scholarly journals Insulin-sparing effects of troglitazone in rat pancreatic islets

2003 ◽  
Vol 31 (1) ◽  
pp. 61-69 ◽  
Author(s):  
LC Bollheimer ◽  
S Troll ◽  
H Landauer ◽  
CE Wrede ◽  
J Scholmerich ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Beta Cell ◽  
Pancreatic Islets ◽  
High Glucose ◽  
Cell Function ◽  
Glucagon Secretion ◽  
Point Of View ◽  
Glucose Levels ◽  
Rat Pancreatic Islets ◽  
Insulin And Glucagon Secretion

Thiazolidinediones (TZDs) have been suggested to act beneficially on pancreatic islet function and on beta-cell viability but data concerning direct effects on isolated islets are controversial. Therefore, we have examined parameters of pancreatic insulin and glucagon secretion and biosynthesis in TZD-exposed rat pancreatic islets under physiological glucose level conditions and under conditions of glucolipotoxicity. Primary rat islets were incubated for 2.5 h with or without troglitazone (10 microM) in 5.6 mM glucose (standard glucose levels) and 16.7 mM glucose (high glucose levels); a subgroup was additionally treated with oleate (200 microM) to simulate acute glucolipotoxicity. Insulin and glucagon secretion, intracellular content and their respective mRNAs were quantified. Newly synthesized insulin was determined by pulse-labeling experiments. Troglitazone reduced insulin secretion at standard and high glucose levels by about one-third (P<or=0.05). Insulin content was decreased at 5.6 mM glucose but increased at 16.7 mM glucose by the presence of troglitazone (P<or=0.05). Newly synthesized insulin mRNA and preproinsulin mRNA decreased by about 20% at standard glucose levels (P<or=0.05). Glucagon secretion was augmented by troglitazone in islets under high glucose conditions by an additional 50% (P<or=0.05). No clear beneficial troglitazone effects were observed under glucolipotoxic conditions. The reduced insulin secretion and biosynthesis at standard glucose levels can be interpreted as an insulin-sparing effect. Troglitazone effects were less pronounced at high glucose alone or in combination with oleate. From a clinical point of view, these results indicate a greater benefit of troglitazone for beta-cell function in hyperinsulinemic, but normoglycemic patients with insulin resistance or early type 2 diabetes without major insulin secretion deficits and/or pronounced hyperglycemia.

scholarly journals Endothelial and beta cell composite aggregates for improved function of a bioartificial pancreas encapsulation device

2018 ◽  
Vol 41 (3) ◽  
pp. 152-159 ◽  
Author(s):  
Katarzyna Skrzypek ◽  
Yazmin Brito Barrera ◽  
Thomas Groth ◽  
Dimitrios Stamatialis
Keyword(s):  
Endothelial Cells ◽  
Insulin Secretion ◽  
Beta Cell ◽  
Pancreatic Islets ◽  
Beta Cells ◽  
Cell Function ◽  
Umbilical Vein ◽  
Human Umbilical Vein ◽  
Min6 Cells ◽  
Umbilical Vein Endothelial Cells

Introduction: Encapsulation of pancreatic islets or beta cells is a promising strategy for treatment of type 1 diabetes by providing an immune isolated environment and allowing for transplantation in a different location than the liver. However, islets used for encapsulation often show lower functionality due to the damaging of islet endothelial cells during the isolation procedure. Factors produced by endothelial cells have great impact on beta cell insulin secretion. Therefore, mutual signaling between endothelial cells and beta cells should be considered for the development of encapsulation systems to achieve high insulin secretion and maintain beta cell viability. Here, we investigate whether co-culture of beta cells with endothelial cells could improve beta cell function within encapsulation devices. Materials and methods: Mouse insulinoma MIN6 cells and human umbilical vein endothelial cells were used for creating composite aggregates on agarose microwell platform. The composite aggregates were encapsulated within flat poly(ether sulfone)/polyvinylpyrrolidone device. Their functionality was assessed by glucose-induced insulin secretion test and compared to non-encapsulated free-floating aggregates. Results: We created composite aggregates of 80–100 µm in diameter, closely mimicking pancreatic islets. Upon glucose stimulation, their insulin secretion is improved in comparison to aggregates consisting of only MIN6 cells. Moreover, the composite aggregates encapsulated within a device secrete more insulin than aggregates consisting of only MIN6 cells. Conclusion: Composite aggregates of MIN6 cells with human umbilical vein endothelial cells have improved insulin secretion in comparison to MIN6 aggregates showing that the interaction of beta cell and endothelial cell is crucial for a functional encapsulation system.

