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de Freitas Mathias PC, Dantas Rodrigues AM, Lisboa PC, Miranda RA, Malta A, Ribeiro TA, Barella LF, Dias G, Lima TAL, Gomes RM, de Moura EG, de Oliveira JC. Maternal Low-Protein Diet During Nursing Leads to Glucose-Insulin Dyshomeostasis and Pancreatic-Islet Dysfunction by Disrupting Glucocorticoid Responsiveness in Male Rats. BIOLOGY 2024; 13:1036. [PMID: 39765703 PMCID: PMC11673749 DOI: 10.3390/biology13121036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Revised: 11/04/2024] [Accepted: 12/06/2024] [Indexed: 01/11/2025]
Abstract
Both perinatal malnutrition and elevated glucocorticoids are pivotal triggers of the growing global pandemic of metabolic diseases. Here, we studied the effects of metabolic stress responsiveness on glucose-insulin homeostasis and pancreatic-islet function in male Wistar offspring whose mothers underwent protein restriction during lactation. During the first two weeks after delivery, lactating dams were fed a low-protein (4% protein, LP group) or normal-protein diet (22.5% protein, NP group). At 90 days of age, male rat offspring were challenged with food deprivation (72 h of fasting), intracerebroventricular (icv) injection of dexamethasone (2 µL, 2.115 mmol/L) or chronic intraperitoneal injection of dexamethasone (1 mg/kg body weight/5 days). Body weight, food intake, intravenous glucose tolerance test (ivGTT) results, insulin secretion and biochemical parameters were assessed. LP rats did not display significant metabolic changes after long-term starvation (p > 0.05) or under the central effect of dexamethasone (p = 0.999). Chronic dexamethasone induced rapid hyperglycemia (~1.2-fold, p < 0.001) and hyperinsulinemia (NP: 65%; LP: 216%; p < 0.001), decreased insulin sensitivity (NP: ~2-fold; LP: ~4-fold; p < 0.001), reduced insulinemia (20%) and increased glycemia (35%) only in NP rats under ivGTT conditions (p < 0.001). Glucose and acetylcholine insulinotropic effects, as well as the muscarinic receptor antagonist response, were reduced by chronic dexamethasone only in pancreatic islets from NP rats (p < 0.05). The direct effect of dexamethasone on pancreatic islets reduced insulin secretion (NP: 60.2%, p < 0.001; LP: 33.8%, p < 0.001). Peripheral glucose-insulin dyshomeostasis and functional failure of pancreatic islets in LP rats, as evidenced by an impaired acute and chronic response to metabolic stress, may be due to excessive corticosterone action as a long-term consequence.
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Affiliation(s)
- Paulo Cezar de Freitas Mathias
- Laboratory of Secretion Cell Biology, Department of Biotechnology, Genetics and Cell Biology, State University of Maringa, Maringá 87020-900, Brazil; (P.C.d.F.M.); (A.M.); (T.A.R.); (L.F.B.)
| | - Aline Milena Dantas Rodrigues
- Research Group on Perinatal Programming of Metabolic Diseases: DOHaD Paradigm, Laboratory of Metabolic and Cardiovascular Diseases, Health Education and Research Center (NUPADS), Institute of Health Sciences, Federal University of Mato Grosso, University Campus of Sinop, Sinop 78556-264, Brazil; (A.M.D.R.); (G.D.); (T.A.L.L.)
| | - Patrícia Cristina Lisboa
- Laboratory of Endocrine Physiology, Department of Physiological Sciences, State University of Rio de Janeiro, Rio de Janeiro 20550-013, Brazil; (P.C.L.); (R.A.M.); (E.G.d.M.)
| | - Rosiane Aparecida Miranda
- Laboratory of Endocrine Physiology, Department of Physiological Sciences, State University of Rio de Janeiro, Rio de Janeiro 20550-013, Brazil; (P.C.L.); (R.A.M.); (E.G.d.M.)
| | - Ananda Malta
- Laboratory of Secretion Cell Biology, Department of Biotechnology, Genetics and Cell Biology, State University of Maringa, Maringá 87020-900, Brazil; (P.C.d.F.M.); (A.M.); (T.A.R.); (L.F.B.)
| | - Tatiane Aparecida Ribeiro
- Laboratory of Secretion Cell Biology, Department of Biotechnology, Genetics and Cell Biology, State University of Maringa, Maringá 87020-900, Brazil; (P.C.d.F.M.); (A.M.); (T.A.R.); (L.F.B.)
| | - Luiz Felipe Barella
- Laboratory of Secretion Cell Biology, Department of Biotechnology, Genetics and Cell Biology, State University of Maringa, Maringá 87020-900, Brazil; (P.C.d.F.M.); (A.M.); (T.A.R.); (L.F.B.)
| | - Ginislene Dias
- Research Group on Perinatal Programming of Metabolic Diseases: DOHaD Paradigm, Laboratory of Metabolic and Cardiovascular Diseases, Health Education and Research Center (NUPADS), Institute of Health Sciences, Federal University of Mato Grosso, University Campus of Sinop, Sinop 78556-264, Brazil; (A.M.D.R.); (G.D.); (T.A.L.L.)
| | - Thalyne Aparecida Leite Lima
- Research Group on Perinatal Programming of Metabolic Diseases: DOHaD Paradigm, Laboratory of Metabolic and Cardiovascular Diseases, Health Education and Research Center (NUPADS), Institute of Health Sciences, Federal University of Mato Grosso, University Campus of Sinop, Sinop 78556-264, Brazil; (A.M.D.R.); (G.D.); (T.A.L.L.)
| | - Rodrigo Mello Gomes
- Laboratory of Endocrine Physiology and Metabolism, Institute of Biological Sciences, Federal University of Goiás, Goiânia 74690-900, Brazil;
| | - Egberto Gaspar de Moura
- Laboratory of Endocrine Physiology, Department of Physiological Sciences, State University of Rio de Janeiro, Rio de Janeiro 20550-013, Brazil; (P.C.L.); (R.A.M.); (E.G.d.M.)
| | - Júlio Cezar de Oliveira
- Research Group on Perinatal Programming of Metabolic Diseases: DOHaD Paradigm, Laboratory of Metabolic and Cardiovascular Diseases, Health Education and Research Center (NUPADS), Institute of Health Sciences, Federal University of Mato Grosso, University Campus of Sinop, Sinop 78556-264, Brazil; (A.M.D.R.); (G.D.); (T.A.L.L.)
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Li Q, Li Z, Guo S, Li S, Yao M, Li Y, Luo X. Increased circulating serpinB1 levels in children with overweight/obesity are associated with obesity-related parameters: a cross‑sectional study. BMC Pediatr 2024; 24:762. [PMID: 39578813 PMCID: PMC11585230 DOI: 10.1186/s12887-024-05251-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 11/13/2024] [Indexed: 11/24/2024] Open
Abstract
BACKGROUND Circulating serpinB1 levels are increased in obese mice and have been shown to promote β-cell proliferation in several species. However, the data on serum serpinB1 levels in children with obesity are scarce. This study aimed to determine serum serpinB1 levels in children with overweight/obesity, and to study its association with obesity-related parameters. METHODS A total of 54 children with overweight/obesity and 36 normal-weight healthy controls aged 6-14 were recruited in this study. Anthropometric parameters, glucolipid metabolic biochemical parameters, sex hormones, and serum serpinB1 levels were measured in all subjects. The association of serum serpinB1 levels with obesity-related parameters and the risk of overweight/obesity were analyzed using correlation analysis and binary regression analysis, respectively. RESULTS The serum serpinB1 level in overweight/obese children was notably greater than in normal-weight controls (2.03 ± 0.70 vs. 1.41 ± 0.58 ng/mL, p < 0.001). SerpinB1 levels were positively correlated with body mass index (BMI), BMI Z-score, triglyceride (TG), uric acid, fasting insulin, C-peptide, and homeostasis model assessment of insulin resistance (HOMA-IR) levels. Additionally, we found that elevated circulating serpinB1 levels were associated with the increased risk of childhood overweight/obesity even after adjustment for age, gender, and HOMA-IR (odds ratio, 4.132; 95% confidence interval, 1.315-12.983; p = 0.015). CONCLUSIONS Circulating serpinB1 level was significantly increased in children with overweight/obesity and positively associated with obesity-related glucolipid metabolic parameters. These results indicate a close association between serum serpinB1 concentrations and childhood overweight/obesity.
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Affiliation(s)
- Qing Li
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhuxi Li
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shusen Guo
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Sujuan Li
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Minglan Yao
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yingying Li
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoping Luo
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Hubei Key Laboratory of Pediatric Genetic Metabolic and Endocrine Rare Diseases, Wuhan, China.
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Hahm J, Thirunavukarasu B, Gadoo R, Andrade JAF, Dalton T, Arany E, Hill DJ. Alpha- to Beta-Cell Transdifferentiation in Neonatal Compared with Adult Mouse Pancreas in Response to a Modest Reduction in Beta-Cells Using Streptozotocin. Int J Mol Sci 2024; 25:11152. [PMID: 39456933 PMCID: PMC11508719 DOI: 10.3390/ijms252011152] [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: 09/20/2024] [Revised: 10/05/2024] [Accepted: 10/13/2024] [Indexed: 10/28/2024] Open
Abstract
Following the near-total depletion of pancreatic beta-cells with streptozotocin (STZ), a partial recovery of beta-cell mass (BCM) can occur, in part due to the alpha- to beta-cell transdifferentiation with an intermediary insulin/glucagon bi-hormonal cell phenotype. However, human type 2 diabetes typically involves only a partial reduction in BCM and it is not known if recovery after therapeutic intervention involves islet cell transdifferentiation, or how this varies with age. Here, we used transgenic mouse models to examine if islet cell transdifferentiation contributes to BCM recovery following only a partial depletion of BCM. Cell lineage tracing was employed using Glucagon-Cre/yellow fluorescent protein (YFP) transgenic mice treated with STZ (25 mg/kg-neonates; 70 mg/kg-adults) or vehicle alone on 3 consecutive days. Mice were euthanized 2-30 days later with a prior glucose tolerance test on day 30, and immunofluorescence histology performed on the pancreata. Beta-cell abundance was reduced by 30-40% two days post STZ in both neonates and adults, and subsequently partially recovered in adult but not neonatal mice. Glucose tolerance recovered in adult females, but not in males or neonates. Bi-hormonal cell abundance increased 2-3-fold in STZ-treated mice vs. controls in both neonates and adults, as did transdifferentiated cells expressing insulin and the YFP lineage tag, but not glucagon. Transdifferentiated cell presence was an order of magnitude lower than that of bi-hormonal cells. We conclude that alpha- to beta-cell transdifferentiation occurs in mice following only a moderate depletion in BCM, and that this was accompanied by a partial recovery of BCM in adults.
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Affiliation(s)
- Jiwon Hahm
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada; (J.H.); (B.T.); (J.A.F.A.); (T.D.)
- Lawson Health Research Institute, St. Joseph’s Health Care, London, ON N6A 4V2, Canada; (R.G.); (E.A.)
| | - Bavina Thirunavukarasu
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada; (J.H.); (B.T.); (J.A.F.A.); (T.D.)
- Lawson Health Research Institute, St. Joseph’s Health Care, London, ON N6A 4V2, Canada; (R.G.); (E.A.)
| | - Reva Gadoo
- Lawson Health Research Institute, St. Joseph’s Health Care, London, ON N6A 4V2, Canada; (R.G.); (E.A.)
- Faculty of Science, McMaster University, Hamilton, ON L8S 4L8, Canada
| | - Juan Andres Fernandez Andrade
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada; (J.H.); (B.T.); (J.A.F.A.); (T.D.)
- Lawson Health Research Institute, St. Joseph’s Health Care, London, ON N6A 4V2, Canada; (R.G.); (E.A.)
| | - Tyler Dalton
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada; (J.H.); (B.T.); (J.A.F.A.); (T.D.)
- Lawson Health Research Institute, St. Joseph’s Health Care, London, ON N6A 4V2, Canada; (R.G.); (E.A.)
| | - Edith Arany
- Lawson Health Research Institute, St. Joseph’s Health Care, London, ON N6A 4V2, Canada; (R.G.); (E.A.)
- Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada
| | - David J. Hill
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada; (J.H.); (B.T.); (J.A.F.A.); (T.D.)
- Lawson Health Research Institute, St. Joseph’s Health Care, London, ON N6A 4V2, Canada; (R.G.); (E.A.)
- Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada
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Yadav U, Kumar N, Sarvottam K. Obese have comparable ankle brachial pressure index but higher β-cell function and insulin resistance as compared to normal-weight type 2 diabetes mellitus patients. Acta Diabetol 2024:10.1007/s00592-024-02379-x. [PMID: 39368013 DOI: 10.1007/s00592-024-02379-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Accepted: 09/22/2024] [Indexed: 10/07/2024]
Abstract
OBJECTIVES To compare ankle brachial pressure index (ABPI) in normal weight and obese/overweight type 2 diabetes mellitus patients (T2DM) to see the impact of obesity on the occurrence of peripheral artery disease (PAD) in T2DM patients. Secondly to investigate the relationship between ABPI, insulin resistance, and beta cell function and between adipocytokines and obesity parameters. METHODS A total of 120 BMI-categorized Normal weight (NW) T2DM (n = 53) patients and obese/overweight T2DM (n = 67) patients were recruited in this study. ABPI measurements were performed for the assessment of PAD. The anthropometry and body composition of the patients were measured. Plasma fasting insulin, adiponectin, and IL-6 levels were measured by ELISA kits. RESULTS ABPI scores were found to be comparable between both groups of patients (p = 0.787). A significant positive correlation was observed between ABPI and beta cell function. Insulin resistance was found to correlate positively while adiponectin negatively with obesity parameters. CONCLUSION The ABPI score was comparable between both groups of patients, suggesting that vascular complications may occur at the same rate in NW as well as in obese/overweight diabetic patients. The positive association of insulin resistance as well as the negative association of adiponectin with obesity parameters, are suggestive of the importance of body fat distribution in predicting insulin resistance and the inflammatory status of the cells.
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Affiliation(s)
- Umashree Yadav
- Department of Physiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
| | - Nilesh Kumar
- Department of General Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
| | - Kumar Sarvottam
- Department of Physiology, All India Institute of Medical Sciences, Gorakhpur, Uttar Pradesh, India.
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Huang P, Zhu Y, Qin J. Research advances in understanding crosstalk between organs and pancreatic β-cell dysfunction. Diabetes Obes Metab 2024; 26:4147-4164. [PMID: 39044309 DOI: 10.1111/dom.15787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 06/25/2024] [Accepted: 06/26/2024] [Indexed: 07/25/2024]
Abstract
Obesity has increased dramatically worldwide. Being overweight or obese can lead to various conditions, including dyslipidaemia, hypertension, glucose intolerance and metabolic syndrome (MetS), which may further lead to type 2 diabetes mellitus (T2DM). Previous studies have identified a link between β-cell dysfunction and the severity of MetS, with multiple organs and tissues affected. Identifying the associations between pancreatic β-cell dysfunction and organs is critical. Research has focused on the interaction between the liver, gut and pancreatic β-cells. However, the mechanisms and related core targets are still not perfectly elucidated. The aims of this review were to summarize the mechanisms of β-cell dysfunction and to explore the potential pathogenic pathways and targets that connect the liver, gut, adipose tissue, muscle, and brain to pancreatic β-cell dysfunction.
