scholarly journals NFIA regulates granule recruitment and exocytosis in the adult pancreas

2019 ◽  
Author(s):  
Marissa A. Scavuzzo ◽  
Jolanta Chmielowiec ◽  
Jessica Teaw ◽  
Diane Yang ◽  
Matthew C. Hill ◽  
...  
Keyword(s):  
Insulin Response ◽  
Rab Gtpase ◽  
Glucose Levels ◽  
Lipid Disorders ◽  
Blood Glucose Levels ◽  
Pancreatic Cells ◽  
Insulin Granules ◽  
New Process ◽  
Glucose Stimulated Insulin Secretion ◽  
First Phase Insulin Response

SummaryAfter food ingestion, pancreatic cells secrete zymogen and hormone-containing granules to precisely control digestion and blood glucose levels. Identifying regulators of this process is paramount to combatting multiple pancreatic diseases. Here we show that pancreatic deletion of the transcription factor nuclear factor IA (NFIA) leads to hyperglycemia, hypoinsulinemia, and hypolipidemia. Surprisingly, insulin and digestive enzymes are produced in the absence of NFIA, however, they are not secreted properly and instead accumulate inside pancreatic cells. In NFIA-deficient mice we saw a reduction of insulin granules in the ready releasable pool and the first-phase insulin response was impaired. We found that NFIA binds to and activates Rab39b, a Rab GTPase critical for exocytosis. Re-expression of Rab39b in NFIA knockout islets restored glucose-stimulated insulin secretion. In sum, the NFIA-Rab39b axis regulates pancreatic physiology through granule recruitment and docking, linking NFIA to a new process with potential effects in diabetes, pancreatitis, and lipid disorders.

scholarly journals Increased Slc12a1 expression in β-cells and improved glucose disposal in Slc12a2 heterozygous mice

2015 ◽  
Vol 227 (3) ◽  
pp. 153-165 ◽  
Author(s):  
Saeed Alshahrani ◽  
Mohammed Mashari Almutairi ◽  
Shams Kursan ◽  
Eduardo Dias-Junior ◽  
Mohamed Mahmoud Almiahuob ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Response ◽  
Chloride Concentration ◽  
Glucose Disposal ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Glucose Levels ◽  
Fasting Glycemia ◽  
Blood Glucose Levels ◽  
Glucose Stimulated Insulin Secretion

The products of theSlc12a1andSlc12a2genes, commonly known as Na+-dependent K+2Cl−co-transporters NKCC2 and NKCC1, respectively, are the targets for the diuretic bumetanide. NKCCs are implicated in the regulation of intracellular chloride concentration ([Cl−]i) in pancreatic β-cells, and as such, they may play a role in glucose-stimulated plasma membrane depolarization and insulin secretion. Unexpectedly, permanent elimination of NKCC1 does not preclude insulin secretion, an event potentially linked to the homeostatic regulation of additional Cl−transporters expressed in β-cells. In this report we provide evidence for such a mechanism. Mice lacking a single allele ofSlc12a2exhibit lower fasting glycemia, increased acute insulin response (AIR) and lower blood glucose levels 15–30 min after a glucose load when compared to mice harboring both alleles of the gene. Furthermore, heterozygous expression or complete absence ofSlc12a2associates with increased NKCC2 protein expression in rodent pancreatic β-cells. This has been confirmed by using chronic pharmacological down-regulation of NKCC1 with bumetanide in the mouse MIN6 β-cell line or permanent molecular silencing of NKCC1 in COS7 cells, which results in increased NKCC2 expression. Furthermore, MIN6 cells chronically pretreated with bumetanide exhibit increased initial rates of Cl−uptake while preserving glucose-stimulated insulin secretion. Together, our results suggest that NKCCs are involved in insulin secretion and that a singleSlc12a2allele may protect β-cells from failure due to increased homeostatic expression ofSlc12a1.

