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Kumar N, Patiyal S, Choudhury S, Tomer R, Dhall A, Raghava GPS. DMPPred: a tool for identification of antigenic regions responsible for inducing type 1 diabetes mellitus. Brief Bioinform 2023; 24:6911429. [PMID: 36524996 DOI: 10.1093/bib/bbac525] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 10/27/2022] [Accepted: 11/04/2022] [Indexed: 12/23/2022] Open
Abstract
There are a number of antigens that induce autoimmune response against β-cells, leading to type 1 diabetes mellitus (T1DM). Recently, several antigen-specific immunotherapies have been developed to treat T1DM. Thus, identification of T1DM associated peptides with antigenic regions or epitopes is important for peptide based-therapeutics (e.g. immunotherapeutic). In this study, for the first time, an attempt has been made to develop a method for predicting, designing, and scanning of T1DM associated peptides with high precision. We analysed 815 T1DM associated peptides and observed that these peptides are not associated with a specific class of HLA alleles. Thus, HLA binder prediction methods are not suitable for predicting T1DM associated peptides. First, we developed a similarity/alignment based method using Basic Local Alignment Search Tool and achieved a high probability of correct hits with poor coverage. Second, we developed an alignment-free method using machine learning techniques and got a maximum AUROC of 0.89 using dipeptide composition. Finally, we developed a hybrid method that combines the strength of both alignment free and alignment-based methods and achieves maximum area under the receiver operating characteristic of 0.95 with Matthew's correlation coefficient of 0.81 on an independent dataset. We developed a web server 'DMPPred' and stand-alone server for predicting, designing and scanning T1DM associated peptides (https://webs.iiitd.edu.in/raghava/dmppred/).
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Affiliation(s)
- Nishant Kumar
- Department of Computational Biology, Indraprastha Institute of Information Technology, Okhla Phase 3, New Delhi-110020, India
| | - Sumeet Patiyal
- Department of Computational Biology, Indraprastha Institute of Information Technology, Okhla Phase 3, New Delhi-110020, India
| | - Shubham Choudhury
- Department of Computational Biology, Indraprastha Institute of Information Technology, Okhla Phase 3, New Delhi-110020, India
| | - Ritu Tomer
- Department of Computational Biology, Indraprastha Institute of Information Technology, Okhla Phase 3, New Delhi-110020, India
| | - Anjali Dhall
- Department of Computational Biology, Indraprastha Institute of Information Technology, Okhla Phase 3, New Delhi-110020, India
| | - Gajendra P S Raghava
- Department of Computational Biology, Indraprastha Institute of Information Technology, Okhla Phase 3, New Delhi-110020, India
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Hoornstra D, Andersson MA, Johansson T, Pirhonen T, Hatakka M, Salkinoja-Salonen MS. Mitochondrial Toxicity Detected in a Health Product with a Boar Spermatozoan Bioassay. Altern Lab Anim 2019; 32:407-16. [PMID: 15651926 DOI: 10.1177/026119290403200413] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Seaweed and organic alfalfa capsules sold as "health promoting" products had repeatedly caused emesis in a consumer. Using the boar spermatozoan bioassay, the capsule contents were found to contain a toxic substance that inhibited boar sperm motility and depolarised mitochondria at low exposure concentrations of 10 microg/ml. The capsule also contained high amounts (10(5)-10(7) cfu/g), of endospore-forming bacteria and Streptomyces-like bacteria. Bacteria from the capsule produced toxic substances when cultured in the laboratory. Three different toxic responses were provoked in the spermatozoa exposed to extracts from the Streptomyces-like isolates: a) hyperpolarisation of the plasma membrane and depolarisation of the mitochondria; b) depolarisation of mitochondria similar to that caused by the capsule content extract; and c) motility inhibition, with no observed change of any cytosolic transmembrane potential. Membrane potential changes in the sperm cells exposed to the bacterial extracts were similar to those provoked by exposure to valinomycin and bafilomycin A1, to nigericin, and to oligomycin and ionomycin, respectively. Extracts prepared from Bacillus isolated from the capsule non-specifically depolarised all the cellular transmembrane potentials. The results demonstrate the potential value of a cell toxicity assay with boar spermatozoa for detecting hazardous substances in products intended for human consumption, without whole-animal exposure or using fetal calf serum for cell cultures.
