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1
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Norlin S, Axelsson J, Ericsson M, Edlund H. O304 ameliorates hyperglycemia in mice by dually promoting muscle glucose effectiveness and preserving β-cell function. Commun Biol 2023; 6:877. [PMID: 37626210 PMCID: PMC10457357 DOI: 10.1038/s42003-023-05255-6] [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: 10/04/2022] [Accepted: 08/18/2023] [Indexed: 08/27/2023] Open
Abstract
Although insulin mediated glucose uptake in skeletal muscle is a major mechanism ensuring glucose disposal in humans, glucose effectiveness, i.e., the ability of glucose itself to stimulate its own uptake independent of insulin, accounts for roughly half of the glucose disposed during an oral glucose tolerance test. Both insulin dependent and insulin independent skeletal muscle glucose uptake are however reduced in individuals with diabetes. We here show that AMPK activator O304 stimulates insulin independent glucose uptake and utilization in skeletal muscle and heart in vivo, while preventing glycogen accumulation. Combined glucose uptake and utilization requires an increased metabolic demand and we show that O304 acts as a mitochondrial uncoupler, i.e., generates a metabolic demand. O304 averts gene expression changes associated with metabolic inflexibility in skeletal muscle and heart of diabetic mice and reverts diabetic cardiomyopathy. In Type 2 diabetes, insulin resistance elicits compensatory insulin hypersecretion, provoking β-cell stress and eventually compensatory failure. In db/db mice O304 preserves β-cell function by preventing decline in insulin secretion, β-cell mass, and pancreatic insulin content. Thus, as a dual AMPK activator and mitochondrial uncoupler O304 mitigates two central defects of T2D; impaired glucose uptake/utilization and β-cell failure, which today lack effective treatment.
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Affiliation(s)
- Stefan Norlin
- Umeå Centre for Molecular Medicine, Umeå University, SE-901 87, Umeå, Sweden
| | - Jan Axelsson
- Department of Radiation Sciences, Radiation Physics, Umeå University, SE-901 87, Umeå, Sweden
| | - Madelene Ericsson
- Umeå Centre for Molecular Medicine, Umeå University, SE-901 87, Umeå, Sweden
| | - Helena Edlund
- Umeå Centre for Molecular Medicine, Umeå University, SE-901 87, Umeå, Sweden.
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2
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Qureshi FM, Panzer JK, Põder J, Malek TR, Caicedo A. Immunotherapy With Low-Dose IL-2/CD25 Prevents β-Cell Dysfunction and Dysglycemia in Prediabetic NOD Mice. Diabetes 2023; 72:769-780. [PMID: 36939730 PMCID: PMC10202767 DOI: 10.2337/db22-0482] [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: 05/24/2022] [Accepted: 03/15/2023] [Indexed: 03/21/2023]
Abstract
Low-dose IL-2 is a promising immunotherapy in clinical trials for treating type 1 diabetes. A new IL-2 analog, IL-2/CD25 fusion protein, has been shown to more efficiently delay or prevent diabetes in NOD mice by expanding the population of activated regulatory T cells. This therapy is intended for use before clinical diagnosis, in the early stages of type 1 diabetes progression. During this prediabetic period, there is a chronic decline in β-cell function that has long-term implications for disease pathogenesis. Yet, to date, the effects of IL-2/CD25 on β-cell function have not been evaluated. In this study, we treated prediabetic NOD mice with low-dose mouse IL-2/CD25 over 5 weeks and determined its impact on β-cell function. This treatment limited the progressive impairment of glucose tolerance and insulin secretion typical of the later stages of prediabetes. Intracellular Ca2+ responses to glucose in β-cells became more robust and synchronous, indicating that changing the local immune cell infiltrate with IL-2/CD25 preserved β-cell function even after treatment cessation. Our study thus provides mechanistic insight and serves as a steppingstone for future research using low-dose IL-2/CD25 immunotherapy in patients. ARTICLE HIGHLIGHTS Immunotherapies such as IL-2/CD25 are known to prevent or delay diabetes. However, their impact on individual β-cell function is not yet understood. Female NOD mice progress from stage 1 to 2 pre-type 1 diabetes between 12 and 17 weeks. Treatment with mouse IL-2 (mIL-2)/CD25 prevents this progression even after treatment cessation. Individual β-cell function (measured via intracellular Ca2+ responses to glucose) declines during the pathogenesis of type 1 diabetes. Treatment with mIL-2/CD25 therapy limits β-cell dysfunction, and function continues to improve after treatment cessation. Insulin secretion is improved with mIL-2/CD25 therapy.
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Affiliation(s)
- Farhan M. Qureshi
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL
- Department of Molecular, Cell and Developmental Biology, University of Miami Miller School of Medicine, Miami, FL
- Medical Scientist Training Program, University of Miami Miller School of Medicine, Miami, FL
| | - Julia K. Panzer
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL
| | - Janika Põder
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL
| | - Thomas R. Malek
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL
| | - Alejandro Caicedo
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL
- Department of Molecular, Cell and Developmental Biology, University of Miami Miller School of Medicine, Miami, FL
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3
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Podraza-Farhanieh A, Raj D, Kao G, Naredi P. A proinsulin-dependent interaction between ENPL-1 and ASNA-1 in neurons is required to maintain insulin secretion in C. elegans. Development 2023; 150:dev201035. [PMID: 36939052 PMCID: PMC10112894 DOI: 10.1242/dev.201035] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 02/13/2023] [Indexed: 03/21/2023]
Abstract
Neuropeptides, including insulin, are important regulators of physiological functions of the organisms. Trafficking through the Golgi is crucial for the regulation of secretion of insulin-like peptides. ASNA-1 (TRC40) and ENPL-1 (GRP94) are conserved insulin secretion regulators in Caenorhabditis elegans (and mammals), and mouse Grp94 mutants display type 2 diabetes. ENPL-1/GRP94 binds proinsulin and regulates proinsulin levels in C. elegans and mammalian cells. Here, we have found that ASNA-1 and ENPL-1 cooperate to regulate insulin secretion in worms via a physical interaction that is independent of the insulin-binding site of ENPL-1. The interaction occurs in DAF-28/insulin-expressing neurons and is sensitive to changes in DAF-28 pro-peptide levels. Consistently, ASNA-1 acted in neurons to promote DAF-28/insulin secretion. The chaperone form of ASNA-1 was likely the interaction partner of ENPL-1. Loss of asna-1 disrupted Golgi trafficking pathways. ASNA-1 localization to the Golgi was affected in enpl-1 mutants and ENPL-1 overexpression partially bypassed the ASNA-1 requirement. Taken together, we find a functional interaction between ENPL-1 and ASNA-1 that is necessary to maintain proper insulin secretion in C. elegans and provides insights into how their loss might cause diabetes in mammals.
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Affiliation(s)
- Agnieszka Podraza-Farhanieh
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, SE413 45 Gothenburg, Sweden
| | - Dorota Raj
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, SE413 45 Gothenburg, Sweden
| | - Gautam Kao
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, SE413 45 Gothenburg, Sweden
| | - Peter Naredi
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, SE413 45 Gothenburg, Sweden
- Department of Surgery, Sahlgrenska University Hospital, SE413 45 Gothenburg, Sweden
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4
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Cook TW, Wilstermann AM, Mitchell JT, Arnold NE, Rajasekaran S, Bupp CP, Prokop JW. Understanding Insulin in the Age of Precision Medicine and Big Data: Under-Explored Nature of Genomics. Biomolecules 2023; 13:257. [PMID: 36830626 PMCID: PMC9953665 DOI: 10.3390/biom13020257] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 01/20/2023] [Accepted: 01/26/2023] [Indexed: 01/31/2023] Open
Abstract
Insulin is amongst the human genome's most well-studied genes/proteins due to its connection to metabolic health. Within this article, we review literature and data to build a knowledge base of Insulin (INS) genetics that influence transcription, transcript processing, translation, hormone maturation, secretion, receptor binding, and metabolism while highlighting the future needs of insulin research. The INS gene region has 2076 unique variants from population genetics. Several variants are found near the transcriptional start site, enhancers, and following the INS transcripts that might influence the readthrough fusion transcript INS-IGF2. This INS-IGF2 transcript splice site was confirmed within hundreds of pancreatic RNAseq samples, lacks drift based on human genome sequencing, and has possible elevated expression due to viral regulation within the liver. Moreover, a rare, poorly characterized African population-enriched variant of INS-IGF2 results in a loss of the stop codon. INS transcript UTR variants rs689 and rs3842753, associated with type 1 diabetes, are found in many pancreatic RNAseq datasets with an elevation of the 3'UTR alternatively spliced INS transcript. Finally, by combining literature, evolutionary profiling, and structural biology, we map rare missense variants that influence preproinsulin translation, proinsulin processing, dimer/hexamer secretory storage, receptor activation, and C-peptide detection for quasi-insulin blood measurements.
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Affiliation(s)
- Taylor W. Cook
- Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA
| | | | - Jackson T. Mitchell
- Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA
| | - Nicholas E. Arnold
- Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA
| | - Surender Rajasekaran
- Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA
- Office of Research, Corewell Health, Grand Rapids, MI 49503, USA
| | - Caleb P. Bupp
- Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA
- Division of Medical Genetics, Corewell Health, Grand Rapids, MI 49503, USA
| | - Jeremy W. Prokop
- Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA
- Office of Research, Corewell Health, Grand Rapids, MI 49503, USA
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5
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Rohli KE, Boyer CK, Bearrows SC, Moyer MR, Elison WS, Bauchle CJ, Blom SE, Zhang J, Wang Y, Stephens SB. ER Redox Homeostasis Regulates Proinsulin Trafficking and Insulin Granule Formation in the Pancreatic Islet β-Cell. FUNCTION 2022; 3:zqac051. [PMID: 36325514 PMCID: PMC9614934 DOI: 10.1093/function/zqac051] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 09/11/2022] [Accepted: 09/21/2022] [Indexed: 01/07/2023] Open
Abstract
Defects in the pancreatic β-cell's secretion system are well-described in type 2 diabetes (T2D) and include impaired proinsulin processing and a deficit in mature insulin-containing secretory granules; however, the cellular mechanisms underlying these defects remain poorly understood. To address this, we used an in situ fluorescent pulse-chase strategy to study proinsulin trafficking. We show that insulin granule formation and the appearance of nascent granules at the plasma membrane are decreased in rodent and cell culture models of prediabetes and hyperglycemia. Moreover, we link the defect in insulin granule formation to an early trafficking delay in endoplasmic reticulum (ER) export of proinsulin, which is independent of overt ER stress. Using a ratiometric redox sensor, we show that the ER becomes hyperoxidized in β-cells from a dietary model of rodent prediabetes and that addition of reducing equivalents restores ER export of proinsulin and insulin granule formation and partially restores β-cell function. Together, these data identify a critical role for the regulation of ER redox homeostasis in proinsulin trafficking and suggest that alterations in ER redox poise directly contribute to the decline in insulin granule production in T2D. This model highlights a critical link between alterations in ER redox and ER function with defects in proinsulin trafficking in T2D. Hyperoxidation of the ER lumen, shown as hydrogen peroxide, impairs proinsulin folding and disulfide bond formation that prevents efficient exit of proinsulin from the ER to the Golgi. This trafficking defect limits available proinsulin for the formation of insulin secretory granules during the development of T2D.
