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1
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Koyama T, Saeed U, Rewitz K, Halberg KV. The Integrative Physiology of Hormone Signaling: Insights from Insect Models. Physiology (Bethesda) 2025; 40:0. [PMID: 39887191 DOI: 10.1152/physiol.00030.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 11/18/2024] [Accepted: 01/24/2025] [Indexed: 02/01/2025] Open
Abstract
Hormones orchestrate virtually all physiological processes in animals and enable them to adjust internal responses to meet diverse physiological demands. Studies in both vertebrates and insects have uncovered many novel hormones and dissected the physiological mechanisms they regulate, demonstrating a remarkable conservation in endocrine signaling across the tree of life. In this review, we focus on recent advances in insect research, which have provided a more integrative view of the conserved interorgan communication networks that control physiology. These new insights have been driven by experimental advantages inherent to insects, which over the past decades have aligned with new technologies and sophisticated genetic tools, to transform insect genetic models into a powerful testbed for posing new questions and exploring longstanding issues in endocrine research. Here, we illustrate how insect studies have addressed classic questions in three main areas, hormonal control of growth and development, neuroendocrine regulation of ion and water balance, and hormonal regulation of behavior and metabolism, and how these discoveries have illuminated our fundamental understanding of endocrine signaling in animals. The application of integrative physiology in insect systems to questions in endocrinology and physiology is expanding and is poised to be a crucible of discovery, revealing fundamental mechanisms of hormonal regulation that underlie animal adaptations to their environments.
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Affiliation(s)
- Takashi Koyama
- Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Usama Saeed
- Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Kim Rewitz
- Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Kenneth V Halberg
- Department of Biology, University of Copenhagen, Copenhagen, Denmark
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2
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Maharwal N, Shrivastava R, Majumder SK. Insight into Optogenetics for Diabetes Management. ACS Synth Biol 2025; 14:1324-1335. [PMID: 40279455 DOI: 10.1021/acssynbio.4c00549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/27/2025]
Abstract
Optogenetics is an interdisciplinary field wherein optical and genetic engineering methods are employed together to impart photounresponsive cells (usually of higher animals) the ability to respond to light through expression of light-sensitive proteins sourced generally from algae or bacteria. It enables precise spatiotemporal control of various cellular activities through light stimulation. Recently, emerging as a synthetic biology-based approach for diabetes management, optogenetics can provide user-control of hormonal secretion by photoactivation of a suitably modified cell. For around a decade, studies have been performed on the applicability of various light-sensitive proteins and their incorporation into pancreatic and nonpancreatic cells for photoinduced insulin secretion. Further, in vivo studies demonstrated amelioration of diabetes in mouse models through photoactivation of the implanted engineered cells. Here, we attempt to highlight the various optogenetic approaches explored in terms of influencing the insulin secretion pathway at different points in light of the natural insulin secretion pathway in pancreatic β cells. We also discuss how transgenic cells of both pancreatic as well as nonpancreatic origin are exploited for photoinduced secretion of insulin. Recent advances on integration of "smart" technologies for remote control of light irradiation and thereby insulin secretion from implanted engineered cells in preclinical models are also described. Additionally, the need for further comprehensive studies on irradiation parameters, red-shifted opsins, and host-cell interaction is stressed to realize the full potential of optogenetics as a clinically applicable modality providing user-controlled "on demand" hormonal secretion for better management of diabetes.
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Affiliation(s)
- Nidhi Maharwal
- Laser Biomedical Applications Division, Laser R&D Block-A1, Raja Ramanna Centre for Advanced Technology, Indore 452013, India
- Homi Bhabha National Institute, 2nd floor, BARC Training School Complex, Anushakti Nagar, Mumbai 400 094, India
| | - Rashmi Shrivastava
- Laser Biomedical Applications Division, Laser R&D Block-A1, Raja Ramanna Centre for Advanced Technology, Indore 452013, India
- Homi Bhabha National Institute, 2nd floor, BARC Training School Complex, Anushakti Nagar, Mumbai 400 094, India
| | - Shovan Kumar Majumder
- Laser Biomedical Applications Division, Laser R&D Block-A1, Raja Ramanna Centre for Advanced Technology, Indore 452013, India
- Homi Bhabha National Institute, 2nd floor, BARC Training School Complex, Anushakti Nagar, Mumbai 400 094, India
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3
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Gheibi S, Cataldo LR, Ardalani H, Nocquet L, Spégel P, Straub SG, Sharp GWG, Fex M, Mulder H. Conversion of glutamate into proline by the leucine analog BCH enhances biphasic insulin secretion in pancreatic β-cells. J Biol Chem 2025; 301:108449. [PMID: 40154614 PMCID: PMC12059337 DOI: 10.1016/j.jbc.2025.108449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 03/17/2025] [Accepted: 03/20/2025] [Indexed: 04/01/2025] Open
Abstract
Biphasic insulin secretion, which fails in type 2 diabetes, can be provoked by various nutrient stimuli, glucose being the superior physiological one. To identify pathways that may play a role in β-cell stimulus-secretion coupling, we compared β-cell and islet functional, secretory, and metabolic responses to glucose and 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH), a leucine analog, that acts as an allosteric activator of glutamate dehydrogenase. We employed a range of techniques, including insulin secretion assays, mitochondrial activity measurements, ATP/ADP ratio assessments, and cytosolic Ca2+ level quantifications. Metabolomics was used to analyze cellular metabolite profiles in response to glucose and BCH. Additionally, we investigated the role of proline synthesis by silencing ALDH18A1, encoding proline 5-carboxylate synthase, in both clonal β-cells and human islets. BCH and glucose similarly induced a biphasic insulin response in INS-1 832/13 cells, paralleled by increased mitochondrial activity and raised ATP/ADP ratios, plasma membrane depolarization, and elevated cytosolic Ca2+ levels. Metabolomics revealed that proline levels increased significantly only in BCH-stimulated β-cells. Silencing ALDH18A1 disrupted insulin secretion in response to both glucose and BCH, accompanied by reduced cytosolic Ca2+ levels, ATP/ADP ratios, and mitochondrial activity. Our findings demonstrated that BCH-induced activation of glutamate dehydrogenase leads to the conversion of glutamate into proline, which apparently enhances β-cell stimulus-secretion coupling. This work identifies a previously unrecognized role of proline metabolism in β-cell function and provides novel insights into the complex regulation of insulin secretion.
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Affiliation(s)
- Sevda Gheibi
- Unit of Molecular Metabolism, Lund University Diabetes Centre, Malmö, Sweden.
| | - Luis Rodrigo Cataldo
- Unit of Molecular Metabolism, Lund University Diabetes Centre, Malmö, Sweden; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Hamidreza Ardalani
- Department of Chemistry, Centre for Analysis and Synthesis, Lund University, Lund, Sweden; Pharmacokinetics, Dynamics, and Metabolism, Pfizer R&D, Pfizer Inc., Bothell, Washington, USA
| | - Lisa Nocquet
- Unit of Molecular Metabolism, Lund University Diabetes Centre, Malmö, Sweden
| | - Peter Spégel
- Department of Chemistry, Centre for Analysis and Synthesis, Lund University, Lund, Sweden
| | - Susanne G Straub
- Department of Molecular Medicine, Cornell University, Ithaca, New York, USA
| | - Geoffrey W G Sharp
- Department of Molecular Medicine, Cornell University, Ithaca, New York, USA
| | - Malin Fex
- Unit of Molecular Metabolism, Lund University Diabetes Centre, Malmö, Sweden
| | - Hindrik Mulder
- Unit of Molecular Metabolism, Lund University Diabetes Centre, Malmö, Sweden
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4
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Gojani EG, Wang B, Li DP, Kovalchuk O, Kovalchuk I. The Impact of Major and Minor Phytocannabinoids on the Maintenance and Function of INS-1 β-Cells Under High-Glucose and High-Lipid Conditions. Molecules 2025; 30:1991. [PMID: 40363798 PMCID: PMC12073157 DOI: 10.3390/molecules30091991] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2025] [Revised: 04/22/2025] [Accepted: 04/27/2025] [Indexed: 05/15/2025] Open
Abstract
Type 2 diabetes mellites (T2DM) is the most common form of diabetes and affects a significant portion of the population. Obesity-related increases in free fatty acids and glucose in the diet contribute to β-cell dysfunction and loss, ultimately leading to the onset of T2DM. The endocannabinoid system, which is present throughout the body, plays a vital role in regulating various physiological processes, including those in the pancreas. This system has been implicated in metabolic disorders like obesity and diabetes, as it helps to regulate appetite, food intake, and fat production. Phytocannabinoids from Cannabis sativa have the potential to influence the endocannabinoid system, offering a promising therapeutic approach for diabetes and its complications. Using high-glucose-high-lipid (HGHL)-induced INS-1 β-cells, we investigated the protective effects of two major (THC and CBD) and three minor (THCV, CBC, and CBG) phytocannabinoids on high glucose-high lipid (HGHL)-induced apoptosis, cell cycle disruption, and impaired function of beta-cells. Our results showed that all five phytocannabinoids reduced HGHL-induced apoptosis, likely by decreasing TXNIP protein levels. Additionally, THC and all three minor phytocannabinoids provided protective effects against functional impairments caused by HGHL exposure.
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Affiliation(s)
| | | | | | - Olga Kovalchuk
- Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K 3M4, Canada; (E.G.G.); (B.W.); (D.-P.L.)
| | - Igor Kovalchuk
- Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K 3M4, Canada; (E.G.G.); (B.W.); (D.-P.L.)
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5
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Aldharee H, Hamdan HZ. In Silico Analysis Identified Putative Pathogenic Missense Single Nucleotide Polymorphisms (SNPs) in the Human HNF1A Gene. Int J Mol Sci 2025; 26:3768. [PMID: 40332430 PMCID: PMC12027519 DOI: 10.3390/ijms26083768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2025] [Revised: 03/29/2025] [Accepted: 04/15/2025] [Indexed: 05/08/2025] Open
Abstract
Maturity-onset diabetes of the young (MODY) is a rare genetic condition that affects children, adolescents, and adults. Studies have shown that genetic changes in the HNF1A gene are associated with MODY-3. However, most of the causative variants and the molecular mechanisms remain underexplored. This study aims to better understand MODY-3 by investigating HNF1A-missense variants with clinical uncertainty. Various bioinformatics tools were utilised to address the clinical uncertainty of missense variants in the HNF1A gene that have not been linked with HNF1A-related conditions, sourced from the Genome Aggregation Database (GnomAD v4.1.0). Among the clinically uncertain 2444 variants, only 138 were classified as missense with clinically uncertain significance. Results show that four variants (Arg168Cys, Glu275Ala, Gly375Asp and Val411Phe) were consistently predicted as pathogenic by all tools. The allele frequency (AF) of the commonly predicted disease-causing variants was very low in the global population. The assessment of the secondary structure of filtered variants indicates that variants (Arg168Cys and Glu275Ala) are located in the helical region of the HNF1A protein. At the same time (Gly375Asp and Val411Phe) are found in the protein's coil, suggesting structural changes at the site of variations. The prediction of protein stability was conducted using I-Mutant and MuPro. Both tools collectively indicate decreased protein stability for the variants (Arg168Cys, Glu275Ala, Gly375Asp and Val411Phe). Predicting the protein's 3D structure for the HNF1A wild-type and mutants indicates potential structural damages in Arg168Cys and Gly375Asp. Additionally, results show that the amino acids at the variation sites of the variants (Arg168Cys, Glu275Ala, Gly375Asp and Val411Phe) were highly conserved. To conclude, 4 out of the 138 missense variants labelled as uncertain significance were found to be consistently pathogenic using in silico tools in this study. Our findings aim to support variant interpretation, understand the genotype-phenotype association of diabetes, and provide better healthcare services for patients with diabetes.
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Affiliation(s)
- Hitham Aldharee
- Department of Pathology, College of Medicine, Qassim University, Buraidah 51452, Saudi Arabia;
- Unit of Genetic Diabetes, Abdullah Al Othaim Diabetes Center, Medical City, Qassim University, Buraidah 51452, Saudi Arabia
| | - Hamdan Z. Hamdan
- Department of Pathology, College of Medicine, Qassim University, Buraidah 51452, Saudi Arabia;
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6
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Davis J, Thornham J, Roper MG. Online LC-MS/MS Analysis for Profiling Peptide Hormone Secretion Dynamics from Islets of Langerhans. Anal Chem 2025; 97:4209-4216. [PMID: 39931908 PMCID: PMC11867101 DOI: 10.1021/acs.analchem.4c06643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2024] [Revised: 01/21/2025] [Accepted: 01/30/2025] [Indexed: 02/26/2025]
Abstract
Multiple peptide hormones are secreted from islets of Langerhans to maintain blood glucose homeostasis. Defects in the amount and patterns of hormone secretion can lead to metabolic disorders, such as diabetes. To understand the relationships between the peptides, analytical methods that can quantify multiple hormones in short time increments are required. To this end, an automated and online system was developed for sampling perfusate from ∼30 human islets held on a glass microfluidic device with sequential liquid chromatography (LC)-MS/MS runs every 2 min to resolve secretion dynamics. Islet perfusate was mixed with an isotopically labeled internal standard and loaded into a 2 μL sample loop which was injected for 0.1 min every 1.9 min onto a 2.1 mm × 30 mm (I.D. × length) C18 column held at 70 °C. Online detection of insulin, C-peptide, glucagon, and somatostatin levels was performed using a triple quadrupole mass spectrometer. Optimization of separation conditions using linear solvent strength theory enabled rapid separation of the four peptides. Calibration curves were linear from 0.5 to 50 nM with an RSD for all analytes between 3-15% and <3% RSD for all retention times. Results showed secretion dynamics such as first-phase insulin release and negatively correlated release of glucagon and insulin. This simple LC-MS method that used a single 6-port valve with a single sample loop is expected to be useful for examining secretion of other biologically relevant molecules from islets and could be applied to other biological systems for rapid and automated sampling to investigate cellular communication.
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Affiliation(s)
- Joshua
J. Davis
- Department
of Chemistry and Biochemistry, Florida State
University, 95 Chieftain Way, Tallahassee, Florida 32306, United
States
| | - James Thornham
- Program
in Molecular Biophysics, Florida State University, Tallahassee, Florida 32306, United States
| | - Michael G. Roper
- Department
of Chemistry and Biochemistry, Florida State
University, 95 Chieftain Way, Tallahassee, Florida 32306, United
States
- Program
in Molecular Biophysics, Florida State University, Tallahassee, Florida 32306, United States
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7
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Peng X, Wang K, Chen L. Biphasic glucose-stimulated insulin secretion over decades: a journey from measurements and modeling to mechanistic insights. LIFE METABOLISM 2025; 4:loae038. [PMID: 39872989 PMCID: PMC11770817 DOI: 10.1093/lifemeta/loae038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 11/10/2024] [Accepted: 11/13/2024] [Indexed: 01/30/2025]
Abstract
Glucose-stimulated insulin release from pancreatic β-cells is critical for maintaining blood glucose homeostasis. An abrupt increase in blood glucose concentration evokes a rapid and transient rise in insulin secretion followed by a prolonged, slower phase. A diminished first phase is one of the earliest indicators of β-cell dysfunction in individuals predisposed to develop type 2 diabetes. Consequently, researchers have explored the underlying mechanisms for decades, starting with plasma insulin measurements under physiological conditions and advancing to single-vesicle exocytosis measurements in individual β-cells combined with molecular manipulations. Based on a chain of evidence gathered from genetic manipulation to in vivo mouse phenotyping, a widely accepted theory posits that distinct functional insulin vesicle pools in β-cells regulate biphasic glucose-stimulated insulin secretion (GSIS) via activation of different metabolic signal pathways. Recently, we developed a high-resolution imaging technique to visualize single vesicle exocytosis from β-cells within an intact islet. Our findings reveal that β-cells within the islet exhibit heterogeneity in their secretory capabilities, which also differs from the heterogeneous Ca2+ signals observed in islet β-cells in response to glucose stimulation. Most importantly, we demonstrate that biphasic GSIS emerges from the interactions among α-, β-, and δ-cells within the islet and is driven by a small subset of hypersecretory β-cells. Finally, we propose that a shift from reductionism to holism may be required to fully understand the etiology of complex diseases such as diabetes.
