Minimal modeling of insulin secretion in the perfused rat pancreas: a drug effect case study

2014 ◽  
Vol 306 (6) ◽  
pp. E627-E634 ◽  
Author(s):  
Michela Riz ◽  
Morten Gram Pedersen ◽  
Gianna Maria Toffolo ◽  
Guido Haschke ◽  
Hans-Christoph Schneider ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Minimal Model ◽  
Cell Function ◽  
Fold Increase ◽  
Second Phase ◽  
Good Precision ◽  
Β Cell ◽  
Perfused Rat Pancreas ◽  
Rat Pancreas ◽  
Β Cell Function

The experimental protocol of the perfused rat pancreas is commonly used to evaluate β-cell function. In this context, mathematical models become useful tools through the determination of indexes that allow the assessment of β-cell function in different experimental groups and the quantification of the effects of antidiabetic drugs, secretagogues, or treatments. However, a minimal model applicable to the isolated perfused rat pancreas has so far been unavailable. In this work, we adapt the C-peptide minimal model applied previously to the intravenous glucose tolerance test to obtain a specific model for the experimental settings of the perfused pancreas. Using the model, it is possible to estimate indexes describing β-cell responsivity for first (ΦD) and second phase (ΦS, T) of insulin secretion. The model was initially applied to untreated pancreata and afterward used for the assessment of pharmacologically relevant agents (the gut hormone GLP-1, the potent GLP-1 receptor agonist lixisenatide, and a GPR40/FFAR1 agonist, SAR1) to quantify and differentiate their effect on insulin secretion. Model fit was satisfactory, and parameters were estimated with good precision for both untreated and treated pancreata. Model application showed that lixisenatide reaches improvement of β-cell function similarly to GLP-1 (11.7- vs. 13.1-fold increase in ΦD and 2.3- vs. 2.8-fold increase in ΦS) and demonstrated that SAR1 leads to an additional improvement of β-cell function in the presence of postprandial GLP-1 levels.

Effects of diazoxide on α- and β-cell function in isolated perfused rat pancreas

1994 ◽  
Vol 25 (2) ◽  
pp. 77-82 ◽  
Author(s):  
Hiroshi Hirose ◽  
Hiroshi Maruyama ◽  
Katsuhiko Ito ◽  
Koichi Kido ◽  
Kazunori Koyama ◽  
...  
Keyword(s):  
Cell Function ◽  
Β Cell ◽  
Perfused Rat Pancreas ◽  
Rat Pancreas ◽  
Isolated Perfused Rat Pancreas ◽  
Β Cell Function

scholarly journals Pancreatic β-cell function increases in a linear dose-response manner following exercise training in adults with prediabetes

2013 ◽  
Vol 305 (10) ◽  
pp. E1248-E1254 ◽  
Author(s):  
Steven K. Malin ◽  
Thomas P. J. Solomon ◽  
Alecia Blaszczak ◽  
Stephen Finnegan ◽  
Julianne Filion ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Dose Response ◽  
Cell Function ◽  
Second Phase ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Linear Dose ◽  
Β Cell Function ◽  
Exercise Dose

Although some studies suggest that a linear dose-response relationship exists between exercise and insulin sensitivity, the exercise dose required to enhance pancreatic β-cell function is unknown. Thirty-five older obese adults with prediabetes underwent a progressive 12-wk supervised exercise intervention (5 days/wk for 60 min at ∼85% HRmax). Insulin and C-peptide responses to an OGTT were used to define the first- and second-phase disposition index (DI; β-cell function = glucose-stimulated insulin secretion × clamp-derived insulin sensitivity). Maximum oxygen consumption (V̇o2max) and body composition (dual-energy X-ray absorptiometry and computed tomography) were also measured before and after the intervention. Exercise dose was computed using V̇o2/heart-rate derived linear regression equations. Subjects expended 474.5 ± 8.8 kcal/session (2,372.5 ± 44.1 kcal/wk) during the intervention and lost ∼8% body weight. Exercise increased first- and second-phase DI ( P < 0.05), and these changes in DI were linearly related to exercise dose (DIfirst phase: r = 0.54, P < 0.001; DIsecond phase: r = 0.56, P = 0.0005). Enhanced DI was also associated with increased V̇o2max (DIfirst phase: r = 0.36, P = 0.04; DIsecond phase: r = 0.41, P < 0.02) but not lower body fat (DIfirst phase: r = −0.21, P = 0.25; DIsecond phase: r = −0.30, P = 0.10) after training. Low baseline DI predicted an increase in DI after the intervention (DIfirst phase: r = −0.37; DIsecond phase: r = −0.41, each P < 0.04). Thus, exercise training plus weight loss increased pancreatic β-cell function in a linear dose-response manner in adults with prediabetes. Our data suggest that higher exercise doses (i.e., >2,000 kcal/wk) are necessary to enhance β-cell function in adults with poor insulin secretion capacity.

