scholarly journals Modelling of dysregulated glucagon secretion in type 2 diabetes by considering mitochondrial alterations in pancreatic α-cells

2020 ◽  
Vol 7 (1) ◽  
pp. 191171 ◽  
Author(s):  
Vladimir Grubelnik ◽  
Rene Markovič ◽  
Saška Lipovšek ◽  
Gerd Leitinger ◽  
Marko Gosak ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cell Metabolism ◽  
Glucagon Secretion ◽  
Pancreatic Tissue ◽  
Β Cells ◽  
High Blood Glucose ◽  
Atp Production ◽  
Mitochondrial Alterations ◽  
Blood Glucose Concentrations

Type 2 diabetes mellitus (T2DM) has been associated with insulin resistance and the failure of β-cells to produce and secrete enough insulin as the disease progresses. However, clinical treatments based solely on insulin secretion and action have had limited success. The focus is therefore shifting towards α-cells, in particular to the dysregulated secretion of glucagon. Our qualitative electron-microscopy-based observations gave an indication that mitochondria in α-cells are altered in Western-diet-induced T2DM. In particular, α-cells extracted from mouse pancreatic tissue showed a lower density of mitochondria, a less expressed matrix and a lower number of cristae. These deformities in mitochondrial ultrastructure imply a decreased efficiency in mitochondrial ATP production, which prompted us to theoretically explore and clarify one of the most challenging problems associated with T2DM, namely the lack of glucagon secretion in hypoglycaemia and its oversecretion at high blood glucose concentrations. To this purpose, we constructed a novel computational model that links α-cell metabolism with their electrical activity and glucagon secretion. Our results show that defective mitochondrial metabolism in α-cells can account for dysregulated glucagon secretion in T2DM, thus improving our understanding of T2DM pathophysiology and indicating possibilities for new clinical treatments.

Beta-cell Defects in Type 2 Diabetes and the Possibility of Treatment Options with GLP-1-based Therapies

2006 ◽  
Vol 00 (02) ◽  
Author(s):  
Baptist Gallwitz
Keyword(s):  
Type 2 Diabetes ◽  
Beta Cell ◽  
Progressive Disease ◽  
Treatment Options ◽  
Glucose Production ◽  
Glucagon Secretion ◽  
Alpha Cells ◽  
Cell Dysfunction ◽  
Blood Glucose Concentrations

Type 2 Diabetes as a Progressive DiseaseIn type 2 diabetes, beta-cell dysfunction plays a major part not only in the pathogenesis of the disease, but also in disease progression over time. Under normal conditions, blood glucose concentrations are regulated within a very tight range. After a meal, insulin secretion from the beta cell is stimulated, whereas glucagon secretion from the alpha cells is suppressed. Insulin facilitates glucose uptake into the cells, whereas glucagon stimulates glucose production in the liver.

scholarly journals Live-cell imaging of glucose-induced metabolic coupling of β and α cell metabolism in health and type 2 diabetes

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Zhongying Wang ◽  
Tatyana Gurlo ◽  
Aleksey V. Matveyenko ◽  
David Elashoff ◽  
Peiyu Wang ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Oxidative Phosphorylation ◽  
Islet Cells ◽  
Cell Metabolism ◽  
Fluorescence Lifetime Imaging ◽  
Β Cells ◽  
Cell Dysfunction ◽  
Metabolic Coupling ◽  
Before And After

AbstractType 2 diabetes is characterized by β and α cell dysfunction. We used phasor-FLIM (Fluorescence Lifetime Imaging Microscopy) to monitor oxidative phosphorylation and glycolysis in living islet cells before and after glucose stimulation. In healthy cells, glucose enhanced oxidative phosphorylation in β cells and suppressed oxidative phosphorylation in α cells. In Type 2 diabetes, glucose increased glycolysis in β cells, and only partially suppressed oxidative phosphorylation in α cells. FLIM uncovers key perturbations in glucose induced metabolism in living islet cells and provides a sensitive tool for drug discovery in diabetes.

scholarly journals Quercetin Alleviates Ferroptosis of Pancreatic β Cells in Type 2 Diabetes