Regulation of insulin and glucagon secretion from rat pancreatic islets in vitro by somatostatin analogues

2007 ◽  
Vol 138 (1) ◽  
pp. 1-9 ◽  
Author(s):  
E. Ludvigsen ◽  
M. Stridsberg ◽  
J.E. Taylor ◽  
M.D. Culler ◽  
K. Öberg ◽  
...  
Keyword(s):  
Pancreatic Islets ◽  
Glucagon Secretion ◽  
Somatostatin Analogues ◽  
Rat Pancreatic Islets ◽  
Insulin And Glucagon Secretion

scholarly journals Relief from glucose-induced over-stimulation sensitizes the adenylate cyclase-cAMP system of rat pancreatic islets

2000 ◽  
Vol 166 (3) ◽  
pp. 537-544 ◽  
Author(s):  
A Bjorklund ◽  
VE Grill
Keyword(s):  
Adenylate Cyclase ◽  
Beta Cell ◽  
Pancreatic Islets ◽  
Cell Function ◽  
Insulin Dose ◽  
Acute Administration ◽  
Camp Content ◽  
Rat Pancreatic Islets ◽  
Camp System ◽  
Releasing Effect

Hyperglycemia impairs beta-cell function. This effect is partly exerted by beta-cell over-stimulation by mechanisms that are not completely clarified. We have presently investigated whether over-stimulation alters the responsiveness of the islet adenylate cyclase-cAMP system. Effects of over-stimulation were assessed from comparisons in rat pancreatic islets after stimulation by culture for 22 h with high (27 mM) glucose or after the additional presence of diazoxide which reversibly blocks secretion. Islet ATP levels were similar under both conditions. Forskolin increased islet cAMP levels dose-dependently after culture under both conditions; however, the cAMP responses to forskolin were enhanced by the previous co-presence of diazoxide: by 354, 183 and 168% respectively in the presence of 0.1, 1.0 and 25 microM forskolin (P<0.05) or less for the effect of diazoxide. Enhancement was not diminished ! by Ca(2+ )omission during final incubations, nor by blocking Gi proteins with pertussis toxin (0.1 microgram/ml). Enhancement was dependent on the glucose concentration during culture, i.e. co-culture with diazoxide at a non-stimulatory concentration of glucose (6.0 mM) failed to affect the subsequent cAMP response to forskolin. Acute administration of glucose (16.7 mM) failed to increase islet cAMP content after culture at high glucose only, whereas a modest (about 20%) but significant stimulation was seen after co-culture with diazoxide. Co-culture with diazoxide left-shifted the insulin dose-response to a cAMP analogue 5,6-dichloro-1-beta-d> -ribofuranosyl-benzimidazole-3',5'-cyclic monophosphorothioate. We conclude that over-stimulation importantly modifies the generation of cAMP, and also affects the insulin-releasing effect of the cyclic nucleotide.

Islet amyloid polypeptide tonally inhibits β-, α-, and δ-cell secretion in isolated rat pancreatic islets

1999 ◽  
Vol 276 (1) ◽  
pp. E19-E24 ◽  
Author(s):  
Feng Wang ◽  
Thomas E. Adrian ◽  
Gunilla T. Westermark ◽  
Xianzhong Ding ◽  
Thomas Gasslander ◽  
...  
Keyword(s):  
Pancreatic Islets ◽  
Islet Amyloid Polypeptide ◽  
Glucagon Secretion ◽  
Cell Secretion ◽  
Islet Amyloid ◽  
Paracrine Effects ◽  
Rat Pancreatic Islets ◽  
Somatostatin Secretion ◽  
Insulin And Glucagon Secretion ◽  
Isolated Rat