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Affiliation(s)
- Peng Huang
- Department of Traditional Chinese Medicine, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Yunling Zhu
- Department of Traditional Chinese Medicine, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Jian Qin
- Department of Traditional Chinese Medicine, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
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Manrique PD, Huo FY, El Oud S, Johnson NF. Non-equilibrium physics of multi-species assembly applied to fibrils inhibition in biomolecular condensates and growth of online distrust. Sci Rep 2024; 14:21911. [PMID: 39300202 DOI: 10.1038/s41598-024-72538-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Accepted: 09/09/2024] [Indexed: 09/22/2024] Open
Abstract
Self-assembly is a key process in living systems-from the microscopic biological level (e.g. assembly of proteins into fibrils within biomolecular condensates in a human cell) through to the macroscopic societal level (e.g. assembly of humans into common-interest communities across online social media platforms). The components in such systems (e.g. macromolecules, humans) are highly diverse, and so are the self-assembled structures that they form. However, there is no simple theory of how such structures assemble from a multi-species pool of components. Here we provide a very simple model which trades myriad chemical and human details for a transparent analysis, and yields results in good agreement with recent empirical data. It reveals a new inhibitory role for biomolecular condensates in the formation of dangerous amyloid fibrils, as well as a kinetic explanation of why so many diverse distrust movements are now emerging across social media. The nonlinear dependencies that we uncover suggest new real-world control strategies for such multi-species assembly.
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Affiliation(s)
- Pedro D Manrique
- Physics Department, George Washington University, Washington, DC, 20052, USA.
| | - Frank Yingjie Huo
- Physics Department, George Washington University, Washington, DC, 20052, USA
| | - Sara El Oud
- Physics Department, George Washington University, Washington, DC, 20052, USA
| | - Neil F Johnson
- Physics Department, George Washington University, Washington, DC, 20052, USA
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Mizukami H. Pathological evaluation of the pathogenesis of diabetes mellitus and diabetic peripheral neuropathy. Pathol Int 2024; 74:438-453. [PMID: 38888200 PMCID: PMC11551828 DOI: 10.1111/pin.13458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 05/29/2024] [Accepted: 06/02/2024] [Indexed: 06/20/2024]
Abstract
Currently, there are more than 10 million patients with diabetes mellitus in Japan. Therefore, the need to explore the pathogenesis of diabetes and the complications leading to its cure is becoming increasingly urgent. Pathological examination of pancreatic tissues from patients with type 2 diabetes reveals a decrease in the volume of beta cells because of a combination of various stresses. In human type 2 diabetes, islet amyloid deposition is a unique pathological change characterized by proinflammatory macrophage (M1) infiltration into the islets. The pathological changes in the pancreas with islet amyloid were different according to clinical factors, which suggests that type 2 diabetes can be further subclassified based on islet pathology. On the other hand, diabetic peripheral neuropathy is the most frequent diabetic complication. In early diabetic peripheral neuropathy, M1 infiltration in the sciatic nerve evokes oxidative stress or attenuates retrograde axonal transport, as clearly demonstrated by in vitro live imaging. Furthermore, islet parasympathetic nerve density and beta cell volume were inversely correlated in type 2 diabetic Goto-Kakizaki rats, suggesting that diabetic peripheral neuropathy itself may contribute to the decrease in beta cell volume. These findings suggest that the pathogenesis of diabetes mellitus and diabetic peripheral neuropathy may be interrelated.
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Affiliation(s)
- Hiroki Mizukami
- Department of Pathology and Molecular Medicine, Biomedical Research CenterHirosaki University Graduate School of MedicineHirosakiAomoriJapan
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Zhou Z, Wang H, Tan S, Zhang H, Zhu Y. The alterations of innate immunity and enhanced severity of infections in diabetes mellitus. Immunology 2024; 171:313-323. [PMID: 37849389 DOI: 10.1111/imm.13706] [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: 07/04/2023] [Accepted: 10/04/2023] [Indexed: 10/19/2023] Open
Abstract
Diabetes mellitus (DM) is a metabolic inflammatory disease with a high incidence worldwide. Patients with DM are at a high risk for all types of infections. Type 1 DM is characterised with immune destruction of pancreatic β cells, while type 2 diabetes is characterised with insulin resistance and β cell dysfunction, both of which result in disorders of glucose and lipid metabolism. This metabolic disorder causes functional defects of immune cells, aberrant production of inflammatory cytokines, dysregulated immune responses, advanced pathophysiological injury of the body, and increased mortality in populations with DM upon infections. Starting with the change of natural immune system in patients with DM, this paper focused on the enhanced severity of infections in DM and the underlying innate immune alterations in preclinical and clinical studies, aiming to better understand the influence of DM on the susceptibility, pathophysiology, and clinical outcomes in infections.
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Affiliation(s)
- Zi Zhou
- Sepsis Translational Medicine Key Lab of Hunan Province, Central South University, Hunan, China
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Hunan, China
| | - Hao Wang
- Sepsis Translational Medicine Key Lab of Hunan Province, Central South University, Hunan, China
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Hunan, China
| | - Sipin Tan
- Sepsis Translational Medicine Key Lab of Hunan Province, Central South University, Hunan, China
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Hunan, China
| | - Huali Zhang
- Sepsis Translational Medicine Key Lab of Hunan Province, Central South University, Hunan, China
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Hunan, China
| | - Yaxi Zhu
- Sepsis Translational Medicine Key Lab of Hunan Province, Central South University, Hunan, China
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Hunan, China
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Kimani CN, Reuter H, Kotzé SH, Venter P, Ramharack P, Muller CJF. Pancreatic beta cell regenerative potential of Zanthoxylum chalybeum Engl. Aqueous stem bark extract. JOURNAL OF ETHNOPHARMACOLOGY 2024; 320:117374. [PMID: 37944876 DOI: 10.1016/j.jep.2023.117374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Revised: 10/18/2023] [Accepted: 10/30/2023] [Indexed: 11/12/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Zanthoxylum chalybeum Engl. is endemic to Africa and has been used traditionally to treat diabetes mellitus. Moreover, its pharmacological efficacy has been confirmed experimentally using in vitro and in vivo models of diabetes. However, the effects of Z. chalybeum extracts and its major constituent compounds on beta cell and islet regeneration are not clear. Further, the mechanisms associated with observed antidiabetic effects at the beta cell level are not fully elucidated. AIM OF THE STUDY We determined the beta cell regenerative efficacy of Z. chalybeum aqueous stem bark extract, identified the chemical compounds in Z. chalybeum aqueous stem bark extracts and explored their putative mechanisms of action. MATERIALS AND METHODS Phytochemical profiling of the Z. chalybeum extract was achieved using ultra high-performance liquid chromatography hyphenated to high-resolution mass spectrometry. Thereafter, molecular interactions of the compounds with beta cell regeneration targets were evaluated via molecular docking. In vitro, effects of the extract on cell viability, proliferation, apoptosis and oxidative stress were investigated in RIN-5F beta cells exposed to palmitate or streptozotocin. In vivo, pancreas tissue sections from streptozotocin-induced diabetic male Wistar rats treated with Z. chalybeum extract were stained for insulin, glucagon, pancreatic duodenal homeobox protein 1 (Pdx-1) and Ki-67. RESULTS Based on ligand target and molecular docking interactions diosmin was identified as a dual specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1A) inhibitor. In vitro, Z. chalybeum augmented cell viability and cell proliferation while in palmitate-pre-treated cells, the extract significantly increased cell activity after 72 h. In vivo, although morphometric analysis showed decreased islet and beta cell size and density, observation of increased Pdx-1 and Ki-67 immunoreactivity in extract-treated islets suggests that Z. chalybeum extract has mild beta cell regenerative potential mediated by increased cell proliferation. CONCLUSIONS Overall, the mitogenic effects observed in vitro, were not robust enough to elicit sufficient recovery of functional beta cell mass in our in vivo model, in the context of a sustained diabetic milieu. However, the identification of diosmin as a potential Dyrk1A inhibitor merits further inquiry into the attendant molecular interactions.
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Affiliation(s)
- Clare Njoki Kimani
- Biomedical Research and Innovation Platform (BRIP), South African Medical Research Council (SAMRC), Tygerberg, 7505, South Africa; Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 241, Cape Town, 8000, South Africa; Department of Non-communicable Diseases, Institute of Primate Research, PO Box 24481, Karen, Nairobi, Kenya.
| | - Helmuth Reuter
- Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 241, Cape Town, 8000, South Africa
| | - Sanet Henriët Kotzé
- Division of Clinical Anatomy, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 241, Cape Town, 8000, South Africa; Division of Anatomy, Department of Biomedical Sciences, School of Veterinary Medicine, Ross University, PO Box 334, Basseterre, Saint Kitts and Nevis
| | - Pieter Venter
- Biomedical Research and Innovation Platform (BRIP), South African Medical Research Council (SAMRC), Tygerberg, 7505, South Africa
| | - Pritika Ramharack
- Biomedical Research and Innovation Platform (BRIP), South African Medical Research Council (SAMRC), Tygerberg, 7505, South Africa; Discipline of Pharmaceutical Sciences, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa
| | - Christo John Frederick Muller
- Biomedical Research and Innovation Platform (BRIP), South African Medical Research Council (SAMRC), Tygerberg, 7505, South Africa; Centre for Cardio-Metabolic Research in Africa, Division of Medical Physiology, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, 7600, South Africa; Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa, 3886, South Africa
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Hsu C, Templin AT, Prosswimmer T, Shea D, Li J, Brooks‐Worrell B, Kahn SE, Daggett V. Human islet amyloid polypeptide-induced β-cell cytotoxicity is linked to formation of α-sheet structure. Protein Sci 2024; 33:e4854. [PMID: 38062941 PMCID: PMC10823758 DOI: 10.1002/pro.4854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 11/10/2023] [Accepted: 12/04/2023] [Indexed: 01/30/2024]
Abstract
Type 2 diabetes (T2D) results from insulin secretory dysfunction arising in part from the loss of pancreatic islet β-cells. Several factors contribute to β-cell loss, including islet amyloid formation, which is observed in over 90% of individuals with T2D. The amyloid is comprised of human islet amyloid polypeptide (hIAPP). Here we provide evidence that early in aggregation, hIAPP forms toxic oligomers prior to formation of amyloid fibrils. The toxic oligomers contain α-sheet secondary structure, a nonstandard secondary structure associated with toxic oligomers in other amyloid diseases. De novo, synthetic α-sheet compounds designed to be nontoxic and complementary to the α-sheet structure in the toxic oligomers inhibit hIAPP aggregation and neutralize oligomer-mediated cytotoxicity in cell-based assays. In vivo administration of an α-sheet design to mice for 4 weeks revealed no evidence of toxicity nor did it elicit an immune response. Furthermore, the α-sheet designs reduced endogenous islet amyloid formation and mitigation of amyloid-associated β-cell loss in cultured islets isolated from an hIAPP transgenic mouse model of islet amyloidosis. Characterization of the involvement of α-sheet in early aggregation of hIAPP and oligomer toxicity contributes to elucidation of the molecular mechanisms underlying amyloid-associated β-cell loss.
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Affiliation(s)
- Cheng‐Chieh Hsu
- Department of BioengineeringUniversity of WashingtonSeattleWashingtonUSA
- Molecular Engineering ProgramUniversity of WashingtonSeattleWashingtonUSA
| | - Andrew T. Templin
- Division of Metabolism, Endocrinology and Nutrition, Department of MedicineVA Puget Sound Health Care System and University of WashingtonSeattleWashingtonUSA
| | - Tatum Prosswimmer
- Molecular Engineering ProgramUniversity of WashingtonSeattleWashingtonUSA
| | - Dylan Shea
- Molecular Engineering ProgramUniversity of WashingtonSeattleWashingtonUSA
| | - Jinzheng Li
- Department of BiochemistryUniversity of WashingtonSeattleWashingtonUSA
| | - Barbara Brooks‐Worrell
- Division of Metabolism, Endocrinology and Nutrition, Department of MedicineVA Puget Sound Health Care System and University of WashingtonSeattleWashingtonUSA
| | - Steven E. Kahn
- Division of Metabolism, Endocrinology and Nutrition, Department of MedicineVA Puget Sound Health Care System and University of WashingtonSeattleWashingtonUSA
| | - Valerie Daggett
- Department of BioengineeringUniversity of WashingtonSeattleWashingtonUSA
- Molecular Engineering ProgramUniversity of WashingtonSeattleWashingtonUSA
- Department of BiochemistryUniversity of WashingtonSeattleWashingtonUSA
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11
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Yang J, Zou Y, Lv X, Chen J, Cui C, Song J, Yang M, Hu H, Gao J, Xia L, Wang L, Chen L, Hou X. Didymin protects pancreatic beta cells by enhancing mitochondrial function in high-fat diet-induced impaired glucose tolerance. Diabetol Metab Syndr 2024; 16:7. [PMID: 38172956 PMCID: PMC10762818 DOI: 10.1186/s13098-023-01244-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Accepted: 12/18/2023] [Indexed: 01/05/2024] Open
Abstract
PURPOSE Prolonged exposure to plasma free fatty acids (FFAs) leads to impaired glucose tolerance (IGT) which can progress to type 2 diabetes (T2D) in the absence of timely and effective interventions. High-fat diet (HFD) leads to chronic inflammation and oxidative stress, impairing pancreatic beta cell (PBC) function. While Didymin, a flavonoid glycoside derived from citrus fruits, has beneficial effects on inflammation dysfunction, its specific role in HFD-induced IGT remains yet to be elucidated. Hence, this study aims to investigate the protective effects of Didymin on PBCs. METHODS HFD-induced IGT mice and INS-1 cells were used to explore the effect and mechanism of Didymin in alleviating IGT. Serum glucose and insulin levels were measured during the glucose tolerance and insulin tolerance tests to evaluate PBC function and insulin resistance. Next, RNA-seq analysis was performed to identify the pathways potentially influenced by Didymin in PBCs. Furthermore, we validated the effects of Didymin both in vitro and in vivo. Mitochondrial electron transport inhibitor (Rotenone) was used to further confirm that Didymin exerts its ameliorative effect by enhancing mitochondria function. RESULTS Didymin reduces postprandial glycemia and enhances 30-minute postprandial insulin levels in IGT mice. Moreover, Didymin was found to enhance mitochondria biogenesis and function, regulate insulin secretion, and alleviate inflammation and apoptosis. However, these effects were abrogated with the treatment of Rotenone, indicating that Didymin exerts its ameliorative effect by enhancing mitochondria function. CONCLUSIONS Didymin exhibits therapeutic potential in the treatment of HFD-induced IGT. This beneficial effect is attributed to the amelioration of PBC dysfunction through improved mitochondrial function.
