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1
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Accili D, Deng Z, Liu Q. Insulin resistance in type 2 diabetes mellitus. Nat Rev Endocrinol 2025; 21:413-426. [PMID: 40247011 DOI: 10.1038/s41574-025-01114-y] [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] [Accepted: 03/28/2025] [Indexed: 04/19/2025]
Abstract
Insulin resistance is an integral pathophysiological feature of type 2 diabetes mellitus. Here, we review established and emerging cellular mechanisms of insulin resistance, their complex integrative features and their relevance to disease progression. While recognizing the heterogeneity of the elusive fundamental disruptions that cause insulin resistance, we endorse the view that effector mechanisms impinge on insulin receptor signalling and its relationship with plasma levels of insulin. We focus on hyperinsulinaemia and its consequences: acutely impaired but persistent insulin action, with reduced ability to lower glucose levels but preserved lipid synthesis and lipoprotein secretion. We emphasize the role of insulin sensitization as a therapeutic goal in type 2 diabetes mellitus.
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Affiliation(s)
- Domenico Accili
- Department of Medicine, Columbia University Vagelos College of Physicians & Surgeons, New York, NY, USA.
| | - Zhaobing Deng
- Department of Medicine, Columbia University Vagelos College of Physicians & Surgeons, New York, NY, USA
| | - Qingli Liu
- Department of Medicine, Columbia University Vagelos College of Physicians & Surgeons, New York, NY, USA
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2
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He W, Loganathan N, Belsham DD. IGF1 Signaling Regulates Neuropeptide Expression in Hypothalamic Neurons Under Physiological and Pathological Conditions. Endocrinology 2025; 166:bqaf051. [PMID: 40105689 PMCID: PMC11949690 DOI: 10.1210/endocr/bqaf051] [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: 01/29/2025] [Revised: 02/28/2025] [Accepted: 03/17/2025] [Indexed: 03/20/2025]
Abstract
Insulin-like growth factor 1 (IGF1) plays a critical role in metabolism and aging, but its role in the brain remains unclear. This study examined whether hypothalamic neurons respond to IGF1 and how its actions are modulated. RT-qPCR and single-cell RNA sequencing indicated that Igf1r mRNA is expressed in neuropeptide Y/Agouti-related peptide (NPY/AgRP) neurons but has higher expression in pro-opiomelanocortin (POMC) neurons. IGF1 binding proteins Igfbp3 and Igfbp5 were significantly expressed, whereby Igfbp5 levels were modulated by fasting, nutrient availability, and circadian rhythms, implying that IGF1 signaling can be controlled by multiple mechanisms. In mouse and human models, IGF1 regulated Agrp, Npy, Pomc, Cartpt, Spx, Gal, and Fam237b expression, producing an overall anorexigenic profile. Hyperinsulinemia induced IGF1 resistance, accompanied by reduced IGF1R protein, as well as Igf1r and Irs2 mRNA expression via over-activation of phosphoinositide 3-kinase/forkhead box O1 (PI3K-FOXO1) signaling. Thus, hypothalamic neurons respond to IGF1 under physiological conditions, and hyperinsulinemia is a novel mechanism that drives cellular IGF1 resistance.
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Affiliation(s)
- Wenyuan He
- Department of Physiology, University of Toronto, Toronto, ON, Canada M5S 1A8
| | - Neruja Loganathan
- Department of Physiology, University of Toronto, Toronto, ON, Canada M5S 1A8
| | - Denise D Belsham
- Department of Physiology, University of Toronto, Toronto, ON, Canada M5S 1A8
- Department of Medicine, University of Toronto, Toronto, ON, Canada M5S 1A8
- Department of Obstetrics and Gynaecology, University of Toronto, Toronto, ON, Canada M5S 1A8
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3
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Kisielewska K, Gudelska M, Kiezun M, Dobrzyn K, Zaobidna E, Rytelewska E, Kopij G, Wasilewska B, Smolinska N, Kaminski T. Expression of the apelin system in the porcine pituitary during the oestrous cycle and early pregnancy and the effect of apelin on LH and FSH secretion. Theriogenology 2024; 230:263-277. [PMID: 39357165 DOI: 10.1016/j.theriogenology.2024.09.028] [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: 06/12/2024] [Revised: 09/23/2024] [Accepted: 09/26/2024] [Indexed: 10/04/2024]
Abstract
Reproductive success requires considerable energy investment. Research has shown that some adipokines, i.e. the hormones produced in adipose tissue, affect reproductive functions by influencing all structures of the hypothalamic-pituitary-ovarian axis. Apelin is a recently identified member of the adipokine family. To the best of the authors' knowledge, this is the first study to investigate the gene and protein expression of the apelin system (the apelin hormone and the apelin receptor, APJ) in the anterior (AP) and posterior (PP) pituitary lobes of the domestic pig during different phases of the oestrous cycle (days 2 to 3, 10 to 12, 14 to 16, and 17 to 19) and in early pregnancy (days 10 to 11, 12 to 13, 15 to 16, and 27 to 28). It was also assumed that apelin participates in the regulation of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion and influences Akt, MAPK/Erk1/2, and AMPK signalling pathways in the AP during the oestrous cycle. Apelin, APJ mRNAs and proteins were detected in both pituitary lobes. Apelin was identified in gonadotropes, somatotropes, lactotropes, and thyrotropes. The study also revealed that apelin and APJ mRNA/protein levels fluctuate during the oestrous cycle and early gestation. Apelin affects basal, GnRH- and/or insulin-stimulated gonadotropin secretion in some phases of the cycle, as well as the phosphorylation of Akt, MAPK/Erk1/2, and AMPK proteins in AP cells. These findings suggest that apelin may be produced locally in the pituitary and that this gland is receptive to apelin's action. The study also suggest that apelin may influence female reproductive functions by controlling the release of LH and FSH from AP cells, and that it affects Akt, MAPK/Erk1/2, and AMPK signalling pathways.
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Affiliation(s)
- Katarzyna Kisielewska
- Department of Human Histology and Embryology, School of Medicine, Collegium Medicum, University of Warmia and Mazury in Olsztyn, 10-082, Olsztyn, Poland.
| | - Marlena Gudelska
- Department of Human Histology and Embryology, School of Medicine, Collegium Medicum, University of Warmia and Mazury in Olsztyn, 10-082, Olsztyn, Poland.
| | - Marta Kiezun
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, 10-719, Olsztyn, Poland.
| | - Kamil Dobrzyn
- Department of Zoology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, 10-719, Olsztyn, Poland.
| | - Ewa Zaobidna
- Department of Biochemistry, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, 10-719, Olsztyn, Poland.
| | - Edyta Rytelewska
- Laboratory of Physiology and Toxicology of Reproduction, Institute of Zoology and Biomedical Research, Jagiellonian University in Krakow, 30-387, Krakow, Poland.
| | - Grzegorz Kopij
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, 10-719, Olsztyn, Poland.
| | - Barbara Wasilewska
- Department of Human Physiology and Pathophysiology, School of Medicine, Collegium Medicum, University of Warmia and Mazury in Olsztyn, 10-082, Olsztyn, Poland.
| | - Nina Smolinska
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, 10-719, Olsztyn, Poland.
| | - Tadeusz Kaminski
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, 10-719, Olsztyn, Poland.
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4
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Jørgensen SH, Emdal KB, Pedersen AK, Axelsen LN, Kildegaard HF, Demozay D, Pedersen TÅ, Grønborg M, Slaaby R, Nielsen PK, Olsen JV. Multi-layered proteomics identifies insulin-induced upregulation of the EphA2 receptor via the ERK pathway which is dependent on low IGF1R level. Sci Rep 2024; 14:28856. [PMID: 39572596 PMCID: PMC11582730 DOI: 10.1038/s41598-024-77817-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Accepted: 10/25/2024] [Indexed: 11/24/2024] Open
Abstract
Insulin resistance impairs the cellular insulin response, and often precedes metabolic disorders, like type 2 diabetes, impacting an increasing number of people globally. Understanding the molecular mechanisms in hepatic insulin resistance is essential for early preventive treatments. To elucidate changes in insulin signal transduction associated with hepatocellular resistance, we employed a multi-layered mass spectrometry-based proteomics approach focused on insulin receptor (IR) signaling at the interactome, phosphoproteome, and proteome levels in a long-term hyperinsulinemia-induced insulin-resistant HepG2 cell line with a knockout of the insulin-like growth factor 1 receptor (IGF1R KO). The analysis revealed insulin-stimulated recruitment of the PI3K complex in both insulin-sensitive and -resistant cells. Phosphoproteomics showed attenuated signaling via the metabolic PI3K-AKT pathway but sustained extracellular signal-regulated kinase (ERK) activity in insulin-resistant cells. At the proteome level, the ephrin type-A receptor 2 (EphA2) showed an insulin-induced increase in expression, which occurred through the ERK signaling pathway and was concordantly independent of insulin resistance. Induction of EphA2 by insulin was confirmed in additional cell lines and observed uniquely in cells with high IR-to-IGF1R ratio. The multi-layered proteomics dataset provided insights into insulin signaling, serving as a resource to generate and test hypotheses, leading to an improved understanding of insulin resistance.
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Affiliation(s)
- Sarah Hyllekvist Jørgensen
- Proteomics Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark
- Global Research Technologies, Novo Nordisk A/S, 2760, Maaloev, Denmark
| | - Kristina Bennet Emdal
- Proteomics Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark.
| | - Anna-Kathrine Pedersen
- Proteomics Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark
| | | | | | - Damien Demozay
- Global Drug Discovery, Novo Nordisk A/S, 2760, Maaloev, Denmark
| | | | - Mads Grønborg
- Global Translation, Novo Nordisk A/S, 2760, Maaloev, Denmark
| | - Rita Slaaby
- Global Drug Discovery, Novo Nordisk A/S, 2760, Maaloev, Denmark
| | | | - Jesper Velgaard Olsen
- Proteomics Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark.