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Affiliation(s)
- Kristen E Rohli
- Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA 52242, USA
- Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa City, IA 52242, USA
- Department of Internal Medicine, Division of Endocrinology and Metabolism, University of Iowa, Iowa City, IA 52242, USA
| | - Cierra K Boyer
- Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA 52242, USA
- Department of Pharmacology, University of Iowa, Iowa City, IA 52242, USA
| | - Shelby C Bearrows
- Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA 52242, USA
- Department of Internal Medicine, Division of Endocrinology and Metabolism, University of Iowa, Iowa City, IA 52242, USA
| | - Marshall R Moyer
- Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA 52242, USA
- Department of Internal Medicine, Division of Endocrinology and Metabolism, University of Iowa, Iowa City, IA 52242, USA
| | - Weston S Elison
- Department of Nutrition, Dietetics, and Food Science, Brigham Young University, Provo, UT 84602, USA
| | - Casey J Bauchle
- Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA 52242, USA
- Department of Internal Medicine, Division of Endocrinology and Metabolism, University of Iowa, Iowa City, IA 52242, USA
| | - Sandra E Blom
- Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA 52242, USA
- Department of Internal Medicine, Division of Endocrinology and Metabolism, University of Iowa, Iowa City, IA 52242, USA
| | - Jianchao Zhang
- Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48103, USA
| | - Yanzhuang Wang
- Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48103, USA
- Department of Neurology, School of Medicine, University of Michigan, Ann Arbor, MI 48103, USA
| | - Samuel B Stephens
- Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA 52242, USA
- Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa City, IA 52242, USA
- Department of Internal Medicine, Division of Endocrinology and Metabolism, University of Iowa, Iowa City, IA 52242, USA
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6
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Rohli KE, Boyer CK, Blom SE, Stephens SB. Nutrient Regulation of Pancreatic Islet β-Cell Secretory Capacity and Insulin Production. Biomolecules 2022; 12:335. [PMID: 35204835 PMCID: PMC8869698 DOI: 10.3390/biom12020335] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 02/16/2022] [Accepted: 02/17/2022] [Indexed: 01/27/2023] Open
Abstract
Pancreatic islet β-cells exhibit tremendous plasticity for secretory adaptations that coordinate insulin production and release with nutritional demands. This essential feature of the β-cell can allow for compensatory changes that increase secretory output to overcome insulin resistance early in Type 2 diabetes (T2D). Nutrient-stimulated increases in proinsulin biosynthesis may initiate this β-cell adaptive compensation; however, the molecular regulators of secretory expansion that accommodate the increased biosynthetic burden of packaging and producing additional insulin granules, such as enhanced ER and Golgi functions, remain poorly defined. As these adaptive mechanisms fail and T2D progresses, the β-cell succumbs to metabolic defects resulting in alterations to glucose metabolism and a decline in nutrient-regulated secretory functions, including impaired proinsulin processing and a deficit in mature insulin-containing secretory granules. In this review, we will discuss how the adaptative plasticity of the pancreatic islet β-cell's secretory program allows insulin production to be carefully matched with nutrient availability and peripheral cues for insulin signaling. Furthermore, we will highlight potential defects in the secretory pathway that limit or delay insulin granule biosynthesis, which may contribute to the decline in β-cell function during the pathogenesis of T2D.
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Affiliation(s)
- Kristen E. Rohli
- Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA 52242, USA; (K.E.R.); (C.K.B.); (S.E.B.)
- Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Cierra K. Boyer
- Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA 52242, USA; (K.E.R.); (C.K.B.); (S.E.B.)
- Department of Neuroscience and Pharmacology, University of Iowa, Iowa City, IA 52242, USA
| | - Sandra E. Blom
- Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA 52242, USA; (K.E.R.); (C.K.B.); (S.E.B.)
- Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Samuel B. Stephens
- Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA 52242, USA; (K.E.R.); (C.K.B.); (S.E.B.)
- Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA
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7
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Weir GC, Butler PC, Bonner-Weir S. The β-cell glucose toxicity hypothesis: Attractive but difficult to prove. Metabolism 2021; 124:154870. [PMID: 34480921 PMCID: PMC8530963 DOI: 10.1016/j.metabol.2021.154870] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 08/11/2021] [Accepted: 08/25/2021] [Indexed: 12/16/2022]
Abstract
β cells in the hyperglycemic environment of diabetes have marked changes in phenotype and function that are largely reversible if glucose levels can be returned to normal. A leading hypothesis is that these changes are caused by the elevated glucose levels leading to the concept of glucose toxicity. Support for the glucose toxicity hypothesis is largely circumstantial, but little progress has been made in defining the responsible mechanisms. Then questions emerge that are difficult to answer. In the very earliest stages of diabetes development, there is a dramatic loss of glucose-induced first-phase insulin release (FPIR) with only trivial elevations of blood glucose levels. A related question is how impaired insulin action on target tissues such as liver, muscle and fat can cause increased insulin secretion. The existence of a sophisticated feedback mechanism between insulin secretion and insulin action on peripheral tissues driven by glucose has been postulated, but it has been difficult to measure increases in blood glucose levels that might have been expected. These complexities force us to challenge the simplicity of the glucose toxicity hypothesis and feedback mechanisms. It may turn out that glucose is somehow driving all of these changes, but we must develop new questions and experimental approaches to test the hypothesis.
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Affiliation(s)
- Gordon C Weir
- Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA.
| | - Peter C Butler
- Larry l. Hillblom Islet Research Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Susan Bonner-Weir
- Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA
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Kahn SE, Chen YC, Esser N, Taylor AJ, van Raalte DH, Zraika S, Verchere CB. The β Cell in Diabetes: Integrating Biomarkers With Functional Measures. Endocr Rev 2021; 42:528-583. [PMID: 34180979 PMCID: PMC9115372 DOI: 10.1210/endrev/bnab021] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Indexed: 02/08/2023]
Abstract
The pathogenesis of hyperglycemia observed in most forms of diabetes is intimately tied to the islet β cell. Impairments in propeptide processing and secretory function, along with the loss of these vital cells, is demonstrable not only in those in whom the diagnosis is established but typically also in individuals who are at increased risk of developing the disease. Biomarkers are used to inform on the state of a biological process, pathological condition, or response to an intervention and are increasingly being used for predicting, diagnosing, and prognosticating disease. They are also proving to be of use in the different forms of diabetes in both research and clinical settings. This review focuses on the β cell, addressing the potential utility of genetic markers, circulating molecules, immune cell phenotyping, and imaging approaches as biomarkers of cellular function and loss of this critical cell. Further, we consider how these biomarkers complement the more long-established, dynamic, and often complex measurements of β-cell secretory function that themselves could be considered biomarkers.
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Affiliation(s)
- Steven E Kahn
- Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, 98108 WA, USA
| | - Yi-Chun Chen
- BC Children's Hospital Research Institute and Centre for Molecular Medicine and Therapeutics, Vancouver, BC, V5Z 4H4, Canada.,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, V5Z 4H4, Canada.,Department of Surgery, University of British Columbia, Vancouver, BC, V5Z 4H4, Canada
| | - Nathalie Esser
- Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, 98108 WA, USA
| | - Austin J Taylor
- BC Children's Hospital Research Institute and Centre for Molecular Medicine and Therapeutics, Vancouver, BC, V5Z 4H4, Canada.,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, V5Z 4H4, Canada.,Department of Surgery, University of British Columbia, Vancouver, BC, V5Z 4H4, Canada
| | - Daniël H van Raalte
- Department of Internal Medicine, Amsterdam University Medical Center (UMC), Vrije Universiteit (VU) University Medical Center, 1007 MB Amsterdam, The Netherlands.,Department of Experimental Vascular Medicine, Amsterdam University Medical Center (UMC), Academic Medical Center, 1007 MB Amsterdam, The Netherlands
| | - Sakeneh Zraika
- Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, 98108 WA, USA
| | - C Bruce Verchere
- BC Children's Hospital Research Institute and Centre for Molecular Medicine and Therapeutics, Vancouver, BC, V5Z 4H4, Canada.,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, V5Z 4H4, Canada.,Department of Surgery, University of British Columbia, Vancouver, BC, V5Z 4H4, Canada
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9
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Yoshino H, Kawakami K, Yoshino K, Yoshino G. Prominent Hyperproinsulinemia in a Middle Age Patient. CLINICAL MEDICINE INSIGHTS-CASE REPORTS 2021; 14:11795476211042241. [PMID: 34483693 PMCID: PMC8414601 DOI: 10.1177/11795476211042241] [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: 05/10/2021] [Accepted: 08/09/2021] [Indexed: 12/02/2022]
Abstract
Introduction: Insulin is synthesized in the β-cells from preproinsulin. Preproinsulin
becomes proinsulin after leaving the signal peptide. Proinsulin is separated
into C-peptide and insulin by 2 enzymes. Hyperproinsulinemia is suspected to
be a pancreatic β-cell defect that is augmented by the increased demand
placed on the β-cell by hyperglycemia. Case presentation: A 39-year-old Japanese man visited to Shin-suma hospital in May 2013. Liver
dysfunction, dyslipidemia, and hyperuricemia had been found in medical
checkups in his workplace. Therefore, he visited Shin-suma hospital in order
to receive intensive examination. Diet and exercise therapy were initiated.
In November 2013, intact proinsulin and proinsulin per insulin (PI/I) ratio
were evaluated as part of an ongoing study. His intact proinsulin level and
PI/I ratio were markedly elevated. A 75 g oral OGTT revealed that his
glucose tolerance was impaired. His glycosylated hemoglobin was 6.9%. He was
diagnosed as having type 2 diabetes mellitus. Although, diet and exercise
therapy continued, his hyperproinslinemia and diabetes mellitus remained.
Therefore, aloguliptin was started in order to recover insulin secretion in
November 2014. Thereafter, pioglitazone was added to improve insulin
resistance. Finally, luseogliflozin was commenced to expect glucose-lowering
effects. His HbA1c was stabilized. To the best of our knowledge, there have
been few reports of patients with hyperproinsulinemia. Conclusion: When the physicians face treatment resistance in diabetes mellitus, we
emphasize that evaluation of proinsulin should be considered as one of the
methods.
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Affiliation(s)
- Hiroshi Yoshino
- Department of Geriatrics and Cognitive
Disorders, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
- Center for Diabetes, Shin-suma General
Hospital, Kobe, Japan
- Hiroshi Yoshino, Department of Geriatrics
and Cognitive Disorders, Fujita Health University School of Medicine, 98-1,
Dengakubo, Kutsugake-cho, Toyoake City, Aichi 470-1192, Japan.
| | - Kyoko Kawakami
- Center for Diabetes, Shin-suma General
Hospital, Kobe, Japan
| | - Kei Yoshino
- Division of Diabetes and Endocrinology,
Department of Internal of Medicine, Kobe University Graduate School of Medicine,
Kobe, Japan
| | - Gen Yoshino
- Center for Diabetes, Shin-suma General
Hospital, Kobe, Japan
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10
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Germanos M, Gao A, Taper M, Yau B, Kebede MA. Inside the Insulin Secretory Granule. Metabolites 2021; 11:metabo11080515. [PMID: 34436456 PMCID: PMC8401130 DOI: 10.3390/metabo11080515] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 08/03/2021] [Accepted: 08/03/2021] [Indexed: 12/19/2022] Open
Abstract
The pancreatic β-cell is purpose-built for the production and secretion of insulin, the only hormone that can remove glucose from the bloodstream. Insulin is kept inside miniature membrane-bound storage compartments known as secretory granules (SGs), and these specialized organelles can readily fuse with the plasma membrane upon cellular stimulation to release insulin. Insulin is synthesized in the endoplasmic reticulum (ER) as a biologically inactive precursor, proinsulin, along with several other proteins that will also become members of the insulin SG. Their coordinated synthesis enables synchronized transit through the ER and Golgi apparatus for congregation at the trans-Golgi network, the initiating site of SG biogenesis. Here, proinsulin and its constituents enter the SG where conditions are optimized for proinsulin processing into insulin and subsequent insulin storage. A healthy β-cell is continually generating SGs to supply insulin in vast excess to what is secreted. Conversely, in type 2 diabetes (T2D), the inability of failing β-cells to secrete may be due to the limited biosynthesis of new insulin. Factors that drive the formation and maturation of SGs and thus the production of insulin are therefore critical for systemic glucose control. Here, we detail the formative hours of the insulin SG from the luminal perspective. We do this by mapping the journey of individual members of the SG as they contribute to its genesis.
