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Ruiz-Pino A, Goncalves-Ramírez A, Jiménez-Palomares M, Merino B, Castellano-Muñoz M, Vettorazzi JF, Rafacho A, Marroquí L, Nadal Á, Alonso-Magdalena P, Perdomo G, Cózar-Castellano I, Quesada I. Hyperglucagonemia and glucagon hypersecretion in early type 2 diabetes result from multifaceted dysregulation of pancreatic mouse α-cells. Pflugers Arch 2025; 477:207-221. [PMID: 39601887 DOI: 10.1007/s00424-024-03045-5] [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: 06/18/2024] [Revised: 11/08/2024] [Accepted: 11/14/2024] [Indexed: 11/29/2024]
Abstract
Hyperglucagonemia has been implicated in the pathogenesis of type 2 diabetes (T2D). In contrast to β-cells, studies on the function of the pancreatic α-cell in T2D are scarce. Consequently, the processes underlying hyperglucagonemia and α-cell dysfunction are largely unknown, limiting the appropriate design of specific pharmacological and therapeutic strategies. In the current study, we aimed to analyze the alterations of the pancreatic α-cell and its glucagon responses in diabetic db/db mice at early stages of the disease. In this context of glucose intolerance, hyperinsulinemia, and β-cell dysfunction, hyperglucagonemia was only present at fed conditions and was associated with insulin resistance. Yet, we found that the glucagon-to-insulin ratio in db/db mice did not change with fed or fasted states, further supporting that the metabolic regulation of glucagon release was impaired. Pancreatic β-cell dysfunction in db/db mice was manifested by increased basal secretion from isolated islets along with reduced insulin content. In contrast, α-cells from diabetic animals presented upregulated secretion and islet content of glucagon compared with controls. Electrophysiological analysis of dispersed α-cells revealed that altered secretion was not the result of impaired exocytosis. Instead, we found defective regulation of Ca2+ signaling by glucose. Besides these functional alterations, we also observed augmented α-cell mass in diabetic mice, which was accompanied by disrupted islet cytoarchitecture as well as increased α-cell size and number, without pieces of evidence of upregulated proliferation. Overall, these findings indicate that hyperglucagonemia in early T2D results from multifaceted α-cell deregulation in mice.
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Affiliation(s)
- Antonia Ruiz-Pino
- Instituto de Investigación, Desarrollo E Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández de Elche, Avenida de La Universidad S/N, 03202, Elche, Spain
- Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas - Universidad Miguel Hernández de Elche, San Juan de Alicante, Alicante, Spain
| | - Arianna Goncalves-Ramírez
- Unidad de Excelencia Instituto de Biomedicina y Genética Molecular (IBGM), Consejo Superior de Investigaciones Científicas (CSIC) y, Universidad de Valladolid (UVa), Valladolid, Spain
| | - Margarita Jiménez-Palomares
- Department of Biomedicine, Biotechnology and Public Health, University of Cádiz, 11003, Cádiz, Spain
- Biomedical Research and Innovation Institute of Cadiz (INIBICA), 11009, Cádiz, Spain
| | - Beatriz Merino
- Unidad de Excelencia Instituto de Biomedicina y Genética Molecular (IBGM), Consejo Superior de Investigaciones Científicas (CSIC) y, Universidad de Valladolid (UVa), Valladolid, Spain
| | - Manuel Castellano-Muñoz
- Instituto de Investigación, Desarrollo E Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández de Elche, Avenida de La Universidad S/N, 03202, Elche, Spain
| | - Jean F Vettorazzi
- Latin American Institute of Life and Nature Sciences (ILACVN), Federal University of Latin American Integration (UNILA), Foz Do Iguaçú, Paraná, Brazil
| | - Alex Rafacho
- Department of Physiological Sciences, Center of Biological Sciences, Federal University of Santa Catarina, Florianopolis, Brazil
| | - Laura Marroquí
- Instituto de Investigación, Desarrollo E Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández de Elche, Avenida de La Universidad S/N, 03202, Elche, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - Ángel Nadal
- Instituto de Investigación, Desarrollo E Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández de Elche, Avenida de La Universidad S/N, 03202, Elche, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - Paloma Alonso-Magdalena
- Instituto de Investigación, Desarrollo E Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández de Elche, Avenida de La Universidad S/N, 03202, Elche, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - Germán Perdomo
- Unidad de Excelencia Instituto de Biomedicina y Genética Molecular (IBGM), Consejo Superior de Investigaciones Científicas (CSIC) y, Universidad de Valladolid (UVa), Valladolid, Spain
| | - Irene Cózar-Castellano
- Unidad de Excelencia Instituto de Biomedicina y Genética Molecular (IBGM), Consejo Superior de Investigaciones Científicas (CSIC) y, Universidad de Valladolid (UVa), Valladolid, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - Ivan Quesada
- Instituto de Investigación, Desarrollo E Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández de Elche, Avenida de La Universidad S/N, 03202, Elche, Spain.