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Affiliation(s)
- Xiaohong Peng
- New Cornerstone Science Laboratory, State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, National Biomedical Imaging Center, The Beijing Laboratory of Biomedical Imaging, Peking-Tsinghua Center for Life Sciences, School of Future Technology, Peking University, Beijing 100871, China
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China
| | - Kai Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China
| | - Liangyi Chen
- New Cornerstone Science Laboratory, State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, National Biomedical Imaging Center, The Beijing Laboratory of Biomedical Imaging, Peking-Tsinghua Center for Life Sciences, School of Future Technology, Peking University, Beijing 100871, China
- PKU-IDG/McGovern Institute for Brain Research, Beijing 100871, China
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8
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Makam AA, Sharma S, Nagle P, Sundaram NM, Prasad VM, Gandasi NR. tPA-GFP is a reliable probe for detecting compound exocytosis in human pancreatic β-cells. FASEB Bioadv 2025; 7:e1482. [PMID: 39917393 PMCID: PMC11795275 DOI: 10.1096/fba.2024-00131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 11/22/2024] [Accepted: 11/25/2024] [Indexed: 02/09/2025] Open
Abstract
Pancreatic β-cells secrete insulin stored in large dense core vesicles (LDCV) by fusion of vesicle and plasma membrane during a process called insulin exocytosis. Insulin secretion is biphasic with a fast first phase and a sustained second phase. Previous studies have pointed out that exocytosis of insulin can occur via (1) single LDCVs fusing with the plasma membrane to release their content or (2) multiple vesicles are involved during a process called compound exocytosis. Compound exocytosis represents a specialized form of secretion in which vesicles undergo homotypic fusion either before (multi-vesicular exocytosis) or continuous fusion in a sequential manner from (sequential exocytosis) within the same site at the plasma membrane. We see that the number of multi-vesicles is few and not localized in the vicinity of the plasma membrane. Studying the kinetics of this process and correlating it with biphasic insulin secretion is not possible since there are no specific probes to detect them. It is challenging to identify compound exocytosis with probes that exist for simple exocytosis. To advance our understanding, we need a fluorescent probe that could detect secretory vesicles undergoing compound exocytosis and allow us to distinguish it from other modes of exocytosis. Here, we used two cargo proteins (NPY and tPA) labeled with different fluorescent proteins (mCherry GFP and eGFP) and employed total internal reflection fluorescence microscopy (TIRF-M) to capture distinct single-granule and multi-granular fusion events. We identified tPA-GFP as a better probe for studying compound exocytosis, as it can detect both simple and sequential exocytosis reliably. Using these probes, we have studied the kinetics of compound exocytosis in human β-cells. These observations, with additional experiments, may open a whole new field to study the impact of compound exocytosis on biphasic secretion of insulin. Identifying targets to increase the compound exocytosis process can help potentiate insulin secretion in diabetics.
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Affiliation(s)
- Aishwarya A. Makam
- Department of Developmental Biology and Genetics (DBG)Indian Institute of Science (IISc)BengaluruKarnatakaIndia
| | - Shruti Sharma
- Molecular Biophysics UnitIndian Institute of ScienceBengaluruKarnatakaIndia
- Center for Infectious Disease ResearchIndian Institute of ScienceBengaluruKarnatakaIndia
| | - Prajwal Nagle
- Department of Developmental Biology and Genetics (DBG)Indian Institute of Science (IISc)BengaluruKarnatakaIndia
| | - Nandhini M. Sundaram
- Molecular Biophysics UnitIndian Institute of ScienceBengaluruKarnatakaIndia
- Center for Infectious Disease ResearchIndian Institute of ScienceBengaluruKarnatakaIndia
| | - Vidya Mangala Prasad
- Molecular Biophysics UnitIndian Institute of ScienceBengaluruKarnatakaIndia
- Center for Infectious Disease ResearchIndian Institute of ScienceBengaluruKarnatakaIndia
| | - Nikhil R. Gandasi
- Department of Developmental Biology and Genetics (DBG)Indian Institute of Science (IISc)BengaluruKarnatakaIndia
- Department of Medical Cell BiologyUppsala UniversityUppsalaSweden
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9
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Lundquist I, Mohammed Al-Amily I, Henningsson R, Salehi A. Islet NO-Synthases, extracellular NO and glucose-stimulated insulin secretion: Possible impact of neuronal NO-Synthase on the pentose phosphate pathway. PLoS One 2025; 20:e0315126. [PMID: 39854399 PMCID: PMC11760571 DOI: 10.1371/journal.pone.0315126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Accepted: 11/20/2024] [Indexed: 01/26/2025] Open
Abstract
The impact of islet neuronal nitric oxide synthase (nNOS) on glucose-stimulated insulin secretion (GSIS) is less understood. We investigated this issue by performing simultaneous measurements of the activity of nNOS versus inducible NOS (iNOS) in GSIS using isolated murine islets. Additionally, the significance of extracellular NO on GSIS was studied. Islets incubated at basal glucose showed modest nNOS but no iNOS activity. Glucose-induced concentration-response studies revealed an increase in both NOS activities in relation to secreted insulin. Culturing at high glucose increased both nNOS and iNOS activities inducing a marked decrease in GSIS in a following short-term incubation at high glucose. Culturing at half-maximal glucose showed strong iNOS expression revealed by fluorescence microscopy also in human islets. Experiments with nNOS-inhibitors revealed that GSIS was inversely related to nNOS activity, the effect of iNOS activity being negligible. The increased GSIS after blockade of nNOS was reversed by the intracellular NO-donor hydroxylamine. The enhancing effect on GSIS by nNOS inhibition was independent of membrane depolarization and most likely exerted in the pentose phosphate pathway (PPP). GSIS was markedly reduced, 50%, by glucose-6-phosphate dehydrogenase (G-6-PD) inhibition both in the absence and presence of nNOS inhibition. NO gas stimulated GSIS at low and inhibited at high NO concentrations. The stimulatory action was dependent on membrane thiol groups. In comparison, carbon monoxide (CO) exclusively potentiated GSIS. CO rather than NO stimulated islet cyclic GMP during GSIS. It is suggested that increased nNOS activity restrains GSIS, and that the alternative pathway along the PPP initially might involve as much as 50% of total GSIS. In the PPP, the acute insulin response is downregulated by a negative feedback effect executed by a marked upregulation of nNOS activity elicited from secreted insulin exciting insulin receptors at exocytotic sites of an nNOS-associated population of secretory granules.
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Affiliation(s)
- Ingmar Lundquist
- Department of Clinical Science, SUS, Division of Islet Cell Physiology, University of Lund, Malmö, Sweden
- Department of Experimental Medical Science, University of Lund, Lund, Sweden
| | - Israa Mohammed Al-Amily
- Department of Clinical Science, SUS, Division of Islet Cell Physiology, University of Lund, Malmö, Sweden
| | - Ragnar Henningsson
- Department of Experimental Medical Science, University of Lund, Lund, Sweden
| | - Albert Salehi
- Department of Clinical Science, SUS, Division of Islet Cell Physiology, University of Lund, Malmö, Sweden
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10
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Gojani EG, Wang B, Li D, Kovalchuk O, Kovalchuk I. Single and Combined Impact of Semaglutide, Tirzepatide, and Metformin on β-Cell Maintenance and Function Under High-Glucose-High-Lipid Conditions: A Comparative Study. Int J Mol Sci 2025; 26:421. [PMID: 39796271 PMCID: PMC11720205 DOI: 10.3390/ijms26010421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 12/31/2024] [Accepted: 01/04/2025] [Indexed: 01/30/2025] Open
Abstract
Type 2 diabetes (T2D), the most common form, is marked by insulin resistance and β-cell failure. β-cell dysfunction under high-glucose-high-lipid (HG-HL) conditions is a key contributor to the progression of T2D. This study evaluates the comparative effects of 10 nM semaglutide, 10 nM tirzepatide, and 1 mM metformin, both alone and in combination, on INS-1 β-cell maintenance and function under HG-HL conditions. INS-1 cells were pretreated for 2 h with single doses of metformin (1 mM), semaglutide (10 nM), tirzepatide (10 nM), or combinations of 1 mM metformin with either 10 nM semaglutide or 10 nM tirzepatide, followed by 48 h of HG-HL stimulation. The results indicate that combining 1 mM metformin with either 10 nM semaglutide or 10 nM tirzepatide significantly enhances the effects of 10 nM semaglutide and 10 nM tirzepatide on HG-HL-induced apoptosis and dysregulated cell cycle. Specifically, the combination treatments demonstrated superior restoration of glucose-stimulated insulin secretion (GSIS) functionality compared to 1 mM metformin, 10 nM semaglutide, and 10 nM tirzepatide.
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Affiliation(s)
| | | | | | | | - Igor Kovalchuk
- Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K 3M4, Canada; (E.G.G.); (B.W.); (D.L.); (O.K.)
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11
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Li Y, Yang Y, Sun Y, He L, Zhao L, Sun H, Chang X, Liang R, Wang S, Han X, Zhu Y. The miR-203/ZBTB20/MAFA Axis Orchestrates Pancreatic β-Cell Maturation and Identity During Weaning and Diabetes. Diabetes 2024; 73:1673-1686. [PMID: 39058664 DOI: 10.2337/db23-0604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 07/23/2024] [Indexed: 07/28/2024]
Abstract
Maturation of postnatal β-cells is regulated in a cell-autonomous manner, and metabolically stressed β-cells regress to an immature state, ensuring defective β-cell function and the onset of type 2 diabetes. The molecular mechanisms connecting the nutritional transition to β-cell maturation remain largely unknown. Here, we report a mature form of miRNA (miR-203)/ZBTB20/MAFA regulatory axis that mediates the β-cell maturation process. We show that the level of the mature form of miRNA (miR-203) in β-cells changes during the nutritional transition and that miR-203 inhibits β-cell maturation at the neonatal stage and under high-fat diet conditions. Using single-cell RNA sequencing, we demonstrated that miR-203 elevation promoted the transition of immature β-cells into CgBHi endocrine cells while suppressing gene expressions associated with β-cell maturation in a ZBTB20/MAFA-dependent manner. ZBTB20 is an authentic target of miR-203 and transcriptionally upregulates MAFA expression. Manipulating the miR-203/ZBTB20/MAFA axis may therefore offer a novel strategy for boosting functional β-cell numbers to alleviate diabetes. ARTICLE HIGHLIGHTS
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Affiliation(s)
- Yating Li
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yuqian Yang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yi Sun
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Lu He
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Lin Zhao
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Haoran Sun
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xiaoai Chang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Rui Liang
- Organ Transplant Center, Tianjin First Central Hospital, Nankai University, Tianjin, China
| | - Shusen Wang
- Organ Transplant Center, Tianjin First Central Hospital, Nankai University, Tianjin, China
| | - Xiao Han
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yunxia Zhu
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, China
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12
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Abu-Nejem R, Hannon TS. Insulin Dynamics and Pathophysiology in Youth-Onset Type 2 Diabetes. J Clin Endocrinol Metab 2024; 109:2411-2421. [PMID: 38963882 DOI: 10.1210/clinem/dgae463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Revised: 06/28/2024] [Accepted: 07/03/2024] [Indexed: 07/06/2024]
Abstract
Youth-onset type 2 diabetes (T2D) is increasing around the globe. The mounting disease burden of youth-onset T2D portends substantial consequences for the health outcomes of young people and for health care systems. The pathophysiology of this condition is characterized by insulin resistance and initial insulin hypersecretion ± an inherent insulin secretory defect, with progressive loss of stimulated insulin secretion leading to pancreatic β-cell failure. Research studies focusing on youth-onset T2D have illuminated key differences for youth- vs adult-onset T2D, with youth having more profound insulin resistance and quicker progression to loss of sufficient insulin secretion to maintain euglycemia. There is a need for therapies that are targeted to improve both insulin resistance and, importantly, maintain sufficient insulin secretory function over the lifespan in youth-onset T2D.
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Affiliation(s)
- Rozan Abu-Nejem
- Department of Pediatrics, Divisions of Pediatric Endocrinology and Diabetology and Pediatric Health Services Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Tamara S Hannon
- Department of Pediatrics, Divisions of Pediatric Endocrinology and Diabetology and Pediatric Health Services Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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13
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Hatanaka R, Taguchi A, Nagao Y, Yorimoto K, Takesato A, Masuda K, Ono T, Samukawa Y, Tanizawa Y, Ohta Y. The flavonoid Sudachitin regulates glucose metabolism via PDE inhibition. Heliyon 2024; 10:e35978. [PMID: 39224336 PMCID: PMC11367099 DOI: 10.1016/j.heliyon.2024.e35978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 07/22/2024] [Accepted: 08/07/2024] [Indexed: 09/04/2024] Open
Abstract
Sudachitin, a member of the flavonoid family, reportedly improves glucose metabolism after long-term administration, but details of the underlying mechanisms are unknown. We found that Sudachitin approximately doubles insulin secretion under high glucose concentrations in mouse pancreatic islets and MIN6 cells. When Sudachitin was orally administered to mice, early-phase insulin secretion was increased and a 30 % reduction in blood glucose levels was demonstrated 30 min after glucose loading. Insulin tolerance tests also showed Sudachitin to increase systemic insulin sensitivity. Additionally, we observed that Sudachitin raised intracellular cAMP levels in pancreatic islets. Phosphodiesterase (PDE) activity assays revealed Sudachitin to inhibit PDE activity and computer simulations predicted a high binding affinity between PDEs and Sudachitin. These findings suggest that Sudachitin enhances both insulin secretion and insulin sensitivity via an increase in intracellular cAMP resulting from PDE inhibition. These insights may facilitate understanding the mechanisms underlying the regulation of glucose metabolism by Sudachitin and other isoflavones.
