scholarly journals Characterization of glucose-insulin responsiveness and impact of fetal number and sex difference on insulin response in the sheep fetus

2011 ◽  
Vol 300 (5) ◽  
pp. E817-E823 ◽  
Author(s):  
Alice S. Green ◽  
Antoni R. Macko ◽  
Paul J. Rozance ◽  
Dustin T. Yates ◽  
Xiaochuan Chen ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Sex Difference ◽  
Cell Mass ◽  
Insulin Response ◽  
Β Cell ◽  
Fetal Sheep ◽  
Square Wave ◽  
Hyperglycemic Clamp ◽  
Insulin Responsiveness ◽  
Sheep Fetus

GSIS is often measured in the sheep fetus by a square-wave hyperglycemic clamp, but maximal β-cell responsiveness and effects of fetal number and sex difference have not been fully evaluated. We determined the dose-response curve for GSIS in fetal sheep (0.9 of gestation) by increasing plasma glucose from euglycemia in a stepwise fashion. The glucose-insulin response was best fit by curvilinear third-order polynomial equations for singletons ( y = 0.018 x3 − 0.26 x2 + 1.2 x − 0.64) and twins ( y = −0.012 x3 + 0.043 x2 + 0.40 x − 0.16). In singles, maximal insulin secretion was achieved at 3.4 ± 0.2 mmol/l glucose but began to plateau after 2.4 ± 0.2 mmol/l glucose (90% of maximum), whereas the maximum for twins was reached at 4.8 ± 0.4 mmol/l glucose. In twin ( n = 18) and singleton ( n = 49) fetuses, GSIS was determined with a square-wave hyperglycemic clamp >2.4 mmol/l glucose. Twins had a lower basal glucose concentration, and plasma insulin concentrations were 59 ( P < 0.01) and 43% ( P < 0.05) lower in twins than singletons during the euglycemic and hyperglycemic periods, respectively. The basal glucose/insulin ratio was approximately doubled in twins vs. singles ( P < 0.001), indicating greater insulin sensitivity. In a separate cohort of fetuses, twins ( n = 8) had lower body weight ( P < 0.05) and β-cell mass ( P < 0.01) than singleton fetuses ( n = 7) as a result of smaller pancreata ( P < 0.01) and a positive correlation ( P < 0.05) between insulin immunopositive area and fetal weight ( P < 0.05). No effects of sex difference on GSIS or β-cell mass were observed. These findings indicate that insulin secretion is less responsive to physiological glucose concentrations in twins, due in part to less β-cell mass.

scholarly journals Pulsatile hyperglycemia increases insulin secretion but not pancreatic β-cell mass in intrauterine growth-restricted fetal sheep

2018 ◽  
Vol 9 (5) ◽  
pp. 492-499 ◽  
Author(s):  
B. H. Boehmer ◽  
L. D. Brown ◽  
S. R. Wesolowski ◽  
W. W. Hay ◽  
P. J. Rozance
Keyword(s):  
Insulin Secretion ◽  
Cell Mass ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Fetal Sheep ◽  
Square Wave ◽  
Cell Numbers ◽  
Intrauterine Growth ◽  
Hyperglycemic Clamp

AbstractImpaired β-cell development and insulin secretion are characteristic of intrauterine growth-restricted (IUGR) fetuses. In normally grown late gestation fetal sheep pancreatic β-cell numbers and insulin secretion are increased by 7–10 days of pulsatile hyperglycemia (PHG). Our objective was to determine if IUGR fetal sheep β-cell numbers and insulin secretion could also be increased by PHG or if IUGR fetal β-cells do not have the capacity to respond to PHG. Following chronic placental insufficiency producing IUGR in twin gestation pregnancies (n=7), fetuses were administered a PHG infusion, consisting of 60 min, high rate, pulsed infusions of dextrose three times a day with an additional continuous, low-rate infusion of dextrose to prevent a decrease in glucose concentrations between the pulses or a control saline infusion. PHG fetuses were compared with their twin IUGR fetus, which received a saline infusion for 7 days. The pulsed glucose infusion increased fetal arterial glucose concentrations an average of 83% during the infusion. Following the 7-day infusion, a square-wave fetal hyperglycemic clamp was performed in both groups to measure insulin secretion. The rate of increase in fetal insulin concentrations during the first 20 min of a square-wave hyperglycemic clamp was 44% faster in the PHG fetuses compared with saline fetuses (P<0.05). There were no differences in islet size, the insulin+ area of the pancreas and of the islets, and β-cell mass between groups (P>0.23). Chronic PHG increases early phase insulin secretion in response to acute hyperglycemia, indicating that IUGR fetal β-cells are functionally responsive to chronic PHG.