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11
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Ward AB, Dail MB, Chambers JE. In vitro effect of DDE exposure on the regulation of B-TC-6 pancreatic beta cell insulin secretion: a potential role in beta cell dysfunction and type 2 diabetes mellitus. Toxicol Mech Methods 2021; 31:667-673. [PMID: 34225579 DOI: 10.1080/15376516.2021.1950251] [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: 10/20/2022]
Abstract
Organochlorine compounds (OC) include synthetic insecticides previously used throughout the world before being banned for their adverse effects and environmental persistence; DDT (dichlorodiphenyltrichloroethane) was one of the most widely used. Epidemiological evidence suggests that higher levels of some OC, including metabolites of DDT, such as dichlorodiphenyldichloroethylene (DDE), are associated with type 2 diabetes mellitus (T2D). DDE exposure may affect pancreatic cellular functions associated with glucose control and possibly cause beta cell dysfunction. The in vitro effect of DDE exposure on pancreatic beta cell insulin secretion was investigated using Beta-Tumor Cell-6 (B-TC-6) murine pancreatic beta cells. DDE exposure significantly increased insulin secretion suggesting a role for DDE in altering insulin synthesis and secretion. Reactive oxygen species (ROS) levels were not significantly increased indicating that oxidative stress is not responsible for the DDE-induced insulin secretion. Pancreatic and duodenal homeobox factor-1 (PDX-1) levels were not significantly increased suggesting that DDE exposure does not alter insulin transcription, but prohormone convertase (PC) levels were increased suggesting a role for DDE in altering insulin translation. Based on these in vitro results, DDE may play a role in beta cell dysfunction by affecting mechanisms that regulate insulin secretion but it is not likely to be the major mechanism behind the DDE/T2D epidemiological association.
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Affiliation(s)
- Antonio B Ward
- Center for Environmental Health Sciences, Department of Comparative Biomedical Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi, MS, USA
| | - Mary B Dail
- Center for Environmental Health Sciences, Department of Comparative Biomedical Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi, MS, USA
| | - Janice E Chambers
- Center for Environmental Health Sciences, Department of Comparative Biomedical Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi, MS, USA
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12
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Skytte MJ, Samkani A, Astrup A, Frystyk J, Rehfeld JF, Holst JJ, Madsbad S, Burling K, Fenger M, Thomsen MN, Larsen TM, Krarup T, Haugaard SB. Effects of carbohydrate restriction on postprandial glucose metabolism, β-cell function, gut hormone secretion, and satiety in patients with Type 2 diabetes. Am J Physiol Endocrinol Metab 2021; 320:E7-E18. [PMID: 33103448 DOI: 10.1152/ajpendo.00165.2020] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Dietary carbohydrate restriction may improve the phenotype of Type 2 diabetes (T2D) patients. We aimed to investigate 6 wk of carbohydrate restriction on postprandial glucose metabolism, pancreatic α- and β-cell function, gut hormone secretion, and satiety in T2D patients. Methods In a crossover design, 28 T2D patients (mean HbA1c: 60 mmol/mol) were randomized to 6 wk of carbohydrate-reduced high-protein (CRHP) diet and 6 wk of conventional diabetes (CD) diet (energy-percentage carbohydrate/protein/fat: 30/30/40 vs. 50/17/33). Twenty-four-hour continuous glucose monitoring (CGM) and mixed-meal tests were undertaken and fasting intact proinsulin (IP), 32,33 split proinsulin concentrations (SP), and postprandial insulin secretion rates (ISR), insulinogenic index (IGI), β-cell sensitivity to glucose (Bup), glucagon, and gut hormones were measured. Gastric emptying was evaluated by postprandial paracetamol concentrations and satiety by visual analog scale ratings. A CRHP diet reduced postprandial glucose area under curve (net AUC) by 60% (P < 0.001), 24 h glucose by 13% (P < 0.001), fasting IP and SP concentrations (both absolute and relative to C-peptide, P < 0.05), and postprandial ISR (24%, P = 0.015), while IGI and Bup improved by 31% and 45% (both P < 0.001). The CRHP diet increased postprandial glucagon net AUC by 235% (P < 0.001), subjective satiety by 18% (P = 0.03), delayed gastric emptying by 15 min (P < 0.001), decreased gastric inhibitory polypeptide net AUC by 29% (P < 0.001), but had no significant effect on glucagon-like-peptide-1, total peptide YY, and cholecystokinin responses. A CRHP diet reduced glucose excursions and improved β-cell function, including proinsulin processing, and increased subjective satiety in patients with T2D.
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Affiliation(s)
- Mads J Skytte
- Department of Endocrinology, Copenhagen University Hospital, Bispebjerg, Denmark
| | - Amirsalar Samkani
- Department of Endocrinology, Copenhagen University Hospital, Bispebjerg, Denmark
| | - Arne Astrup
- Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark
| | - Jan Frystyk
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Jens F Rehfeld
- Department. of Clinical Biochemistry, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Jens J Holst
- Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Sten Madsbad
- Department of Endocrinology, Copenhagen University Hospital Hvidovre, Copenhagen, Denmark
| | - Keith Burling
- Core Biochemical Assay Laboratory, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, United Kingdom
| | - Mogens Fenger
- Department of Clinical Biochemistry, Copenhagen University Hospital Hvidovre, Copenahagen, Denmark
| | - Mads N Thomsen
- Department of Endocrinology, Copenhagen University Hospital, Bispebjerg, Denmark
| | - Thomas M Larsen
- Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark
| | - Thure Krarup
- Department of Endocrinology, Copenhagen University Hospital, Bispebjerg, Denmark
| | - Steen B Haugaard
- Department of Endocrinology, Copenhagen University Hospital, Bispebjerg, Denmark
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Podraza-Farhanieh A, Natarajan B, Raj D, Kao G, Naredi P. ENPL-1, the Caenorhabditis elegans homolog of GRP94, promotes insulin secretion via regulation of proinsulin processing and maturation. Development 2020; 147:dev190082. [PMID: 33037039 PMCID: PMC10666919 DOI: 10.1242/dev.190082] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 09/28/2020] [Indexed: 12/27/2022]
Abstract
Insulin/IGF signaling in Caenorhabditis elegans is crucial for proper development of the dauer larva and growth control. Mutants disturbing insulin processing, secretion and downstream signaling perturb this process and have helped identify genes that affect progression of type 2 diabetes. Insulin maturation is required for its proper secretion by pancreatic β cells. The role of the endoplasmic reticulum (ER) chaperones in insulin processing and secretion needs further study. We show that the C. elegans ER chaperone ENPL-1/GRP94 (HSP90B1), acts in dauer development by promoting insulin secretion and signaling. Processing of a proinsulin likely involves binding between the two proteins via a specific domain. We show that, in enpl-1 mutants, an unprocessed insulin exits the ER lumen and is found in dense core vesicles, but is not secreted. The high ER stress in enpl-1 mutants does not cause the secretion defect. Importantly, increased ENPL-1 levels result in increased secretion. Taken together, our work indicates that ENPL-1 operates at the level of insulin availability and is an essential modulator of insulin processing and secretion.
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Affiliation(s)
- Agnieszka Podraza-Farhanieh
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, SE413 45 Gothenburg, Sweden
| | | | - Dorota Raj
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, SE413 45 Gothenburg, Sweden
| | - Gautam Kao
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, SE413 45 Gothenburg, Sweden
| | - Peter Naredi
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, SE413 45 Gothenburg, Sweden
- Department of Surgery, Sahlgrenska University Hospital, SE413 45 Gothenburg, Sweden
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Comparisons between dipeptidyl peptidase-4 inhibitors and other classes of hypoglycemic drugs using two distinct biomarkers of pancreatic beta-cell function: A meta-analysis. PLoS One 2020; 15:e0236603. [PMID: 32706828 PMCID: PMC7380634 DOI: 10.1371/journal.pone.0236603] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 07/08/2020] [Indexed: 01/09/2023] Open
Abstract
Background and objective Dipeptidyl peptidase-4 (DPP-4) inhibitors have been suggested to have pancreatic beta-cell preserving effect according to studies using homeostatic model of assessment for beta-cell function (HOMA-β). However, whether HOMA-β is a suitable biomarker for comparisons between hypoglycemic drugs with different mechanisms of action remains unclear. Therefore, we conducted a meta-analysis to compare the effects of DPP-4 inhibitors and other classes of hypoglycemic drugs on HOMA-β and proinsulin-to-insulin ratio (PIR). Methods We searched MEDLINE, CENTRAL, and Ichushi-web for the period of 1966 to May 2020. We collected randomized, controlled clinical trials in patients with type 2 diabetes mellitus comparing DPP-4 inhibitors and other classes of hypoglycemic agents [α-glucosidase inhibitors (α-GIs), glucagon-like peptide-1 (GLP-1) analogues, metformin, sodium-glucose cotransporter 2 (SGLT2) inhibitors, sulfonylureas, or thiazolidinediones]. Weighted mean differences and 95% confidence intervals of changes in HOMA-β or PIR during study periods were calculated for pairwise comparisons. Results Thirty-seven and 21 relevant trials were retrieved for comparisons of HOMA-β and PIR, respectively. HOMA-β and PIR consistently showed superiority of DPP-4 inhibitors compared with α-GIs. Both biomarkers consistently supported inferiority of DPP-4 inhibitors compared with GLP-1 analogues. However, PIR showed inferiority of DPP-4 inhibitors compared with metformin, and superiority compared with SGLT2 inhibitors, whereas HOMA-β showed no significant differences between DPP-4 inhibitors and the two other agents. Conclusion DPP-4 inhibitors appear to be superior to α-GIs but inferior to GLP-1 analogues in preservation of beta-cell function assessed by either HOMA-β or PIR. DPP-4 inhibitors seem to be superior to SGLT2 inhibitors but inferior to metformin on islet function assessed only by PIR. Because HOMA-β and PIR may indicate different aspects of beta-cell function, results of beta-cell function preserving effects of hypoglycemic agents should be interpreted with caution.
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15
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Yin Q, Ni Q, Wang Y, Zhang H, Li W, Nie A, Wang S, Gu Y, Wang Q, Ning G. Raptor determines β-cell identity and plasticity independent of hyperglycemia in mice. Nat Commun 2020; 11:2538. [PMID: 32439909 PMCID: PMC7242325 DOI: 10.1038/s41467-020-15935-0] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Accepted: 03/05/2020] [Indexed: 02/07/2023] Open
Abstract
Compromised β-cell identity is emerging as an important contributor to β-cell failure in diabetes; however, the precise mechanism independent of hyperglycemia is under investigation. We have previously reported that mTORC1/Raptor regulates functional maturation in β-cells. In the present study, we find that diabetic β-cell specific Raptor-deficient mice (βRapKOGFP) show reduced β-cell mass, loss of β-cell identity and acquisition of α-cell features; which are not reversible upon glucose normalization. Deletion of Raptor directly impairs β-cell identity, mitochondrial metabolic coupling and protein synthetic activity, leading to β-cell failure. Moreover, loss of Raptor activates α-cell transcription factor MafB (via modulating C/EBPβ isoform ratio) and several α-cell enriched genes i.e. Etv1 and Tspan12, thus initiates β- to α-cell reprograming. The present findings highlight mTORC1 as a metabolic rheostat for stabilizing β-cell identity and repressing α-cell program at normoglycemic level, which might present therapeutic opportunities for treatment of diabetes.
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Affiliation(s)
- Qinglei Yin
- Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China
| | - Qicheng Ni
- Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China
| | - Yichen Wang
- Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China
| | - Hongli Zhang
- Department of Endocrinology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, 200137, Shanghai, China
| | - Wenyi Li
- Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China
| | - Aifang Nie
- Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China
| | - Shu Wang
- Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China
| | - Yanyun Gu
- Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China
| | - Qidi Wang
- Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China.
- Sino-French Research Center for Life Sciences and Genomics, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China.
| | - Guang Ning
- Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China.
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16
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Human Physiology of Genetic Defects Causing Beta-cell Dysfunction. J Mol Biol 2020; 432:1579-1598. [PMID: 31953147 DOI: 10.1016/j.jmb.2019.12.038] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 12/17/2019] [Accepted: 12/18/2019] [Indexed: 02/07/2023]
Abstract
The last decade has revealed hundreds of genetic variants associated with type 2 diabetes, many especially with insulin secretion. However, the evidence for their single or combined effect on beta-cell function relies mostly on genetic association of the variants or genetic risk scores with simple traits, and few have been functionally fully characterized even in cell or animal models. Translating the measured traits into human physiology is not straightforward: none of the various indices for beta-cell function or insulin sensitivity recapitulates the dynamic interplay between glucose sensing, endogenous glucose production, insulin production and secretion, insulin clearance, insulin resistance-to name just a few factors. Because insulin sensitivity is a major determinant of physiological need of insulin, insulin secretion should be evaluated in parallel with insulin sensitivity. On the other hand, multiple physiological or pathogenic processes can either mask or unmask subtle defects in beta-cell function. Even in monogenic diabetes, a clearly pathogenic genetic variant can result in different phenotypic characteristics-or no phenotype at all. In this review, we evaluate the methods available for studying beta-cell function in humans, critically examine the evidence linking some identified variants to a specific beta-cell phenotype, and highlight areas requiring further study.
