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Noge S, Kumamoto K, Matsukawa H, Ando Y, Suto H, Kondo A, Kishino T, Oshima M, Suzuki Y, Okano K. Intravenous D‑allose administration improves blood glucose control by maintaining insulin secretion in diabetic mice with transplanted islets. Exp Ther Med 2025; 29:63. [PMID: 39991726 PMCID: PMC11843210 DOI: 10.3892/etm.2025.12813] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Accepted: 01/17/2025] [Indexed: 02/25/2025] Open
Abstract
Although pancreatic islet transplantation outcomes have improved, further refinements are required to extend the insulin withdrawal period. The present study examined whether intravenous D-allose administration improves insulin secretion when pancreatic islets are transplanted into type 1 diabetes model mice. Alterations in casual blood glucose levels, intraperitoneal glucose tolerance test (IPGGT) results, the number of apoptotic cells in the engrafted cells, and caspase 3, heme oxygenase 1 and nitric oxide synthase 2 (NOS2) expression in the engrafted cells were examined using the following groups of type 1 diabetic model mice with transplanted pancreatic islets: Mice that received an intravenous injection of D-allose (D-group) and those that received physiological saline as a control (C-group). The mice in the D-group had significantly lower casual blood sugar levels for a longer duration than those in the C-group. Regarding IPGGT, mice treated with D-allose exhibited smaller changes in blood glucose levels compared with untreated mice. Consequently, the incremental area under the curve of glucose in D-allose-treated mice was significantly lower than that in D-allose-untreated mice. No difference was observed in the number of engrafted cells between the groups. NOS2 mRNA expression in the engrafted cells of the D-group tended to be higher than that in the C-group. In conclusion, intravenous administration of D-allose significantly improved hyperglycemia and maintained stable blood glucose levels in type 1 diabetic mice after islet transplantation. Since there was no difference in the number of engrafted cells or apoptotic cells with or without intravenous D-allose administration, D-allose was considered to be effective in maintaining the cellular function of insulin secretion.
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Affiliation(s)
- Seiji Noge
- Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Kensuke Kumamoto
- Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
- Department of Genome Medical Science and Medical Genetics, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Hiroyuki Matsukawa
- Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Yasuhisa Ando
- Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Hironobu Suto
- Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Akihiro Kondo
- Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Takayoshi Kishino
- Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Minoru Oshima
- Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Yasuyuki Suzuki
- Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
- Department of Surgery, Hyogo Prefectural Awaji Medical Center, Sumoto, Hyogo 656-0021, Japan
| | - Keiichi Okano
- Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
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Merlin E, Salio C, Ferrini F. Painful Diabetic Neuropathy: Sex-Specific Mechanisms and Differences from Animal Models to Clinical Outcomes. Cells 2024; 13:2024. [PMID: 39682771 DOI: 10.3390/cells13232024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 12/01/2024] [Accepted: 12/04/2024] [Indexed: 12/18/2024] Open
Abstract
Diabetes is a chronic and progressive disease associated with high blood glucose levels. Several co-morbidities arise from diabetes, the most common and severe one is diabetic neuropathy whose symptoms also include pain hypersensitivity. Currently, there are no effective therapies to counteract painful diabetic neuropathy or slow down the progression of the disease, and the underlying mechanisms are yet to be fully understood. Emerging data in recent decades have provided compelling evidence that the molecular and cellular mechanisms underlying chronic pain are different across the sexes. Interestingly, relevant differences have also been observed in the course and clinical presentation of painful diabetic neuropathy in humans. Here, we reviewed the current state of the art on sex differences in diabetic neuropathy, from animal models to clinical data. Comparing the output of both preclinical and clinical studies is necessary for properly orienting future choices in pain research, refining animal models, and interpreting clinical data. The identification of sex-specific mechanisms may help to develop more targeted therapies to counteract pain symptoms in diabetes.
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Affiliation(s)
- Emma Merlin
- Department of Veterinary Sciences, University of Turin, Largo Braccini 2, 10095 Grugliasco, TO, Italy
| | - Chiara Salio
- Department of Veterinary Sciences, University of Turin, Largo Braccini 2, 10095 Grugliasco, TO, Italy
| | - Francesco Ferrini
- Department of Veterinary Sciences, University of Turin, Largo Braccini 2, 10095 Grugliasco, TO, Italy
- Department of Psychiatry and Neurosciences, Université Laval, Québec, QC G1K 7P4, Canada
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Fernandes-Costa F, Gomes da Silva RT, de Almeida AJPO, de Medeiros IA, de Assis Tafuri LS, Dos Santos GJ, Carlstrom M, Cruz JC. Organic vs. inorganic nitrates: Metabolic and vascular outcomes in STZ-induced diabetes in mice. Life Sci 2024; 359:123257. [PMID: 39561873 DOI: 10.1016/j.lfs.2024.123257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 11/09/2024] [Accepted: 11/15/2024] [Indexed: 11/21/2024]
Abstract
BACKGROUND Diabetic animals often display dysregulated nitric oxide (NO) metabolism, contributing to vascular dysfunction. This study evaluates the metabolic and vascular effects of organic nitrate isosorbide mononitrate (ISMN) versus inorganic sodium nitrate (NaNO3) in mice with type 1 diabetes mellitus (T1DM) induced by streptozotocin (STZ). EXPERIMENTAL APPROACH T1DM was induced in male C57Bl6 mice with STZ ip and confirmed by fasting glucose. Mice were treated with ISMN (10 mg·kg-1) or NaNO3 (85 mg·L-1) for 14 days. A combination of in vivo, in vitro, and ex vivo studies assessed cardiometabolic benefits. RESULTS Both nitrates reduced blood and urinary hyperglycemia in T1DM mice, with ISMN exhibiting more significant reductions in blood glucose. ISMN and NaNO3 similarly reduced water and food intake, urinary volume, glucose intolerance, and insulin resistance while increasing insulin and nitrite levels in serum and urine. Both nitrates improved endothelium-independent vascular function and attenuated reactive oxygen species (ROS) while increasing NO levels in the aortic rings of T1DM mice. Furthermore, both nitrates similarly reduced mean arterial pressure in T1DM mice. CONCLUSION AND IMPLICATIONS ISMN and NaNO₃ have demonstrated comparable hypotensive and antioxidant effects, offering metabolic and vascular benefits in STZ-TDM1 mice. The more pronounced reduction in blood glucose with ISMN treatment compared to NaNO₃ is particularly promising. The antihyperglycemic effects of both nitrates were linked to increased serum insulin levels and enhanced insulin sensitivity. These results provide a foundation for future clinical studies to evaluate the potential of ISMN or NaNO3 as antidiabetogenic and antihypertensive adjuvant therapies in diabetic patients.
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Affiliation(s)
- Francineide Fernandes-Costa
- Graduate Program in Bioactive Synthetic and Natural Products, Center for Health Sciences, Federal University of Paraíba, João Pessoa, Brazil
| | | | | | - Isac Almeida de Medeiros
- Department of Pharmaceutical Sciences, Health Sciences Center, Federal University of Paraíba, João Pessoa, Brazil
| | | | - Gustavo Jorge Dos Santos
- Multicenter Graduate Program in Physiological Sciences, Department of Physiological Sciences, Center for Biological Sciences, Federal University of Santa Catarina - UFSC, Brazil
| | - Mattias Carlstrom
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
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Ha SE, Singh R, Jin B, Baek G, Jorgensen BG, Zogg H, Debnath S, Park HS, Cho H, Watkins CM, Cho S, Kim MS, Lee MY, Yu TY, Jeong JW, Ro S. miR-10a/b-5p-NCOR2 Regulates Insulin-Resistant Diabetes in Female Mice. Int J Mol Sci 2024; 25:10147. [PMID: 39337631 PMCID: PMC11432729 DOI: 10.3390/ijms251810147] [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: 08/24/2024] [Revised: 09/14/2024] [Accepted: 09/16/2024] [Indexed: 09/30/2024] Open
Abstract
Gender and biological sex have distinct impacts on the pathogenesis of type 2 diabetes (T2D). Estrogen deficiency is known to predispose female mice to T2D. In our previous study, we found that a high-fat, high-sucrose diet (HFHSD) induces T2D in male mice through the miR-10b-5p/KLF11/KIT pathway, but not in females, highlighting hormonal disparities in T2D susceptibility. However, the underlying molecular mechanisms of this hormonal protection in females remain elusive. To address this knowledge gap, we utilized ovariectomized, estrogen-deficient female mice, fed them a HFHSD to induce T2D, and investigated the molecular mechanisms involved in estrogen-deficient diabetic female mice, relevant cell lines, and female T2D patients. Initially, female mice fed a HFHSD exhibited a delayed onset of T2D, but ovariectomy-induced estrogen deficiency promptly precipitated T2D without delay. Intriguingly, insulin (INS) was upregulated, while insulin receptor (INSR) and protein kinase B (AKT) were downregulated in these estrogen-deficient diabetic female mice, indicating insulin-resistant T2D. These dysregulations of INS, INSR, and AKT were mediated by a miR-10a/b-5p-NCOR2 axis. Treatment with miR-10a/b-5p effectively alleviated hyperglycemia in estrogen-deficient T2D female mice, while β-estradiol temporarily reduced hyperglycemia. Consistent with the murine findings, plasma samples from female T2D patients exhibited significant reductions in miR-10a/b-5p, estrogen, and INSR, but increased insulin levels. Our findings suggest that estrogen protects against insulin-resistant T2D in females through miR-10a/b-5p/NCOR2 pathway, indicating the potential therapeutic benefits of miR-10a/b-5p restoration in female T2D management.
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Affiliation(s)
- Se Eun Ha
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA; (S.E.H.); (B.J.); (G.B.); (H.Z.); (H.S.P.); (S.C.)
| | - Rajan Singh
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA; (S.E.H.); (B.J.); (G.B.); (H.Z.); (H.S.P.); (S.C.)
| | - Byungchang Jin
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA; (S.E.H.); (B.J.); (G.B.); (H.Z.); (H.S.P.); (S.C.)
| | - Gain Baek
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA; (S.E.H.); (B.J.); (G.B.); (H.Z.); (H.S.P.); (S.C.)
| | - Brian G. Jorgensen
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA; (S.E.H.); (B.J.); (G.B.); (H.Z.); (H.S.P.); (S.C.)
| | - Hannah Zogg
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA; (S.E.H.); (B.J.); (G.B.); (H.Z.); (H.S.P.); (S.C.)
| | - Sushmita Debnath
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA; (S.E.H.); (B.J.); (G.B.); (H.Z.); (H.S.P.); (S.C.)
| | - Hahn Sung Park
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA; (S.E.H.); (B.J.); (G.B.); (H.Z.); (H.S.P.); (S.C.)
| | - Hayeong Cho
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA; (S.E.H.); (B.J.); (G.B.); (H.Z.); (H.S.P.); (S.C.)
| | - Claudia Marie Watkins
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA; (S.E.H.); (B.J.); (G.B.); (H.Z.); (H.S.P.); (S.C.)
| | - Sumin Cho
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA; (S.E.H.); (B.J.); (G.B.); (H.Z.); (H.S.P.); (S.C.)
| | - Min-Seob Kim
- Department of Physiology, Wonkwang Digestive Disease Research Institute & Institute of Wonkwang Medical Science, School of Medicine, Wonkwang University, Iksan 54538, Republic of Korea; (M.-S.K.); (M.Y.L.)
| | - Moon Young Lee
- Department of Physiology, Wonkwang Digestive Disease Research Institute & Institute of Wonkwang Medical Science, School of Medicine, Wonkwang University, Iksan 54538, Republic of Korea; (M.-S.K.); (M.Y.L.)
| | - Tae Yang Yu
- Division of Endocrinology and Metabolism, Department of Medicine, Wonkwang University School of Medicine, Iksan 54538, Republic of Korea; (T.Y.Y.); (J.W.J.)
| | - Jin Woo Jeong
- Division of Endocrinology and Metabolism, Department of Medicine, Wonkwang University School of Medicine, Iksan 54538, Republic of Korea; (T.Y.Y.); (J.W.J.)
| | - Seungil Ro
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA; (S.E.H.); (B.J.); (G.B.); (H.Z.); (H.S.P.); (S.C.)
