scholarly journals Pharmacological inhibition of thioredoxin reductase increases insulin secretion and diminishes beta cell viability

2021 ◽  
Author(s):  
Dennis Brüning ◽  
Kathrin Hatlapatka ◽  
Verena Lier-Glaubitz ◽  
Vincent Andermark ◽  
Stephan Scherneck ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Beta Cell ◽  
Cell Viability ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Thioredoxin Reductase ◽  
Dual Function ◽  
Min6 Cells ◽  
Thioredoxin System ◽  
Beta Cell Viability

AbstractApparently, both a decrease in beta cell function and in beta cell mass contribute to the progressive worsening of type 2 diabetes. So, it is of particular interest to define factors which are relevant for the regulation of insulin secretion and at the same time for the maintenance of beta cell mass. The NADPH-thioredoxin system has a candidate role for such a dual function. Here, we have characterized the effects of a highly specific inhibitor of thioredoxin reductase, AM12, on the viability and function of insulin-secreting MIN6 cells and isolated NMRI mouse islets. Viability was checked by MTT testing and the fluorescent live-dead assay. Apoptosis was assessed by annexin V assay. Insulin secretion of perifused islets was measured by ELISA. The cytosolic Ca2+ concentration was measured by the Fura technique. Acute exposure of perifused pancreatic islets to 5 μM AM12 was without significant effect on insulin secretion. Islets cultured for 24 h in 0.5 or 5 μM AM12 showed unchanged basal secretion during perifusion, but the response to 30 mM glucose was significantly enhanced by 5 μM. Twenty-four-hour exposure to 5 μM AM12 proved to be without effect on the viability of MIN6 cells, whereas longer exposure was clearly toxic. Islets were more susceptible, showing initial signs of apoptosis after 24-h exposure to 5 μM AM12. The activity of the NADPH-thioredoxin system is indispensable for beta cell viability but may have a limiting effect on glucose-induced insulin secretion.

2295-PUB: Impaired First-Phase Insulin Secretion Predicts the Development of Hyperglycemia in a Human Model of Acute Beta-Cell Mass Reduction

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 2295-PUB
Author(s):  
TERESA MEZZA ◽  
PIETRO MANUEL FERRARO ◽  
GIANFRANCO DI GIUSEPPE ◽  
CHIARA MARIA ASSUNTA CEFALO ◽  
SIMONA MOFFA ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Beta Cell ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Human Model ◽  
Mass Reduction ◽  
First Phase Insulin Secretion

scholarly journals Disruption of beta cell acetyl-CoA carboxylase-1 in mice impairs insulin secretion and beta cell mass

Diabetologia ◽  
2018 ◽  
Vol 62 (1) ◽  
pp. 99-111 ◽  
Author(s):  
James Cantley ◽  
Aimee Davenport ◽  
Laurène Vetterli ◽  
Nandor J. Nemes ◽  
P. Tess Whitworth ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Beta Cell ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Acetyl Coa Carboxylase ◽  
Acetyl Coa

scholarly journals Loss of beta-cell mass leads to a reduction of pulse mass with normal periodicity, regularity and entrainment of pulsatile insulin secretion in G�ttingen minipigs

Diabetologia ◽  
2004 ◽  
Vol 47 (1) ◽  
pp. 155-155
Author(s):  
M. O. Larsen ◽  
C. F. Gotfredsen ◽  
M. Wilken ◽  
R. D. Carr ◽  
N. P�rksen ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Beta Cell ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Pulsatile Insulin Secretion

scholarly journals GK-rats respond to gastric bypass surgery with improved glycemia despite unaffected insulin secretion and beta cell mass

Peptides ◽  
2021 ◽  
Vol 136 ◽  
pp. 170445
Author(s):  
Michael G. Miskelly ◽  
Liliya Shcherbina ◽  
Ann-Helen Thorén Fischer ◽  
Mia Abels ◽  
Andreas Lindqvist ◽  
...  
Keyword(s):  
Gastric Bypass ◽  
Insulin Secretion ◽  
Beta Cell ◽  
Bypass Surgery ◽  
Gastric Bypass Surgery ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Gk Rats

059. POOR GROWTH BEFORE BIRTH IMPAIRS INSULIN SECRETION - WHAT WE HAVE LEARNT ABOUT THE MECHANISMS FROM THE PLACENTALLY-RESTRICTED SHEEP

2009 ◽  
Vol 21 (9) ◽  
pp. 14
Author(s):  
K. L. Gatford
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
Beta Cell ◽  
Insulin Action ◽  
Cell Function ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Poor Growth ◽  
Impaired Insulin ◽  
Impaired Insulin Action