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Seifi N, Bahari H, Foroumandi E, Hasanpour E, Nikoumanesh M, Ferns GA, Esmaily H, Ghayour‐Mobarhan M. The association of dietary indices for hyperinsulinemia and insulin resistance with the risk of metabolic syndrome: a population-based cross-sectional study. J Clin Hypertens (Greenwich) 2024; 26:832-841. [PMID: 38980195 PMCID: PMC11232453 DOI: 10.1111/jch.14832] [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: 12/30/2023] [Revised: 04/07/2024] [Accepted: 04/16/2024] [Indexed: 07/10/2024]
Abstract
We aimed to investigate the association between an empirical dietary index for hyperinsulinemia (EDIH), empirical dietary index for insulin resistance (EDIR), and MetS and its components in an adult Iranian population. In this cross-sectional study, a total of 6482 participants aged 35-65 years were recruited as part of the MASHAD cohort study. Dietary intakes were assessed using a validated food frequency questionnaire (FFQ). The International Diabetes Federation (IDF) criteria were used to define MetS. Multivariable logistic regression models were applied to determine the association between EDIH, EDIR, and MetS and its components. The mean age and BMI of participants were 48.44±8.20 years, and 27.98±4.73 kg/m2, respectively. Around 59% of the population was female. Of the total population, 35.4% had MetS. According to the full-adjusted model, there was no significant association between higher quartiles of EDIH and EDIR and odds of MetS (Q4 EDIH; OR (95%CI):0.93 (0.74-1.18), Q4 EDIR; OR (95%CI):1.14 (0.92-1.40). Regarding MetS components, EDIR was associated with increased odds of hypertension and diabetes (Q4 EDIR; OR (95%CI):1.22 (1.04-1.44) and 1.22 (1.01-1.47), respectively). EDIH was also associated with decreased odds of hypertriglyceridemia (Q4 EDIH; OR (95%CI): 0.72 (0.60-0.87)). This study showed no significant association between hyperinsulinemia and insulin resistance potential of diet and odds of MetS among Iranian adults. However, EDIR was significantly associated with increased odds of hypertension and diabetes as MetS components.
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Affiliation(s)
- Najmeh Seifi
- International UNESCO Center for Health‐Related Basic Sciences and Human NutritionMashhad University of Medical SciencesMashhadIran
| | - Hossein Bahari
- Transplant Research CenterClinical Research InstituteMashhad University of Medical SciencesMashhadIran
| | - Elaheh Foroumandi
- Non‐Communicable Diseases Research CenterDepartment of Nutrition & BiochemistrySchool of MedicineSabzevar University of Medical SciencesSabzevarIran
| | - Elahe Hasanpour
- International UNESCO Center for Health‐Related Basic Sciences and Human NutritionMashhad University of Medical SciencesMashhadIran
| | - Mahya Nikoumanesh
- International UNESCO Center for Health‐Related Basic Sciences and Human NutritionMashhad University of Medical SciencesMashhadIran
| | - Gordon A. Ferns
- Division of Medical EducationBrighton & Sussex Medical School, FalmerBrightonSussexUK
| | - Habibollah Esmaily
- Department of BiostatisticsSchool of HealthMashhad University of Medical SciencesMashhadIran
- Social Determinants of Health Research CenterMashhad University of Medical SciencesMashhadIran
| | - Majid Ghayour‐Mobarhan
- International UNESCO Center for Health‐Related Basic Sciences and Human NutritionMashhad University of Medical SciencesMashhadIran
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Mlyczyńska E, Rytelewska E, Zaobidna E, Respekta-Długosz N, Kopij G, Dobrzyń K, Kieżun M, Smolińska N, Kamiński T, Rak A. In vitro effect of visfatin on endocrine functions of the porcine corpus luteum. Sci Rep 2024; 14:14780. [PMID: 38926439 PMCID: PMC11208563 DOI: 10.1038/s41598-024-65102-4] [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: 02/12/2024] [Accepted: 06/17/2024] [Indexed: 06/28/2024] Open
Abstract
Previously, we demonstrated the expression of visfatin in porcine reproductive tissues and its effect on pituitary endocrinology. The objective of this study was to examine the visfatin effect on the secretion of steroid (P4, E2) and prostaglandin (PGE2, PGF2α), the mRNA and protein abundance of steroidogenic markers (STAR, CYP11A1, HSD3B, CYP19A1), prostaglandin receptors (PTGER2, PTGFR), insulin receptor (INSR), and activity of kinases (MAPK/ERK1/2, AKT, AMPK) in the porcine corpus luteum. We noted that the visfatin effect strongly depends on the phase of the estrous cycle: on days 2-3 and 14-16 it reduced P4, while on days 10-12 it stimulated P4. Visfatin increased secretion of E2 on days 2-3, PGE2 on days 2-3 and 10-12, reduced PGF2α release on days 14-16, as well as stimulated the expression of steroidogenic markers on days 10-12 of the estrous cycle. Moreover, visfatin elevated PTGER mRNA expression and decreased its protein level, while we noted the opposite changes for PTGFR. Additionally, visfatin activated ERK1/2, AKT, and AMPK, while reduced INSR phosphorylation. Interestingly, after inhibition of INSR and signalling pathways visfatin action was abolished. These findings suggest a regulatory role of visfatin in the porcine corpus luteum.
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Affiliation(s)
- Ewa Mlyczyńska
- Laboratory of Physiology and Toxicology of Reproduction, Institute of Zoology and Biomedical Research, Jagiellonian University in Krakow, Krakow, Poland
- Doctoral School of Exact and Natural Sciences, Jagiellonian University in Krakow, Krakow, Poland
| | - Edyta Rytelewska
- Laboratory of Physiology and Toxicology of Reproduction, Institute of Zoology and Biomedical Research, Jagiellonian University in Krakow, Krakow, Poland
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Olsztyn-Kortowo, Poland
| | - Ewa Zaobidna
- Department of Biochemistry, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Olsztyn-Kortowo, Poland
| | - Natalia Respekta-Długosz
- Laboratory of Physiology and Toxicology of Reproduction, Institute of Zoology and Biomedical Research, Jagiellonian University in Krakow, Krakow, Poland
- Doctoral School of Exact and Natural Sciences, Jagiellonian University in Krakow, Krakow, Poland
| | - Grzegorz Kopij
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Olsztyn-Kortowo, Poland
| | - Kamil Dobrzyń
- Department of Zoology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Olsztyn-Kortowo, Poland
| | - Marta Kieżun
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Olsztyn-Kortowo, Poland
| | - Nina Smolińska
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Olsztyn-Kortowo, Poland
| | - Tadeusz Kamiński
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Olsztyn-Kortowo, Poland
| | - Agnieszka Rak
- Laboratory of Physiology and Toxicology of Reproduction, Institute of Zoology and Biomedical Research, Jagiellonian University in Krakow, Krakow, Poland.
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7
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Janssen JAMJL. Overnutrition, Hyperinsulinemia and Ectopic Fat: It Is Time for A Paradigm Shift in the Management of Type 2 Diabetes. Int J Mol Sci 2024; 25:5488. [PMID: 38791525 PMCID: PMC11121669 DOI: 10.3390/ijms25105488] [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: 04/15/2024] [Revised: 05/12/2024] [Accepted: 05/15/2024] [Indexed: 05/26/2024] Open
Abstract
The worldwide incidence of prediabetes/type 2 has continued to rise the last 40 years. In the same period, the mean daily energy intake has increased, and the quality of food has significantly changed. The chronic exposure of pancreatic β-cells to calorie excess (excessive energy intake) and food additives may increase pancreatic insulin secretion, decrease insulin pulses and/or reduce hepatic insulin clearance, thereby causing chronic hyperinsulinemia and peripheral insulin resistance. Chronic calorie excess and hyperinsulinemia may promote lipogenesis, inhibit lipolysis and increase lipid storage in adipocytes. In addition, calorie excess and hyperinsulinemia can induce insulin resistance and contribute to progressive and excessive ectopic fat accumulation in the liver and pancreas by the conversion of excess calories into fat. The personal fat threshold hypothesis proposes that in susceptible individuals, excessive ectopic fat accumulation may eventually lead to hepatic insulin receptor resistance, the loss of pancreatic insulin secretion, hyperglycemia and the development of frank type 2 diabetes. Thus, type 2 diabetes seems (partly) to be caused by hyperinsulinemia-induced excess ectopic fat accumulation in the liver and pancreas. Increasing evidence further shows that interventions (hypocaloric diet and/or bariatric surgery), which remove ectopic fat in the liver and pancreas by introducing a negative energy balance, can normalize insulin secretion and glucose tolerance and induce the sustained biochemical remission of type 2 diabetes. This pathophysiological insight may have major implications and may cause a paradigm shift in the management of type 2 diabetes: avoiding/reducing ectopic fat accumulation in the liver and pancreas may both be essential to prevent and cure type 2 diabetes.
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Affiliation(s)
- Joseph A M J L Janssen
- Department of Internal Medicine, Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands
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Szymanska K, Rytelewska E, Zaobidna E, Kiezun M, Gudelska M, Kopij G, Dobrzyn K, Mlyczynska E, Kurowska P, Kaminska B, Nynca A, Smolinska N, Rak A, Kaminski T. The Effect of Visfatin on the Functioning of the Porcine Pituitary Gland: An In Vitro Study. Cells 2023; 12:2835. [PMID: 38132154 PMCID: PMC10742260 DOI: 10.3390/cells12242835] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 12/11/2023] [Accepted: 12/12/2023] [Indexed: 12/23/2023] Open
Abstract
Visfatin (VIS), also known as nicotinamide phosphoribosyltransferase (NAMPT), is the rate-limiting enzyme in the biosynthesis of nicotinamide adenine dinucleotide (NAD+). Recently, VIS has been also recognized as an adipokine. Our previous study revealed that VIS is produced in the anterior and posterior lobes of the porcine pituitary. Moreover, the expression and secretion of VIS are dependent on the phase of the estrous cycle and/or the stage of early pregnancy. Based on this, we hypothesized that VIS may regulate porcine pituitary function. This study was conducted on anterior pituitary (AP) glands harvested from pigs during specific phases of the estrous cycle. We have shown the modulatory effect of VIS in vitro on LH and FSH secretion by porcine AP cells (determined by ELISA). VIS was also found to stimulate cell proliferation (determined by Alamar Blue) without affecting apoptosis in these cells (determined using flow cytometry technique). Moreover, it was indicated that VIS may act in porcine AP cells through the INSR, AKT/PI3K, MAPK/ERK1/2, and AMPK signaling pathways (determined by ELISA or Western Blot). This observation was further supported by the finding that simultaneous treatment of cells with VIS and inhibitors of these pathways abolished the observed VIS impact on LH and FSH secretion (determined by ELISA). In addition, our research indicated that VIS affected the mentioned processes in a manner that was dependent on the dose of VIS and/or the phase of the estrous cycle. Thus, these findings suggest that VIS may regulate the functioning of the porcine pituitary gland during the estrous cycle.