Quantitative indexes of β-cell function during graded up&down glucose infusion from C-peptide minimal models

2001 ◽  
Vol 280 (1) ◽  
pp. E2-E10 ◽  
Author(s):  
Gianna Toffolo ◽  
Elena Breda ◽  
Melissa K. Cavaghan ◽  
David A. Ehrmann ◽  
Kenneth S. Polonsky ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Minimal Model ◽  
Cell Function ◽  
Glucose Infusion ◽  
Β Cell ◽  
Intravenous Glucose ◽  
C Peptide ◽  
Β Cell Function ◽  
Quantitative Indexes ◽  
Infusion Protocol

Availability of quantitative indexes of insulin secretion is important for definition of the alterations in β-cell responsivity to glucose associated with different physiopathological states. This is presently possible by using the intravenous glucose tolerance test (IVGTT) in conjunction with the C-peptide minimal model. However, the secretory response to a more physiological slowly increasing/decreasing glucose stimulus may uncover novel features of β-cell function. Therefore, plasma C-peptide and glucose data from a graded glucose infusion protocol (seven 40-min periods of 0, 4, 8, 16, 8, 4, and 0 mg · kg−1 · min−1) in eight normal subjects were analyzed by use of a new model of insulin secretion and kinetics. The model assumes a two-compartment description of C-peptide kinetics and describes the stimulatory effect on insulin secretion of both glucose concentration and the rate at which glucose increases. It provides in each individual the insulin secretion profile and three indexes of pancreatic sensitivity to glucose: Φs, Φd, and Φb, related, respectively, to the control of insulin secretion by the glucose level (static control), the rate at which glucose increases (dynamic control), and basal glucose. Indexes (means ± SE) were Φs = 18.8 ± 1.8 (109min−1), Φd = 222 ± 30 (109), and Φb = 5.2 ± 0.4 (109 min−1). The model also allows one to quantify the β-cell times of response to increasing and decreasing glucose stimulus, equal to 5.7 ± 2.2 (min) and 17.8 ± 2.0 (min), respectively. In conclusion, the graded glucose infusion protocol, interpreted with a minimal model of C-peptide secretion and kinetics, provides a quantitative assessment of pancreatic function in an individual. Its application to various physiopathological states should provide novel insights into the role of insulin secretion in the development of glucose intolerance.

Differential Loss of β-cell Function in Youth vs. Adults Following Treatment Withdrawal in the Restoring Insulin Secretion (RISE) Study

2021 ◽  
pp. 108948
Author(s):  
Kristina M. Utzschneider ◽  
Mark T. Tripputi ◽  
Alexandra Kozedub ◽  
Elena Barengolts ◽  
Sonia Caprio ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Cell Function ◽  
Treatment Withdrawal ◽  
Β Cell ◽  
Β Cell Function

scholarly journals Functional Role of Serotonin in Insulin Secretion in a Diet-Induced Insulin-Resistant State

Endocrinology ◽  
2014 ◽  
Vol 156 (2) ◽  
pp. 444-452 ◽  
Author(s):  
Kyuho Kim ◽  
Chang-Myung Oh ◽  
Mica Ohara-Imaizumi ◽  
Sangkyu Park ◽  
Jun Namkung ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Cell Function ◽  
Β Cell ◽  
Pancreas Perfusion ◽  
Insulin Resistant ◽  
Β Cell Function ◽  
Resistant State ◽  
Insulin Resistant State

The physiological role of serotonin, or 5-hydroxytryptamine (5-HT), in pancreatic β-cell function was previously elucidated using a pregnant mouse model. During pregnancy, 5-HT increases β-cell proliferation and glucose-stimulated insulin secretion (GSIS) through the Gαq-coupled 5-HT2b receptor (Htr2b) and the 5-HT3 receptor (Htr3), a ligand-gated cation channel, respectively. However, the role of 5-HT in β-cell function in an insulin-resistant state has yet to be elucidated. Here, we characterized the metabolic phenotypes of β-cell-specific Htr2b−/− (Htr2b βKO), Htr3a−/− (Htr3a knock-out [KO]), and β-cell-specific tryptophan hydroxylase 1 (Tph1)−/− (Tph1 βKO) mice on a high-fat diet (HFD). Htr2b βKO, Htr3a KO, and Tph1 βKO mice exhibited normal glucose tolerance on a standard chow diet. After 6 weeks on an HFD, beginning at 4 weeks of age, both Htr3a KO and Tph1 βKO mice developed glucose intolerance, but Htr2b βKO mice remained normoglycemic. Pancreas perfusion assays revealed defective first-phase insulin secretion in Htr3a KO mice. GSIS was impaired in islets isolated from HFD-fed Htr3a KO and Tph1 βKO mice, and 5-HT treatment improved insulin secretion from Tph1 βKO islets but not from Htr3a KO islets. Tph1 and Htr3a gene expression in pancreatic islets was not affected by an HFD, and immunostaining could not detect 5-HT in pancreatic islets from mice fed an HFD. Taken together, these results demonstrate that basal 5-HT levels in β-cells play a role in GSIS through Htr3, which becomes more evident in a diet-induced insulin-resistant state.