- RosVivo Therapeutics, Applied Research Facility, 1664 N. Virginia St., Reno, NV 89557, USA
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Shang R, Lee CS, Wang H, Dyer R, Noll C, Carpentier A, Sultan I, Alitalo K, Boushel R, Hussein B, Rodrigues B. Reduction in Insulin Uncovers a Novel Effect of VEGFB on Cardiac Substrate Utilization. Arterioscler Thromb Vasc Biol 2024; 44:177-191. [PMID: 38150518 DOI: 10.1161/atvbaha.123.319972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 11/06/2023] [Indexed: 12/29/2023]
Abstract
BACKGROUND The heart relies heavily on external fatty acid (FA) for energy production. VEGFB (vascular endothelial growth factor B) has been shown to promote endothelial FA uptake by upregulating FA transporters. However, its impact on LPL (lipoprotein lipase)-mediated lipolysis of lipoproteins, a major source of FA for cardiac use, is unknown. METHODS VEGFB transgenic (Tg) rats were generated by using the α-myosin heavy chain promoter to drive cardiomyocyte-specific overexpression. To measure coronary LPL activity, Langendorff hearts were perfused with heparin. In vivo positron emission tomography imaging with [18F]-triglyceride-fluoro-6-thia-heptadecanoic acid and [11C]-palmitate was used to determine cardiac FA uptake. Mitochondrial FA oxidation was evaluated by high-resolution respirometry. Streptozotocin was used to induce diabetes, and cardiac function was monitored using echocardiography. RESULTS In Tg hearts, the vectorial transfer of LPL to the vascular lumen is obstructed, resulting in LPL buildup within cardiomyocytes, an effect likely due to coronary vascular development with its associated augmentation of insulin action. With insulin insufficiency following fasting, VEGFB acted unimpeded to facilitate LPL movement and increase its activity at the coronary lumen. In vivo PET imaging following fasting confirmed that VEGFB induced a greater FA uptake to the heart from circulating lipoproteins as compared with plasma-free FAs. As this was associated with augmented mitochondrial oxidation, lipid accumulation in the heart was prevented. We further examined whether this property of VEGFB on cardiac metabolism could be useful following diabetes and its associated cardiac dysfunction, with attendant loss of metabolic flexibility. In Tg hearts, diabetes inhibited myocyte VEGFB gene expression and protein secretion together with its downstream receptor signaling, effects that could explain its lack of cardioprotection. CONCLUSIONS Our study highlights the novel role of VEGFB in LPL-derived FA supply and utilization. In diabetes, loss of VEGFB action may contribute toward metabolic inflexibility, lipotoxicity, and development of diabetic cardiomyopathy.
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Affiliation(s)
- Rui Shang
- Faculty of Pharmaceutical Sciences (R.S., C.S.L., H.W., B.H., B.R.), University of British Columbia, Vancouver
| | - Chae Syng Lee
- Faculty of Pharmaceutical Sciences (R.S., C.S.L., H.W., B.H., B.R.), University of British Columbia, Vancouver
| | - Hualin Wang
- Faculty of Pharmaceutical Sciences (R.S., C.S.L., H.W., B.H., B.R.), University of British Columbia, Vancouver
| | - Roger Dyer
- Department of Pediatrics (R.D.), University of British Columbia, Vancouver
| | - Christophe Noll
- Department of Medicine, Université de Sherbrooke, QC, Canada (C.N., A.C.)
| | - André Carpentier
- Department of Medicine, Université de Sherbrooke, QC, Canada (C.N., A.C.)
| | - Ibrahim Sultan
- Wihuri Research Institute and Translational Cancer Medicine Program, Biomedicum Helsinki, University of Helsinki, Finland (I.S., K.A.)
| | - Kari Alitalo
- Wihuri Research Institute and Translational Cancer Medicine Program, Biomedicum Helsinki, University of Helsinki, Finland (I.S., K.A.)
| | - Robert Boushel
- School of Kinesiology (R.B.), University of British Columbia, Vancouver
| | - Bahira Hussein
- Faculty of Pharmaceutical Sciences (R.S., C.S.L., H.W., B.H., B.R.), University of British Columbia, Vancouver
| | - Brian Rodrigues
- Faculty of Pharmaceutical Sciences (R.S., C.S.L., H.W., B.H., B.R.), University of British Columbia, Vancouver
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Saksida T, Paunović V, Koprivica I, Mićanović D, Jevtić B, Jonić N, Stojanović I, Pejnović N. Development of Type 1 Diabetes in Mice Is Associated with a Decrease in IL-2-Producing ILC3 and FoxP3 + Treg in the Small Intestine. Molecules 2023; 28:molecules28083366. [PMID: 37110604 PMCID: PMC10141349 DOI: 10.3390/molecules28083366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 03/20/2023] [Accepted: 04/03/2023] [Indexed: 04/29/2023] Open
Abstract
Recent data indicate the link between the number and function of T regulatory cells (Treg) in the gut immune tissue and initiation and development of autoimmunity associated with type 1 diabetes (T1D). Since type 3 innate lymphoid cells (ILC3) in the small intestine are essential for maintaining FoxP3+ Treg and there are no data about the possible role of ILC3 in T1D pathogenesis, the aim of this study was to explore ILC3-Treg link during the development of T1D. Mature diabetic NOD mice had lower frequencies of IL-2-producing ILC3 and Treg in small intestine lamina propria (SILP) compared to prediabetic NOD mice. Similarly, in multiple low doses of streptozotocin (MLDS)-induced T1D in C57BL/6 mice, hyperglycemic mice exhibited lower numbers of ILC3, IL-2+ ILC3 and Treg in SILP compared to healthy controls. To boost T1D severity, mice were treated with broad-spectrum antibiotics (ABX) for 14 days prior to T1D induction by MLDS. The higher incidence of T1D in ABX-treated mice was associated with significantly lower frequencies of IL-2+ ILC3 and FoxP3+ Treg in SILP compared with mice without ABX treatment. The obtained findings show that the lower proportions of IL-2-expressing ILC3 and FoxP3+ Treg in SILP coincided with diabetes progression and severity.
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Affiliation(s)
- Tamara Saksida
- Department of Immunology, Institute for Biological Research "Siniša Stanković"-National Institute of Republic of Serbia, University of Belgrade, Bulevar Despota Stefana 142, 11060 Belgrade, Serbia
| | - Verica Paunović
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Pasterova 2, 11000 Belgrade, Serbia
| | - Ivan Koprivica
- Department of Immunology, Institute for Biological Research "Siniša Stanković"-National Institute of Republic of Serbia, University of Belgrade, Bulevar Despota Stefana 142, 11060 Belgrade, Serbia
| | - Dragica Mićanović
- Department of Immunology, Institute for Biological Research "Siniša Stanković"-National Institute of Republic of Serbia, University of Belgrade, Bulevar Despota Stefana 142, 11060 Belgrade, Serbia
| | - Bojan Jevtić
- Department of Immunology, Institute for Biological Research "Siniša Stanković"-National Institute of Republic of Serbia, University of Belgrade, Bulevar Despota Stefana 142, 11060 Belgrade, Serbia
| | - Natalija Jonić
- Department of Immunology, Institute for Biological Research "Siniša Stanković"-National Institute of Republic of Serbia, University of Belgrade, Bulevar Despota Stefana 142, 11060 Belgrade, Serbia
| | - Ivana Stojanović
- Department of Immunology, Institute for Biological Research "Siniša Stanković"-National Institute of Republic of Serbia, University of Belgrade, Bulevar Despota Stefana 142, 11060 Belgrade, Serbia
| | - Nada Pejnović
- Department of Immunology, Institute for Biological Research "Siniša Stanković"-National Institute of Republic of Serbia, University of Belgrade, Bulevar Despota Stefana 142, 11060 Belgrade, Serbia
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Brownrigg GP, Xia YH, Chu CMJ, Wang S, Chao C, Zhang JA, Skovsø S, Panzhinskiy E, Hu X, Johnson JD, Rideout EJ. Sex differences in islet stress responses support female β cell resilience. Mol Metab 2023; 69:101678. [PMID: 36690328 PMCID: PMC9971554 DOI: 10.1016/j.molmet.2023.101678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 01/07/2023] [Accepted: 01/17/2023] [Indexed: 01/21/2023] Open
Abstract
OBJECTIVE Pancreatic β cells play a key role in maintaining glucose homeostasis; dysfunction of this critical cell type causes type 2 diabetes (T2D). Emerging evidence points to sex differences in β cells, but few studies have examined male-female differences in β cell stress responses and resilience across multiple contexts, including diabetes. Here, we address the need for high-quality information on sex differences in β cell and islet gene expression and function using both human and rodent samples. METHODS In humans, we compared β cell gene expression and insulin secretion in donors with T2D to non-diabetic donors in both males and females. In mice, we generated a well-powered islet RNAseq dataset from 20-week-old male and female siblings with similar insulin sensitivity. Our unbiased gene expression analysis pointed to a sex difference in the endoplasmic reticulum (ER) stress response. Based on this analysis, we hypothesized female islets would be more resilient to ER stress than male islets. To test this, we subjected islets isolated from age-matched male and female mice to thapsigargin treatment and monitored protein synthesis, cell death, and β cell insulin production and secretion. Transcriptomic and proteomic analyses were used to characterize sex differences in islet responses to ER stress. RESULTS Our single-cell analysis of human β cells revealed sex-specific changes to gene expression and function in T2D, correlating with more robust insulin secretion in human islets isolated from female donors with T2D compared to male donors with T2D. In mice, RNA sequencing revealed differential enrichment of unfolded protein response pathway-associated genes, where female islets showed higher expression of genes linked with protein synthesis, folding, and processing. This differential expression was physiologically significant, as islets isolated from female mice were more resilient to ER stress induction with thapsigargin. Specifically, female islets showed a greater ability to maintain glucose-stimulated insulin production and secretion during ER stress compared with males. CONCLUSIONS Our data demonstrate sex differences in β cell gene expression in both humans and mice, and that female β cells show a greater ability to maintain glucose-stimulated insulin secretion across multiple physiological and pathological contexts.
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Affiliation(s)
- George P Brownrigg
- Department of Cellular and Physiological Sciences, Life Sciences Institute, The University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada
| | - Yi Han Xia
- Department of Cellular and Physiological Sciences, Life Sciences Institute, The University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada
| | - Chieh Min Jamie Chu
- Department of Cellular and Physiological Sciences, Life Sciences Institute, The University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada
| | - Su Wang
- Department of Cellular and Physiological Sciences, Life Sciences Institute, The University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada
| | - Charlotte Chao
- Department of Cellular and Physiological Sciences, Life Sciences Institute, The University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada
| | - Jiashuo Aaron Zhang
- Department of Cellular and Physiological Sciences, Life Sciences Institute, The University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada
| | - Søs Skovsø
- Department of Cellular and Physiological Sciences, Life Sciences Institute, The University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada
| | - Evgeniy Panzhinskiy
- Department of Cellular and Physiological Sciences, Life Sciences Institute, The University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada
| | - Xiaoke Hu
- Department of Cellular and Physiological Sciences, Life Sciences Institute, The University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada
| | - James D Johnson
- Department of Cellular and Physiological Sciences, Life Sciences Institute, The University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada.
| | - Elizabeth J Rideout
- Department of Cellular and Physiological Sciences, Life Sciences Institute, The University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada.