Measurements of insulin responses as predictive markers of pancreatic β-cell mass in normal and β-cell-reduced lean and obese Göttingen minipigs in vivo

2006 ◽  
Vol 290 (4) ◽  
pp. E670-E677 ◽  
Author(s):  
Marianne O. Larsen ◽  
Bidda Rolin ◽  
Jeppe Sturis ◽  
Michael Wilken ◽  
Richard D. Carr ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Cell Mass ◽  
Insulin Response ◽  
Study Groups ◽  
Β Cell ◽  
Intravenous Glucose ◽  
Body Weights ◽  
In Vivo Tests ◽  
Insulin Responses

At present, the best available estimators of β-cell mass in humans are those based on measurement of insulin levels or appearance rates in the circulation. In several animal models, these estimators have been validated against β-cell mass in lean animals. However, as many diabetic humans are obese, a correlation between in vivo tests and β-cell mass must be evaluated over a range of body weights to include different levels of insulin sensitivity. For this purpose, obese ( n = 10) and lean ( n = 25) Göttingen minipigs were studied. β-Cell mass had been reduced ( n = 16 lean, n = 5 obese) with a combination of nicotinamide (67 mg/kg) and streptozotocin (125 mg/kg), acute insulin response (AIR) to intravenous glucose and/or arginine was tested, pulsatile insulin secretion was evaluated by deconvolution ( n = 30), and β-cell mass was determined histologically. AIR to 0.3 ( r2= 0.4502, P < 0.0001) or 0.6 g/kg glucose ( r2= 0.6806, P < 0.0001), 67 mg/kg arginine ( r2= 0.5730, P < 0.001), and maximum insulin concentration ( r2= 0.7726, P < 0.0001) were all correlated to β-cell mass when evaluated across study groups, and regression lines were not different between lean and obese groups except for AIR to 0.3 g/kg glucose. Baseline pulse mass was not significantly correlated to β-cell mass across the study groups ( r2= 0.1036, NS), whereas entrained pulse mass did show a correlation across groups ( r2= 0.4049, P < 0.001). This study supports the use of in vivo tests of insulin responses to evaluate β-cell mass over a range of body weights in the minipig. Extensive stimulation of insulin secretion by a combination of glucose and arginine seems to give the best correlation to β-cell mass.

scholarly journals Free fatty acid receptor 3 differentially contributes to β-cell compensation under high-fat diet and streptozotocin stress

2020 ◽  
Vol 318 (4) ◽  
pp. R691-R700 ◽  
Author(s):  
Medha Priyadarshini ◽  
Connor Cole ◽  
Gautham Oroskar ◽  
Anton E. Ludvik ◽  
Barton Wicksteed ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Fatty Acid ◽  
Free Fatty Acid ◽  
Cell Mass ◽  
Insulin Response ◽  
High Fat ◽  
Β Cell ◽  
Acid Receptor ◽  
Free Fatty Acid Receptor ◽  
Fatty Acid Receptor

The free fatty acid receptor 3 (FFA3) is a nutrient sensor of gut microbiota-generated nutrients, the short-chain fatty acids. Previously, we have shown that FFA3 is expressed in β-cells and inhibits islet insulin secretion ex vivo. Here, we determined the physiological relevance of the above observation by challenging wild-type (WT) and FFA3 knockout (KO) male mice with 1) hyperglycemia and monitoring insulin response via highly sensitive hyperglycemic clamps, 2) dietary high fat (HF), and 3) chemical-induced diabetes. As expected, FFA3 KO mice exhibited significantly higher insulin secretion and glucose infusion rate in hyperglycemic clamps. Predictably, under metabolic stress induced by HF-diet feeding, FFA3 KO mice exhibited less glucose intolerance compared with the WT mice. Moreover, similar islet architecture and β-cell area in HF diet-fed FFA3 KO and WT mice was observed. Upon challenge with streptozotocin (STZ), FFA3 KO mice initially exhibited a tendency for an accelerated incidence of diabetes compared with the WT mice. However, this difference was not maintained. Similar glycemia and β-cell mass loss was observed in both genotypes 10 days post-STZ challenge. Higher resistance to STZ-induced diabetes in WT mice could be due to higher basal islet autophagy. However, this difference was not protective because in response to STZ, similar autophagy induction was observed in both WT and FFA3 KO islets. These data demonstrate that FFA3 plays a role in modulating insulin secretion and β-cell response to stressors. The β-cell FFA3 and autophagy link warrant further research.