Nutrients ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2954
Author(s):  
Dan Li ◽  
Chunjie Jiang ◽  
Guibin Mei ◽  
Ying Zhao ◽  
Li Chen ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Pancreatic Tissue ◽  
Iron Deposition ◽  
Iron Level ◽  
Model Assessment ◽  
Mice Model ◽  
Homeostasis Model Assessment ◽  
Β Cells ◽  
Pancreatic Β Cells

(1) Background: Pancreatic iron deposition has been found in the progression of type 2 diabetes (T2DM); however, whether ferroptosis contributes to the dysfunction of pancreatic β cells (PBC) remains enigmatic. Moreover, the potential protective effect of quercetin is also elusive; (2) Methods: T2DM mice model was established by multiple low dose streptozocin (STZ) injection, after which quercetin was intervened for 4 months; (3) Results: Substantially normalized glucose tolerance, diabetic symptoms, homeostasis model assessment for insulin resistance (HOMA-IR), and homeostasis model assessment for β cell (HOMA-β) index in comparison with the findings of T2DM control. Distorted pancreatic islets and especially shrunken mitochondria with cristae loss in PBC were observed in T2DM mice, which was ameliorated by quercetin. Meanwhile, quercetin lowered the iron level particularly in the islet in T2DM mice. In spite of compensatory xCT up-regulation, T2DM molding depleted glutathione (GSH), down-regulated glutathione peroxidase 4 (GPX4), and induced oxidative stress in pancreatic tissue, which was abolished partially by quercetin. More importantly, insulin secretion was worsened by ferroptosis-inducing erastin or RAS-selective lethal compounds 3 (RSL-3). Quercetin, ferroptosis inhibitor ferrostatin-1 and iron-chelating deferoxamine, rescued cell viability when cells were challenged with high-glucose; (4) Conclusions: Our findings identify that ferroptosis contributes to the PBC loss and dysfunction. Quercetin exerts beneficial effects on T2DM potentially by inhibiting pancreatic iron deposition and PBC ferroptosis, highlighting promising control strategies of T2DM by quercetin.

scholarly journals Mechanisms of the Regulation and Dysregulation of Glucagon Secretion

2020 ◽  
Vol 2020 ◽  
pp. 1-9 ◽  
Author(s):  
Arnold N. Onyango
Keyword(s):  
Type 2 Diabetes ◽  
Blood Glucose ◽  
Protein Kinase ◽  
Signaling Pathway ◽  
Blood Glucose Concentration ◽  
Hepatic Glucose Production ◽  
Glucagon Secretion ◽  
Alpha Cell ◽  
High Blood Glucose

Glucagon, a hormone secreted by pancreatic alpha cells, contributes to the maintenance of normal blood glucose concentration by inducing hepatic glucose production in response to declining blood glucose. However, glucagon hypersecretion contributes to the pathogenesis of type 2 diabetes. Moreover, diabetes is associated with relative glucagon undersecretion at low blood glucose and oversecretion at normal and high blood glucose. The mechanisms of such alpha cell dysfunctions are not well understood. This article reviews the genesis of alpha cell dysfunctions during the pathogenesis of type 2 diabetes and after the onset of type 1 and type 2 diabetes. It unravels a signaling pathway that contributes to glucose- or hydrogen peroxide-induced glucagon secretion, whose overstimulation contributes to glucagon dysregulation, partly through oxidative stress and reduced ATP synthesis. The signaling pathway involves phosphatidylinositol-3-kinase, protein kinase B, protein kinase C delta, non-receptor tyrosine kinase Src, and phospholipase C gamma-1. This knowledge will be useful in the design of new antidiabetic agents or regimens.