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Affiliation(s)
- Jingwen Yang
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, 250012, Jinan, Shandong, China
| | - Ying Zou
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, 250012, Jinan, Shandong, China
| | - Xiaoyu Lv
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, 250012, Jinan, Shandong, China
| | - Jun Chen
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, 250012, Jinan, Shandong, China
| | - Chen Cui
- Department of Endocrinology, The Second Hospital of Shandong University, Jinan, China
| | - Jia Song
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, 250012, Jinan, Shandong, China
| | - Mengmeng Yang
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, 250012, Jinan, Shandong, China
| | - Huiqing Hu
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, 250012, Jinan, Shandong, China
| | - Jing Gao
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, 250012, Jinan, Shandong, China
| | - Longqing Xia
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, 250012, Jinan, Shandong, China
| | - Liming Wang
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, 250012, Jinan, Shandong, China
| | - Li Chen
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, 250012, Jinan, Shandong, China
- Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China
- Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan, China
- Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, China
- National Key Laboratory for Innovation and Transformation of Luobing Theory, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Jinan, China
| | - Xinguo Hou
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, 250012, Jinan, Shandong, China.
- Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China.
- Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan, China.
- Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, China.
- National Key Laboratory for Innovation and Transformation of Luobing Theory, Jinan, China.
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Jinan, China.
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12
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Chatanaka MK, Sohaei D, Diamandis EP, Prassas I. Beyond the amyloid hypothesis: how current research implicates autoimmunity in Alzheimer's disease pathogenesis. Crit Rev Clin Lab Sci 2023; 60:398-426. [PMID: 36941789 DOI: 10.1080/10408363.2023.2187342] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 03/01/2023] [Indexed: 03/23/2023]
Abstract
The amyloid hypothesis has so far been at the forefront of explaining the pathogenesis of Alzheimer's Disease (AD), a progressive neurodegenerative disorder that leads to cognitive decline and eventual death. Recent evidence, however, points to additional factors that contribute to the pathogenesis of this disease. These include the neurovascular hypothesis, the mitochondrial cascade hypothesis, the inflammatory hypothesis, the prion hypothesis, the mutational accumulation hypothesis, and the autoimmunity hypothesis. The purpose of this review was to briefly discuss the factors that are associated with autoimmunity in humans, including sex, the gut and lung microbiomes, age, genetics, and environmental factors. Subsequently, it was to examine the rise of autoimmune phenomena in AD, which can be instigated by a blood-brain barrier breakdown, pathogen infections, and dysfunction of the glymphatic system. Lastly, it was to discuss the various ways by which immune system dysregulation leads to AD, immunomodulating therapies, and future directions in the field of autoimmunity and neurodegeneration. A comprehensive account of the recent research done in the field was extracted from PubMed on 31 January 2022, with the keywords "Alzheimer's disease" and "autoantibodies" for the first search input, and "Alzheimer's disease" with "IgG" for the second. From the first search, 19 papers were selected, because they contained recent research on the autoantibodies found in the biofluids of patients with AD. From the second search, four papers were selected. The analysis of the literature has led to support the autoimmune hypothesis in AD. Autoantibodies were found in biofluids (serum/plasma, cerebrospinal fluid) of patients with AD with multiple methods, including ELISA, Mass Spectrometry, and microarray analysis. Through continuous research, the understanding of the synergistic effects of the various components that lead to AD will pave the way for better therapeutic methods and a deeper understanding of the disease.
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Affiliation(s)
- Miyo K Chatanaka
- Department of Laboratory and Medicine Pathobiology, University of Toronto, Toronto, Canada
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada
| | - Dorsa Sohaei
- Faculty of Medicine and Health Sciences, McGill University, Montreal, Canada
| | - Eleftherios P Diamandis
- Department of Laboratory and Medicine Pathobiology, University of Toronto, Toronto, Canada
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada
- Department of Clinical Biochemistry, University Health Network, Toronto, Canada
| | - Ioannis Prassas
- Laboratory Medicine Program, University Health Network, Toronto, Canada
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13
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Morsy MHE, Nabil ZI, Darwish ST, Al-Eisa RA, Mehana AE. Anti-Diabetic and Anti-Adipogenic Effect of Harmine in High-Fat-Diet-Induced Diabetes in Mice. Life (Basel) 2023; 13:1693. [PMID: 37629550 PMCID: PMC10455780 DOI: 10.3390/life13081693] [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: 07/03/2023] [Revised: 07/31/2023] [Accepted: 08/03/2023] [Indexed: 08/27/2023] Open
Abstract
One of the most important health issues facing the world today is obesity. It is an important independent risk factor for developing type 2 diabetes. Harmine offers various pharmacological effects, such as anti-inflammatory and anti-tumor effects. The current study aims to investigate Harmine's anti-diabetic and anti-adipogenic properties in albino mice after inducing low-grade inflammation with a high-fat diet (HFD). About forty-eight male albino mice were divided into four groups. Group 1: control mice were injected with daily saline and fed a normal chow diet of 21% protein for 5 months. Group 2: mice were treated daily with IP-injected Harmine (30 mg/kg body weight) and were fed a normal chow diet for 5 months. Group 3: mice were fed HFD to induce type 2 Diabetes Mellitus (T2DM) for 5 months. Group 4: mice were fed HFD for 14 weeks and treated with Harmine for the last 6 weeks. A figh-fat diet caused a significant increase in body and organ weight, lipid profiles, and destructive changes within the pancreas, kidney, and liver tissue. The administration of Harmine led to a remarkable improvement in the histological and ultrastructural changes induced by HFD. The findings indicate that mice cured using Harmine had lower oxidative stress, a higher total antioxidant capacity, and a reduced lipid profile compared to HFD mice. Harmine led to the hepatocytes partly restoring their ordinary configuration. Furthermore, it was noticed that the pathological incidence of damage in the structure of both the kidney and pancreas sections reduced in comparison with the diabetic group. Additional research will be required to fully understand Harmine and its preventive effects on the two forms of diabetes.
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Affiliation(s)
- Menna H E Morsy
- Department of Zoology, Faculty of Science, Arish University, Arish 45511, Egypt
- Department of Zoology, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt
| | - Zohour I Nabil
- Department of Zoology, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt
| | - Samah T Darwish
- Department of Zoology, Faculty of Science, Arish University, Arish 45511, Egypt
| | - Rasha A Al-Eisa
- Department of Biology, College of Sciences, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Amir E Mehana
- Department of Zoology, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt
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Hao S, Umpierrez GE, Daley T, Vellanki P. Intervention with Therapeutic Agents, Understanding the Path to Remission in Type 2 Diabetes: Part 1. Endocrinol Metab Clin North Am 2023; 52:27-38. [PMID: 36754495 DOI: 10.1016/j.ecl.2022.07.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Type 2 diabetes is characterized by progressive decline in pancreatic β-cell function. Studies in adult subjects with newly diagnosed type 2 diabetes have reported that intensive insulin therapy followed by various antihyperglycemic medications can delay β-cell decline. However, this improvement is lost after cessation of therapy. In contrast, youth with type 2 diabetes experience a more rapid loss in β-cell function compared with adults and have loss of β-cell function despite being on insulin and other antihyperglycemic medications. In part one of this two-part review, we discuss studies aiming to achieve diabetes remission with insulin and oral antidiabetic medications.
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Affiliation(s)
- Shuai Hao
- Division of Pediatric Endocrinology, Children's Healthcare of Atlanta, Emory University School of Medicine, 1400 Tullie Road Northeast, Atlanta, GA 30329, USA
| | - Guillermo E Umpierrez
- Division of Endocrinology, Metabolism & Lipids, Emory University School of Medicine, 69 Jesse Hill Jr Drive Southeast, Glenn Building, Room 205, Suite 200, Atlanta, GA 30303, USA
| | - Tanicia Daley
- Division of Pediatric Endocrinology, Children's Healthcare of Atlanta, Emory University School of Medicine, 1400 Tullie Road Northeast, Atlanta, GA 30329, USA
| | - Priyathama Vellanki
- Division of Endocrinology, Metabolism & Lipids, Emory University School of Medicine, 69 Jesse Hill Jr Drive Southeast, Glenn Building, Room 205, Suite 200, Atlanta, GA 30303, USA.
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15
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Liu Y, Yang Y, Xu C, Liu J, Chen J, Li G, Huang B, Pan Y, Zhang Y, Wei Q, Pandol SJ, Zhang F, Li L, Jin L. Circular RNA circGlis3 protects against islet β-cell dysfunction and apoptosis in obesity. Nat Commun 2023; 14:351. [PMID: 36681689 PMCID: PMC9867769 DOI: 10.1038/s41467-023-35998-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 01/12/2023] [Indexed: 01/22/2023] Open
Abstract
Pancreatic β-cell compensation is a major mechanism in delaying T2DM progression. Here we report the abnormal high expression of circGlis3 in islets of male mice with obesity and serum of people with obesity. Increasing circGlis3 is regulated by Quaking (QKI)-mediated splicing circularization. circGlis3 overexpression enhances insulin secretion and inhibits obesity-induced apoptosis in vitro and in vivo. Mechanistically, circGlis3 promotes insulin secretion by up-regulating NeuroD1 and Creb1 via sponging miR-124-3p and decreases apoptosis via interacting with the pro-apoptotic factor SCOTIN. The RNA binding protein FUS recruits circGlis3 and collectively assemble abnormal stable cytoplasmic stress granules (SG) in response to cellular stress. These findings highlight a physiological role for circRNAs in β-cell compensation and indicate that modulation of circGlis3 expression may represent a potential strategy to prevent β-cell dysfunction and apoptosis after obesity.
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Affiliation(s)
- Yue Liu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of life Science and Technology, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, Jiangsu province, P. R. China
| | - Yue Yang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of life Science and Technology, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, Jiangsu province, P. R. China
| | - Chenying Xu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of life Science and Technology, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, Jiangsu province, P. R. China
| | - Jianxing Liu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of life Science and Technology, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, Jiangsu province, P. R. China
| | - Jiale Chen
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of life Science and Technology, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, Jiangsu province, P. R. China
| | - Guoqing Li
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Dingjiaqiao, Nanjing, Jiangsu, 210009, China
| | - Bin Huang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of life Science and Technology, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, Jiangsu province, P. R. China
| | - Yi Pan
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of life Science and Technology, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, Jiangsu province, P. R. China
| | - Yanfeng Zhang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of life Science and Technology, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, Jiangsu province, P. R. China
| | - Qiong Wei
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Dingjiaqiao, Nanjing, Jiangsu, 210009, China
| | - Stephen J Pandol
- Departments of Medicine and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Fangfang Zhang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of life Science and Technology, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, Jiangsu province, P. R. China.
| | - Ling Li
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Dingjiaqiao, Nanjing, Jiangsu, 210009, China.
| | - Liang Jin
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of life Science and Technology, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, Jiangsu province, P. R. China.
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16
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Alam A, Ali M, Latif A, Rehman NU, Saher S, Zainab, Faryal, Khan A, Ullah S, Ullah O, Halim SA, Sani F, Al-Harrasi A, Ahmad M. Novel Bis-Schiff’s base derivatives of 4-nitroacetophenone as potent α-glucosidase agents: Design, synthesis and in silico approach. Bioorg Chem 2022; 128:106058. [DOI: 10.1016/j.bioorg.2022.106058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 06/01/2022] [Accepted: 07/21/2022] [Indexed: 11/29/2022]
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17
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Erfidan S, Dede S, Usta A, Yüksek V, Çetin S. The effect of quinoa (Chenopodium quinoa) on apoptotic, autophagic, antioxidant and inflammation markers in glucocorticoid-induced insulin resistance in rats. Mol Biol Rep 2022; 49:6509-6516. [PMID: 35618936 DOI: 10.1007/s11033-022-07479-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 04/14/2022] [Indexed: 11/26/2022]
Abstract
BACKGROUND Insulin resistance plays an important role in predicting type 2 diabetes that may develops. This study was planned in order to investigate the beneficial effects of quinoa (Chenopodium quinoa) use in glucocorticoid induced-insulin resistance. METHODS AND RESULTS Forty-two rats were used as the material (experimental) groups: the control group (C), the quinoa-administered group (Q), the insulin resistance-created group (IR), the IR + metformin group (IM), the IR + quinoa for treatment group (IQ) and the quinoa + IR for prophylaxis group (QI). Blood glucose, insulin levels and HOMA-IR were found to be highest (p < 0.05) in the IR group (p < 0.05). Glucose levels decreased significantly with the administration of quinoa and approached the levels of the control, but the insulin levels and the HOMA-IR did not significantly change. It was also observed that other biochemical parameters (ALT, AST, ALP, total cholesterol, total protein, urea and creatinine) changed significantly in the IR group and approached the levels of the control group with the administration of quinoa. Apoptotic (BCL2 5, BAX 9, CAS 3), autophagic (SQSTM1 7, ATG5) and inflammation (IL-1β, TNF-α) genes were upregulated by 5-11-fold in the IR group. In the groups in which quinoa was administered for treatment and protection, all these genes were found to be upregulated to a lower extent than the IR group. Antioxidant genes (GPX1, SOD1) increased by nine to tenfold in the quinoa groups. CONCLUSION As a result, after administration of quinoa, it was determined that the glucose level increased due to experimental insulin resistance and the liver and kidney damage indicators decreased. It was determined that quinoa (Chenopodium quinoa) had significant beneficial effects on biochemical parameters and apoptotic, autophagic, antioxidant and inflammatory markers in experimental glucocorticoid-induced insulin resistance.