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17
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Bharmal SH, Pendharkar SA, Singh RG, Petrov MS. Associations between gastrointestinal humoral factors and pancreatic proteolytic enzymes in alcohol-related versus non-alcohol-related pancreatitis. Alcohol 2019; 76:1-10. [PMID: 30529016 DOI: 10.1016/j.alcohol.2018.06.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2017] [Revised: 06/25/2018] [Accepted: 06/25/2018] [Indexed: 02/08/2023]
Abstract
BACKGROUND Alcohol-related pancreatitis is common and the gastrointestinal tract plays an important role in the regulation of pancreatic exocrine function. While the relationship between pancreatic proteolytic enzymes and insulin (as well as other pancreatic hormones) has been investigated in detail, little is known about the relationship between pancreatic proteolytic enzymes and gastrointestinal humoral factors. The aim of this study was to study the associations between trypsin, chymotrypsin, and a panel of gastrointestinal humoral factors in patients after an episode of alcohol-related versus non-alcohol-related pancreatitis. METHODS Fasting venous blood samples were analyzed for trypsin, chymotrypsin, cholecystokinin, gastrin, ghrelin, gastrin-related peptide, neuropeptide Y, peptide YY, secretin, and vasoactive intestinal peptide. Linear regression analysis was used in three statistical models, adjusting for covariates (age, sex, ethnicity, smoking, exercise, body mass index, dysglycemia, recurrence of pancreatitis, duration of pancreatitis, and severity of pancreatitis). RESULTS The study included 21 patients with alcohol-related pancreatitis and 72 with non-alcohol-related pancreatitis. Gastrin, cholecystokinin, and vasoactive intestinal peptide were significantly associated with chymotrypsin in all three statistical models and resulted in a 1.06, 1.98, and 2.74 times higher chymotrypsin level in alcohol-related pancreatitis, respectively. Ghrelin was significantly associated with trypsin in all three statistical models and resulted in a 2.64 times higher trypsin level in alcohol-related pancreatitis. Other associations did not demonstrate a consistent significant pattern. CONCLUSION In alcohol-related pancreatitis, several gut-related peptides are significantly associated with pancreatic exocrine function. Further studies to investigate the effect of alcohol on the interaction between cholecystokinin (as well as gastrin, ghrelin, and vasoactive intestinal peptide) and pancreatic exocrine function are warranted.
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18
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Takahashi N, Chujo D, Kajio H, Ueki K. Contribution of pancreatic α-cell function to insulin sensitivity and glycemic variability in patients with type 1 diabetes. J Diabetes Investig 2019; 10:690-698. [PMID: 30290079 PMCID: PMC6497601 DOI: 10.1111/jdi.12949] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2018] [Revised: 09/18/2018] [Accepted: 09/30/2018] [Indexed: 12/25/2022] Open
Abstract
AIMS/INTRODUCTION To evaluate the contribution of pancreatic α-cell function to the dawn phenomenon, insulin sensitivity, hepatic glucose uptake and glycemic variability in patients with type 1 diabetes. MATERIALS AND METHODS In 40 patients with type 1 diabetes, arginine stimulation tests were carried out, and the area under the curve (AUC) of glucagon was measured using radioimmunoassays (AUCglc RIA ) and enzyme-linked immunosorbent assays (AUCglc ELISA ). The ratio of the insulin dose delivered by an artificial pancreas to maintain euglycemia between 04.00 and 08.00 hours or between 00.00 and 04.00 hours was measured as the dawn index. The glucose infusion rate and hepatic glucose uptake were measured using hyperinsulinemic euglycemic clamp and clamp oral glucose loading tests. Glycemic variability in 96 h was measured by continuous glucose monitoring. RESULTS The median dawn index (1.7, interquartile range 1.0-2.8) was not correlated with AUCglc RIA (R2 = 0.03, P = 0.39) or AUCglc ELISA (R2 = 0.04, P = 0.32). The median glucose infusion rate (7.3 mg/kg/min, interquartile range 6.4-9.2 mg/kg/min) was significantly correlated with AUCglc RIA (R2 = 0.20, P = 0.02) and AUCglc ELISA (R2 = 0.21, P = 0.02). The median hepatic glucose uptake (65.3%, interquartile range 40.0-87.3%) was not correlated with AUCglc RIA (R2 = 0.07, P = 0.26) or AUCglc ELISA (R2 = 0.26, P = 0.79). The standard deviation of glucose levels measured by continuous glucose monitoring was significantly correlated with AUCglc RIA (R2 = 0.11, P = 0.049), but not with AUCglc ELISA (R2 = 0.01, P = 0.75). CONCLUSIONS Pancreatic α-cell function contributed to insulin sensitivity in patients with type 1 diabetes.
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Affiliation(s)
- Nobuyuki Takahashi
- Department of Diabetes, Endocrinology, and MetabolismCenter HospitalNational Center for Global Health and MedicineTokyoJapan
- Department of Molecular DiabetologyGraduate School of MedicineThe University of TokyoTokyoJapan
| | - Daisuke Chujo
- Department of Diabetes, Endocrinology, and MetabolismCenter HospitalNational Center for Global Health and MedicineTokyoJapan
| | - Hiroshi Kajio
- Department of Diabetes, Endocrinology, and MetabolismCenter HospitalNational Center for Global Health and MedicineTokyoJapan
| | - Kohjiro Ueki
- Department of Diabetes, Endocrinology, and MetabolismCenter HospitalNational Center for Global Health and MedicineTokyoJapan
- Department of Molecular DiabetologyGraduate School of MedicineThe University of TokyoTokyoJapan
- Diabetes Research CenterResearch InstituteNational Center for Global Health and MedicineTokyoJapan
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Teitelman G. Heterogeneous Expression of Proinsulin Processing Enzymes in Beta Cells of Non-diabetic and Type 2 Diabetic Humans. J Histochem Cytochem 2019; 67:385-400. [PMID: 30759032 DOI: 10.1369/0022155419831641] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Although there is evidence indicating transcriptional and functional heterogeneity in human beta cells, it is unclear whether this heterogeneity extends to the expression level of the enzymes that process proinsulin to insulin in beta cells. To address this question, the expression levels of prohormone convertases (PC) 1/3, proprotein convertase 2 (PC2), and carboxypeptidase E (CPE) were determined in immune-stained sections of human pancreas. In non-diabetic donors, the level of proprotein convertase 1/3 (PC1/3) expression varied among beta cells of each islet but the average per islet was similar for all islets of each donor. Although the average PC1/3 expression of all islets examined per sample was unique for each pancreas, donors had similar levels of proinsulin/insulin expression. PC2 expression in beta cells showed less pronounced inter- and intraislet variation while CPE levels were fairly constant. The relationship between PC1/3 and PC2 expression levels was variable among different donors. Type 2 diabetes had an uneven effect on the expression levels of all three enzymes as they decrease only in some islets in a section. These findings suggest the presence of intraislet, but not interislet, variation in the expression of the proinsulin processing enzymes in non-diabetic subjects and a heterogeneous effect of type 2 diabetes on enzyme expression in islets.
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Affiliation(s)
- Gladys Teitelman
- Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, New York
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Tam V, Turcotte M, Meyre D. Established and emerging strategies to crack the genetic code of obesity. Obes Rev 2019; 20:212-240. [PMID: 30353704 DOI: 10.1111/obr.12770] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Revised: 08/27/2018] [Accepted: 08/28/2018] [Indexed: 12/11/2022]
Abstract
Tremendous progress has been made in the genetic elucidation of obesity over the past two decades, driven largely by technological, methodological and organizational innovations. Current strategies for identifying obesity-predisposing loci/genes, including cytogenetics, linkage analysis, homozygosity mapping, admixture mapping, candidate gene studies, genome-wide association studies, custom genotyping arrays, whole-exome sequencing and targeted exome sequencing, have achieved differing levels of success, and the identified loci in aggregate explain only a modest fraction of the estimated heritability of obesity. This review outlines the successes and limitations of these approaches and proposes novel strategies, including the use of exceptionally large sample sizes, the study of diverse ethnic groups and deep phenotypes and the application of innovative methods and study designs, to identify the remaining obesity-predisposing genes. The use of both established and emerging strategies has the potential to crack the genetic code of obesity in the not-too-distant future. The resulting knowledge is likely to yield improvements in obesity prediction, prevention and care.
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Affiliation(s)
- V Tam
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada
| | - M Turcotte
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada
| | - D Meyre
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada.,Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
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Guest PC. Biogenesis of the Insulin Secretory Granule in Health and Disease. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1134:17-32. [PMID: 30919330 DOI: 10.1007/978-3-030-12668-1_2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The secretory granules of pancreatic beta cells are specialized organelles responsible for the packaging, storage and secretion of the vital hormone insulin. The insulin secretory granules also contain more than 100 other proteins including the proteases involved in proinsulin-to insulin conversion, other precursor proteins, minor co-secreted peptides, membrane proteins involved in cell trafficking and ion translocation proteins essential for regulation of the intragranular environment. The synthesis, transport and packaging of these proteins into nascent granules must be carried out in a co-ordinated manner to ensure correct functioning of the granule. The process is regulated by many circulating nutrients such as glucose and can change under different physiological states. This chapter discusses the various processes involved in insulin granule biogenesis with a focus on the granule composition in health and disease.
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Affiliation(s)
- Paul C Guest
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil.
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22
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Treatment with specific soluble factors promotes the functional maturation of transcription factor-mediated, pancreatic transdifferentiated cells. PLoS One 2018; 13:e0197175. [PMID: 29768476 PMCID: PMC5955553 DOI: 10.1371/journal.pone.0197175] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2017] [Accepted: 04/28/2018] [Indexed: 12/19/2022] Open
Abstract
Pancreatic lineage-specific transcription factors (TFs) display instructive roles in converting adult cells to endocrine pancreatic cells through a process known as transdifferentiation. However, little is known about potential factors capable of accelerating transdifferentiation following transduction to achieve the functional maturation of transdifferentiated cells. In this study, we demonstrated, using adult liver-derived progenitor cells, that soluble factors utilized in pancreatic differentiation protocols of pluripotent stem cells promote functional maturation of TFs-mediated transdifferentiated cells. Treatment with an N2 supplement in combination with three soluble factors (glucagon-like peptide-1 [GLP-1] receptor agonist, notch inhibitor, and transforming growth factor-β [TGF-β] inhibitor) enhanced liver-to-pancreas transdifferentiation based on the following findings: i) the incidence of c-peptide-positive cells increased by approximately 1.2-fold after the aforementioned treatment; ii) the c-peptide expression level in the treated cells increased by approximately 12-fold as compared with the level in the untreated cells; iii) the treated cells secreted insulin in a glucose-dependent manner, whereas the untreated cells did not; and iv) transplantation of treated-transdifferentiated cells into streptozotocin-induced immunodeficient diabetic mice led to the amelioration of hyperglycemia. These results suggest that treatment with specific soluble factors promotes the functional maturation of transdifferentiated cells. Our findings could facilitate the development of new modalities for cell-replacement therapy for patients with diabetes.