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Affiliation(s)
- Karolina Szymanska
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland; (K.S.); (E.R.); (M.K.); (G.K.); (B.K.); (A.N.); (N.S.)
| | - Edyta Rytelewska
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland; (K.S.); (E.R.); (M.K.); (G.K.); (B.K.); (A.N.); (N.S.)
| | - Ewa Zaobidna
- Department of Biochemistry, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland;
| | - Marta Kiezun
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland; (K.S.); (E.R.); (M.K.); (G.K.); (B.K.); (A.N.); (N.S.)
| | - Marlena Gudelska
- Department of Human Histology and Embryology, School of Medicine, Collegium Medicum, University of Warmia and Mazury in Olsztyn, 10-082 Olsztyn, Poland;
| | - Grzegorz Kopij
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland; (K.S.); (E.R.); (M.K.); (G.K.); (B.K.); (A.N.); (N.S.)
| | - Kamil Dobrzyn
- Department of Zoology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland;
| | - Ewa Mlyczynska
- Laboratory of Physiology and Toxicology of Reproduction, Institute of Zoology and Biomedical Research, Jagiellonian University in Krakow, 30-387 Krakow, Poland; (E.M.); (P.K.); (A.R.)
- Doctoral School of Exact and Natural Sciences, Jagiellonian University in Krakow, 30-348 Krakow, Poland
| | - Patrycja Kurowska
- Laboratory of Physiology and Toxicology of Reproduction, Institute of Zoology and Biomedical Research, Jagiellonian University in Krakow, 30-387 Krakow, Poland; (E.M.); (P.K.); (A.R.)
| | - Barbara Kaminska
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland; (K.S.); (E.R.); (M.K.); (G.K.); (B.K.); (A.N.); (N.S.)
| | - Anna Nynca
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland; (K.S.); (E.R.); (M.K.); (G.K.); (B.K.); (A.N.); (N.S.)
| | - Nina Smolinska
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland; (K.S.); (E.R.); (M.K.); (G.K.); (B.K.); (A.N.); (N.S.)
| | - Agnieszka Rak
- Laboratory of Physiology and Toxicology of Reproduction, Institute of Zoology and Biomedical Research, Jagiellonian University in Krakow, 30-387 Krakow, Poland; (E.M.); (P.K.); (A.R.)
| | - Tadeusz Kaminski
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland; (K.S.); (E.R.); (M.K.); (G.K.); (B.K.); (A.N.); (N.S.)
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9
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Szymanska K, Zaobidna E, Rytelewska E, Mlyczynska E, Kurowska P, Dobrzyn K, Kiezun M, Kaminska B, Smolinska N, Rak A, Kaminski T. Visfatin in the porcine pituitary gland: expression and regulation of secretion during the oestrous cycle and early pregnancy. Sci Rep 2023; 13:18253. [PMID: 37880346 PMCID: PMC10600231 DOI: 10.1038/s41598-023-45255-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 10/17/2023] [Indexed: 10/27/2023] Open
Abstract
Visfatin is a multifunctional protein which, besides the control of energy homeostasis, seems to be also involved in the regulation of female fertility through the influence on the endocrine hypothalamus-pituitary-gonadal axis, including the pituitary. The aim of this study was to investigate the expression of visfatin mRNA and protein in the anterior (AP) and posterior pituitary lobes of the pig during the oestrous cycle and early pregnancy. In AP, we also examined colocalisation of visfatin with pituitary tropic hormones. Moreover, we aimed to evaluate the in vitro effects of GnRH, FSH, LH, and insulin on visfatin protein concentration and secretion in AP cells during the cycle. The study showed that visfatin is present in all types of porcine pituitary endocrine cells and its expression is reliant on stage of the cycle or pregnancy. GnRH, FSH, LH and insulin stimulated visfatin secretion by AP cells on days 17 to 19 of the cycle, while on days 2 to 3 visfatin release was enhanced only by LH. Summarising, visfatin is locally produced in the pituitary in a way dependent on hormonal milieu typical for reproductive status of pigs. Further research is required to clarify the role of visfatin in the pituitary gland.
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Affiliation(s)
- Karolina Szymanska
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 1A, 10-719, Olsztyn, Poland
| | - Ewa Zaobidna
- Department of Biochemistry, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 1A, 10-719, Olsztyn, Poland
| | - Edyta Rytelewska
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 1A, 10-719, Olsztyn, Poland
| | - Ewa Mlyczynska
- Laboratory of Physiology and Toxicology of Reproduction, Institute of Zoology and Biomedical Research, Jagiellonian University in Krakow, Gronostajowa 9, 30-387, Krakow, Poland
- Doctoral School of Exact and Natural Sciences, Jagiellonian University in Krakow, Lojasiewicza 11, 30-348, Krakow, Poland
| | - Patrycja Kurowska
- Laboratory of Physiology and Toxicology of Reproduction, Institute of Zoology and Biomedical Research, Jagiellonian University in Krakow, Gronostajowa 9, 30-387, Krakow, Poland
| | - Kamil Dobrzyn
- Department of Zoology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 5, 10-719, Olsztyn, Poland
| | - Marta Kiezun
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 1A, 10-719, Olsztyn, Poland
| | - Barbara Kaminska
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 1A, 10-719, Olsztyn, Poland
| | - Nina Smolinska
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 1A, 10-719, Olsztyn, Poland
| | - Agnieszka Rak
- Laboratory of Physiology and Toxicology of Reproduction, Institute of Zoology and Biomedical Research, Jagiellonian University in Krakow, Gronostajowa 9, 30-387, Krakow, Poland
| | - Tadeusz Kaminski
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 1A, 10-719, Olsztyn, Poland.
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10
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E L, Lu R, Zheng Y, Zhang L, Ma X, Lv Y, Gao M, Zhang S, Wang L, Liu H, Zhang R. Effect of Insulin on Bone Formation Ability of Rat Alveolar Bone Marrow Mesenchymal Stem Cells. Stem Cells Dev 2023; 32:652-666. [PMID: 37282516 DOI: 10.1089/scd.2023.0091] [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] [Indexed: 06/08/2023] Open
Abstract
The alveolar bone marrow mesenchymal stem cells (ABM-MSCs) play an important role in oral bone healing and regeneration. Insulin is considered to improve impaired oral bones due to local factors, systemic factors and pathological conditions. However, the effect of insulin on bone formation ability of ABM-MSCs still needs to be elucidated. The aim of this study was to determine the responsiveness of rat ABM-MSCs to insulin and to explore the underlying mechanism. We found that insulin promoted ABM-MSCs proliferation in a concentration-dependent manner, in which 10-6 M insulin exerted the most significant effect. 10-6 M insulin significantly promoted the type I collagen (COL-1) synthesis, alkaline phosphatase (ALP) activity, osteocalcin (OCN) expression, and mineralized matrix formation in ABM-MSCs, significantly enhanced the gene and protein expressions of intracellular COL-1, ALP, and OCN. Acute insulin stimulation significantly promoted insulin receptor (IR) phosphorylation, IR substrate-1 (IRS-1) protein expression, and mammalian target of rapamycin (mTOR) phosphorylation, but chronic insulin stimulation decreased these values, while inhibitor NT219 could attenuate these responses. When seeded on β-tricalcium phosphate (β-TCP), ABM-MSCs adhered and grew well, during the 28-day culture period, ABM-MSCs+β-TCP +10-6 M insulin group showed significantly higher extracellular total COL-1 amino-terminus prolongation peptide content, ALP activity, OCN secretion, and Ca and P concentration. When implanted subcutaneously in severe combined immunodeficient mice for 1 month, the ABM-MSCs+β-TCP +10-6 M insulin group obtained the most bone formation and blood vessels. These results showed that insulin promoted the proliferation and osteogenic differentiation of ABM-MSCs in vitro, and enhance osteogenesis and angiogenesis of ABM-MSCs in vivo. Inhibition studies demonstrated that the insulin-induced osteogenic differentiation of ABM-MSCs was dependent of insulin/mTOR signaling. It suggests that insulin has a direct anabolic effect on ABM-MSCs.
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Affiliation(s)
- Lingling E
- Institute of Stomatology and Oral Maxilla Facial Key Laboratory, First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Rongjian Lu
- Department of Stomatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Ying Zheng
- Institute of Stomatology and Oral Maxilla Facial Key Laboratory, First Medical Center of Chinese PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
| | - Li Zhang
- Traditional Chinese Medicine Physiotherapy Department, Yantai Special Service Rehabilitation Center of the Chinese People Armed Police Force, Yantai, China
| | - Xiaocao Ma
- Institute of Stomatology and Oral Maxilla Facial Key Laboratory, First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Yan Lv
- Institute of Stomatology and Oral Maxilla Facial Key Laboratory, First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Mingzhu Gao
- Institute of Stomatology and Oral Maxilla Facial Key Laboratory, First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Shaoli Zhang
- The Second Department of Naval Recuperation, First District of Recuperation, Yantai Special Service Rehabilitation Center of the Chinese People Armed Police Force, Yantai, China
| | - Limei Wang
- Reception Office, First District of Recuperation, Yantai Special Service Rehabilitation Center of the Chinese People Armed Police Force, Yantai, China
| | - Hongchen Liu
- Institute of Stomatology and Oral Maxilla Facial Key Laboratory, First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Rong Zhang
- Institute of Stomatology and Oral Maxilla Facial Key Laboratory, First Medical Center of Chinese PLA General Hospital, Beijing, China
- The Second Department of Naval Recuperation, First District of Recuperation, Yantai Special Service Rehabilitation Center of the Chinese People Armed Police Force, Yantai, China
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11
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Khajavi N, Riçku K, Schreier PCF, Gentz T, Beyerle P, Cruz E, Breit A, Reinach PS, Gudermann T. Chronic Mg 2+ Deficiency Does Not Impair Insulin Secretion in Mice. Cells 2023; 12:1790. [PMID: 37443824 PMCID: PMC10340716 DOI: 10.3390/cells12131790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 06/28/2023] [Accepted: 07/03/2023] [Indexed: 07/15/2023] Open
Abstract
Magnesium is an essential mediator of a vast number of critical enzymatic cellular reactions in the human body. Some clinical epidemiological studies suggest that hypomagnesemia accounts for declines in insulin secretion in patients with type 2 diabetes (T2D); however, the results of various experimental studies do not support this notion. To address this discrepancy, we assessed the short- and long-term effects of hypomagnesemia on β-cell function and insulin secretion in primary mouse islets of Langerhans and in a mouse model of hypomagnesemia known as Trpm6Δ17 /fl;Villin1-Cre mice. We found that lowering the extracellular Mg2+ concentration from 1.2 mM to either 0.6 or 0.1 mM remarkably increased glucose-induced insulin secretion (GIIS) in primary islets isolated from C57BL/6 mice. Similarly, both the plasma insulin levels and GIIS rose in isolated islets of Trpm6Δ17 /fl;Villin1-Cre mice. We attribute these rises to augmented increases in intracellular Ca2+ oscillations in pancreatic β-cells. However, the glycemic metabolic profile was not impaired in Trpm6Δ17 /fl;Villin1-Cre mice, suggesting that chronic hypomagnesemia does not lead to insulin resistance. Collectively, the results of this study suggest that neither acute nor chronic Mg2+ deficiency suppresses glucose-induced rises in insulin secretion. Even though hypomagnesemia can be symptomatic of T2D, such deficiency may not account for declines in insulin release in this disease.