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Affiliation(s)
- Ryoko Hatanaka
- Division of Endocrinology, Metabolism, Hematological Science and Therapeutics, Yamaguchi University, Graduate School of Medicine, 1-1-1, Minami Kogushi, Ube, 755-8505, Japan
| | - Akihiko Taguchi
- Division of Endocrinology, Metabolism, Hematological Science and Therapeutics, Yamaguchi University, Graduate School of Medicine, 1-1-1, Minami Kogushi, Ube, 755-8505, Japan
| | - Yuko Nagao
- Division of Endocrinology, Metabolism, Hematological Science and Therapeutics, Yamaguchi University, Graduate School of Medicine, 1-1-1, Minami Kogushi, Ube, 755-8505, Japan
| | - Kaito Yorimoto
- Division of Endocrinology, Metabolism, Hematological Science and Therapeutics, Yamaguchi University, Graduate School of Medicine, 1-1-1, Minami Kogushi, Ube, 755-8505, Japan
| | - Akari Takesato
- Division of Endocrinology, Metabolism, Hematological Science and Therapeutics, Yamaguchi University, Graduate School of Medicine, 1-1-1, Minami Kogushi, Ube, 755-8505, Japan
| | - Konosuke Masuda
- Division of Endocrinology, Metabolism, Hematological Science and Therapeutics, Yamaguchi University, Graduate School of Medicine, 1-1-1, Minami Kogushi, Ube, 755-8505, Japan
| | - Takao Ono
- Division of Endocrinology, Metabolism, Hematological Science and Therapeutics, Yamaguchi University, Graduate School of Medicine, 1-1-1, Minami Kogushi, Ube, 755-8505, Japan
| | - Yoshishige Samukawa
- Quality Assurance Headquarters, Taisho Pharmaceutical Co., Ltd., 3-24-1, Takada, Toshima-ku, Tokyo, 170-8633, Japan
| | - Yukio Tanizawa
- Yamaguchi University, 1677-1, Yoshida, Yamaguchi, 753-8511, Japan
| | - Yasuharu Ohta
- Division of Endocrinology, Metabolism, Hematological Science and Therapeutics, Yamaguchi University, Graduate School of Medicine, 1-1-1, Minami Kogushi, Ube, 755-8505, Japan
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14
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Rodríguez-Rivera NS, Barrera-Oviedo D. Exploring the Pathophysiology of ATP-Dependent Potassium Channels in Insulin Resistance. Int J Mol Sci 2024; 25:4079. [PMID: 38612888 PMCID: PMC11012456 DOI: 10.3390/ijms25074079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 03/15/2024] [Accepted: 03/29/2024] [Indexed: 04/14/2024] Open
Abstract
Ionic channels are present in eucaryotic plasma and intracellular membranes. They coordinate and control several functions. Potassium channels belong to the most diverse family of ionic channels that includes ATP-dependent potassium (KATP) channels in the potassium rectifier channel subfamily. These channels were initially described in heart muscle and then in other tissues such as pancreatic, skeletal muscle, brain, and vascular and non-vascular smooth muscle tissues. In pancreatic beta cells, KATP channels are primarily responsible for maintaining the membrane potential and for depolarization-mediated insulin release, and their decreased density and activity may be related to insulin resistance. KATP channels' relationship with insulin resistance is beginning to be explored in extra-pancreatic beta tissues like the skeletal muscle, where KATP channels are involved in insulin-dependent glucose recapture and their activation may lead to insulin resistance. In adipose tissues, KATP channels containing Kir6.2 protein subunits could be related to the increase in free fatty acids and insulin resistance; therefore, pathological processes that promote prolonged adipocyte KATP channel inhibition might lead to obesity due to insulin resistance. In the central nervous system, KATP channel activation can regulate peripheric glycemia and lead to brain insulin resistance, an early peripheral alteration that can lead to the development of pathologies such as obesity and Type 2 Diabetes Mellitus (T2DM). In this review, we aim to discuss the characteristics of KATP channels, their relationship with clinical disorders, and their mechanisms and potential associations with peripheral and central insulin resistance.
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Affiliation(s)
- Nidia Samara Rodríguez-Rivera
- Laboratorio de Farmacología y Bioquímica Clínica, Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico;
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15
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Li W, Li A, Yu B, Zhang X, Liu X, White KL, Stevens RC, Baumeister W, Sali A, Jasnin M, Sun L. In situ structure of actin remodeling during glucose-stimulated insulin secretion using cryo-electron tomography. Nat Commun 2024; 15:1311. [PMID: 38346988 PMCID: PMC10861521 DOI: 10.1038/s41467-024-45648-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 01/30/2024] [Indexed: 02/15/2024] Open
Abstract
Actin mediates insulin secretion in pancreatic β-cells through remodeling. Hampered by limited resolution, previous studies have offered an ambiguous depiction as depolymerization and repolymerization. We report the in situ structure of actin remodeling in INS-1E β-cells during glucose-stimulated insulin secretion at nanoscale resolution. After remodeling, the actin filament network at the cell periphery exhibits three marked differences: 12% of actin filaments reorient quasi-orthogonally to the ventral membrane; the filament network mainly remains as cell-stabilizing bundles but partially reconfigures into a less compact arrangement; actin filaments anchored to the ventral membrane reorganize from a "netlike" to a "blooming" architecture. Furthermore, the density of actin filaments and microtubules around insulin secretory granules decreases, while actin filaments and microtubules become more densely packed. The actin filament network after remodeling potentially precedes the transport and release of insulin secretory granules. These findings advance our understanding of actin remodeling and its role in glucose-stimulated insulin secretion.
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Affiliation(s)
- Weimin Li
- iHuman Institute, ShanghaiTech University, Shanghai, 201210, China
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
| | - Angdi Li
- iHuman Institute, ShanghaiTech University, Shanghai, 201210, China
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
| | - Bing Yu
- iHuman Institute, ShanghaiTech University, Shanghai, 201210, China
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
| | - Xiaoxiao Zhang
- iHuman Institute, ShanghaiTech University, Shanghai, 201210, China
| | - Xiaoyan Liu
- iHuman Institute, ShanghaiTech University, Shanghai, 201210, China
| | - Kate L White
- Department of Chemistry, Bridge Institute, USC Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA, 90089, USA
| | - Raymond C Stevens
- iHuman Institute, ShanghaiTech University, Shanghai, 201210, China
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
| | - Wolfgang Baumeister
- iHuman Institute, ShanghaiTech University, Shanghai, 201210, China.
- Department of Molecular Structural Biology, Max Planck Institute of Biochemistry, 82152, Martinsried, Germany.
| | - Andrej Sali
- Quantitative Biosciences Institute, University of California, San Francisco, San Francisco, CA, 94158, USA.
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, 94158, USA.
- Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, 94158, USA.
| | - Marion Jasnin
- Helmholtz Pioneer Campus, Helmholtz Zentrum München, 85764, Neuherberg, Germany.
- Department of Chemistry, Technical University of Munich, 85748, Garching, Germany.
| | - Liping Sun
- iHuman Institute, ShanghaiTech University, Shanghai, 201210, China.
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16
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Kal S, Mahata S, Jati S, Mahata SK. Mitochondrial-derived peptides: Antidiabetic functions and evolutionary perspectives. Peptides 2024; 172:171147. [PMID: 38160808 PMCID: PMC10838678 DOI: 10.1016/j.peptides.2023.171147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 12/27/2023] [Accepted: 12/27/2023] [Indexed: 01/03/2024]
Abstract
Mitochondrial-derived peptides (MDPs) are a novel class of bioactive microproteins encoded by short open-reading frames (sORF) in mitochondrial DNA (mtDNA). Currently, three types of MDPs have been identified: Humanin (HN), MOTS-c (Mitochondrial ORF within Twelve S rRNA type-c), and SHLP1-6 (small Humanin-like peptide, 1 to 6). The 12 S ribosomal RNA (MT-RNR1) gene harbors the sequence for MOTS-c, whereas HN and SHLP1-6 are encoded by the 16 S ribosomal RNA (MT-RNR2) gene. Special genetic codes are used in mtDNA as compared to nuclear DNA: (i) ATA and ATT are used as start codons in addition to the standard start codon ATG; (ii) AGA and AGG are used as stop codons instead of coding for arginine; (iii) the standard stop codon UGA is used to code for tryptophan. While HN, SHLP6, and MOTS-c are encoded by the H (heavy owing to high guanine + thymine base composition)-strand of the mtDNA, SHLP1-5 are encoded by the L (light owing to less guanine + thymine base composition)-strand. MDPs attenuate disease pathology including Type 1 diabetes (T1D), Type 2 diabetes (T2D), gestational diabetes, Alzheimer's disease (AD), cardiovascular diseases, prostate cancer, and macular degeneration. The current review will focus on the MDP regulation of T2D, T1D, and gestational diabetes along with an emphasis on the evolutionary pressures for conservation of the amino acid sequences of MDPs.
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Affiliation(s)
- Satadeepa Kal
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Sumana Mahata
- Department of Anesthesiology, Riverside University Health System, Moreno Valley, CA, USA
| | - Suborno Jati
- Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA, USA
| | - Sushil K Mahata
- Department of Medicine, University of California San Diego, La Jolla, CA, USA; VA San Diego Healthcare System, San Diego, CA, USA.
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17
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Kind L, Driver M, Raasakka A, Onck PR, Njølstad PR, Arnesen T, Kursula P. Structural properties of the HNF-1A transactivation domain. Front Mol Biosci 2023; 10:1249939. [PMID: 37908230 PMCID: PMC10613711 DOI: 10.3389/fmolb.2023.1249939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 09/26/2023] [Indexed: 11/02/2023] Open
Abstract
Hepatocyte nuclear factor 1α (HNF-1A) is a transcription factor with important gene regulatory roles in pancreatic β-cells. HNF1A gene variants are associated with a monogenic form of diabetes (HNF1A-MODY) or an increased risk for type 2 diabetes. While several pancreatic target genes of HNF-1A have been described, a lack of knowledge regarding the structure-function relationships in HNF-1A prohibits a detailed understanding of HNF-1A-mediated gene transcription, which is important for precision medicine and improved patient care. Therefore, we aimed to characterize the understudied transactivation domain (TAD) of HNF-1A in vitro. We present a bioinformatic approach to dissect the TAD sequence, analyzing protein structure, sequence composition, sequence conservation, and the existence of protein interaction motifs. Moreover, we developed the first protocol for the recombinant expression and purification of the HNF-1A TAD. Small-angle X-ray scattering and synchrotron radiation circular dichroism suggested a disordered conformation for the TAD. Furthermore, we present functional data on HNF-1A undergoing liquid-liquid phase separation, which is in line with in silico predictions and may be of biological relevance for gene transcriptional processes in pancreatic β-cells.
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Affiliation(s)
- Laura Kind
- Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Mark Driver
- Zernike Institute for Advanced Materials, University of Groningen, Groningen, Netherlands
| | - Arne Raasakka
- Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Patrick R. Onck
- Zernike Institute for Advanced Materials, University of Groningen, Groningen, Netherlands
| | - Pål Rasmus Njølstad
- Mohn Center for Diabetes Precision Medicine, Department of Clinical Science, University of Bergen, Bergen, Norway
- Section of Endocrinology and Metabolism, Children and Youth Clinic, Haukeland University Hospital, Bergen, Norway
| | - Thomas Arnesen
- Department of Biomedicine, University of Bergen, Bergen, Norway
- Department of Surgery, Haukeland University Hospital, Bergen, Norway
| | - Petri Kursula
- Department of Biomedicine, University of Bergen, Bergen, Norway
- Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, Oulu, Finland
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18
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Kabra UD, Jastroch M. Mitochondrial Dynamics and Insulin Secretion. Int J Mol Sci 2023; 24:13782. [PMID: 37762083 PMCID: PMC10530730 DOI: 10.3390/ijms241813782] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Revised: 08/30/2023] [Accepted: 09/04/2023] [Indexed: 09/29/2023] Open
Abstract
Mitochondria are involved in the regulation of cellular energy metabolism, calcium homeostasis, and apoptosis. For mitochondrial quality control, dynamic processes, such as mitochondrial fission and fusion, are necessary to maintain shape and function. Disturbances of mitochondrial dynamics lead to dysfunctional mitochondria, which contribute to the development and progression of numerous diseases, including Type 2 Diabetes (T2D). Compelling evidence has been put forward that mitochondrial dynamics play a significant role in the metabolism-secretion coupling of pancreatic β cells. The disruption of mitochondrial dynamics is linked to defects in energy production and increased apoptosis, ultimately impairing insulin secretion and β cell death. This review provides an overview of molecular mechanisms controlling mitochondrial dynamics, their dysfunction in pancreatic β cells, and pharmaceutical agents targeting mitochondrial dynamic proteins, such as mitochondrial division inhibitor-1 (mdivi-1), dynasore, P110, and 15-oxospiramilactone (S3).
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Affiliation(s)
- Uma D. Kabra
- Department of Pharmaceutical Chemistry, Parul Institute of Pharmacy, Parul University, Vadodara 391760, India;
| | - Martin Jastroch
- The Arrhenius Laboratories F3, Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, SE-106 91 Stockholm, Sweden
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19
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Davis JJ, Donohue MJ, Ogunkunle EO, Eaton WJ, Steyer DJ, Roper MG. Simultaneous monitoring of multiple hormones from human islets of Langerhans using solid-phase extraction-mass spectrometry. Anal Bioanal Chem 2023; 415:5671-5680. [PMID: 37442843 PMCID: PMC10528007 DOI: 10.1007/s00216-023-04837-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Accepted: 06/29/2023] [Indexed: 07/15/2023]
Abstract
Islets of Langerhans release peptide hormones in controlled amounts and patterns to ensure proper maintenance of blood glucose levels. The overall release of the hormones is shaped by external factors and by autocrine and paracrine interactions occurring within the islets. To better understand what controls the secretion of islet-secreted peptides, and how these processes go awry in diabetes, methods to monitor the release of multiple hormones simultaneously are needed. While antibody-based assays are typically used, they are most often applied to quantification of a single hormone. Mass spectrometry (MS), on the other hand, is well suited for quantifying multiple hormones simultaneously but typically requires time-consuming separation steps with biological samples. In this report, response surface methodology was used to identify a set of optimal solid-phase extraction (SPE) conditions for the islet-secreted peptides, insulin, C-peptide, glucagon, and somatostatin. The optimized SPE method was used with multiple reaction monitoring and isotopically labeled standards to quantify secretion levels. Calibrations were linear from 0.5 to 50 nM with < 15% RSD peak area ratios. A microfluidic system was used to perfuse 30 human islets with different glucose conditions, and fractions were collected every 2 min for SPE-MS analysis. Results showed the release dynamics of the individual peptides, as well as patterns, such as positively and negatively correlated release and oscillations. This rapid SPE-MS method is expected to be useful for examining other peptide and small-molecule secretions from islets and could be applied to a number of other biological systems for investigating cellular communication.
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Affiliation(s)
- Joshua J Davis
- Department of Chemistry and Biochemistry, Florida State University, 95 Chieftain Way, Tallahassee, FL, 32306, USA
| | - Matthew J Donohue
- Department of Chemistry and Biochemistry, Florida State University, 95 Chieftain Way, Tallahassee, FL, 32306, USA
| | - Emmanuel O Ogunkunle
- Department of Chemistry and Biochemistry, Florida State University, 95 Chieftain Way, Tallahassee, FL, 32306, USA
| | - Wesley J Eaton
- Department of Chemistry and Biochemistry, Florida State University, 95 Chieftain Way, Tallahassee, FL, 32306, USA
| | - Daniel J Steyer
- Department of Chemistry and Biochemistry, Florida State University, 95 Chieftain Way, Tallahassee, FL, 32306, USA
| | - Michael G Roper
- Department of Chemistry and Biochemistry, Florida State University, 95 Chieftain Way, Tallahassee, FL, 32306, USA.