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8
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Taneera J, Ali A, Hamad M. The Role of Estrogen Signaling in Cellular Iron Metabolism in Pancreatic β Cells. Pancreas 2022; 51:121-127. [PMID: 35404886 DOI: 10.1097/mpa.0000000000001978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
ABSTRACT Several lines of evidence suggest that estrogen (17-β estradiol; E2) protects against diabetes mellitus and plays important roles in pancreatic β-cell survival and function. Mounting clinical and experimental evidence also suggest that E2 modulates cellular iron metabolism by regulating the expression of several iron regulatory genes, including hepcidin (HAMP), hypoxia-inducible factor 1-α, ferroportin (SLC40A1), and lipocalin (LCN2). However, whether E2 regulates cellular iron metabolism in pancreatic β cells and whether the antidiabetic effects of E2 can be, at least partially, attributed to its role in iron metabolism is not known. In this context, pancreatic β cells express considerable levels of conventional E2 receptors (ERs; mainly ER-α) and nonconventional G protein-coupled estrogen receptors and hence responsive to E2 signals. Moreover, pancreatic islet cells require significant amounts of iron for proper functioning, replication and survival and, hence, well equipped to manage cellular iron metabolism (acquisition, utilization, storage, and release). In this review, we examine the link between E2 and cellular iron metabolism in pancreatic β cells and discuss the bearing of such a link on β-cell survival and function.
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Affiliation(s)
| | - Amjad Ali
- From the Research Institute for Medical and Health Sciences
| | - Mawieh Hamad
- Department of Medical Laboratory Sciences, College of Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
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Pitale PM, Gorbatyuk MS. Diabetic Retinopathy: From Animal Models to Cellular Signaling. Int J Mol Sci 2022; 23:ijms23031487. [PMID: 35163410 PMCID: PMC8835767 DOI: 10.3390/ijms23031487] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 01/24/2022] [Accepted: 01/26/2022] [Indexed: 12/24/2022] Open
Abstract
Diabetic retinopathy (DR) is an ocular complication of diabetes mellitus (DM), a metabolic disorder characterized by elevation in blood glucose level. The pathogenesis of DR includes vascular, neuronal, and inflammatory components leading to activation of complex cellular molecular signaling. If untreated, the disease can culminate in vision loss that eventually leads to blindness. Animal models mimicking different aspects of DM complications have been developed to study the development and progression of DR. Despite the significant contribution of the developed DR models to discovering the mechanisms of DR and the recent achievements in the research field, the sequence of cellular events in diabetic retinas is still under investigation. Partially, this is due to the complexity of molecular mechanisms, although the lack of availability of models that adequately mimic all the neurovascular pathobiological features observed in patients has also contributed to the delay in determining a precise molecular trigger. In this review, we provide an update on the status of animal models of DR to help investigators choose an appropriate system to validate their hypothesis. We also discuss the key cellular and physiological events of DR in these models.
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Affiliation(s)
- Priyamvada M. Pitale
- Department of Ophthalmology, Baylor College of Medicine, Houston, TX 77030, USA;
| | - Marina S. Gorbatyuk
- Department of Optometry and Vision Science, School of Optometry, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Correspondence: ; Tel.: +1-205-934-6762; Fax: +1-205-934-3425
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10
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The Effect of Testosterone on Cardiovascular Disease and Cardiovascular Risk Factors in Men: A Review of Clinical and Preclinical Data. CJC Open 2021; 3:1238-1248. [PMID: 34888506 PMCID: PMC8636244 DOI: 10.1016/j.cjco.2021.05.007] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 05/09/2021] [Indexed: 11/20/2022] Open
Abstract
Cardiovascular disease (CVD) is the leading cause of death worldwide. The effects of testosterone, the primary male sex hormone, on cardiovascular risk have been of special interest due to the increased risk of CVD in men. Although it is well established that testosterone levels decline and cardiovascular mortality increases with age, the association between testosterone and CVD remains unclear. Observational and randomized studies on the effects of endogenous and exogenous testosterone have produced conflicting data, and meta-analyses have been inconclusive, suggesting significant study heterogeneity. Despite a lack of adequately powered randomized controlled trials, large observational studies in the early 2010s led to advisories on the use of testosterone replacement therapy. Similar advisories have been mandated for certain types of androgen deprivation therapy. Additional research suggests that testosterone shortens the heart-rate-corrected QT interval, improves glycemic control, induces vasodilation, is prothrombotic, and has anti-obesity effects, whereas associations with atherosclerosis and inflammation are less clear. Despite inconclusive evidence on cardiovascular risk and inconsistencies among clinical practice guidelines, millions of men continue to use testosterone replacement and androgen deprivation therapy. In addition to summarizing clinical and preclinical data, this review provides insight on potential mechanisms of action of testosterone on CVD, applications of this knowledge to clinical settings, and avenues for future research.
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Chen X, Chu C, Doebis C, von Baehr V, Hocher B. Sex-Dependent Association of Vitamin D With Insulin Resistance in Humans. J Clin Endocrinol Metab 2021; 106:e3739-e3747. [PMID: 34406392 DOI: 10.1210/clinem/dgab213] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND Animal studies suggested that vitamin D might decrease insulin resistance. Estrogen increased insulin sensitivity and glucose tolerance in rodents. However, sex-specific association of vitamin D with insulin resistance in humans remains unclear. OBJECTIVES To investigate the sex-dependency of the association of insulin resistance and 25-hydroxyvitamin D [25(OH)D] in a large Caucasian population. METHODS Cross-sectional study from out-patients' blood samples with measurements of 25(OH)D and homeostatic model assessment of insulin resistance (HOMA-IR) drawn at exactly the same day (n = 1887). This cohort was divided into 3 groups: (1) group with vitamin D deficiency (n = 1190), (2) group with vitamin D sufficiency (n = 686), and (3) vitamin D excess groups (n = 11); the vitamin D excess group was excluded from further analysis due to the small size. RESULTS Analysis of the entire study population showed that serum 25(OH)D was inversely associated with HOMA-IR [Spearman correlation coefficient (rs) = -0.19, P < 0.0001]. When considering the vitamin D status, this association was only seen in the vitamin D deficiency group but not in the vitamin D sufficient group. The correlation was sex-dependent: HOMA-IR was inversely correlated with vitamin D in women with vitamin D deficiency (rs = -0.26, P < 0.0001) but not in men with vitamin D deficiency (rs = 0.01, P = 0.714). After multivariate linear regression analysis considering confounding factors, this relationship was again only seen in women. CONCLUSION Vitamin D was inversely and independently associated with insulin resistance only in women with vitamin D deficiency. Based on our data, we suggest that in particular vitamin D deficient women might benefit from vitamin D substitution by improving insulin resistance. This, however, needs to be proven in adequately designed double-blind placebo-controlled clinical studies.
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Affiliation(s)
- Xin Chen
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany
- Department of Nephrology, Charité-Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany
| | - Chang Chu
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany
- Department of Nephrology, Charité-Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany
| | - Cornelia Doebis
- Institute of Medical Diagnostics, IMD Berlin-Potsdam, Berlin, Germany
| | - Volker von Baehr
- Institute of Medical Diagnostics, IMD Berlin-Potsdam, Berlin, Germany
| | - Berthold Hocher
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany
- Institute of Medical Diagnostics, IMD Berlin-Potsdam, Berlin, Germany
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, School of Medicine, Hunan Normal University, Changsha, China
- Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China
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Abstract
Streptozotocin (STZ) is an antibiotic that causes pancreatic islet β-cell destruction and is widely used experimentally to produce a model of type 1 diabetes mellitus (T1DM). Detailed in this article are protocols for producing STZ-induced insulin deficiency and hyperglycemia in mice and rats. Also described are protocols for creating animal models for type 2 diabetes using STZ. These animals are employed for assessing the pathological consequences of diabetes and for screening potential therapies for the treatment of this condition. © 2021 The Authors.
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Affiliation(s)
- Brian L Furman
- Strathclyde Institute of Pharmacy & Biomedical Sciences, Glasgow, Scotland, United Kingdom
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13
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Sexual hormones and diabetes: The impact of estradiol in pancreatic β cell. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2021. [PMID: 33832654 DOI: 10.1016/bs.ircmb.2021.02.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/13/2023]
Abstract
Diabetes is one of the most prevalent metabolic diseases and its incidence is increasing throughout the world. Data from World Health Organization (WHO) point-out that diabetes is a major cause of blindness, kidney failure, heart attacks, stroke and lower limb amputation and estimated 1.6 million deaths were directly caused by it in 2016. Population studies show that the incidence of this disease increases in women after menopause, when the production of estrogen is decreasing in them. Knowing the impact that estrogenic signaling has on insulin-secreting β cells is key to prevention and design of new therapeutic targets. This chapter explores the role of estrogen and their receptors in the regulation of insulin secretion and biosynthesis, proliferation, regeneration and survival in pancreatic β cells. In addition, delves into the genetic animal models developed and its application for the specific study of the different estrogen signaling pathways. Finally, discusses the impact of menopause and hormone replacement therapy on pancreatic β cell function.
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Iannantuoni F, Salazar JD, Martinez de Marañon A, Bañuls C, López-Domènech S, Rocha M, Hurtado-Murillo F, Morillas C, Gómez-Balaguer M, Víctor VM. Testosterone administration increases leukocyte-endothelium interactions and inflammation in transgender men. Fertil Steril 2021; 115:483-489. [PMID: 33032814 DOI: 10.1016/j.fertnstert.2020.08.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Revised: 07/29/2020] [Accepted: 08/03/2020] [Indexed: 12/31/2022]
Abstract
OBJECTIVE To evaluate the effect of testosterone treatment on metabolic and inflammation parameters and leukocyte-endothelium interactions in transgender men (TGM). DESIGN Prospective observational study. SETTING University hospital. PATIENT(S) One hundred fifty-seven TGM. INTERVENTION(S) Administration of testosterone undecanoate (1,000 mg, intramuscular) every 12 weeks. MAIN OUTCOME MEASURE(S) Endocrine parameters, adhesion molecules (vascular cell adhesion molecule-1, intercellular cell adhesion molecule-1, and E-selectin), proinflammatory cytokines interleukin-6, and tumor necrosis factor alpha were evaluated in serum before and after treatment using Luminex's xMAP technology. In addition, interactions between human umbilical vein endothelial cells and polymorphonuclear leukocytes were assessed by flow chamber microscopy. RESULT(S) Testosterone treatment led to an increase in leukocyte-endothelium interactions due to an increase in polymorphonuclear leukocytes rolling and adhesion and decreased rolling velocity. It also boosted levels of vascular cell adhesion molecule-1, E-selectin, interleukin-6, and tumor necrosis factor alpha. As expected, testosterone also produced a significant increase in free androgenic index, androstenedione, total testosterone, and atherogenic index of plasma and a decrease in sex hormone-binding globulin and high-density lipoprotein cholesterol. CONCLUSION(S) Treatment of TGM with testosterone induces an increase in leukocyte-endothelium interactions and adhesion molecules and proinflammatory cytokines. These effects are a reason to monitor cardiovascular risk in these patients.