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Affiliation(s)
- Douwe Hoornstra
- Department of Applied Chemistry and Microbiology, University of Helsinki, Finland
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Caporarello N, Salmeri M, Scalia M, Motta C, Parrino C, Frittitta L, Olivieri M, Cristaldi M, Avola R, Bramanti V, Toscano MA, Anfuso CD, Lupo G. Cytosolic and Calcium-Independent Phospholipases A2 Activation and Prostaglandins E2 Are Associated with Escherichia coli-Induced Reduction of Insulin Secretion in INS-1E Cells. PLoS One 2016; 11:e0159874. [PMID: 27631977 PMCID: PMC5024995 DOI: 10.1371/journal.pone.0159874] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Accepted: 09/02/2016] [Indexed: 01/01/2023] Open
Abstract
It is suspected that microbial infections take part in the pathogenesis of diabetes mellitus type 1 (T1DM). Glucose-induced insulin secretion is accompanied by the release of free arachidonic acid (AA) mainly by cytosolic- and calcium independent phospholipases A2 (cPLA2 and iPLA2). Insulinoma cell line (INS-1E) was infected with E. coli isolated from the blood culture of a patient with sepsis. Invasion assay, Scanning Electron Microscopy and Transmission Electron Microscopy demonstrated the capacity of E. coli to enter cells, which was reduced by PLA2 inhibitors. Glucose-induced insulin secretion was significantly increased after acute infection (8h) but significantly decreased after chronic infection (72h). PLA2 activities, cPLA2, iPLA2, phospho-cPLA2, and COX-2 expressions were increased after acute and, even more, after chronic E. coli infection. The silencing of the two isoforms of PLA2s, with specific cPLA2- or iPLA2-siRNAs, reduced insulin secretion after acute infection and determined a rise in insulin release after chronic infection. Prostaglandins E2 (PGE2) production was significantly elevated in INS-1E after long-term E. coli infection and the restored insulin secretion in presence of L798106, a specific EP3 antagonist, and NS-398, a COX-2 inhibitor, and the reduction of insulin secretion in presence of sulprostone, a specific EP3 agonist, revealed their involvement in the effects triggered by bacterial infection. The results obtained demonstrated that cPLA2 and iPLA2 play a key role in insulin secretion process after E. coli infection. The high concentration of AA released is transformed into PGE2, which could be responsible for the reduced insulin secretion.
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Affiliation(s)
- Nunzia Caporarello
- Dept. of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy
| | - Mario Salmeri
- Dept. of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy
| | - Marina Scalia
- Dept. of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy
| | - Carla Motta
- Dept. of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy
| | - Cristina Parrino
- Dept. of Clinical and Experimental Medicine, School of Medicine, University of Catania, Catania, Italy
| | - Lucia Frittitta
- Dept. of Clinical and Experimental Medicine, School of Medicine, University of Catania, Catania, Italy
| | - Melania Olivieri
- Dept. of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy
| | - Martina Cristaldi
- Dept. of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy
| | - Roberto Avola
- Dept. of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy
| | - Vincenzo Bramanti
- Dept. of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy
| | - Maria Antonietta Toscano
- Dept. of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy
| | - Carmelina Daniela Anfuso
- Dept. of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy
| | - Gabriella Lupo
- Dept. of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy
- * E-mail:
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Virtanen SM. Dietary factors in the development of type 1 diabetes. Pediatr Diabetes 2016; 17 Suppl 22:49-55. [PMID: 27411437 DOI: 10.1111/pedi.12341] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Revised: 11/02/2015] [Accepted: 11/06/2015] [Indexed: 12/13/2022] Open
Abstract
There are several indicators concerning the putative importance of dietary factors during the fetal period lactation, infancy and childhood in the etiology of type 1 diabetes. Among foods, cow's milk consumption has been associated with an increased risk of preclinical and/or clinical type 1 diabetes and sugars with a progression from preclinical to clinical disease. Breast milk, on the other hand, may be protective. Processed foods may be related to a greater risk of type 1 diabetes because they contain higher amounts of advanced glycation end-products. Nitrites or N-nitroso compounds in processed meat products could increase the risk of this disease. Among nutrients, n-3 fatty acids, vitamins D and E, and zinc may protect from preclinical and/or clinical type 1 diabetes. The microbial composition of foods or food's other effects on gut microbiota are receiving increasing attention, also due to their putative role in the development of type 1 diabetes. Still the number of prospective studies in this research field is limited and most of the findings remain to be replicated.
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Affiliation(s)
- Suvi M Virtanen
- Unit of Nutrition, Department of Health, National Institute for Health and Welfare, Helsinki, Finland.,School of Health Sciences, University of Tampere, Tampere, Finland.,Science Center of Pirkanmaa Hospital District, Tampere, Finland.,Center for Child Health Research, University of Tampere and University Hospital of Tampere, Tampere, Finland
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Bergamin CS, Dib SA. Enterovirus and type 1 diabetes: What is the matter? World J Diabetes 2015; 6:828-839. [PMID: 26131324 PMCID: PMC4478578 DOI: 10.4239/wjd.v6.i6.828] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2014] [Revised: 01/30/2015] [Accepted: 04/09/2015] [Indexed: 02/05/2023] Open
Abstract
A complex interaction of genetic and environmental factors can trigger the immune-mediated mechanism responsible for type 1 diabetes mellitus (T1DM) establishment. Environmental factors may initiate and possibly sustain, accelerate, or retard damage to β-cells. The role of environmental factors in this process has been exhaustive studied and viruses are among the most probable ones, especially enteroviruses. Improvements in enterovirus detection methods and randomized studies with patient follow-up have confirmed the importance of human enterovirus in the pathogenesis of T1DM. The genetic risk of T1DM and particular innate and acquired immune responses to enterovirus infection contribute to a tolerance to T1DM-related autoantigens. However, the frequency, mechanisms, and pathways of virally induced autoimmunity and β-cell destruction in T1DM remain to be determined. It is difficult to investigate the role of enterovirus infection in T1DM because of several concomitant mechanisms by which the virus damages pancreatic β-cells, which, consequently, may lead to T1DM establishment. Advances in molecular and genomic studies may facilitate the identification of pathways at earlier stages of autoimmunity when preventive and therapeutic approaches may be more effective.