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Affiliation(s)
- Noushafarin Khajavi
- Walther Straub Institute of Pharmacology and Toxicology, LMU Munich, 80539 Munich, Germany; (K.R.); (P.C.F.S.); (T.G.); (P.B.); (E.C.); (A.B.)
| | - Klea Riçku
- Walther Straub Institute of Pharmacology and Toxicology, LMU Munich, 80539 Munich, Germany; (K.R.); (P.C.F.S.); (T.G.); (P.B.); (E.C.); (A.B.)
| | - Pascale C. F. Schreier
- Walther Straub Institute of Pharmacology and Toxicology, LMU Munich, 80539 Munich, Germany; (K.R.); (P.C.F.S.); (T.G.); (P.B.); (E.C.); (A.B.)
| | - Tanja Gentz
- Walther Straub Institute of Pharmacology and Toxicology, LMU Munich, 80539 Munich, Germany; (K.R.); (P.C.F.S.); (T.G.); (P.B.); (E.C.); (A.B.)
| | - Philipp Beyerle
- Walther Straub Institute of Pharmacology and Toxicology, LMU Munich, 80539 Munich, Germany; (K.R.); (P.C.F.S.); (T.G.); (P.B.); (E.C.); (A.B.)
| | - Emmanuel Cruz
- Walther Straub Institute of Pharmacology and Toxicology, LMU Munich, 80539 Munich, Germany; (K.R.); (P.C.F.S.); (T.G.); (P.B.); (E.C.); (A.B.)
| | - Andreas Breit
- Walther Straub Institute of Pharmacology and Toxicology, LMU Munich, 80539 Munich, Germany; (K.R.); (P.C.F.S.); (T.G.); (P.B.); (E.C.); (A.B.)
| | - Peter S. Reinach
- Ophthalmology Department, Wenzhou Medical University, Wenzhou 325015, China;
| | - Thomas Gudermann
- Walther Straub Institute of Pharmacology and Toxicology, LMU Munich, 80539 Munich, Germany; (K.R.); (P.C.F.S.); (T.G.); (P.B.); (E.C.); (A.B.)
- German Center for Lung Research, 81377 Munich, Germany
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12
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Hall LG, Thyfault JP, Johnson JD. Exercise and inactivity as modifiers of β cell function and type 2 diabetes risk. J Appl Physiol (1985) 2023; 134:823-839. [PMID: 36759159 PMCID: PMC10042613 DOI: 10.1152/japplphysiol.00472.2022] [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: 08/15/2022] [Revised: 01/31/2023] [Accepted: 01/31/2023] [Indexed: 02/11/2023] Open
Abstract
Exercise and regular physical activity are beneficial for the prevention and management of metabolic diseases such as obesity and type 2 diabetes, whereas exercise cessation, defined as deconditioning from regular exercise or physical activity that has lasted for a period of months to years, can lead to metabolic derangements that drive disease. Adaptations to the insulin-secreting pancreatic β-cells are an important benefit of exercise, whereas less is known about how exercise cessation affects these cells. Our aim is to review the impact that exercise and exercise cessation have on β-cell function, with a focus on the evidence from studies examining glucose-stimulated insulin secretion (GSIS) using gold-standard techniques. Potential mechanisms by which the β-cell adapts to exercise, including exerkine and incretin signaling, autonomic nervous system signaling, and changes in insulin clearance, will also be explored. We will highlight areas for future research.
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Affiliation(s)
- Liam G Hall
- Department of Cellular and Physiological Sciences, Life Sciences Institute, The University of British Columbia, Vancouver, British Columbia, Canada
| | - John P Thyfault
- Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, Kansas, United States
- Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas, United States
- KU Diabetes Institute, University of Kansas Medical Center, Kansas City, Kansas, United States
| | - James D Johnson
- Department of Cellular and Physiological Sciences, Life Sciences Institute, The University of British Columbia, Vancouver, British Columbia, Canada
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13
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Accili D, Du W, Kitamoto T, Kuo T, McKimpson W, Miyachi Y, Mukhanova M, Son J, Wang L, Watanabe H. Reflections on the state of diabetes research and prospects for treatment. Diabetol Int 2023; 14:21-31. [PMID: 36636157 PMCID: PMC9829952 DOI: 10.1007/s13340-022-00600-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 08/02/2022] [Indexed: 01/16/2023]
Abstract
Research on the etiology and treatment of diabetes has made substantial progress. As a result, several new classes of anti-diabetic drugs have been introduced in clinical practice. Nonetheless, the number of patients achieving glycemic control targets has not increased for the past 20 years. Two areas of unmet medical need are the restoration of insulin sensitivity and the reversal of pancreatic beta cell failure. In this review, we integrate research advances in transcriptional regulation of insulin action and pathophysiology of beta cell dedifferentiation with their potential impact on prospects of a durable "cure" for patients suffering from type 2 diabetes.
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Affiliation(s)
- Domenico Accili
- Department of Medicine and Berrie Diabetes Center, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY 10032 USA
| | - Wen Du
- Department of Medicine and Berrie Diabetes Center, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY 10032 USA
| | - Takumi Kitamoto
- Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine, Chiba, Chiba 260-8670 Japan
| | - Taiyi Kuo
- Department of Neurobiology, Physiology, and Behavior, University of California at Davis, Davis, CA 95616 USA
| | - Wendy McKimpson
- Department of Medicine and Berrie Diabetes Center, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY 10032 USA
| | - Yasutaka Miyachi
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka Japan
| | - Maria Mukhanova
- Department of Medicine and Berrie Diabetes Center, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY 10032 USA
| | - Jinsook Son
- Department of Medicine and Berrie Diabetes Center, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY 10032 USA
| | - Liheng Wang
- Department of Medicine and Berrie Diabetes Center, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY 10032 USA
| | - Hitoshi Watanabe
- Department of Medicine and Berrie Diabetes Center, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY 10032 USA
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14
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Liu X, Wang K, Hou S, Jiang Q, Ma C, Zhao Q, Kong L, Chen J, Wang Z, Zhang H, Yuan T, Li Y, Huan Y, Shen Z, Hu Z, Huang Z, Cui B, Li P. Insulin induces insulin receptor degradation in the liver through EphB4. Nat Metab 2022; 4:1202-1213. [PMID: 36131205 DOI: 10.1038/s42255-022-00634-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 08/08/2022] [Indexed: 11/09/2022]
Abstract
Insulin signaling is essential for glucose metabolism, and insulin decreases insulin receptor (InsR) levels in a dose-dependent and time-dependent manner. However, the regulatory mechanisms of InsR reduction upon insulin stimulation remain poorly understood. Here, we show that Eph receptor B4 (EphB4), a tyrosine kinase receptor that modulates cell adhesion and migration, can bind directly to InsR, and this interaction is markedly enhanced by insulin. Due to the adaptor protein 2 (Ap2) complex binding motif in EphB4, the interaction of EphB4 and InsR facilitates clathrin-mediated InsR endocytosis and degradation in lysosomes. Hepatic overexpression of EphB4 decreases InsR and increases hepatic and systemic insulin resistance in chow-fed mice, whereas genetic or pharmacological inhibition of EphB4 improve insulin resistance and glucose intolerance in obese mice. These observations elucidate a role for EphB4 in insulin signaling, suggesting that EphB4 might represent a therapeutic target for the treatment of insulin resistance and type 2 diabetes.
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Affiliation(s)
- Xingfeng Liu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing, China
- CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Beijing, China
| | - Kai Wang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing, China
- CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Beijing, China
| | - Shaocong Hou
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing, China
- CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Beijing, China
| | - Qian Jiang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing, China
- CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Beijing, China
| | - Chunxiao Ma
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing, China
- CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Beijing, China
| | - Qijin Zhao
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing, China
- CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Beijing, China
| | - Lijuan Kong
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing, China
- CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Beijing, China
| | - Jingwen Chen
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing, China
- CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Beijing, China
| | - Zhenhe Wang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Huabing Zhang
- Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing, China
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Beijing, China
| | - Tao Yuan
- Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing, China
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Beijing, China
| | - Yuxiu Li
- Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing, China
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Beijing, China
| | - Yi Huan
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing, China
- CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Beijing, China
| | - Zhufang Shen
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing, China
- CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Beijing, China
| | - Zhuowei Hu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- The National Clinical Research Center for Metabolic Diseases, Department of Metabolism and Endocrinology, the Second Xiangya Hospital, Central Sothern University, Changsha, China
| | - Zhifeng Huang
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Bing Cui
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Pingping Li
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
- Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing, China.
- CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Beijing, China.
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15
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De Meyts P. [The insulin receptor discovery is 50 years old - A review of achieved progress]. Biol Aujourdhui 2022; 216:7-28. [PMID: 35876517 DOI: 10.1051/jbio/2022007] [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: 04/23/2022] [Indexed: 06/15/2023]
Abstract
The isolation of insulin from the pancreas and its purification to a degree permitting its safe administration to type 1 diabetic patients were accomplished 100 years ago at the University of Toronto by Banting, Best, Collip and McLeod and constitute undeniably one of the major medical therapeutic revolutions, recognized by the attribution of the 1923 Nobel Prize in Physiology or Medicine to Banting and McLeod. The clinical spin off was immediate as well as the internationalization of insulin's commercial production. The outcomes regarding basic research were much slower, in particular regarding the molecular mechanisms of insulin action on its target cells. It took almost a half-century before the determination of the tri-dimensional structure of insulin in 1969 and the characterization of its cell receptor in 1970-1971. The demonstration that the insulin receptor is in fact an enzyme named tyrosine kinase came in the years 1982-1985, and the crystal structure of the intracellular kinase domain 10 years later. The crystal structure of the first intracellular kinase substrate (IRS-1) in 1991 paved the way for the elucidation of the intracellular signalling pathways but it took 15 more years to obtain the complete crystal structure of the extracellular receptor domain (without insulin) in 2006. Since then, the determination of the structure of the whole insulin-receptor complex in both the inactive and activated states has made considerable progress, not least due to recent improvement in the resolution power of cryo-electron microscopy. I will here review the steps in the development of the concept of hormone receptor, and of our knowledge of the structure and molecular mechanism of activation of the insulin receptor.