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
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Shestopalov AV, Krolenko EV, Nedorubov AA, Borisenko OV, Popruga KE, Makarov VV, Yudin SM, Gaponov AM, Rumyantsev SA. Features of Metabolism and Its Regulation in the Dynamics of Experimental Models of Metabolic Disorders. Bull Exp Biol Med 2024; 178:280-286. [PMID: 39760942 DOI: 10.1007/s10517-025-06321-1] [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: 02/05/2024] [Indexed: 01/07/2025]
Abstract
Changes in the lipid and carbohydrate metabolism, adipokines, and growth factors during the development of metabolic disorders were studied in three mouse models: C57BL/6 (alimentary obesity), db/db (leptin-resistant obesity), and NOD (diabetes mellitus) lines. In the group of alimentary obesity, moderate fatty infiltration of the liver and hypertrophy of the adipose tissue, hyperglycemia, and increased concentrations of adiponectin, transforming growth factor β1 (TGF-β1), leptin, and cholesterol were detected. In the group of leptin-resistant obesity, multiple pathological changes in tissues, severe hyperglycemia and hyperleptinemia, hyperinsulinemia, and reduced concentrations of triglycerides, adiponectin, myostatin, and TGF-β1 were detected. In NOD mice, reduced number of insulin-positive β cells, hyperinsulinemia, and a decrease in adiponectin, TGF-β1, leptin, and myostatin concentrations were detected.
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Affiliation(s)
- A V Shestopalov
- Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Ministry of Health of the Russian Federation, Moscow, Russia
- Pirogov Russian National Research Medical University, Ministry of Health of the Russian Federation, Moscow, Russia
- National Medical Research Center of Endocrinology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - E V Krolenko
- Pirogov Russian National Research Medical University, Ministry of Health of the Russian Federation, Moscow, Russia.
| | - A A Nedorubov
- Center for Digital and Translational Biomedicine, Center for Molecular Health LLC, Moscow, Russia
| | - O V Borisenko
- Pirogov Russian National Research Medical University, Ministry of Health of the Russian Federation, Moscow, Russia
| | - K E Popruga
- Centre for Strategic Planning and Management of Biomedical Health Risks, Federal Medical-Biological Agency of Russia, Moscow, Russia
| | - V V Makarov
- National Medical Research Center of Endocrinology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - S M Yudin
- Centre for Strategic Planning and Management of Biomedical Health Risks, Federal Medical-Biological Agency of Russia, Moscow, Russia
| | - A M Gaponov
- Center for Digital and Translational Biomedicine, Center for Molecular Health LLC, Moscow, Russia
| | - S A Rumyantsev
- Center for Digital and Translational Biomedicine, Center for Molecular Health LLC, Moscow, Russia
- Pirogov Russian National Research Medical University, Ministry of Health of the Russian Federation, Moscow, Russia
- National Medical Research Center of Endocrinology, Ministry of Health of the Russian Federation, Moscow, Russia
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Abstract
Leptin for over 25 years has been a central theme in the study of appetite, obesity, and starvation. As the major site of leptin production is peripheral, and the site of action of greatest interest is the hypothalamus, how leptin accesses the central nervous system (CNS) and crosses the blood-brain barrier (BBB) has been of great interest. We review here the ongoing research that addresses fundamental questions such as the sites of leptin resistances in obesity and other conditions, the causes of resistances and their relations to one another, the three barrier sites of entry into the CNS, why recent studies using suprapharmacological doses cannot address these questions but give insight into nonsaturable entry of leptin into the CNS, and how that might be useful in using leptin therapeutically. The current status of the controversy of whether the short form of the leptin receptor acts as the BBB leptin transporter and how obesity may transform leptin transport is reviewed. Review of these and other topics summarizes in a new appreciation of what leptin may have actually evolved to do and what physiological role leptin resistance may play. © 2021 American Physiological Society. Compr Physiol 11:1-19, 2021.