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Virtanen SM, Uusitalo L, Knip M. Early introduction of complementary foods: is there a link with Type 1 diabetes? ACTA ACUST UNITED AC 2013. [DOI: 10.2217/dmt.12.55] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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La Torre D. Immunobiology of beta-cell destruction. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2013; 771:194-218. [PMID: 23393680 DOI: 10.1007/978-1-4614-5441-0_16] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Type 1 diabetes is a chronic disease characterized by severe insulin deficiency and hyperglycemia, due to autoimmune destruction of pancreatic islets of Langerhans. A susceptible genetic background is necessary, but not sufficient, for the development of the disease. Epidemiological and clinical observations underscore the importance of environmental factors as triggers of type 1 diabetes, currently under investigation. Islet-specific autoantibodies precede clinical onset by months to years and are established tools for risk prediction, yet minor players in the pathogenesis of the disease. Many efforts have been made to elucidate disease-relevant defects in the key immune effectors of islet destruction, from the early failure of specific tolerance to the vicious circle of destructive insulitis. However, the events triggering islet autoimmunity as well as the transition to overt diabetes are still largely unknown, making prevention and treatment strategies still a challenge.
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Affiliation(s)
- Daria La Torre
- Lund University, Clinical Research Center (CRC), Department of Clinical Sciences, Malmö, Sweden.
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Virtanen SM, Takkinen HM, Nevalainen J, Kronberg-Kippilä C, Salmenhaara M, Uusitalo L, Kenward MG, Erkkola M, Veijola R, Simell O, Ilonen J, Knip M. Early introduction of root vegetables in infancy associated with advanced ß-cell autoimmunity in young children with human leukocyte antigen-conferred susceptibility to Type 1 diabetes. Diabet Med 2011; 28:965-71. [PMID: 21418094 DOI: 10.1111/j.1464-5491.2011.03294.x] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
AIMS Early introduction of supplementary foods has been implicated to play a role in the development of ß-cell autoimmunity. We set out to study the effects of breastfeeding and age at introduction of supplementary foods on the development of ß-cell autoimmunity. METHODS A prospective birth cohort of 6069 infants with HLA-DQB-conferred susceptibility to Type 1 diabetes was recruited between 1996 and 2004. Antibodies against islet cells, insulin, glutamate dehydroxylase and islet antigen 2 were measured at 3- to 12-month intervals. The families recorded at home the age at introduction of new foods and, for each visit, completed a structured dietary questionnaire. The endpoint was repeated positivity for islet cell antibodies plus at least one other antibody and/or clinical Type 1 diabetes (n = 265). RESULTS Early introduction of root vegetables (by the age of 4 months) was related to increased risk of developing positivity for the endpoint [hazard ratio (95% CI) for the earliest third 1.75 (1.11-2.75) and for the middle third 1.79 (1.22-2.62) compared with the last third (> 4 months), likelihood ratio test P = 0.006], independently of the introduction of other foods and of several putative socio-demographic and perinatal confounding factors. Introducing wheat, rye, oats and/or barley cereals (P = 0.013) and egg (P = 0.031) early was related to an increased risk of the endpoint, but only during the first 3 years of life. CONCLUSIONS Early introduction of root vegetables during infancy is independently associated with increased risk of ß-cell autoimmunity among Finnish children with increased genetic susceptibility to Type 1 diabetes.
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Affiliation(s)
- S M Virtanen
- Department of Lifestyle and Participation, Nutrition Unit, National Institute for Health and Welfare, Helsinki, Finland.
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Virtanen SM, Uusitalo L, Kenward MG, Nevalainen J, Uusitalo U, Kronberg-Kippilä C, Ovaskainen ML, Arkkola T, Niinistö S, Hakulinen T, Ahonen S, Simell O, Ilonen J, Veijola R, Knip M. Maternal food consumption during pregnancy and risk of advanced β-cell autoimmunity in the offspring. Pediatr Diabetes 2011; 12:95-9. [PMID: 21352426 DOI: 10.1111/j.1399-5448.2010.00668.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND Evidence for a putative role of maternal diet during pregnancy in the development of β-cell autoimmunity in the child is scarce. The authors study the association of food consumption during pregnancy and the development of β-cell autoimmunity in the offspring. SUBJECTS AND METHODS A prospective Finnish birth cohort of 4297 infants with human leukocyte antigen (HLA)-DQB1-conferred susceptibility to type 1 diabetes and their mothers. Blood samples were collected from the children at 3-12 months intervals to measure type 1 diabetes-associated antibodies: antibodies against islet cells (ICA), insulin, glutamate dehydroxylase, and islet antigen 2. The mothers completed a validated food frequency questionnaire. The end-point was repeated positivity for ICA together with at least one of the other three antibodies. Piecewise-exponential survival models were used. The effective sample size was 3723, with 138 end-points. The median follow-up time was 4.4 years. RESULTS Maternal consumption of butter, low-fat margarines, berries, and coffee were inversely associated with the development of advanced β-cell autoimmunity in the offspring, adjusted for genetic risk group and familial diabetes. These associations for low-fat margarines (use vs. non-use HR 0.60, 95% CI: 0.38-0.93, p = 0.02), berries (continuous variable HR 0.90, 95% CI: 0.83-0.98, p = 0.02) and coffee (highest quarter vs. lowest HR 0.62, 95% CI: 0.40-0.97, p = 0.04), remained significant when adjusting for potential confounding sociodemographic, perinatal, and other dietary factors. CONCLUSIONS In this study assessing total food consumption of the mother during pregnancy, only few among the 27 food groups tested were weakly related to the development of advanced β-cell autoimmunity in Finnish children.
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Affiliation(s)
- S M Virtanen
- Tampere School of Public Health, University of Tampere, 33014 Tampere, Finland.