- Program in Molecular Biophysics, Florida State University, 95 Chieftain Way, Tallahassee, FL, 32306, USA.
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20
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Buckels EJ, Tan J, Hsu H, Zhu Y, Buchanan CM, Matthews BG, Lee KL. Preptin Deficiency Does Not Protect against High-Fat Diet-Induced Metabolic Dysfunction or Bone Loss in Mice. JBMR Plus 2023; 7:e10777. [PMID: 37614298 PMCID: PMC10443080 DOI: 10.1002/jbm4.10777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 04/27/2023] [Accepted: 05/18/2023] [Indexed: 08/25/2023] Open
Abstract
Preptin is derived from the cleavage of the E-peptide of pro-insulin-like growth factor (IGF)-II and is an insulin secretagogue. Observational studies have linked elevated circulating preptin to metabolic dysfunction in humans; however, a causal role for preptin in metabolic dysfunction has not been established. Additionally, preptin can promote osteoblast proliferation and differentiation, suggesting a link with skeletal health. We previously described a global preptin knockout (KO) model. In this study, we sought to uncover the impact of preptin KO in mice on the response to a moderately high-fat diet (HFD) and low-fat diet (LFD). HFD groups had higher weight and fat mass gain, lower trabecular and cortical bone volume and fracture load, and higher liver triglycerides. In males, preptin deficiency led to lower blood glucose than wild-type (WT) mice under LFD conditions. This was accompanied by differences in bone microarchitecture, including lower trabecular bone volume fraction, trabecular number, and lower cortical thickness. These differences were absent in female mice, although KO females had a HFD-driven increase in fat mass and liver triglycerides that was absent in WT mice. Female WT mice had increased glucose-stimulated insulin secretion under HFD conditions that was absent in female KO mice. Overall, preptin may have a detrimental impact on metabolism and a positive impact on bone health in male mice and may protect against liver fat storage in females while enabling islet compensation under HFD conditions. When we consider that serum preptin levels are elevated in humans of both sexes in pathological states in which insulin levels are elevated, the impact of preptin on comorbidity risk needs to be better understood. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- Emma J. Buckels
- Department of Molecular Medicine and PathologyUniversity of AucklandAucklandNew Zealand
- Maurice Wilkins Centre for Molecular BiodiscoveryUniversity of AucklandAucklandNew Zealand
| | - Joey Tan
- Department of Molecular Medicine and PathologyUniversity of AucklandAucklandNew Zealand
| | - Huai‐Ling Hsu
- Department of Molecular Medicine and PathologyUniversity of AucklandAucklandNew Zealand
| | - Yuting Zhu
- Department of Engineering ScienceUniversity of AucklandAucklandNew Zealand
| | - Christina M. Buchanan
- Department of Molecular Medicine and PathologyUniversity of AucklandAucklandNew Zealand
| | - Brya G. Matthews
- Department of Molecular Medicine and PathologyUniversity of AucklandAucklandNew Zealand
- Maurice Wilkins Centre for Molecular BiodiscoveryUniversity of AucklandAucklandNew Zealand
| | - Kate L. Lee
- Department of Molecular Medicine and PathologyUniversity of AucklandAucklandNew Zealand
- Maurice Wilkins Centre for Molecular BiodiscoveryUniversity of AucklandAucklandNew Zealand
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21
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Thoduvayil S, Weerakkody JS, Sundaram RVK, Topper M, Bera M, Coleman J, Li X, Mariappan M, Ramakrishnan S. Rapid Quantification of First and Second Phase Insulin Secretion Dynamics using an In vitro Platform for Improving Insulin Therapy. Cell Calcium 2023; 113:102766. [PMID: 37295201 PMCID: PMC10450995 DOI: 10.1016/j.ceca.2023.102766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 06/01/2023] [Accepted: 06/02/2023] [Indexed: 06/12/2023]
Abstract
High-throughput quantification of the first- and second-phase insulin secretion dynamics is intractable with current methods. The fact that independent secretion phases play distinct roles in metabolism necessitates partitioning them separately and performing high-throughput compound screening to target them individually. We developed an insulin-nanoluc luciferase reporter system to dissect the molecular and cellular pathways involved in the separate phases of insulin secretion. We validated this method through genetic studies, including knockdown and overexpression, as well as small-molecule screening and their effects on insulin secretion. Furthermore, we demonstrated that the results of this method are well correlated with those of single-vesicle exocytosis experiments conducted on live cells, providing a quantitative reference for the approach. Thus, we have developed a robust methodology for screening small molecules and cellular pathways that target specific phases of insulin secretion, resulting in a better understanding of insulin secretion, which in turn will result in a more effective insulin therapy through the stimulation of endogenous glucose-stimulated insulin secretion.
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Affiliation(s)
- Sikha Thoduvayil
- Nanobiology Institute, Yale University School of Medicine, West Haven, CT, 06516 USA; Department of Pathology, Yale University School of Medicine, New Haven, CT, 06520 USA
| | - Jonathan S Weerakkody
- Nanobiology Institute, Yale University School of Medicine, West Haven, CT, 06516 USA; Department of Pathology, Yale University School of Medicine, New Haven, CT, 06520 USA
| | - Ramalingam Venkat Kalyana Sundaram
- Nanobiology Institute, Yale University School of Medicine, West Haven, CT, 06516 USA; Department of Cell Biology, Yale University School of Medicine, New Haven, CT, 06520 USA
| | - Mackenzie Topper
- Nanobiology Institute, Yale University School of Medicine, West Haven, CT, 06516 USA
| | - Manindra Bera
- Nanobiology Institute, Yale University School of Medicine, West Haven, CT, 06516 USA; Department of Cell Biology, Yale University School of Medicine, New Haven, CT, 06520 USA
| | - Jeff Coleman
- Nanobiology Institute, Yale University School of Medicine, West Haven, CT, 06516 USA; Department of Cell Biology, Yale University School of Medicine, New Haven, CT, 06520 USA
| | - Xia Li
- Nanobiology Institute, Yale University School of Medicine, West Haven, CT, 06516 USA; Department of Cell Biology, Yale University School of Medicine, New Haven, CT, 06520 USA
| | - Malaiyalam Mariappan
- Nanobiology Institute, Yale University School of Medicine, West Haven, CT, 06516 USA; Department of Cell Biology, Yale University School of Medicine, New Haven, CT, 06520 USA
| | - Sathish Ramakrishnan
- Nanobiology Institute, Yale University School of Medicine, West Haven, CT, 06516 USA; Department of Pathology, Yale University School of Medicine, New Haven, CT, 06520 USA.
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22
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Adeoye DI, Wang Y, Davis JJ, Roper MG. Automated cellular stimulation with integrated pneumatic valves and fluidic capacitors. Analyst 2023; 148:1227-1234. [PMID: 36786685 PMCID: PMC10023383 DOI: 10.1039/d2an01985j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/15/2023]
Abstract
Microfluidic technologies have proven to be a reliable tool in profiling dynamic insulin secretion from islets of Langerhans. Most of these systems rely on external pressure sources to induce flow, leading to difficulties moving to more elaborate systems. To reduce complexity, a microfluidic system was developed that used a single vacuum source at the outlet to drive fluidic transport of immunoassay reagents and stimulation solutions throughout the device. A downside to this approach is the lack of flow control over the reagents delivered to the islet chamber. To address this challenge, 4-layer pneumatic valves were integrated into the perfusion lines to automate and control the delivery of stimulants; however, it was found that as the valves closed, spikes in the flow would lead to abnormal insulin secretion profiles. Fluidic capacitors were then incorporated after the valves and found to remove the spikes. The combination of the valves and capacitors resulted in automated collection of insulin secretion profiles from single murine islets that were similar to those previously reported in the literature. In the future, these integrated fluidic components may enable more complex channel designs to be used with a relatively simple flow control solution.
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Affiliation(s)
- Damilola I Adeoye
- Department of Chemistry & Biochemistry, Florida State University, 95 Chieftain Way, Tallahassee, FL 32306, USA.
| | - Yao Wang
- Department of Chemistry & Biochemistry, Florida State University, 95 Chieftain Way, Tallahassee, FL 32306, USA.
| | - Joshua J Davis
- Department of Chemistry & Biochemistry, Florida State University, 95 Chieftain Way, Tallahassee, FL 32306, USA.
| | - Michael G Roper
- Department of Chemistry & Biochemistry, Florida State University, 95 Chieftain Way, Tallahassee, FL 32306, USA. .,Program in Molecular Biophysics, Florida State University, 95 Chieftain Way, Tallahassee, FL 32306, USA
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Rached G, Saliba Y, Maddah D, Hajal J, Smayra V, Bakhos J, Groschner K, Birnbaumer L, Fares N. TRPC3 Regulates Islet Beta-Cell Insulin Secretion. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2204846. [PMID: 36642838 PMCID: PMC9951314 DOI: 10.1002/advs.202204846] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 11/18/2022] [Indexed: 06/17/2023]
Abstract
Insulin release is tightly controlled by glucose-stimulated calcium (GSCa) through hitherto equivocal pathways. This study investigates TRPC3, a non-selective cation channel, as a critical regulator of insulin secretion and glucose control. TRPC3's involvement in glucose-stimulated insulin secretion (GSIS) is studied in human and animal islets. TRPC3-dependent in vivo insulin secretion is investigated using pharmacological tools and Trpc3-/- mice. TRPC3's involvement in islet glucose uptake and GSCa is explored using fluorescent glucose analogue 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-D-glucose and calcium imaging. TRPC3 modulation by a small-molecule activator, GSK1702934A, is evaluated in type 2 diabetic mice. TRPC3 is functionally expressed in human and mouse islet beta cells. TRPC3-controlled insulin secretion is KATP -independent and primarily mediated by diacylglycerol channel regulation of the cytosolic calcium oscillations following glucose stimulation. Conversely, glucose uptake in islets is independent of TRPC3. TRPC3 pharmacologic inhibition and knockout in mice lead to defective insulin secretion and glucose intolerance. Subsequently, TRPC3 activation through targeted small-molecule enhances insulin secretion and alleviates diabetes hallmarks in animals. This study imputes a function for TRPC3 at the onset of GSIS. These insights strengthen one's knowledge of insulin secretion physiology and set forth the TRPC3 channel as an appealing candidate for drug development in the treatment of diabetes.
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Affiliation(s)
- Gaëlle Rached
- Physiology and Pathophysiology Research LaboratoryPole of Technology and HealthFaculty of MedicineSaint Joseph University of BeirutPOBox. 17‐5208 ‐ Mar MikhaëlBeirut1104 2020Lebanon
| | - Youakim Saliba
- Physiology and Pathophysiology Research LaboratoryPole of Technology and HealthFaculty of MedicineSaint Joseph University of BeirutPOBox. 17‐5208 ‐ Mar MikhaëlBeirut1104 2020Lebanon
| | - Dina Maddah
- Physiology and Pathophysiology Research LaboratoryPole of Technology and HealthFaculty of MedicineSaint Joseph University of BeirutPOBox. 17‐5208 ‐ Mar MikhaëlBeirut1104 2020Lebanon
| | - Joelle Hajal
- Physiology and Pathophysiology Research LaboratoryPole of Technology and HealthFaculty of MedicineSaint Joseph University of BeirutPOBox. 17‐5208 ‐ Mar MikhaëlBeirut1104 2020Lebanon
| | - Viviane Smayra
- Faculty of MedicineSaint Joseph UniversitySaint Joseph University of BeirutPOBox. 17‐5208 ‐ Mar MikhaëlBeirut1104 2020Lebanon
| | - Jules‐Joel Bakhos
- Physiology and Pathophysiology Research LaboratoryPole of Technology and HealthFaculty of MedicineSaint Joseph University of BeirutPOBox. 17‐5208 ‐ Mar MikhaëlBeirut1104 2020Lebanon
| | - Klaus Groschner
- Gottfried‐Schatz‐Research‐Centre‐BiophysicsMedical University of GrazGraz8010Austria
| | - Lutz Birnbaumer
- School of Medical SciencesInstitute of Biomedical Research (BIOMED)Catholic University of ArgentinaBuenos AiresC1107AAZArgentina
- Signal Transduction LaboratoryNational Institute of Environmental Health SciencesResearch Triangle ParkDurhamNCC1107AAZUSA
| | - Nassim Fares
- Physiology and Pathophysiology Research LaboratoryPole of Technology and HealthFaculty of MedicineSaint Joseph University of BeirutPOBox. 17‐5208 ‐ Mar MikhaëlBeirut1104 2020Lebanon
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Fathi FEZM, Sadek KM, Khafaga AF, Al Senosy AW, Ghoniem HA, Fayez S, Zeweil MF. Vitamin D regulates insulin and ameliorates apoptosis and oxidative stress in pancreatic tissues of rats with streptozotocin-induced diabetes. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:90219-90229. [PMID: 35864405 PMCID: PMC9722851 DOI: 10.1007/s11356-022-22064-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 07/13/2022] [Indexed: 06/15/2023]
Abstract
This study was designed to evaluate the potential therapeutic efficacy of vitamin D (Vit D) in averting the harmful effects of type 2 diabetes mellitus (T2D). Forty male Wistar rats were allotted into four groups: (1) the control, (2) Vit D, (3) streptozotocin (STZ), and (4) STZ + Vit D groups. Rats co-treated with Vit D had significantly (p < 0.05) decreased levels of cortisol; proinflammatory cytokines, including interleukin-6 (IL-6); and malondialdehyde (MDA). Meanwhile, the levels of insulin significantly (p < 0.05) increased, whereas the activity of the antioxidant system, including glutathione (GSH), superoxide dismutase (SOD), catalase, and total antioxidant capacity (TAC), significantly (p < 0.05) decreased. Histopathological examination revealed the destruction of beta cells in the islets of Langerhans in rats with diabetes. Meanwhile, immunoexpression revealed an increase in the immunoreactivity of caspase-3 and endothelial nitric oxide synthase and a reduction in the immunoreactivity of insulin in rats with diabetes. In conclusion, Vit D ameliorated the harmful biochemical impact of diabetes mellitus, probably by increasing insulin secretion and sensitivity, ameliorating β-cell function, and decreasing cortisol levels; also, the anti-inflammatory effect of Vit D reduces the number of proinflammatory cytokines (e.g., IL-6) and increases the activity of the antioxidant system, such as GSH, SOD, TAC, and catalase while reducing lipid peroxidation enzymes (e.g., MDA).