Islet amyloid polypeptide (IAPP, or amylin) is produced in pancreatic β-cells. The intraislet significance of IAPP is still uncertain. In the present study, paracrine effects of endogenous IAPP and somatostatin were investigated in isolated rat pancreatic islets. The intraislet IAPP activity was inhibited with an IAPP antiserum or a specific antagonist [IAPP-(8—37)]. Somatostatin activity was inhibited by immunoneutralization. Basal insulin and glucagon secretion were not affected by the somatostatin and/or IAPP blockade. Arginine-stimulated insulin and glucagon secretion were dose dependently increased by IAPP antiserum, IAPP-(8—37), and somatostatin antiserum, respectively. Arginine-stimulated somatostatin secretion was dose dependently potentiated by IAPP antiserum. Insulin secretion induced by 16.7 mM glucose was enhanced by IAPP antiserum and IAPP-(8—37), respectively. A combination of somatostatin antiserum with IAPP antiserum or IAPP-(8—37) further enhanced the arginine-stimulated insulin and glucagon secretion compared with effects when the blocking reagents were used individually. These results indicate that endogenously produced IAPP tonally inhibits stimulated insulin, glucagon, and somatostatin secretion. Furthermore, the paracrine effects of IAPP and somatostatin are additive.

Roles of GTP and phospholipase C in the potentiation of Ca2+-induced insulin secretion by glucose in rat pancreatic islets

1997 ◽  
Vol 153 (1) ◽  
pp. 61-71 ◽  
Author(s):  
J Vadakekalam ◽  
M E Rabaglia ◽  
S A Metz
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Phospholipase C ◽  
Mycophenolic Acid ◽  
High Glucose ◽  
Secretory Response ◽  
Rat Pancreatic Islets ◽  
Isolated Rat Islets ◽  
Effect Of Glucose ◽  
Isolated Rat

Abstract Glucose can augment insulin secretion independently of K+ channel closure, provided cytoplasmic free Ca2+ concentration is elevated. A role for phospholipase C (PLC) in this phenomenon has been both claimed and refuted. Recently, we have shown a role for GTP in the secretory effect of glucose as well as in glucose-induced PLC activation, using islets pre-treated with GTP synthesis inhibitors such as mycophenolic acid (MPA). Therefore, in the current studies, we examined first, whether glucose augments Ca2+-induced PLC activation and second, whether GTP is required for this effect, when K+(ATP) channels are kept open using diazoxide. Isolated rat islets pre-labeled with [3H]myo-inositol were studied with or without first priming with glucose. There was a 98% greater augmentation of insulin secretion by 16·7 mm glucose (in the presence of diazoxide and 40 mm K+) in primed islets; however, the ability of high glucose to augment PLC activity bore no relationship to the secretory response. MPA markedly inhibited PLC in both conditions; however, insulin secretion was only inhibited (by 46%) in primed islets. None of these differences were attributable to alterations in labeling of phosphoinositides or levels of GTP or ATP. These data indicate that an adequate level of GTP is critical for glucose's potentiation of Ca2+-induced insulin secretion in primed islets but that PLC activation can clearly be dissociated from insulin secretion and therefore cannot be the major cause of glucose's augmentation of Ca2+-induced insulin secretion. Journal of Endocrinology (1997) 153, 61–71

scholarly journals Effects of High Glucose Levels and Glycated Serum on GIP Responsiveness in the Pancreatic Beta Cell Line HIT-T15

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Alessandra Puddu ◽  
Roberta Sanguineti ◽  
Fabrizio Montecucco ◽  
Giorgio Luciano Viviani
Keyword(s):  
Insulin Secretion ◽  
Beta Cell ◽  
Cell Line ◽  
High Glucose ◽  
Intracellular Signaling ◽  
Pancreatic Beta Cells ◽  
Pancreatic Beta Cell ◽  
Diabetic Patients ◽  
Glucose Levels ◽  
Beta Cell Line

Glucose-dependent insulinotropic peptide (GIP) is an incretin hormone produced in the gastrointestinal tract that stimulates glucose dependent insulin secretion. Impaired incretin response has been documented in diabetic patients and was mainly related to the inability of the pancreatic beta cells to secrete insulin in response to GIP. Advanced Glycation End Products (AGEs) have been shown to play an important role in pancreatic beta cell dysfunction. The aim of this study is to investigate whether the exposure to AGEs can induce GIP resistance in the pancreatic beta cell line HIT-T15. Cells were cultured for 5 days in low (CTR) or high glucose (HG) concentration in the presence of AGEs (GS) to evaluate the expression of GIP receptor (GIPR), the intracellular signaling activated by GIP, and secretion of insulin in response to GIP. The results showed that incubation with GS alone altered intracellular GIP signaling and decreased insulin secretion as compared to CTR. GS in combination with HG reduced the expression of GIPR and PI3K and abrogated GIP-induced AKT phosphorylation and GIP-stimulated insulin secretion. In conclusion, we showed that treatment with GS is associated with the loss of the insulinotropic effect of GIP in hyperglycemic conditions.