Diabetes occurs when insulin secretion fails to increase sufficiently to compensate for developing insulin resistance. This implies that the increased risk of diabetes in adults who were small at birth reflects impaired insulin secretion as well as their well-known insulin resistance. More recently, direct evidence has been obtained that adults and children who were growth-restricted before birth secrete less insulin than they should, given their level of insulin resistance. Our research group is using the placentally-restricted (PR) sheep to investigate the mechanisms underlying impaired insulin action (sensitivity and secretion) induced by poor growth before birth. Like the intra-uterine growth-restricted (IUGR) human, the PR sheep develops impaired insulin action by adulthood, but has enhanced insulin sensitivity in infancy, associated with neonatal catch-up growth1, 2. Impaired insulin action begins to develop in early postnatal life, where although basal insulin action is high due to enhanced insulin sensitivity, maximal glucose-stimulated insulin action is already impaired in males3. Our cellular and molecular studies have identified impaired beta-cell function rather than mass as the likely cause of impaired insulin secretion, and we have reported a novel molecular defect in the calcium channels involved in the insulin secretion pathway in the pancreas of these lambs3. Upregulation of IGF-II and insulin receptor are implicated as key molecular regulators of beta-cell mass in the PR lamb3. By adulthood, both basal and maximal insulin action are profoundly impaired in the male lamb who was growth-restricted at birth2. These studies suggest therapies to prevent diabetes in the individual who grew poorly before birth should target beta-cell function, possibly in addition to further increasing beta-cell mass, to improve insulin secretion capacity, and its ability to increase in response to development of insulin resistance. We are now using the PR sheep to test potential therapies, since the timing of pancreatic development and hence exposure to a growth-restricting environment, is similar to that of the human.

scholarly journals Postnatal activation of hypoxia pathway disrupts β-cell functional maturation

2021 ◽  
Author(s):  
Juxiang Yang ◽  
Batoul Hammoud ◽  
Abigail Ridler ◽  
Amanda M Ackermann ◽  
Kyoung-Jae Won ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Beta Cell ◽  
Beta Cells ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Beta Cell Proliferation ◽  
Rat Pups ◽  
Functional Maturation ◽  
The Impact ◽  
Glucose Threshold

Objective: Hypoxic injuries occurring during the perinatal period can lead to persistent hyperinsulinism and profound hypoglycemia in newborns. We studied the impact of hypoxia-inducible pathway on the postnatal beta-cell function. Methods: Rat pups were treated daily between postnatal day (P)7 to P10 with adaptaquin (AQ), an inhibitor of prolyl hydroxylases, leading to stabilization of hypoxia-inducible factor 1A (HIF1A). In parallel, mouse pups were placed in a hypoxic chamber between embryonic day (E)19 to P6. Dynamic insulin secretion was assessed in both models by islet perifusions. Changes in gene expression were assessed by whole-islet RNA sequencing. Results: AQ-treated rat pups and hypoxic mouse pups were hypoglycemic and had higher levels of serum insulin. The AQ-/hypoxia-treated islets showed a decreased glucose threshold for insulin secretion compared to controls, indicative of a delay in beta-cell postnatal functional maturation. Islet morphometric analysis in the AQ-treated pups showed an increase in insulin area per pancreas, but no change in the number of islets or in the number of beta-cells per islet, consistent with a higher average size of beta-cells. Differential transcriptomic analysis showed upregulation of the expected HIF1A target genes. AQ-treated rat pups had decreased expression of cell cycle genes and decreased numbers of proliferating beta;-cells. Conclusion: We showed that hypoxia and pharmacologic activation of the hypoxia inducible pathway in early postnatal period leads to hyperinsulinism, due to the persistence of a low glucose threshold for insulin secretion. This exaggerated activation of hypoxia pathway also decreased early postnatal beta-cell proliferation, suggesting it can impact adult beta-cell mass and diabetes risk.

scholarly journals Therapeutic potential of VIP vs PACAP in diabetes

2012 ◽  
Vol 49 (3) ◽  
pp. R157-R167 ◽  
Author(s):  
Ahter D Sanlioglu ◽  
Bahri Karacay ◽  
Mustafa Kemal Balci ◽  
Thomas S Griffith ◽  
Salih Sanlioglu
Keyword(s):  
Insulin Secretion ◽  
Beta Cell ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Diabetic Patients ◽  
Inflammatory Factor ◽  
Cell Replication ◽  
Pancreatic Islet Cell ◽  
Beta Cell Replication ◽  
Postprandial Insulin