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Affiliation(s)
- Siber Erfidan
- Health Sciences Institute, Van Yuzuncu Yil University, Van, Turkey
| | - Semiha Dede
- Biochemistry Department, Faculty of Veterinary Medicine, Van Yuzuncu Yil University, Van, Turkey.
| | - Ayşe Usta
- Faculty of Science, Van Yuzuncu Yil University, Van, Turkey
| | - Veysel Yüksek
- Ozalp Regional High School, Van Yuzuncu Yil University, Van, Turkey
| | - Sedat Çetin
- Biochemistry Department, Faculty of Veterinary Medicine, Van Yuzuncu Yil University, Van, Turkey
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18
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Kim HT, Desouza AH, Umhoefer H, Han J, Anzia L, Sacotte SJ, Williams RA, Blumer JT, Bartosiak JT, Fontaine DA, Baan M, Kibbe CR, Davis DB. Cholecystokinin attenuates β-cell apoptosis in both mouse and human islets. Transl Res 2022; 243:1-13. [PMID: 34740874 PMCID: PMC9504967 DOI: 10.1016/j.trsl.2021.10.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 09/23/2021] [Accepted: 10/24/2021] [Indexed: 11/17/2022]
Abstract
Loss of functional pancreatic β-cell mass and increased β-cell apoptosis are fundamental to the pathophysiology of type 1 and type 2 diabetes. Pancreatic islet transplantation has the potential to cure type 1 diabetes but is often ineffective due to the death of the islet graft within the first few years after transplant. Therapeutic strategies to directly target pancreatic β-cell survival are needed to prevent and treat diabetes and to improve islet transplant outcomes. Reducing β-cell apoptosis is also a therapeutic strategy for type 2 diabetes. Cholecystokinin (CCK) is a peptide hormone typically produced in the gut after food intake, with positive effects on obesity and glucose metabolism in mouse models and human subjects. We have previously shown that pancreatic islets also produce CCK. The production of CCK within the islet promotes β-cell survival in rodent models of diabetes and aging. We demonstrate a direct effect of CCK to reduce cytokine-mediated apoptosis in a β-cell line and in isolated mouse islets in a receptor-dependent manner. However, whether CCK can protect human β-cells was previously unknown. Here, we report that CCK can also reduce cytokine-mediated apoptosis in isolated human islets and CCK treatment in vivo decreases β-cell apoptosis in human islets transplanted into the kidney capsule of diabetic NOD/SCID mice. Collectively, these data identify CCK as a novel therapy that can directly promote β-cell survival in human islets and has therapeutic potential to preserve β-cell mass in diabetes and as an adjunct therapy after transplant.
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Affiliation(s)
- Hung Tae Kim
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Wisconsin-Madison, Madison, Wisconsin
| | - Arnaldo H Desouza
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Wisconsin-Madison, Madison, Wisconsin
| | - Heidi Umhoefer
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Wisconsin-Madison, Madison, Wisconsin
| | - Jeeyoung Han
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Wisconsin-Madison, Madison, Wisconsin
| | - Lucille Anzia
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Wisconsin-Madison, Madison, Wisconsin
| | - Steven J Sacotte
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Wisconsin-Madison, Madison, Wisconsin
| | - Rashaun A Williams
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Wisconsin-Madison, Madison, Wisconsin
| | - Joseph T Blumer
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Wisconsin-Madison, Madison, Wisconsin
| | - Jacob T Bartosiak
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Wisconsin-Madison, Madison, Wisconsin
| | - Danielle A Fontaine
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Wisconsin-Madison, Madison, Wisconsin
| | - Mieke Baan
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Wisconsin-Madison, Madison, Wisconsin
| | - Carly R Kibbe
- Department of Human Biology, University of Wisconsin-Green Bay, Green Bay, Wisconsin.
| | - Dawn Belt Davis
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Wisconsin-Madison, Madison, Wisconsin; William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin.
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Wang HL, Wang L, Zhao CY, Lan HY. Role of TGF-Beta Signaling in Beta Cell Proliferation and Function in Diabetes. Biomolecules 2022; 12:373. [PMID: 35327565 PMCID: PMC8945211 DOI: 10.3390/biom12030373] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 02/21/2022] [Accepted: 02/24/2022] [Indexed: 12/27/2022] Open
Abstract
Beta (β) cell dysfunction or loss is the common pathological feature in all types of diabetes mellitus (diabetes). Resolving the underlying mechanism may facilitate the treatment of diabetes by preserving the β cell population and function. It is known that TGF-β signaling plays diverse roles in β cell development, function, proliferation, apoptosis, and dedifferentiation. Inhibition of TGF-β signaling expands β cell lineage in the development. However, deletion of Tgfbr1 has no influence on insulin demand-induced but abolishes inflammation-induced β cell proliferation. Among canonical TGF-β signaling, Smad3 but not Smad2 is the predominant repressor of β cell proliferation in response to systemic insulin demand. Deletion of Smad3 simultaneously improves β cell function, apoptosis, and systemic insulin resistance with the consequence of eliminated overt diabetes in diabetic mouse models, revealing Smad3 as a key mediator and ideal therapeutic target for type-2 diabetes. However, Smad7 shows controversial effects on β cell proliferation and glucose homeostasis in animal studies. On the other hand, overexpression of Tgfb1 prevents β cells from autoimmune destruction without influence on β cell function. All these findings reveal the diverse regulatory roles of TGF-β signaling in β cell biology.
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Affiliation(s)
- Hong-Lian Wang
- Research Center for Integrative Medicine, The Affiliated Traditional Medicine Hospital of Southwest Medical University, Luzhou 646000, China; (H.-L.W.); (L.W.)
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Li Wang
- Research Center for Integrative Medicine, The Affiliated Traditional Medicine Hospital of Southwest Medical University, Luzhou 646000, China; (H.-L.W.); (L.W.)
| | - Chang-Ying Zhao
- Department of Endocrinology, The Affiliated Traditional Medicine Hospital of Southwest Medical University, Luzhou 646000, China;
| | - Hui-Yao Lan
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China
- Guangdong Academy of Sciences, Guangdong Provincial People’s Hospital Joint Research Laboratory on Immunological and Genetic Kidney Diseases, The Chinese University of Hong Kong, Hong Kong 999077, China
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20
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Floris S, Fais A, Medda R, Pintus F, Piras A, Kumar A, Kuś PM, Westermark GT, Era B. Washingtonia filifera seed extracts inhibit the islet amyloid polypeptide fibrils formations and α-amylase and α-glucosidase activity. J Enzyme Inhib Med Chem 2021; 36:517-524. [PMID: 33494628 PMCID: PMC7850368 DOI: 10.1080/14756366.2021.1874945] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Revised: 12/27/2020] [Accepted: 01/07/2021] [Indexed: 01/13/2023] Open
Abstract
Washingtonia filifera seeds have revealed to possess antioxidant properties, butyrylcholinesterase and xanthine oxidase inhibition activities. The literature has indicated a relationship between Alzheimer's disease (AD) and type-2 diabetes (T2D). Keeping this in mind, we have now evaluated the inhibitory properties of W. filifera seed extracts on α-amylase, α-glucosidase enzyme activity and the Islet Amyloid Polypeptide (IAPP) fibrils formation. Three extracts from seeds of W. filifera were evaluated for their enzyme inhibitory effect and IC50 values were calculated for all the extracts. The inhibition mode was investigated by Lineweaver-Burk plot analysis and the inhibition of IAPP aggregate formation was monitored. W. filifera methanol seed extract appears as the most potent inhibitor of α-amylase, α-glucosidase, and for the IAPP fibril formation. Current findings indicate new potential of this extract that could be used for the identification or development of novel potential agents for T2D and AD.
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Affiliation(s)
- Sonia Floris
- Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy
| | - Antonella Fais
- Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy
| | - Rosaria Medda
- Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy
| | - Francesca Pintus
- Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy
| | - Alessandra Piras
- Department of Chemical and Geological Sciences, University of Cagliari, Cagliari, Italy
| | - Amit Kumar
- Department of Electrical and Electronic Engineering, University of Cagliari, Cagliari, Italy
| | - Piotr Marek Kuś
- Department of Pharmacognosy and Herbal Medicines, Wroclaw Medical University, Wrocław, Poland
| | | | - Benedetta Era
- Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy
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21
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Wali S, Atia-Tul-Wahab, Ullah S, Khan MA, Hussain S, Shaikh M, Atta-Ur-Rahman, Choudhary MI. Synthesis of new clioquinol derivatives as potent α-glucosidase inhibitors; molecular docking, kinetic and structure-activity relationship studies. Bioorg Chem 2021; 119:105506. [PMID: 34896920 DOI: 10.1016/j.bioorg.2021.105506] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 11/11/2021] [Accepted: 11/17/2021] [Indexed: 12/14/2022]
Abstract
Diabetes mellitus is a chronic metabolic disorder with increasing prevalence and long-term complications. The aim of this study was to identify α-glucosidase inhibitory compounds with potential anti-hyperglycemic activity. For this purpose, a series of new clioquinol derivatives 2a-11a was synthesized, and characterized by various spectroscopic techniques. The enzyme inhibitory activities of the resulting derivatives were assessed using an in-vitro mechanism-based assay. All the tested compounds 2a-11a of the series showed a significant α-glucosidase inhibition with IC50 values 43.86-325.81 µM, as compared to the standard drug acarbose 1C50: 875.75 ± 2.08 µM. Among them, compounds 4a, 5a, 10a, and 11a showed IC50 values of 105.51 ± 2.41, 119.24 ± 2.37, 99.15 ± 2.06, and 43.86 ± 2.71 µM, respectively. Kinetic study of the active analogues showed competitive, non-competitive, and mixed-type inhibitions. Furthermore, the molecular docking study was performed to elucidate the binding interactions of most active analogues with the various sites of α-glucosidase enzyme. The results indicate that these compounds have the potential to be further studied as new anti-diabetic agents.
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Affiliation(s)
- Shoukat Wali
- H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan
| | - Atia-Tul-Wahab
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
| | - Saeed Ullah
- H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan
| | - Maria Aqeel Khan
- Third World Center for Science and Technology International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan
| | - Shahid Hussain
- Toronto General Hospital Research Institute (TGHRI), Toronto M5G 2C4, Canada
| | - Muniza Shaikh
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan
| | - Atta-Ur-Rahman
- H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan; Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan
| | - M Iqbal Choudhary
- H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan; Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan; Department of Biochemistry, Faculty of Science King Abdulaziz University, Jeddah 22254, Saudi Arabia.
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22
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Anti-IAPP Monoclonal Antibody Improves Clinical Symptoms in a Mouse Model of Type 2 Diabetes. Vaccines (Basel) 2021; 9:vaccines9111316. [PMID: 34835247 PMCID: PMC8622146 DOI: 10.3390/vaccines9111316] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Revised: 11/05/2021] [Accepted: 11/08/2021] [Indexed: 01/09/2023] Open
Abstract
Type 2 Diabetes Mellitus (T2DM) is a chronic progressive disease, defined by insulin resistance and insufficient insulin secretion to maintain normoglycemia. Amyloidogenic aggregates are a hallmark of T2DM patients; they are cytotoxic for the insulin producing β-cells, and cause inflammasome-dependent secretion of IL-1β. To avoid the associated β-cell loss and inflammation in advanced stage T2DM, we developed a novel monoclonal therapy targeting the major component of aggregates, islet amyloid polypeptide (IAPP). The here described monoclonal antibody (mAb) m81, specific for oligomeric and fibrils, but not for soluble free IAPP, is able to prevent oligomer growth and aggregate formation in vitro, and blocks islet inflammation and disease progression in vivo. Collectively, our data show that blocking fibril formation and prevention of new amyloidogenic aggregates by monoclonal antibody therapy may be a potential therapy for T2DM.
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23
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Pathak BK, Dey S, Mozumder S, Sengupta J. The role of membranes in function and dysfunction of intrinsically disordered amyloidogenic proteins. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2021; 128:397-434. [PMID: 35034725 DOI: 10.1016/bs.apcsb.2021.08.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Membrane-protein interactions play a major role in human physiology as well as in diseases pathology. Interaction of a protein with the membrane was previously thought to be dependent on well-defined three-dimensional structure of the protein. In recent decades, however, it has become evident that a large fraction of the proteome, particularly in eukaryotes, stays disordered in solution and these proteins are termed as intrinsically disordered proteins (IDPs). Also, a vast majority of human proteomes have been reported to contain substantially long disordered regions, called intrinsically disordered regions (IDRs), in addition to the structurally ordered regions. IDPs exist in an ensemble of conformations and the conformational flexibility enables IDPs to achieve functional diversity. IDPs (and IDRs) are found to be important players in cell signaling, where biological membranes act as anchors for signaling cascades. Therefore, IDPs modulate the membrane architectures, at the same time membrane composition also affects the binding of IDPs. Because of intrinsic disorders, misfolding of IDPs often leads to formation of oligomers, protofibrils and mature fibrils through progressive self-association. Accumulation of amyloid-like aggregates of some of the IDPs is a known causative agent for numerous diseases. In this chapter we highlight recent advances in understanding membrane interactions of some of the intrinsically disordered proteins involved in the pathogenesis of human diseases.
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Affiliation(s)
- Bani Kumar Pathak
- Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, Jadavpur, Kolkata, India
| | - Sandip Dey
- Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, Jadavpur, Kolkata, India
| | - Sukanya Mozumder
- Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, Jadavpur, Kolkata, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Jayati Sengupta
- Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, Jadavpur, Kolkata, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.
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24
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Zhu C, Xu R, Li Y, Andrade M, Yin DP. Gastric bypass prevents diabetes in genetically modified mice and chemically induced diabetic mice. PLoS One 2021; 16:e0258942. [PMID: 34673835 PMCID: PMC8530305 DOI: 10.1371/journal.pone.0258942] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 10/09/2021] [Indexed: 01/09/2023] Open
Abstract
Obese subjects have increase probabilities of developing type 2 diabetes (T2D). In this study, we sought to determine whether gastric bypass prevents the progression of prediabetes to overt diabetes in genetically modified mice and chemically induced diabetic mice. Roux-en-Y gastric bypass (RYGB) was performed in C57BL/KsJ-db/db null (BKS-db/db,) mice, high-fat diet (HFD)-fed NONcNZO10/LtJ (NZO) mice, C57BL/6 db/db null (B6-db/db) mice and streptozotocin (STZ)-induced diabetic mice. Food consumption, body weight, fat mass, fast blood glucose level, circulating insulin and adiponectin and glucose tolerance test were analyzed. The liver and pancreatic tissues were subjected to H&E and immunohistochemistry staining and islet cells to flow cytometry for apoptotic analysis. RYGB resulted in sustained normoglycemia and improved glucose tolerance in young prediabetic BKS-db/db mice (at the age of 6 weeks with hyperglycemia and normal insulinemia) and HFD-fed NZO and B6-db/db mice. Remarkably, RYGB improved liver steatosis, preserved the pancreatic β-cells and reduced β-cell apoptosis with increases in circulating insulin and adiponectin in young prediabetic BKS-db/db mice. However, RYGB neither reversed hyperglycemia in adult diabetic BKS-db/db mice (12 weeks old) nor attenuated hyperglycemia in STZ-induced diabetic mice. These results demonstrate that gastric bypass improves hyperglycemia in genetically modified prediabetic mice; however, it should be performed prior to β-cells exhaustion.