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Affiliation(s)
- Pierre De Meyts
- de Duve Institute, Department of Cell Signalling, Avenue Hippocrate 74, B-1200 Bruxelles, Belgique - Novo Nordisk A/S, Department of Stem Cell Research, Novo Nordisk Park 1, DK-2760 Maaloev, Danemark
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16
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Jensen VFH, Mølck AM, Nowak J, Wohlfarth M, Nüsken E, Demozay D, Nüsken KD, Bøgh IB. Placental nutrient transporters adapt during persistent maternal hypoglycaemia in rats. PLoS One 2022; 17:e0265988. [PMID: 35344549 PMCID: PMC8959168 DOI: 10.1371/journal.pone.0265988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 03/14/2022] [Indexed: 12/03/2022] Open
Abstract
Maternal malnutrition is associated with decreased nutrient transfer to the foetus, which may lead to foetal growth restriction, predisposing children to a variety of diseases. However, regulation of placental nutrient transfer during decreased nutrient availability is not fully understood. In the present study, the aim was to investigate changes in levels of placental nutrient transporters accompanying maternal hypoglycaemia following different durations and stages of gestation in rats. Maternal hypoglycaemia was induced by insulin-infusion throughout gestation until gestation day (GD)20 or until end of organogenesis (GD17), with sacrifice on GD17 or GD20. Protein levels of placental glucose transporters GLUT1 (45/55 kDa isotypes) and GLUT3, amino acid transporters SNAT1 and SNAT2, and insulin receptor (InsR) were assessed. On GD17, GLUT1-45, GLUT3, and SNAT1 levels were increased and InsR levels decreased versus controls. On GD20, following hypoglycaemia throughout gestation, GLUT3 levels were increased, GLUT1-55 showed the same trend. After cessation of hypoglycaemia at end of organogenesis, GLUT1-55, GLUT3, and InsR levels were increased versus controls, whereas SNAT1 levels were decreased. The increases in levels of placental nutrient transporters seen during maternal hypoglycaemia and hyperinsulinemia likely reflect an adaptive response to optimise foetal nutrient supply and development during limited availability of glucose.
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Affiliation(s)
- Vivi F. H. Jensen
- Department of Safety Sciences, Imaging & Data Management, Novo Nordisk A/S, Maaloev, Denmark
- * E-mail:
| | - Anne-Marie Mølck
- Department of Safety Sciences, Imaging & Data Management, Novo Nordisk A/S, Maaloev, Denmark
| | - Jette Nowak
- Department of Safety Sciences, Imaging & Data Management, Novo Nordisk A/S, Maaloev, Denmark
| | - Maria Wohlfarth
- Department of Pediatrics, Medical Faculty, University of Cologne, Cologne, Germany
| | - Eva Nüsken
- Department of Pediatrics, Medical Faculty, University of Cologne, Cologne, Germany
| | - Damien Demozay
- Department of Diabetes Pharmacology 1, Novo Nordisk A/S, Maaloev, Denmark
| | - Kai-Dietrich Nüsken
- Department of Pediatrics, Medical Faculty, University of Cologne, Cologne, Germany
| | - Ingrid B. Bøgh
- Department of Safety Sciences, Imaging & Data Management, Novo Nordisk A/S, Maaloev, Denmark
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17
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Moore J, Bartholomae EM, Ward K, Hooshmand S, Kressler J. Three minutes of moderate-intensity stair walking improves glucose and insulin but not insulin sensitivity or total antioxidant capacity. Nutr Metab Cardiovasc Dis 2022; 32:479-486. [PMID: 34896000 DOI: 10.1016/j.numecd.2021.10.016] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 10/14/2021] [Accepted: 10/19/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND AND AIMS This study examined the effect of moderate intensity stair stepping exercise on the glycemic response, and antioxidant capacity (TAC) during an oral glucose tolerance test (OGTT). METHODS AND RESULTS Thirty participants (women = 12) completed 4 OGTTs during rest or stair walking bouts of 1, 3, and 10 min in a randomized order. Blood was collected at baseline and 30 min during the OGTTs and analyzed for glucose, insulin, TAC, and lactate. Glucose concentrations were decreased following the 10 min (-22.69 (-34.66 to -10.72) mg/dL, p < 0.002) and 3 min (-15.37 (-25.05 to -5.69) mg/dL, p < 0.004) bouts but not the 1 min bout (-6.18 (-19.54 to 7.18) mg/dL, p = 0.352). Insulin concentrations were decreased following the 10 min (-6.11 (-8.86 to -3.36 μIU/dL), p < 0.001) and 3 min (-2.589 (-4.54 to -0.63) μIU/dL, p < 0.012) bouts but not the 1 min bout (-0.37 (-1.87 to 1.13) μIU/dL, p = 0.616). Insulin sensitivity index values showed a significant increase in the 10-min trial (1.81 (0.03-3.58), p < 0.048), but not during the 3 min (0.65 (-0.66 to 1.96) p = 0.317) or 1 min trial (0.13 (-1.58 to 1.84) p = 0.878). There was no omnibus effect for trial in TAC (p = 0.132, η2 = 0.07). There was no interaction between trial and time for blood lactate (p = 0.621, η2 = 0.02). CONCLUSION This study provides evidence bouts as short as 3 min decrease postprandial blood glucose and insulin levels but longer bouts are needed to affect insulin sensitivity.
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Affiliation(s)
- Jeff Moore
- School of Exercise and Nutritional Sciences, San Diego State University, San Diego, CA, 92182, USA; The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, 1124 West Carson Street, Torrance, CA, 90502, USA.
| | - Eric M Bartholomae
- School of Exercise and Nutritional Sciences, San Diego State University, San Diego, CA, 92182, USA; College of Health Solutions, Arizona State University, Phoenix, AZ, 85004, USA
| | - Kathryn Ward
- School of Exercise and Nutritional Sciences, San Diego State University, San Diego, CA, 92182, USA
| | - Shirin Hooshmand
- School of Exercise and Nutritional Sciences, San Diego State University, San Diego, CA, 92182, USA
| | - Jochen Kressler
- School of Exercise and Nutritional Sciences, San Diego State University, San Diego, CA, 92182, USA
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18
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Pérez-García A, Torrecilla-Parra M, Fernández-de Frutos M, Martín-Martín Y, Pardo-Marqués V, Ramírez CM. Posttranscriptional Regulation of Insulin Resistance: Implications for Metabolic Diseases. Biomolecules 2022; 12:biom12020208. [PMID: 35204710 PMCID: PMC8961590 DOI: 10.3390/biom12020208] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 01/14/2022] [Accepted: 01/17/2022] [Indexed: 12/14/2022] Open
Abstract
Insulin resistance defines an impairment in the biologic response to insulin action in target tissues, primarily the liver, muscle, adipose tissue, and brain. Insulin resistance affects physiology in many ways, causing hyperglycemia, hypertension, dyslipidemia, visceral adiposity, hyperinsulinemia, elevated inflammatory markers, and endothelial dysfunction, and its persistence leads to the development metabolic disease, including diabetes, obesity, cardiovascular disease, or nonalcoholic fatty liver disease (NAFLD), as well as neurological disorders such as Alzheimer’s disease. In addition to classical transcriptional factors, posttranscriptional control of gene expression exerted by microRNAs and RNA-binding proteins constitutes a new level of regulation with important implications in metabolic homeostasis. In this review, we describe miRNAs and RBPs that control key genes involved in the insulin signaling pathway and related regulatory networks, and their impact on human metabolic diseases at the molecular level, as well as their potential use for diagnosis and future therapeutics.
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19
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Hongdusit A, Liechty ET, Fox JM. Analysis of Three Architectures for Controlling PTP1B with Light. ACS Synth Biol 2022; 11:61-68. [PMID: 34898189 DOI: 10.1021/acssynbio.1c00398] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Photosensory domains are powerful tools for placing proteins under optical control, but their integration into light-sensitive chimeras is often challenging. Many designs require structural iterations, and direct comparisons of alternative approaches are rare. This study uses protein tyrosine phosphatase 1B (PTP1B), an influential regulatory enzyme, to compare three architectures for controlling PTPs with light: a protein fusion, an insertion chimera, and a split construct. All three designs permitted optical control of PTP1B activity in vitro (i.e., kinetic assays of purified enzyme) and in mammalian cells; photoresponses measured under both conditions, while different in magnitude, were linearly correlated. The fusion- and insertion-based architectures exhibited the highest dynamic range and maintained native localization patterns in mammalian cells. A single insertion architecture enabled optical control of both PTP1B and TCPTP, but not SHP2, where the analogous chimera was active but not photoswitchable. Findings suggest that PTPs are highly tolerant of domain insertions and support the use of in vitro screens to evaluate different optogenetic designs.
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Affiliation(s)
- Akarawin Hongdusit
- Department of Chemical and Biological Engineering, University of Colorado Boulder, 3415 Colorado Avenue, Boulder, Colorado 80303, United States
| | - Evan T. Liechty
- Department of Chemical and Biological Engineering, University of Colorado Boulder, 3415 Colorado Avenue, Boulder, Colorado 80303, United States
| | - Jerome M. Fox
- Department of Chemical and Biological Engineering, University of Colorado Boulder, 3415 Colorado Avenue, Boulder, Colorado 80303, United States
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20
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Mirzadeh Z, Faber CL, Schwartz MW. Central Nervous System Control of Glucose Homeostasis: A Therapeutic Target for Type 2 Diabetes? Annu Rev Pharmacol Toxicol 2022; 62:55-84. [PMID: 34990204 PMCID: PMC8900291 DOI: 10.1146/annurev-pharmtox-052220-010446] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Historically, pancreatic islet beta cells have been viewed as principal regulators of glycemia, with type 2 diabetes (T2D) resulting when insulin secretion fails to compensate for peripheral tissue insulin resistance. However, glycemia is also regulated by insulin-independent mechanisms that are dysregulated in T2D. Based on evidence supporting its role both in adaptive coupling of insulin secretion to changes in insulin sensitivity and in the regulation of insulin-independent glucose disposal, the central nervous system (CNS) has emerged as a fundamental player in glucose homeostasis. Here, we review and expand upon an integrative model wherein the CNS, together with the islet, establishes and maintains the defended level of glycemia. We discuss the implications of this model for understanding both normal glucose homeostasis and T2D pathogenesis and highlight centrally targeted therapeutic approaches with the potential to restore normoglycemia to patients with T2D.