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Ip WKE, Sokolovska A, Charriere GM, Boyer L, Dejardin S, Cappillino MP, Yantosca LM, Takahashi K, Moore KJ, Lacy-Hulbert A, Stuart LM. Phagocytosis and phagosome acidification are required for pathogen processing and MyD88-dependent responses to Staphylococcus aureus. THE JOURNAL OF IMMUNOLOGY 2010; 184:7071-81. [PMID: 20483752 DOI: 10.4049/jimmunol.1000110] [Citation(s) in RCA: 112] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Innate immunity is vital for protection from microbes and is mediated by humoral effectors, such as cytokines, and cellular immune defenses, including phagocytic cells (e.g., macrophages). After internalization by phagocytes, microbes are delivered into a phagosome, a complex intracellular organelle with a well-established and important role in microbial killing. However, the role of this organelle in cytokine responses and microbial sensing is less well defined. In this study, we assess the role of the phagosome in innate immune sensing and demonstrate the critical interdependence of phagocytosis and pattern recognition receptor signaling during response to the Gram-positive bacteria Staphylococcus aureus. We show that phagocytosis is essential to initiate an optimal MyD88-dependent response to Staphylococcus aureus. Prior to TLR-dependent cytokine production, bacteria must be engulfed and delivered into acidic phagosomes where acid-activated host enzymes digest the internalized bacteria to liberate otherwise cryptic bacterial-derived ligands that initiate responses from the vacuole. Importantly, in macrophages in which phagosome acidification is perturbed, the impaired response to S. aureus can be rescued by the addition of lysostaphin, a bacterial endopeptidase active at neutral pH that can substitute for the acid-activated host enzymes. Together, these observations delineate the interdependence of phagocytosis with pattern recognition receptor signaling and suggest that therapeutics to augment functions and signaling from the vacuole may be useful strategies to increase host responses to S. aureus.
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Affiliation(s)
- W K Eddie Ip
- Developmental Immunology and Lipid Metabolism Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02144, USA
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Zipris D. Epidemiology of type 1 diabetes and what animal models teach us about the role of viruses in disease mechanisms. Clin Immunol 2009; 131:11-23. [PMID: 19185542 DOI: 10.1016/j.clim.2008.12.011] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2008] [Revised: 12/23/2008] [Accepted: 12/23/2008] [Indexed: 01/12/2023]
Abstract
There is a consensus among epidemiologists that the worldwide incidence rate of type 1 diabetes has been rising in recent decades. The cause of this rise is unknown, but epidemiological studies suggest the involvement of environmental factors, and viral infections in particular. Data demonstrating a cause-and-effect relationship between microbial infections and type 1 diabetes and how viruses may cause disease in humans are currently lacking. However, new evidence from animal models supports the hypothesis that viruses induce disease via mechanisms linked with innate immune upregulation. In the BioBreeding Diabetes Resistant rat, infection with a parvovirus induces islet destruction via upregulation of the toll-like receptor 9 (TLR9) signaling pathway. Data from mouse models of diabetes implicate TLR2, TLR3, and TLR7 in the disease process. Understanding the link between environmental agents and innate immune pathways involved in early stages of diabetes may advance the design of immune interventions to prevent disease in genetically susceptible individuals.
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Affiliation(s)
- Danny Zipris
- Department of Pediatrics, Barbara Davis Center for Childhood Diabetes, University of Colorado, Aurora, CO 80045-6511, USA.
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Hettiarachchi KD, Zimmet PZ, Danial NN, Myers MA. Transplacental exposure to the vacuolar-ATPase inhibitor bafilomycin disrupts survival signaling in β cells and delays neonatal remodeling of the endocrine pancreas. ACTA ACUST UNITED AC 2008; 60:295-306. [DOI: 10.1016/j.etp.2008.02.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2007] [Accepted: 02/15/2008] [Indexed: 12/31/2022]
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In vitro toxicity of cereulide on porcine pancreatic Langerhans islets. Toxicon 2008; 51:1029-37. [PMID: 18374382 DOI: 10.1016/j.toxicon.2008.01.019] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2007] [Revised: 12/31/2007] [Accepted: 01/28/2008] [Indexed: 11/22/2022]
Abstract
Cereulide is a K(+) ionophore cytotoxic and mitochondriotoxic to primary cells and cell lines of human and other mammalian origins. It is a heat-stable, highly lipophilic (logK(ow) 5.96) peptide (1152 g mol(-1)) produced by certain strains of Bacillus cereus, a bacterium connected to emetic food poisonings. In this study the pancreatic toxicity of purified cereulide, and cereulide-containing bacterial extracts, was studied using fetal porcine Langerhans islets in culture. Exposure to 1ngml(-1) of purified cereulide caused necrotic cell death of the islet cells impairing their insulin content within 2 days. Cell extracts of cereulide-positive B. cereus strains connected to food poisoning or isolated from foodstuffs were toxic, corresponding to their measured cereulide content. Extracts of B. cereus strains producing or not producing the B. cereus diarrheal toxin, but no cereulide, were tolerated by the porcine islet cultures up to concentrations 1000-fold higher compared to extracts from strains containing cereulide, and up to exposure times of 7d. Cereulide thus was identified as the B. cereus-produced substance toxic towards porcine fetal Langerhans islets and beta cells.
