Transgenic mice overexpressing human vasoactive intestinal peptide (VIP) gene in pancreatic beta cells. Evidence for improved glucose tolerance and enhanced insulin secretion by VIP and PHM-27 in vivo.

Previous studies using in vitro cell culture systems have shown the role of the dynamin-related GTPase Opa1 in apoptosis prevention and mitochondrial DNA (mtDNA) maintenance. However, it remains to be tested whether these functions of Opa1 are physiologically important in vivo in mammals. Here, using the Cre-loxP system, we deleted mouse Opa1 in pancreatic beta cells, in which glucose-stimulated ATP production in mitochondria plays a key role in insulin secretion. Beta cells lacking Opa1 maintained normal copy numbers of mtDNA; however, the amount and activity of electron transport chain complex IV were significantly decreased, leading to impaired glucose-stimulated ATP production and insulin secretion. In addition, in Opa1-null beta cells, cell proliferation was impaired, whereas apoptosis was not promoted. Consequently, mice lacking Opa1 in beta cells develop hyperglycemia. The data suggest that the function of Opa1 in the maintenance of the electron transport chain is physiologically relevant in beta cells.

Download Full-text

Evaluation of Anti-diabetic Effects of Eryngium Billardieri on Streptozotocin-induced Diabetes in Male Mice

10.21203/rs.3.rs-561153/v1 ◽

2021 ◽

Author(s):

Kamran Hosseini ◽

Elaheh Touri ◽

Haleh Vaez ◽

Alireza Garjani ◽

Parina Asgharian ◽

...

Keyword(s):

Insulin Secretion ◽

Glucose Tolerance ◽

Beta Cells ◽

Pancreatic Beta Cells ◽

Serum Insulin ◽

Control Group ◽

High Dose ◽

Male Mice ◽

Serum Samples ◽

Streptozotocin Induced Diabetes

Abstract Background: One of the largest plant genera of the Umbelliferae family is Eryngium including 274 species, of which only 9 species are native to Iran and one of the most dominant species is E. billardieri. Numerous pharmacological effects of E. billardieri such as anti-inflammatory, antimicrobial, antioxidant have been reported in several studies. Objective: The present study aimed to investigate the anti-diabetic effects of E. billardieri on streptozotocin-induced diabetes in male mice.Methods: The extraction was performed by maceration with 70% ethanol solvent. Forty eight mice, weighing 32 g, were randomly divided into 8 groups (6 mice per group): healthy control, diabetic control (151 mg/kg STZ; IP), healthy extract control group (receiving the high dose of the extract orally), diabetic groups (receiving low dose and high dose of extract in the form of IP and Oral), the treatment group which received STZ (IP) and high dose of the extract group (Oral) for five days. To induce diabetes, a single dose of STZ (151 mg/kg) was injected intra-peritoneally. After diabetes, 100 mg/kg and 300 mg/kg of extract were injected into diabetic animals for 18 days as IP and Oral were given, and finally, serum samples were isolated and stored at -71 °C. Three days before surgery, OGTT test was performed.Results: IP injection of 300 mg/kg of hydroalcoholic extract of E. billardieri reduced the weight of diabetic rats and significantly reduced glucose tolerance. Furthermore, gavage at a dose of 300 mg/kg of extract caused significantly the increase in serum insulin while the decrease in blood sugar, glucose tolerance and malondialdehyde. Conclusion: E. billardieri extract, due to its components, probably increases serum insulin and decreases serum malondialdehyde by two mechanisms including protects pancreatic beta cells from further damage by streptozotocin and stimulation of insulin secretion from the remaining healthy pancreatic beta cells. In other words, part of the beneficial effects of the extract is associated with inhibition of oxidative stress and increased insulin secretion.