scholarly journals Transgenerational metabolic outcomes associated with uteroplacental insufficiency

2013 ◽  
Vol 217 (1) ◽  
pp. 105-118 ◽  
Author(s):  
Melanie Tran ◽  
Linda A Gallo ◽  
Andrew J Jefferies ◽  
Karen M Moritz ◽  
Mary E Wlodek
Keyword(s):  
Insulin Secretion ◽  
Birth Weight ◽  
Glucose Tolerance ◽  
Cell Mass ◽  
Insulin Response ◽  
Whole Body ◽  
Model Assessment ◽  
Β Cell ◽  
Pancreatic Morphology ◽  
First Phase Insulin Response

Intrauterine growth restriction increases adult metabolic disease risk with evidence to suggest that suboptimal conditions in utero can have transgenerational effects. We determined whether impaired glucose tolerance, reduced insulin secretion, and pancreatic deficits are evident in second-generation (F2) male and female offspring from growth-restricted mothers, in a rat model of uteroplacental insufficiency. Late gestation uteroplacental insufficiency was induced by bilateral uterine vessel ligation (restricted) or sham surgery (control) in Wistar-Kyoto rats. First-generation (F1) control and restricted females were mated with normal males and F2 offspring studied at postnatal day 35 and at 6 and 12 months. F2 glucose tolerance, insulin secretion, and sensitivity were assessed at 6 and 12 months and pancreatic morphology was quantified at all study ages. At 6 months, F2 restricted male offspring exhibited blunted first-phase insulin response (−35%), which was associated with reduced pancreatic β-cell mass (−29%). By contrast, F2 restricted females had increased β-cell mass despite reduced first-phase insulin response (−38%). This was not associated with any changes in plasma estradiol concentrations. Regardless of maternal birth weight, F2 control and restricted males had reduced homeostatic model assessment of insulin resistance and elevated plasma triglyceride concentrations at 6 months and reduced whole-body insulin sensitivity at 6 and 12 months compared with females. We report that low maternal birth weight is associated with reduced first-phase insulin response and gender-specific differences in pancreatic morphology in the F2. Further studies will define the mode(s) of disease transmission, including direct insults to developing gametes, adverse maternal responses to pregnancy, or inherited mechanisms.

scholarly journals Increased amino acid supply potentiates glucose-stimulated insulin secretion but does not increase β-cell mass in fetal sheep

2013 ◽  
Vol 304 (4) ◽  
pp. E352-E362 ◽  
Author(s):  
Monika M. Gadhia ◽  
Anne M. Maliszewski ◽  
Meghan C. O'Meara ◽  
Stephanie R. Thorn ◽  
Jinny R. Lavezzi ◽  
...  
Keyword(s):  
Amino Acids ◽  
Insulin Secretion ◽  
Amino Acid ◽  
Cell Mass ◽  
Late Gestation ◽  
Insulin Content ◽  
Acid Mixture ◽  
Β Cell ◽  
Fetal Sheep ◽  
Glucose Stimulated Insulin Secretion

Amino acids and glucose acutely stimulate fetal insulin secretion. In isolated adult pancreatic islets, amino acids potentiate glucose-stimulated insulin secretion (GSIS), but whether amino acids have this same effect in the fetus is unknown. Therefore, we tested the effects of increased fetal amino acid supply on GSIS and morphology of the pancreas. We hypothesized that increasing fetal amino acid supply would potentiate GSIS. Singleton fetal sheep received a direct intravenous infusion of an amino acid mixture (AA) or saline (CON) for 10–14 days during late gestation to target a 25–50% increase in fetal branched-chain amino acids (BCAA). Early-phase GSIS increased 150% in the AA group ( P < 0.01), and this difference was sustained for the duration of the hyperglycemic clamp (105 min) ( P < 0.05). Glucose-potentiated arginine-stimulated insulin secretion (ASIS), pancreatic insulin content, and pancreatic glucagon content were similar between groups. β-Cell mass and area were unchanged between groups. Baseline and arginine-stimulated glucagon concentrations were increased in the AA group ( P < 0.05). Pancreatic α-cell mass and area were unchanged. Fetal and pancreatic weights were similar. We conclude that a sustained increase of amino acid supply to the normally growing late-gestation fetus potentiated fetal GSIS but did not affect the morphology or insulin content of the pancreas. We speculate that increased β-cell responsiveness (insulin secretion) following increased amino acid supply may be due to increased generation of secondary messengers in the β-cell. This may be enhanced by the paracrine action of glucagon on the β-cell.