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Lammi N, Moltchanova E, Blomstedt P, Eriksson JG, Taskinen O, Sarti C, Tuomilehto J, Karvonen M. The effect of birth order and parental age on the risk of type 1 and 2 diabetes among young adults. Diabetologia 2007; 50:2433-8. [PMID: 17943268 DOI: 10.1007/s00125-007-0843-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2007] [Accepted: 09/06/2007] [Indexed: 11/30/2022]
Abstract
AIMS/HYPOTHESIS The aim of this study was to examine the effects of birth order and parental age on the risk of type 1 and type 2 diabetes among Finnish individuals aged 15-39 years. METHODS Data on all cases of type 1 diabetes (n = 1,345) and type 2 diabetes (n = 1,072), diagnosed between 1992 and 1996, were collected from four sources: standardised national reports from diabetes nurses, the National Hospital Discharge Register, the Drug Prescription Register and the Drug Reimbursement Register. Information on matched controls and the family members of all study subjects were obtained from the National Population Registry. The odds ratios (ORs) for both types of diabetes were estimated using a conditional logistic regression model. RESULTS There was a U-shaped relationship between maternal age and the risk of type 2 diabetes in the offspring: the risk was higher in children born to young and old mothers compared with children born to mothers aged around 30 years. The children born second (OR 0.76, 95% CI 0.62-0.94), third (OR 0.73, 95% CI 0.55-0.95), or fourth (OR 0.66, 95% CI 0.47-0.94) had a lower risk of type 2 diabetes than the first-born children. Maternal age, paternal age, and birth order did not have an effect on the risk of type 1 diabetes in the individuals aged 15-39 years at the time of diagnosis. CONCLUSIONS/INTERPRETATION Maternal age and birth order are both associated with the risk of early-onset type 2 diabetes. However, part of these associations may be due to low birthweight. In this study neither parental age nor birth order showed a significant association with the risk of type 1 diabetes diagnosed after 15 years of age.
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Affiliation(s)
- N Lammi
- Diabetes Unit, Department of Health Promotion and Chronic Disease Prevention, National Public Health Institute, Helsinki, Finland.
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15
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Abstract
The primary objective of this multicenter, multinational, epidemiological study is the identification of infectious agents, dietary factors, or other environmental exposures that are associated with increased risk of autoimmunity and type 1 diabetes mellitus (T1DM). Factors affecting specific phenotypic manifestations such as early age of onset or rate of progression or with protection from the development of T1DM will also be identified. The Environmental Determinants of Diabetes in the Young (TEDDY) is an observational cohort study in which newborns who are younger than 4 months and have high-risk human leukocyte antigen alleles in the general population or are first-degree relatives (FDRs) of patients affected with T1DM will be enrolled. Six clinical centers in the USA and Europe will screen 361,588 newborns, of which it is anticipated that 17,804 will be eligible for enrollment with just over 7,800 followed. Recruitment will occur over 5 yr, with children being followed to the age of 15 yr. Identification of such factors will lead to a better understanding of disease pathogenesis and result in new strategies to prevent, delay, or reverse T1DM.
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Hettiarachchi KD, Zimmet PZ, Myers MA. The effects of repeated exposure to sub-toxic doses of plecomacrolide antibiotics on the endocrine pancreas. Food Chem Toxicol 2006; 44:1966-77. [PMID: 16905235 DOI: 10.1016/j.fct.2006.06.023] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2005] [Revised: 03/14/2006] [Accepted: 06/19/2006] [Indexed: 11/25/2022]
Abstract
The plecomacrolide vacuolar ATPase inhibitors bafilomycin and concanamycin contaminate tuberous vegetables and damage pancreatic islets in mice. The consequences of repeated exposure of adult mice to sub-toxic doses of bafilomycin A1 or concanamycin A was examined by injection of the plecomacrolides on each of five consecutive days. There was a significant reduction in islet size in female C57BL/6j mice (p<0.004 and p<0.0001 respectively). There were no significant differences in fasted insulin levels and beta cell mass between treated and control groups but oral glucose tolerance worsened with increasing age in BALB/c female mice injected with concanamycin A. Streptozotocin reduced glucose tolerance and islet number but not islet size in all strains and sexes. Chronic exposure of C57BL/6j mice to concanamycin A for 16 weeks caused a significant reduction in islet size in both sexes and a significant increase in the spleen weight of female mice (p<0.001). We conclude that repeated exposure to small quantities of vacuolar proton-translocating ATPase inhibitory plecomacrolides reduces islet size and can lead to glucose intolerance, possibly due to impaired maintenance of pancreatic islets. This may lead to earlier progression to beta cell failure and insulin deficiency in those at risk of diabetes.