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Affiliation(s)
- Chenyu Zhu
- The First College of Clinical Medical Science, CTGU, and Yichang Central People’s Hospital, Yichang, Hubei, China
| | - Rui Xu
- The First College of Clinical Medical Science, CTGU, and Yichang Central People’s Hospital, Yichang, Hubei, China
| | - Yuxin Li
- The Department of Surgery at University of Chicago, Chicago, Illinois United States of America
| | - Michael Andrade
- The Department of Surgery at University of Chicago, Chicago, Illinois United States of America
| | - Deng Ping Yin
- The Department of Surgery at University of Chicago, Chicago, Illinois United States of America
- * E-mail:
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25
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Lv X, Zhao Y, Yang X, Han H, Ge Y, Zhang M, Zhang H, Zhang M, Chen L. Berberine Potentiates Insulin Secretion and Prevents β-cell Dysfunction Through the miR-204/SIRT1 Signaling Pathway. Front Pharmacol 2021; 12:720866. [PMID: 34630099 PMCID: PMC8493072 DOI: 10.3389/fphar.2021.720866] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Accepted: 09/06/2021] [Indexed: 01/16/2023] Open
Abstract
Pancreatic β-cell dysfunction is a key link during the progression of type 2 diabetes (T2DM), and SIRT1 participates in the regulation of various physiological activities of islet β-cells. However, as a key link in signal transduction, it is not clear how SIRT1 is regulated. By TargetScan prediction, we found that miR-204, which is enriched in islets, has highly complementary binding sites with SIRT1. Therefore, we speculate that miR-204 may be the upstream regulatory target of SIRT1 in islets and thus participate in the occurrence of β-cell dysfunction. In this study, we explored the association between miR-204 and β-cell dysfunction, the therapeutic effects of berberine (BBR) on β-cell function and the possible mechanisms. We found that miR-204 increased and SIRT1 mRNA and protein levels decreased significantly in islets both in vivo and in vitro. MIN6 cells induced by palmitic acid exhibited increased apoptosis, and the accumulation of insulin and ATP in the supernatant decreased. Importantly, palmitic acid treatment combined with miR-204 silencing showed opposite changes. MiR-204 overexpression in MIN6 cells increased apoptosis and decreased insulin and ATP production and SIRT1 expression. SIRT1 overexpression reversed the damage to β-cells caused by miR-204. The BBR treatment effectively improved insulin synthesis, reduced miR-204 levels, and increased SIRT1 expression in islet tissue in diabetic mice. Overexpression of miR-204 reversed the protective effect of BBR on apoptosis and insulin secretion in MIN6 cells. Our study identifies a novel correlation between miR-204 and β-cell dysfunction in T2DM and shows that administration of BBR leads to remission of β-cell dysfunction by regulating the miR-204/SIRT1 pathway.
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Affiliation(s)
- Xiaoyan Lv
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun, China.,Department of Clinical Laboratory, The Second Hospital of Jilin University, Changchun, China
| | - Yali Zhao
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Xuehan Yang
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Hao Han
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Yue Ge
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Meishuang Zhang
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun, China.,Department of Pharmacology, School of Nursing, Jilin University, Changchun, China
| | - Hansi Zhang
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Ming Zhang
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Li Chen
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun, China.,Department of Pharmacology, School of Nursing, Jilin University, Changchun, China
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26
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Cayli S, Alimogullari E, Piskin I, Bilginoglu A, Nakkas H. Effect of pioglitazone on the expression of ubiquitin proteasome system and autophagic proteins in rat pancreas with metabolic syndrome. J Mol Histol 2021; 52:929-942. [PMID: 34410563 DOI: 10.1007/s10735-021-10013-1] [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: 07/26/2020] [Accepted: 08/10/2021] [Indexed: 11/28/2022]
Abstract
The metabolic syndrome (MetS) and pathologies associated with metabolic dysregulations a worldwide growing problem. Our previous study demonstrated that pioglitazone (PGZ) has beneficial effects on metabolic syndrome associated disturbances in the heart. However, mechanism mediating the molecular alterations of Ubiquitin proteasome system (UPS) and autophagy has not been investigated in rat pancreas with metabolic syndrome. For this reason, we first aimed to detect whether MetS effects on the expression of UPS (p97/VCP, SVIP, Ubiquitin) and autophagic (p62, LC3) proteins in rat pancreas. The second aim of the study was to find impact of pioglitazone on the expression of UPS and autophagic proteins in MetS rat pancreas. To answer these questions, metabolic syndrome induced rats were used as a model and treated with pioglitazone for 2 weeks. Pancreatic tissue injuries, fibrosis and lipid accumulation were evaluated histopathologically in control, MetS and MetS-PGZ groups. Apoptosis and cell proliferation of pancreatic islet cells were assessed in all groups. UPS and autophagic protein expressions of pancreas in all groups were detected by using immunohistochemistry, double-immunfluorescence and Western blotting. Compared with the controls, the rat fed with high sucrose exhibited signs of metabolic syndrome, such as higher body weight, insulin resistance, higher triglyceride level and hyperglycaemia. MetS rats showed pancreatic tissue degeneration, fibrosis and lipid accumulation when their pancreas were examined with Hematoxilen-eozin and Mallory trichrome staining. Metabolic, histopathologic parameters and cell proliferation showed greater improvement in MetS-PGZ rats and pioglitazone decreased apoptosis of islet cells. Moreover, SVIP, ubiquitin, LC3 and p62 expressions were significantly increased while only p97/VCP expression was significantly decreased in MetS-rat pancreas compared to control. PGZ treatment significantly decreased the MetS-induced increases in autophagy markers. Additionally, UPS and autophagy markers were found to colocalizated with insulin and glucagon. Colocalization ratio of UPS markers with insulin showed significant decrease in MetS rats and PGZ increased this ratio, whereas LC3-insulin colocalization displayed significant increase in MetS rats and PGZ reversed this effect. In conclusion, PGZ improved the pancreatic tissue degeneration by increasing the level of p97/VCP and decreasing autophagic proteins, SVIP and ubiquitin expressions in MetS-rats. Moreover, PGZ has an effect on the colocalization ratio of UPS and autophagy markers with insulin.
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Affiliation(s)
- Sevil Cayli
- Department of Histology and Embryology, Medical Faculty, Ankara Yıldırım Beyazıt University, 06800, Ankara, Turkey.
| | - Ebru Alimogullari
- Department of Histology and Embryology, Medical Faculty, Ankara Yıldırım Beyazıt University, 06800, Ankara, Turkey
| | - Ilkay Piskin
- Department of Histology and Embryology, Medical Faculty, Ankara Yıldırım Beyazıt University, 06800, Ankara, Turkey
| | - Ayca Bilginoglu
- Department of Biophysics, Medical Faculty, Ankara Yıldırım Beyazıt University, Ankara, Turkey
| | - Hilal Nakkas
- Department of Histology and Embryology, Medical Faculty, Ankara Yıldırım Beyazıt University, 06800, Ankara, Turkey
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27
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Mizukami H, Kudoh K. Diversity of pathophysiology in type 2 diabetes shown by islet pathology. J Diabetes Investig 2021; 13:6-13. [PMID: 34562302 PMCID: PMC8756316 DOI: 10.1111/jdi.13679] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 09/19/2021] [Indexed: 12/18/2022] Open
Abstract
The etiology of type 2 diabetes is multifactorial, in which environmental and genetic factors are involved to varying degrees. This suggests that its pathophysiology might vary depending on the individuals. Knowledge of the differences is critical, because these differences are directly linked to the care and treatment of the patients. Recent studies have attempted to carry out subclassifications of type 2 diabetes based on clinical and genetic differences. However, there is no pathological evidence to support these subclassifications. The pathophysiology of type 2 diabetes is generally divided into insulin resistance in peripheral tissues and pancreatic islet dysfunction. Among them, islet dysfunction causes a deficit in insulin secretion from β-cells. In particular, a deficit in insulin secretion is ascribed to a combination of disruption of the insulin secretory machinery and a decrease in β-cell volume in type 2 diabetes. Recent research has suggested that transdifferentiation and dedifferentiation are involved in the decrease in β-cell volume, and that it might change dynamically depending on the glucose metabolic state. However, it is possible that the numbers of islet cells are decreased in type 2 diabetes. In particular, the loss of endocrine cells due to islet amyloid deposits is an important pathological change in type 2 diabetes in humans. These results show that pathological changes of the islets can be different in each individuals with type 2 diabetes and reflect each pathophysiology, which is useful in establishing further subclassifications and developing tailor-made therapies for type 2 diabetes.
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Affiliation(s)
- Hiroki Mizukami
- Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Kazuhiro Kudoh
- Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
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28
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A Brief Review of the Mechanisms of β-Cell Dedifferentiation in Type 2 Diabetes. Nutrients 2021; 13:nu13051593. [PMID: 34068827 PMCID: PMC8151793 DOI: 10.3390/nu13051593] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 04/30/2021] [Accepted: 05/07/2021] [Indexed: 01/09/2023] Open
Abstract
Diabetes is a metabolic disease characterized by hyperglycemia. Over 90% of patients with diabetes have type 2 diabetes. Pancreatic β-cells are endocrine cells that produce and secrete insulin, an essential endocrine hormone that regulates blood glucose levels. Deficits in β-cell function and mass play key roles in the onset and progression of type 2 diabetes. Apoptosis has been considered as the main contributor of β-cell dysfunction and decrease in β-cell mass for a long time. However, recent studies suggest that β-cell failure occurs mainly due to increased β-cell dedifferentiation rather than limited β-cell proliferation or increased β-cell death. In this review, we summarize the current advances in the understanding of the pancreatic β-cell dedifferentiation process including potential mechanisms. A better understanding of β-cell dedifferentiation process will help to identify novel therapeutic targets to prevent and/or reverse β-cell loss in type 2 diabetes.
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29
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Chabosseau P, Rutter GA, Millership SJ. Importance of Both Imprinted Genes and Functional Heterogeneity in Pancreatic Beta Cells: Is There a Link? Int J Mol Sci 2021; 22:1000. [PMID: 33498234 PMCID: PMC7863946 DOI: 10.3390/ijms22031000] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/12/2021] [Accepted: 01/14/2021] [Indexed: 02/02/2023] Open
Abstract
Diabetes mellitus now affects more than 400 million individuals worldwide, with significant impacts on the lives of those affected and associated socio-economic costs. Although defects in insulin secretion underlie all forms of the disease, the molecular mechanisms which drive them are still poorly understood. Subsets of specialised beta cells have, in recent years, been suggested to play critical roles in "pacing" overall islet activity. The molecular nature of these cells, the means through which their identity is established and the changes which may contribute to their functional demise and "loss of influence" in both type 1 and type 2 diabetes are largely unknown. Genomic imprinting involves the selective silencing of one of the two parental alleles through DNA methylation and modified imprinted gene expression is involved in a number of diseases. Loss of expression, or loss of imprinting, can be shown in mouse models to lead to defects in beta cell function and abnormal insulin secretion. In the present review we survey the evidence that altered expression of imprinted genes contribute to loss of beta cell function, the importance of beta cell heterogeneity in normal and disease states, and hypothesise whether there is a direct link between the two.
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Affiliation(s)
| | | | - Steven J. Millership
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN, UK; (P.C.); (G.A.R.)
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30
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Sahukari R, Punabaka J, Bhasha S, Ganjikunta VS, Ramudu SK, Kesireddy SR. Plant Compounds for the Treatment of Diabetes, a Metabolic Disorder: NF-κB as a Therapeutic Target. Curr Pharm Des 2020; 26:4955-4969. [DOI: 10.2174/1381612826666200730221035] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 06/04/2020] [Indexed: 12/12/2022]
Abstract
Background:
The prevalence of diabetes in the world population hás reached 8.8 % and is expected to
rise to 10.4% by 2040. Hence, there is an urgent need for the discovery of drugs against therapeutic targets to
sojourn its prevalence. Previous studies proved that NF-κB serves as a central agent in the development of diabetic
complications.
Objectives:
This review intended to list the natural plant compounds that would act as inhibitors of NF-κB signalling
in different organs under the diabetic condition with their possible mechanism of action.
Methods:
Information on NF-κB, diabetes, natural products, and relation in between them, was gathered from
scientific literature databases such as Pubmed, Medline, Google scholar, Science Direct, Springer, Wiley online
library.
Results and Conclusion:
NF-κB plays a crucial role in the development of diabetic complications because of its
link in the expression of genes that are responsible for organs damage such as kidney, brain, eye, liver, heart,
muscle, endothelium, adipose tissue and pancreas by inflammation, apoptosis and oxidative stress. Activation of
PPAR-α, SIRT3/1, and FXR through many cascades by plant compounds such as terpenoids, iridoids, flavonoids,
alkaloids, phenols, tannins, carbohydrates, and phytocannabinoids recovers diabetic complications. These compounds
also exhibit the prevention of NF-κB translocation into the nucleus by inhibiting NF-κB activators, such
as VEGFR, RAGE and TLR4 receptors, which in turn, prevent the activation of many genes involved in tissue
damage. Current knowledge on the treatment of diabetes by targeting NF-κB is limited, so future studies would
enlighten accordingly.
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Affiliation(s)
- Ravi Sahukari
- Division of Molecular Biology and Ethnopharmacology, Department of Zoology, Sri Venkateswara University, Tirupati, India
| | - Jyothi Punabaka
- Division of Molecular Biology and Ethnopharmacology, Department of Zoology, Sri Venkateswara University, Tirupati, India
| | - Shanmugam Bhasha
- Division of Molecular Biology and Ethnopharmacology, Department of Zoology, Sri Venkateswara University, Tirupati, India
| | - Venkata S. Ganjikunta
- Division of Molecular Biology and Ethnopharmacology, Department of Zoology, Sri Venkateswara University, Tirupati, India
| | - Shanmugam K. Ramudu
- Division of Molecular Biology and Ethnopharmacology, Department of Zoology, Sri Venkateswara University, Tirupati, India
| | - Sathyavelu R. Kesireddy
- Division of Molecular Biology and Ethnopharmacology, Department of Zoology, Sri Venkateswara University, Tirupati, India
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Zhang P, Zeng L, Gao W, Li H, Gao Z. Peroxynitrite scavenger FeTPPS effectively inhibits hIAPP aggregation and protects against amyloid induced cytotoxicity. Int J Biol Macromol 2020; 161:336-344. [DOI: 10.1016/j.ijbiomac.2020.06.034] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 06/01/2020] [Accepted: 06/04/2020] [Indexed: 12/11/2022]
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Tang X, Gao G, Zhang T, Li J, Yu M, He M, Sun T. Charge effects at nano-bio interfaces: a model of charged gold nanoclusters on amylin fibrillation. NANOSCALE 2020; 12:18834-18843. [PMID: 32895690 DOI: 10.1039/d0nr03877f] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
The misfolding and abnormal amyloid fibrillation of proteins/peptides are associated with more than 20 human diseases. Although dozens of nanoparticles have been investigated for the inhibition effect on the misfolding and fibrillation of pathogenesis-related proteins/peptides, there are few reports on charge effects of nano inhibitors on amyloid fibrillation. Herein, same-sized gold nanoclusters modified with 2-aminoethanethiol hydrochloride (CSH-AuNCs, positively charged in pH 7.4) or 3-mercaptopropionic acid (MPA-AuNCs, negatively charged in pH 7.4) were synthesized and adopted as models to explore the charge effect of nano inhibitors on amylin fibrillation at the nano-bio interface. ThT fluorescence kinetics analysis, AFM images and circular dichroism (CD) spectra showed that electropositive CSH-AuNCs inhibited the misfolding and fibrillation of amylin in a dosage-dependent manner, but electronegative MPA-AuNCs accelerated the misfolding and fibrillation of amylin in a dosage-dependent manner. Moreover, the theoretical and experimental results revealed the interaction mechanism between amylin and ligands of AuNCs at the nano-bio interfaces. Electropositive CSH-AuNCs could be bound to the main nucleating region of amylin via hydrogen bonding and endowed the nanocomplex with more positive net charges (amylin monomer with a positive +26.23 ± 0.80 mV zeta potential), which would inhibit the misfolding and aggregation of amylin via electrostatic repulsion and steric hindrance. In contrast, electronegative MPA-AuNCs could absorb electropositive amylin via strong electrostatic attractions, which accelerated the fibrillation process of amylin via enhancing local concentrations. Moreover, cell experiments showed that both the charged AuNCs had good biocompatibility and electronegetive MPA-AuNCs showed a better protective effect in the amylin-induced cell model than electropositive CSH-AuNCs. These results provide an insight into structure-based nanodrug design for protein conformational diseases.