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Affiliation(s)
- William A Banks
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA.,Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA
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Xiong X, Liu C, Shen M, Yang Q, Zhao Q, Li X, Zhong X, Wang Z. Circular RNA expression profile in transgenic diabetic mouse kidneys. Cell Mol Biol Lett 2021; 26:25. [PMID: 34098865 PMCID: PMC8182942 DOI: 10.1186/s11658-021-00270-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 05/24/2021] [Indexed: 12/15/2022] Open
Abstract
Background Diabetic nephropathy is one of the most important complications in patients with diabetes. The etiology and pathogenesis of diabetic nephropathy remain unclear. Several studies have indicated that circular RNAs (circRNAs) play crucial regulatory roles in numerous human diseases and normal physiology; however, to date, no study has focused on the comprehensive expression profile of circRNAs in the kidneys of diabetic mice. Therefore, we aimed to identify differentially expressed circRNAs in diabetic mouse kidneys to explore the possible roles of dysregulated circRNAs in diabetic nephropathy development. Results Diabetic BKS-Leprem2Cd479/Nju (BKS-DB/Nju) mice and their nondiabetic wild-type littermates of C57BL/KsJ wild-type (WT) mice were used as experimental animals. Among all circRNAs identified by high-throughput RNA sequencing, four circRNAs were upregulated and ten were downregulated in diabetic mouse kidneys compared to those in nondiabetic mouse kidneys. After verification using quantitative reverse transcriptase polymerase chain reaction assays, we found that circR_1084, circR_182, circR_4, circR_50, circR_596, circR_897, and circR_203 were downregulated, whereas circR_627, circR_628, circR_735, and circR_801 were upregulated in the renal tissues of 8- and 16-week-old BKS-DB/Nju mice compared to those in WT mice. Conclusion We studied the circRNA expression profile in the kidneys of diabetic mice. Differentially expressed circRNAs may be useful as candidate biomarkers for diabetic nephropathy. Collectively, our results provide a novel theoretical basis for further investigation of the regulatory roles of circRNA in the etiology and pathogenesis of diabetic nephropathy. Supplementary Information The online version contains supplementary material available at 10.1186/s11658-021-00270-z.
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Affiliation(s)
- Xuan Xiong
- Department of Nephrology, The Affiliated Shunde Hospital of Guangzhou Medical University, Foshan, 528315, China.,Department of Nephrology, Guangzhou Red Cross Hospital, Medical School of Jinan University, Guangzhou, 510220, China
| | - Changchun Liu
- Department of Nephrology, The Affiliated Shunde Hospital of Guangzhou Medical University, Foshan, 528315, China
| | - Meiren Shen
- Department of Nephrology, The Affiliated Shunde Hospital of Guangzhou Medical University, Foshan, 528315, China
| | - Qian Yang
- Department of Nephrology, The Affiliated Shunde Hospital of Guangzhou Medical University, Foshan, 528315, China
| | - Qiang Zhao
- Department of Cardiology, The Affiliated Shunde Hospital of Guangzhou Medical University, Foshan, 528315, China
| | - Xiaoyan Li
- Laboratory Medicine Centre, The Affiliated Shunde Hospital of Guangzhou Medical University, Foshan, 528315, China
| | - Xiaoshi Zhong
- Department of Nephrology, Guangzhou Red Cross Hospital, Medical School of Jinan University, Guangzhou, 510220, China. .,Guangzhou Institute of Disease-Oriented Nutritional Research, Guangzhou Red Cross Hospital, Medical School of Jinan University, Guangzhou, 510220, China.
| | - Zhiwei Wang
- Laboratory Medicine Centre, The Affiliated Shunde Hospital of Guangzhou Medical University, Foshan, 528315, China.