Cell-wide analysis of secretory granule dynamics in three dimensions in living pancreatic β-cells: evidence against a role for AMPK-dependent phosphorylation of KLC1 at Ser517/Ser520 in glucose-stimulated insulin granule movement

2010 ◽  
Vol 38 (1) ◽  
pp. 205-208 ◽  
Author(s):  
Angela McDonald ◽  
Sarah Fogarty ◽  
Isabelle Leclerc ◽  
Elaine V. Hill ◽  
D. Grahame Hardie ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glutathione Transferase ◽  
Three Dimensions ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Glucose Levels ◽  
Insulin Granules ◽  
Elevated Glucose ◽  
Glucose Stimulated Insulin Secretion

Glucose-stimulated insulin secretion from pancreatic β-cells requires the kinesin-1/Kif5B-mediated transport of insulin granules along microtubules. 5′-AMPK (5′-AMP-activated protein kinase) is a heterotrimeric serine/threonine kinase which is activated in β-cells at low glucose concentrations, but inhibited as glucose levels increase. Active AMPK blocks glucose-stimulated insulin secretion and the recruitment of insulin granules to the cell surface, suggesting motor proteins may be targets for this kinase. While both kinesin-1/Kif5B and KLC1 (kinesin light chain-1) contain consensus AMPK phosphorylation sites (Thr693 and Ser520, respectively) only recombinant GST (glutathione transferase)–KLC1 was phosphorylated by purified AMPK in vitro. To test the hypothesis that phosphorylation at this site may modulate kinesin-1-mediated granule movement, we developed an approach to study the dynamics of all the resolvable granules within a cell in three dimensions. This cell-wide approach revealed that the number of longer excursions (>10 μm) increased significantly in response to elevated glucose concentration (30 versus 3 mM) in control MIN6 β-cells. However, similar changes were seen in cells overexpressing wild-type KLC1, phosphomimetic (S517D/S520D) or non-phosphorylatable (S517A/S520A) mutants of KLC1. Thus, changes in the phosphorylation state of KLC1 at Ser517/Ser520 seem unlikely to affect motor function.

scholarly journals Activity of Water Soluble Polysaccharide White Bentul (Colocasia Esculenta Schott [L]) As a Candidate for Antidiabetic Agent

2018 ◽  
Vol 2 (1) ◽  
pp. 1
Author(s):  
Sentot Joko Raharjo
Keyword(s):  
Blood Glucose ◽  
Blood Glucose Level ◽  
Glucose Level ◽  
Pancreatic Beta Cells ◽  
Water Soluble ◽  
Antidiabetic Activity ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Pancreatic Cells ◽  
Soluble Polysaccharide

White bentul tuber is one of tuber plant species which have bioactive compound of Water Soluble Polysaccharide (WSP) and potentially healthy nutrition in the therapy of metabolic syndrome disease. The purpose of this research is to prove the ability of WSP isolate to reduce blood glucose level in white mice.  Research method include the yield of WSP isolates white bentul tuber using enzymatic method, WSP identification using HPLC with Aminex HPX-87C BIORAD5 columns, and antidiabetic activity test using white mices. Test activity was performed in six treatment groups (Normal, Induction STZ 20 mg/ kgBW, Induction STZ 20 mg / kgBW + metformin 195mg / KgBW, three treatment with STZ induction 20 mg/ kgBW and WSP isolate with concentration 200, 400, and 600mg / kgBW). Determination of blood glucose levels using glucometer and supported by observation of histologic improvement of beta pancreatic cells in white mice that have necrosis. The result research are WSP yield of 4.81% and WSP level of 94.45%. Results of blood glucose levels of mice induced STZ 20mg/kgBW decreased optimal blood glucose with a dose of WSP 400mg/kgBW in the first week and histologic improvement of beta pancreatic cells that experienced the most optimal necrosis at WSP dose of 200 mg/kgBW. The conclusion of this research is the provision WSP isolate of white bentul tubers at doses of 200, 400, 600 mg/kgBW can decrease the blood glucose level induced STZ 20mg/kg BW and histological improvement in pancreatic beta cells at the most optimal dose of 200 mg / kgKeywords: White bentul tuber, water soluble polysaccharides, diabetes mellitus, beta pancratic cells   

scholarly journals The acute effect of baobab fruit on cognitive performance, cerebral blood flow and blood glucose levels.

