Reduced insulin clearance contributes to the increased insulin levels after administration of glucagon-like peptide 1 in mice

DPP-4 is an important biological target related to the treatment of diabetes since some inhibitors can lead to an increase in the insulin levels and the prolonged activity of glucagon-like peptide-1 and gastric inhibitory polypeptide, being effective in glycemic control.

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Increased insulin clearance in mice with double deletion of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptors

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00181.2017 ◽

2018 ◽

Vol 314 (5) ◽

pp. R639-R646 ◽

Cited By ~ 7

Author(s):

Andrea Tura ◽

Roberto Bizzotto ◽

Yuchiro Yamada ◽

Yutaka Seino ◽

Giovanni Pacini ◽

...

Keyword(s):

Insulin Secretion ◽

Insulin Clearance ◽

Second Phase ◽

Incretin Hormones ◽

Intravenous Glucose ◽

C Peptide ◽

Double Deletion ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

First Phase Insulin Secretion

To establish whether incretin hormones affect insulin clearance, the aim of this study was to assess insulin clearance in mice with genetic deletion of receptors for both glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), so called double incretin receptor knockout mice (DIRKO). DIRKO ( n = 31) and wild-type (WT) C57BL6J mice ( n = 45) were intravenously injected with d-glucose (0.35 g/kg). Blood was sampled for 50 min and assayed for glucose, insulin, and C-peptide. Data were modeled to calculate insulin clearance; C-peptide kinetics was established after human C-peptide injection. Assessment of C-peptide kinetics revealed that C-peptide clearance was 1.66 ± 0.10 10−3 1/min. After intravenous glucose administration, insulin clearance during first phase insulin secretion was markedly higher in DIRKO than in WT mice (0.68 ± 0.06 10−3 l/min in DIRKO mice vs. 0.54 ± 0.03 10−3 1/min in WT mice, P = 0.02). In contrast, there was no difference between the two groups in insulin clearance during second phase insulin secretion ( P = 0.18). In conclusion, this study evaluated C-peptide kinetics in the mouse and exploited a mathematical model to estimate insulin clearance. Results showed that DIRKO mice have higher insulin clearance than WT mice, following intravenous injection of glucose. This suggests that incretin hormones reduce insulin clearance at physiological, nonstimulated levels.

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Hepatic and Extrahepatic Insulin Clearance in Mice with Double Deletion of Glucagon-Like Peptide-1 and Glucose-Dependent Insulinotropic Polypeptide Receptors

Biomedicines ◽

10.3390/biomedicines9080973 ◽

2021 ◽

Vol 9 (8) ◽

pp. 973

Author(s):

Micaela Morettini ◽

Agnese Piersanti ◽

Laura Burattini ◽

Giovanni Pacini ◽

Christian Göbl ◽

...

Keyword(s):

Tolerance Test ◽

Intravenous Glucose Tolerance Test ◽

Insulin Clearance ◽

Wild Type ◽

Intravenous Glucose ◽

Double Deletion ◽

Significant Difference ◽

Second Phases ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

The aim of this study was to investigate whether incretins, at physiological levels, affect hepatic and/or extrahepatic insulin clearance. Hepatic and extrahepatic insulin clearance was studied in 31 double incretin receptor knockout (DIRKO) and 45 wild-type (WT) mice, which underwent an Intravenous Glucose Tolerance Test (IVGTT). A novel methodology based on mathematical modeling was designed to provide two sets of values (FEL-P1, CLP-P1; FEL-P2, CLP-P2) accounting for hepatic and extrahepatic clearance in the IVGTT first and second phases, respectively, plus the respective total clearances, CLT-P1 and CLT-P2. A statistically significant difference between DIRKO and WT was found in CLT-P1 (0.61 [0.48–0.82] vs. 0.51 [0.46–0.65] (median [interquartile range]); p = 0.02), which was reflected in the peripheral component, CLP-P1 (0.18 [0.13–0.27] vs. 0.15 [0.11–0.22]; p = 0.04), but not in the hepatic component, FEL-P1 (29.7 [26.7–34.9] vs. 28.9 [25.7–32.0]; p = 0.18). No difference was detected between DIRKO and WT in CLT-P2 (1.38 [1.13–1.75] vs. 1.69 [1.48–1.87]; p = 0.10), neither in CLP-P2 (0.72 [0.64–0.81] vs. 0.79 [0.69–0.87]; p = 0.27) nor in FEL-P2 (37.8 [35.1–43.1] vs. 39.8 [35.8–44.2]; p = 0.46). In conclusion, our findings suggest that the higher insulin clearance observed in DIRKO compared with WT during the IVGTT first phase may be due to its extrahepatic component.

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Oral Triacylglycerols Regulate Plasma Glucagon-Like Peptide-1(7–36) and Insulin Levels in Normal and Especially in Obese Rats

Journal of Nutrition ◽

10.1093/jn/129.1.46 ◽

1999 ◽

Vol 129 (1) ◽

pp. 46-50 ◽

Cited By ~ 19

Author(s):

Nobuko Iritani ◽

Tomomi Sugimoto ◽

Hitomi Fukuda ◽

Masumi Komiya ◽

Hitoshi Ikeda

Keyword(s):

Plasma Glucagon ◽

Insulin Levels ◽

Obese Rats ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

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Reduction of hepatic insulin clearance after oral glucose ingestion is not mediated by glucagon-like peptide 1 or gastric inhibitory polypeptide in humans

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00289.2007 ◽

2007 ◽

Vol 293 (3) ◽

pp. E849-E856 ◽

Cited By ~ 46

Author(s):

Juris J. Meier ◽

Jens J. Holst ◽

Wolfgang E. Schmidt ◽

Michael A. Nauck

Keyword(s):

Gastric Inhibitory Polypeptide ◽

Insulin Clearance ◽

Oral Glucose ◽

Intravenous Glucose ◽

C Peptide ◽

Glucose Administration ◽

Glucose Ingestion ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Hepatic Insulin Clearance

Changes in hepatic insulin clearance can occur after oral glucose or meal ingestion. This has been attributed to the secretion and action of gastric inhibitory polypeptide (GIP) and glucagon-like peptide (GLP)−1. Given the recent availability of drugs based on incretin hormones, such clearance effects may be important for the future treatment of type 2 diabetes. Therefore, we determined insulin clearance in response to endogenously secreted and exogenously administered GIP and GLP-1. Insulin clearance was estimated from the molar C-peptide-to-insulin ratio calculated at basal conditions and from the respective areas under the curve after glucose, GIP, or GLP-1 administration. Oral glucose administration led to an ∼60% reduction in the C-peptide-to-insulin ratio ( P < 0.0001), whereas intravenous glucose administration had no effect ( P = 0.09). The endogenous secretion of GIP or GLP-1 was unrelated to the changes in insulin clearance. The C-peptide-to-insulin ratio was unchanged after the intravenous administration of GIP or GLP-1 in the fasting state ( P = 0.27 and P = 0.35, respectively). Likewise, infusing GLP-1 during a meal course did not alter insulin clearance ( P = 0.87). An inverse nonlinear relationship was found between the C-peptide-to-insulin ratio and the integrated insulin levels after oral and during intravenous glucose administration. Insulin clearance is reduced by oral but not by intravenous glucose administration. Neither GIP nor GLP-1 has significant effects on insulin extraction. An inverse relationship between insulin concentrations and insulin clearance suggests that the secretion of insulin itself determines the rate of hepatic insulin clearance.

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Intraportal GLP-1 stimulates insulin secretion predominantly through the hepatoportal-pancreatic vagal reflex pathways

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00565.2012 ◽

2013 ◽

Vol 305 (3) ◽

pp. E376-E387 ◽

Cited By ~ 32

Author(s):

Makoto Nishizawa ◽

Hajime Nakabayashi ◽

Keigo Uehara ◽

Atsushi Nakagawa ◽

Kenzo Uchida ◽

...

Keyword(s):

Insulin Secretion ◽

Portal Vein ◽

Sham Operation ◽

Insulin Levels ◽

Reflex Pathways ◽

Vagal Reflex ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Insulinotropic Effect ◽

Vagal Efferents

We previously reported that glucagon-like peptide-1 (GLP-1) appearance in the portal vein facilitates hepatic vagal afferent activity, and this further augments reflexively the pancreatic vagal efferents in anesthetized rats, suggesting a neuroincretin effect of GLP-1. To determine whether the GLP-1-induced vagal pathways lead to a neuronal-mediated component (NMC) of insulin secretion, we infused GLP-1 at a physiological or pharmacological dose (1 or 3 pmol·kg−1·min−1, respectively) into the portal vein in conscious rats with selective hepatic vagotomy (Vagox) or sham operation (Sham). The experiments consisted of two sequential 10-min intraportal infusions (P1 and P2): glucose at a physiological rate (56 μmol·kg−1·min−1) in P1 and the glucose plus GLP-1 or vehicle in P2. Under arterial isoglycemia across the groups, the physiological GLP-1 infusion in Sham augmented promptly and markedly arterial insulin levels, approximately twofold the levels in glucose alone infusion ( P < 0.005), and insulin levels in Vagox diminished apparently ( P < 0.05). Almost 60% of the GLP-1-induced insulin secretion (AUC) in Sham met the NMC, i.e., difference between insulin secretion in Sham and Vagox, (AUC 976 ± 65 vs. 393 ± 94 pmol·min/l, respectively, P < 0.005). Intraportal pharmacological GLP-1 infusion further augmented insulin secretion in both groups, but the NMC remained in 46% (NS; Sham vs. Vagox). In contrast, “isoglycemic” intravenous GLP-1 infusion (3 pmol·kg−1·min−1) evoked an equal insulin secretion in both groups. Thus, the present results indicate that GLP-1 appearing in the portal vein evokes a powerful neuronal-mediated insulinotropic effect, suggesting the neuroincretin effect.

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