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Affiliation(s)
- Zaman Mirzadeh
- Ivy Brain Tumor Center, Department of Neurosurgery, Barrow Neurological Institute, Phoenix, Arizona 85013, USA;
| | - Chelsea L Faber
- Ivy Brain Tumor Center, Department of Neurosurgery, Barrow Neurological Institute, Phoenix, Arizona 85013, USA;
- UW Medicine Diabetes Institute, Department of Medicine, University of Washington, Seattle, Washington 98109, USA;
| | - Michael W Schwartz
- UW Medicine Diabetes Institute, Department of Medicine, University of Washington, Seattle, Washington 98109, USA;
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21
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Janssen JAMJL. Hyperinsulinemia and Its Pivotal Role in Aging, Obesity, Type 2 Diabetes, Cardiovascular Disease and Cancer. Int J Mol Sci 2021; 22:ijms22157797. [PMID: 34360563 PMCID: PMC8345990 DOI: 10.3390/ijms22157797] [Citation(s) in RCA: 131] [Impact Index Per Article: 32.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 07/11/2021] [Accepted: 07/13/2021] [Indexed: 01/10/2023] Open
Abstract
For many years, the dogma has been that insulin resistance precedes the development of hyperinsulinemia. However, recent data suggest a reverse order and place hyperinsulinemia mechanistically upstream of insulin resistance. Genetic background, consumption of the “modern” Western diet and over-nutrition may increase insulin secretion, decrease insulin pulses and/or reduce hepatic insulin clearance, thereby causing hyperinsulinemia. Hyperinsulinemia disturbs the balance of the insulin–GH–IGF axis and shifts the insulin : GH ratio towards insulin and away from GH. This insulin–GH shift promotes energy storage and lipid synthesis and hinders lipid breakdown, resulting in obesity due to higher fat accumulation and lower energy expenditure. Hyperinsulinemia is an important etiological factor in the development of metabolic syndrome, type 2 diabetes, cardiovascular disease, cancer and premature mortality. It has been further hypothesized that nutritionally driven insulin exposure controls the rate of mammalian aging. Interventions that normalize/reduce plasma insulin concentrations might play a key role in the prevention and treatment of age-related decline, obesity, type 2 diabetes, cardiovascular disease and cancer. Caloric restriction, increasing hepatic insulin clearance and maximizing insulin sensitivity are at present the three main strategies available for managing hyperinsulinemia. This may slow down age-related physiological decline and prevent age-related diseases. Drugs that reduce insulin (hyper) secretion, normalize pulsatile insulin secretion and/or increase hepatic insulin clearance may also have the potential to prevent or delay the progression of hyperinsulinemia-mediated diseases. Future research should focus on new strategies to minimize hyperinsulinemia at an early stage, aiming at successfully preventing and treating hyperinsulinemia-mediated diseases.
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Affiliation(s)
- Joseph A M J L Janssen
- Department of internal Medicine, Division of Endocrinology, Erasmus Medical Center, 40, 3015 GD Rotterdam, The Netherlands
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22
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White MF, Kahn CR. Insulin action at a molecular level - 100 years of progress. Mol Metab 2021; 52:101304. [PMID: 34274528 PMCID: PMC8551477 DOI: 10.1016/j.molmet.2021.101304] [Citation(s) in RCA: 113] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 07/07/2021] [Accepted: 07/13/2021] [Indexed: 12/15/2022] Open
Abstract
The discovery of insulin 100 years ago and its application to the treatment of human disease in the years since have marked a major turning point in the history of medicine. The availability of purified insulin allowed for the establishment of its physiological role in the regulation of blood glucose and ketones, the determination of its amino acid sequence, and the solving of its structure. Over the last 50 years, the function of insulin has been applied into the discovery of the insulin receptor and its signaling cascade to reveal the role of impaired insulin signaling-or resistance-in the progression of type 2 diabetes. It has also become clear that insulin signaling can impact not only classical insulin-sensitive tissues, but all tissues of the body, and that in many of these tissues the insulin signaling cascade regulates unexpected physiological functions. Despite these remarkable advances, much remains to be learned about both insulin signaling and how to use this molecular knowledge to advance the treatment of type 2 diabetes and other insulin-resistant states.
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Affiliation(s)
- Morris F White
- Boston Children's Hospital and Harvard Medical School, Boston, MA, 02215, USA.
| | - C Ronald Kahn
- Joslin Diabetes Center, Harvard Medical School, Boston, MA, 02215, USA.
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23
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Li Y, Wang Y, Yao Y, Lyu J, Qiao Q, Mao J, Xu Z, Ye M. Rapid Enzyme-Mediated Biotinylation for Cell Surface Proteome Profiling. Anal Chem 2021; 93:4542-4551. [PMID: 33660993 DOI: 10.1021/acs.analchem.0c04970] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Cell surface is the primary site for sensing extracellular stimuli. The knowledge of the transient changes on the surfaceome upon a perturbation is very important as the initial changed proteins could be driving molecules for some phenotype. In this study, we report a fast cell surface labeling strategy based on peroxidase-mediated oxidative tyrosine coupling strategy, enabling efficient and selective cell surface labeling within seconds. With a labeling time of 1 min, 2684 proteins, including 1370 (51%) cell surface-annotated proteins (cell surface/plasma membrane/extracellular), 732 transmembrane proteins, and 81 cluster of differentiation antigens, were identified from HeLa cells. By comparison with the negative control experiment using quantitative proteomics, 500 (68%) out of the 731 significantly enriched proteins (p-value < 0.05, ≥2-fold) in positive experimental samples were cell surface-annotated proteins. Finally, this technology was applied to track the dynamic changes of the surfaceome upon insulin stimulation at two time points (5 min and 2 h) in HepG2 cells. Thirty-two proteins, including INSR, CTNNB1, TFRC, IGF2R, and SORT1, were found to be significantly regulated (p-value < 0.01, ≥1.5-fold) after insulin exposure by different mechanisms. We envision that this technique could be a powerful tool to analyze the transient changes of the surfaceome with a good time resolution and to delineate the temporal and spatial regulation of cellular signaling.
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Affiliation(s)
- Yanan Li
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences (CAS), Dalian 116023, China
| | - Yan Wang
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences (CAS), Dalian 116023, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yating Yao
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences (CAS), Dalian 116023, China
| | - Jiawen Lyu
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences (CAS), Dalian 116023, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Qinglong Qiao
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences (CAS), Dalian 116023, China
| | - Jiawei Mao
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences (CAS), Dalian 116023, China
| | - Zhaochao Xu
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences (CAS), Dalian 116023, China
| | - Mingliang Ye
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences (CAS), Dalian 116023, China
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24
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Rossi A, Eid M, Dodgson J, Davies G, Musial B, Wabitsch M, Church C, Hornigold D. In vitro characterization of the effects of chronic insulin stimulation in mouse 3T3-L1 and human SGBS adipocytes. Adipocyte 2020; 9:415-426. [PMID: 32718202 PMCID: PMC7469436 DOI: 10.1080/21623945.2020.1798613] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Hyperinsulinemia is the hallmark of the development of insulin resistance and precedes the diagnosis of type 2 diabetes. Here we evaluated the effects of prolonged exposure (≥4 days) to high insulin doses (150 nM) in vitro in two adipose cell types, mouse 3T3-L1 and human SGBS. Chronic insulin treatment significantly decreased lipid droplet size, insulin signalling and insulin-stimulated glucose uptake. 3T3-L1 displayed an increased basal glucose internalization following chronic insulin treatment, which was associated with increased GLUT1 expression. In addition, both cells showed increased basal lipolysis. In conclusion, we report the effects of prolonged hyperinsulinemia in 3T3-L1 and SGBS, highlighting similarities and discrepancies between the cell types, to be considered when using these cells to model insulin-induced insulin resistance.
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Affiliation(s)
- A. Rossi
- Bioscience Metabolism, Research And Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - M. Eid
- Bioscience Metabolism, Research And Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - J. Dodgson
- Biologics Therapeutics, Antibody and Protein Engineering, R&D, AstraZeneca, Cambridge, UK
| | - G. Davies
- Bioscience Metabolism, Research And Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - B. Musial
- Bioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - M. Wabitsch
- Division of Paediatric Endocrinology and Diabetes, Department of Paediatrics and Adolescent Medicine, University Medical Center, Ulm, Germany
| | - C. Church
- Bioscience Metabolism, Research And Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - D.C. Hornigold
- Bioscience Metabolism, Research And Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
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25
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Berlanga-Acosta J, Guillén-Nieto G, Rodríguez-Rodríguez N, Bringas-Vega ML, García-del-Barco-Herrera D, Berlanga-Saez JO, García-Ojalvo A, Valdés-Sosa MJ, Valdés-Sosa PA. Insulin Resistance at the Crossroad of Alzheimer Disease Pathology: A Review. Front Endocrinol (Lausanne) 2020; 11:560375. [PMID: 33224105 PMCID: PMC7674493 DOI: 10.3389/fendo.2020.560375] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 08/13/2020] [Indexed: 12/16/2022] Open
Abstract
Insulin plays a major neuroprotective and trophic function for cerebral cell population, thus countering apoptosis, beta-amyloid toxicity, and oxidative stress; favoring neuronal survival; and enhancing memory and learning processes. Insulin resistance and impaired cerebral glucose metabolism are invariantly reported in Alzheimer's disease (AD) and other neurodegenerative processes. AD is a fatal neurodegenerative disorder in which progressive glucose hypometabolism parallels to cognitive impairment. Although AD may appear and progress in virtue of multifactorial nosogenic ingredients, multiple interperpetuative and interconnected vicious circles appear to drive disease pathophysiology. The disease is primarily a metabolic/energetic disorder in which amyloid accumulation may appear as a by-product of more proximal events, especially in the late-onset form. As a bridge between AD and type 2 diabetes, activation of c-Jun N-terminal kinase (JNK) pathway with the ensued serine phosphorylation of the insulin response substrate (IRS)-1/2 may be at the crossroads of insulin resistance and its subsequent dysmetabolic consequences. Central insulin axis bankruptcy translates in neuronal vulnerability and demise. As a link in the chain of pathogenic vicious circles, mitochondrial dysfunction, oxidative stress, and peripheral/central immune-inflammation are increasingly advocated as major pathology drivers. Pharmacological interventions addressed to preserve insulin axis physiology, mitochondrial biogenesis-integral functionality, and mitophagy of diseased organelles may attenuate the adjacent spillover of free radicals that further perpetuate mitochondrial damages and catalyze inflammation. Central and/or peripheral inflammation may account for a local flood of proinflammatory cytokines that along with astrogliosis amplify insulin resistance, mitochondrial dysfunction, and oxidative stress. All these elements are endogenous stressor, pro-senescent factors that contribute to JNK activation. Taken together, these evidences incite to identify novel multi-mechanistic approaches to succeed in ameliorating this pandemic affliction.