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Affiliation(s)
- Francesca Iannantuoni
- Department of Endocrinology and Nutrition, Gender Identity Unit, University Hospital Dr. Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Valencia, Spain
| | - Juan Diego Salazar
- Department of Endocrinology and Nutrition, Gender Identity Unit, University Hospital Dr. Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Valencia, Spain
| | - Aranzazu Martinez de Marañon
- Department of Endocrinology and Nutrition, Gender Identity Unit, University Hospital Dr. Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Valencia, Spain
| | - Celia Bañuls
- Department of Endocrinology and Nutrition, Gender Identity Unit, University Hospital Dr. Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Valencia, Spain
| | - Sandra López-Domènech
- Department of Endocrinology and Nutrition, Gender Identity Unit, University Hospital Dr. Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Valencia, Spain
| | - Milagros Rocha
- Department of Endocrinology and Nutrition, Gender Identity Unit, University Hospital Dr. Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Valencia, Spain; CIBERehd, Valencia, Spain
| | - Felipe Hurtado-Murillo
- Gender Identity Unit, University Hospital Dr. Peset, Centro de Salud Sexual y Reproductiva Fuente de San Luis, Valencia, Spain
| | - Carlos Morillas
- Department of Endocrinology and Nutrition, Gender Identity Unit, University Hospital Dr. Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Valencia, Spain
| | - Marcelino Gómez-Balaguer
- Department of Endocrinology and Nutrition, Gender Identity Unit, University Hospital Dr. Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Valencia, Spain
| | - Víctor Manuel Víctor
- Department of Endocrinology and Nutrition, Gender Identity Unit, University Hospital Dr. Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Valencia, Spain; CIBERehd, Valencia, Spain; Department of Physiology, University of Valencia, Valencia, Spain.
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Kato M, Abdollahi M, Tunduguru R, Tsark W, Chen Z, Wu X, Wang J, Chen ZB, Lin FM, Lanting L, Wang M, Huss J, Fueger PT, Chan D, Natarajan R. miR-379 deletion ameliorates features of diabetic kidney disease by enhancing adaptive mitophagy via FIS1. Commun Biol 2021; 4:30. [PMID: 33398021 PMCID: PMC7782535 DOI: 10.1038/s42003-020-01516-w] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 11/23/2020] [Indexed: 01/29/2023] Open
Abstract
Diabetic kidney disease (DKD) is a major complication of diabetes. Expression of members of the microRNA (miRNA) miR-379 cluster is increased in DKD. miR-379, the most upstream 5'-miRNA in the cluster, functions in endoplasmic reticulum (ER) stress by targeting EDEM3. However, the in vivo functions of miR-379 remain unclear. We created miR-379 knockout (KO) mice using CRISPR-Cas9 nickase and dual guide RNA technique and characterized their phenotype in diabetes. We screened for miR-379 targets in renal mesangial cells from WT vs. miR-379KO mice using AGO2-immunopreciptation and CLASH (cross-linking, ligation, sequencing hybrids) and identified the redox protein thioredoxin and mitochondrial fission-1 protein. miR-379KO mice were protected from features of DKD as well as body weight loss associated with mitochondrial dysfunction, ER- and oxidative stress. These results reveal a role for miR-379 in DKD and metabolic processes via reducing adaptive mitophagy. Strategies targeting miR-379 could offer therapeutic options for DKD.
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Affiliation(s)
- Mitsuo Kato
- Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA.
| | - Maryam Abdollahi
- Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA
| | - Ragadeepthi Tunduguru
- Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA
| | - Walter Tsark
- Transgenic Mouse Facility, Center for Comparative Medicine, Beckman Research Institute of City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA
| | - Zhuo Chen
- Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA
| | - Xiwei Wu
- Integrative Genomics Core, Beckman Research Institute of City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA
| | - Jinhui Wang
- Integrative Genomics Core, Beckman Research Institute of City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA
| | - Zhen Bouman Chen
- Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA
- Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA
| | - Feng-Mao Lin
- Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA
| | - Linda Lanting
- Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA
| | - Mei Wang
- Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA
| | - Janice Huss
- Department of Cellular and Molecular Endocrinology, Diabetes & Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Patrick T Fueger
- Department of Cellular and Molecular Endocrinology, Diabetes & Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA, USA
- Comprehensive Metabolic Phenotyping Core, Beckman Research Institute of City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA
| | - David Chan
- Division of Biology and Biological Engineering, Caltech, 1200 East California Boulevard, Pasadena, CA, 91125, USA
| | - Rama Natarajan
- Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA.
- Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA.
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16
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Saadane A, Lessieur EM, Du Y, Liu H, Kern TS. Successful induction of diabetes in mice demonstrates no gender difference in development of early diabetic retinopathy. PLoS One 2020; 15:e0238727. [PMID: 32941450 PMCID: PMC7498040 DOI: 10.1371/journal.pone.0238727] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 08/21/2020] [Indexed: 01/29/2023] Open
Abstract
Purpose Female mice have been found to be resistant to streptozotocin (STZ)-induced diabetes, and pre-clinical research related to diabetic complications commonly omits females. The purpose of this study was to develop a method to induce diabetes in female mice, and to determine if retinas of diabetic female mice develop molecular changes and histopathological abnormalities comparable to those which develop in male diabetic mice. Methods To induce diabetes, animals of both sexes received daily intraperitoneal (i.p.) injection of STZ for 5 consecutive days at 55 mg/kg BW (a dose that is known to induce diabetes in male mice) or for females, 75 mg/kg BW of STZ. Retinal abnormalities that have been implicated in the development of the retinopathy (superoxide generation and expression of inflammatory proteins, iNOS and ICAM-1) were evaluated at 2 months of diabetes, and retinal capillary degeneration was evaluated at 8 months of diabetes. Results Daily i.p. injection of STZ for 5 consecutive days at a concentration of 55 mg/kg BW was sufficient to induce diabetes in 100% of male mice, but only 33% of female mice. However, females did become hyperglycemic when the dose of STZ administered was increased to 75 mg/kg BW. The resulting STZ-induced hyperglycemia in female and male mice was sustained for at least 8 months. After induction of the diabetes, both sexes responded similarly with respect to the oxidative stress, expression of iNOS, and degeneration of retinal capillaries, but differed in the limited population evaluated with respect to expression of ICAM-1. Conclusions The resistance of female mice to STZ-induced diabetes can be overcome by increasing the dose of STZ used. Female mice can, and should, be included in pre-clinical studies of diabetes and its complications.
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Affiliation(s)
- Aicha Saadane
- Department of Ophthalmology, University of California-Irvine, Irvine, California, United States of America
- * E-mail:
| | - Emma M. Lessieur
- Department of Ophthalmology, University of California-Irvine, Irvine, California, United States of America
| | - Yunpeng Du
- Department of Ophthalmology, University of California-Irvine, Irvine, California, United States of America
| | - Haitao Liu
- Department of Ophthalmology, Children's Hospital of University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America
| | - Timothy S. Kern
- Department of Ophthalmology, University of California-Irvine, Irvine, California, United States of America
- Veterans Administration Medical Center Research Service, Long Beach, California, United States of America
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De Paoli M, Werstuck GH. Role of Estrogen in Type 1 and Type 2 Diabetes Mellitus: A Review of Clinical and Preclinical Data. Can J Diabetes 2020; 44:448-452. [DOI: 10.1016/j.jcjd.2020.01.003] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 09/17/2019] [Accepted: 01/06/2020] [Indexed: 02/06/2023]
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18
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Koprivica I, Gajic D, Saksida T, Cavalli E, Auci D, Despotovic S, Pejnovic N, Stosic-Grujicic S, Nicoletti F, Stojanovic I. Orally delivered all-trans-retinoic acid- and transforming growth factor-β-loaded microparticles ameliorate type 1 diabetes in mice. Eur J Pharmacol 2019; 864:172721. [DOI: 10.1016/j.ejphar.2019.172721] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Revised: 10/01/2019] [Accepted: 10/02/2019] [Indexed: 02/06/2023]
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19
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Rebolledo-Solleiro D, Fernández-Guasti A. Influence of sex and estrous cycle on blood glucose levels, body weight gain, and depressive-like behavior in streptozotocin-induced diabetic rats. Physiol Behav 2018; 194:560-567. [DOI: 10.1016/j.physbeh.2018.06.033] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Revised: 05/10/2018] [Accepted: 06/20/2018] [Indexed: 12/14/2022]
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Mauvais-Jarvis F, Le May C, Tiano JP, Liu S, Kilic-Berkmen G, Kim JH. The Role of Estrogens in Pancreatic Islet Physiopathology. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1043:385-399. [PMID: 29224104 DOI: 10.1007/978-3-319-70178-3_18] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
In rodent models of insulin-deficient diabetes, 17β-estradiol (E2) protects pancreatic insulin-producing β-cells against oxidative stress, amyloid polypeptide toxicity, gluco-lipotoxicity, and apoptosis. Three estrogen receptors (ERs)-ERα, ERβ, and the G protein-coupled ER (GPER)-have been identified in rodent and human β-cells. This chapter describes recent advances in our understanding of the role of ERs in islet β-cell function, nutrient homeostasis, survival from pro-apoptotic stimuli, and proliferation. We discuss why and how ERs represent potential therapeutic targets for the maintenance of functional β-cell mass.
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Affiliation(s)
- Franck Mauvais-Jarvis
- Department of Medicine, Section of Endocrinology and Metabolism, Tulane University Health Sciences Center, School of Medicine, New Orleans, LA, USA.
| | - Cedric Le May
- L'institut du Thorax, INSERM-CNRS, University of Nantes, Nantes, France
| | - Joseph P Tiano
- Diabetes, Endocrinology, and Obesity Branch, NIDDK, Bethesda, MD, USA
| | - Suhuan Liu
- Xiamen Diabetes Institute, the First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Gamze Kilic-Berkmen
- Department of Pediatric, Emory University School of Medicine, Atlanta, GA, USA
| | - Jun Ho Kim
- Department of Food and Biotechnology, Korea University, Sejong, South Korea
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Huffman J, Hoffmann C, Taylor GT. Integrating insulin-like growth factor 1 and sex hormones into neuroprotection: Implications for diabetes. World J Diabetes 2017; 8:45-55. [PMID: 28265342 PMCID: PMC5320748 DOI: 10.4239/wjd.v8.i2.45] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Revised: 09/24/2016] [Accepted: 11/22/2016] [Indexed: 02/05/2023] Open
Abstract
Brain integrity and cognitive aptitude are often impaired in patients with diabetes mellitus, presumably a result of the metabolic complications inherent to the disease. However, an increasing body of evidence has demonstrated the central role of insulin-like growth factor 1 (IGF1) and its relation to sex hormones in many neuroprotective processes. Both male and female patients with diabetes display abnormal IGF1 and sex-hormone levels but the comparison of these fluctuations is seldom a topic of interest. It is interesting to note that both IGF1 and sex hormones have the ability to regulate phosphoinositide 3-kinase-Akt and mitogen-activated protein kinases-extracellular signal-related kinase signaling cascades in animal and cell culture models of neuroprotection. Additionally, there is considerable evidence demonstrating the neuroprotective coupling of IGF1 and estrogen. Androgens have also been implicated in many neuroprotective processes that operate on similar signaling cascades as the estrogen-IGF1 relation. Yet, androgens have not been directly linked to the brain IGF1 system and neuroprotection. Despite the sex-specific variations in brain integrity and hormone levels observed in diabetic patients, the IGF1-sex hormone relation in neuroprotection has yet to be fully substantiated in experimental models of diabetes. Taken together, there is a clear need for the comprehensive analysis of sex differences on brain integrity of diabetic patients and the relationship between IGF1 and sex hormones that may influence brain-health outcomes. As such, this review will briefly outline the basic relation of diabetes and IGF1 and its role in neuroprotection. We will also consider the findings on sex hormones and diabetes as a basis for separately analyzing males and females to identify possible hormone-induced brain abnormalities. Finally, we will introduce the neuroprotective interplay of IGF1 and estrogen and how androgen-derived neuroprotection operates through similar signaling cascades. Future research on both neuroprotection and diabetes should include androgens into the interplay of IGF1 and sex hormones.