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Yoshino H, Kawakami K, Yoshino G, Hirose T. Age-related changes of proinsulin processing in diabetic and non-diabetic Japanese individuals. Geriatr Gerontol Int 2018; 18:1046-1050. [PMID: 29665183 DOI: 10.1111/ggi.13303] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Revised: 01/17/2018] [Accepted: 02/05/2018] [Indexed: 12/01/2022]
Abstract
AIM The present study was carried out to examine whether the insulin secretory mechanism deteriorates during the aging process using the new intact proinsulin assay system in non-diabetic and diabetic individuals. METHODS A total of 172 participants were separated into four groups according to their age (<64 years and >65 years) and an association of type 2 diabetes; that is, 46 older diabetics (mean age 74.5 ± 6.2 years, glycated hemoglobin [National Glycohemoglobin Standardization Program] 7.5 ± 1.3%), 27 older non-diabetics (mean age 76.9 ± 7.5 years), 48 middle-aged diabetics (mean age 50.8 ± 10.4, glycated hemoglobin 7.8 ± 1.5%) and 51 middle aged non-diabetics (mean age 46.6 ± 13.0 years) participants were enrolled. RESULTS The proinsulin/insulin (PI/I) ratio of the diabetic group was higher than that of the non-diabetic group in the older group (0.19 ± 0.12 vs 0.11 ± 0.06, P = 0.002). In the middle-aged groups, the PI/I ratio of the diabetic group was higher than that of the non-diabetic group (0.16 ± 0.15 vs 0.09 ± 0.09, P = 0.003). Simple regression analysis showed that male sex (95% CI 0.02-0.01, P = 0.004), age (95% CI 0.00-0.002, P = 0.03), lower body mass index (95% CI -0.06 to 0.00, P = 0.02) and the presence of diabetes mellitus (95% CI 0.04-0.012, P < 0.0001) were significantly associated with the increase in the PI/I ratio. Multivariate regression analysis showed that male sex and age were the independent factors determining the increase in the PI/I ratio in the non-diabetic group. After adjusted for body mass index, the PI/I ratio correlated significantly with age only in the non-diabetic group (r = 0.5, P = 0.004). CONCLUSIONS The proinsulin processing system might deteriorate not only in diabetics, but also in non-diabetic Japanese individuals with age. Also, sex-related hormones can be protective for the proinsulin processing system. Geriatr Gerontol Int 2018; 18: 1046-1050.
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Affiliation(s)
- Hiroshi Yoshino
- Diabetes Center, Shin-Suma Hospital, Kobe, Japan.,Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Toho University Graduate School of Medicine, Tokyo, Japan
| | | | - Gen Yoshino
- Diabetes Center, Shin-Suma Hospital, Kobe, Japan
| | - Takahisa Hirose
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Toho University Graduate School of Medicine, Tokyo, Japan
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Bright DJ, Dunseath GJ, Peter R, Luzio S. Stability of proinsulin in whole blood. Clin Biochem 2017; 52:153-155. [PMID: 29051035 DOI: 10.1016/j.clinbiochem.2017.10.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Revised: 10/13/2017] [Accepted: 10/13/2017] [Indexed: 10/18/2022]
Abstract
Proinsulin, the precursor for insulin, is secreted in higher concentrations when β-cells are under stress and previous studies have shown that elevated proinsulin could be used as a marker for individuals in a pre-diabetic state. The aim of this study was to assess the stability of proinsulin across a wide concentration range (3-882 and 2-187pmol/L; total and intact proinsulin respectively) in whole blood to determine whether it could be used in routine clinical care. 51 subjects (26 normal glucose tolerance, 17 impaired glucose tolerance and 8 type 2 diabetes) had blood taken into EDTA tubes at 0, 60 & 120min following a glucose load. The samples were kept at room temperature (~20°C) with aliquots taken, centrifuged and frozen at 0, 24, 48 and 72h. Comparison of the combined data (pre and post-glucose load) of baseline with 72h as a percentage of baseline gave an average of 123% (95% CI: 119-127) and 107% (95% CI: 105-109) for total and intact proinsulin respectively. A small change in the stability of total proinsulin was observed whilst there was no clinical difference over the 72h period for intact proinsulin.
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Affiliation(s)
- Dominic J Bright
- Diabetes Research Unit Cymru, Swansea University, Singleton Park, Swansea SA2 8PP, Wales, UK.
| | - Gareth J Dunseath
- Diabetes Research Unit Cymru, Swansea University, Singleton Park, Swansea SA2 8PP, Wales, UK
| | - Rajesh Peter
- Neath Port Talbot Hospital, Baglan Way, Neath Port Talbot, SA12 7BX, Wales, UK
| | - Stephen Luzio
- Diabetes Research Unit Cymru, Swansea University, Singleton Park, Swansea SA2 8PP, Wales, UK
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Tsiolaki PL, Louros NN, Zompra AA, Hamodrakas SJ, Iconomidou VA. Unraveling the aggregation propensity of human insulin C-peptide. Biopolymers 2017; 108. [PMID: 27257781 DOI: 10.1002/bip.22882] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Revised: 05/19/2016] [Accepted: 05/31/2016] [Indexed: 12/27/2022]
Abstract
Over the last 20 years, proinsulin C-peptide emerged as an important player in various biological events. Much time and effort has been spent in exploring all functional features of C-peptide and recording its implications in Diabetes mellitus. Only a few studies, though, have addressed C-peptide oligomerization and link this procedure with Diabetes. The aim of our work was to examine the aggregation propensity of C-peptide, utilizing Transmission Electron Microscopy, Congo Red staining, ATR-FTIR, and X-ray fiber diffraction at a 10 mg ml-1 concentration. Our experimental work clearly shows that C-peptide self-assembles into amyloid-like fibrils and therefore, the aggregation propensity of C-peptide is a characteristic novel feature that should be related to physiological and also pathological conditions. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 108: 1-8, 2017.
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Affiliation(s)
- Paraskevi L Tsiolaki
- Department of Cell Biology and Biophysics, Faculty of Biology, University of Athens, Panepistimiopolis, Athens, 15701, Greece
| | - Nikolaos N Louros
- Department of Cell Biology and Biophysics, Faculty of Biology, University of Athens, Panepistimiopolis, Athens, 15701, Greece
| | | | - Stavros J Hamodrakas
- Department of Cell Biology and Biophysics, Faculty of Biology, University of Athens, Panepistimiopolis, Athens, 15701, Greece
| | - Vassiliki A Iconomidou
- Department of Cell Biology and Biophysics, Faculty of Biology, University of Athens, Panepistimiopolis, Athens, 15701, Greece
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Tang W, Yuan Q, Xu B, Osei K, Wang J. Exenatide substantially improves proinsulin conversion and cell survival that augment Ins2 +/Akita beta cell function. Mol Cell Endocrinol 2017; 439:297-307. [PMID: 27658750 DOI: 10.1016/j.mce.2016.09.015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Revised: 09/16/2016] [Accepted: 09/16/2016] [Indexed: 02/06/2023]
Abstract
Proinsulin folding imperfections cause extensive beta-cell defects known in diabetes. Here, we investigated whether exenatide can alleviate such defects in proinsulin conversion, beta-cell survival, and insulin secretion, in the Ins2+/Akita beta-cells that have a spontaneous mutation (Cys 96 Tyr) in the insulin 2 gene caused dominant negative misfolding problem. 15 or 120 min exenatide administration substantially improves glucose-stimulated insulin secretion, marked in the secreted insulin levels and proinsulin/insulin ratio. This improvement is mainly due to enhanced conversion of proinsulin to insulin, having nothing to do with the prohormone convertase PC1/3 and PC2 levels. The 15 min improvement is calcium-independent. The 120 min improvement is linked to calcium and/or cAMP dependent mechanisms. This efficacy is validated during longer treatment and in Akita islets. Exenatide improves Ins2+/Akita beta-cell survival and Akita mouse's glucose tolerance. The results suggest a potential of incretin mimetics in alleviating defective proinsulin conversion and other proinsulin misfolding consequences.
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Affiliation(s)
- Wei Tang
- Department of Endocrinology, Jiangsu Province Geriatric Institute Islet Cell Senescence and Function Research Laboratory, Jiangsu Province Official Hospital, 65 Jiangsu Road, Nanjing 210024, China.
| | - Qingxin Yuan
- Department of Endocrinology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Bo Xu
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 211166, China
| | - Kwame Osei
- Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Jie Wang
- Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA; Division of Endocrinology, Jiangsu Province Hospital on Integration of Chinese and Western Medicine, Nanjing University of Chinese and Western Medicine, Nanjing, Jiangsu 210028, China.
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Bharmal SH, Pendharkar SA, Singh RG, Goodarzi MO, Pandol SJ, Petrov MS. Relationship between circulating levels of pancreatic proteolytic enzymes and pancreatic hormones. Pancreatology 2017; 17:876-883. [PMID: 28958690 PMCID: PMC6880952 DOI: 10.1016/j.pan.2017.09.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Revised: 08/15/2017] [Accepted: 09/18/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND While the close morphological relationship between the exocrine and endocrine pancreas is well established, their functional interaction remains poorly understood. The aim of this study was to investigate the associations between circulating levels of pancreatic proteolytic enzymes and insulin, as well as other pancreatic hormones. METHODS Fasting venous blood samples were collected and analyzed for trypsin, chymotrypsin, insulin, glucagon, somatostatin, and pancreatic polypeptide. Linear regression analysis was used in unadjusted and two adjusted (accounting for prediabetes/diabetes, body mass index, smoking, and other covariates) statistical models. RESULTS A total of 93 individuals with a history of acute pancreatitis were included in this cross-sectional study. Chymotrypsin was significantly associated with insulin in the two adjusted models (p = 0.005; p = 0.003) and just missed statistical significance in the unadjusted model (p = 0.066). Chymotrypsin was significantly associated with glucagon in both unadjusted (p = 0.025) and adjusted models (p = 0.014; p = 0.015); as well as with somatostatin - in both unadjusted (p = 0.001) and adjusted models (p = 0.001; p = 0.002). Trypsin was not significantly associated with insulin in any of the models but was significantly associated with glucagon in both unadjusted (p < 0.001) and adjusted models (p < 0.001), and pancreatic polypeptide in both unadjusted (p < 0.001) and adjusted (p < 0.001) models. CONCLUSION The state of hyperinsulinemia is characterized by a dysfunction of the exocrine pancreas. In particular, chymotrypsin is increased in the state of hyperinsulinemia and trypsin is significantly associated with glucagon and pancreatic polypeptide.
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Affiliation(s)
- Sakina H. Bharmal
- Department of Surgery, University of Auckland, Auckland, New Zealand
| | | | - Ruma G. Singh
- Department of Surgery, University of Auckland, Auckland, New Zealand
| | - Mark O. Goodarzi
- Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Stephen J. Pandol
- Departments of Medicine and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Maxim S. Petrov
- Department of Surgery, University of Auckland, Auckland, New Zealand,Corresponding author. Room 12.085 A, Level 12, Auckland City Hospital, Auckland 1023, New Zealand. (M.S. Petrov)
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Ramos JS, Dalleck LC, Borrani F, Mallard AR, Clark B, Keating SE, Fassett RG, Coombes JS. The effect of different volumes of high-intensity interval training on proinsulin in participants with the metabolic syndrome: a randomised trial. Diabetologia 2016; 59:2308-2320. [PMID: 27480182 DOI: 10.1007/s00125-016-4064-7] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Accepted: 06/28/2016] [Indexed: 01/09/2023]
Abstract
AIMS/HYPOTHESIS The continuous demand for insulin in the face of insulin resistance, coupled with the glucolipotoxic environment associated with the metabolic syndrome (MetS), adversely affects the quality of insulin produced and secreted by the pancreatic beta cells. This is depicted by increased circulating intact proinsulin concentration, which is associated with increased MetS severity and risk of cardiovascular (CV) mortality. High-intensity interval training (HIIT) has been shown to reduce insulin resistance and other CV disease risk factors to a greater degree than moderate-intensity continuous training (MICT). We therefore aimed to investigate the impact of MICT and different volumes of HIIT on circulating intact proinsulin concentration. METHODS This was a substudy of the 'Exercise in prevention of Metabolic Syndrome' (EX-MET) multicentre trial. Sixty-six individuals with MetS were randomised to 16 weeks of: (1) MICT (n = 21, 30 min at 60-70% peak heart rate [HRpeak], five times/week); (2) 4HIIT (n = 22, 4 × 4 min bouts at 85-95% HRpeak, interspersed with 3 min of active recovery at 50-70% HRpeak, three times/week); or (3) 1HIIT (n = 23, 1 × 4 min bout at 85-95% HRpeak, three times/week). A subanalysis investigated the differential impact of these training programmes on intact proinsulin concentration in MetS individuals with type 2 diabetes (MICT, n = 6; 4HIIT, n = 9; 1HIIT, n = 12) and without type 2 diabetes (MICT, n = 15; 4HIIT, n = 13; 1HIIT, n = 11). Intact proinsulin, insulin and C-peptide concentrations were measured in duplicate via ELISA, following a 12 h fast, before and after the exercise programme. Fasting intact proinsulin concentration was also expressed relative to insulin and C-peptide concentrations. RESULTS Following the exercise training, there were no significant (p > 0.05) changes in fasting intact proinsulin concentration indices in all participants (pre- vs post-programme proinsulin, proinsulin:insulin, proinsulin:C-peptide: MICT 19% decrease, 6% increase, 4% increase; 4HIIT 19% decrease, 8% decrease, 11% decrease; 1HIIT 34% increase, 49% increase, 36% increase). In participants who did not have type 2 diabetes, only 4HIIT significantly (p < 0.05) reduced fasting intact proinsulin concentration indices from pre to post intervention (pre- vs post-programme proinsulin, proinsulin:insulin, proinsulin:C-peptide: 4HIIT 32% decrease, 26% decrease, 32% decrease, p < 0.05; 1HIIT, 14% increase, 32% increase, 16% increase, p > 0.05; MICT 27% decrease, 17% decrease, 11% decrease), with a group × time interaction effect, indicating a greater reduction in intact proinsulin indices following 4HIIT compared with MICT and 1HIIT. There were no significant (p > 0.05) changes in intact proinsulin concentration indices in participants with type 2 diabetes. CONCLUSIONS/INTERPRETATION Higher-volume HIIT (4HIIT) improved insulin quality in MetS participants without type 2 diabetes. TRIAL REGISTRATION ClinicalTrials.gov NCT01676870 FUNDING: The study was funded by the Norwegian University of Science and Technology and from an unrestricted research grant from the Coca-Cola company. Funding for the collection of physical activity data was derived from a 'UQ New Staff Start Up' grant awarded to B. Clark.