Download Full-text

Glucose-induced oscillatory insulin secretion in perifused rat pancreatic islets and clonal beta-cells (HIT)

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1996.271.4.e702 ◽

1996 ◽

Vol 271 (4) ◽

pp. E702-E710 ◽

Cited By ~ 16

Author(s):

B. A. Cunningham ◽

J. T. Deeney ◽

C. R. Bliss ◽

B. E. Corkey ◽

K. Tornheim

Keyword(s):

Insulin Secretion ◽

Beta Cells ◽

Pancreatic Beta Cells ◽

Basal Secretion ◽

Oscillation Pattern ◽

Glucose Stimulation ◽

High Concentrations ◽

Perifused Islets ◽

Stimulation Of

Normal insulin secretion is oscillatory in vivo and from groups of perifused islets. Stimulation of rat islets with different glucose concentrations gave insulin oscillations of similar period (5-8 min) but increasing amplitude. It has been assumed that oscillatory secretion is due to oscillations in intracellular free Ca2+, as seen in single islets and single pancreatic beta-cells. However, when islets were perifused with diazoxide and high KCl to maintain high intracellular free Ca2+, insulin oscillations of similar amplitude and period still occurred on glucose stimulation, although superimposed on elevated basal secretion. Several likely possibilities for a diffusible synchronizing factor were tested, including pyruvate, lactate, ATP, and insulin itself; nevertheless, perifusion with high concentrations of these did not prevent insulin oscillations. Clonal pancreatic beta-cells (HIT) and dissociated islets also exhibited oscillatory insulin secretion, but with the 5- to 8-min period oscillations superimposed on 15- to 20-min period oscillations. These results indicate that the mechanisms for generating and synchronizing insulin oscillations reside in the beta-cell, although the structure of the islet may modulate the oscillation pattern.

Download Full-text

Expression of yeast hexokinase in pancreatic beta cells of transgenic mice reduces blood glucose, enhances insulin secretion, and decreases diabetes.

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.89.24.12038 ◽

1992 ◽

Vol 89 (24) ◽

pp. 12038-12042 ◽

Cited By ~ 46

Author(s):

P. N. Epstein ◽

A. C. Boschero ◽

I. Atwater ◽

X. Cai ◽

P. A. Overbeek

Keyword(s):

Insulin Secretion ◽

Blood Glucose ◽

Transgenic Mice ◽

Beta Cells ◽

Pancreatic Beta Cells ◽

Yeast Hexokinase

Download Full-text

The nucleotide exchange factor SIL1 is required for glucose-stimulated insulin secretion from mouse pancreatic beta cells in vivo

Diabetologia ◽

10.1007/s00125-014-3230-z ◽

2014 ◽

Vol 57 (7) ◽

pp. 1410-1419 ◽

Cited By ~ 11

Author(s):

Arne A. Ittner ◽

Josefine Bertz ◽

Tse Yan Becky Chan ◽

Janet van Eersel ◽

Patsie Polly ◽

...

Keyword(s):

Insulin Secretion ◽

Beta Cells ◽

Pancreatic Beta Cells ◽

Nucleotide Exchange ◽

Exchange Factor ◽

Nucleotide Exchange Factor ◽

Glucose Stimulated Insulin Secretion

Download Full-text

Mechanisms of Impaired Glucose Tolerance and Insulin Secretion during Isoflurane Anesthesia

Anesthesiology ◽

10.1097/aln.0b013e3181bbcb0d ◽

2009 ◽

Vol 111 (5) ◽

pp. 1044-1051 ◽

Cited By ~ 34

Author(s):

Katsuya Tanaka ◽

Takashi Kawano ◽

Takehito Tomino ◽

Hiroaki Kawano ◽

Tsuyoshi Okada ◽

...

Keyword(s):