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Affiliation(s)
- Fatima El Zahra M Fathi
- Department of Biochemistry, Faculty of Veterinary Medicine, Damanhur University, Damanhour, 22516, Egypt
| | - Kadry M Sadek
- Department of Biochemistry, Faculty of Veterinary Medicine, Damanhur University, Damanhour, 22516, Egypt
| | - Asmaa F Khafaga
- Department of Pathology, Faculty of Veterinary Medicine, Alexandria University, Edfina, 22758, Egypt.
| | - Abdel Wahab Al Senosy
- Department of Histology, Faculty of Veterinary Medicine, Damanhur University, Damanhour, 22516, Egypt
| | - Hanan A Ghoniem
- Department of Histology, Faculty of Veterinary Medicine, Damanhur University, Damanhour, 22516, Egypt
| | - Sahar Fayez
- Department of Histology, Faculty of Veterinary Medicine, Damanhur University, Damanhour, 22516, Egypt
| | - Mohamed F Zeweil
- Department of Biochemistry, Faculty of Veterinary Medicine, Damanhur University, Damanhour, 22516, Egypt
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25
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Buckels EJ, Hsu HL, Buchanan CM, Matthews BG, Lee KL. Genetic ablation of the preptin-coding portion of Igf2 impairs pancreatic function in female mice. Am J Physiol Endocrinol Metab 2022; 323:E467-E479. [PMID: 36459047 DOI: 10.1152/ajpendo.00401.2021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Preptin is a 34-amino acid peptide derived from the E-peptide of pro-insulin-like growth factor 2 and is co-secreted with insulin from β-cells. Little is understood about the effects of endogenous preptin on whole body glucose metabolism. We developed a novel mouse model in which the preptin portion of Igf2 was genetically ablated in all tissues, hereafter referred to as preptin knockout (KO), and tested the hypothesis that the removal of preptin will lead to a decreased insulin response to a metabolic challenge. Preptin KO and wild-type (WT) mice underwent weekly fasting blood glucose measurements, intraperitoneal insulin tolerance tests (ITT) at 9, 29, and 44 wk of age, and an oral glucose tolerance test (GTT) at 45 wk of age. Preptin KO mice of both sexes had similar Igf2 exon 2-3 mRNA expression in the liver and kidney compared with WT mice, but Igf2 exon 3-4 (preptin) expression was not detectable. Western blot analysis of neonatal serum indicated that processing of pro-IGF2 translated from the KO allele may be altered. Preptin KO mice had similar body weight, body composition, β-cell area, and fasted glucose concentrations compared with WT mice in both sexes up to 47 wk of age. Female KO mice had a diminished ability to mount an insulin response following glucose stimulation in vivo. This effect was absent in male KO mice. Although preptin is not essential for glucose homeostasis, when combined with previous in vitro and ex vivo findings, these data show that preptin positively impacts β-cell function.NEW & NOTEWORTHY This is the first study to describe a model in which the preptin-coding portion of the Igf2 gene has been genetically ablated in mice. The mice do not show reduced size at birth associated with Igf2 knockout suggesting that IGF2 functionality is maintained, yet we demonstrate a change in the processing of mature Igf2. Female knockout mice have diminished glucose-stimulated insulin secretion, whereas the insulin response in males is not different to wild type.
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Affiliation(s)
- E J Buckels
- Department of Molecular Medicine and Pathology, University of Auckland, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, New Zealand
| | - H-L Hsu
- Department of Molecular Medicine and Pathology, University of Auckland, New Zealand
| | - C M Buchanan
- Department of Molecular Medicine and Pathology, University of Auckland, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, New Zealand
| | - B G Matthews
- Department of Molecular Medicine and Pathology, University of Auckland, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, New Zealand
| | - K L Lee
- Department of Molecular Medicine and Pathology, University of Auckland, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, New Zealand
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26
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Boutari C, Pappas PD, Theodoridis TD, Vavilis D. Humanin and diabetes mellitus: A review of in vitro and in vivo studies. World J Diabetes 2022; 13:213-223. [PMID: 35432758 PMCID: PMC8984571 DOI: 10.4239/wjd.v13.i3.213] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 10/24/2021] [Accepted: 02/23/2022] [Indexed: 02/06/2023] Open
Abstract
Humanin (HN) is a 24-amino acid mitochondrial-derived polypeptide with cyto-protective and anti-apoptotic effects that regulates the mitochondrial functions under stress conditions. Accumulating evidence suggests the role of HN against age-related diseases, such as Alzheimer’s disease. The decline in insulin action is a metabolic feature of aging and thus, type 2 diabetes mellitus is considered an age-related disease, as well. It has been suggested that HN increases insulin sensitivity, improves the survival of pancreatic beta cells, and delays the onset of diabetes, actions that could be deployed in the treatment of diabetes. The aim of this review is to present the in vitro and in vivo studies that examined the role of HN in insulin resistance and diabetes and to discuss its newly emerging role as a therapeutic option against those conditions.
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Affiliation(s)
- Chrysoula Boutari
- Second Propedeutic Department of Internal Medicine, Hippocration Hospital, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Panagiotis D Pappas
- First Department of Obstetrics and Gynaecology, Papageorgiou Hospital, Aristotle University of Thessaloniki, Thessaloniki 56429, Greece
| | - Theodoros D Theodoridis
- First Department of Obstetrics and Gynaecology, Papageorgiou Hospital, Aristotle University of Thessaloniki, Thessaloniki 56429, Greece
| | - Dimitrios Vavilis
- First Department of Obstetrics and Gynaecology, Papageorgiou Hospital, Aristotle University of Thessaloniki, Thessaloniki 56429, Greece
- Medical School, University of Cyprus, Nicosia, Cyprus 20537 1678, Cyprus
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27
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Singh A, Kukreti R, Saso L, Kukreti S. Mechanistic Insight into Oxidative Stress-Triggered Signaling Pathways and Type 2 Diabetes. Molecules 2022; 27:950. [PMID: 35164215 PMCID: PMC8840622 DOI: 10.3390/molecules27030950] [Citation(s) in RCA: 142] [Impact Index Per Article: 47.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 01/20/2022] [Accepted: 01/26/2022] [Indexed: 02/07/2023] Open
Abstract
Oxidative stress (OS) is a metabolic dysfunction mediated by the imbalance between the biochemical processes leading to elevated production of reactive oxygen species (ROS) and the antioxidant defense system of the body. It has a ubiquitous role in the development of numerous noncommunicable maladies including cardiovascular diseases, cancers, neurodegenerative diseases, aging and respiratory diseases. Diseases associated with metabolic dysfunction may be influenced by changes in the redox balance. Lately, there has been increasing awareness and evidence that diabetes mellitus (DM), particularly type 2 diabetes, is significantly modulated by oxidative stress. DM is a state of impaired metabolism characterized by hyperglycemia, resulting from defects in insulin secretion or action, or both. ROS such as hydrogen peroxide and the superoxide anion introduce chemical changes virtually in all cellular components, causing deleterious effects on the islets of β-cells, in turn affecting insulin production. Under hyperglycemic conditions, various signaling pathways such as nuclear factor-κβ (NF-κβ) and protein kinase C (PKC) are also activated by ROS. All of these can be linked to a hindrance in insulin signaling pathways, leading to insulin resistance. Hyperglycemia-induced oxidative stress plays a substantial role in complications including diabetic nephropathy. DM patients are more prone to microvascular as well as atherosclerotic macrovascular diseases. This systemic disease affects most countries around the world, owing to population explosion, aging, urbanization, obesity, lifestyle, etc. However, some modulators, with their free radical scavenging properties, can play a prospective role in overcoming the debilitating effects of OS. This review is a modest approach to summarizing the basics and interlinkages of oxidative stress, its modulators and diabetes mellitus. It may add to the understanding of and insight into the pathophysiology of diabetes and the crucial role of antioxidants to weaken the complications and morbidity resulting from this chronic disease.
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Affiliation(s)
- Anju Singh
- Nucleic Acids Research Lab, Department of Chemistry, University of Delhi (North Campus), Delhi 110007, India;
- Department of Chemistry, Ramjas College, University of Delhi, Delhi 110007, India
| | - Ritushree Kukreti
- Genomics and Molecular Medicine Unit, CSIR-Institute of Genomics and Integrative Biology (IGIB), Mall Road, Delhi 110007, India;
| | - Luciano Saso
- Department of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy;
| | - Shrikant Kukreti
- Nucleic Acids Research Lab, Department of Chemistry, University of Delhi (North Campus), Delhi 110007, India;
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Lim LY, Ching C, Kong D, Chan SY, Teo AKK. Generating pancreatic beta-like cells from human pluripotent stem cells. Methods Cell Biol 2022; 170:127-146. [DOI: 10.1016/bs.mcb.2022.02.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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Saleh M, Mohamed NA, Sehrawat A, Zhang T, Thomas M, Wang Y, Kalsi R, Molitoris J, Prasadan K, Gittes GK. β-cell Smad2 null mice have improved β-cell function and are protected from diet-induced hyperglycemia. J Biol Chem 2021; 297:101235. [PMID: 34582892 PMCID: PMC8605249 DOI: 10.1016/j.jbc.2021.101235] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 09/15/2021] [Accepted: 09/21/2021] [Indexed: 11/25/2022] Open
Abstract
Understanding signaling pathways that regulate pancreatic β-cell function to produce, store, and release insulin, as well as pathways that control β-cell proliferation, is vital to find new treatments for diabetes mellitus. Transforming growth factor-beta (TGF-β) signaling is involved in a broad range of β-cell functions. The canonical TGF-β signaling pathway functions through intracellular smads, including smad2 and smad3, to regulate cell development, proliferation, differentiation, and function in many organs. Here, we demonstrate the role of TGF-β/smad2 signaling in regulating mature β-cell proliferation and function using β-cell-specific smad2 null mutant mice. β-cell-specific smad2-deficient mice exhibited improved glucose clearance as demonstrated by glucose tolerance testing, enhanced in vivo and ex vivo glucose-stimulated insulin secretion, and increased β-cell mass and proliferation. Furthermore, when these mice were fed a high-fat diet to induce hyperglycemia, they again showed improved glucose tolerance, insulin secretion, and insulin sensitivity. In addition, ex vivo analysis of smad2-deficient islets showed that they displayed increased glucose-stimulated insulin secretion and upregulation of genes involved in insulin synthesis and insulin secretion. Thus, we conclude that smad2 could represent an attractive therapeutic target for type 2 diabetes mellitus.
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Affiliation(s)
- Mohamed Saleh
- Division of Pediatric Surgery, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA; Division of Pediatric Endocrinology, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Nada A Mohamed
- Division of Pediatric Surgery, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Anuradha Sehrawat
- Division of Pediatric Surgery, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Ting Zhang
- Division of Pediatric Surgery, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Madison Thomas
- Division of Pediatric Surgery, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Yan Wang
- Division of Pediatric Surgery, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Ranjeet Kalsi
- Division of Pediatric Surgery, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Justin Molitoris
- Division of Pediatric Surgery, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Krishna Prasadan
- Division of Pediatric Surgery, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - George K Gittes
- Division of Pediatric Surgery, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.
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Yu S, Meng S, Xiang M, Ma H. Phosphoenolpyruvate carboxykinase in cell metabolism: Roles and mechanisms beyond gluconeogenesis. Mol Metab 2021; 53:101257. [PMID: 34020084 PMCID: PMC8190478 DOI: 10.1016/j.molmet.2021.101257] [Citation(s) in RCA: 125] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Revised: 05/12/2021] [Accepted: 05/13/2021] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND Phosphoenolpyruvate carboxykinase (PCK) has been almost exclusively recognized as a critical enzyme in gluconeogenesis, especially in the liver and kidney. Accumulating evidence has shown that the enhanced activity of PCK leads to increased glucose output and exacerbation of diabetes, whereas the defects of PCK result in lethal hypoglycemia. Genetic mutations or polymorphisms are reported to be related to the onset and progression of diabetes in humans. SCOPE OF REVIEW Recent studies revealed that the PCK pathway is more complex than just gluconeogenesis, depending on the health or disease condition. Dysregulation of PCK may contribute to the development of obesity, cardiac hypertrophy, stroke, and cancer. Moreover, a regulatory network with multiple layers, from epigenetic regulation, transcription regulation, to posttranscription regulation, precisely tunes the expression of PCK. Deciphering the molecular basis that regulates PCK may pave the way for developing practical strategies to treat metabolic dysfunction. MAJOR CONCLUSIONS In this review, we summarize the metabolic and non-metabolic roles of the PCK enzyme in cells, especially beyond gluconeogenesis. We highlight the distinct functions of PCK isoforms (PCK1 and PCK2), depict a detailed network regulating PCK's expression, and discuss its clinical relevance. We also discuss the therapeutic potential targeting PCK and the future direction that is highly in need to better understand PCK-mediated signaling under diverse conditions.
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Affiliation(s)
- Shuo Yu
- Anesthesiology Department, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China
| | - Simin Meng
- Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China
| | - Meixiang Xiang
- Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China.
| | - Hong Ma
- Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China.
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Hyun J, Park MH, Lee YH, Lee Y, Jeong SJ, Choi SS, Khim KW, Eom HJ, Hur JH, Park CY, Kim JI, Park J, Ryu HW, Jang HJ, Oh SR, Choi JH. Vernicia fordii (Hemsl.) Airy Shaw extract stimulates insulin secretion in pancreatic β-cells and improves insulin sensitivity in diabetic mice. JOURNAL OF ETHNOPHARMACOLOGY 2021; 278:114238. [PMID: 34048878 DOI: 10.1016/j.jep.2021.114238] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 04/15/2021] [Accepted: 05/21/2021] [Indexed: 06/12/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Vernicia fordii (Hemsl.) Airy Shaw (V. fordii) is also known as the tung tree and its leaves and fruit are used as an oriental treatment for dyspepsia, edema, and skin diseases, which are known as diabetic complications. AIM OF THE STUDY In this study, we aimed to investigate the methanolic extract (VF5) of the leaves of V. fordii as an insulin secretagogue and its probable mechanism and verify the effect in HFD-fed mice. MATERIALS AND METHODS The insulin secretagogue activity of different doses of VF5 (0.1, 0.3 and 1.0 μg/ml) was assessed using in vitro insulin secretion assay and confirmed the anti-diabetic effect in mice fed HFD for 4 weeks with different doses of VF5 (10, 20 and 50 mg/kg oral) for another 6 weeks. Glbenclamide (30 mg/kg, oral) was used as positive control drug. The possible mechanisms were evaluated by using Gö6983 (10 μM), U73122 (10 μM) and nifedipine (10 μM). The major constituents of VF5 were analyzed by UPLC-QToF-MS and 1H and 13C NMR spectroscopy. RESULTS UPLC-QToF-MS and NMR spectroscopy analysis indicated that one of the main active components of VF5 was tigliane-diterpene esters. VF5 functioned as an insulin secretagogue and enhanced mitochondria respiration and insulin homeostasis. We confirmed that VF5 preserved the β-cell and reduced the β-cell expansion which caused by metabolic stress under HFD. The antidiabetic role of VF5 in HFD fed mice was assessed by glucose tolerance test (GTT) and insulin tolerance test (ITT), fasting plasma insulin level, fasting blood glucose level, AKT signal in peripheral tissue in the absence of toxic effects. Mechanistically, insulinotropic effect of VF5 was mediated by activation of PKCα via intracellular Ca2+ influx and enhanced mitochondria function. CONCLUSION VF5 exhibits potent insulin secretagogue function and improves insulin sensitivity and protection of pancreatic β-cells from metabolic stress without toxicity. Taken together, our study suggests that VF5 could be potentially used for treating diabetes and metabolic diseases through improving β-cell function.