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Affiliation(s)
- Kalindi D Hettiarachchi
- Department of Biochemistry and Molecular Biology, Monash University, Wellington Road, Clayton, Vic. 3800, Australia
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17
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Shacka JJ, Klocke BJ, Shibata M, Uchiyama Y, Datta G, Schmidt RE, Roth KA. Bafilomycin A1 inhibits chloroquine-induced death of cerebellar granule neurons. Mol Pharmacol 2006; 69:1125-36. [PMID: 16391239 DOI: 10.1124/mol.105.018408] [Citation(s) in RCA: 135] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Treatment of cells with the macrolide antibiotic bafilomycin A1, an inhibitor of vacuolar (V)-ATPase, or with the lysosomotropic agent chloroquine, has been shown to pharmacologically inhibit autophagy as evidenced by an accumulation of autophagosomes, which in turn causes Bax-dependent apoptosis. However, bafilomycin A1 has also been reported to inhibit chloroquine-induced apoptosis, suggesting a complex interrelationship between these two inhibitors of autophagy. To determine whether the cytoprotective effect of bafilomycin A1 on chloroquine-treated cells was dependent on inhibition of V-ATPase, we examined the single and combined effects of bafilomycin and chloroquine on cultured cerebellar granule neurons. When added separately, chloroquine or high concentrations of bafilomycin A1 (> or =10 nM) induced a dose-dependent inhibition of autophagy (as measured by an increase in LC3-II, a marker specific for autophagosomes), followed by caspase-3 activation and cell death. When added in combination, bafilomycin A1 potently inhibited chloroquine-induced caspase-3 activity and cell death at concentrations (< or =1 nM) that neither altered vacuolar acidification nor inhibited autophagy. The neuroprotective effects of bafilomycin A1 against chloroquine were substantially greater than those produced by Bax deficiency. Bafilomycin A1-induced neuroprotection seemed to be stimulus-specific, in that staurosporine-induced death was not attenuated by coaddition of bafilomycin A1. Together, these data suggest that in addition to promoting death via inhibition of V-ATPase and autophagy, bafilomycin A1 possesses novel, neuroprotective properties that inhibit Bax-dependent activation of the intrinsic apoptotic pathway resulting from the pharmacological inhibition of autophagy.
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Affiliation(s)
- John J Shacka
- Department of Pathology, Division of Neuropathology, University of Alabama at Birmingham, SC961, 1530 3rd Ave South, Birmingham, AL 35294-0017, USA
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18
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Abstract
The relative risk of type 1 (autoimmune) diabetes mellitus for a sibling of an affected patient is fifteen times that of the general population, indicating a strong genetic contribution to the disease. Yet, the incidence of diabetes in most Western communities has doubled every fifteen years since the Second World War - a rate of increase that can only possibly be explained by a major etiological effect of environment. Here, the authors provide a selective review of risk factors identified to date. Recent reports of linkage of type 1 diabetes to genes encoding pathogen pattern recognition molecules, such as toll-like receptors, are discussed, providing a testable hypothesis regarding a mechanism by which genetic and environmental influences on disease progress are integrated.
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Affiliation(s)
| | | | - Alan G. Baxter
- Comparative Genomics Centre, Molecular Sciences Building 21, James Cook University, Townsville QLD 4811, Australia
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19
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Kilkkinen A, Virtanen SM, Klaukka T, Kenward MG, Salkinoja-Salonen M, Gissler M, Kaila M, Reunanen A. Use of antimicrobials and risk of type 1 diabetes in a population-based mother-child cohort. Diabetologia 2006; 49:66-70. [PMID: 16344923 DOI: 10.1007/s00125-005-0078-2] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2004] [Accepted: 08/08/2005] [Indexed: 10/25/2022]
Abstract
AIMS/HYPOTHESIS The aim of this study was to investigate whether the use of antimicrobials is associated with the risk of childhood type 1 diabetes. MATERIALS AND METHODS The study population included all children born in Finland between 1996 and 2000 who were diagnosed with type 1 diabetes by the end of 2002. For each case (n=437), four matched controls were selected. Data on diabetes and the maternal use of antimicrobials was derived from nationwide registries. RESULTS Maternal use of phenoxymethyl penicillins (odds ratio [OR]=1.70, 95% CI 1.08-2.68, p=0.022) or quinolone antimicrobials (OR=2.43, 95% CI 1.16-5.10, p=0.019) before pregnancy was associated with an increased risk of type 1 diabetes in the child, whereas the use of other specific antimicrobials was not related to the risk. The risk was also higher among mother-child pairs where macrolides were used both by the mother before pregnancy and by the child, compared with pairs where neither used macrolides (OR=1.76, 95% CI 1.05-2.94, p=0.032). Maternal use of antimicrobials during pregnancy was not associated with an increased risk. The high use of antimicrobials by the child (more than seven vs seven or less purchases) was related to greater risk (OR=1.66, 95% CI 1.24-2.24, p=0.001). CONCLUSIONS/INTERPRETATION Overall, the use of antimicrobials before pregnancy, during pregnancy or during childhood was not related to the risk of childhood type 1 diabetes. However, the use of some specific antimicrobials by the mother before pregnancy and by the child may be associated with an increased risk. Further studies are needed to confirm these associations and to elucidate the underlying mechanisms of action.
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Affiliation(s)
- A Kilkkinen
- Department of Epidemiology and Health Promotion, National Public Health Institute, Mannerheimintie 166, 00300 Helsinki, Finland.
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20
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Hettiarachchi KD, Zimmet PZ, Myers MA. Transplacental exposure to bafilomycin disrupts pancreatic islet organogenesis and accelerates diabetes onset in NOD mice. J Autoimmun 2004; 22:287-96. [PMID: 15120752 DOI: 10.1016/j.jaut.2004.02.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2003] [Revised: 01/28/2004] [Accepted: 02/19/2004] [Indexed: 10/26/2022]
Abstract
Bafilomycin, a plecomacrolide produced by plant-pathogenic Streptomyces, contaminates tuberous vegetables and has adverse effects on beta cells in adult mice. We therefore determined whether dietary bafilomycin influenced the progression of diabetes in the non-obese diabetic (NOD) mouse model of autoimmune Type 1 diabetes. Parent NOD mice were fed sub-toxic doses of bafilomycin in drinking water from conception until weaning, or various times after birth and blood glucose was monitored in the offspring. Pancreatic islets in neonatal offspring were examined histologically by quantitative morphometry and islet cell apoptosis was estimated by TUNEL assay. Exposure in utero to bafilomycin but not after birth significantly accelerated onset and increased the frequency of diabetes. In exposed mice, pancreatic islet organogenesis was disrupted, characterized by a striking increase in beta-cell mass and a shift in timing of the normal wave of neonatal islet cell apoptosis from 2 weeks to 4 weeks of age. We postulate that accelerated onset and increased incidence of diabetes later in life result from disruption of the normal turnover of beta cells in the neonatal pancreas. Since bafilomycin and related plecomacrolides contaminate Streptomyces-infected vegetables, dietary exposure during pregnancy could be an important and previously unsuspected environmental component of human Type 1 diabetes.