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Affiliation(s)
- Jorge Berlanga-Acosta
- The Clinical Hospital of Chengdu Brain Science Institute, MOE Key Lab for Neuroinformation, University of Electronic Science and Technology of China, Chengdu, China
- Tissue Repair and Cytoprotection Research Group, Center for Genetic Engineering and Biotechnology, Havana, Cuba
| | - Gerardo Guillén-Nieto
- The Clinical Hospital of Chengdu Brain Science Institute, MOE Key Lab for Neuroinformation, University of Electronic Science and Technology of China, Chengdu, China
- Tissue Repair and Cytoprotection Research Group, Center for Genetic Engineering and Biotechnology, Havana, Cuba
| | - Nadia Rodríguez-Rodríguez
- Tissue Repair and Cytoprotection Research Group, Center for Genetic Engineering and Biotechnology, Havana, Cuba
| | - Maria Luisa Bringas-Vega
- The Clinical Hospital of Chengdu Brain Science Institute, MOE Key Lab for Neuroinformation, University of Electronic Science and Technology of China, Chengdu, China
- Cuban Neurosciences Center, Cubanacan, Havana, Cuba
| | | | - Jorge O. Berlanga-Saez
- Applied Mathematics Department, Institute of Mathematics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Ariana García-Ojalvo
- Tissue Repair and Cytoprotection Research Group, Center for Genetic Engineering and Biotechnology, Havana, Cuba
| | - Mitchell Joseph Valdés-Sosa
- The Clinical Hospital of Chengdu Brain Science Institute, MOE Key Lab for Neuroinformation, University of Electronic Science and Technology of China, Chengdu, China
- Cuban Neurosciences Center, Cubanacan, Havana, Cuba
| | - Pedro A. Valdés-Sosa
- The Clinical Hospital of Chengdu Brain Science Institute, MOE Key Lab for Neuroinformation, University of Electronic Science and Technology of China, Chengdu, China
- Cuban Neurosciences Center, Cubanacan, Havana, Cuba
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26
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Chung W, Promrat K, Wands J. Clinical implications, diagnosis, and management of diabetes in patients with chronic liver diseases. World J Hepatol 2020; 12:533-557. [PMID: 33033564 PMCID: PMC7522556 DOI: 10.4254/wjh.v12.i9.533] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 08/03/2020] [Accepted: 08/15/2020] [Indexed: 02/06/2023] Open
Abstract
Diabetes mellitus (DM) negatively affects the development and progression of chronic liver diseases (CLD) of various etiologies. Concurrent DM and CLD are also associated with worse clinical outcomes with respect to mortality, the occurrence of hepatic decompensation, and the development of hepatocellular carcinoma (HCC). Unfortunately, early diagnosis and optimal treatment of DM can be challenging, due to the lack of established clinical guidelines as well as the medical complexity of this patient population. We conducted an exploratory review of relevant literature to provide an up-to-date review for internists and hepatologists caring for this patient population. We reviewed the epidemiological and pathophysiological associations between DM and CLD, the impact of insulin resistance on the progression and manifestations of CLD, the pathogenesis of hepatogenic diabetes, as well as the practical challenges in diagnosis and monitoring of DM in this patient population. We also reviewed the latest clinical evidence on various pharmacological antihyperglycemic therapies with an emphasis on liver disease-related clinical outcomes. Finally, we proposed an algorithm for managing DM in patients with CLD and discussed the clinical and research questions that remain to be addressed.
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Affiliation(s)
- Waihong Chung
- Division of Gastroenterology, Department of Medicine, Rhode Island Hospital, Providence, RI 02905, United States.
| | - Kittichai Promrat
- Division of Gastroenterology and Hepatology, Providence VA Medical Center, Providence, RI 02908, United States
| | - Jack Wands
- Liver Research Center, The Warren Alpert Medical School of Brown University, Providence, RI 02903, United States
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27
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Kisielewska K, Rytelewska E, Gudelska M, Kiezun M, Dobrzyn K, Bogus-Nowakowska K, Kaminska B, Smolinska N, Kaminski T. Relative abundance of chemerin mRNA transcript and protein in pituitaries of pigs during the estrous cycle and early pregnancy and associations with LH and FSH secretion during the estrous cycle. Anim Reprod Sci 2020; 219:106532. [PMID: 32828407 DOI: 10.1016/j.anireprosci.2020.106532] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 06/18/2020] [Accepted: 06/19/2020] [Indexed: 01/15/2023]
Abstract
Adipokines such as chemerin affect metabolic status and reproductive function in many species. The hypothesis in the present study was that there were chemerin mRNA transcript and protein in the pituitary of pigs and that relative abundances fluctuate during the estrous cycle and early pregnancy. Chemerin is thought to modulate luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion during the estrous cycle. Changes in the relative abundance of chemerin mRNA transcript and protein in anterior (AP) and posterior (PP) pituitaries of pigs were investigated, for the first time in the present study, during four phases of the estrous cycle and four periods of early pregnancy. Chemerin protein was localized in gonadotrophs, thyrotrophs and somatotrophs during the estrous cycle and early gestation. Chemerin treatments affected both basal, GnRH- and/or insulin-induced LH and FSH production, with there being variations with phase of the estrous cycle when tissues were collected. These findings indicate chemerin may be produced locally in the pituitary and may affect female reproductive function by controlling the release of LH and FSH from AP cells.
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Affiliation(s)
- Katarzyna Kisielewska
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 1A, 10-719 Olsztyn, Poland
| | - Edyta Rytelewska
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 1A, 10-719 Olsztyn, Poland
| | - Marlena Gudelska
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 1A, 10-719 Olsztyn, Poland
| | - Marta Kiezun
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 1A, 10-719 Olsztyn, Poland
| | - Kamil Dobrzyn
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 1A, 10-719 Olsztyn, Poland
| | - Krystyna Bogus-Nowakowska
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 1A, 10-719 Olsztyn, Poland
| | - Barbara Kaminska
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 1A, 10-719 Olsztyn, Poland
| | - Nina Smolinska
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 1A, 10-719 Olsztyn, Poland
| | - Tadeusz Kaminski
- Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 1A, 10-719 Olsztyn, Poland.
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28
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Puttabyatappa M, Sargis RM, Padmanabhan V. Developmental programming of insulin resistance: are androgens the culprits? J Endocrinol 2020; 245:R23-R48. [PMID: 32240982 PMCID: PMC7219571 DOI: 10.1530/joe-20-0044] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Accepted: 04/02/2020] [Indexed: 02/06/2023]
Abstract
Insulin resistance is a common feature of many metabolic disorders. The dramatic rise in the incidence of insulin resistance over the past decade has enhanced focus on its developmental origins. Since various developmental insults ranging from maternal disease, stress, over/undernutrition, and exposure to environmental chemicals can all program the development of insulin resistance, common mechanisms may be involved. This review discusses the possibility that increases in maternal androgens associated with these various insults are key mediators in programming insulin resistance. Additionally, the intermediaries through which androgens misprogram tissue insulin sensitivity, such as changes in inflammatory, oxidative, and lipotoxic states, epigenetic, gut microbiome and insulin, as well as data gaps to be filled are also discussed.
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Affiliation(s)
| | - Robert M. Sargis
- Department of Medicine, University of Illinois at Chicago, Chicago, IL
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Tosi F, Dal Molin F, Zamboni F, Saggiorato E, Salvagno GL, Fiers T, Kaufman JM, Bonora E, Moghetti P. Serum Androgens Are Independent Predictors of Insulin Clearance but Not of Insulin Secretion in Women With PCOS. J Clin Endocrinol Metab 2020; 105:5771404. [PMID: 32119099 DOI: 10.1210/clinem/dgaa095] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 02/26/2020] [Indexed: 12/15/2022]
Abstract
CONTEXT/OBJECTIVE In insulin-resistant individuals, hyperinsulinemia is a key compensatory mechanism, aimed at maintaining glucose homeostasis. Increased secretion and reduced clearance of insulin may both potentially contribute to this phenomenon. Insulin resistance and hyperinsulinemia are common findings in women with polycystic ovary syndrome (PCOS). While there is some information on insulin secretion, very few studies have investigated metabolic clearance rate of insulin (MCRI) in these women. Moreover, there is paucity of data on the relationships between MCRI and the pathophysiological characteristics of PCOS. The aim of the study was to explore these issues. PATIENTS One hundred ninety women with PCOS, diagnosed according to the Rotterdam criteria, with normal glucose tolerance. DESIGN Assessment of MCRI and clinical, hormonal, and metabolic characteristics of subjects. MCRI and insulin sensitivity were measured by the hyperinsulinemic euglycemic clamp. Serum androgens were assessed by liquid chromatography-mass spectrometry and equilibrium dialysis. A historical sample of healthy women was used to define the corresponding reference intervals. RESULTS MCRI was impaired in about two-thirds of women with PCOS. Subjects with low MCRI differed from those with normal MCRI for a number of anthropometric, metabolic, and endocrine features. In multivariate analysis, the degree of adiposity, estimates of insulin secretion, and serum androgen concentrations were independent predictors of MCRI. Conversely, age, adiposity, MCRI, and insulin sensitivity, but not serum androgens, were independent predictors of insulin secretion. CONCLUSIONS In women with PCOS, metabolic clearance of insulin is reduced, contributing to generating hyperinsulinemia. Serum androgens are independent predictors of this phenomenon.