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Affiliation(s)
- Jimin Hyun
- Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, 44919, Republic of Korea
| | - Mi Hyeon Park
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheong-ju Si, Chungcheongbuk-do, 28116, Republic of Korea
| | - Yo Han Lee
- Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, 44919, Republic of Korea
| | - Youngeun Lee
- Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, 44919, Republic of Korea
| | - Su Ji Jeong
- Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, 44919, Republic of Korea
| | - Sun Sil Choi
- Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, 44919, Republic of Korea
| | - Keon Woo Khim
- Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, 44919, Republic of Korea
| | - Hye Jin Eom
- Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, 44919, Republic of Korea
| | - Jin-Hoe Hur
- UNIST-Optical Biomed Imaging Center (UOBC), UNIST, Ulsan, 44919, Republic of Korea
| | - Chan Young Park
- Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, 44919, Republic of Korea
| | - Jae-Ick Kim
- Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, 44919, Republic of Korea
| | - Jiyoung Park
- Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, 44919, Republic of Korea
| | - Hyung Won Ryu
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheong-ju Si, Chungcheongbuk-do, 28116, Republic of Korea
| | - Hyun-Jun Jang
- Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, 44919, Republic of Korea.
| | - Sei-Ryang Oh
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheong-ju Si, Chungcheongbuk-do, 28116, Republic of Korea.
| | - Jang Hyun Choi
- Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, 44919, Republic of Korea.
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Ochoa-Guzmán A, Guillén-Quintero D, Muñoz-Hernández L, García A, Díaz-Díaz E, Pérez-Méndez O, Rodríguez-Guillén R, Mitre-Aguilar IB, Zentella-Dehesa A, Aguilar-Salinas CA, Tusié-Luna MT. The influence of high-density lipoprotein (HDL) and HDL subfractions on insulin secretion and cholesterol efflux in pancreatic derived β-cells. J Endocrinol Invest 2021; 44:1897-1904. [PMID: 33486704 DOI: 10.1007/s40618-021-01504-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Accepted: 01/08/2021] [Indexed: 10/22/2022]
Abstract
BACKGROUND High-density lipoprotein (HDL) is considered a complex plasma-circulating particle with subfractions that vary in function, size, and chemical composition. We sought to test the effects of HDL, and HDL subfractions on insulin secretion and cholesterol efflux in the β-cell line MIN-6. METHODS We used total HDL and HDL subfractions 2a, 2b, 3a, 3b, and 3c, isolated from human plasma, to test insulin secretion under different glucose concentrations as well as insulin content and cholesterol efflux in the insulinoma MIN-6 cell line. RESULTS Incubation of MIN-6 cells with low glucose and total HDL increased insulin release two-fold. Meanwhile, when high glucose and HDL were used, insulin release increased more than five times. HDL subfractions 2a, 2b, 3a, 3b, and 3c elicited higher insulin secretion and cholesterol efflux than their respective controls, at both low and high glucose concentrations. The insulin content of the MIN-6 cells incubated with low glucose and any of the five HDL subclasses had a modest reduction compared with their controls. However, there were no statistically significant differences between each HDL subfraction on their capacity of eliciting insulin secretion, insulin content, or cholesterol efflux. CONCLUSIONS HDL can trigger insulin secretion under low, normal, and high glucose conditions. We found that all HDL subfractions exhibit very similar capacity to increase insulin secretion and cholesterol efflux. This is the first report demonstrating that HDL subfractions act both as insulin secretagogues (under low glucose) and insulin secretion enhancers (under high glucose) in the MIN-6 cell line.
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Affiliation(s)
- A Ochoa-Guzmán
- Unit of Molecular Biology and Genomic Medicine, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga #15, Tlalpan, Belisario Domínguez Sección XVI, P.C. 14080, Mexico City, Mexico
| | - D Guillén-Quintero
- Unit of Molecular Biology and Genomic Medicine, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga #15, Tlalpan, Belisario Domínguez Sección XVI, P.C. 14080, Mexico City, Mexico
| | - L Muñoz-Hernández
- Research Unit on Metabolic Diseases, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - A García
- Unit of Biochemistry Dr. Guillermo Soberón Acevedo, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - E Díaz-Díaz
- Department of Reproductive Biology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - O Pérez-Méndez
- Department of Molecular Biology, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
- School of Engineering and Sciences, Tecnológico de Monterrey, Campus CDMX, Mexico City, Mexico
| | - R Rodríguez-Guillén
- Unit of Molecular Biology and Genomic Medicine, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga #15, Tlalpan, Belisario Domínguez Sección XVI, P.C. 14080, Mexico City, Mexico
| | - I B Mitre-Aguilar
- Unit of Biochemistry Dr. Guillermo Soberón Acevedo, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - A Zentella-Dehesa
- Unit of Biochemistry Dr. Guillermo Soberón Acevedo, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
- Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - C A Aguilar-Salinas
- Research Unit on Metabolic Diseases, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
- Division of Nutrition, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
- Departamento de Endocrinología y Metabolismo, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
- Tecnológico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, NL, Mexico
| | - M T Tusié-Luna
- Unit of Molecular Biology and Genomic Medicine, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga #15, Tlalpan, Belisario Domínguez Sección XVI, P.C. 14080, Mexico City, Mexico.
- Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico.
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Chen Y, He M, Lei MML, Ko WKW, Lin C, Bian Z, Wong AOL. Mouse Spexin: (III) Differential Regulation by Glucose and Insulin in Glandular Stomach and Functional Implication in Feeding Control. Front Endocrinol (Lausanne) 2021; 12:681648. [PMID: 34025589 PMCID: PMC8138665 DOI: 10.3389/fendo.2021.681648] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 04/19/2021] [Indexed: 11/24/2022] Open
Abstract
Spexin (SPX), a neuropeptide with diverse functions, is a novel satiety factor in fish models and its role in feeding control has been recently confirmed in mammals. In mouse, food intake was shown to trigger SPX expression in glandular stomach with parallel rise in serum SPX and these SPX signals could inhibit feeding via central actions within the hypothalamus. However, the mechanisms for SPX regulation by food intake are still unclear. To examine the role of insulin signal caused by glucose uptake in SPX regulation, the mice were IP injected with glucose and insulin, respectively. In this case, serum SPX was elevated by glucose but not altered by insulin. Meanwhile, SPX transcript expression in the glandular stomach was up-regulated by glucose but the opposite was true for insulin treatment. Using in situ hybridization, the differential effects on SPX gene expression were located in the gastric mucosa of glandular stomach. Co-injection experiments also revealed that glucose stimulation on serum SPX and SPX mRNA expressed in glandular stomach could be blocked by insulin. In gastric mucosal cells prepared from glandular stomach, the opposite effects on SPX transcript expression by glucose and insulin could still be noted with similar blockade of the stimulatory effects of glucose by insulin. In this cell model, SPX gene expression induced by glucose was mediated by glucose uptake via GLUT, ATP synthesis by glycolysis/respiratory chain, and subsequent modulation of KATP channel activity, but the voltage-sensitive Ca2+ channels were not involved. The corresponding inhibition by insulin, however, was mediated by PI3K/Akt, MEK1/2/ERK1/2, and P38MAPK cascades coupled to insulin receptor but not IGF-1 receptor. Apparently, glucose uptake in mice can induce SPX expression in the glandular stomach through ATP synthesis via glucose metabolism and subsequent modification of KATP channel activity, which may contribute to SPX release into circulation to act as the satiety signal after food intake. The insulin rise caused by glucose uptake, presumably originated from the pancreas, may serve as a negative feedback to inhibit the SPX response by activating MAPK and PI3K/Akt pathways in the stomach.
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Affiliation(s)
- Yuan Chen
- School of Biological Sciences, The University of Hong Kong, Hong Kong, Hong Kong
| | - Mulan He
- School of Biological Sciences, The University of Hong Kong, Hong Kong, Hong Kong
| | - Martina M. L. Lei
- School of Biological Sciences, The University of Hong Kong, Hong Kong, Hong Kong
| | - Wendy K. W. Ko
- School of Biological Sciences, The University of Hong Kong, Hong Kong, Hong Kong
| | - Chengyuan Lin
- School of Biological Sciences, The University of Hong Kong, Hong Kong, Hong Kong
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, Hong Kong
| | - Zhaoxiang Bian
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, Hong Kong
| | - Anderson O. L. Wong
- School of Biological Sciences, The University of Hong Kong, Hong Kong, Hong Kong
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Guzmán TJ, Gurrola-Díaz CM. Glucokinase activation as antidiabetic therapy: effect of nutraceuticals and phytochemicals on glucokinase gene expression and enzymatic activity. Arch Physiol Biochem 2021; 127:182-193. [PMID: 31210550 DOI: 10.1080/13813455.2019.1627458] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Diabetes represents an important public health problem. Recently, new molecular targets have been identified and exploited to treat this disease. Due to its pivotal role in glucose homeostasis, glucokinase (GCK) is a promising target for the development of novel antidiabetic drugs; however, pharmacological agents that modulate GCK activity have been linked to undesirable side-effects, limiting its use. Interestingly, plants might be a valuable source of new therapeutic compounds with GCK-activating properties and presumably no adverse effects. In this review, we describe biochemical characteristics related to the physiological and pathological importance of GCK, as well as the mechanisms involved in its regulation at different molecular levels. Posteriorly, we present a compendium of findings supporting the potential use of nutraceuticals and phytochemicals in the management of diabetes through modulation of GCK expression and activity. Finally, we propose critical aspects to keep in mind when designing experiments to evaluate GCK modulation properly.
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Affiliation(s)
- Tereso J Guzmán
- Departamento de Biología Molecular y Genómica, Instituto Transdisciplinar de Investigación e Innovación en Salud/Instituto de Investigación en Enfermedades Crónico-Degenerativas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco, México
| | - Carmen M Gurrola-Díaz
- Departamento de Biología Molecular y Genómica, Instituto Transdisciplinar de Investigación e Innovación en Salud/Instituto de Investigación en Enfermedades Crónico-Degenerativas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco, México
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Ježek P, Holendová B, Jabůrek M, Tauber J, Dlasková A, Plecitá-Hlavatá L. The Pancreatic β-Cell: The Perfect Redox System. Antioxidants (Basel) 2021; 10:antiox10020197. [PMID: 33572903 PMCID: PMC7912581 DOI: 10.3390/antiox10020197] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 01/20/2021] [Accepted: 01/25/2021] [Indexed: 12/12/2022] Open
Abstract
Pancreatic β-cell insulin secretion, which responds to various secretagogues and hormonal regulations, is reviewed here, emphasizing the fundamental redox signaling by NADPH oxidase 4- (NOX4-) mediated H2O2 production for glucose-stimulated insulin secretion (GSIS). There is a logical summation that integrates both metabolic plus redox homeostasis because the ATP-sensitive K+ channel (KATP) can only be closed when both ATP and H2O2 are elevated. Otherwise ATP would block KATP, while H2O2 would activate any of the redox-sensitive nonspecific calcium channels (NSCCs), such as TRPM2. Notably, a 100%-closed KATP ensemble is insufficient to reach the -50 mV threshold plasma membrane depolarization required for the activation of voltage-dependent Ca2+ channels. Open synergic NSCCs or Cl- channels have to act simultaneously to reach this threshold. The resulting intermittent cytosolic Ca2+-increases lead to the pulsatile exocytosis of insulin granule vesicles (IGVs). The incretin (e.g., GLP-1) amplification of GSIS stems from receptor signaling leading to activating the phosphorylation of TRPM channels and effects on other channels to intensify integral Ca2+-influx (fortified by endoplasmic reticulum Ca2+). ATP plus H2O2 are also required for branched-chain ketoacids (BCKAs); and partly for fatty acids (FAs) to secrete insulin, while BCKA or FA β-oxidation provide redox signaling from mitochondria, which proceeds by H2O2 diffusion or hypothetical SH relay via peroxiredoxin "redox kiss" to target proteins.
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Abstract
Anaplerosis and the associated mitochondrial metabolite transporters generate unique cytosolic metabolic signaling molecules that can regulate insulin release from pancreatic β-cells. It has been shown that mitochondrial metabolites, transported by the citrate carrier (CIC), dicarboxylate carrier (DIC), oxoglutarate carrier (OGC), and mitochondrial pyruvate carrier (MPC) play a vital role in the regulation of glucose-stimulated insulin secretion (GSIS). Metabolomic studies on static and biphasic insulin secretion, suggests that several anaplerotic derived metabolites, including α-ketoglutarate (αKG), are strongly associated with nutrient regulated insulin secretion. Support for a role of αKG in the regulation of insulin secretion comes from studies looking at αKG dependent enzymes, including hypoxia-inducible factor-prolyl hydroxylases (PHDs) in clonal β-cells, and rodent and human islets. This review will focus on the possible link between defective anaplerotic-derived αKG, PHDs, and the development of type 2 diabetes (T2D).
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Affiliation(s)
- M. Hoang
- School of Pharmacy, University of Waterloo, Kitchener, Ontario, Canada
| | - J. W. Joseph
- School of Pharmacy, University of Waterloo, Kitchener, Ontario, Canada
- CONTACT J. W. Joseph School of Pharmacy, University of Waterloo, Kitchener, ONN2G1C5, Canada
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Aghelan Z, Kiani S, Nasiri A, Sadeghi M, Farrokhi A, Khodarahmi R. Factors Influencing Mitochondrial Function as a Key Mediator of Glucose-Induced Insulin Release: Highlighting Nicotinamide Nucleotide Transhydrogenase. INTERNATIONAL JOURNAL OF MOLECULAR AND CELLULAR MEDICINE 2020; 9:107-122. [PMID: 32934948 PMCID: PMC7489113 DOI: 10.22088/ijmcm.bums.9.2.107] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Accepted: 08/04/2020] [Indexed: 12/13/2022]
Abstract
Pancreatic β-cells recognize blood glucose changes and release insulin that is a peptide hormone responsible for stable glycemia. Diabetes, a chronic disorder of insulin insufficiency, leads to disturbed glucose homeostasis and multi-organ problems. Glucose and insulin are key markers in the follow-up and control of this disease. Mitochondrial metabolism of pancreatic beta cells is a crucial part of glucose-stimulated cascade of insulin secretion. Effective factors on β-cells mitochondrial function in production of compounds such as tricarboxylic acid intermediates, glutamate, nicotinamide adenine dinucleotide phosphate, and reactive oxygen species can have great effects on the secretion of insulin under diabetes. This review enhances our knowledge of factors influencing mitochondrial function as a key mediator of glucose-induced insulin release that accordingly will be helpful to further our understanding of the mechanisms implicated in the progressive beta cell failure that results in diabetes.