2020 ◽  
Vol 79 (OCE2) ◽  
Author(s):  
Sarah Docherty ◽  
Crystal Haskell-Ramsay
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Blood Glucose ◽  
Phenolic Compounds ◽  
Vitamin C ◽  
Cognitive Performance ◽  
Insulin Response ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Fruit Powder

AbstractBaobab fruit contains high levels of phenolic compounds and vitamin C. Previous work has associated these phenolic compounds and vitamin C with a range of health benefits including improvements in cerebral blood flow and cognition. In vivo, it has been demonstrated that consumption of baobab fruit can reduce the glycaemic response, which may provide a mechanism for cognitive benefits as other research has shown that variations in blood glucose levels can modulate cognitive performance. Preliminary work found that consumption of 15 g baobab fruit extract significantly improved reaction time but increased number of errors on an executive function task. Taken together it would suggest baobab fruit has the potential to improve cognitive performance that could be attributed to changes in cerebral blood flow and blood glucose levels.The current study aimed to determine the effect of baobab fruit on cognitive performance, cerebral blood flow and blood glucose levels in a healthy young sample.This randomised, placebo-controlled, double-blind, counterbalanced-crossover study assessed the effect of 10 g baobab fruit powder or sugar matched control in 24 healthy participants (17 female, 7 male, mean age = 22.91 SD = 3.37). All participants completed the cognitive assessments, a subset of 14 completed the cerebral blood flow and blood glucose assessments (mean age = 23.21, SD = 2.46). Participants completed baseline tasks before consuming a drink containing either 10 g baobab fruit powder or placebo, there was then a 45-minute absorption period before participants completed cognitive tasks again. Seven days after participants returned and completed the same procedure but consumed the opposite drink. In the 14 participant subset, cerebral blood flow was measured throughout using Near Infrared Spectroscopy (NIRS) and blood glucose was measured before testing, after absorption period and upon completion of post doseUsing the MIXED procedure in SPSS, results showed that after consumption of baobab there was improved accuracy on a sustained attention task and fewer errors on the last repetition of a serial subtraction task. Baobab consumption led to increased blood glucose levels but there was no significant effect on cerebral blood flow.Results show that, in this sample, 10 g baobab fruit can improve certain aspects of cognitive performance and increase circulating blood glucose levels, which may explain these improvements. However, there was no significant effect on any cerebral blood flow measures. Future work may wish to explore further glucoregulation activity (in particular insulin response) after baobab consumption as a potential underlying mechanism.

Obstacles in the Application of Microencapsulation in Islet Transplantation

1993 ◽  
Vol 16 (4) ◽  
pp. 205-212 ◽  
Author(s):  
P. De Vos ◽  
G.H.J. Wolters ◽  
W.M. Fritschy ◽  
R. Van Schilfgaarde
Keyword(s):  
Islet Transplantation ◽  
Insulin Response ◽  
Limiting Factors ◽  
Survival Times ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Functional Aspects ◽  
Second Category ◽  
Transplantation Site ◽  
Insight Into

Several factors stand in the way of successful clinical transplantation of alginate-polylysine-alginate microencapsulated pancreatic islets. These obstacles can be classified into three categories. The first regards the technical aspects of the production process. Limiting factors are the insufficient ability to produce small capsules with an adequate production rate, and insufficient insight into the factors determining the optimal chemical and mechanical properties of the capsules. The second category regards the functional aspects of the microencapsulated islets, such as the limitations of the transplantation site and the absence of a physiologic insulin response of the encapsulated islets to elevated blood glucose levels. The third category regards the fact that survival times of encapsulated islet grafts are still limited to several weeks or months, which is mainly explained by a pericapsular fibrotic overgrowth reaction as a consequence of the bioincom-patibility of the capsule membrane. This study describes these obstacles, and thereby summarizes the requirements needed for successful clinical application of encapsulated islet transplantation.