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Klimontov VV, Korbut AI, Taskaeva IS, Bgatova NP, Dashkin MV, Orlov NB, Khotskina AS, Zavyalov EL, Klein T. Empagliflozin alleviates podocytopathy and enhances glomerular nephrin expression in db/db diabetic mice. World J Diabetes 2020; 11:596-610. [PMID: 33384767 PMCID: PMC7754166 DOI: 10.4239/wjd.v11.i12.596] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 09/28/2020] [Accepted: 10/13/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Modern guidelines recommend sodium-glucose cotransporter-2 (SGLT2) inhibitors as the preferred antihyperglycemic agents for patients with type 2 diabetes and chronic kidney disease. However, the mechanisms underlying the renal protective effect of SGLT2 inhibitors are not fully understood. AIM To estimate the effect of the SGLT2 inhibitor, empagliflozin (EMPA), on the structure of podocytes and nephrin expression in glomeruli in db/db diabetic mice. METHODS We treated 8-wk-old male db/db mice with EMPA (10 mg/kg/d) or vehicle for 8 wk. Age-matched male db/+ mice were included as non-diabetic controls. Parameters of body composition, glycemic and lipid control, and plasma concentrations of leptin, insulin and glucagon were assessed. We evaluated renal hypertrophy as kidney weight adjusted to lean mass, renal function as plasma levels of creatinine, and albuminuria as the urinary albumin-to-creatinine ratio (UACR). Renal structures were studied by light and transmission electron microscopy with a focus on mesangial volume and podocyte structure, respectively. Glomerular nephrin and transforming growth factor beta (TGF-β) were assessed by immunohistochemistry. RESULTS Severe obesity and hyperglycemia developed in db/db mice prior to the start of the experiment; increased plasma concentrations of fructosamine, glycated albumin, cholesterol, leptin, and insulin, and elevated UACR were detected. Mesangial expansion, glomerular basement membrane thickening, and increased area of TGF-β staining in glomeruli were revealed in vehicle-treated mice. Podocytopathy was manifested by effacement of foot processes; nephrin-positive areas in glomeruli were reduced. EMPA decreased the levels of glucose, fructosamine and glycated albumin, UACR, kidney hypertrophy, mesangial expansion, glomerular basement membrane thickening, and glomerular TGF-β staining, alleviated podocytopathy and restored glomerular staining of nephrin. CONCLUSION These data indicate that EMPA attenuates podocytopathy in experimental diabetic kidney disease. The anti-albuminuric effect of EMPA could be attributed to mitigation of podocyte injury and enhancement of nephrin expression.
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Affiliation(s)
- Vadim V Klimontov
- Laboratory of Endocrinology, Research Institute of Clinical and Experimental Lymphology – Branch of the Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (RICEL–Branch of IC&G SB RAS), Novosibirsk 630060, Russia
| | - Anton I Korbut
- Laboratory of Endocrinology, Research Institute of Clinical and Experimental Lymphology – Branch of the Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (RICEL–Branch of IC&G SB RAS), Novosibirsk 630060, Russia
| | - Iuliia S Taskaeva
- Laboratory of Ultrastructural Research, Research Institute of Clinical and Experimental Lymphology – Branch of the Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (RICEL–Branch of IC&G SB RAS), Novosibirsk 630060, Russia
| | - Nataliya P Bgatova
- Laboratory of Ultrastructural Research, Research Institute of Clinical and Experimental Lymphology – Branch of the Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (RICEL–Branch of IC&G SB RAS), Novosibirsk 630060, Russia
| | - Maksim V Dashkin
- Laboratory of Endocrinology, Research Institute of Clinical and Experimental Lymphology – Branch of the Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (RICEL–Branch of IC&G SB RAS), Novosibirsk 630060, Russia
| | - Nikolai B Orlov
- Laboratory of Clinical Immunogenetics, Research Institute of Clinical and Experimental Lymphology – Branch of the Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (RICEL–Branch of IC&G SB RAS), Novosibirsk 630060, Russia
| | - Anna S Khotskina
- Center for Genetic Resources of Laboratory Animals, Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, Novosibirsk 630090, Russia
| | - Evgenii L Zavyalov
- Center for Genetic Resources of Laboratory Animals, Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, Novosibirsk 630090, Russia
| | - Thomas Klein
- Department of Cardiometabolic Diseases Research, Boehringer Ingelheim Pharma GmbH, Biberach 88397, Germany
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