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22
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Pepe GJ, Maniu A, Aberdeen G, Lynch TJ, Kim SO, Nadler J, Albrecht ED. Insulin resistance elicited in postpubertal primate offspring deprived of estrogen in utero. Endocrine 2016; 54:788-797. [PMID: 27770396 PMCID: PMC6038696 DOI: 10.1007/s12020-016-1145-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Accepted: 10/05/2016] [Indexed: 12/25/2022]
Abstract
We recently demonstrated that offspring delivered to baboons deprived of estrogen during the second half of gestation exhibited insulin resistance prior to onset of puberty. Because gonadal hormones have a profound effect on insulin action and secretion in adults, we determined whether insulin resistance is retained after initiation of gonadal secretion of testosterone and estradiol. Glucose tolerance tests were performed in postpubertal baboon offspring of untreated and letrozole-treated animals (serum estradiol reduced >95 %). Basal fasting levels of insulin (P < 0.05) and peak 1 min and 1 + 3 + 5 min levels of glucose after glucose tolerance tests challenge (P < 0.03) were greater in offspring delivered to letrozole-treated, estrogen-deprived baboons than untreated animals. Moreover, the value for the HOMA-IR, an accepted index of insulin resistance, was 2-fold greater (P < 0.05) in offspring delivered to baboons treated with letrozole than in untreated animals. Collectively these results support the proposal that estrogen normally has an important role in programming mechanisms in utero within the developing fetus that lead to insulin sensitivity after birth.
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Affiliation(s)
- Gerald J Pepe
- Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, VA, USA.
| | - Adina Maniu
- Department of Obstetrics/Gynecology/Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Graham Aberdeen
- Department of Obstetrics/Gynecology/Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Terrie J Lynch
- Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, VA, USA
| | - Soon Ok Kim
- Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, VA, USA
| | - Jerry Nadler
- Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, VA, USA
| | - Eugene D Albrecht
- Departments of Obstetrics/Gynecology/Reproductive Sciences and Physiology, University of Maryland School of Medicine, Baltimore, MD, USA
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Maniu A, Aberdeen GW, Lynch TJ, Nadler JL, Kim SOK, Quon MJ, Pepe GJ, Albrecht ED. Estrogen deprivation in primate pregnancy leads to insulin resistance in offspring. J Endocrinol 2016; 230:171-83. [PMID: 27207093 PMCID: PMC4946970 DOI: 10.1530/joe-15-0530] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Accepted: 05/20/2016] [Indexed: 12/29/2022]
Abstract
This study tested the hypothesis that estrogen programs mechanisms within the primate fetus that promote insulin sensitivity and glucose homeostasis in offspring. Glucose tolerance tests were performed longitudinally in prepubertal offspring of baboons untreated or treated on days 100 to 165/175 of gestation (term is 184 days) with the aromatase inhibitor letrozole, which decreased fetal estradiol levels by 95%. Basal plasma insulin levels were over two-fold greater in offspring delivered to letrozole-treated than untreated animals. Moreover, the peak 1min, average of the 1, 3, and 5min, and area under the curve blood glucose and plasma insulin levels after an i.v. bolus of glucose were greater (P<0.05 and P<0.01, respectively) in offspring deprived of estrogen in utero than in untreated animals and partially or completely restored in letrozole plus estradiol-treated baboons. The value for the homeostasis model assessment of insulin resistance was 2.5-fold greater (P<0.02) and quantitative insulin sensitivity check index lower (P<0.01) in offspring of letrozole-treated versus untreated animals and returned to almost normal in letrozole plus estradiol-treated animals. The exaggerated rise in glucose and insulin levels after glucose challenge in baboon offspring deprived of estrogen in utero indicates that pancreatic beta cells had the capacity to secrete insulin, but that peripheral glucose uptake and/or metabolism were impaired, indicative of insulin resistance and glucose intolerance. We propose that estrogen normally programs mechanisms in utero within the developing primate fetus that lead to insulin sensitivity, normal glucose tolerance, and the capacity to metabolize glucose after birth.
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Affiliation(s)
- Adina Maniu
- Department of ObstetricsGynecology, and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Graham W Aberdeen
- Department of ObstetricsGynecology, and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Terrie J Lynch
- Department of Physiological SciencesEastern Virginia Medical School, Norfolk, Virginia, USA
| | - Jerry L Nadler
- Department of Internal MedicineEastern Virginia Medical School, Norfolk, Virginia, USA
| | - Soon O K Kim
- Department of Physiological SciencesEastern Virginia Medical School, Norfolk, Virginia, USA
| | - Michael J Quon
- Department of MedicineUniversity of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Gerald J Pepe
- Department of Physiological SciencesEastern Virginia Medical School, Norfolk, Virginia, USA
| | - Eugene D Albrecht
- Department of ObstetricsGynecology, and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, Maryland, USA
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Varlamov O. Western-style diet, sex steroids and metabolism. Biochim Biophys Acta Mol Basis Dis 2016; 1863:1147-1155. [PMID: 27264336 DOI: 10.1016/j.bbadis.2016.05.025] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2016] [Revised: 05/27/2016] [Accepted: 05/28/2016] [Indexed: 12/14/2022]
Abstract
The evolutionary transition from hunting to farming was associated with introduction of carbohydrate-rich diets. Today, the increased consumption of simple sugars and high-fat food brought about by Western-style diet and physical inactivity are leading causes of the growing obesity epidemic in the Western society. The extension of human lifespan far beyond reproductive age increased the burden of metabolic disorders associated with overnutrition and age-related hypogonadism. Sex steroids are essential regulators of both reproductive function and energy metabolism, whereas their imbalance causes infertility, obesity, glucose intolerance, dyslipidemia, and increased appetite. Clinical and translational studies suggest that dietary restriction and weight control can improve metabolic and reproductive outcomes of sex hormone-related pathologies, including testosterone deficiency in men and natural menopause and hyperandrogenemia in women. Minimizing metabolic and reproductive decline through rationally designed diet and exercise can help extend human reproductive age and promote healthy aging. This article is part of a Special Issue entitled: Oxidative Stress and Mitochondrial Quality in Diabetes/Obesity and Critical Illness Spectrum of Diseases - edited by P. Hemachandra Reddy.
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Affiliation(s)
- Oleg Varlamov
- Division of Diabetes, Obesity, and Metabolism, Oregon National Primate Research Center, Beaverton, OR 97006, United States.
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Ben-Shmuel S, Scheinman EJ, Rashed R, Orr ZS, Gallagher EJ, LeRoith D, Rostoker R. Ovariectomy is associated with metabolic impairments and enhanced mammary tumor growth in MKR mice. J Endocrinol 2015; 227:143-151. [PMID: 26383532 PMCID: PMC4618719 DOI: 10.1530/joe-15-0310] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/10/2015] [Indexed: 12/29/2022]
Abstract
Obesity and type 2 diabetes (T2D) are associated with an increased risk of breast cancer incidence and mortality. Common features of obesity and T2D are insulin resistance and hyperinsulinemia. A mammary tumor promoting effect of insulin resistance and hyperinsulinemia was demonstrated in the transgenic female MKR mouse model of pre-diabetes inoculated with mammary cancer cells. Interestingly, in MKR mice, as well as in other diabetic mouse models, males exhibit severe hyperglycemia, while females display insulin resistance and hyperinsulinemia with only a mild increase in blood glucose levels. This gender-specific protection from hyperglycemia may be attributed to estradiol, a key player in the regulation of the metabolic state, including obesity, glucose homeostasis, insulin resistance, and lipid profile. The aim of this study was to investigate the effects of ovariectomy (including the removal of endogenous estradiol) on the metabolic state of MKR female mice and subsequently on the growth of Mvt-1 mammary cancer cells, inoculated into the mammary fat pad of ovariectomized mice, compared with sham-operated mice. The results showed an increase in body weight, accompanied by increased fat mass, elevated blood glucose levels, and hypercholesterolemia, in ovariectomized MKR mice. In addition, mammary tumor growth was significantly higher in these mice. The results suggest that ovarian hormone deficiency may promote impaired metabolic homeostasis in the hyperinsulinemic MKR female mice, which in turn is associated with an increased growth of mammary tumors.
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Affiliation(s)
- Sarit Ben-Shmuel
- Diabetes and Metabolism Clinical Research Center of Excellence, Clinical Reseasch Institute at Rambam (CRIR), Rambam Medical Center, P.O.B 9602, Haifa 31096, Israel
| | - Eyal J. Scheinman
- Diabetes and Metabolism Clinical Research Center of Excellence, Clinical Reseasch Institute at Rambam (CRIR), Rambam Medical Center, P.O.B 9602, Haifa 31096, Israel
| | - Rola Rashed
- Diabetes and Metabolism Clinical Research Center of Excellence, Clinical Reseasch Institute at Rambam (CRIR), Rambam Medical Center, P.O.B 9602, Haifa 31096, Israel
| | - Zila Shen Orr
- Diabetes and Metabolism Clinical Research Center of Excellence, Clinical Reseasch Institute at Rambam (CRIR), Rambam Medical Center, P.O.B 9602, Haifa 31096, Israel
| | - Emily J. Gallagher
- Division of Endocrinology, Diabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1055, Atran 4-36, New York, NY 10029, USA
| | - Derek LeRoith
- Diabetes and Metabolism Clinical Research Center of Excellence, Clinical Reseasch Institute at Rambam (CRIR), Rambam Medical Center, P.O.B 9602, Haifa 31096, Israel
- Division of Endocrinology, Diabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1055, Atran 4-36, New York, NY 10029, USA
- Corresponding author: Derek LeRoith, Diabetes and Metabolism Clinical Research Center of Excellence, Clinical Research Institute at Rambam (CRIR), Rambam Medical Center, P.O.B 9602, Haifa, 31096, Israel.
| | - Ran Rostoker
- Diabetes and Metabolism Clinical Research Center of Excellence, Clinical Reseasch Institute at Rambam (CRIR), Rambam Medical Center, P.O.B 9602, Haifa 31096, Israel
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Abstract
Streptozotocin (STZ) is an antibiotic that produces pancreatic islet β-cell destruction and is widely used experimentally to produce a model of type 1 diabetes mellitus (T1DM). Detailed in this unit are protocols for producing STZ-induced insulin deficiency and hyperglycemia in mice and rats. Also described are protocols for creating animal models for type 2 diabetes using STZ. These animals are employed for assessing the pathological consequences of diabetes and for screening potential therapies for the treatment of this condition.
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Affiliation(s)
- Brian L Furman
- Strathclyde Institute of Pharmacy & Biomedical Sciences, Glasgow, Scotland, United Kingdom
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Abstract
Diabetic nephropathy (DN) is a term used to describe kidney damage cause by diabetes. With DN as one of the leading causes of end-stage renal disease worldwide, there is a strong need for appropriate animal models to study DN pathogenesis and develop therapeutic strategies. To date, most experiments are carried out in mouse models as opposed to other species for several reasons including lower cost, ease of handling, and easy manipulation of the mouse genome to generate transgenic and knockout animals. This unit provides detailed insights and technical knowledge in setting up one of the most widely used models of DN, the streptozotocin (STZ)-induced model. This model has been extensively exploited to study the mechanism of diabetic renal injury. The advantages and limitations of the STZ model and the availability of other genetic models of DN are also discussed.