scholarly journals Age-dependent transition from islet insulin hypersecretion to hyposecretion in mice with the long QT-syndrome loss-of-function mutation Kcnq1-A340V

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Anniek F. Lubberding ◽  
Jinyi Zhang ◽  
Morten Lundh ◽  
Thomas Svava Nielsen ◽  
Mathilde S. Søndergaard ◽  
...  
Keyword(s):  
Beta Cell ◽  
Ex Vivo ◽  
Fasting Blood Glucose ◽  
Qt Prolongation ◽  
Cell Area ◽  
Loss Of Function ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Glucose Stimulated Insulin Secretion ◽  
Beta Cell Area

AbstractLoss-of-function (LoF) mutations in KCNQ1, encoding the voltage-gated K+ channel Kv7.1, lead to long QT syndrome 1 (LQT1). LQT1 patients also present with post-prandial hyperinsulinemia and hypoglycaemia. In contrast, KCNQ1 polymorphisms are associated with diabetes, and LQTS patients have a higher prevalence of diabetes. We developed a mouse model with a LoF Kcnq1 mutation using CRISPR-Cas9 and hypothesized that this mouse model would display QT prolongation, increased glucose-stimulated insulin secretion and allow for interrogation of Kv7.1 function in islets. Mice were characterized by electrocardiography and oral glucose tolerance tests. Ex vivo, islet glucose-induced insulin release was measured, and beta-cell area quantified by immunohistochemistry. Homozygous mice had QT prolongation. Ex vivo, glucose-stimulated insulin release was increased in islets from homozygous mice at 12–14 weeks, while beta-cell area was reduced. Non-fasting blood glucose levels were decreased at this age. In follow-up studies 8–10 weeks later, beta-cell area was similar in all groups, while glucose-stimulated insulin secretion was now reduced in islets from hetero- and homozygous mice. Non-fasting blood glucose levels had normalized. These data suggest that Kv7.1 dysfunction is involved in a transition from hyper- to hyposecretion of insulin, potentially explaining the association with both hypoglycemia and hyperglycemia in LQT1 patients.

Anaesthesia and changes in parameters that reflect glucose metabolism in pigs – a pilot study

2016 ◽  
Vol 51 (5) ◽  
pp. 509-517 ◽  
Author(s):  
Elin Manell ◽  
Marianne Jensen-Waern ◽  
Patricia Hedenqvist
Keyword(s):  
Blood Glucose ◽  
Pilot Study ◽  
Insulin Response ◽  
Growing Pigs ◽  
Laboratory Animals ◽  
Oral Glucose ◽  
Diabetes Research ◽  
Imaging Procedures ◽  
Glucose Levels ◽  
Blood Glucose Levels

Pigs are commonly used in diabetes research due to their many physiological similarities to humans. They are especially useful in imaging procedures because of their large size. However, to achieve imaging procedures the pig must lie completely still, and thus needs to be anaesthetized. Most anaesthetic drugs used in laboratory animals affect carbohydrate metabolism by the inhibition of insulin release. The aim of this pilot study was primarily to develop an anaesthetic protocol for pigs that did not have an effect on blood glucose levels throughout the 3 h of anaesthesia; and secondly, to evaluate the most promising protocol in combination with an oral glucose tolerance test (OGTT). Two anaesthetic protocols were used in four growing pigs. Intravenous propofol infusion caused hyperglycaemia in three out of four pigs within 5–10 min after induction and was therefore excluded. Intravenous infusion with tiletamine, zolazepam and butorphanol (TZB) for 3 h did not affect blood glucose levels. The pigs underwent OGTT twice, once without anaesthesia and once with TZB induction after glucose intake. Anaesthesia during OGTT resulted in a lower area under the curve (AUC) of glucose ( P < 0.05), higher AUC of glucagon ( P < 0.05) and an insulin response less than 10% of that during OGTT without anaesthesia. In conclusion, long-term infusion anaesthesia with TZB does not affect glucose homeostasis in pigs. However, the protocol is not effective when combined with OGTT, as glucose, insulin and glucagon levels are affected.