scholarly journals Increased fetal insulin concentrations for one week fail to improve insulin secretion or β-cell mass in fetal sheep with chronically reduced glucose supply

2013 ◽  
Vol 304 (1) ◽  
pp. R50-R58 ◽  
Author(s):  
Jinny R. Lavezzi ◽  
Stephanie R. Thorn ◽  
Meghan C. O'Meara ◽  
Dan LoTurco ◽  
Laura D. Brown ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Infusion ◽  
Cell Mass ◽  
Placental Insufficiency ◽  
Late Gestation ◽  
Β Cell ◽  
Fetal Sheep ◽  
Maternal Undernutrition ◽  
Pregnant Sheep ◽  
Glucose Supply

Maternal undernutrition during pregnancy and placental insufficiency are characterized by impaired development of fetal pancreatic β-cells. Prolonged reduced glucose supply to the fetus is a feature of both. It is unknown if reduced glucose supply, independent of other complications of maternal undernutrition and placental insufficiency, would cause similar β-cell defects. Therefore, we measured fetal insulin secretion and β-cell mass following prolonged reduced fetal glucose supply in sheep. We also tested whether restoring physiological insulin concentrations would correct any β-cell defects. Pregnant sheep received either a direct saline infusion (CON = control, n = 5) or an insulin infusion (HG = hypoglycemic, n = 5) for 8 wk in late gestation (75 to 134 days) to decrease maternal glucose concentrations and reduce fetal glucose supply. A separate group of HG fetuses also received a direct fetal insulin infusion for the final week of the study with a dextrose infusion to prevent a further fall in glucose concentration [hypoglycemic + insulin (HG+I), n = 4]. Maximum glucose-stimulated insulin concentrations were 45% lower in HG fetuses compared with CON fetuses. β-Cell, pancreatic, and fetal mass were 50%, 37%, and 40% lower in HG compared with CON fetuses, respectively ( P < 0.05). Insulin secretion and β-cell mass did not improve in the HG+I fetuses. These results indicate that chronically reduced fetal glucose supply is sufficient to reduce pancreatic insulin secretion in response to glucose, primarily due to reduced pancreatic and β-cell mass, and is not correctable with insulin.

β-Cell function and islet morphology in normal, obese, and obese β-cell mass-reduced Göttingen minipigs

2005 ◽  
Vol 288 (2) ◽  
pp. E412-E421 ◽  
Author(s):  
M. O. Larsen ◽  
C. B. Juhl ◽  
N. Pørksen ◽  
C. F. Gotfredsen ◽  
R. D. Carr ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Cell Function ◽  
Cell Mass ◽  
Insulin Response ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Islet Morphology ◽  
Pancreatic Fat ◽  
Β Cell Function ◽  
Pulsatile Insulin Secretion

Herein, we bridge β-cell function and morphology in minipigs. We hypothesized that different aspects of β-cell dysfunction are present in obesity and obesity with reduced β-cell mass by using pulsatile insulin secretion as an early marker. Measures for β-cell function (glucose and arginine stimulation plus baseline and glucose-entrained pulsatile insulin secretion) and islet morphology were studied in long-term (19–20 mo) obese ( n = 5) and obese β-cell-reduced [nicotinamide + streptozotocin (STZ), n = 5] minipigs and normal controls, representing different stages in the development toward type 2 diabetes. Acute insulin response (AIR) to glucose and arginine were, surprisingly, normal in obese (0.3 g/kg glucose: AIR = 246 ± 119 vs. 255 ± 61 pM in control; 67 mg/kg arginine: AIR = 230 ± 124 vs. 214 ± 85 pM in control) but reduced in obese-STZ animals (0.3 g/kg glucose: AIR = 22 ± 36, P < 0.01; arginine: AIR = 87 ± 92 pM, P < 0.05 vs. control). Baseline pulsatile insulin secretion was reduced in obese (59 ± 16 vs. 76 ± 16% in control, P < 0.05) and more so in obese-STZ animals (43 ± 13%, P < 0.01), whereas regularity during entrainment was increased in obese animals (approximate entropy: 0.85 ± 0.14 vs. 1.13 ± 0.13 in control, P < 0.01). β-Cell mass (mg/kg body wt) was normal in obese and reduced in obese-STZ animals, with pancreatic fat infiltration in both groups. In conclusion, obesity and insulin resistance are not linked with a general reduction of β-cell function, but dynamics of insulin secretion are perturbed. The data suggest a sequence in the development of β-cell dysfunction, with the three groups representing stages in the progression from normal physiology to diabetes, and assessment of pulsatility as the single most sensitive marker of β-cell dysfunction.