Type 2 diabetes (T2D) is characterized by chronic insulin resistance and a progressive decline in beta-cell function. Although rigorous glucose control can reduce morbidity and mortality associated with diabetes, achieving optimal long-term glycemic control remains to be accomplished in many diabetic patients. As beta-cell mass and function inevitably decline in T2D, exogenous insulin administration is almost unavoidable as a final outcome despite the use of oral antihyperglycemic agents in many diabetic patients. Pancreatic islet cell death, but not the defect in new islet formation or beta-cell replication, has been blamed for the decrease in beta-cell mass observed in T2D patients. Thus, therapeutic approaches designed to protect islet cells from apoptosis could significantly improve the management of T2D, because of its potential to reverse diabetes not just ameliorate glycemia. Therefore, an ideal beta-cell-preserving agent is expected to protect beta cells from apoptosis and stimulate postprandial insulin secretion along with increasing beta-cell replication and/or islet neogenesis. One such potential agent, the islet endocrine neuropeptide vasoactive intestinal peptide (VIP) strongly stimulates postprandial insulin secretion. Because of its broad spectrum of biological functions such as acting as a potent anti-inflammatory factor through suppression of Th1 immune response, and induction of immune tolerance via regulatory T cells, VIP has emerged as a promising therapeutic agent for the treatment of many autoimmune diseases including diabetes.

The Effects of Beta-cell Mass and Function, Intercellular Coupling, and islet Synchrony on Ca2+ Dynamics in Patients with Type 2 Diabetes Mellitus

2020 ◽  
Author(s):  
Maryam Saadati ◽  
Yousef Jamali
Keyword(s):  
Insulin Secretion ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function ◽  
Cell Mass ◽  
Electrical Coupling ◽  
Beta Cell Mass ◽  
Intercellular Coupling ◽  
And Function

Abstract Type 2 diabetes (T2D) is a challenging metabolic disorder characterized by a substantial loss of beta-cell mass via progressive programmed cell death and alteration of beta-cell function in the islets of Langerhans, disrupting insulin secretion and glucose homeostasis. The mechanisms for deficiency in beta-cell mass and function during the hyperglycemia development and T2D pathogenesis are complex. To study the relative contribution of beta-cell mass to beta-cell function in T2D, we make use of a comprehensive electrophysiological model from human beta-cell clusters. We find that defect in beta-cell mass causes a functional decline in single beta-cell, impairment in intra-islet synchrony, and changes in the form of oscillatory patterns of membrane potential and intracellular Ca2+ concentration, which can lead to changes in insulin secretion dynamics and insulin levels. The model demonstrates good correspondence between suppression of synchronizing electrical activity and pulsatile insulin release, and published experimental measurements. We then compare the role of gap junction-mediated electrical coupling with both beta-cell synchronization and metabolic coupling in the behavior of Ca2+ concentration dynamics within human islets. Our results indicate that inter-beta-cellular electrical coupling depicts a more important factor in shaping the physiological regulation of islet function and in human T2D. We further predict that varying the conductance gating of delayed rectifier K+ channels modifies oscillatory activity patterns of the beta-cell population lacking intercellular coupling, which significantly affects Ca2+ concentration and insulin secretion.

scholarly journals Islet Brain 1 Protects Insulin Producing Cells against Lipotoxicity

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Saška Brajkovic ◽  
Mourad Ferdaoussi ◽  
Valérie Pawlowski ◽  
Hélène Ezanno ◽  
Valérie Plaisance ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Beta Cell ◽  
Cell Survival ◽  
Cell Mass ◽  
Ectopic Expression ◽  
Beta Cell Mass ◽  
Mitogen Activated Protein Kinase ◽  
Interacting Protein ◽  
Mitogen Activated Protein ◽  
And Function

Chronic intake of saturated free fatty acids is associated with diabetes and may contribute to the impairment of functional beta cell mass. Mitogen activated protein kinase 8 interacting protein 1 also called islet brain 1 (IB1) is a candidate gene for diabetes that is required for beta cell survival and glucose-induced insulin secretion (GSIS). In this study we investigated whether IB1 expression is required for preserving beta cell survival and function in response to palmitate. Chronic exposure of MIN6 and isolated rat islets cells to palmitate led to reduction of the IB1 mRNA and protein content. Diminution of IB1 mRNA and protein level relied on the inducible cAMP early repressor activity and proteasome-mediated degradation, respectively. Suppression of IB1 level mimicked the harmful effects of palmitate on the beta cell survival and GSIS. Conversely, ectopic expression of IB1 counteracted the deleterious effects of palmitate on the beta cell survival and insulin secretion. These findings highlight the importance in preserving the IB1 content for protecting beta cell against lipotoxicity in diabetes.

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