scholarly journals RAMPs regulate signalling bias and internalisation of the GIPR

2021 ◽  
Author(s):  
Matthew Harris ◽  
Duncan I. Mackie ◽  
John B. Pawlak ◽  
Sabrina Carvalho ◽  
Tin T. Truong ◽  
...  
Keyword(s):  
G Protein ◽  
Gastric Inhibitory Polypeptide ◽  
General Role ◽  
Protein Activation ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
G Protein Activation ◽  
Glucose Stimulated Insulin Secretion ◽  
Acute And Chronic Effects

AbstractGastric inhibitory polypeptide (GIP) receptor is a class B1 GPCR, that responds to GIP and physiologically potentiates glucose-stimulated insulin secretion. Like most class B1 GPCRs, GIPR has been shown to interact with RAMPs, yet the effects of RAMPs on its signalling and trafficking remain poorly understood. We demonstrate that RAMPs modulate G protein activation and GIPR internalisation profiles. RAMP3 reduced GIPR Gs activation and cAMP production but retained GIPR at the cell surface, and this was associated with prolonged ERK1/2 phosphorylation and β-arrestin association. By contrast, RAMP1/2 reduced Gq/11/15 activation of the GIPR. Through knockout mice studies, we show that RAMP1 is important to the normal physiological functioning of GIPR to regulate blood glucose levels. Thus, RAMPs act on G protein/β-arrestin complexes, having both acute and chronic effects on GIPR function, while this study also raises the possibility of a more general role of RAMP3 to enhance GPCR plasma membrane localisation.

Evidence for defective glucose sensing by islets of fa/fa obese Zucker rats

1993 ◽  
Vol 71 (1) ◽  
pp. 34-39 ◽  
Author(s):  
Catherine B. Chan ◽  
Ruth M. MacPhail ◽  
Katherine Mitton
Keyword(s):  
Insulin Secretion ◽  
Insulin Response ◽  
Glucose Sensing ◽  
Zucker Rats ◽  
Rat Islets ◽  
Glucose Levels ◽  
Half Maximal Effective Concentration ◽  
Glucose Stimulated Insulin Secretion

The hypothesis that a defect in glucose sensing by islets of fa/fa Zucker rats contributes to hyperinsulinemia in these animals was tested. Islets from lean and fa/fa rats were isolated by collagenase digestion and step-density gradient purification and then cultured overnight in Dulbecco's modified Eagle's medium containing 12.5 mM glucose. Obese rat islets were more sensitive to hypoglycemic glucose levels with half-maximal effective concentration (EC50) of 5.6 mM compared with an EC50 of 8.2 mM for lean rat islets. In contrast, responsiveness of both phenotypes to α-ketoisocaproate and quinine was similar. Mannoheptulose did not inhibit insulin secretion from fa/fa islets, although inhibitors of later events in the stimulus–secretion coupling pathway were normally inhibited by iodoacetate and diazoxide. Finally, starvation in vivo and culture of islets in low glucose concentrations (5 mM) in vitro both decreased glucose-stimulated insulin secretion from lean but not fa/fa rat islets. We conclude that fa/fa rat islets have an exaggerated insulin response to hypoglycemic stimuli, possibly as a result of a defect in B-cell glucokinase function.Key words: insulin secretion, obesity, glucose metabolism, starvation.

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