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Affiliation(s)
- Bryna S M Chow
- Diabetic Complications Group, Baker IDI Heart and Diabetes Research Institute, Melbourne, Victoria, Australia
| | - Terri J Allen
- Diabetic Complications Group, Baker IDI Heart and Diabetes Research Institute, Melbourne, Victoria, Australia
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Navarro G, Allard C, Xu W, Mauvais-Jarvis F. The role of androgens in metabolism, obesity, and diabetes in males and females. Obesity (Silver Spring) 2015; 23:713-9. [PMID: 25755205 PMCID: PMC4380643 DOI: 10.1002/oby.21033] [Citation(s) in RCA: 185] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2014] [Accepted: 12/22/2014] [Indexed: 12/11/2022]
Abstract
OBJECTIVE In men, androgen deprivation contributes to the development of metabolic syndrome and type 2 diabetes (T2D). In women, androgen excess predisposes to insulin resistance and T2D. There is a bidirectional modulation of glucose homeostasis by androgens in males and females that is analyzed in this review. METHODS We reviewed the literature in both rodents and humans on the role of androgens and the androgen receptor (AR) in the control of glucose and energy metabolism in health, obesity, and T2D. RESULTS Sex-specific activation of AR in the hypothalamus, skeletal muscle, liver, adipose tissue, and pancreatic islet β-cells accounts for maintenance or disruption in energy metabolism and glucose homeostasis. CONCLUSIONS We argue that AR is a target to prevent androgen-related metabolic disorders.
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Affiliation(s)
- Guadalupe Navarro
- Division of Endocrinology & Metabolism, Department of Medicine, Stanford University, Stanford, CA 94305-5165, USA
| | - Camille Allard
- Section of Endocrinology & Metabolism, Tulane University Health Sciences Center, School of Medicine, New Orleans, LA 70112, USA
| | - Weiwei Xu
- Section of Endocrinology & Metabolism, Tulane University Health Sciences Center, School of Medicine, New Orleans, LA 70112, USA
| | - Franck Mauvais-Jarvis
- Section of Endocrinology & Metabolism, Tulane University Health Sciences Center, School of Medicine, New Orleans, LA 70112, USA
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29
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Oliveira RB, Maschio DA, Carvalho CPF, Collares-Buzato CB. Influence of gender and time diet exposure on endocrine pancreas remodeling in response to high fat diet-induced metabolic disturbances in mice. Ann Anat 2015; 200:88-97. [PMID: 25819502 DOI: 10.1016/j.aanat.2015.01.007] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2014] [Revised: 01/15/2015] [Accepted: 01/26/2015] [Indexed: 10/23/2022]
Abstract
In this study, we investigated a possible sexual dimorphism regarding metabolic response and structural and functional adaptations of the endocrine pancreas after exposure to a high-fat diet (HFd). On chow diet, male and female C57BL/6/JUnib mice showed similar metabolic and morphometric parameters, except that female islets displayed a relatively lower β-cell:non-β-cell ratio. After 30 days on HFd, both male and female mice showed increased weight gain, however only the males displayed glucose intolerance associated with high postprandial glycemia when compared to their controls. After 60 days on HFd, both genders became obese, hyperglycemic, hyperinsulinemic, insulin resistant and glucose intolerant, although the metabolic changes were more pronounced in males, while females displayed greater weight gain. In both genders, insulin resistance induced by HFd feeding was compensated by expansion of β-cell mass without changes in islet cytoarchitecture. Interestingly, we found a strong correlation between the degree of β-cell expansion and the levels of hyperglycemia in the fed state: male mice fed a 60d-HFd, showing higher glycemic levels also displayed a greater β-cell mass increase in comparison with female mice. Additionally, sexual dimorphism was also observed regarding the source of β-cell mass expansion following 60d-HFd: while in males, both hypertrophy and hyperplasia (revealed by morphometry and Ki67 immunoreaction) of β-cells were observed, female islets displayed only a significant increase in β-cell size. In conclusion, this study describes gender differences in metabolic response to high fat diet, paralleled by distinct compensatory morphometric changes in pancreatic islets.
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Affiliation(s)
- R B Oliveira
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, SP, Brazil
| | - D A Maschio
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, SP, Brazil
| | - C P F Carvalho
- Department of Biosciences, Federal University of São Paulo, Santos, SP, Brazil
| | - C B Collares-Buzato
- Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, SP, Brazil.
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30
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Abstract
The purpose of this paper is to review male-female differences in the incidence and prevalence of diabetes and diabetic retinopathy. These differences will be established primarily through results from our present research and a review of related literature. Previously, we have demonstrated that neuroretinal dysfunction can be used to predict the location of future retinopathy up to three years before it is manifest. Our current research suggests that, for type 2 diabetes, the normal differences in neuroretinal function between nondiabetic males and females under 50 years of age are altered in patients with type 2 diabetes. Furthermore, local neuroretinal function in type 2 diabetes is more abnormal in adult males compared with adult females. The literature also suggests that there are male-female differences in the occurrence of diabetes. In adolescence, the incidence of type 1 diabetes is greater in males, whereas in type 2 diabetes, the incidence is greater in females. This excess of females in type 2 diabetes shifts to a more equal incidence between the two sexes in adults. In addition, advanced retinopathy in type 1 diabetes appears to be more common in males, and the presence and severity of diabetic retinopathy at the time of diagnosis in type 2 diabetes appears to be more associated with male sex. Although the reasons for male-female differences identified in this review are unknown, sex appears to be a significant factor in certain aspects of diabetes incidence and diabetic retinopathy.
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Affiliation(s)
- Glen Y Ozawa
- Berkeley School of Optometry, University of California , Berkeley, CA , USA
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31
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Schindler CE, Partap U, Patchen BK, Swoap SJ. Chronic rapamycin treatment causes diabetes in male mice. Am J Physiol Regul Integr Comp Physiol 2014; 307:R434-43. [PMID: 24965794 DOI: 10.1152/ajpregu.00123.2014] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Current evidence indicates that the mammalian target of rapamycin inhibitor rapamycin both increases longevity and, seemingly contradictorily, impairs glucose homeostasis. Most studies exploring the dimensions of this paradox have been based on rapamycin treatment in mice for up to 20 wk. We sought to better understand the metabolic effects of oral rapamycin over a substantially longer period of time in HET3 mice. We observed that treatment with rapamycin for 52 wk induced diabetes in male mice, characterized by hyperglycemia, significant urine glucose levels, and severe glucose and pyruvate intolerance. Glucose intolerance occurred in male mice by 4 wk on rapamycin and could be only partially reversed with cessation of rapamycin treatment. Female mice developed moderate glucose intolerance over 1 yr of rapamycin treatment, but not diabetes. The role of sex hormones in the differential development of diabetic symptoms in male and female mice was further explored. HET3 mice treated with rapamycin for 52 wk were gonadectomized and monitored over 10 wk. Castrated male mice remained glucose intolerant, while ovariectomized females developed significant glucose intolerance over the same time period. Subsequent replacement of 17β-estradiol (E2) in ovariectomized females promoted a recovery of glucose tolerance over a 4-wk period, suggesting the protective role of E2 against rapamycin-induced diabetes. These results indicate that 1) oral rapamycin treatment causes diabetes in male mice, 2) the diabetes is partially reversible with cessation of treatment, and 3) E2 plays a protective role against the development of rapamycin-induced diabetes.
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Affiliation(s)
| | - Uttara Partap
- Department of Biology, Williams College, Williamstown, Massachusetts
| | - Bonnie K Patchen
- Department of Biology, Williams College, Williamstown, Massachusetts
| | - Steven J Swoap
- Department of Biology, Williams College, Williamstown, Massachusetts
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32
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Victor VM, Rocha M, Bañuls C, Rovira‐Llopis S, Gómez M, Hernández‐Mijares A. Mitochondrial Impairment and Oxidative Stress in Leukocytes after Testosterone Administration to Female‐To‐Male Transsexuals. J Sex Med 2014; 11:454-61. [PMID: 24251401 DOI: 10.1111/jsm.12376] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Varlamov O, Bethea CL, Roberts CT. Sex-specific differences in lipid and glucose metabolism. Front Endocrinol (Lausanne) 2014; 5:241. [PMID: 25646091 PMCID: PMC4298229 DOI: 10.3389/fendo.2014.00241] [Citation(s) in RCA: 209] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2014] [Accepted: 12/19/2014] [Indexed: 12/12/2022] Open
Abstract
Energy metabolism in humans is tuned to distinct sex-specific functions that potentially reflect the unique requirements in females for gestation and lactation, whereas male metabolism may represent a default state. These differences are the consequence of the action of sex chromosomes and sex-specific hormones, including estrogens and progesterone in females and androgens in males. In humans, sex-specific specialization is associated with distinct body-fat distribution and energy substrate-utilization patterns; i.e., females store more lipids and have higher whole-body insulin sensitivity than males, while males tend to oxidize more lipids than females. These patterns are influenced by the menstrual phase in females, and by nutritional status and exercise intensity in both sexes. This minireview focuses on sex-specific mechanisms in lipid and glucose metabolism and their regulation by sex hormones, with a primary emphasis on studies in humans and the most relevant pre-clinical model of human physiology, non-human primates.
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Affiliation(s)
- Oleg Varlamov
- Division of Diabetes, Obesity, and Metabolism, Oregon National Primate Research Center, Beaverton, OR, USA
- Division of Developmental and Reproductive Sciences, Oregon National Primate Research Center, Beaverton, OR, USA
- *Correspondence: Oleg Varlamov, Divisions of Diabetes, Obesity, and Metabolism and Developmental and Reproductive Sciences, Oregon National Primate Research Center, 505 NW 185th Avenue, Beaverton, OR 97006, USA e-mail:
| | - Cynthia L. Bethea
- Division of Developmental and Reproductive Sciences, Oregon National Primate Research Center, Beaverton, OR, USA
- Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR, USA
| | - Charles T. Roberts
- Division of Diabetes, Obesity, and Metabolism, Oregon National Primate Research Center, Beaverton, OR, USA
- Division of Developmental and Reproductive Sciences, Oregon National Primate Research Center, Beaverton, OR, USA
- Department of Medicine, Oregon Health and Science University, Portland, OR, USA
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34
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Holdcraft RW, Gazda LS, Circle L, Adkins H, Harbeck SG, Meyer ED, Bautista MA, Martis PC, Laramore MA, Vinerean HV, Hall RD, Smith BH. Enhancement of in vitro and in vivo function of agarose-encapsulated porcine islets by changes in the islet microenvironment. Cell Transplant 2013; 23:929-44. [PMID: 23635430 DOI: 10.3727/096368913x667033] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
The transplantation of porcine islets of Langerhans to treat type 1 diabetes may provide a solution to the demand for insulin-producing cells. Porcine islets encapsulated in agarose-agarose macrobeads have been shown to function in nonimmunosuppressed xenogeneic models of both streptozotocin-induced and autoimmune type 1 diabetes. One advantage of agarose encapsulation is the ability to culture macrobeads for extended periods, permitting microbiological and functional assessment. Herein we describe optimization of the agarose matrix that results in improved islet function. Porcine islets (500 IEQs) from retired breeding sows were encapsulated in 1.5% SeaKem Gold (SG), 0.8% SG, or 0.8% Litex (Li) agarose, followed by an outer capsule of 5% SG agarose. Insulin production by the encapsulated islets exhibited an agarose-specific effect with 20% (0.8% SG) to 50% (0.8% Li) higher initial insulin production relative to 1.5% SG macrobeads. Insulin production was further increased by 40-50% from week 2 to week 12 in both agarose types at the 0.8% concentration, whereas islets encapsulated in 1.5% SG agarose increased insulin production by approximately 20%. Correspondingly, fewer macrobeads were required to restore normoglycemia in streptozotocin-induced diabetic female CD(SD) rats that received 0.8% Li (15 macrobeads) or 0.8% SG (17 macrobeads) as compared to 1.5% SG (19 macrobeads). Islet cell proliferation was also observed during the first 2 months postencapsulation, peaking at 4 weeks, where approximately 50% of islets contained proliferative cells, including β-cells, regardless of agarose type. These results illustrate the importance of optimizing the microenvironment of encapsulated islets to improve islet performance and advance the potential of islet xenotransplantation for the treatment of type 1 diabetes.