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Affiliation(s)
- Zahra Aghelan
- Department of Clinical Biochemistry, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Sara Kiani
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Abolfazl Nasiri
- Department of Clinical Biochemistry, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Masoud Sadeghi
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Alireza Farrokhi
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Reza Khodarahmi
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
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Bakhtiyari A, Haghani K, Bakhtiyari S, Zaimy MA, Noori-Zadeh A, Gheysarzadeh A, Darabi S, Seidkhani-Nahal A, Amraei M, Alipourfard I. Association between ABCC8 Ala1369Ser Polymorphism (rs757110 T/G) and Type 2 Diabetes Risk in an Iranian Population: A Case-Control Study. Endocr Metab Immune Disord Drug Targets 2020; 21:441-447. [PMID: 32660410 DOI: 10.2174/1871530320666200713091827] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 05/20/2020] [Accepted: 05/21/2020] [Indexed: 11/22/2022]
Abstract
OBJECTIVE Glucose metabolism increases ATP/ADP ratio within the β-cells and causes ATP-sensitive K+ (KATP) channel closure and consequently insulin secretion. The enhanced activity of the channel may be a mechanism contributing to the reduced first-phase of insulin secretion observed in T2DM. There is no study to date in the Kurdish ethnic group regarding the relationship between SNP Ala1369Ser (rs757110 T/G) of SUR1 gene and T2DM, and additionally, the results of this association in other populations are inconsistent. Therefore, our aim in this study was to explore the possible association between SNP Ala1369Ser and type 2 diabetes in an Iranian Kurdish ethnic group. METHODS In this study, we checked out the frequency of alleles and genotypes of SNP Ala1369Ser in T2DM individuals (207 patients; men/women: 106/101) and non-T2DM subjects (201 controls; men/women: 97/104), and their effects on anthropometric, clinical, and biochemical parameters. Genomic DNA was extracted from the leukocytes of blood specimens using a standard method. We amplified the ABCC8 rs757110 polymorphic site (T/G) using a polymerase chain reaction (PCR) method and a designed primer pair. To perform the PCR-RFLP method, the amplicons were subjected to restriction enzymes and the resulting fragments separated by gel electrophoresis. RESULTS The frequency of the G-allele of Ala1369Ser polymorphism was significantly (0.01) higher in the case group than the control group (19% vs. 9%, respectively). In the dominant model (TT vs. TG+GG), there was a significant relationship between this SNP and an increased risk of T2DM (P = 0.00). T2DM patients with TG+GG genotypes had significantly higher fasting plasma insulin and HOMA-IR than those who had the TT genotype (P = 0.02 and 0.01, respectively). CONCLUSION Our study is the first study to investigate the association between Ala1369Ser ABCC8 genetic variation and T2DM in the Kurdish population of western Iran. The obtained results clearly show that Ala1369Ser polymorphism of ABCC8 is associated with an increased risk of T2DM in this population.
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Affiliation(s)
- Amin Bakhtiyari
- Department of Genetics, Biology Research Center, Zanjan Branch, Islamic Azad University, Zanjan, Iran.,Clinical Microbiology Research Center, Ilam University of Medical Sciences, Ilam, Iran
| | - Karimeh Haghani
- Department of Clinical Biochemistry, Faculty of Medicine, Ilam University of Medical Sciences, Ilam, Iran
| | - Salar Bakhtiyari
- Clinical Microbiology Research Center, Ilam University of Medical Sciences, Ilam, Iran.,Department of Clinical Biochemistry, Faculty of Medicine, Ilam University of Medical Sciences, Ilam, Iran
| | - Mohammad A Zaimy
- Department of Medical Genetics, Faculty of Medicine, Ilam University of Medical Sciences, Ilam, Iran
| | - Ali Noori-Zadeh
- Department of Clinical Biochemistry, Faculty of Allied Medical Sciences, Ilam University of Medical Sciences, Ilam, Iran
| | - Ali Gheysarzadeh
- Clinical Microbiology Research Center, Ilam University of Medical Sciences, Ilam, Iran.,Department of Biology, Faculty of Science, Ilam University, Ilam, Iran
| | - Shahram Darabi
- Cellular and Molecular Research Center, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Ali Seidkhani-Nahal
- Department of Clinical Biochemistry, Faculty of Medicine, Ilam University of Medical Sciences, Ilam, Iran
| | - Mansour Amraei
- Department of Physiology, Faculty of Medicine, Ilam University of Medical Sciences, Ilam, Iran
| | - Iraj Alipourfard
- School of Pharmacy, Faculty of Sciences, University of Rome Tor Vergata, Rome, Italy
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Lu Y, Li Y, Li G, Lu H. Identification of potential markers for type 2 diabetes mellitus via bioinformatics analysis. Mol Med Rep 2020; 22:1868-1882. [PMID: 32705173 PMCID: PMC7411335 DOI: 10.3892/mmr.2020.11281] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Accepted: 01/20/2020] [Indexed: 12/15/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a multifactorial and multigenetic disease, and its pathogenesis is complex and largely unknown. In the present study, microarray data (GSE201966) of β-cell enriched tissue obtained by laser capture microdissection were downloaded, including 10 control and 10 type 2 diabetic subjects. A comprehensive bioinformatics analysis of microarray data in the context of protein-protein interaction (PPI) networks was employed, combined with subcellular location information to mine the potential candidate genes for T2DM and provide further insight on the possible mechanisms involved. First, differential analysis screened 108 differentially expressed genes. Then, 83 candidate genes were identified in the layered network in the context of PPI via network analysis, which were either directly or indirectly linked to T2DM. Of those genes obtained through literature retrieval analysis, 27 of 83 were involved with the development of T2DM; however, the rest of the 56 genes need to be verified by experiments. The functional analysis of candidate genes involved in a number of biological activities, demonstrated that 46 upregulated candidate genes were involved in ‘inflammatory response’ and ‘lipid metabolic process’, and 37 downregulated candidate genes were involved in ‘positive regulation of cell death’ and ‘positive regulation of cell proliferation’. These candidate genes were also involved in different signaling pathways associated with ‘PI3K/Akt signaling pathway’, ‘Rap1 signaling pathway’, ‘Ras signaling pathway’ and ‘MAPK signaling pathway’, which are highly associated with the development of T2DM. Furthermore, a microRNA (miR)-target gene regulatory network and a transcription factor-target gene regulatory network were constructed based on miRNet and NetworkAnalyst databases, respectively. Notably, hsa-miR-192-5p, hsa-miR-124-5p and hsa-miR-335-5p appeared to be involved in T2DM by potentially regulating the expression of various candidate genes, including procollagen C-endopeptidase enhancer 2, connective tissue growth factor and family with sequence similarity 105, member A, protein phosphatase 1 regulatory inhibitor subunit 1 A and C-C motif chemokine receptor 4. Smad5 and Bcl6, as transcription factors, are regulated by ankyrin repeat domain 23 and transmembrane protein 37, respectively, which might also be used in the molecular diagnosis and targeted therapy of T2DM. Taken together, the results of the present study may offer insight for future genomic-based individualized treatment of T2DM and help determine the underlying molecular mechanisms that lead to T2DM.
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Affiliation(s)
- Yana Lu
- Key Laboratory of Dai and Southern Medicine of Xishuangbanna Dai Autonomous Prefecture, Yunnan Branch, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Jinghong, Yunnan 666100, P.R. China
| | - Yihang Li
- Key Laboratory of Dai and Southern Medicine of Xishuangbanna Dai Autonomous Prefecture, Yunnan Branch, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Jinghong, Yunnan 666100, P.R. China
| | - Guang Li
- Key Laboratory of Dai and Southern Medicine of Xishuangbanna Dai Autonomous Prefecture, Yunnan Branch, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Jinghong, Yunnan 666100, P.R. China
| | - Haitao Lu
- Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, P.R. China
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Cassiano C, Eletto D, Tosco A, Riccio R, Monti MC, Casapullo A. Determining the Effect of Pterostilbene on Insulin Secretion Using Chemoproteomics. Molecules 2020; 25:E2885. [PMID: 32585851 PMCID: PMC7356329 DOI: 10.3390/molecules25122885] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 06/18/2020] [Accepted: 06/22/2020] [Indexed: 12/13/2022] Open
Abstract
Pterostilbene, the 3,5-dimethoxy derivative of resveratrol, is a well-known polyphenolic compound, mainly found in blueberries, grapevines, and Pterocarpus marsupium heartwood, which has recently attracted a great deal of attention due to its wide bio-pharmacological profile. Moreover, pterostilbene is more lipophilic than resveratrol, with a consequently better bioavailability and a more interesting therapeutic potential. In this work, a chemoproteomic approach, based on affinity chromatography, was applied on pterostilbene in the attempt to identify the biological targets responsible for its bioactivity. On this basis, syntaxins, a group of proteins involved in the formation of SNARE complexes mediating vesicles exocytosis, were selected among the most interesting pterostilbene interactors. In vitro and in cell assays gave evidence of the pterostilbene ability to reduce insulin secretion on glucose-stimulated pancreatic beta cells, opening the way to potential applications of pterostilbene as a supplement in the care of insulin-dependent metabolic disorders.
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Affiliation(s)
- Chiara Cassiano
- Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Italy; (C.C.); (D.E.); (A.T.); (R.R.)
- Department of Pharmacy, University of Naples “Federico II”, Via D., Montesano 49, 80131 Naples, Italy
| | - Daniela Eletto
- Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Italy; (C.C.); (D.E.); (A.T.); (R.R.)
| | - Alessandra Tosco
- Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Italy; (C.C.); (D.E.); (A.T.); (R.R.)
| | - Raffaele Riccio
- Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Italy; (C.C.); (D.E.); (A.T.); (R.R.)
| | - Maria Chiara Monti
- Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Italy; (C.C.); (D.E.); (A.T.); (R.R.)
| | - Agostino Casapullo
- Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Italy; (C.C.); (D.E.); (A.T.); (R.R.)
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Abstract
Background Insulin is stored within large dense-core granules in pancreatic beta (β)-cells and is released by Ca2+-triggered exocytosis with increasing blood glucose levels. Polarized and targeted secretion of insulin from β-cells in pancreatic islets into the vasculature has been proposed; however, the mechanisms related to cellular and molecular localization remain largely unknown. Within nerve terminals, the Ca2+-dependent release of a polarized transmitter is limited to the active zone, a highly specialized area of the presynaptic membrane. Several active zone-specific proteins have been characterized; among them, the CAST/ELKS protein family members have the ability to form large protein complexes with other active zone proteins to control the structure and function of the active zone for tight regulation of neurotransmitter release. Notably, ELKS but not CAST is also expressed in β-cells, implying that ELKS may be involved in polarized insulin secretion from β-cells. Scope of review This review provides an overview of the current findings regarding the role(s) of ELKS and other active zone proteins in β-cells and focuses on the molecular mechanism underlying ELKS regulation within polarized insulin secretion from islets. Major conclusions ELKS localizes at the vascular-facing plasma membrane of β-cells in mouse pancreatic islets. ELKS forms a potent insulin secretion complex with L-type voltage-dependent Ca2+ channels on the vascular-facing plasma membrane of β-cells, enabling polarized Ca2+ influx and first-phase insulin secretion from islets. This model provides novel insights into the functional polarity observed during insulin secretion from β-cells within islets at the molecular level. This active zone-like region formed by ELKS at the vascular side of the plasma membrane is essential for coordinating physiological insulin secretion and may be disrupted in diabetes.
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Affiliation(s)
- Mica Ohara-Imaizumi
- Department of Cellular Biochemistry, Kyorin University School of Medicine, Tokyo 181-8611, Japan.
| | - Kyota Aoyagi
- Department of Cellular Biochemistry, Kyorin University School of Medicine, Tokyo 181-8611, Japan
| | - Toshihisa Ohtsuka
- Department of Biochemistry, Graduate School of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan
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ELKS/Voltage-Dependent Ca 2+ Channel-β Subunit Module Regulates Polarized Ca 2+ Influx in Pancreatic β Cells. Cell Rep 2020; 26:1213-1226.e7. [PMID: 30699350 DOI: 10.1016/j.celrep.2018.12.106] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2018] [Revised: 10/29/2018] [Accepted: 12/27/2018] [Indexed: 12/14/2022] Open
Abstract
Pancreatic β cells secrete insulin by Ca2+-triggered exocytosis. However, there is no apparent secretory site similar to the neuronal active zones, and the cellular and molecular localization mechanism underlying polarized exocytosis remains elusive. Here, we report that ELKS, a vertebrate active zone protein, is used in β cells to regulate Ca2+ influx for insulin secretion. β cell-specific ELKS-knockout (KO) mice showed impaired glucose-stimulated first-phase insulin secretion and reduced L-type voltage-dependent Ca2+ channel (VDCC) current density. In situ Ca2+ imaging of β cells within islets expressing a membrane-bound G-CaMP8b Ca2+ sensor demonstrated initial local Ca2+ signals at the ELKS-localized vascular side of the β cell plasma membrane, which were markedly decreased in ELKS-KO β cells. Mechanistically, ELKS directly interacted with the VDCC-β subunit via the GK domain. These findings suggest that ELKS and VDCCs form a potent insulin secretion complex at the vascular side of the β cell plasma membrane for polarized Ca2+ influx and first-phase insulin secretion from pancreatic islets.
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Abstract
Glucose-induced (physiological) insulin secretion from the islet β-cell involves interplay between cationic (i.e., changes in intracellular calcium) and metabolic (i.e., generation of hydrophobic and hydrophilic second messengers) events. A large body of evidence affirms support for novel regulation, by G proteins, of specific intracellular signaling events, including actin cytoskeletal remodeling, transport of insulin-containing granules to the plasma membrane for fusion, and secretion of insulin into the circulation. This article highlights the following aspects of GPCR-G protein biology of the islet. First, it overviews our current understanding of the identity of a wide variety of G protein regulators and their modulatory roles in GPCR-G protein-effector coupling, which is requisite for optimal β-cell function under physiological conditions. Second, it describes evidence in support of novel, noncanonical, GPCR-independent mechanisms of activation of G proteins in the islet. Third, it highlights the evidence indicating that abnormalities in G protein function lead to islet β-cell dysregulation and demise under the duress of metabolic stress and diabetes. Fourth, it summarizes observations of potential beneficial effects of GPCR agonists in preventing/halting metabolic defects in the islet β-cell under various pathological conditions (e.g., metabolic stress and inflammation). Lastly, it identifies knowledge gaps and potential avenues for future research in this evolving field of translational islet biology. Published 2020. Compr Physiol 10:453-490, 2020.
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Affiliation(s)
- Anjaneyulu Kowluru
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Center for Translational Research in Diabetes, Biomedical Research Service, John D. Dingell VA Medical Center, Wayne State University, Detroit, Michigan, USA
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Prentki M, Corkey BE, Madiraju SRM. Lipid-associated metabolic signalling networks in pancreatic beta cell function. Diabetologia 2020; 63:10-20. [PMID: 31423551 DOI: 10.1007/s00125-019-04976-w] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Accepted: 05/29/2019] [Indexed: 01/01/2023]
Abstract
Significant advances have been made in deciphering the mechanisms underlying fuel-stimulated insulin secretion by pancreatic beta cells. The contribution of the triggering/ATP-sensitive potassium (KATP)-dependent Ca2+ signalling and KATP-independent amplification pathways, that include anaplerosis and lipid signalling of glucose-stimulated insulin secretion (GSIS), are well established. A proposed model included a key role for a metabolic partitioning 'switch', the acetyl-CoA carboxylase (ACC)/malonyl-CoA/carnitine palmitoyltransferase-1 (CPT-1) axis, in beta cell glucose and fatty acid signalling for insulin secretion. This model has gained overwhelming support from a number of studies in recent years and is now refined through its link to the glycerolipid/NEFA cycle that provides lipid signals through its lipolysis arm. Furthermore, acetyl-CoA carboxylase may also control beta cell growth. Here we review the evidence supporting a role for the ACC/malonyl-CoA/CPT-1 axis in the control of GSIS and its particular importance under conditions of elevated fatty acids (e.g. fasting, excess nutrients, hyperlipidaemia and diabetes). We also document how it is linked to a more global lipid signalling system that includes the glycerolipid/NEFA cycle.