scholarly journals Effect of Glucagon-Like Peptide-1 on β- and α-Cell Function in Isolated Islet and Whole Pancreas Transplant Recipients

2009 ◽  
Vol 94 (1) ◽  
pp. 181-189 ◽  
Author(s):  
Michael R. Rickels ◽  
Rebecca Mueller ◽  
James F. Markmann ◽  
Ali Naji
Keyword(s):  
Insulin Secretion ◽  
Cell Mass ◽  
Pancreas Transplant ◽  
Second Phase ◽  
Transplant Recipients ◽  
Β Cell ◽  
Hyperglycemic Clamp ◽  
Glucagon Suppression ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Abstract Context: Glucose-dependent insulin secretion is often impaired after islet transplantation where reduced β-cell secretory capacity indicates a low functional β-cell mass. Objective: We sought to determine whether glucagon-like peptide-1 (GLP-1) enhanced glucose-dependent insulin secretion and glucagon suppression in islet recipients, and whether GLP-1 effects were dependent on functional β-cell mass by simultaneously studying recipients of whole pancreas transplants. Setting: The study was performed in a clinical and translational research center. Participants: Five intraportal islet and six portally drained pancreas transplant recipients participated in the study. Intervention: Subjects underwent glucose-potentiated arginine testing with GLP-1 (1.5 pmol · kg−1 · min−1) or placebo infused on alternate randomized occasions, with 5 g arginine injected under basal and hyperglycemic clamp conditions. Results: Basal glucose was lower with increases in insulin and decreases in glucagon during GLP-1 vs. placebo in both groups. During the hyperglycemic clamp, a significantly greater glucose infusion rate was required with GLP-1 vs. placebo in both groups (P &lt; 0.05), an effect more pronounced in the pancreas vs. islet group (P &lt; 0.01). The increased glucose infusion rate was associated with significant increases in second-phase insulin secretion in both groups (P &lt; 0.05) that also tended to be greater in the pancreas vs. islet group (P = 0.08), whereas glucagon was equivalently suppressed by the hyperglycemic clamp during GLP-1 and placebo infusions in both groups. The GLP-1-induced increase in second-phase insulin correlated with the β-cell secretory capacity (P &lt; 0.001). The proinsulin secretory ratio (PISR) during glucose-potentiated arginine was significantly greater with GLP-1 vs. placebo infusion in both groups (P &lt; 0.05). Conclusions: GLP-1 induced enhancement of glucose-dependent insulin secretion, but not glucagon suppression, in islet and pancreas transplant recipients, an effect dependent on the functional β-cell mass that may be associated with depletion of mature β-cell secretory granules.

scholarly journals Ontology of the apelinergic system in mouse pancreas during pregnancy and relationship with β-cell mass

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Brenda Strutt ◽  
Sandra Szlapinski ◽  
Thineesha Gnaneswaran ◽  
Sarah Donegan ◽  
Jessica Hill ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Insulin Secretion ◽  
Glucose Transporter ◽  
Cell Mass ◽  
Elevated Serum ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Glucose Transporter 2 ◽  
Glucose Stimulated Insulin Secretion

AbstractThe apelin receptor (Aplnr) and its ligands, Apelin and Apela, contribute to metabolic control. The insulin resistance associated with pregnancy is accommodated by an expansion of pancreatic β-cell mass (BCM) and increased insulin secretion, involving the proliferation of insulin-expressing, glucose transporter 2-low (Ins+Glut2LO) progenitor cells. We examined changes in the apelinergic system during normal mouse pregnancy and in pregnancies complicated by glucose intolerance with reduced BCM. Expression of Aplnr, Apelin and Apela was quantified in Ins+Glut2LO cells isolated from mouse pancreata and found to be significantly higher than in mature β-cells by DNA microarray and qPCR. Apelin was localized to most β-cells by immunohistochemistry although Aplnr was predominantly associated with Ins+Glut2LO cells. Aplnr-staining cells increased three- to four-fold during pregnancy being maximal at gestational days (GD) 9–12 but were significantly reduced in glucose intolerant mice. Apelin-13 increased β-cell proliferation in isolated mouse islets and INS1E cells, but not glucose-stimulated insulin secretion. Glucose intolerant pregnant mice had significantly elevated serum Apelin levels at GD 9 associated with an increased presence of placental IL-6. Placental expression of the apelinergic axis remained unaltered, however. Results show that the apelinergic system is highly expressed in pancreatic β-cell progenitors and may contribute to β-cell proliferation in pregnancy.

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