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Abstract
Protecting the functional mass of insulin-producing β cells of the pancreas is a major therapeutic challenge in patients with type 1 (T1DM) or type 2 diabetes mellitus (T2DM). The gonadal hormone 17β-oestradiol (E2) is involved in reproductive, bone, cardiovascular and neuronal physiology. In rodent models of T1DM and T2DM, treatment with E2 protects pancreatic β cells against oxidative stress, amyloid polypeptide toxicity, lipotoxicity and apoptosis. Three oestrogen receptors (ERs)--ERα, ERβ and the G protein-coupled ER (GPER)--have been identified in rodent and human β cells. Whereas activation of ERα enhances glucose-stimulated insulin biosynthesis, reduces islet toxic lipid accumulation and promotes β-cell survival from proapoptotic stimuli, activation of ERβ increases glucose-stimulated insulin secretion. However, activation of GPER protects β cells from apoptosis, raises glucose-stimulated insulin secretion and lipid homeostasis without affecting insulin biosynthesis. Oestrogens are also improving islet engraftment in rodent models of pancreatic islet transplantation. This Review describes developments in the role of ERs in islet insulin biosynthesis and secretion, lipid homeostasis and survival. Moreover, we discuss why and how enhancing ER action in β cells without the undesirable effect of general oestrogen therapy is a therapeutic avenue to preserve functional β-cell mass in patients with diabetes mellitus.
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Affiliation(s)
- Joseph P Tiano
- Feinberg School of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine and Comprehensive Center on Obesity, Northwestern University, Chicago, IL 60611, USA
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Mauvais-Jarvis F. Estrogen and androgen receptors: regulators of fuel homeostasis and emerging targets for diabetes and obesity. Trends Endocrinol Metab 2011; 22:24-33. [PMID: 21109497 PMCID: PMC3011051 DOI: 10.1016/j.tem.2010.10.002] [Citation(s) in RCA: 223] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2010] [Revised: 10/08/2010] [Accepted: 10/11/2010] [Indexed: 01/31/2023]
Abstract
Because of increasing life expectancy, the contribution of age-related estrogen or androgen deficiency to obesity and type 2 diabetes will become a new therapeutic challenge. This review integrates current concepts on the mechanisms through which estrogen receptors (ERs) and androgen receptor (AR) regulate energy homeostasis in rodents and humans. In females, estrogen maintains energy homeostasis via ERα and ERβ, by suppressing energy intake and lipogenesis, enhancing energy expenditure, and ameliorating insulin secretion and sensitivity. In males, testosterone is converted to estrogen and maintains fuel homeostasis via ERs and AR, which share related functions to suppress adipose tissue accumulation and improve insulin sensitivity. We suggest that ERs and AR could be potential targets in the prevention of age-related metabolic disorders.
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Affiliation(s)
- Franck Mauvais-Jarvis
- Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
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37
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Androgen excess produces systemic oxidative stress and predisposes to beta-cell failure in female mice. PLoS One 2010; 5:e11302. [PMID: 20585581 PMCID: PMC2892018 DOI: 10.1371/journal.pone.0011302] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2010] [Accepted: 06/06/2010] [Indexed: 12/13/2022] Open
Abstract
In women, excess production of the male hormone, testosterone (T), is accompanied by insulin resistance. However, hyperandrogenemia is also associated with beta-cell dysfunction and type 2 diabetes raising the possibility that androgen receptor (AR) activation predisposes to beta-cell failure. Here, we tested the hypothesis that excess AR activation produces systemic oxidative stress thereby contributing to beta-cell failure. We used normal female mice (CF) and mice with androgen resistance by testicular feminization (Tfm). These mice were exposed to androgen excess and a beta-cell stress induced by streptozotocin (STZ). We find that following exposure to T, or the selective AR-agonist dehydrotestosterone (DHT), CF mice challenged with STZ, which are normally protected, are prone to beta-cell failure and insulin-deficient diabetes. Conversely, T-induced predisposition to beta-cell failure is abolished in Tfm mice. We do not observe any proapoptotic effect of DHT alone or in the presence of H(2)O(2) in cultured mouse and human islets. However, we observe that exposure of CF mice to T or DHT provokes systemic oxidative stress, which is eliminated in Tfm mice. This work has significance for hyperandrogenic women; excess activation of AR by testosterone may provoke systemic oxidative stress. In the presence of a prior beta-cell stress, this may predispose to beta-cell failure.
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38
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Abstract
The prevalence of diabetes is lower in premenopausal women, especially diabetic syndromes with insulin deficiency, suggesting that the female hormone 17beta-estradiol protects pancreatic beta-cell function. In classical rodent models of beta-cell failure, 17beta-estradiol at physiological concentrations protects pancreatic beta-cells against lipotoxicity, oxidative stress, and apoptosis. In this review, we integrate evidence showing that estrogens and their receptors have direct effects on islet biology. The estrogen receptor (ER)-alpha, ER beta, and the G-protein coupled ER are present in beta-cells and enhance islet survival. They also improve islet lipid homeostasis and insulin biosynthesis. We also discuss evidence that ERs modulate insulin sensitivity and energy homeostasis, which indirectly alter beta-cell biology in diabetic and obese conditions.
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Affiliation(s)
- Suhuan Liu
- Department of Medicine, Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University, Feinberg School of Medicine, 303 East Chicago Avenue, Tarry 15-761, Chicago, Illinois 60611, USA
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39
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Abstract
OBJECTIVES To investigate the protective role of steroid hormones on streptozotocin (STZ)-induced apoptosis in rat pancreatic beta cells. METHODS Two sets of experiments were performed. In the first, male rats were orchidectomized and substituted 72 hours later with testosterone, estradiol, or progesterone, and 24 hours later, administered with STZ. Subjects were killed 6 hours later, and apoptosis was determined in sections of the pancreas. In the second experiment, male or female rats were gonadectomized, were further substituted with testosterone, and then administered STZ. Six hours later, the animals were killed, and apoptosis, as well as immunoreactive expression of insulin, catalase, or Cu/Zn superoxide dismutase, was determined in sections of the pancreas. In addition, gonadectomized male or female subjects were substituted with testosterone and administered STZ, and 24 hours later, serum glucose and insulin were measured. RESULTS It was found that the cytoprotective effect was only shown in testosterone-treated male rats but not progesterone- or estradiol-treated male rats. In addition, the effect was seen in male rats but not in female rats, and there was an inverse correlation between apoptotic index and antioxidant enzyme immunoreactivity. CONCLUSIONS The cytoprotective effect of testosterone is sex specific and is related to the induction of antioxidant enzyme activities in pancreatic beta cells.
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Kim NN. Sex steroid hormones in diabetes-induced sexual dysfunction: focus on the female gender. J Sex Med 2009; 6 Suppl 3:239-46. [PMID: 19267847 DOI: 10.1111/j.1743-6109.2008.01182.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Diabetes is associated with gender-specific changes in sex steroid hormones. However, the mechanisms responsible for these associations as well as the link to sexual dysfunction are not well understood. AIM To discuss key clinical and laboratory findings linking diabetes, sex steroid hormones, and sexual dysfunction, with particular focus on the female gender. METHODS A comprehensive literature review was conducted using the PubMed database. Search terms were used in appropriate combinations, including diabetes, insulin, insulin sensitivity, androgen, estrogen, sexual function, women, men, estrogen receptor, and androgen receptor. Over 400 citations were selected, based on topical relevance, and examined for study methodology and major findings. MAIN OUTCOME MEASURES Data from peer-reviewed publications. RESULTS Imbalances in sex steroid hormone levels are strongly associated with diabetes and this may negatively impact upon sexual function. Although numerous factors are likely to contribute to the development of diabetes and its complications, the role of sex steroid hormones must be acknowledged. CONCLUSIONS Research related to diabetic women and sexual dysfunction is severely lacking. Identifying underlying causes for a given hormonal imbalance in diabetic patients, as well as determination of genetic and age-dependent factors, will become important in identifying the subpopulations in which hormonal replacement regimens will be most effective. Investigation into treating diabetic patients with adjunct hormonal therapies or steroid hormone receptor modulators holds much promise.
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Affiliation(s)
- Noel N Kim
- The Institute for Sexual Medicine, San Diego, CA 92121, USA.
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Kissebah AH, Peiris AN, Evans DJ. Mechanisms associating body fat distribution to glucose intolerance and diabetes mellitus: window with a view. ACTA MEDICA SCANDINAVICA. SUPPLEMENTUM 2009; 723:79-89. [PMID: 3293360 DOI: 10.1111/j.0954-6820.1987.tb05931.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Affiliation(s)
- A H Kissebah
- Department of Medicine, Medical College of Wisconsin, Milwaukee
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Abstract
BACKGROUND Obesity has become a serious global public health issue and has consequences for nearly all areas of medicine. Within obstetrics, obesity not only has direct implications for the health of a pregnancy but also impacts on the weight of the child in infancy and beyond. As such, maternal weight may influence the prevalence and severity of obesity in future generations. Pregnancy has been identified as a key time to target a weight control or weight loss strategy to help curb the rapidly growing obesity epidemic. In addition, if delivered sensitively, pregnancy may be a good time to target health behaviour changes by using the extra motivation women tend to have at this time to maximise the health of their child. AIM This study reviews the current evidence for interventions to promote weight control or weight loss in women around the time of pregnancy. A comprehensive review of medical research--PubMed, Embase, Ovid Medline and the Cochrane Clinical Trials register--showed that despite numerous reports of the prevalence and complications of maternal obesity, few intervention strategies have been suggested. CONCLUSION This study finds that there is a deficiency of appropriately designed interventions for maternal obesity and it concludes by highlighting areas for developing a more effective strategy.
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Affiliation(s)
- K M Birdsall
- Department of Women's Health, St Thomas' Hospital, London, UK
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Liepa GU, Sengupta A, Karsies D. Polycystic Ovary Syndrome (PCOS) and Other Androgen Excess–Related Conditions: Can Changes in Dietary Intake Make a Difference? Nutr Clin Pract 2008; 23:63-71. [DOI: 10.1177/011542650802300163] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Affiliation(s)
- George U. Liepa
- School of Health Sciences and Department of Chemistry, Eastern Michigan University, Ypsilanti, Michigan
| | - Aditi Sengupta
- School of Health Sciences and Department of Chemistry, Eastern Michigan University, Ypsilanti, Michigan
| | - Danielle Karsies
- School of Health Sciences and Department of Chemistry, Eastern Michigan University, Ypsilanti, Michigan
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Gurley SB, Clare SE, Snow KP, Hu A, Meyer TW, Coffman TM. Impact of genetic background on nephropathy in diabetic mice. Am J Physiol Renal Physiol 2005; 290:F214-22. [PMID: 16118394 DOI: 10.1152/ajprenal.00204.2005] [Citation(s) in RCA: 222] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
With the goal of identifying optimal platforms for developing better models of diabetic nephropathy in mice, we compared renal effects of streptozotocin (STZ)-induced diabetes among five common inbred mouse strains (C57BL/6, MRL/Mp, BALB/c, DBA/2, and 129/SvEv). We also evaluated the renal consequences of chemical and genetic diabetes on the same genetic background (C57BL/6). There was a hierarchical response of blood glucose level to the STZ regimen among the strains (DBA/2 > C57BL/6 > MRL/MP > 129/SvEv > BALB/c). In all five strains, males demonstrated much more robust hyperglycemia with STZ than females. STZ-induced diabetes was associated with modest levels of albuminuria in all of the strains but was greatest in the DBA/2 strain, which also had the most marked hyperglycemia. Renal structural changes on light microscopy were limited to the development of mesangial expansion, and, while there were some apparent differences among strains in susceptibility to renal pathological changes, there was a significant positive correlation between blood glucose and the degree of mesangial expansion, suggesting that most of the variability in renal pathological abnormalities was because of differences in hyperglycemia. Although the general character of renal involvement was similar between chemical and genetic diabetes, Akita mice developed more marked hyperglycemia, elevated blood pressures, and less variability in renal structural responses. Thus, among the strains and models tested, the DBA/2 genetic background and the Akita (Ins2(+/C96Y)) model may be the most useful platforms for model development.