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Affiliation(s)
- Joyce S Ramos
- Centre for Research on Exercise, Physical Activity and Health, School of Human Movement and Nutrition Sciences, The University of Queensland, Blair Drive, St Lucia, QLD, Australia
| | - Lance C Dalleck
- Recreation, Exercise, and Sport Science Department, Western State Colorado University, Gunnison, CO, USA
| | - Fabio Borrani
- Institut des Sciences du Sport de l'Université de Lausanne (ISSUL), University of Lausanne, Lausanne, Switzerland
- Department of Physiology, Faculty of Biology and Medicine, Lausanne University, Lausanne, Switzerland
| | - Alistair R Mallard
- Centre for Research on Exercise, Physical Activity and Health, School of Human Movement and Nutrition Sciences, The University of Queensland, Blair Drive, St Lucia, QLD, Australia
| | - Bronwyn Clark
- School of Public Health, Faculty of Medicine and Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia
| | - Shelley E Keating
- Centre for Research on Exercise, Physical Activity and Health, School of Human Movement and Nutrition Sciences, The University of Queensland, Blair Drive, St Lucia, QLD, Australia
| | - Robert G Fassett
- Centre for Research on Exercise, Physical Activity and Health, School of Human Movement and Nutrition Sciences, The University of Queensland, Blair Drive, St Lucia, QLD, Australia
| | - Jeff S Coombes
- Centre for Research on Exercise, Physical Activity and Health, School of Human Movement and Nutrition Sciences, The University of Queensland, Blair Drive, St Lucia, QLD, Australia.
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29
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Alarcon C, Boland BB, Uchizono Y, Moore PC, Peterson B, Rajan S, Rhodes OS, Noske AB, Haataja L, Arvan P, Marsh BJ, Austin J, Rhodes CJ. Pancreatic β-Cell Adaptive Plasticity in Obesity Increases Insulin Production but Adversely Affects Secretory Function. Diabetes 2016; 65:438-50. [PMID: 26307586 PMCID: PMC4747460 DOI: 10.2337/db15-0792] [Citation(s) in RCA: 85] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Accepted: 08/17/2015] [Indexed: 12/17/2022]
Abstract
Pancreatic β-cells normally produce adequate insulin to control glucose homeostasis, but in obesity-related diabetes, there is a presumed deficit in insulin production and secretory capacity. In this study, insulin production was assessed directly in obese diabetic mouse models, and proinsulin biosynthesis was found to be contrastingly increased, coupled with a significant expansion of the rough endoplasmic reticulum (without endoplasmic reticulum stress) and Golgi apparatus, increased vesicular trafficking, and a depletion of mature β-granules. As such, β-cells have a remarkable capacity to produce substantial quantities of insulin in obesity, which are then made available for immediate secretion to meet increased metabolic demand, but this comes at the price of insulin secretory dysfunction. Notwithstanding, it can be restored. Upon exposing isolated pancreatic islets of obese mice to normal glucose concentrations, β-cells revert back to their typical morphology with restoration of regulated insulin secretion. These data demonstrate an unrealized dynamic adaptive plasticity of pancreatic β-cells and underscore the rationale for transient β-cell rest as a treatment strategy for obesity-linked diabetes.
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Affiliation(s)
- Cristina Alarcon
- Kovler Diabetes Center, Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, The University of Chicago, Chicago, IL
| | - Brandon B Boland
- Kovler Diabetes Center, Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, The University of Chicago, Chicago, IL
| | - Yuji Uchizono
- Kovler Diabetes Center, Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, The University of Chicago, Chicago, IL
| | - Patrick C Moore
- Kovler Diabetes Center, Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, The University of Chicago, Chicago, IL
| | - Bryan Peterson
- Kovler Diabetes Center, Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, The University of Chicago, Chicago, IL
| | - Suryalekha Rajan
- Kovler Diabetes Center, Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, The University of Chicago, Chicago, IL
| | - Olivia S Rhodes
- Kovler Diabetes Center, Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, The University of Chicago, Chicago, IL
| | - Andrew B Noske
- Institute for Molecular Bioscience, Queensland Bioscience Precinct, The University of Queensland, Brisbane, Queensland, Australia
| | - Leena Haataja
- Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical School, Ann Arbor, MI
| | - Peter Arvan
- Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical School, Ann Arbor, MI
| | - Bradly J Marsh
- Institute for Molecular Bioscience, Queensland Bioscience Precinct, The University of Queensland, Brisbane, Queensland, Australia
| | - Jotham Austin
- Advanced Electron Microscope Core Facility, The University of Chicago, Chicago, IL
| | - Christopher J Rhodes
- Kovler Diabetes Center, Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, The University of Chicago, Chicago, IL
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Imai S, Takahashi T, Naito S, Yamauchi A, Okada C, Notsu Y, Sakikawa I, Hatanaka M, Iwasaki T, Morita A, Fujii I, Yamane S. Development of a novel immunoassay specific for mouse intact proinsulin. Anal Biochem 2015; 484:91-8. [DOI: 10.1016/j.ab.2015.05.012] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Revised: 05/13/2015] [Accepted: 05/18/2015] [Indexed: 11/16/2022]
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Vangipurapu J, Stančáková A, Kuulasmaa T, Kuusisto J, Laakso M. Both fasting and glucose-stimulated proinsulin levels predict hyperglycemia and incident type 2 diabetes: a population-based study of 9,396 Finnish men. PLoS One 2015; 10:e0124028. [PMID: 25853252 PMCID: PMC4390238 DOI: 10.1371/journal.pone.0124028] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2014] [Accepted: 03/09/2015] [Indexed: 01/11/2023] Open
Abstract
Background Hyperproinsulinemia is an indicator of β-cell dysfunction, and fasting proinsulin levels are elevated in patients with hyperglycemia. It is not known whether proinsulin levels after a glucose load are better predictors of hyperglycemia and type 2 diabetes than fasting proinsulin. Methods Participants were 9,396 Finnish men (mean±SD, age 57.3±7.1 years, BMI 27.0±4.0 kg/m2) of the population-based METabolic Syndrome In Men Study who were non-diabetic at the recruitment, and who participated in a 6-year follow-up study. Proinsulin and insulin levels were measured in the fasting state and 30 and 120 min after an oral glucose load. Area under the curve (AUC) and proinsulin to insulin ratios were calculated. Results Fasting proinsulin, proinsulin at 30 min and proinsulin AUC during the first 30 min of an oral glucose tolerance test significantly predicted both the worsening of hyperglycemia and type 2 diabetes after adjustment for confounding factors. Further adjustment for insulin sensitivity (Matsuda index) or insulin secretion (Disposition index) weakened these associations. Insulin sensitivity had a major impact on these associations. Conclusion Our results suggest that proinsulin in the fasting state and after an oral glucose load similarly predict the worsening of hyperglycemia and conversion to type 2 diabetes.
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Affiliation(s)
- Jagadish Vangipurapu
- Faculty of Health Sciences, Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland
| | - Alena Stančáková
- Faculty of Health Sciences, Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland
| | - Teemu Kuulasmaa
- Faculty of Health Sciences, Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland
| | - Johanna Kuusisto
- Faculty of Health Sciences, Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland; Department of Medicine, Kuopio University Hospital, Kuopio, Finland
| | - Markku Laakso
- Faculty of Health Sciences, Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland; Department of Medicine, Kuopio University Hospital, Kuopio, Finland
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Katsuta H, Ozawa S, Suzuki K, Takahashi K, Tanaka T, Sumitani Y, Nishida S, Kondo T, Hosaka T, Inukai K, Ishida H. The association between impaired proinsulin processing and type 2 diabetes mellitus in non-obese Japanese individuals. Endocr J 2015; 62:485-92. [PMID: 25892189 DOI: 10.1507/endocrj.ej14-0611] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
We aimed to examine the association between impaired proinsulin processing in pancreatic beta cells and type 2 diabetes mellitus in non-obese Japanese patients. Participants were divided into groups for normal glucose tolerance, prediabetes, and type 2 diabetes based on the oral glucose tolerance test (OGTT). Activities of prohormone convertase (PC) 1/3 and PC2 in fasting states were estimated. Multiple regression analysis was undertaken to ascertain if alteration of the activities of these enzymes contributes to the development of impaired glucose tolerance by comparison with HOMA-β and the oral disposition index (DI(O)). Overall, 452 subjects were included. PC1/3 activity tended to decrease in type 2 diabetes compared with normal glucose tolerance. PC2 activity showed no difference among the three groups. Decreased estimated PC1/3 activity was significantly associated with type 2 diabetes after adjustment for sex, age, creatinine, triglycerides, HOMA-β and DI(O). Odds ratios (95% CI) of PC1/3, HOMA-β, and DI(O) were 2.16 (1.12-4.19), 3.44 (1.82-6.52) and 14.60 (7.87-27.11), respectively. Furthermore, decreased PC1/3(≤1.7) combined with decreased HOMA-β (≤30) had a sensitivity of 73% and specificity of 62%. Decreased PC1/3 activity may be a useful measurement of beta-cell function alongside decreased HOMA-β or DI(O). A combined decrease in estimated fasting PC1/3 activity and HOMA-β measurement led to suspicion of type 2 diabetes in the non-obese Japanese population studied.
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Affiliation(s)
- Hidenori Katsuta
- Third Department of Internal Medicine, Division of Diabetes, Endocrinology and Metabolism, Kyorin University School of Medicine, Tokyo 181-8611, Japan
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Bonnemaison M, Bäck N, Lin Y, Bonifacino JS, Mains R, Eipper B. AP-1A controls secretory granule biogenesis and trafficking of membrane secretory granule proteins. Traffic 2014; 15:1099-121. [PMID: 25040637 DOI: 10.1111/tra.12194] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2013] [Revised: 07/07/2014] [Accepted: 07/07/2014] [Indexed: 02/06/2023]
Abstract
The adaptor protein 1A complex (AP-1A) transports cargo between the trans-Golgi network (TGN) and endosomes. In professional secretory cells, AP-1A also retrieves material from immature secretory granules (SGs). The role of AP-1A in SG biogenesis was explored using AtT-20 corticotrope tumor cells expressing reduced levels of the AP-1A μ1A subunit. A twofold reduction in μ1A resulted in a decrease in TGN cisternae and immature SGs and the appearance of regulated secretory pathway components in non-condensing SGs. Although basal secretion of endogenous SG proteins was unaffected, secretagogue-stimulated release was halved. The reduced μ1A levels interfered with the normal trafficking of carboxypeptidase D (CPD) and peptidylglycine α-amidating monooxygenase-1 (PAM-1), integral membrane enzymes that enter immature SGs. The non-condensing SGs contained POMC products and PAM-1, but not CPD. Based on metabolic labeling and secretion experiments, the cleavage of newly synthesized PAM-1 into PHM was unaltered, but PHM basal secretion was increased in sh-μ1A PAM-1 cells. Despite lacking a canonical AP-1A binding motif, yeast two-hybrid studies demonstrated an interaction between the PAM-1 cytosolic domain and AP-1A. Coimmunoprecipitation experiments with PAM-1 mutants revealed an influence of the luminal domains of PAM-1 on this interaction. Thus, AP-1A is crucial for normal SG biogenesis, function and composition.