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Affiliation(s)
- K D Hettiarachchi
- Department of Biochemistry and Molecular Biology, Monash University, Building 13D, Wellington Road, Clayton, Victoria 3800, Australia
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21
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Strotmeyer ES, Yang Z, LaPorte RE, Chang YF, Steenkiste AR, Pietropaolo M, Nucci AM, Shen S, Wang L, Wang B, Dorman JS. Infant diet and type 1 diabetes in China. Diabetes Res Clin Pract 2004; 65:283-92. [PMID: 15331209 DOI: 10.1016/j.diabres.2004.02.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2003] [Revised: 01/20/2004] [Accepted: 02/06/2004] [Indexed: 10/26/2022]
Abstract
Infant milk and food introduction may be linked to type 1 diabetes risk in high incidence populations. Dietary data through age 12 months was collected for 247 type 1 diabetic cases and 443 controls in China, a low incidence population, to determine if milk and solid food intake differed. Age range at introduction to milk and formulas was similar in cases and controls but solid food introduction more often occurred before age 3 months in cases. Logistic regression analyses showed soy milk formula consumption at 4-6 (OR = 2.0; 95% CI: 1.1-3.4) and 7-12 months of age (OR = 1.5; 95% CI: 1.0-2.1) was associated with a twofold higher risk of type 1 diabetes, while steamed bread consumption (4-6 months, OR = 0.44; 95% CI: 0.28-0.68; 7-12 months, OR = 0.48; 95% CI: 0.34-0.69) and higher SES (4-6 months, OR = 0.55; 95% CI: 0.39-0.78; 7-12 months, OR = 0.57; 95% CI: 0.40-0.83) were negatively associated. Drinking cow's milk at 7-12 months (OR = 0.60; 95% CI: 0.43-0.85) was negatively associated with type 1 diabetes while consuming vegetables at 4-6 months (OR = 1.5; 95% CI: 1.0-2.2) was positively associated. Results suggest that infant milk and solid food intake are associated with type 1 diabetes in China. Prospective studies may determine how these dietary factors impact disease etiology, particularly for at-risk-populations.
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Affiliation(s)
- Elsa S Strotmeyer
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA
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22
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Myers MA, Hettiarachchi KD, Ludeman JP, Wilson AJ, Wilson CR, Zimmet PZ. Dietary microbial toxins and type 1 diabetes. Ann N Y Acad Sci 2004; 1005:418-22. [PMID: 14679104 DOI: 10.1196/annals.1288.071] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Toxins may promote type 1 diabetes by modifying or damaging the beta cell causing release of autoantigens. Streptomyces is a common soil bacterium that produces many toxic compounds. Some Streptomyces can infect vegetables, raising the possibility of dietary exposure to toxins. We aimed to identify toxins that erode cellular proton gradients in extracts of Streptomyces and infested vegetables and to establish the effect of low doses of these toxins on pancreatic islets in mice. The vacuolar ATPase inhibitors, bafilomycin and concanamycin, and the ionophore, nigericin, were identified in extracts from 4 of 13 Streptomyces isolated from infested potatoes and in potatoes themselves. Injection of bafilomycin A1 into mice impaired glucose tolerance, reduced islet size, and decreased relative beta cell mass. Thus, exposure to small quantities of bafilomycin in the diet may contribute to the cause of type 1 diabetes.
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Affiliation(s)
- M A Myers
- Monash University, Melbourne, Australia.
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23
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Virtanen SM, Knip M. Nutritional risk predictors of beta cell autoimmunity and type 1 diabetes at a young age. Am J Clin Nutr 2004; 78:1053-67. [PMID: 14668264 DOI: 10.1093/ajcn/78.6.1053] [Citation(s) in RCA: 110] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Type 1 diabetes is an immune-mediated disease characterized by a preclinical prodrome during which beta cell autoimmunity proceeds at a variable rate. Large geographic differences and a conspicuous increase in incidence, especially among young children since the 1950s, and the relatively low concordance in identical twins are factors that favor a critical role of environmental factors in the etiology of this disease. Only approximately 5% or fewer subjects with HLA-conferred genetic susceptibility to type 1 diabetes actually develop the clinical disease. Breastfeeding, nicotinamide, zinc, and vitamins C, D, and E have been reported as possibly protecting against type 1 diabetes, whereas N-nitroso compounds, cow milk, increased linear growth, and obesity may increase the risk. Thus far, only the significance of infant feeding, cow milk, and vitamin D have been studied in both case-control and cohort settings. The major shortcoming of most studies done so far is that only single dietary exposures have been assessed at single time points. Putative nutritional and other confounding factors have received little attention as have the limitations of the dietary methods used. There is little firm evidence of the significance of nutritional factors in the etiology of type 1 diabetes. The availability of good markers of preclinical type 1 diabetes and of genetic risk have decreased the sample sizes needed and made longitudinal cohort studies of the assessment of children's diets feasible.