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Affiliation(s)
- Susan B Gurley
- Division of Nephrology, Department of Medicine, Duke University Medical Center, Durham, NC, USA
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Zhu Q, Chang H, Chen Y, Fang F, Xue C, Zhang F, Qiu M, Wang H, Wang B, Chen Z. Protection of inactivated influenza virus vaccine against lethal influenza virus infection in diabetic mice. Biochem Biophys Res Commun 2005; 329:87-94. [PMID: 15721277 DOI: 10.1016/j.bbrc.2005.01.109] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2005] [Indexed: 10/25/2022]
Abstract
Influenza virus infection frequently causes complications and some excess mortality in the patients with diabetes. Vaccination is an effective measure to prevent influenza virus infection. In this paper, antibody response and protection against influenza virus infection induced by vaccination were studied in mouse model of diabetes. Healthy and diabetic BALB/c mice were immunized once or twice with inactivated influenza virus vaccine at various dosages. Four weeks after the first immunization or 1 week after the second immunization, the mice were challenged with influenza virus at a lethal dose. The result showed that the antibody responses in diabetic mice were inhibited. Immunization once with high dose or twice with low dose of vaccine provided full protection against lethal influenza virus challenge in diabetic mice, however, in healthy mice, immunization only once with low dose provided a full protection.
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Affiliation(s)
- Qiang Zhu
- College of Life Science, Hunan Normal University, Changsha, 410081 Hunan, People's Republic of China
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46
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Louet JF, LeMay C, Mauvais-Jarvis F. Antidiabetic actions of estrogen: insight from human and genetic mouse models. Curr Atheroscler Rep 2004; 6:180-5. [PMID: 15068742 DOI: 10.1007/s11883-004-0030-9] [Citation(s) in RCA: 200] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
There is increasing evidence both in humans and rodents linking the endogenous estrogen 17b-estradiol (E2) to the maintenance of glucose homeostasis. Postmenopausal women develop visceral obesity and insulin resistance and are at increased risk for type 2 diabetes mellitus, but hormone replacement therapy leads to a reduction in the incidence of diabetes. In various spontaneous rodent models of type 2 diabetes, female rodents are protected against hyperglycemia unless they are ovariectomized, and E2 perfusion reverses diabetes in male rodents. Finally, the study of transgenic mice and mice with genetic alteration of E2 secretion or E2 action has shed light on the antidiabetic properties of E2 at a tissue-specific level. Thus, E2 secretion and action in rodents seems to be implicated 1) in adipose tissue biology and the prevention of obesity, 2) in the stimulation of liver fatty acid metabolism and suppression of hepatic glucose production, and 3) in the protection of pancreatic b-cell function/survival and insulin secretion in conditions of oxidative stress.
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Affiliation(s)
- Jean-Francois Louet
- Department of Medicine, Division of Diabetes, Endocrinology & Metabolism, Baylor College of Medicine, One Baylor Plaza, 520B, Houston, TX 77030, USA
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Ajayi AA, Ogungbade GO, Okorodudu AO. Sex hormone regulation of systemic endothelial and renal microvascular reactivity in type-2 diabetes: studies in gonadectomized and sham-operated Zucker diabetic rats. Eur J Clin Invest 2004; 34:349-57. [PMID: 15147332 DOI: 10.1111/j.1365-2362.2004.01339.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
BACKGROUND Male Zucker diabetic rats exhibit a more severe endotheliopathy in comparison with their female diabetic litter mates. The plasma concentrations of both thromboxanes and endothelins are elevated in diabetes, and the receptor cross-talk between TXA(2) and ET-1 receptors may be enhanced in type-2 diabetic Zucker rats. AIMS To determine the role of the endogenous sex steroid hormones, testosterone and estradiol on the systemic and renal microvascular reactivity to ET-1, thromboxane-mimetic U46619, ET-TXA(2) receptor interaction, and the nitric oxide vasodilator system in Zucker hypertensive-diabetic rats. METHODS Male and female Zucker rats aged 8-10 weeks were each divided into two groups. The male rats were castrated or underwent a sham operation. The female rats were spayed (bilateral ovariectomy and hysterectomy) or had a sham operation. All rats were studied 4-6 weeks after the gonadectomy or sham operations. Blood glucose and insulin as well as plasma concentrations of testosterone and estradiol were determined. Haemodynamic studies were undertaken with determination of the dose-response curve for mean arterial pressure (MAP), renal cortical flow (RCF) and renal medullary blood flow (MBF) in response to ET-1 and U46619, and the effect of interdiction of the ET-TXA(2) interaction with ET-antagonists BQ610 and BQ788. The role of endogenous NO was assessed by its response to graded acetylcholine doses and to a L-NG-nitro-arginine methyl ester (L-NAME) infusion. RESULTS Castrated male rats had a significantly lower blood glucose concentration (295 +/- 33 mg dL(-1)) compared with their sham-controls (481 +/- 40 mg dL(-1)), P = 0.008. Mean arterial pressure tended to be lower in the castrated rats. Gonadectomy reduced the plasma testosterone and estradiol concentrations. Castration abolished the hypotensive action of U46619 compared with sham-operated male rats (P < 0.0001, anova). Conversely, the pressor action of U46619 seen in the sham-operated female rats was reversed to a profound hypotensive action in the spayed rats (P < 0.001, anova). The change in MAP after U46619 was inversely correlated to the plasma testosterone concentration (r = -0.73, P = 0.027). The paradoxical hypotensive response elicited by ET-1 in the Zucker diabetic rats of both sexes was abolished by castration only (P < 0.005, anova). Castration caused a significant (P = 0.011) augmentation of the vasodilator response to acetylcholine, while spaying caused a slight attenuation. Castration, but not spaying, resulted in significant increases in MBF after U46619 (P = 0.003, anova), ET-1 (P = 0.005, anova) and acetylcholine (P = 0.053, anova). The ET-(B) antagonist BQ788 augmented the U46619-induced rise in MAP in castrated male rats, and also abolished the U46619-induced increase in MBF (P < 0.01 anova). L-NAME (25 mg kg(-1)) increased MAP and decreased MBF in the gonadectomized and sham-operated rats, except for the castrated male Zucker rats, where it significantly increased MBF (+90 +/- 31 PU) (P = 0.0004, anova) despite the increase in MAP. CONCLUSIONS Testosterone and estradiol regulate systemic and microvascular reactivity to TXA(2) receptor stimulation in type-2 diabetic Zucker rats. The impact of testosterone on blood glucose concentration, blood pressure, and the systemic and renal microcirculatory response to ET-1 and NO, as well as the endothelin-thromboxane receptor cross talk, is greater, and opposite to that of estradiol. The effects of testosterone withdrawal may at least in part be mediated by the ET-B receptor subtype and NO generation. Androgen blockade should be investigated further for the reversal or delay of hypertensive-diabetic endotheliopathy.
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Affiliation(s)
- A A Ajayi
- Center for Cardiovascular Diseases, Texas Southern University, Houston, Texas 77004, USA.
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Vanheest JL, Rodgers CD. Effects of exercise in diabetic rats before and during gestation on maternal and neonatal outcomes. THE AMERICAN JOURNAL OF PHYSIOLOGY 1997; 273:E727-33. [PMID: 9357802 DOI: 10.1152/ajpendo.1997.273.4.e727] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
This study was designed to evaluate the effects of chronic endurance training on glucose and lipid homeostasis in diabetic mothers and their offspring. Female Sprague-Dawley rats were rendered diabetic (>20 mmol/l glucose) by streptozotocin and subdivided into three treatments (n = 10/group): exercise (20 m/min; 0% grade; 1 h/day; 5 days/wk) before and during gestation (EE), exercise before gestation with cessation on conception (ES), and sedentary before and during gestation (SS). Response of dams to a preconception and third trimester glucose tolerance test, litter number (EE = ES = SS = 3), and average litter size (EE = 9.7 +/- 1.5; ES = 9.0 +/- 1.5; SS = 8.3 +/- 0.3) did not differ among groups. Number of offspring remaining viable was significantly different among groups (EE = 17; ES = 0; SS = 14). Response to a glucose challenge and fasting glucose and insulin were different between the EE and SS pups. Exercise before and during gestation did not reduce the viability of offspring. Cessation of exercise during early pregnancy negatively affected offspring viability.
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Affiliation(s)
- J L Vanheest
- Department of Physical Education and Exercise Science, Michigan State University, East Lansing 48824, USA
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McLean MP, Nanjo K, Irby RB, Warden KJ, Billheimer JT. Reduced hepatic sterol carrier protein-2 expression in the streptozotocin treated diabetic rat. Endocrine 1995; 3:563-71. [PMID: 21153133 DOI: 10.1007/bf02953020] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/1995] [Accepted: 04/05/1995] [Indexed: 11/26/2022]
Abstract
While a strong relationship between the hypercholesterolemia of diabetes and premature atherosclerosis is established, the etiology for the elevation in serum cholesterol in this disease is unknown. To determine whether diabetic hypercholesterolemia may be related to alterations in hepatic cholesterol transport capacity, sterol carrier protein-2 (SCP2) expression was examined in rats treated with streptozotocin (SZT). Furthermore, this study examined whether 17β-estradiol and insulin confer a protective effect on liver cholesterol homeostasis by maintaining hepatic SCP2 levels. SCP2 protein and mRNA expression were examined 13 days following SZT-induced diabetes onset and in diabetic rats treated with estradiol (1 cm silastic implant) or insulin (12 units/day). Data indicate that SCP2 protein levels were significantly reduced in the diabetic animals and that SCP2 protein expression in the liver was inversely related to the level of serum cholesterol in the diabetic animals. In contrast, SCP2 mRNA levels examined by slot blot, ribonuclease protection assay, and Northern blot analysis were significantly elevated. Both insulin and estradiol were able to enhance the expression of SCP2 protein in the liver following SZT treatment. The results of this investigation clearly indicate that hepatic SCP2 protein levels are significantly altered in the diabetic state suggesting that cholesterol transport capacity is reduced in the SZT-treated diabetic rat. The inverse relationship between serum cholesterol and hepatic SCP2 protein content suggests that the reduction in this protein may be a contributing factor in diabetic hypercholesterolemia.
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Affiliation(s)
- M P McLean
- Department of Obstetrics and Gynecology, University of South Florida College of Medicine, 33606, Tampa, Florida
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Babichev VN, Adamskaya EI, Peryshkova TA. Analysis of hypothalamohypophyseogonadal interrelationships in female rats in experimentally-induced diabetes. NEUROSCIENCE AND BEHAVIORAL PHYSIOLOGY 1995; 25:46-51. [PMID: 7777145 DOI: 10.1007/bf02359249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Affiliation(s)
- V N Babichev
- Laboratory of the Physiology of the Endocrine System, Institute of Experimental Endocrinology, Endocrinological Scientific Center, Russian Academy of Medical Sciences, Moscow
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