Hyperinsulinism-Induced Hypoglycaemia: Towards an Understanding of the Molecular Mechanisms of Unregulated Insulin Release

2003 ◽  
pp. 259-292
Author(s):  
K.E. Cosgrove ◽  
R.M. Shepherd ◽  
A. Natarajan ◽  
K.J. Lindley ◽  
A. Aynsley-Green ◽  
...  
Keyword(s):  
Insulin Release ◽  
Molecular Mechanisms

scholarly journals Pathophysiology of Type 2 Diabetes Mellitus

2020 ◽  
Vol 21 (17) ◽  
pp. 6275 ◽  
Author(s):  
Unai Galicia-Garcia ◽  
Asier Benito-Vicente ◽  
Shifa Jebari ◽  
Asier Larrea-Sebal ◽  
Haziq Siddiqi ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Insulin Release ◽  
Molecular Mechanisms ◽  
Metabolic Memory ◽  
Insulin Metabolism ◽  
Insulin Synthesis

Type 2 Diabetes Mellitus (T2DM), one of the most common metabolic disorders, is caused by a combination of two primary factors: defective insulin secretion by pancreatic β-cells and the inability of insulin-sensitive tissues to respond appropriately to insulin. Because insulin release and activity are essential processes for glucose homeostasis, the molecular mechanisms involved in the synthesis and release of insulin, as well as in its detection are tightly regulated. Defects in any of the mechanisms involved in these processes can lead to a metabolic imbalance responsible for the development of the disease. This review analyzes the key aspects of T2DM, as well as the molecular mechanisms and pathways implicated in insulin metabolism leading to T2DM and insulin resistance. For that purpose, we summarize the data gathered up until now, focusing especially on insulin synthesis, insulin release, insulin sensing and on the downstream effects on individual insulin-sensitive organs. The review also covers the pathological conditions perpetuating T2DM such as nutritional factors, physical activity, gut dysbiosis and metabolic memory. Additionally, because T2DM is associated with accelerated atherosclerosis development, we review here some of the molecular mechanisms that link T2DM and insulin resistance (IR) as well as cardiovascular risk as one of the most important complications in T2DM.

scholarly journals Molecular mechanisms responsible for the sexual dimorphism in pancreatic β-cell insulin release

2021 ◽  
Vol 154 (9) ◽  
Author(s):  
Noelia Jacobo-Piqueras ◽  
Tamara Theiner ◽  
Stefanie M. Geisler ◽  
Petronel Tuluc
Keyword(s):  
Sexual Dimorphism ◽  
Electrical Activity ◽  
Insulin Release ◽  
Molecular Mechanisms ◽  
Resting Membrane Potential ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Specific Expression ◽  
Extracellular Glucose Concentration

In humans, type 2 diabetes mellitus (T2DM) has a higher incidence in males compared to females, a phenotype recapitulated by many rodent models. While the sex difference in insulin sensitivity partially accounts for this phenomenon, hitherto uncharacterized differences in pancreatic β-cell insulin release strongly contribute. Here, we show that stepwise increase in extracellular glucose concentration (2, 5, 7.5, 10, 15, 20 mM) induced electrical activity in β cells of both sexes with similar glucose sensitivity (female, EC50 = 9.45 ± 0.15 mM; male, EC50 = 9.42 ± 0.16 mM). However, female β cells’ resting membrane potential (RMP) and inter-spike potential (IP) were significantly higher compared to males (e.g., at 15 mM glucose: male RMP = −82.7 ± 6.3, IP = −74.3 ± 6.8 mV; female RMP = −50.0 ± 7.1, IP = −41.2 ± 7.3 mV). Females also showed higher frequency of trains of action potential (AP; at 10 mM glucose: male F = 1.13 ± 0.15 trains/min; female F = 1.78 ± 0.25 trains/min) and longer AP-burst duration (e.g., at 10 mM glucose: male, 241 ± 30.8 ms; female, 419 ± 60.2 ms). The higher RMP in females reduced the voltage-gated calcium channel (CaV) availability by ∼60%. This explains the paradoxical observation that, despite identical CaV expression levels and higher electrical activity, the islet Ca2+ transients were smaller in females compared to males. Interestingly, the different RMPs are not caused by altered KATP, TASK, or TALK K+ currents. However, stromatoxin-1–sensitive KV2.1 K+ current amplitude was almost double in males (IK = 130.93 ± 7.05 pA/pF) compared to females (IK = 75.85 ± 11.3 pA/pF) when measured at +80 mV. Our results are in agreement with previous findings showing that KV2.1 genetic deletion or pharmacological block leads to higher insulin release and β-cell survival. Therefore, we propose the sex-specific expression of KV2.1 to be the mechanism underlying the observed sexual dimorphism in insulin release and the incidence of T2DM.