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Affiliation(s)
- Marc Prentki
- Department of Nutrition, University of Montreal, Montréal, QC, Canada.
- Department of Biochemistry and Molecular Medicine, University of Montreal, Montréal, QC, Canada.
- Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Viger Tour, 900 rue Saint Denis, Room R08-412, Montréal, QC, H2X 0A9, Canada.
| | - Barbara E Corkey
- Evans Department of Medicine, Obesity Research Center, Boston University School of Medicine, Boston, MA, USA
| | - S R Murthy Madiraju
- Department of Nutrition, University of Montreal, Montréal, QC, Canada
- Department of Biochemistry and Molecular Medicine, University of Montreal, Montréal, QC, Canada
- Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Viger Tour, 900 rue Saint Denis, Room R08-412, Montréal, QC, H2X 0A9, Canada
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45
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Yari Z, Behrouz V, Zand H, Pourvali K. New Insight into Diabetes Management: From Glycemic Index to Dietary Insulin Index. Curr Diabetes Rev 2020; 16:293-300. [PMID: 31203801 DOI: 10.2174/1573399815666190614122626] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Revised: 04/05/2019] [Accepted: 05/03/2019] [Indexed: 12/31/2022]
Abstract
BACKGROUND Despite efforts to control hyperglycemia, diabetes management is still challenging. This may be due to focusing on reducing hyperglycemia and neglecting the importance of hyperinsulinemia; while insulin resistance and resultant hyperinsulinemia preceded diabetes onset and may contribute to disease pathogenesis. OBJECTIVE The present narrative review attempts to provide a new insight into the management of diabetes by exploring different aspects of glycemic index and dietary insulin index. RESULTS The current data available on this topic is limited and heterogeneous. Conventional diet therapy for diabetes management is based on reducing postprandial glycemia through carbohydrate counting, choosing foods with low-glycemic index and low-glycemic load. Since these indicators are only reliant on the carbohydrate content of foods and do not consider the effects of protein and fat on the stimulation of insulin secretion, they cannot provide a comprehensive approach to determine the insulin requirements. CONCLUSION Selecting foods based on carbohydrate counting, glycemic index or glycemic load are common guides to control glycemia in diabetic patients, but neglect the insulin response, thus leading to failure in diabetes management. Therefore, paying attention to insulinemic response along with glycemic response seems to be more effective in managing diabetes.
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Affiliation(s)
- Zahra Yari
- Student Research Committee, Department of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Vahideh Behrouz
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamid Zand
- Department of Cellular and Molecular Nutrition, Faculty of Nutrition and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Katayoun Pourvali
- Department of Cellular and Molecular Nutrition, Faculty of Nutrition and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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46
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Liu Y, Wang Q, Nie D, Zhang Y, Wang Z, Zhang Y. Novel Modified GLP-1 Derivatives with Prolonged Glucose-Lowering Ability In Vivo. Int J Pept Res Ther 2019. [DOI: 10.1007/s10989-019-09991-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Hoang M, Paglialunga S, Bombardier E, Tupling AR, Joseph JW. The Loss of ARNT/HIF1β in Male Pancreatic β-Cells Is Protective Against High-Fat Diet-Induced Diabetes. Endocrinology 2019; 160:2825-2836. [PMID: 31580427 PMCID: PMC6846328 DOI: 10.1210/en.2018-00936] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Accepted: 09/25/2019] [Indexed: 11/19/2022]
Abstract
The transcription factor aryl hydrocarbon receptor nuclear translocator (ARNT)/hypoxia-inducible factor (HIF)-1β (ARNT/HIF1β) plays a key role in maintaining β-cell function and has been shown to be one of the most downregulated transcription factors in islets from patients with type 2 diabetes. We have shown a role for ARNT/HIF1β in glucose sensing and insulin secretion in vitro and no defects in in vivo glucose homeostasis. To gain a better understanding of the role of ARNT/HIF1β in the development of diabetes, we placed control (+/+/Cre) and β-cell-specific ARNT/HIF1β knockout (fl/fl/Cre) mice on a high-fat diet (HFD). Unlike the control (+/+/Cre) mice, HFD-fed fl/fl/Cre mice had no impairment in in vivo glucose tolerance. The lack of impairment in HFD-fed fl/fl/Cre mice was partly due to an improved islet glucose-stimulated NADPH/NADP+ ratio and glucose-stimulated insulin secretion. The effects of the HFD-rescued insulin secretion in fl/fl/Cre islets could be reproduced by treating low-fat diet (LFD)-fed fl/fl/Cre islets with the lipid signaling molecule 1-monoacylglcyerol. This suggests that the defects seen in LFD-fed fl/fl/Cre islet insulin secretion involve lipid signaling molecules. Overall, mice lacking ARNT/HIF1β in β-cells have altered lipid signaling in vivo and are resistant to an HFD's ability to induce diabetes.
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Affiliation(s)
- Monica Hoang
- School of Pharmacy, University of Waterloo, Kitchener, Ontario, Canada
| | | | - Eric Bombardier
- Department of Kinesiology, University of Waterloo, Waterloo, Ontario, Canada
| | - A Russell Tupling
- Department of Kinesiology, University of Waterloo, Waterloo, Ontario, Canada
| | - Jamie W Joseph
- School of Pharmacy, University of Waterloo, Kitchener, Ontario, Canada
- Correspondence: Jamie W. Joseph, PhD, University of Waterloo, 10 Victoria Street South, Building A, Kitchener, Ontario N2G 1C5, Canada. E-mail:
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48
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Ye F, Liu Y, Li S, Chen JDZ. Hypoglycemic Effects of Intestinal Electrical Stimulation by Enhancing Nutrient-Stimulated Secretion of GLP-1 in Rats. Obes Surg 2019; 28:2829-2835. [PMID: 29728986 DOI: 10.1007/s11695-018-3257-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
PURPOSE To find out the best location for intestinal electrical stimulation (IES) to decrease hyperglycemia, and mechanisms involving intraluminal nutrients and plasma glucagon-like peptide-1 (GLP-1) MATERIALS AND METHODS: Eight rats had electrodes implanted at the duodenum and ileums for IES. The oral glucose tolerance test (OGTT) was performed with IES and sham-IES and with/without GLP-1 antagonist, exendin. To study the role of intraluminal nutrients, the experiment was repeated using intraperitoneal glucose tolerance test (IPGTT). Glucagon was administrated in the OGTT/IPGTT to induce temporary hyperglycemia. RESULTS (1) In the OGTT, IES at the duodenum reduced blood glucose from 30 to 120 min after oral glucose (P < 0.05, vs. sham-IES) and the hypoglycemic effect was more potent than IES at the ileum. (2) The hypoglycemic effect of IES was absent in IPGTT experiment, suggesting the important role of intraluminal nutrients. (3) An increase in GLP-1 was noted in the OGTT with IES at the duodenum in comparison with sham-IES. Moreover, the blocking effect of exendin suggested the role of GLP-1 in the hypoglycemic effect of IES. CONCLUSIONS The best stimulation location for IES to decrease hyperglycemia is in the duodenum. The hypoglycemic effect of IES is attributed to the enhancement in nutrient-stimulated release of GLP-1.
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Affiliation(s)
- Feng Ye
- Veterans Research and Education Foundation, VA Medical Center, Oklahoma City, OK, USA
- The 1st Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
- Division of Gastroenterology and Hepatology, Johns Hopkins Center for Neurogastroenterology, John's Hopkins University School of Medicine, Baltimore, MD, USA
| | - Yi Liu
- Veterans Research and Education Foundation, VA Medical Center, Oklahoma City, OK, USA
- The 1st Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
- Division of Gastroenterology and Hepatology, Johns Hopkins Center for Neurogastroenterology, John's Hopkins University School of Medicine, Baltimore, MD, USA
| | - Shiying Li
- Veterans Research and Education Foundation, VA Medical Center, Oklahoma City, OK, USA
| | - Jiande D Z Chen
- Veterans Research and Education Foundation, VA Medical Center, Oklahoma City, OK, USA.
- Division of Gastroenterology and Hepatology, Johns Hopkins Center for Neurogastroenterology, John's Hopkins University School of Medicine, Baltimore, MD, USA.
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49
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Hwang HJ, Yang YR, Kim HY, Choi Y, Park KS, Lee H, Ma JS, Yamamoto M, Kim J, Chae YC, Choi JH, Cocco L, Berggren PO, Jang HJ, Suh PG. Phospholipase C‐β1 potentiates glucose‐stimulated insulin secretion. FASEB J 2019; 33:10668-10679. [DOI: 10.1096/fj.201802732rr] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Affiliation(s)
- Hyeon-Jeong Hwang
- School of Life SciencesUlsan National Institute of Science and TechnologyUlsanSouth Korea
| | - Yong Ryoul Yang
- Aging Research CenterKorea Research Institute of Bioscience and BiotechnologyDaejeonSouth Korea
| | - Hye Yun Kim
- School of Life SciencesUlsan National Institute of Science and TechnologyUlsanSouth Korea
| | - Yoonji Choi
- School of Life SciencesUlsan National Institute of Science and TechnologyUlsanSouth Korea
| | - Kyoung-Su Park
- School of Life SciencesUlsan National Institute of Science and TechnologyUlsanSouth Korea
| | - Ho Lee
- Cancer Experimental Resources BranchNational Cancer CenterGoyang-siSouth Korea
| | - Ji Su Ma
- Department of ImmunoparasitologyResearch Institute for Microbial DiseasesOsaka UniversitySuitaJapan
| | - Masahiro Yamamoto
- Department of ImmunoparasitologyResearch Institute for Microbial DiseasesOsaka UniversitySuitaJapan
| | - Jaeyoon Kim
- Department of Molecular Medicine and SurgeryThe Rolf Luft Research Center for Diabetes and EndocrinologyKarolinska InstitutetStockholmSweden
- Division of Integrative Biosciences and BiotechnologyPohang University of Science and TechnologyPohangSouth Korea
| | - Young Chan Chae
- School of Life SciencesUlsan National Institute of Science and TechnologyUlsanSouth Korea
| | - Jang Hyun Choi
- School of Life SciencesUlsan National Institute of Science and TechnologyUlsanSouth Korea
- Korea Mouse Phenotyping CenterUlsan National Institute of Science and TechnologyUlsanSouth Korea
| | - Lucio Cocco
- Department of Biomedical SciencesSignalling LaboratoryUniversity of BolognaBolognaItaly
| | - Per-Olof Berggren
- Department of Molecular Medicine and SurgeryThe Rolf Luft Research Center for Diabetes and EndocrinologyKarolinska InstitutetStockholmSweden
- Division of Integrative Biosciences and BiotechnologyPohang University of Science and TechnologyPohangSouth Korea
| | - Hyun-Jun Jang
- School of Life SciencesUlsan National Institute of Science and TechnologyUlsanSouth Korea
| | - Pann-Ghill Suh
- School of Life SciencesUlsan National Institute of Science and TechnologyUlsanSouth Korea
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50
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Zbinden A, Marzi J, Schlünder K, Probst C, Urbanczyk M, Black S, Brauchle EM, Layland SL, Kraushaar U, Duffy G, Schenke-Layland K, Loskill P. Non-invasive marker-independent high content analysis of a microphysiological human pancreas-on-a-chip model. Matrix Biol 2019; 85-86:205-220. [PMID: 31238092 DOI: 10.1016/j.matbio.2019.06.008] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2019] [Revised: 06/20/2019] [Accepted: 06/20/2019] [Indexed: 12/15/2022]
Abstract
The increasing prevalence of diabetes, its heterogeneity, and the limited number of treatment options drive the need for physiologically relevant assay platforms with human genetic background that have the potential to improve mechanistic understanding and e\xpedite diabetes-related research and treatment. In this study, we developed an endocrine pancreas-on-a-chip model based on a tailored microfluidic platform, which enables self-guided trapping of single human pseudo-islets. Continuous, low-shear perfusion provides a physiologically relevant microenvironment especially important for modeling and monitoring of the endocrine function as well as sufficient supply with nutrients and oxygen. Human pseudo-islets, generated from the conditionally immortalized EndoC-βH3 cell line, were successfully injected by hydrostatic pressure-driven flow without altered viability. To track insulin secretion kinetics in response to glucose stimulation in a time-resolved manner, dynamic sampling of the supernatant as well as non-invasive real-time monitoring using Raman microspectroscopy was established on-chip. Dynamic sampling indicated a biphasic glucose-stimulated insulin response. Raman microspectroscopy allowed to trace glucose responsiveness in situ and to visualize different molecular structures such as lipids, mitochondria and nuclei. In-depth spectral analyses demonstrated a glucose stimulation-dependent, increased mitochondrial activity, and a switch in lipid composition of insulin secreting vesicles, supporting the high performance of our pancreas-on-a-chip model.
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Affiliation(s)
- Aline Zbinden
- Dept. of Women's Health, Research Institute of Women's Health, Eberhard Karls University Tübingen, Germany
| | - Julia Marzi
- Dept. of Women's Health, Research Institute of Women's Health, Eberhard Karls University Tübingen, Germany; The Natural and Medical Sciences Institute (NMI) at the University of Tübingen, Reutlingen, Germany
| | - Katharina Schlünder
- Fraunhofer Institute for Interfacial Engineering and Biotechnology (IGB), Stuttgart, Germany
| | - Christopher Probst
- Fraunhofer Institute for Interfacial Engineering and Biotechnology (IGB), Stuttgart, Germany
| | - Max Urbanczyk
- Dept. of Women's Health, Research Institute of Women's Health, Eberhard Karls University Tübingen, Germany
| | - Scott Black
- The Natural and Medical Sciences Institute (NMI) at the University of Tübingen, Reutlingen, Germany
| | - Eva M Brauchle
- Dept. of Women's Health, Research Institute of Women's Health, Eberhard Karls University Tübingen, Germany; The Natural and Medical Sciences Institute (NMI) at the University of Tübingen, Reutlingen, Germany
| | - Shannon L Layland
- Dept. of Women's Health, Research Institute of Women's Health, Eberhard Karls University Tübingen, Germany
| | - Udo Kraushaar
- The Natural and Medical Sciences Institute (NMI) at the University of Tübingen, Reutlingen, Germany
| | - Garry Duffy
- Discipline of Anatomy and the Regenerative Medicine Institute, School of Medicine, College of Medicine Nursing and Health Sciences, National University of Ireland Galway, Ireland; Science Foundation Ireland (SFI), Centre for Research in Advanced Materials for Biomedical Engineering (AMBER), Trinity College Dublin, National University of Ireland Galway, Galway, Ireland
| | - Katja Schenke-Layland
- Dept. of Women's Health, Research Institute of Women's Health, Eberhard Karls University Tübingen, Germany; The Natural and Medical Sciences Institute (NMI) at the University of Tübingen, Reutlingen, Germany; Dept. of Medicine/Cardiology, University of California Los Angeles (UCLA), Los Angeles, CA, USA.
| | - Peter Loskill
- Dept. of Women's Health, Research Institute of Women's Health, Eberhard Karls University Tübingen, Germany; Fraunhofer Institute for Interfacial Engineering and Biotechnology (IGB), Stuttgart, Germany.
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