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Affiliation(s)
- Flavia Tosi
- Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy
| | - Francesca Dal Molin
- Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy
| | - Federica Zamboni
- Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy
| | - Enrica Saggiorato
- Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy
| | - Gian Luca Salvagno
- Clinical Chemistry Laboratory, University of Verona, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy
| | - Tom Fiers
- Laboratory for Hormonology and Department of Endocrinology, Ghent University Hospital, Ghent, Belgium
| | - Jean-Marc Kaufman
- Laboratory for Hormonology and Department of Endocrinology, Ghent University Hospital, Ghent, Belgium
| | - Enzo Bonora
- Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy
| | - Paolo Moghetti
- Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy
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Pelletier RM, Layeghkhavidaki H, Vitale ML. Glucose, insulin, insulin receptor subunits α and β in normal and spontaneously diabetic and obese ob/ob and db/db infertile mouse testis and hypophysis. Reprod Biol Endocrinol 2020; 18:25. [PMID: 32183843 PMCID: PMC7079543 DOI: 10.1186/s12958-020-00583-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 03/04/2020] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND Type 2 diabetes touches young subjects of reproductive age in epidemic proportion. This study assesses glucose, total InsulinT, Insulin2 and insulin receptor subunits α and β in testis during mouse development then, in the spontaneously type 2 diabetes models associated with infertility db/db and ob/ob mice. IR-β and α were also assessed in spermatozoa (SPZ), anterior pituitary (AP) and serum. METHODS Serum and tissue glucose were measured with enzymatic colorimetric assays and InsulinT and Insulin2 by ELISAs in serum, interstitial tissue- (ITf) and seminiferous tubule (STf) fractions in14- > 60-day-old normal and db/db, ob/ob and wild type (WT) mice. IR subunits were assessed by immunoblotting in tissues and by immunoprecipitation followed by immunoblotting in serum. RESULTS Development: Glucose increased in serum, ITf and STf. InsulinT and Insulin2 dropped in serum; both were higher in STf than in ITf. In > 60-day-old mouse ITf, insulinT rose whereas Insulin2 decreased; InsulinT and Insulin2 rose concurrently in STf. Glucose and insulin were high in > 60-day-old ITf; in STf high insulin2 accompanied low glucose. One hundred ten kDa IR-β peaked in 28-day-old ITf and 14-day-old STf. One hundred thirty five kDa IR-α was high in ITf but decreased in STf. Glucose escalated in db/db and ob/ob sera. Glucose doubled in ITf while being halved in STf in db/db mice. Glucose significantly dropped in db/db and ob/ob mice spermatozoa. InsulinT and Insulin2 rose significantly in the serum, ITf and STf in db/db and ob/ob mice. One hundred ten kDa IR-β and 135 kDa IR-α decreased in db/db and ob/ob ITf. Only 110 kDa IR-β dropped in db/db and ob/ob STf and AP. One hundred ten kDa IR-β fell in db/db and ob/ob SPZ. One hundred ten kDa sIR-α rose in the db/db and ob/ob mouse sera. CONCLUSION Insulin regulates glucose in tubules not in the interstitium. The mouse interstitium contains InsulinT and Insulin2 whereas tubules contain Insulin2. Decreased 110 kDa IR-β and 135 kDa IR-α in the db/db and ob/ob interstitial tissue suggest a loss of active receptor sites that could alter the testicular cell insulin binding and response to the hormone. Decreased IR-β levels were insufficient to stimulate downstream effectors in AP and tubules. IR-α shedding increased in db/db and ob/ob mice.
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Affiliation(s)
- R-Marc Pelletier
- Department of Pathology and Cell Biology, Université de Montréal, Montréal, Québec, Canada.
- Department of Pathology and Cell Biology, Faculty of Medicine, Université de Montréal, Pavillon Roger Gaudry, Case Postale 6128, Succursale Centre-ville, Montréal, Québec, H3C 3J7, Canada.
| | - Hamed Layeghkhavidaki
- Department of Pathology and Cell Biology, Université de Montréal, Montréal, Québec, Canada
| | - María L Vitale
- Department of Pathology and Cell Biology, Université de Montréal, Montréal, Québec, Canada
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Rachdaoui N. Insulin: The Friend and the Foe in the Development of Type 2 Diabetes Mellitus. Int J Mol Sci 2020; 21:ijms21051770. [PMID: 32150819 PMCID: PMC7084909 DOI: 10.3390/ijms21051770] [Citation(s) in RCA: 119] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2020] [Revised: 02/29/2020] [Accepted: 03/02/2020] [Indexed: 12/14/2022] Open
Abstract
Insulin, a hormone produced by pancreatic β-cells, has a primary function of maintaining glucose homeostasis. Deficiencies in β-cell insulin secretion result in the development of type 1 and type 2 diabetes, metabolic disorders characterized by high levels of blood glucose. Type 2 diabetes mellitus (T2DM) is characterized by the presence of peripheral insulin resistance in tissues such as skeletal muscle, adipose tissue and liver and develops when β-cells fail to compensate for the peripheral insulin resistance. Insulin resistance triggers a rise in insulin demand and leads to β-cell compensation by increasing both β-cell mass and insulin secretion and leads to the development of hyperinsulinemia. In a vicious cycle, hyperinsulinemia exacerbates the metabolic dysregulations that lead to β-cell failure and the development of T2DM. Insulin and IGF-1 signaling pathways play critical roles in maintaining the differentiated phenotype of β-cells. The autocrine actions of secreted insulin on β-cells is still controversial; work by us and others has shown positive and negative actions by insulin on β-cells. We discuss findings that support the concept of an autocrine action of secreted insulin on β-cells. The hypothesis of whether, during the development of T2DM, secreted insulin initially acts as a friend and contributes to β-cell compensation and then, at a later stage, becomes a foe and contributes to β-cell decompensation will be discussed.
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Affiliation(s)
- Nadia Rachdaoui
- Department of Animal Sciences, Room 108, Foran Hall, Rutgers, the State University of New Jersey, 59 Dudley Rd, New Brunswick, NJ 08901, USA
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Karatug Kacar A. Indomethacin decreases insulin secretion by reducing KCa3.1 as a biomarker of pancreatic tumor and causes apoptotic cell death. J Biochem Mol Toxicol 2020; 34:e22488. [PMID: 32128977 DOI: 10.1002/jbt.22488] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 01/14/2020] [Accepted: 02/21/2020] [Indexed: 01/05/2023]
Abstract
Insulinomas originate from pancreatic β cells and it is the most widely known tumor. Indomethacin is a nonsteroidal anti-inflammatory drug, which is used for blocking the production of some natural substances that cause inflammation and decrease pain. In this study, I aimed to investigate the effects of indomethacin on rat insulinoma INS-1 cells. The relationship between cell death and insulin metabolism was determined with the administration of indomethacin. The cell viability by WST-1; the apoptosis and necrosis levels by ELISA kits; malondialdehyde levels by spectrophotometer; and beclin, intracellular insulin, insulin secretion, KCa3.1, insulin receptor (IR), glucose transporter type 2 (GLUT2), activating transcription factor 2 (ATF2), Elk1, c-Jun, Akt and phosphorylated ATF2, Elk1, c-Jun, Akt, intracellular betacellulin and betacellulin secretion levels by Western blot analysis investigated. The Ins1, Ins2, IR, GLUT2, ATF2, Elk1, c-Jun, Akt, and Betacellulin gene expression levels were determined by the real-time quantitative reverse transcription-polymerase chain reaction method. Apoptotic cell death was observed with the administration of indomethacin. The insulin secretion and Ins1, Ins2 gene expression levels decreased. The insulin receptor and GLUT2 levels increased, while KCa3.1 (KCNN4) levels decreased with the administration of indomethacin to insulinoma INS-1 cells. A decrease was observed in the total c-Jun, phosphorylated ATF2, Elk1, c-Jun, and Akt levels. Betacellulin secretion levels increased. In insulinoma INS-1 cells, apoptotic cell death occurred in the following manner: (i) indomethacin might decrease insulin secretion by reducing KCa3.1, (ii) might inactivate the JNK/ERK pathway with the inactivity of transcription factors.
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Affiliation(s)
- Ayse Karatug Kacar
- Department of Biology, Faculty of Science, Istanbul University, Istanbul, Turkey
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Payankaulam S, Raicu AM, Arnosti DN. Transcriptional Regulation of INSR, the Insulin Receptor Gene. Genes (Basel) 2019; 10:genes10120984. [PMID: 31795422 PMCID: PMC6947883 DOI: 10.3390/genes10120984] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 11/19/2019] [Accepted: 11/23/2019] [Indexed: 01/19/2023] Open
Abstract
The insulin receptor gene encodes an evolutionarily conserved signaling protein with a wide spectrum of functions in metazoan development. The insulin signaling pathway plays key roles in processes such as metabolic regulation, growth control, and neuronal function. Misregulation of the pathway features in diabetes, cancer, and neurodegenerative diseases, making it an important target for clinical interventions. While much attention has been focused on differential pathway activation through ligand availability, sensitization of overall signaling may also be mediated by differential expression of the insulin receptor itself. Although first characterized as a “housekeeping” gene with stable expression, comparative studies have shown that expression levels of the human INSR mRNA differ by tissue and in response to environmental signals. Our recent analysis of the transcriptional controls affecting expression of the Drosophila insulin receptor gene indicates that a remarkable amount of DNA is dedicated to encoding sophisticated feedback and feed forward signals. The human INSR gene is likely to contain a similar level of transcriptional complexity; here, we summarize over three decades of molecular biology and genetic research that points to a still incompletely understood regulatory control system. Further elucidation of transcriptional controls of INSR will provide the basis for understanding human genetic variation that underlies population-level physiological differences and disease.
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Affiliation(s)
- Sandhya Payankaulam
- Department of Biochemistry and Molecular Biology, Michigan State University, 603 Wilson Rd. 413 Biochemistry, East Lansing, MI 48824, USA;
| | - Ana-Maria Raicu
- Cell and Molecular Biology Program, Michigan State University, 603 Wilson Rd. 413 Biochemistry, East Lansing, MI 48824, USA;
| | - David N. Arnosti
- Department of Biochemistry and Molecular Biology, Michigan State University, 603 Wilson Rd. 413 Biochemistry, East Lansing, MI 48824, USA;
- Cell and Molecular Biology Program, Michigan State University, 603 Wilson Rd. 413 Biochemistry, East Lansing, MI 48824, USA;
- Correspondence: ; Tel.: +1-(517)-432-5504
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Hurcombe JA, