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

2018 ◽  
Vol 314 (5) ◽  
pp. R639-R646 ◽  
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.

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

Biomedicines ◽  
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.

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

2007 ◽  
Vol 293 (3) ◽  
pp. E849-E856 ◽  
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.

Effect of loss of first-phase insulin secretion on hepatic glucose production and tissue glucose disposal in humans

1989 ◽  
Vol 257 (2) ◽  
pp. E241-E246 ◽  
Author(s):  
L. Luzi ◽  
R. A. DeFronzo
Keyword(s):  
Insulin Secretion ◽  
Insulin Infusion ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Second Phase ◽  
C Peptide ◽  
Hyperglycemic Clamp ◽  
Study Protocols ◽  
Hepatic Glucose ◽  
First Phase Insulin Secretion

To examine the importance of first-phase insulin secretion on total body glucose homeostasis, six normal subjects (age, 24 +/- 1 yr; ideal body wt, 100 +/- 1%) received three hyperglycemic (+75 mg/100 ml) clamp studies in combination with [3-3H]glucose: study I, 150 min hyperglycemic clamp; study II, hyperglycemic clamp plus somatostatin (6 micrograms/min) plus basal glucagon replacement (0.4 ng.kg-1.min-1) plus an insulin infusion designed to mimic only the second phase of insulin secretion; and study III, hyperglycemic clamp plus somatostatin plus basal glucagon plus an insulin infusion designed to mimic both the first and second phase of insulin secretion. Basal plasma C-peptide concentrations averaged 0.21 +/- 0.01 pmol/ml in the three study protocols. In study I the plasma C-peptide response demonstrated an early burst within the first 10 min followed by a gradually increasing phase of C-peptide secretion that lasted until the end of the study. In studies II and III plasma C-peptide declined within the first 10 min after somatostatin was started and averaged 0.06 +/- 0.01 and 0.05 +/- 0.01 pmol/min, respectively. Basal hepatic glucose production (2.3 +/- 0.2 mg.kg-1.min-1) was suppressed by 90% at 20 min and remained suppressed thereafter in studies I and III. In contrast, in study II hepatic glucose production was inhibited by only 50% (1.1 +/- 0.2 mg.kg-1.min-1) at 60 min (P less than 0.01 vs. studies I and III) and remained incompletely suppressed even after 150 min.(ABSTRACT TRUNCATED AT 250 WORDS)

DPP-4 Inhibition as a Newly Emerging Therapy for Type 2 Diabetes

2006 ◽  
Vol 00 (02) ◽  
Author(s):  
Carolyn F Deacon ◽  
Jens Juul Holst
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Progressive Disease ◽  
Incretin Hormones ◽  
New Approach ◽  
Current Therapies ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Emerging Therapy

Type 2 diabetes mellitus (T2DM) is a progressive disease, characterized by insulin resistance, impaired glucose-induced insulin secretion, inappropriately elevated glucagon concentrations, and hyperglycemia. Many patients cannot obtain satisfactory glycemic control with current therapies, and eventually develop microvascular and macrovascular diabetic complications. New and more effective agents, targeted not only at treatment, but also at prevention of the disease, its progression, and its associated complications, are, therefore, required. One new approach focuses on the effects of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which enhance mealinduced insulin secretion.1

Sensory nerves contribute to insulin secretion by glucagon-like peptide-1 in mice

2004 ◽  
Vol 286 (2) ◽  
pp. R269-R272 ◽  
Author(s):  
Bo Ahrén
Keyword(s):  
Insulin Secretion ◽  
Direct Action ◽  
Insulin Response ◽  
Sensory Nerves ◽  
High Dose ◽  
Intravenous Glucose ◽  
Insulin Response To Glucose ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

It has been hypothesized that the potent insulinotropic action of the gut incretin hormone glucagon-like peptide-1 (GLP-1) is exerted not only through a direct action on the beta cells but may be partially dependent on sensory nerves. We therefore examined the influence of GLP-1 in mice rendered sensory denervated by neonatal administration of capsaicin performed at days 2 and 5 (50 mg/kg). Control mice were given vehicle. Results show that at 10-16 wk of age in control mice, intravenous GLP-1 at 0.1 or 10 nmol/kg augmented the insulin response to intravenous glucose (1 g/kg) in association with improved glucose elimination. In contrast, in capsaicin-pretreated mice, GLP-1 at 0.1 nmol/kg could not augment the insulin response to intravenous glucose and no effect on glucose elimination was observed. Nevertheless, at the high dose of 10 nmol/kg, GLP-1 augmented the insulin response to glucose in capsaicin-pretreated mice as efficiently as in control mice. The insulin response to GLP-1 from isolated islets was not affected by neonatal capsaicin, and, furthermore, the in vivo insulin response to glucose was augmented whereas that to arginine was not affected by capsaicin. It is concluded that GLP-1-induced insulin secretion at a low dose in mice is dependent on intact sensory nerves and therefore indirectly mediated and that this distinguishes GLP-1 from other examined insulin secretagogues.

GLP-1-(9–36) amide reduces blood glucose in anesthetized pigs by a mechanism that does not involve insulin secretion

2002 ◽  
Vol 282 (4) ◽  
pp. E873-E879 ◽  
Author(s):  
Carolyn F. Deacon ◽  
Astrid Plamboeck ◽  
Søren Møller ◽  
Jens J. Holst
Keyword(s):  
Insulin Secretion ◽  
Therapeutic Potential ◽  
Intravenous Glucose ◽  
Dpp Iv ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Independent Effects ◽  
Insulinotropic Effect ◽  
Insulin Responses

Glucagon-like peptide 1 (GLP-1) is a potent anti-hyperglycemic hormone currently under investigation for its therapeutic potential. However, due to rapid degradation by dipeptidyl peptidase IV (DPP IV), which limits its metabolic stability and eliminates its insulinotropic activity, it has been impossible to assess its true efficacy in vivo. In chloralose-anesthetized pigs given valine-pyrrolidide (to block endogenous DPP IV activity), the independent effects of GLP-1-(7–36) amide on glucose and insulin responses to intravenous glucose were assessed, and the metabolite generated by DPP IV, GLP-1-(9–36) amide, was investigated for any ability to influence these responses. GLP-1-(7–36) amide enhanced insulin secretion ( P < 0.03 vs. vehicle), but GLP-1-(9–36) amide was without effect, either alone or when coinfused with GLP-1-(7–36) amide. In contrast, GLP-1-(9–36) amide did affect glucose responses ( P < 0.03). Glucose excursions were greater after saline (121 ± 17 mmol · l−1 · min) than after GLP-1-(9–36) amide (73 ± 19 mmol · l−1 · min; P < 0.05), GLP-1-(7–36) amide (62 ± 13 mmol · l−1 · min; P < 0.02) or GLP-1-(7–36) amide + GLP-1-(9–36) amide (50 ± 13 mmol · l−1 · min; P < 0.005). Glucose elimination rates were faster after GLP-1-(7–36) amide + (9–36) amide (10.3 ± 1.2%/min) than after GLP-1-(7–36) amide (7.0 ± 0.9%/min; P < 0.04), GLP-1-(9–36) amide (6.8 ± 1.0%/min; P < 0.03), or saline (5.4 ± 1.2%/min; P < 0.005). Glucagon concentrations were unaffected. These results demonstrate that GLP-1-(9–36) amide neither stimulates insulin secretion nor antagonizes the insulinotropic effect of GLP-1-(7–36) amide in vivo. Moreover, the metabolite itself possesses anti-hyperglycemic effects, supporting the hypothesis that selective DPP IV action is important in glucose homeostasis.

scholarly journals Patterns of Insulin Secretion During First-Phase Insulin Secretion in Normal Chinese Adults

2021 ◽  
Vol 12 ◽  
Author(s):  
Tao Yuan ◽  
Shuoning Song ◽  
Tianyi Zhao ◽  
Yanbei Duo ◽  
Shihan Wang ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Linear Trend ◽  
Insulin Response ◽  
Density Lipoprotein ◽  
Intravenous Glucose Tolerance Test ◽  
Intravenous Glucose ◽  
C Peptide ◽  
Significant Difference ◽  
First Phase Insulin Secretion

BackgroundThe increase in diabetes worldwide is alarming. Decreased acute insulin response to intravenous glucose tolerance test (IVGTT) during first-phase insulin secretion (FPIS) is a characteristic of diabetes. However, knowledge of the insulin secretion characteristics identified by different time to glucose peak in subjects with different metabolic state is sparse.AimsThis study aimed to find different patterns of FPIS in subjects with normal glucose tolerance (NGT) and analyzed the relationship between insulin secretion patterns and the risk for development of type 2 diabetes mellitus (T2DM).MethodsA total of 126 subjects were divided into three groups during a 10-min IVGTT, including NGT with time to glucose peak after 3 min (G1, n = 21), NGT with time to glucose peak at 3 min (G2, n = 95), and prediabetes or diabetes with time to glucose peak at 3 min (G3, n = 10). Glucose, insulin, and C-peptide concentrations at 0, 3, 5, 7, and 10 min during the IVGTT were tested. IVGTT-based indices were calculated to evaluate the insulin secretion and insulin sensitivity.ResultsAge, body mass index (BMI), waist-to-hip ratio, triglyceride (TG), and hemoglobin A1c (HbA1c) of subjects were gradually higher, while high-density lipoprotein cholesterol (HDL-C) was gradually lower from G1 to G3 (p for linear trend &lt;0.05), and the differences between G1 and G2 were also statistically significant (p &lt; 0.05). Glucose peak of most participants in G1 converged at 5 min, and the curves shape of insulin and C-peptide in G2 were the sharpest among three groups. There was no significant difference in all IVGTT-based indices between G1 and G2, but AUCIns, AUCIns/AUCGlu, and △Ins3/△Glu3 in G2 were the highest, and the p-value for linear trend of those indices among three groups were statistically significant (p &lt; 0.05).ConclusionsTwo patterns of FPIS were in subjects with NGT, while subjects with later time to glucose peak during FPIS might be less likely to develop T2DM in the future.