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Affiliation(s)
- Mathilde Bonnemaison
- Department of Molecular Biology and Biophysics, University of Connecticut Health Center, Farmington, CT, 06030, USA
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Lorenzo C, Hanley AJ, Rewers MJ, Haffner SM. Disproportionately elevated proinsulinemia is observed at modestly elevated glucose levels within the normoglycemic range. Acta Diabetol 2014; 51:617-23. [PMID: 24532116 DOI: 10.1007/s00592-014-0565-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2013] [Accepted: 01/27/2014] [Indexed: 12/31/2022]
Abstract
We aimed to evaluate disproportional proinsulinemia in the pre-diabetic state by analyzing the cross-sectional differences between proinsulin (PI) ratios across the entire range of fasting and 2-h plasma glucose. The study sample was 1,016 participants in the insulin resistance atherosclerosis study, who had no previous diagnosis of diabetes. Insulin sensitivity index (SI) and acute insulin response (AIR) were measured by the frequently sampled intravenous glucose tolerance test. Fasting intact and split PI-to-insulin ratios (PI/I, SPI/I), intact and split PI-to-C-peptide ratios (PI/C-pep, SPI/C-pep), and SI-adjusted AIR were assessed as a function of fasting and 2-h glucose levels. SI-adjusted AIR was decreased (fasting glucose 96-98 mg/dl; 2-h glucose 120-131 mg/dl) and SPI/C-pep increased at modestly elevated fasting glucose and 2-h glucose within the normal glucose tolerance range (fasting glucose 96-98 mg/dl; 2-h glucose 132-142 mg/dl). PI/I was not increased until plasma glucose values were in the diabetic range of fasting glucose (>126 mg/dl) or the impaired glucose tolerance range of 2-h glucose (143-156 mg/dl). SPI/I and PI/C-pep as a function of fasting and 2-h glucose were situated between the curves for SPI/C-pep and PI/I. In conclusion, inappropriate amounts of PI and conversion intermediaries are demonstrated at modestly elevated glucose levels within the normoglycemic range. Ratios that use SPI in the numerator or C-pep in the denominator (and especially SPI/C-pep) are more sensitive to early glycemic excursions than PI/I. Disordered processing of PI may accompany derangements in early insulin secretory response.
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Affiliation(s)
- Carlos Lorenzo
- Department of Medicine, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX, 78229, USA,
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Alarcon C, Verchere CB, Rhodes CJ. Translational control of glucose-induced islet amyloid polypeptide production in pancreatic islets. Endocrinology 2012; 153:2082-7. [PMID: 22408171 PMCID: PMC3339648 DOI: 10.1210/en.2011-2019] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Dysfunctional islet amyloid polypeptide (IAPP) biosynthesis and/or processing are thought contribute to formation of islet amyloid in type 2 diabetes. However, it is unclear how normal pro-IAPP biosynthesis and processing are regulated to be able to define such dysfunction. Here, it was found that acute exposure to high glucose concentrations coordinately regulated the biosynthesis of pro-IAPP, proinsulin, and its proprotein convertase PC1/3 in normal isolated rat islets, without affecting their respective mRNA levels. Pro-7B2 biosynthesis, like that of pro-PC2, did not appreciably change, but this was likely due to a much higher expression in pancreatic α-cells masking glucose regulation of their biosynthesis in β-cells. Biosynthesis of pro-SAAS, the putative PC1/3 chaperone, was unaffected by glucose, consistent with its scarce expression in β-cells. We conclude that translational control of pro-IAPP biosynthesis, in parallel to the pro-PC1/3, pro-PC2, and pro-7B2 proprotein-processing endopeptidases/chaperones, is the predominate mechanism to produce IAPP in islet β-cells.
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Affiliation(s)
- Cristina Alarcon
- The Kovler Diabetes Center, Department of Medicine, Section on Endocrinology, Diabetes, and Metabolism, The University of Chicago, Chicago, Illinois 60637, USA
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Wang J, Osei K. Proinsulin maturation disorder is a contributor to the defect of subsequent conversion to insulin in β-cells. Biochem Biophys Res Commun 2011; 411:150-5. [DOI: 10.1016/j.bbrc.2011.06.119] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2011] [Accepted: 06/17/2011] [Indexed: 11/24/2022]
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Ionescu-Tirgoviste C, Despa F. Biophysical alteration of the secretory track in β-cells due to molecular overcrowding: the relevance for diabetes. Integr Biol (Camb) 2010; 3:173-9. [PMID: 21180710 DOI: 10.1039/c0ib00029a] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Recent data demonstrate that accumulation of misfolded proteins within the early part of the secretory track of β-cells causes impaired insulin synthesis and development of diabetes. The molecular mechanism of this cellular dysfunction remains largely unknown. Using basic molecular principles and computer simulations, we suggested recently that hyperglycemic conditions can generate substantial molecular crowding effects in the secretory track of β-cells leading to significant alterations of the insulin biosynthesis capabilities. Here, we review the major molecular mechanisms that may be implicated in the alteration of insulin synthesis in susceptible β-cells. Steric repulsions and volume exclusion in the endoplasmic reticulum (ER) increase the propensity of misfolding of proinsulin (the precursor molecule of insulin). In addition, similar forces might act in the next secretory compartments (Golgi and vesicles) leading to (i) altered packaging of proinsulin in vesicles (ii) entrapment of proinsulin convertases and/or restricted accessibility for these convertases to the cleavage sites on the surface of the proinsulin and (iii) depressed kinetic rate of the transformation of the native proinsulin in active insulin and C-peptide. These concepts are expressed in simple mathematical terms relating the kinetic coefficient of proinsulin to insulin conversion to the levels of proinsulin misfolding and hyperglycemic stress. The present approach is useful for understanding molecular phenomena associated with the pathogenesis of diabetes. It also offers practical means for predicting the state of pancreatic β-cells from measurements of the insulin to proinsulin ratio in the blood. This is of immediate clinical relevance and may improve the diagnosis of diabetes.
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Abstract
BACKGROUND Pancreatic β cells respond to chronic hyperglycemia by increasing the synthesis of proinsulin (the precursor molecule of insulin). Prolonged stimulations lead to accumulation of misfolded proinsulin in the secretory track, delayed insulin secretion, and release of unprocessed proinsulin in the blood. The molecular mechanisms connecting the state of endoplasmic reticulum overloading with the efficiency of proinsulin to insulin conversion remain largely unknown. METHODS Computer simulations can help us to understand mechanistic features of the β-cell secretory defect and to design experiments that may reveal the molecular basis of this dysfunction. We used molecular crowding concepts and statistical thermodynamics to dissect possible biophysical mechanisms underlying the alteration of the secretory track of β cells and to elucidate the chemistry aspects of the secretory dysfunction. We then used numerical algorithms to relate the degree of biophysical alteration of these secretory compartments with the change of proinsulin to insulin conversion rate. RESULTS Our computer simulations suggest that overloading the endoplasmic reticulum initiates downstream molecular crowding effects that affect protein translational mechanisms, including proinsulin misfolding, delayed packing of proinsulin in secretory vesicles, and low kinetic coefficient of proinsulin to insulin conversion. CONCLUSIONS Together with previous experimental data, the present study can help us to better understand chemistry aspects related to the secondary translational mechanisms in β cells and how hyperglycemic stress can alter secretory function. This can give a further impetus to the development of novel software to be used in a clinical setup for prediction and assessment of diabetic states in susceptible patients.
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Affiliation(s)
- Florin Despa
- Department of Pharmacology, University of California Davis, Davis, California 95616, USA.
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Rossdale PD, Ousey JC. Fetal programming for athletic performance in the horse: potential effects of IUGR. EQUINE VET EDUC 2010. [DOI: 10.1111/j.2042-3292.2003.tb01811.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Rossdale PD, Ousey JC. Fetal programming for athletic performance in the horse: potential effects of IUGR. EQUINE VET EDUC 2010. [DOI: 10.1111/j.2042-3292.2002.tb00148.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Abstract
Type 1 and type 2 diabetes mellitus together are predicted to affect over 300 million people worldwide by the year 2020. A relative or absolute paucity of functional β-cells is a central feature of both types of disease, and identifying the pathways that mediate the embryonic origin of new β-cells and mechanisms that underlie the proliferation of existing β-cells are major efforts in the fields of developmental and islet biology. A poor secretory response of existing β-cells to nutrients and hormones and the defects in hormone processing also contribute to the hyperglycemia observed in type 2 diabetes and has prompted studies aimed at enhancing β-cell function. The factors that contribute to a greater susceptibility in aging individuals to develop diabetes is currently unclear and may be linked to a poor turnover of β-cells and/or enhanced susceptibility of β-cells to apoptosis. This review is an update on the recent work in the areas of islet/β-cell regeneration and hormone processing that are relevant to the pathophysiology of the endocrine pancreas in type 1, type 2 and obesity-associated diabetes.
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Affiliation(s)
- Anke Assmann
- Research Division, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA
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Ferrannini E, Muscelli E, Natali A, Gabriel R, Mitrakou A, Flyvbjerg A, Golay A, Hojlund K. Association of fasting glucagon and proinsulin concentrations with insulin resistance. Diabetologia 2007; 50:2342-7. [PMID: 17846745 DOI: 10.1007/s00125-007-0806-x] [Citation(s) in RCA: 68] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2007] [Accepted: 07/24/2007] [Indexed: 01/29/2023]
Abstract
AIMS/HYPOTHESIS Hyperproinsulinaemia and relative hyperglucagonaemia are features of type 2 diabetes. We hypothesised that raised fasting glucagon and proinsulin concentrations may be associated with insulin resistance (IR) in non-diabetic individuals. METHODS We measured IR [by a euglycaemic-hyperinsulinaemic (240 pmol min(-1) m(-2)) clamp technique] in 1,296 non-diabetic (on a 75 g OGTT) individuals [716 women and 579 men, mean age 44 years, BMI 26 kg/m(2) (range 18-44 kg/m(2))] recruited at 19 centres in 14 European countries. IR was related to fasting proinsulin or pancreatic glucagon concentrations in univariate and multivariate analyses. Given its known relationship to IR, serum adiponectin was used as a positive control. RESULTS In either sex, both glucagon and proinsulin were directly related to IR, while adiponectin was negatively associated with it (all p < 0.0001). In multivariate models, controlling for known determinants of insulin sensitivity (i.e. sex, age, BMI and glucose tolerance) as well as factors potentially affecting glucagon and proinsulin (i.e. fasting plasma glucose and C-peptide concentrations), glucagon and proinsulin were still positively associated, and adiponectin was negatively associated, with IR. Finally, when these associations were tested as the probability that individuals in the top IR quartile would have hormone levels in the top quartile of their distribution independently of covariates, the odds ratio was approximately 2 for both glucagon (p = 0.05) and proinsulin (p = 0.02) and 0.36 for adiponectin (p < 0.0001). CONCLUSIONS/INTERPRETATION Whole-body IR is independently associated with raised fasting plasma glucagon and proinsulin concentrations, possibly as a result of IR at the level of alpha cells and beta cells in pancreatic islets.
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Affiliation(s)
- E Ferrannini
- Department of Internal Medicine and CNR Institute of Clinical Physiology, University of Pisa, Pisa, Italy.