Islet Amyloid Polypeptide, Islet Amyloid, and Diabetes Mellitus

2011 ◽  
Vol 91 (3) ◽  
pp. 795-826 ◽  
Author(s):  
Per Westermark ◽  
Arne Andersson ◽  
Gunilla T. Westermark
Keyword(s):  
Type 2 Diabetes ◽  
Pancreatic Islets ◽  
Amyloid Fibrils ◽  
Mammalian Species ◽  
Islet Amyloid Polypeptide ◽  
Glucagon Secretion ◽  
Β Cells ◽  
Islet Amyloid ◽  
Pancreatic Islets Of Langerhans

Islet amyloid polypeptide (IAPP, or amylin) is one of the major secretory products of β-cells of the pancreatic islets of Langerhans. It is a regulatory peptide with putative function both locally in the islets, where it inhibits insulin and glucagon secretion, and at distant targets. It has binding sites in the brain, possibly contributing also to satiety regulation and inhibits gastric emptying. Effects on several other organs have also been described. IAPP was discovered through its ability to aggregate into pancreatic islet amyloid deposits, which are seen particularly in association with type 2 diabetes in humans and with diabetes in a few other mammalian species, especially monkeys and cats. Aggregated IAPP has cytotoxic properties and is believed to be of critical importance for the loss of β-cells in type 2 diabetes and also in pancreatic islets transplanted into individuals with type 1 diabetes. This review deals both with physiological aspects of IAPP and with the pathophysiological role of aggregated forms of IAPP, including mechanisms whereby human IAPP forms toxic aggregates and amyloid fibrils.

scholarly journals Inhibition of the malate–aspartate shuttle in mouse pancreatic islets abolishes glucagon secretion without affecting insulin secretion

2015 ◽  
Vol 468 (1) ◽  
pp. 49-63 ◽  
Author(s):  
Jelena A. Stamenkovic ◽  
Lotta E. Andersson ◽  
Alice E. Adriaenssens ◽  
Annika Bagge ◽  
Vladimir V. Sharoyko ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Glucagon Secretion ◽  
Nutrient Sensing ◽  
Β Cells ◽  
Mouse Pancreatic Islets ◽  
Glucagon And Insulin ◽  
Malate Aspartate Shuttle

Secretion of both glucagon and insulin is perturbed in Type 2 diabetes (T2D). In the present study, we identify a difference in mitochondrial shuttling between α- and β-cells that adjusts nutrient sensing and which potentially could be employed to specifically target secretion of either hormone.

scholarly journals Synergistic Effects of Milk-Derived Exosomes and Galactose on α-Synuclein Pathology in Parkinson’s Disease and Type 2 Diabetes Mellitus

2021 ◽  
Vol 22 (3) ◽  
pp. 1059
Author(s):  
Bodo C. Melnik
Keyword(s):  
Oxidative Stress ◽  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Dopaminergic Neurons ◽  
Vagal Nerve ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
The Brain

Epidemiological studies associate milk consumption with an increased risk of Parkinson’s disease (PD) and type 2 diabetes mellitus (T2D). PD is an α-synucleinopathy associated with mitochondrial dysfunction, oxidative stress, deficient lysosomal clearance of α-synuclein (α-syn) and aggregation of misfolded α-syn. In T2D, α-syn promotes co-aggregation with islet amyloid polypeptide in pancreatic β-cells. Prion-like vagal nerve-mediated propagation of exosomal α-syn from the gut to the brain and pancreatic islets apparently link both pathologies. Exosomes are critical transmitters of α-syn from cell to cell especially under conditions of compromised autophagy. This review provides translational evidence that milk exosomes (MEX) disturb α-syn homeostasis. MEX are taken up by intestinal epithelial cells and accumulate in the brain after oral administration to mice. The potential uptake of MEX miRNA-148a and miRNA-21 by enteroendocrine cells in the gut, dopaminergic neurons in substantia nigra and pancreatic β-cells may enhance miRNA-148a/DNMT1-dependent overexpression of α-syn and impair miRNA-148a/PPARGC1A- and miRNA-21/LAMP2A-dependent autophagy driving both diseases. MiRNA-148a- and galactose-induced mitochondrial oxidative stress activate c-Abl-mediated aggregation of α-syn which is exported by exosome release. Via the vagal nerve and/or systemic exosomes, toxic α-syn may spread to dopaminergic neurons and pancreatic β-cells linking the pathogenesis of PD and T2D.

Genes of Type 2 Diabetes in β Cells

2006 ◽  
Vol 35 (2) ◽  
pp. 357-369 ◽  
Author(s):  
Mirko Trajkovski ◽  
Hassan Mziaut ◽  
Peter E. Schwarz ◽  
Michele Solimena
Keyword(s):  
Type 2 Diabetes ◽  
Β Cells
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