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Affiliation(s)
- Suvi M Virtanen
- Department of Epidemiology and Health Promotion, National Public Health Institute, Mannerheimintie 166, FIN-00300 Helsinki, Finland.
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Thorsdottir I, Ramel A. Dietary Intake of 10- to 16-Year-Old Children and Adolescents in Central and Northern Europe and Association with the Incidence of Type 1 Diabetes. ANNALS OF NUTRITION AND METABOLISM 2003; 47:267-75. [PMID: 14520022 DOI: 10.1159/000072399] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/02/2002] [Accepted: 02/26/2003] [Indexed: 11/19/2022]
Abstract
BACKGROUND/AIMS The highest incidence of type 1 diabetes is among 10- to 15-year-old adolescents. The aim of this study was to investigate a possible relationship between the dietary intake of this group and the incidence of type 1 diabetes. METHODS Dietary intake data of 10- to 16-year-old adolescents (n = 4,701) from 11 European countries and the incidence rates of type 1 diabetes were used to examine the relation between food and the disease. RESULTS The incidence of type 1 diabetes correlated with the consumption of total fat (r = 0.674; p = 0.023), saturated fatty acids (r = 0.714; p = 0.047) and the intake of fruits and vegetables (r = 0.786; p = 0.036). Fruit intake or vegetable intake alone did not correlate with the incidence. Cow's milk and animal product consumption correlated with the incidence when Icelandic data were excluded (r = 0.829; p = 0.042 and r = 0.999; p = 0.001). A negative correlation of borderline significance was found between sugar intake and the incidence of type 1 diabetes (r = -0.721; p = 0.068). CONCLUSION The results indicate for the first time that an adolescent's diet high in fat and fruits and vegetables is associated with an increased risk of type 1 diabetes. Fruit or vegetable intake separately was not associated with type 1 diabetes. It is important to characterize and minimize diabetogenic factors in fruits and vegetables as the general health benefits of a diet rich in fruits and vegetables are well known and such a diet is therefore recommended. This study supports previous research about the importance of cow's milk and animal products in the aetiology of type 1 diabetes.
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Affiliation(s)
- I Thorsdottir
- Unit for Nutrition Research, Department of Food Science, Landspitali-University Hospital, IS-101 Reykjavik, Iceland.
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Affiliation(s)
- Mark A Myers
- Department of Biochemistry and Molecular Biology, Monash University, Wellington Road, Clayton, Victoria, 3800 Australia.
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26
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Affiliation(s)
- Mikael Knip
- Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland.
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Akerblom HK, Vaarala O, Hyöty H, Ilonen J, Knip M. Environmental factors in the etiology of type 1 diabetes. AMERICAN JOURNAL OF MEDICAL GENETICS 2002; 115:18-29. [PMID: 12116173 DOI: 10.1002/ajmg.10340] [Citation(s) in RCA: 178] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Type 1 diabetes is considered to be an autoimmune disease in which T lymphocytes infiltrate the islets of pancreas and destroy the insulin producing beta cell population. Besides antigen specificity, the quality of immune reactivity against islet cell antigen(s) is an important determinant of the beta cell destruction. Much evidence indicates that the function of the gut immune system is central in the pathogenesis, as the regulation of the gut immune system may be aberrant in type 1 diabetes. The role of virus infections in the pathogenesis of type 1 diabetes has been supported by substantial new evidence suggesting that one virus group, enteroviruses, may trigger the beta-cell damaging process in a considerable proportion of patients. The latest evidence comes from studies indicating the presence of viral genome in diabetic patients and from prospective studies confirming epidemiological risk effect. If this association holds still true in ongoing large-scale studies, intervention trials should be considered to confirm causality. Of the dietary putative etiological factors, cow's milk proteins have received the main attention. Many studies indicate an association between early exposure to dietary cow's milk proteins and an increased risk of type 1 diabetes. The question will be answered by a large scale, prospective, randomized, international intervention trial. Another dietary factor in need of more studies is the deficiency of vitamin D. Among toxins, N-nitroso compounds are the main candidates. An interaction of genetic and environmental factors is important in evaluating the possible role of a certain environmental factor in the etiology of type 1 diabetes.
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Myers MA, Mackay IR, Zimmet PZ. A dietary cause of type 1 diabetes: unearthing a new twist to the tale. Diabetes Technol Ther 2002; 4:193-8. [PMID: 12079623 DOI: 10.1089/15209150260007417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Affiliation(s)
- M A Myers
- Department of Biochemistry and Molecular Biology, Monash University, Wellington Road, Clayton, Victoria 3800, Australia.
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29
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Abstract
Changes in human behaviour and lifestyle over the last century have resulted in a dramatic increase in the incidence of diabetes worldwide. The epidemic is chiefly of type 2 diabetes and also the associated conditions known as 'diabesity' and 'metabolic syndrome'. In conjunction with genetic susceptibility, particularly in certain ethnic groups, type 2 diabetes is brought on by environmental and behavioural factors such as a sedentary lifestyle, overly rich nutrition and obesity. The prevention of diabetes and control of its micro- and macrovascular complications will require an integrated, international approach if we are to see significant reduction in the huge premature morbidity and mortality it causes.
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Affiliation(s)
- P Zimmet
- International Diabetes Institute, 260 Kooyong Road, Caulfield, Victoria 3162, Australia.
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