1 and GIP secretion (10,14,20,27). Less is known, however, regarding relationships between the incretin responses and changes in insulin and glucagon levels after meal or noncarbohydrate macronutrient ingestions.GLP-1 and GIP are rapidly degraded by dipeptidyl peptidase-4 (DPP-4), which cleaves the two NH 2 -terminal amino acids of the peptides, making them largely inactive (9). Accurate estimation of the relationship between incretin hormone secretion and islet hormones therefore requires measurement of both the total and the active intact forms of the two incretins. How this is related to macronutrient ingestion is not known. Indeed, we recently showed in mice that protein ingestion increased intact incretin hormone levels compared with carbohydrate ingestion, and this was associated with reduced intestinal DPP-4...

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“…Recent studies have shown that signal transduction initiated by GPCRs and RTKs is organized in mutually related signaling cassettes, leading to crosstalk between the RTK and GPCR signaling pathways (Natarajan et al, 2006). In pancreatic β-cells, in addition to GLP-1 and glucose-dependent insulinotropic polypeptide, insulin, insulin-like growth factor (IGF), and other growth factors are known to regulate insulin secretion as well as proliferation and apoptosis of β-cells (Creutzfeldt and Ebert, 1985;Loreti et al, 1974;Shepherd, 2004). Insulin secretion and proliferation by β-cells are inhibited in model systems in which the insulin receptor (IR), IGF receptor (IGFR), or IRS (IR substrate, an IR and IGFR downstream molecule) are knocked out/down (Da Silva Xavier et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Insulin Contributes to Fine-Tuning of the Pancreatic Beta-Cell Response to Glucagon-Like Peptide-1

Moon

Kim

Park

et al. 2011

Molecules and Cells

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Glucagon-like peptide-1 (GLP-1) stimulates insulin secretion from pancreatic β-cells in a glucose-dependent manner. However, factors other than glucose that regulate the β-cell response to GLP-1 remain poorly understood. In this study, we examined the possible involvement of insulin and receptor tyrosine kinase signaling in regulation of the GLP-1 responsiveness of β-cells. Pretreatment of β-cells with HNMPA, an insulin receptor inhibitor, and AG1478, an epidermal growth factor receptor inhibitor, further increased the cAMP level and Erk phosphorylation in the presence of exendin-4 (exe-4), a GLP-1 agonist. When β-cells were exposed to a high concentration of glucose (25 mM), which stimulates insulin secretion, exe-4-induced cAMP formation declined gradually as exposure time was increased. This decreased cAMP formation was not observed in the presence of HNMPA. HNMPA was able to further increase the exe-4-induced insulin secretion when β-cells were exposed to high glucose for 18 h. Treatment of β-cells with insulin significantly decreased exe-4-induced cAMP formation in a dose-dependent manner. Lowering the phospho-Akt level by HNMPA or LY294002, a PI3K inhibitor, further augmented exe-4-induced cAMP formation and Erk phosphorylation. These results suggest that insulin contributes to fine-tuning of the β-cell response to GLP-1.

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New developments in the incretin concept

Cited by 281 publications

References 99 publications

Tissue‐specific expression of the human receptor for glucagon‐like peptide‐I: brain, heart and pancreatic forms have the same deduced amino acid sequences

Tissue‐specific expression of the human receptor for glucagon‐like peptide‐I: brain, heart and pancreatic forms have the same deduced amino acid sequences

Incretin and islet hormonal responses to fat and protein ingestion in healthy men

Insulin Contributes to Fine-Tuning of the Pancreatic Beta-Cell Response to Glucagon-Like Peptide-1

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