Glucose intolerance and pancreatic β-cell dysfunction in the anorectic anx/anx mouse

2015 ◽  
Vol 309 (4) ◽  
pp. E418-E427 ◽  
Author(s):  
Charlotte Lindfors ◽  
Abram Katz ◽  
Lars Selander ◽  
Jeanette E. Johansen ◽  
Giulia Marconi ◽  
...  
Keyword(s):  
Eating Disorders ◽  
Insulin Release ◽  
Glucose Intolerance ◽  
Nadh Dehydrogenase ◽  
Molecular Mechanisms ◽  
Endocrine Pancreas ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Cell Dysfunction ◽  
Assembly Factor

Inflammation and impaired mitochondrial oxidative phosphorylation are considered key players in the development of several metabolic disorders, including diabetes. We have previously shown inflammation and mitochondrial dysfunction in the hypothalamus of an animal model for anorexia, the anx/ anx mouse. Moreover, increased incidence of eating disorders, e.g., anorexia nervosa, has been observed in diabetic individuals. In the present investigation we evaluated whether impaired mitochondrial phosphorylation and inflammation also occur in endocrine pancreas of anorectic mice, and if glucose homeostasis is disturbed. We show that anx/ anx mice exhibit marked glucose intolerance associated with reduced insulin release following an intraperitoneal injection of glucose. In contrast, insulin release from isolated anx/ anx islets is increased after stimulation with glucose or KCl. In isolated anx/ anx islets there is a strong downregulation of the mitochondrial complex I (CI) assembly factor, NADH dehydrogenase (ubiquinone) 1α subcomplex, assembly factor 1 ( Ndufaf1), and a reduced CI activity. In addition, we show elevated concentrations of free fatty acids (FFAs) in anx/ anx serum and increased macrophage infiltration (indicative of inflammation) in anx/ anx islets. However, isolated islets from anx/ anx mice cultured in the absence of FFAs do not exhibit increased inflammation. We conclude that the phenotype of the endocrine pancreas of the anx/ anx mouse is characterized by increased levels of circulating FFAs, as well as inflammation, which can inhibit insulin secretion in vivo. The anx/ anx mouse may represent a useful tool for studying molecular mechanisms underlying the association between diabetes and eating disorders.

scholarly journals Enhanced expression of β cell CaV3.1 channels impairs insulin release and glucose homeostasis

2019 ◽  
Vol 117 (1) ◽  
pp. 448-453 ◽  
Author(s):  
Jia Yu ◽  
Yue Shi ◽  
Kaixuan Zhao ◽  
Guang Yang ◽  
Lina Yu ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Release ◽  
Glucose Homeostasis ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Recombinant Adenovirus ◽  
Β Cells ◽  
Β Cell ◽  
Nuclear Retention ◽  
Enhanced Expression