Let7b-5p is Upregulated in the Serum of Emirati Patients with Type 2 Diabetes and Regulates Insulin Secretion in INS-1 Cells

2020 ◽  
Author(s):  
Hayat Aljaibeji ◽  
Noha Mousaad Elemam ◽  
Abdul Khader Mohammed ◽  
Hind Hasswan ◽  
Mahammad Al Thahyabat ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Cell Viability ◽  
Cell Function ◽  
Serum Levels ◽  
Insulin Content ◽  
Β Cell ◽  
Control Subjects ◽  
Β Cell Function

Abstract Let7b-5p is a member of the Let-7 miRNA family and one of the top expressed miRNAs in human islets that implicated in glucose homeostasis. The levels of Let7b-5p in type 2 diabetes (T2DM) patients or its role in β-cell function is still unclear. In the current study, we measured the serum levels of let7b-5p in Emirati patients with T2DM (with/without complications) and control subjects. Overexpression or silencing of let7b-5p in INS-1 (832/13) cells was performed to investigate the impact on insulin secretion, content, cell viability, apoptosis, and key functional genes. We found that serum levels of let7b-5p are significantly (p<0.05) higher in T2DM-patients or T2DM with complications compared to control subjects. Overexpression of let7b-5p increased insulin content and decreased glucose-stimulated insulin secretion, whereas silencing of let7b-5p reduced insulin content and secretion. Modulation of the expression levels of let7b-5p did not influence cell viability nor apoptosis. Analysis of mRNA and protein expression of hallmark genes in let7b-5p transfected cells revealed a marked dysregulation of Insulin, Pancreatic And Duodenal Homeobox 1 (PDX1), glucokinase (GCK), glucose transporter 2 (GLUT2), and INSR. In conclusion, an appropriate level of let7b-5p is essential to maintain β-cell function and may be regarded as a biomarker for T2DM.

Impact of lack of suppression of glucagon on glucose tolerance in humans

1999 ◽  
Vol 277 (2) ◽  
pp. E283-E290 ◽  
Author(s):  
Pankaj Shah ◽  
Ananda Basu ◽  
Rita Basu ◽  
Robert Rizza
Keyword(s):  
Insulin Secretion ◽  
Glucose Concentration ◽  
Cell Function ◽  
Hormone Secretion ◽  
Glucose Production ◽  
Glucagon Secretion ◽  
Β Cell ◽  
Β Cell Function ◽  
Glucagon Suppression

People with type 2 diabetes have defects in both α- and β-cell function. To determine whether lack of suppression of glucagon causes hyperglycemia when insulin secretion is impaired but not when insulin secretion is intact, twenty nondiabetic subjects were studied on two occasions. On both occasions, a “prandial” glucose infusion was given over 5 h while endogenous hormone secretion was inhibited. Insulin was infused so as to mimic either a nondiabetic ( n = 10) or diabetic ( n = 10) postprandial profile. Glucagon was infused at a rate of 1.25 ng ⋅ kg−1 ⋅ min−1, beginning either at time zero to prevent a fall in glucagon (nonsuppressed study day) or at 2 h to create a transient fall in glucagon (suppressed study day). During the “diabetic” insulin profile, lack of glucagon suppression resulted in a marked increase ( P < 0.002) in both the peak glucose concentration (11.9 ± 0.4 vs. 8.9 ± 0.4 mmol/l) and the area above basal of glucose (927 ± 77 vs. 546 ± 112 mmol ⋅ l−1 ⋅ 6 h) because of impaired ( P < 0.001) suppression of glucose production. In contrast, during the “nondiabetic” insulin profile, lack of suppression of glucagon resulted in only a slight increase ( P< 0.02) in the peak glucose concentration (9.1 ± 0.4 vs. 8.4 ± 0.3 mmol/l) and the area above basal of glucose (654 ± 146 vs. 488 ± 118 mmol ⋅ l−1 ⋅ 6 h). Of interest, when glucagon was suppressed, glucose concentrations differed only minimally during the nondiabetic and diabetic insulin profiles. These data indicate that lack of suppression of glucagon can cause substantial hyperglycemia when insulin availability is limited, therefore implying that inhibitors of glucagon secretion and/or glucagon action are likely to be useful therapeutic agents in such individuals.

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