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Affiliation(s)
- Xintong Tang
- State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, Wuhan University of Technology, 122 Luoshi Road, Wuhan 430070, China.
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Ueberberg S, Nauck MA, Uhl W, Montemurro C, Tannapfel A, Clark A, Meier JJ. Islet Amyloid in Patients With Diabetes Due to Exocrine Pancreatic Disorders, Type 2 Diabetes, and Nondiabetic Patients. J Clin Endocrinol Metab 2020; 105:5818378. [PMID: 32271378 DOI: 10.1210/clinem/dgaa176] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Accepted: 04/08/2020] [Indexed: 01/06/2023]
Abstract
BACKGROUND Amyloid deposits are a typical finding in pancreatic islets from patients with type 2 diabetes. Whether this is linked to the pathogenesis of type 2 diabetes is currently unknown. Therefore, we compared the occurrence of islet amyloid in patients with type 2 diabetes, diabetes secondary to pancreatic disorders, and nondiabetic individuals. PATIENTS AND METHODS Pancreatic tissue from 15 nondiabetic patients, 22 patients with type 2 diabetes, and 11 patients with diabetes due to exocrine pancreatic disorders (chronic pancreatitis, pancreatic carcinoma) were stained for insulin, amyloid, and apoptosis. β-cell area, amyloid deposits, and β-cell apoptosis were quantified by morphometric analysis. RESULTS The proportion of islets containing amyloid deposits was significantly higher in both type 2 diabetes and diabetes due to exocrine pancreatic disorders than in healthy subjects. Islets with both amyloid and apoptosis were observed more frequently in type 2 diabetes and significantly more so in diabetes due to exocrine pancreatic disorders. In both diabetic groups, apoptotic ß-cells were found significantly more frequently in islets with more prominent amyloid deposits. CONCLUSIONS The occurrence of amyloid deposits in both type 2 diabetes and diabetes secondary to exocrine pancreatic disorders suggests that islet amyloid formation is a common feature of diabetes mellitus of different etiologies and may be associated with a loss of pancreatic ß-cells.
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Affiliation(s)
- Sandra Ueberberg
- Diabetes Division St. Josef-Hospital, Ruhr University Bochum, Bochum, Germany
| | - Michael A Nauck
- Diabetes Division St. Josef-Hospital, Ruhr University Bochum, Bochum, Germany
| | - Waldemar Uhl
- Department of General and Visceral Surgery, St. Josef-Hospital, Ruhr University Bochum, Bochum, Germany
| | - Chiara Montemurro
- Diabetes Division St. Josef-Hospital, Ruhr University Bochum, Bochum, Germany
- David Geffen School of Medicine, University of California, Los Angeles, CA, US
| | | | - Anne Clark
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
| | - Juris J Meier
- Diabetes Division St. Josef-Hospital, Ruhr University Bochum, Bochum, Germany
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El-Kersh AOFO, El-Akabawy G, Al-Serwi RH. Transplantation of human dental pulp stem cells in streptozotocin-induced diabetic rats. Anat Sci Int 2020; 95:523-539. [PMID: 32476103 DOI: 10.1007/s12565-020-00550-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Accepted: 05/20/2020] [Indexed: 12/11/2022]
Abstract
Type 1 diabetes mellitus (T1DM) is a chronic metabolic disease caused by the destruction of pancreatic β-cells. Human dental pulp stem cells represent a promising source for cell-based therapies, owing to their easy, minimally invasive surgical access, and high proliferative capacity. It was reported that human dental pulp stem cells can differentiate into a pancreatic cell lineage in vitro; however, few studies have investigated their effects on diabetes. Our study aimed to investigate the therapeutic potential of intravenous and intrapancreatic transplantation of human dental pulp stem cells in a rat model of streptozotocin-induced type 1 diabetes. Forty Sprague Dawley male rats were randomly categorized into four groups: control, diabetic (STZ), intravenous treatment group (IV), and intrapancreatic treatment group (IP). Human dental pulp stem cells (1 × 106 cells) or vehicle were injected into the pancreas or tail vein 7 days after streptozotocin injection. Fasting blood glucose levels were monitored weekly. Glucose tolerance test, rat and human serum insulin and C-peptide, pancreas histology, and caspase-3, vascular endothelial growth factor, and Ki67 expression in pancreatic tissues were assessed 28 days post-transplantation. We found that both IV and IP transplantation of human dental pulp stem cells reduced blood glucose and increased levels of rat and human serum insulin and C-peptide. The cells engrafted and survived in the streptozotocin-injured pancreas. Islet-like clusters and scattered human dental pulp stem cells expressing insulin were observed in the pancreas of diabetic rats with some difference in the distribution pattern between the two injection routes. RT-PCR analyses revealed the expression of the human-specific pancreatic β-cell genes neurogenin 3 (NGN3), paired box 4 (PAX4), glucose transporter 2 (GLUT2), and insulin in the pancreatic tissues of both the IP and IV groups. In addition, the transplanted cells downregulated the expression of caspase-3 and upregulated the expression of vascular endothelial growth factor and Ki67, suggesting that the injected cells exerted pro-angiogenetic and antiapoptotic effects, and promoted endogenous β-cell replication. Our study is the first to show that human dental pulp stem cells can migrate and survive within streptozotocin-injured pancreas, and induce antidiabetic effects through the differentiation and replacement of lost β-cells and paracrine-mediated pancreatic regeneration. Thus, human dental pulp stem cells may have therapeutic potential to treat patients with long term T1DM.
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Affiliation(s)
| | - Gehan El-Akabawy
- Department of Basic Sciences, College of Medicine, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia. .,Department of Anatomy and Embryology, Faculty of Medicine, Menoufia University, Menoufia, Egypt.
| | - Rasha H Al-Serwi
- Basic Dental Sciences, College of Dentistry, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia.,Oral Biology Department, Faculty of Dentistry, Mansoura University, Mansoura, Egypt
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CHL1 promotes insulin secretion and negatively regulates the proliferation of pancreatic β cells. Biochem Biophys Res Commun 2020; 525:1095-1102. [PMID: 32184019 DOI: 10.1016/j.bbrc.2020.03.040] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2020] [Accepted: 03/09/2020] [Indexed: 12/28/2022]
Abstract
Cell adhesion molecule L1-like protein (CHL1) is a member of neural recognition molecules of immunoglobulin superfamily primarily expressing in the nervous system. CHL1 regulates neuronal migration, axonal growth, and dendritic projection. Downregulation of CHL1 has been reported in β cells of patients with type 2 diabetes (T2DM). However, the detailed role of CHL1 in β cells has not been characterized. In this study, Real-Time PCR and Western blot were applied to investigate the tissue/cell distribution and expression of CHL1. Gain- or loss-of function studies were conducted in MIN6 cells to determine the effects of CHL1 on cell proliferation, apoptosis, cell cycle, and insulin secretion. Following silencing of CHL1 in MIN6 cells (si-CHL1), insulin secretion and the number of insulin secretary granules <50 nm from the cell membrane decreased in response to 20 mM glucose. Besides, silencing of CHL1 induced cell proliferation, reduced apoptosis, and prolonged S phase and shortened G1 phase of the cell cycle, contrary to overexpressing of CHL1. The inhibitor of ERK1/2MAPK eliminated the effect of CHL1 deficiency on the proliferation of MIN6 cells. In addition, high-fat diet could result in increased islet volume and β cell proliferation, decreased CHL1 expression and activation of ERK pathway in mice islets. Consequently, CHL1 expression was decreased in islets of high-fat induced mice, which resulted in cell proliferation via ERK pathway and regulation of the cell cycle through p53 pathway. These mechanisms may contribute to pancreatic β cell compensatory hyperplasia in obesity-induced pre-diabetes.
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Lee D, Shin Y, Jang J, Park Y, Ahn J, Jeong S, Shin SS, Yoon M. The herbal extract ALS-L1023 from Melissa officinalis alleviates visceral obesity and insulin resistance in obese female C57BL/6J mice. JOURNAL OF ETHNOPHARMACOLOGY 2020; 253:112646. [PMID: 32027997 DOI: 10.1016/j.jep.2020.112646] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 01/13/2020] [Accepted: 02/01/2020] [Indexed: 06/10/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Melissa officinalis L. (Labiatae; lemon balm) has traditionally been used as a medicinal herb to treat stress, anxiety, and insomnia. Current reports suggest that not only chronic stress stimulates angiogenesis, but angiogenesis also regulates adipogenesis and obesity. Because the herbal extract ALS-L1023 from Melissa officinalis inhibits angiogenesis, we hypothesized that ALS-L1023 could suppress visceral obesity and insulin resistance in obese female C57BL/6J mice, a mouse model of obese premenopausal women. MATERIALS AND METHODS The mice were grouped and fed for 16 weeks as follows: 1) low-fat diet (LFD), 2) high-fat diet (HFD), or 3) HFD supplemented with 0.4 or 0.8% ALS-L1023. Variables and determinants of visceral obesity, insulin resistance, and pancreatic dysfunction were then assessed via blood analysis, histology, immunohistochemistry, and real-time polymerase chain reaction. RESULTS ALS-L1023 decreased weight gain, visceral adipocyte size, and serum lipid levels in HFD-fed obese mice. ALS-L1023 also normalized hyperglycemia and hyperinsulinemia and concomitantly reduced blood glucose levels during oral glucose tolerance tests. The pancreatic islet size and insulin-positive β-cell area were significantly reduced in ALS-L1023-treated mice compared with untreated obese controls, reaching a level similar to that of LFD-fed lean mice. ALS-L1023 suppressed pancreatic lipid accumulation, infiltration of inflammatory cells, and collagen levels. ALS-L1023 treatment altered the pancreatic expression of genes involved in steatosis, inflammation, and fibrosis. CONCLUSIONS Our findings indicate that the herbal extract ALS-L1023 from Melissa officinalis not only inhibits visceral obesity, but also attenuates the increased fasting blood glucose, impaired glucose tolerance, and pancreatic dysfunction seen in female obese mice. These results suggest that ALS-L1023 may be effective in the prevention of visceral obesity and insulin resistance in obese premenopausal women.
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Affiliation(s)
- Dongju Lee
- Department of Biomedical Engineering, Mokwon University, Daejeon, 35349, South Korea
| | - Yujin Shin
- Department of Biomedical Engineering, Mokwon University, Daejeon, 35349, South Korea
| | - Joonseong Jang
- Department of Biomedical Engineering, Mokwon University, Daejeon, 35349, South Korea
| | - Yonghyun Park
- Department of Biomedical Engineering, Mokwon University, Daejeon, 35349, South Korea
| | - Jiwon Ahn
- Genome Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, South Korea
| | - Sunhyo Jeong
- Department of Biomedical Engineering, Mokwon University, Daejeon, 35349, South Korea
| | - Soon Shik Shin
- Department of Formula Sciences, College of Oriental Medicine, Dongeui University, Busan, 47340, South Korea.
| | - Michung Yoon
- Department of Biomedical Engineering, Mokwon University, Daejeon, 35349, South Korea.
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Abstract
OBJECTIVES The present study aimed to investigate the dynamic change of α cells and β cells, and their ratios in prediabetes and type 2 diabetes in the Chinese population. METHODS Pancreata from 27 nondiabetic (ND), 8 prediabetic (PreD), and 19 type 2 diabetic (T2D) organ donors were subjected to immunofluorescence staining with insulin and glucagon. RESULTS The β to α ratio in islets (β/α) in PreD was significantly higher than that in ND, resulting from an increase of β cells and a decrease of α cells per islet, but that in T2D was significantly lower than that in ND, resulting from a decrease of β cells and an increase of α cells per islet. The β-cell percentage and β/α ratio positively correlated and α-cell percentage negatively correlated with HbA1c (glycated hemoglobin) in ND and PreD, but these correlations disappeared when T2D subjects were included. CONCLUSIONS The islet β to α ratio increased in PreD individuals because of a relative α-cell loss and β-cell compensation and decreased after T2D onset because of both β-cell loss and α-cell reexpansion.
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Cholinergic-pathway-weakness-associated pancreatic islet dysfunction: a low-protein-diet imprint effect on weaned rat offspring. J Dev Orig Health Dis 2020; 11:484-491. [DOI: 10.1017/s2040174420000215] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
AbstractCurrently, metabolic disorders are one of the major health problems worldwide, which have been shown to be related to perinatal nutritional insults, and the autonomic nervous system and endocrine pancreas are pivotal targets of the malprogramming of metabolic function. We aimed to assess glucose–insulin homeostasis and the involvement of cholinergic responsiveness (vagus nerve activity and insulinotropic muscarinic response) in pancreatic islet capacity to secrete insulin in weaned rat offspring whose mothers were undernourished in the first 2 weeks of the suckling phase. At delivery, dams were fed a low-protein (4% protein, LP group) or a normal-protein diet (20.5% protein, NP group) during the first 2 weeks of the suckling period. Litter size was adjusted to six pups per mother, and rats were weaned at 21 days old. Weaned LP rats presented a lean phenotype (P < 0.01); hypoglycaemia, hypoinsulinaemia and hypoleptinaemia (P < 0.05); and normal corticosteronaemia (P > 0.05). In addition, milk insulin levels in mothers of the LP rats were twofold higher than those of mothers of the NP rats (P < 0.001). Regarding glucose–insulin homeostasis, weaned LP rats were glucose-intolerant (P < 0.01) and displayed impaired pancreatic islet insulinotropic function (P < 0.05). The M3 subtype of the muscarinic acetylcholine receptor (M3mAChR) from weaned LP rats was less responsive, and the superior vagus nerve electrical activity was reduced by 30% (P < 0.01). A low-protein diet in the suckling period malprogrammes the vagus nerve to low tonus and impairs muscarinic response in the pancreatic β-cells of weaned rats, which are imprinted to secrete inadequate insulin amounts from an early age.