Voltage-gated calcium 3.1 (CaV3.1) channels are absent in healthy mouse β cells and mediate minor T-type Ca2+currents in healthy rat and human β cells but become evident under diabetic conditions. Whether more active CaV3.1 channels affect insulin secretion and glucose homeostasis remains enigmatic. We addressed this question by enhancing de novo expression of β cell CaV3.1 channels and exploring the consequent impacts on dynamic insulin secretion and glucose homeostasis as well as underlying molecular mechanisms with a series of in vitro and in vivo approaches. We now demonstrate that a recombinant adenovirus encoding enhanced green fluorescent protein–CaV3.1 subunit (Ad-EGFP-CaV3.1) efficiently transduced rat and human islets as well as dispersed islet cells. The resulting CaV3.1 channels conducted typical T-type Ca2+currents, leading to an enhanced basal cytosolic-free Ca2+concentration ([Ca2+]i). Ad-EGFP-CaV3.1-transduced islets released significantly less insulin under both the basal and first phases following glucose stimulation and could no longer normalize hyperglycemia in recipient rats rendered diabetic by streptozotocin treatment. Furthermore, Ad-EGFP-CaV3.1 transduction reduced phosphorylated FoxO1 in the cytoplasm of INS-1E cells, elevated FoxO1 nuclear retention, and decreased syntaxin 1A, SNAP-25, and synaptotagmin III. These effects were prevented by inhibiting CaV3.1 channels or the Ca2+-dependent phosphatase calcineurin. Enhanced expression of β cell CaV3.1 channels therefore impairs insulin release and glucose homeostasis by means of initial excessive Ca2+influx, subsequent activation of calcineurin, consequent dephosphorylation and nuclear retention of FoxO1, and eventual FoxO1-mediated down-regulation of β cell exocytotic proteins. The present work thus suggests an elevated expression of CaV3.1 channels plays a significant role in diabetes pathogenesis.

Transcription factor/DNA interactions visualized by electron spectroscopic imaging

1992 ◽  
Vol 50 (1) ◽  
pp. 450-451
Author(s):  
David P. Bazett-Jones ◽  
Mark L. Brown
Keyword(s):  
Transcription Factor ◽  
Dna Sequences ◽  
Transcription Initiation ◽  
Molecular Mechanisms ◽  
Phosphorus Content ◽  
Spectroscopic Imaging ◽  
Electron Spectroscopic Imaging ◽  
Dna Backbone ◽  
Two Parameters ◽  
High Level

A multisubunit RNA polymerase enzyme is ultimately responsible for transcription initiation and elongation of RNA, but recognition of the proper start site by the enzyme is regulated by general, temporal and gene-specific trans-factors interacting at promoter and enhancer DNA sequences. To understand the molecular mechanisms which precisely regulate the transcription initiation event, it is crucial to elucidate the structure of the transcription factor/DNA complexes involved. Electron spectroscopic imaging (ESI) provides the opportunity to visualize individual DNA molecules. Enhancement of DNA contrast with ESI is accomplished by imaging with electrons that have interacted with inner shell electrons of phosphorus in the DNA backbone. Phosphorus detection at this intermediately high level of resolution (≈lnm) permits selective imaging of the DNA, to determine whether the protein factors compact, bend or wrap the DNA. Simultaneously, mass analysis and phosphorus content can be measured quantitatively, using adjacent DNA or tobacco mosaic virus (TMV) as mass and phosphorus standards. These two parameters provide stoichiometric information relating the ratios of protein:DNA content.

Dissection of the molecular mechanisms of protein targeting to the peroxisome using immunofluorescence and immunocryoelectron microscopies

1990 ◽  
Vol 48 (3) ◽  
pp. 44-45
Author(s):  
G-A. Keller ◽  
S. J. Gould ◽  
S. Subramani ◽  
S. Krisans
Keyword(s):  
Mammalian Cells ◽  
Molecular Mechanisms ◽  
Protein Targeting ◽  
Firefly Luciferase ◽  
Peroxisomal Enzyme ◽  
Transfected Cells ◽  
Peroxisomal Targeting ◽  
Targeting Signal ◽  
Series Of Experiments ◽  
Peroxisomal Targeting Signal

Subcellular compartments within eukaryotic cells must each be supplied with unique sets of proteins that must be directed to, and translocated across one or more membranes of the target organelles. This transport is mediated by cis- acting targeting signals present within the imported proteins. The following is a chronological account of a series of experiments designed and carried out in an effort to understand how proteins are targeted to the peroxisomal compartment.-We demonstrated by immunocryoelectron microscopy that the enzyme luciferase is a peroxisomal enzyme in the firefly lantern. -We expressed the cDNA encoding firefly luciferase in mammalian cells and demonstrated by immunofluorescence that the enzyme was transported into the peroxisomes of the transfected cells. -Using deletions, linker insertions, and gene fusion to identify regions of luciferase involved in its transport to the peroxisomes, we demonstrated that luciferase contains a peroxisomal targeting signal (PTS) within its COOH-terminal twelve amino acid.

High resolution mapping of nucleic acid containing complexes in vitro and in situ

1996 ◽  
Vol 54 ◽  
pp. 48-49
Author(s):  
D. P. Bazett-Jones ◽  
M. J. Hendzel
Keyword(s):  
Nucleic Acid ◽  
High Resolution ◽  
Transcription Initiation ◽  
Molecular Mechanisms ◽  
Heavy Atom ◽  
Regulation Of Transcription ◽  
High Exposure ◽  
Resolution Mapping ◽  
Tata Sequence

Structural analysis of combinations of nucleosomes and transcription factors on promoter and enhancer elements is necessary in order to understand the molecular mechanisms responsible for the regulation of transcription initiation. Such complexes are often not amenable to study by high resolution crystallographic techniques. We have been applying electron spectroscopic imaging (ESI) to specific problems in molecular biology related to transcription regulation. There are several advantages that this technique offers in studies of nucleoprotein complexes. First, an intermediate level of spatial resolution can be achieved because heavy atom contrast agents are not necessary. Second, mass and stoichiometric relationships of protein and nucleic acid can be estimated by phosphorus detection, an element in much higher proportions in nucleic acid than protein. Third, wrapping or bending of the DNA by the protein constituents can be observed by phosphorus mapping of the complexes. Even when ESI is used with high exposure of electrons to the specimen, important macromolecular information may be provided. For example, an image of the TATA binding protein (TBP) bound to DNA is shown in the Figure (top panel). It can be seen that the protein distorts the DNA away from itself and much of its mass sits off the DNA helix axis. Moreover, phosphorus and mass estimates demonstrate whether one or two TBP molecules interact with this particular promoter TATA sequence.

How do histone modifications contribute to transgenerational epigenetic inheritance in C. elegans?

2020 ◽  
Vol 48 (3) ◽  
pp. 1019-1034 ◽  
Author(s):  
Rachel M. Woodhouse ◽  
Alyson Ashe
Keyword(s):  
Histone Modifications ◽  
Molecular Mechanisms ◽  
Epigenetic Inheritance ◽  
Nematode Caenorhabditis Elegans ◽  
Histone Methyltransferases ◽  
Transgenerational Epigenetic Inheritance ◽  
C Elegans ◽  
Recent Developments ◽  
Gene Regulatory

Gene regulatory information can be inherited between generations in a phenomenon termed transgenerational epigenetic inheritance (TEI). While examples of TEI in many animals accumulate, the nematode Caenorhabditis elegans has proven particularly useful in investigating the underlying molecular mechanisms of this phenomenon. In C. elegans and other animals, the modification of histone proteins has emerged as a potential carrier and effector of transgenerational epigenetic information. In this review, we explore the contribution of histone modifications to TEI in C. elegans. We describe the role of repressive histone marks, histone methyltransferases, and associated chromatin factors in heritable gene silencing, and discuss recent developments and unanswered questions in how these factors integrate with other known TEI mechanisms. We also review the transgenerational effects of the manipulation of histone modifications on germline health and longevity.

Mesophyll conductance: the leaf corridors for photosynthesis

2020 ◽  
Vol 48 (2) ◽  
pp. 429-439 ◽  
Author(s):  
Jorge Gago ◽  
Danilo M. Daloso ◽  
Marc Carriquí ◽  
Miquel Nadal ◽  
Melanie Morales ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Main Role ◽  
Mesophyll Conductance ◽  
Future Studies ◽  
Cell Structures ◽  
Leaf Tissues ◽  
Change Framework ◽  
Chloroplast Stroma

Besides stomata, the photosynthetic CO2 pathway also involves the transport of CO2 from the sub-stomatal air spaces inside to the carboxylation sites in the chloroplast stroma, where Rubisco is located. This pathway is far to be a simple and direct way, formed by series of consecutive barriers that the CO2 should cross to be finally assimilated in photosynthesis, known as the mesophyll conductance (gm). Therefore, the gm reflects the pathway through different air, water and biophysical barriers within the leaf tissues and cell structures. Currently, it is known that gm can impose the same level of limitation (or even higher depending of the conditions) to photosynthesis than the wider known stomata or biochemistry. In this mini-review, we are focused on each of the gm determinants to summarize the current knowledge on the mechanisms driving gm from anatomical to metabolic and biochemical perspectives. Special attention deserve the latest studies demonstrating the importance of the molecular mechanisms driving anatomical traits as cell wall and the chloroplast surface exposed to the mesophyll airspaces (Sc/S) that significantly constrain gm. However, even considering these recent discoveries, still is poorly understood the mechanisms about signaling pathways linking the environment a/biotic stressors with gm responses. Thus, considering the main role of gm as a major driver of the CO2 availability at the carboxylation sites, future studies into these aspects will help us to understand photosynthesis responses in a global change framework.

Inflammageing in the cardiovascular system: mechanisms, emerging targets, and novel therapeutic strategies

2020 ◽  
Vol 134 (17) ◽  
pp. 2243-2262
Author(s):  
Danlin Liu ◽  
Gavin Richardson ◽  
Fehmi M. Benli ◽  
Catherine Park ◽  
João V. de Souza ◽  
...  
Keyword(s):  
Cardiovascular Diseases ◽  
Cardiovascular System ◽  
Nlrp3 Inflammasome ◽  
Molecular Mechanisms ◽  
Molecular Targets ◽  
Therapeutic Interventions ◽  
Low Grade ◽  
Cardiovascular Research ◽  
Inflammatory Processes ◽  
Ach Receptors

Abstract In the elderly population, pathological inflammation has been associated with ageing-associated diseases. The term ‘inflammageing’, which was used for the first time by Franceschi and co-workers in 2000, is associated with the chronic, low-grade, subclinical inflammatory processes coupled to biological ageing. The source of these inflammatory processes is debated. The senescence-associated secretory phenotype (SASP) has been proposed as the main origin of inflammageing. The SASP is characterised by the release of inflammatory cytokines, elevated activation of the NLRP3 inflammasome, altered regulation of acetylcholine (ACh) nicotinic receptors, and abnormal NAD+ metabolism. Therefore, SASP may be ‘druggable’ by small molecule therapeutics targeting those emerging molecular targets. It has been shown that inflammageing is a hallmark of various cardiovascular diseases, including atherosclerosis, hypertension, and adverse cardiac remodelling. Therefore, the pathomechanism involving SASP activation via the NLRP3 inflammasome; modulation of NLRP3 via α7 nicotinic ACh receptors; and modulation by senolytics targeting other proteins have gained a lot of interest within cardiovascular research and drug development communities. In this review, which offers a unique view from both clinical and preclinical target-based drug discovery perspectives, we have focused on cardiovascular inflammageing and its molecular mechanisms. We have outlined the mechanistic links between inflammageing, SASP, interleukin (IL)-1β, NLRP3 inflammasome, nicotinic ACh receptors, and molecular targets of senolytic drugs in the context of cardiovascular diseases. We have addressed the ‘druggability’ of NLRP3 and nicotinic α7 receptors by small molecules, as these proteins represent novel and exciting targets for therapeutic interventions targeting inflammageing in the cardiovascular system and beyond.

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