scholarly journals Changes induced by sucrose administration on glucose metabolism in pancreatic islets in normal hamsters

2001 ◽  
Vol 171 (3) ◽  
pp. 551-556 ◽  
Author(s):  
ML Massa ◽  
MI Borelli ◽  
H Del Zotto ◽  
JJ Gagliardino
Keyword(s):  
Insulin Secretion ◽  
Blood Glucose ◽  
Glucose Metabolism ◽  
Beta Cell ◽  
Cell Function ◽  
Normal Male ◽  
Insulin Levels ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Glucose Phosphorylation

We correlated the changes in glucose-induced insulin secretion with those observed in glucose metabolism and hexokinase/glucokinase activity in islets from normal sucrose-fed hamsters. Blood glucose and insulin levels were measured in normal male hamsters fed with (S5) or without (C5) 10% sucrose in the drinking water for 5 weeks. Isolated islets (collagenase digestion) from both groups of animals were used to study insulin secretion, (14)CO(2) and (3)H(2)O production from D-[U-(14)C]-glucose and D-[5-(3)H]-glucose respectively, with 3.3 or 16.7 mM glucose in the medium, and hexokinase/glucokinase activity (fluorometric assay) in islet homogenates. Whereas S5 and C5 animals had comparable normal blood glucose levels, S5 showed higher insulin levels than C5 hamsters (2.3+/-0.1 vs 0.6+/-0.03 ng/ml, P<0.001). Islets from S5 hamsters released significantly more insulin than C5 islets in the presence of low and high glucose (3.3 mM glucose: 0.77+/-0.04 vs 0.20+/-0.06 pg/ng DNA/min, P<0.001; 16.7 mM glucose: 2.77+/-0.12 vs 0.85+/-0.06 pg/ng DNA/min, P<0.001) and produced significantly higher amounts of (14)CO(2) and (3)H(2)O at both glucose concentrations ((14)CO(2): 3.3 mM glucose: 0.27+/-0.01 vs 0.18+/-0.01, P<0.001; 16.7 mM glucose: 1.44+/-0.15 vs 0.96+/-0.08, P<0.02; (3)H(2)O: 3.3 mM glucose: 0.31+/-0.02 vs 0.15+/-0.01, P<0.001; 16.7 mM glucose: 1.46+/-0.20 vs 0.76+/-0.05 pmol glucose/ng DNA/min, P<0.005). The hexokinase K(m) and V(max) values from S5 animals were significantly higher than those from C5 ones (K(m): 100.14+/-7.01 vs 59.90+/- 3.95 microM, P<0.001; V(max): 0.010+/-0.0005 vs 0.008+/- 0.0006 pmol glucose/ng DNA/min, P<0.02). Conversely, the glucokinase K(m) value from S5 animals was significantly lower than in C5 animals (K(m): 15.31+/-2.64 vs 35.01+/-1.65 mM, P<0.001), whereas V(max) figures were within a comparable range in both groups (V(max): 0.048+/-0.009 vs 0.094+/-0.035 pmol glucose/ng DNA/min, not significant). The glucose phosphorylation ratio measured at 1 and 100 mM (hexokinase/glucokinase ratio) was significantly higher in S5 (0.26+/-0.02) than in C5 animals (0.11+/-0.01, P<0.005), and it was attributable to an increase in the hexokinase activity in S5 animals. In conclusion, sucrose administration increased the hexokinase/glucokinase activity ratio in the islets, which would condition the increase in glucose metabolism by beta-cells, and in beta-cell sensitivity and responsiveness to glucose. These results support the concept that increased hexokinase rather than glucokinase activity causes the beta-cell hypersensitivity to glucose, hexokinase being metabolically more active than glucokinase to up-regulate beta-cell function.

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