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Watanabe H, Kawano K, Shimizu Y, Iikuni S, Nakamoto Y, Togashi K, Ono M. Development of Novel PET Imaging Probes for Detection of Amylin Aggregates in the Pancreas. Mol Pharm 2020; 17:1293-1299. [PMID: 32202808 DOI: 10.1021/acs.molpharmaceut.9b01309] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The deposition of islet amyloid is associated with β-cell mass dysfunction in type 2 diabetes mellitus (T2DM). Since the amylin aggregate is the main component of islet amyloid, in vivo imaging of amylin may be useful for diagnosis and elucidation of the pathogenic mechanism of T2DM. In the present study, we newly designed, synthesized, and evaluated two 18F labeled compounds ([18F]DANIR-F 2b and [18F]DANIR-F 2c) as positron emission tomography (PET) probes targeting amylin aggregates. In an in vitro binding study, DANIR-F 2b and DANIR-F 2c showed binding affinity for amylin aggregates (Ki = 160 and 29 nM, respectively). In addition, [18F]DANIR-F 2b and [18F]DANIR-F 2c clearly labeled islet amyloids in in vitro autoradiography of T2DM pancreatic sections. In the biodistribution study using normal mice, [18F]DANIR-F 2b and [18F]DANIR-F 2c displayed favorable pharamacokinetics in the pancreas and some organs located near the pancreas. Furthermore, in an ex vivo autoradiographic study, [18F]DANIR-F 2c also bound to amylin aggregates in the pancreas of the amylin transplanted mice. The results of this study suggest that [18F]DANIR-F 2c shows fundamental properties as a PET imaging probe targeting amylin aggregates in the T2DM pancreas.
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Affiliation(s)
- Hiroyuki Watanabe
- Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Kiyoshiro Kawano
- Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Yoichi Shimizu
- Department of Diagnostic Imaging and Nuclear Medicine, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Shimpei Iikuni
- Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Yuji Nakamoto
- Department of Diagnostic Imaging and Nuclear Medicine, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Kaori Togashi
- Department of Diagnostic Imaging and Nuclear Medicine, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Masahiro Ono
- Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan
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Alpha1-antitrypsin ameliorates islet amyloid-induced glucose intolerance and β-cell dysfunction. Mol Metab 2020; 37:100984. [PMID: 32229246 PMCID: PMC7186564 DOI: 10.1016/j.molmet.2020.100984] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 03/21/2020] [Indexed: 02/07/2023] Open
Abstract
Objective Pancreatic β-cell failure is central to the development and progression of type 2 diabetes (T2D). The aggregation of human islet amyloid polypeptide (hIAPP) has been associated with pancreatic islet inflammation and dysfunction in T2D. Alpha1-antitrypsin (AAT) is a circulating protease inhibitor with anti-inflammatory properties. Here, we sought to investigate the potential therapeutic effect of AAT treatment in a mouse model characterized by hIAPP overexpression in pancreatic β-cells. Methods Mice overexpressing hIAPP (hIAPP-Tg) in pancreatic β-cells were used as a model of amyloid-induced β-cell dysfunction. Glucose homeostasis was evaluated by glucose tolerance tests and insulin secretion assays. Apoptosis and amyloid formation was assessed in hIAPP-Tg mouse islets cultured at high glucose levels. Dissociated islet cells were cocultured with macrophages obtained from the peritoneal cavity. Results Nontreated hIAPP-Tg mice were glucose intolerant and exhibited impaired insulin secretion. Interestingly, AAT treatment improved glucose tolerance and restored the insulin secretory response to glucose in hIAPP-Tg mice. Moreover, AAT administration normalized the expression of the essential β-cell genes MafA and Pdx1, which were downregulated in pancreatic islets from hIAPP-Tg mice. AAT prevented the formation of amyloid deposits and apoptosis in hIAPP-Tg islets cultured at high glucose concentrations. Since islet macrophages mediate hIAPP-induced β-cell dysfunction, we investigated the effect of AAT in cocultures of macrophages and islet cells. AAT prevented hIAPP-induced β-cell apoptosis in these cocultures without reducing the hIAPP-induced secretion of IL-1β by macrophages. Remarkably, AAT protected β-cells against the cytotoxic effects of conditioned medium from hIAPP-treated macrophages. Similarly, AAT also abrogated the cytotoxic effects of exogenous proinflammatory cytokines on pancreatic β-cells. Conclusions These results demonstrate that treatment with AAT improves glucose homeostasis in mice overexpressing hIAPP and protects pancreatic β-cells from the cytotoxic actions of hIAPP mediated by macrophages. These results support the use of AAT-based therapies to recover pancreatic β-cell function for the treatment of T2D.
Alpha1-antitrypsin (AAT) ameliorates glucose intolerance in hIAPP transgenic mice. AAT improves insulin secretion in hIAPP transgenic mice. AAT prevents apoptosis and amyloid deposition in cultured hIAPP transgenic islets. AAT protects β-cells from hIAPP-induced cytotoxicity mediated by macrophages. AAT abrogates the cytotoxic effects of proinflammatory cytokines on β-cells.
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Protection from β-cell apoptosis by inhibition of TGF-β/Smad3 signaling. Cell Death Dis 2020; 11:184. [PMID: 32170115 PMCID: PMC7070087 DOI: 10.1038/s41419-020-2365-8] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 02/11/2020] [Accepted: 02/14/2020] [Indexed: 12/18/2022]
Abstract
Prevailing insulin resistance and the resultant hyperglycemia elicits a compensatory response from pancreatic islet beta cells (β-cells) that involves increases in β-cell function and β-cell mass. However, the sustained metabolic stress eventually leads to β-cell failure characterized by severe β-cell dysfunction and progressive loss of β-cell mass. Whereas, β-cell dysfunction is relatively well understood at the mechanistic level, the avenues leading to loss of β-cell mass are less clear with reduced proliferation, dedifferentiation, and apoptosis all potential mechanisms. Butler and colleagues documented increased β-cell apoptosis in pancreas from lean and obese human Type 2 diabetes (T2D) subjects, with no changes in rates of β-cell replication or neogenesis, strongly suggesting a role for apoptosis in β-cell failure. Here, we describe a permissive role for TGF-β/Smad3 in β-cell apoptosis. Human islets undergoing β-cell apoptosis release increased levels of TGF-β1 ligand and phosphorylation levels of TGF-β's chief transcription factor, Smad3, are increased in human T2D islets suggestive of an autocrine role for TGF-β/Smad3 signaling in β-cell apoptosis. Smad3 phosphorylation is similarly increased in diabetic mouse islets undergoing β-cell apoptosis. In mice, β-cell-specific activation of Smad3 promotes apoptosis and loss of β-cell mass in association with β-cell dysfunction, glucose intolerance, and diabetes. In contrast, inactive Smad3 protects from apoptosis and preserves β-cell mass while improving β-cell function and glucose tolerance. At the molecular level, Smad3 associates with Foxo1 to propagate TGF-β-dependent β-cell apoptosis. Indeed, genetic or pharmacologic inhibition of TGF-β/Smad3 signals or knocking down Foxo1 protects from β-cell apoptosis. These findings reveal the importance of TGF-β/Smad3 in promoting β-cell apoptosis and demonstrate the therapeutic potential of TGF-β/Smad3 antagonism to restore β-cell mass lost in diabetes.
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Davey JR, Estevez E, Thomson RE, Whitham M, Watt KI, Hagg A, Qian H, Henstridge DC, Ludlow H, Hedger MP, McGee SL, Coughlan MT, Febbraio MA, Gregorevic P. Intravascular Follistatin gene delivery improves glycemic control in a mouse model of type 2 diabetes. FASEB J 2020; 34:5697-5714. [PMID: 32141144 DOI: 10.1096/fj.201802059rrr] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Revised: 02/10/2020] [Accepted: 02/17/2020] [Indexed: 01/09/2023]
Abstract
Type 2 diabetes (T2D) manifests from inadequate glucose control due to insulin resistance, hypoinsulinemia, and deteriorating pancreatic β-cell function. The pro-inflammatory factor Activin has been implicated as a positive correlate of severity in T2D patients, and as a negative regulator of glucose uptake by skeletal muscle, and of pancreatic β-cell phenotype in mice. Accordingly, we sought to determine whether intervention with the Activin antagonist Follistatin can ameliorate the diabetic pathology. Here, we report that an intravenous Follistatin gene delivery intervention with tropism for striated muscle reduced the serum concentrations of Activin B and improved glycemic control in the db/db mouse model of T2D. Treatment reversed the hyperglycemic progression with a corresponding reduction in the percentage of glycated-hemoglobin to levels similar to lean, healthy mice. Follistatin gene delivery promoted insulinemia and abundance of insulin-positive pancreatic β-cells, even when treatment was administered to mice with advanced diabetes, supporting a mechanism for improved glycemic control associated with maintenance of functional β-cells. Our data demonstrate that single-dose intravascular Follistatin gene delivery can ameliorate the diabetic progression and improve prognostic markers of disease. These findings are consistent with other observations of Activin-mediated mechanisms exerting deleterious effects in models of obesity and diabetes, and suggest that interventions that attenuate Activin signaling could help further understanding of T2D and the development of novel T2D therapeutics.
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Affiliation(s)
- Jonathan R Davey
- Centre for Muscle Research, Department of Physiology, The University of Melbourne, Parkville, VIC, Australia.,Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Emma Estevez
- Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Rachel E Thomson
- Centre for Muscle Research, Department of Physiology, The University of Melbourne, Parkville, VIC, Australia.,Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Martin Whitham
- Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.,College of Life and Environmental Sciences, University of Birmingham, Edgbaston, UK
| | - Kevin I Watt
- Centre for Muscle Research, Department of Physiology, The University of Melbourne, Parkville, VIC, Australia.,Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.,Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC, Australia
| | - Adam Hagg
- Centre for Muscle Research, Department of Physiology, The University of Melbourne, Parkville, VIC, Australia.,Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.,Department of Physiology, Monash University, Clayton, VIC, Australia
| | - Hongwei Qian
- Centre for Muscle Research, Department of Physiology, The University of Melbourne, Parkville, VIC, Australia.,Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Darren C Henstridge
- School of Health Sciences, University of Tasmania, Launceston, TAS, Australia
| | - Helen Ludlow
- School of Life Sciences, Oxford Brookes University, Oxford, UK
| | - Mark P Hedger
- The Hudson Institute of Medical Research, Clayton, VIC, Australia
| | - Sean L McGee
- School of Medicine, Deakin University, Waurn Ponds, VIC, Australia
| | - Melinda T Coughlan
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC, Australia
| | - Mark A Febbraio
- Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
| | - Paul Gregorevic
- Centre for Muscle Research, Department of Physiology, The University of Melbourne, Parkville, VIC, Australia.,Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.,Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia.,Department of Neurology, University of Washington, Seattle, WA, USA
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Cui J, Duan J, Chu J, Guo C, Xi M, Li Y, Weng Y, Wei G, Yin Y, Wen A, Qiao B. Chikusetsu saponin IVa protects pancreatic β cell against intermittent high glucose-induced injury by activating Wnt/β-catenin/TCF7L2 pathway. Aging (Albany NY) 2020; 12:1591-1609. [PMID: 31969494 PMCID: PMC7053639 DOI: 10.18632/aging.102702] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Accepted: 12/27/2019] [Indexed: 12/24/2022]
Abstract
Islet β cell mass reduction induced by glucose fluctuation is crucial for the development and progression of T2DM. Chikusetsu saponin IVa (CHS) had protective effects against DM and related injuries. Here we aimed to investigate the role of CHS in β cell injuries and its possible mechanism involved. Isolated rat islets, βTC3 cells and T2DM mice were used in this study. The results showed that CHS restored the secretion activity, promoted β cell survival by increasing β cell proliferation and decreasing apoptosis which induced by intermittent high glucose (IHG). In vivo, CHS protected β cell apoptosis to normalize blood glucose and improve insulin sensitivity in DM mice. Further studies showed that CHS activated Wnt3a signaling, inhibited HBP1, promoted β-catenin nuclear translocation, enhanced expressions of TCF7L2, GIPR and GLP-1R, inhibited p53, p27 and p21. The protective effect of CHS was remarkably suppressed by siRNAs against TCF7L2 or XAV-939 (a Wnt/β-catenin antagonist) in vitro and in β-catenin-/- mice. In conclusion, we identified a novel role of CHS in protecting β cell survival and regeneration by mechanisms involving the activation of Wnt3a/β-catenin/TCF7L2 signaling. Our results indicated the potential value of CHS as a possible intervention drug for T2DM.
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Affiliation(s)
- Jia Cui
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shaanxi, China
| | - Jialin Duan
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shaanxi, China.,Department of Chinese Medicine, School of Life Science, Northwestern University, Xi'an 710032, Shaanxi, China
| | - Jianjie Chu
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shaanxi, China
| | - Chao Guo
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shaanxi, China
| | - Miaomiao Xi
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shaanxi, China
| | - Yi Li
- Department of Pharmacy, Chongqing Dazu District Hospital of Traditional Chinese Medicine, Chongqing 402360, China
| | - Yan Weng
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shaanxi, China
| | - Guo Wei
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shaanxi, China
| | - Ying Yin
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shaanxi, China
| | - Aidong Wen
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shaanxi, China
| | - Boling Qiao
- Department of Chinese Medicine, School of Life Science, Northwestern University, Xi'an 710032, Shaanxi, China
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Nackiewicz D, Dan M, Speck M, Chow SZ, Chen YC, Pospisilik JA, Verchere CB, Ehses JA. Islet Macrophages Shift to a Reparative State following Pancreatic Beta-Cell Death and Are a Major Source of Islet Insulin-like Growth Factor-1. iScience 2019; 23:100775. [PMID: 31962237 PMCID: PMC6971395 DOI: 10.1016/j.isci.2019.100775] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Revised: 09/24/2019] [Accepted: 12/10/2019] [Indexed: 12/21/2022] Open
Abstract
Macrophages play a dynamic role in tissue repair following injury. Here we found that following streptozotocin (STZ)-induced beta-cell death, mouse islet macrophages had increased Igf1 expression, decreased proinflammatory cytokine expression, and transcriptome changes consistent with macrophages undergoing efferocytosis and having an enhanced state of metabolism. Macrophages were the major, if not sole, contributors to islet insulin-like growth factor-1 (IGF-1) production. Adoptive transfer experiments showed that macrophages can maintain insulin secretion in vivo following beta-cell death with no effects on islet cell turnover. IGF-1 neutralization during STZ treatment decreased insulin secretion without affecting islet cell apoptosis or proliferation. Interestingly, high-fat diet (HFD) combined with STZ further skewed islet macrophages to a reparative state. Finally, islet macrophages from db/db mice also expressed decreased proinflammatory cytokines and increased Igf1 mRNA. These data have important implications for islet biology and pathology and show that islet macrophages preserve their reparative state following beta-cell death even during HFD feeding and severe hyperglycemia.