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Jia EZ, Yang ZJ, Zhu TB, Wang LS, Chen B, Cao KJ, Huang J, Ma WZ. Proinsulin Is an Independent Predictor of the Angiographical Characteristics of Coronary Atherosclerosis. Cardiology 2007; 110:106-11. [DOI: 10.1159/000110488] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2006] [Accepted: 02/17/2007] [Indexed: 11/19/2022]
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DESAI M, HALES CN. ROLE OF FETAL AND INFANT GROWTH IN PROGRAMMING METABOLISM IN LATER LIFE. Biol Rev Camb Philos Soc 2007. [DOI: 10.1111/j.1469-185x.1997.tb00016.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Jia EZ, Yang ZJ, Yuan B, Zang XL, Wang RH, Zhu TB, Wang LS, Chen BO, Cao KJ, Huang J, Ma WZ. Relationship between true fasting plasma insulin level and angiographic characteristics of coronary atherosclerosis. Clin Cardiol 2006; 29:25-30. [PMID: 16477774 PMCID: PMC6654690 DOI: 10.1002/clc.4960290107] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND Reports about the relationships between specific insulin concentration and coronary heart disease risk are controversial. HYPOTHESIS The objective of this study was to examine the association between insulin level and the severity of coronary atherosclerosis. METHODS The study population consisted of 507 consecutive patients (376 men and 131 women) who underwent coronary angiography for suspected or known coronary atherosclerosis. The patients' habits of smoking and drinking were investigated, and anthropometric measurements including body mass index, systolic and diastolic blood pressures, as well as plasma measurements including lipids and blood glucose were taken. The true insulin level was measured using a highly sensitive two-site sandwich ELISA. The severity of coronary atherosclerosis was defined by the Gensini score system. The statistical methods including Kruskal-Wallis test, chi-square analysis, Spearman correlation analysis, and multivariate stepwise linear regression analysis were employed to explore the relationship between specific insulin level and coronary atherosclerosis. RESULTS When the Gensini score was examined as a categorical variable classified by tertile values, subjects with a high Gensini score had significantly higher values of fasting plasma specific insulin level (p = 0.022). The Spearman correlation analysis suggest that the Gensini score correlated significantly with true insulin (mIU/l) (r = 0.095, p = 0.033). However, the results from the multivariate stepwise linear regression analysis show that the association between specific insulin level and severity of coronary atherosclerosis lost its significance. CONCLUSIONS The level of plasma fasting specific insulin was associated significantly with the severity of coronary atherosclerosis, as measured by Gensini score, but hyperinsulinemia showed no association with the severity of coronary atherosclerosis in multivariate analyses.
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Affiliation(s)
- En-Zhi Jia
- Department of Cardiovascular Medicine, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
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Huang K, Dong J, Phillips NB, Carey PR, Weiss MA. Proinsulin Is Refractory to Protein Fibrillation. J Biol Chem 2005; 280:42345-55. [PMID: 16239223 DOI: 10.1074/jbc.m507110200] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Insulin is susceptible to fibrillation, a misfolding process leading to well ordered cross-beta assembly. Protection from fibrillation in beta cells is provided by sequestration of the susceptible monomer within zinc hexamers. We demonstrate that proinsulin is refractory to fibrillation under conditions that promote the rapid fibrillation of zinc-free insulin. Proinsulin fibrils, as probed by Raman microscopy, are nonetheless similar in structure to insulin fibrils. The connecting peptide, although not well ordered in native proinsulin, participates in a fibril-specific beta-sheet. Native insulin and proinsulin exhibit similar free energies of unfolding as inferred from guanidine denaturation studies: relative amyloidogenicities are thus not correlated with global stability. Strikingly, the susceptibility of proinsulin to fibrillation is increased by scission of the connecting peptide at single sites. We thus propose that the connecting peptide constrains a large scale conformational change in the misfolded protein. A tethering mechanism is proposed based on a model of an insulin protofilament derived from electron-microscopic image reconstruction. The proposed relationship between cross-beta assembly and protein topology is supported by studies of single-chain analogs (mini-proinsulin and insulin-like growth factor I) in which foreshortened connecting peptides further retard fibrillation. In addition to its classic function to facilitate disulfide pairing, the connecting peptide may protect beta cells from toxic protein misfolding in the endoplasmic reticulum.
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Affiliation(s)
- Kun Huang
- Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio 44106, USA
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Jia EZ, Yang ZJ, Chen SW, Qi GY, You CF, Ma JF, Zhang JX, Wang ZZ, Qian WC, Li XL, Wang HY, Ma WZ. Significant association of insulin and proinsulin with clustering of cardiovascular risk factors. World J Gastroenterol 2005; 11:149-53. [PMID: 15609415 PMCID: PMC4205375 DOI: 10.3748/wjg.v11.i1.149] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the association between true insulin and proinsulin and clustering of cardiovascular risk factors.
METHODS: Based on the random stratified sampling principles, 1196 Chinese people (533 males and 663 females, aged 35-59 years with an average age of 46.69 years) were recruited. Biotin-avidin based double monoclonal antibody ELISA method was used to detect the true insulin and proinsulin, and a risk factor score was set to evaluate individuals according to the number of risk factors.
RESULTS: The median (quartile range) of true insulin and proinsulin was 4.91 mIu/L (3.01-7.09 mIu/L) and 3.49 pmol/L (2.14-5.68 pmol/L) respectively, and the true insulin level of female subjects was significantly higher than that of male subjects (P = 0.000), but the level of proinsulin displayed no significant difference between males and females (P = 0.566). The results of covariate ANOVA after age and sex were controlled showed that subjects with any of the risk factors had a significantly higher true insulin level (P = 0.002 for hypercholesterolemia, P = 0.021 for high low-density lipoprotein cholesterol, P = 0.003 for low high-density lipoprotein cholesterol, and P = 0.000 for other risk factors) and proinsulin level (P = 0.001 for low high-density lipoprotein cholesterol, and P = 0.000 for other risk factors) than those with no risk factors. Furthermore, subjects with higher risk factor scores had a higher true insulin and proinsulin level than those with lower risk factor scores (P = 0.000). The multiple linear regression models showed that true insulin and proinsulin were significantly related to cardiovascular risk factor scores respectively (P = 0.000).
CONCLUSION: True insulin and proinsulin are significantly associated with the clustering of cardiovascular risk factors.
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Affiliation(s)
- En-Zhi Jia
- Department of Cardiovascular Epidemiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China.
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Song SH, Rhodes CJ, Veldhuis JD, Butler PC. Diazoxide attenuates glucose-induced defects in first-phase insulin release and pulsatile insulin secretion in human islets. Endocrinology 2003; 144:3399-405. [PMID: 12865318 DOI: 10.1210/en.2003-0056] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Humans with type-2 diabetes mellitus (TTDM) have hyperglycemia ( approximately 11 mM) and impaired glucose-mediated insulin secretion characterized by impaired first-phase insulin release (FPIR) and pulsatile insulin release. Culture of islets from nondiabetic humans in very high glucose concentrations ( approximately 20-30 mM) for 96 h causes impaired FPIR. We sought to determine 1). whether human islets cultured at a glucose concentration of approximately 11 mM (comparable to TTDM) recapitulates impaired insulin secretion in TTDM, specifically impaired FPIR and insulin pulse mass with an increased proinsulin/insulin (PI/I) secretion ratio; and 2). whether these changes can be attenuated by addition of diazoxide to islets cultured with 11 mM glucose. Islets cultured with 11 mM glucose for 96 h had 75% depleted insulin stores (P < 0.05), decreased FPIR and insulin pulse mass (P < 0.05), and an approximately 3-fold increase in the ratio of PI/I islet content and in secretion ratio (P < 0.05). Addition of diazoxide to islets cultured with 11 mM glucose decreased insulin secretion during static incubation, leading to relative preservation of insulin stores and enhanced insulin secretion during subsequent perifusion; FPIR increased by 162% (P < 0.05) and insulin pulse mass by 150% (P < 0.05) vs. no diazoxide. The mean islet PI/I content and islet PI/I secretion ratio were also decreased by approximately 70% (P < 0.05) by prior addition of diazoxide to islets during culture with 11 mM glucose. FPIR and insulin pulse mass were related to islet insulin stores (P < 0.001 for FPIR and P < 0.001 for pulse amplitude). In conclusion, the pattern of defects of insulin secretion present in TTDM (impaired FPIR and pulsatile insulin secretion, increased PI/I ratio) can be recapitulated in human islets cultured with 11 mM glucose for 96 h. These defects can be at least partially offset by concurrent inhibition of insulin secretion by diazoxide, which also preserves insulin stores. Defective insulin secretion in TTDM may be, at least in part, due to depletion of available insulin stores secondary to chronic increased demand (insulin resistance and hyperglycemia) in the setting of a decreased beta-cell mass.
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Affiliation(s)
- Soon H Song
- Division of Endocrinology and Diabetes, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA
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Pradhan AD, Manson JE, Meigs JB, Rifai N, Buring JE, Liu S, Ridker PM. Insulin, proinsulin, proinsulin:insulin ratio, and the risk of developing type 2 diabetes mellitus in women. Am J Med 2003; 114:438-44. [PMID: 12727576 DOI: 10.1016/s0002-9343(03)00061-5] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
PURPOSE To assess the associations among baseline levels of fasting insulin and proinsulin, proinsulin:insulin ratio, and the development of type 2 diabetes mellitus in apparently healthy middle-aged women. METHODS In a nested case-control study involving a nationwide cohort of 27,628 participants from the Women's Health Study, 126 women with diabetes diagnosed during a 4-year follow-up period were compared with 225 age-matched controls. Fasting insulin level and proinsulin:insulin ratio were assessed in quartiles, and proinsulin level was assessed in categories (< or =4.0 pmol/L, 4.01 to 6.99 pmol/L, > or =7.0 pmol/L). The risk of developing type 2 diabetes was determined using conditional logistic regression analysis that adjusted for body mass index and other diabetes risk factors. RESULTS Baseline insulin and proinsulin levels and proinsulin:insulin ratios were significantly higher among cases than among controls. Women with elevated insulin levels in the highest as compared with the lowest quartile were more likely to develop diabetes (odds ratio [OR] = 5.6; 95% confidence interval [CI]: 1.8 to 17.6), as were women with elevated (> or =7.0 pmol/L vs. < or =4.0 pmol/L) proinsulin levels (OR = 16.4; 95% CI: 5.8 to 46.8) and women with proinsulin:insulin ratios in the highest quartile (OR = 9.6; 95% CI: 3.1 to 30.8). Similar results were observed among women with a baseline hemoglobin A(1c) level < or =6.0%. In time-trend analyses, fasting insulin was a consistent predictor of long-term risk. Proinsulin and proinsulin:insulin ratio, although predictive throughout the study, were especially strong predictors of rapid progression to type 2 diabetes. CONCLUSION Elevated fasting insulin and proinsulin levels and proinsulin:insulin ratio are associated with an increased risk of developing type 2 diabetes in apparently healthy middle-aged women.
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Affiliation(s)
- Aruna D Pradhan
- Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02215, USA.
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Ohkubo K, Naito Y, Fujiwara T, Miyazaki JI, Ikehara Y, Ono J. Inhibitory effect of the alpha1-antitrypsin Pittsburgh type-mutant (alpha1-PIM/R) on proinsulin processing in the regulated secretory pathway of the pancreatic beta-cell line MIN6. Endocr J 2003; 50:9-20. [PMID: 12733705 DOI: 10.1507/endocrj.50.9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
To elucidate its effect on proinsulin processing, we introduced the expression of a Pittsburgh type-mutant, alpha1-protease inhibitor M/R (alpha1-PIM/R) and its chimera protein with growth hormone (GH) (GHalpha1-PIM/R) into MIN6 cells. In metabolic labeling and chasing experiments with [3H]-Leu and [35S]-Met, proinsulin appeared in the medium during stimulatory secretion only from MIN6 clones expressing GHalpha1-PIM/R and, surprisingly, alpha1-PIM/R, but not from the clones of either the control or alpha1-PI. The major part of alpha1-PIM/R was secreted through the constitutive pathway and about 10% of total secreted alpha1-PIM/R in the chase periods entered the regulated pathway. On the other hand, GHalpha1-PIM/R was mainly transported to the secretory granules and about 80% of the total secreted GHalpha1-PIM/R in the chase periods was secreted during stimulatory secretion. In the first 3 h chase periods without stimulation, only alpha1-PIM/R and no GHalpha1-PIM/R appeared in the medium, thus suggesting that alpha1-PIM/R might be transported through a constitutive-like pathway for those periods. The alpha1-PI, which had no inhibitory effect on proinsulin processing, showed similar secretion pathways to those of alpha1-PIM/R. This implies that some part of alpha1-PIM/R and alpha1-PI entered the regulated pathway, not due to any specific interaction between the processing endoproteases and serine protease inhibitors, but due to some type of passive transport in a nonselective manner. The inhibitory effect of alpha1-PIM/R in the regulated secretory pathway was slightly but clearly evident when it was expressed in MIN6 beta-cells.
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Affiliation(s)
- Kumiko Ohkubo
- Department of Laboratory Medicine, Fukuoka University School of Medicine, Fukuoka 814-0180, Japan
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