A minimal model of insulin secretion and kinetics to assess hepatic insulin extraction

2006 ◽  
Vol 290 (1) ◽  
pp. E169-E176 ◽  
Author(s):  
Gianna Toffolo ◽  
Marco Campioni ◽  
Rita Basu ◽  
Robert A. Rizza ◽  
Claudio Cobelli
Keyword(s):  
Insulin Secretion ◽  
Minimal Model ◽  
Insulin Delivery ◽  
Intravenous Glucose Tolerance Test ◽  
Insulin Degradation ◽  
Second Phase ◽  
Hepatic Extraction ◽  
Minimal Models ◽  
Intravenous Glucose ◽  
C Peptide

The liver is the principal site of insulin degradation, and assessing its ability to extract insulin is important to understand several pathological states. Noninvasive quantification of hepatic extraction (HE) in an individual requires comparing the profiles of insulin secretion (ISR) and posthepatic insulin delivery rate (IDR). To do this, we propose here the combined use of the classical C-peptide minimal model with a new minimal model of insulin delivery and kinetics. The models were identified on insulin-modified intravenous glucose tolerance test (IM-IVGTT) data of 20 healthy subjects. C-peptide kinetics were fixed to standard population values, whereas insulin kinetics were assessed in each individual, along with IDR parameters, thanks to the presence of insulin decay data observed after exogenous insulin administration. From the two models, profiles of ISR and IDR were predicted, and ISR and IDR indexes of β-cell responsivity to glucose in the basal state, as well as during first- and second-phase secretion, were estimated. HE profile, obtained by comparing ISR and IDR profiles, showed a rapid suppression immediately after the glucose administration. HE indexes, obtained by comparing ISR and IDR indexes, indicated that the liver is able to extract 70 ± 9% of insulin passing through it in the basal state and 54 ± 14% during IM-IVGTT. In conclusion, insulin secretion, kinetics, and hepatic extraction can be reliably assessed during an IM-IVGTT by using insulin and C-peptide minimal models.

Dose-dependent effects of oral and intravenous glucose on insulin secretion and clearance in normal humans

1988 ◽  
Vol 254 (3) ◽  
pp. E349-E357 ◽  
Author(s):  
H. Tillil ◽  
E. T. Shapiro ◽  
M. A. Miller ◽  
T. Karrison ◽  
B. H. Frank ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Compartmental Analysis ◽  
Normal Subjects ◽  
Insulin Clearance ◽  
Base Line ◽  
Metabolic Clearance ◽  
Intravenous Glucose ◽  
C Peptide ◽  
Endogenous Insulin ◽  
Normal Humans

Insulin secretion and clearance were studied in 2 groups of 7 normal subjects who each received 25, 50, and 100 g of glucose either orally or intravenously (iv) on separate occasions. Insulin secretion rates were calculated during a 1-h base line and for 5 h after glucose administration from a two-compartmental analysis of peripheral C-peptide concentrations using individual kinetic parameters derived after iv bolus injections of biosynthetic human C-peptide. Incremental glucose areas after oral or iv glucose increased as a function of the glucose dose (P = 0.0001). Incremental insulin secretion increased with increasing doses of both oral and iv glucose (P = 0.0001). The metabolic clearance rate (MCR) of endogenous insulin was calculated as the ratio of the total area under the insulin secretion rate curve and the simultaneous peripheral insulin concentration curve. The basal MCR was 1,879.5 +/- 110.5 ml/min (mean +/- SE). The poststimulatory MCR decreased with increasing doses of both oral and iv glucose concomitant with the greater insulin secretory response (P = 0.0014). This decrease in insulin clearance was not significantly different between oral and iv administration of glucose (P = 0.495). In conclusion diminished insulin clearance may be seen after marked stimulation of insulin secretion with larger doses of oral and iv glucose.

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