Macrophages are a major source of IGF-1 protein within mouse pancreatic islets Post-beta-cell death islet macrophages shift to a reparative state Beta-cell death causes macrophage transcriptome changes consistent with efferocytosis This change can occur even in the presence of HFD feeding or severe hyperglycemia
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Affiliation(s)
- Dominika Nackiewicz
- Department of Surgery, Faculty of Medicine, University of British Columbia, BC Children's Hospital Research Institute, 950 W 28 Avenue, Vancouver V5Z 4H4, Canada
| | - Meixia Dan
- Department of Surgery, Faculty of Medicine, University of British Columbia, BC Children's Hospital Research Institute, 950 W 28 Avenue, Vancouver V5Z 4H4, Canada
| | - Madeleine Speck
- Department of Surgery, Faculty of Medicine, University of British Columbia, BC Children's Hospital Research Institute, 950 W 28 Avenue, Vancouver V5Z 4H4, Canada
| | - Samuel Z Chow
- Department of Surgery, Faculty of Medicine, University of British Columbia, BC Children's Hospital Research Institute, 950 W 28 Avenue, Vancouver V5Z 4H4, Canada
| | - Yi-Chun Chen
- Department of Surgery, Faculty of Medicine, University of British Columbia, BC Children's Hospital Research Institute, 950 W 28 Avenue, Vancouver V5Z 4H4, Canada
| | - J Andrew Pospisilik
- Van Andel Research Institute, 333 Bostwick Avenue NE, Grand Rapids, MI 49503, USA
| | - C Bruce Verchere
- Department of Surgery, Faculty of Medicine, University of British Columbia, BC Children's Hospital Research Institute, 950 W 28 Avenue, Vancouver V5Z 4H4, Canada; Department of Pathology and Laboratory Medicine, BC Children's Hospital Research Institute, 950 W 28 Avenue, Vancouver V5Z 4H4, Canada.
| | - Jan A Ehses
- Department of Surgery, Faculty of Medicine, University of British Columbia, BC Children's Hospital Research Institute, 950 W 28 Avenue, Vancouver V5Z 4H4, Canada; Department of Health Sciences and Technology, Institute of Food, Nutrition, and Health, Swiss Federal Institute of Technology, ETH Zürich, Schwerzenbach CH-8603, Switzerland.
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Lee YR, Lee SH, Jang GY, Lee YJ, Kim MY, Kim YB, Lee J, Jeong HS. Antioxidative and antidiabetic effects of germinated rough rice extract in 3T3-L1 adipocytes and C57BLKS/J- db/db mice. Food Nutr Res 2019; 63:3603. [PMID: 31839788 PMCID: PMC6894429 DOI: 10.29219/fnr.v63.3603] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Revised: 08/06/2019] [Accepted: 08/13/2019] [Indexed: 11/20/2022] Open
Abstract
Background To overcome disadvantages of germinated brown rice, we germinated rough rice and tested effects of its useful ingredients on prevention of diabetes. Objective This study investigated the in vitro antioxidant and in vivo antidiabetic effects of rough rice (Oryza sativa L.) with hulls, before and after germination. Rough rice was germinated for 4 days and extracted with water at 120°C. Design This study measured antioxidants and antioxidative effects and inhibitory activities against α-amylase and α-glucosidase of rough rice before and after germination and investigated antidiabetic effects of rough rice through animal experiments. Results All these factors increased after germination. Also, α-amylase and α-glucosidase inhibition and glucose uptake by 3T3-L1 adipocytes were significantly increased after germination. Oral administration of the germinated rough rice extract for 8 weeks significantly increased insulin levels and decreased blood glucose levels in a C57BLKS/J-db/db mice model. Immunohistochemical analysis showed that germinated rough rice effectively protected against liver, kidney, and pancreatic tissue damage. Discussion Useful ingredients in germinated rough rice could be used to prevent diabetes. Conclusions These results suggest that germinated rough rice extract had a beneficial effect on diabetes by increasing the antioxidant activity and further purification studies are necessary to elucidate the mechanism of the extract’s antidiabetic activity.
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Affiliation(s)
- Youn Ri Lee
- Department of Food and Nutrition, Daejeon Health Sciences College, Daejeon, Korea
| | - Sang Hoon Lee
- Department of Agrofood Resources, National Academy of Agricultural Science, Rural Development Administration, Wanju, Korea
| | - Gwi Yeong Jang
- Department of Herbal Crop Research, National Institute of Horticultural and Herbal Science, Rural Development Administration, Eumseong, Korea
| | - Yoon Jeong Lee
- Department of Food Science and Biotechnology, Chungbuk National University, Cheongju, Korea
| | - Min Young Kim
- Department of Food Science and Biotechnology, Chungbuk National University, Cheongju, Korea
| | - Yun-Bae Kim
- College of Veterinary Medicine, Chungbuk National University, Cheongju, Korea
| | - Junsoo Lee
- Department of Food Science and Biotechnology, Chungbuk National University, Cheongju, Korea
| | - Heon Sang Jeong
- Department of Food Science and Biotechnology, Chungbuk National University, Cheongju, Korea
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Yang HW, Son M, Choi J, Oh S, Jeon YJ, Byun K, Ryu B. Effect of Ishophloroglucin A, A Component of Ishige okamurae, on Glucose Homeostasis in the Pancreas and Muscle of High Fat Diet-Fed Mice. Mar Drugs 2019; 17:E608. [PMID: 31731426 PMCID: PMC6891760 DOI: 10.3390/md17110608] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2019] [Revised: 10/16/2019] [Accepted: 10/21/2019] [Indexed: 12/24/2022] Open
Abstract
Ishophloroglucin A (IPA), a component of Ishige okamurae (IO), was previously evaluated to standardize the antidiabetic potency of IO. However, the potential of IPA as a functional food for diabetes prevention has not yet been evaluated. Here, we investigated if 1.35 mg/kg IPA, which is the equivalent content of IPA in 75 mg/kg IO, improved glucose homeostasis in high-fat diet (HFD)-induced diabetes after 12 weeks of treatment. IPA significantly ameliorated glucose intolerance, reducing fasting glucose levels as well as 2 h glucose levels in HFD mice. In addition, IPA exerted a protective effect on the pancreatic function in HFD mice via pancreatic β-cells and C-peptide. The level of glucose transporter 4 (GLUT4) in the muscles of HFD mice was stimulated by IPA intake. Our results suggested that IPA, which is a component of IO, can improve glucose homeostasis via GLUT4 in the muscles of HFD mice. IO may be used as a functional food for the prevention of diabetes.
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Affiliation(s)
- Hye-Won Yang
- Department of Marine Life Science, School of Marine Biomedical Sciences, Jeju National University, 1 Ara 1-dong, Jejudaehak-ro, Jeju 63243, Korea; (H.-W.Y.); (Y.-J.J.)
| | - Myeongjoo Son
- Department of Anatomy & Cell Biology, Gachon University College of Medicine, Incheon 21936, Korea; (M.S.); (J.C.)
- Functional Cellular Networks Laboratory, College of Medicine, Department of Medicine, Graduate School and Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Korea;
| | - Junwon Choi
- Department of Anatomy & Cell Biology, Gachon University College of Medicine, Incheon 21936, Korea; (M.S.); (J.C.)
- Functional Cellular Networks Laboratory, College of Medicine, Department of Medicine, Graduate School and Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Korea;
| | - Seyeon Oh
- Functional Cellular Networks Laboratory, College of Medicine, Department of Medicine, Graduate School and Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Korea;
| | - You-Jin Jeon
- Department of Marine Life Science, School of Marine Biomedical Sciences, Jeju National University, 1 Ara 1-dong, Jejudaehak-ro, Jeju 63243, Korea; (H.-W.Y.); (Y.-J.J.)
- Marine Science Institute, Jeju National University, Jeju 63333, Korea
| | - Kyunghee Byun
- Department of Anatomy & Cell Biology, Gachon University College of Medicine, Incheon 21936, Korea; (M.S.); (J.C.)
- Functional Cellular Networks Laboratory, College of Medicine, Department of Medicine, Graduate School and Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Korea;
| | - BoMi Ryu
- Department of Marine Life Science, School of Marine Biomedical Sciences, Jeju National University, 1 Ara 1-dong, Jejudaehak-ro, Jeju 63243, Korea; (H.-W.Y.); (Y.-J.J.)
- Marine Science Institute, Jeju National University, Jeju 63333, Korea
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The cytokine alterations/abnormalities and oxidative damage in the pancreas during hypertension development. Pflugers Arch 2019; 471:1331-1340. [PMID: 31624954 PMCID: PMC6814849 DOI: 10.1007/s00424-019-02312-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 08/30/2019] [Accepted: 09/20/2019] [Indexed: 02/04/2023]
Abstract
The aim of the present study was to compare the content of cytokines, chemokines, and oxidative stress markers in the pancreas of spontaneously hypertensive rats (SHRs) and Wistar Kyoto Rats (WKYs) serving as controls. Enzyme-like immunosorbent assay (ELISA) and biochemical methods were used to measure pancreatic levels of interleukin-1ß, interleukin-6, tumor necrosis factor α, transforming growth factor β, RANES, monocyte chemoattractant protein 1, interferon gamma-induced protein 10, malondialdehyde, and sulfhydryl groups. The results showed that the pancreatic concentrations of all studied cytokines and chemokines did not differ between 5-week-old SHRs and WKYs, except RANTES which was significantly reduced in juvenile SHRs. In 10-week-old animals, except interleukin-1ß, the levels of all these proteins were significantly reduced in SHRs. The pancreatic levels of malondialdehyde were significantly reduced in 5-week-old SHRs and significantly elevated in 10-week-old SHRs while the contents of sulfhydryl groups were similar in both rat strains at any age studied. In conclusion, these data provide evidence that in maturating SHRs, the pancreatic levels of cytokines and chemokines are significantly reduced, while malondialdehyde significantly elevated. This suggests that in the pancreas of mature SHRs, the inflammation process is suppressed but there is ongoing oxidative damage.
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Masuda A, Seino Y, Murase M, Hidaka S, Shibata M, Takayanagi T, Sugimura Y, Hayashi Y, Suzuki A. Short-Term High-Starch, Low-Protein Diet Induces Reversible Increase in β-cell Mass Independent of Body Weight Gain in Mice. Nutrients 2019; 11:nu11051045. [PMID: 31083314 PMCID: PMC6566232 DOI: 10.3390/nu11051045] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Revised: 05/08/2019] [Accepted: 05/08/2019] [Indexed: 12/26/2022] Open
Abstract
Long-term exposure to a high starch, low-protein diet (HSTD) induces body weight gain and hyperinsulinemia concomitantly with an increase in β-cell mass (BCM) and pancreatic islets number in mice; however, the effect of short-term exposure to HSTD on BCM and islet number has not been elucidated. In the present study, we investigated changes in body weight, plasma insulin levels, BCM and islet number in mice fed HSTD for 5 weeks followed by normal chow (NC) for 2 weeks. BCM and islet number were increased in mice fed HSTD for 5 weeks compared with those in mice fed NC. On the other hand, mice fed HSTD for 5 weeks followed by NC for 2 weeks (SN) showed decreased BCM and insulin levels, compared to mice fed HSTD for 7 weeks, and no significant differences in these parameters were observed between SN and the control NC at 7 weeks. No significant difference in body weight was observed among HSTD, NC and SN fed groups. These results suggest that a high-starch diet induces an increase in BCM in a manner independent of body weight gain, and that 2 weeks of NC feeding is sufficient for the reversal of the morphological changes induced in islets by HSTD feeding.
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Affiliation(s)
- Atsushi Masuda
- Department of Endocrinology and Metabolism, Fujita Health University, Graduate School of Medicine, Toyoake 470-1192, Japan.
| | - Yusuke Seino
- Department of Endocrinology and Metabolism, Fujita Health University, Graduate School of Medicine, Toyoake 470-1192, Japan.
| | - Masatoshi Murase
- Departments of Endocrinology and Diabetes, Toyota Memorial Hospital, Toyota 471-8513, Japan.
| | - Shihomi Hidaka
- Department of Endocrinology and Metabolism, Fujita Health University, Graduate School of Medicine, Toyoake 470-1192, Japan.
| | - Megumi Shibata
- Department of Endocrinology and Metabolism, Fujita Health University, Graduate School of Medicine, Toyoake 470-1192, Japan.
| | - Takeshi Takayanagi
- Department of Endocrinology and Metabolism, Fujita Health University, Graduate School of Medicine, Toyoake 470-1192, Japan.
| | - Yoshihisa Sugimura
- Department of Endocrinology and Metabolism, Fujita Health University, Graduate School of Medicine, Toyoake 470-1192, Japan.
| | - Yoshitaka Hayashi
- Department of Endocrinology, Research Institute of Environmental Medicine, Nagoya University, Nagoya 467-8601 Japan.
| | - Atsushi Suzuki
- Department of Endocrinology and Metabolism, Fujita Health University, Graduate School of Medicine, Toyoake 470-1192, Japan.
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Murovets VO, Sozontov EA, Zachepilo TG. The Effect of the Taste Receptor Protein T1R3 on the Development of Islet Tissue of the Murine Pancreas. DOKLADY BIOLOGICAL SCIENCES : PROCEEDINGS OF THE ACADEMY OF SCIENCES OF THE USSR, BIOLOGICAL SCIENCES SECTIONS 2019; 484:1-4. [PMID: 31016494 DOI: 10.1134/s0012496619010010] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Indexed: 01/06/2023]
Abstract
T1R3 protein, the main subunit of the sweet taste receptor and receptor of amino acid taste, is expressed in the epithelium of the tongue and gastrointestinal tract, in β cells of the pancreas, hypothalamus, and numerous other organs. Recently, convincing evidences on the involvement of T1R3 in the control of carbohydrate and lipid metabolism, and the control of incretin and insulin production were obtained. In the study on Tas1r3-gene knockout mouse strain and parent C57BL/6J strain as a control, the data on the effect of T1R3 on morphological characteristics of Langerhans islets in the pancreas were obtained. In Tas1r3 knockout animals, we found a reduction in the size of islets and their density in pancreatic tissue as compared to the parent strain. In addition, a decrease in the expression of active caspase-3 in the islets of gene-knockout mice was demonstrated. The data obtained indicate that the lack of functioning gene encoding sweet taste receptor protein causes a dystrophy of the islet tissue and is associated with the development of pathological changes in the pancreas specific to type 2 diabetes mellitus and obesity in humans.
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Affiliation(s)
- V O Murovets
- Pavlov Institute of Physiology, Russian Academy of Sciences, 199034, St. Petersburg, Russia.
| | - E A Sozontov
- Pavlov Institute of Physiology, Russian Academy of Sciences, 199034, St. Petersburg, Russia.,St. Petersburg State University, 199034, St. Petersburg, Russia
| | - T G Zachepilo
- Pavlov Institute of Physiology, Russian Academy of Sciences, 199034, St. Petersburg, Russia
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