Insulin Secretion ◽

Patch Clamp ◽

Glucose Tolerance ◽

Potassium Channel ◽

Beta Cells ◽

Mechanism Of Action ◽

Pancreatic Beta Cells ◽

Glucose Utilization ◽

Channel Activity ◽

Potassium Channel Activity

Background Volatile anesthetics impair insulin secretion and glucose utilization; however, the precise mechanism of action that underlies these effects is unknown. The authors hypothesized that isoflurane inhibits glucose-induced inhibition of adenosine triphosphate-sensitive potassium channel activity in pancreatic beta cells, which could result in impaired insulin secretion and glucose tolerance. Methods Intravenous glucose tolerance tests were performed on 28 male Japanese White rabbits anesthetized with sodium pentobarbital. Glibenclamide (50 microg/kg + 33.5 microg x kg x h) or vehicle was administered 75 min before intravenous administration of 0.6 g/kg glucose. Half of the animals (n = 7) in the vehicle and glibenclamide groups received isoflurane at 1.0 minimum alveolar concentration 30 min before administration of glucose, and the other half received a vehicle control. Hemodynamics, blood glucose, and plasma insulin were measured. A cell-attached patch clamp configuration was used to record single channel currents in the pancreas from male Swiss-Webster mice. Results Isoflurane alone or a combination of isoflurane and glibenclamide inhibited the insulinogenic index to a greater extent than in the vehicle and glibenclamide groups. In the patch clamp experiments, channel activity was significantly decreased as the glucose concentration was increased from 0 to 10 mm. The subsequent application of 0.5 mm isoflurane reversed the effects of glucose on channel activity. Conclusion These results show that isoflurane impairs insulin secretion and glucose utilization. The mechanism of action responsible for these effects may involve a decrease in glucose-induced inhibition of adenosine triphosphate-sensitive potassium channel activity in pancreatic beta cells.

Download Full-text

In vivo phosphoproteomics reveals pathogenic signaling changes in diabetic islets

10.1101/439638 ◽

2018 ◽

Author(s):

Francesca Sacco ◽

Anett Seelig ◽

Sean J. Humphrey ◽

Natalie Krahmer ◽

Francesco Volta ◽

...

Keyword(s):

Type 2 Diabetes ◽

Insulin Secretion ◽

Beta Cells ◽

Pancreatic Beta Cells ◽

Drug Targets ◽

High Sensitivity ◽

Glucose Stimulated Insulin Secretion

SUMMARYProgressive decline of pancreatic beta cells function is key to the pathogenesis of type 2 diabetes. Protein phosphorylation is the central mechanism controlling glucose-stimulated insulin secretion in beta cells. However, if and how signaling networks are remodeled in diabetic isletsin vivoremain unknowns. Here we applied high-sensitivity mass spectrometry-based proteomics and quantified the levels of about 6,500 proteins and 13,000 phosphopeptides in islets of obese diabetic mice and matched controls. This highlighted drastic remodeling of key kinase hubs and signaling pathways. We integrated our phosphoproteomic dataset with a literature-derived signaling network, which revealed a crucial and conserved role of GSK3 kinase in the control of the beta cells-specific transcription factor PDX1 and insulin secretion, which we functionally verified. Our resource will enable the community to investigate potential mechanisms and drug targets in type 2 diabetes.

Download Full-text

The Transcription Factor COUP-TFII Is Negatively Regulated by Insulin and Glucose via Foxo1- and ChREBP-Controlled Pathways

Molecular and Cellular Biology ◽

10.1128/mcb.02211-07 ◽

2008 ◽

Vol 28 (21) ◽

pp. 6568-6579 ◽

Cited By ~ 30

Author(s):

Anaïs Perilhou ◽

Cécile Tourrel-Cuzin ◽

Ilham Kharroubi ◽

Carole Henique ◽

Véronique Fauveau ◽

...

Keyword(s):

Gene Expression ◽

Insulin Secretion ◽

Beta Cells ◽

Pancreatic Beta Cells ◽

Feedback Loop ◽

Ex Vivo ◽

Insulin Production ◽

Glucose Effect ◽

Positive Feedback Loop

ABSTRACT COUP-TFII has an important role in regulating metabolism in vivo. We showed this previously by deleting COUP-TFII from pancreatic beta cells in heterozygous mutant mice, which led to abnormal insulin secretion. Here, we report that COUP-TFII expression is reduced in the pancreas and liver of mice refed with a carbohydrate-rich diet and in the pancreas and liver of hyperinsulinemic and hyperglycemic mice. In pancreatic beta cells, COUP-TFII gene expression is repressed by secreted insulin in response to glucose through Foxo1 signaling. Ex vivo COUP-TFII reduces insulin production and secretion. Our results suggest that beta cell insulin secretion is under the control of an autocrine positive feedback loop by alleviating COUP-TFII repression. In hepatocytes, both insulin, through Foxo1, and high glucose concentrations repress COUP-TFII expression. We demonstrate that this negative glucose effect involves ChREBP expression. We propose that COUP-TFII acts in a coordinate fashion to control insulin secretion and glucose metabolism.

Download Full-text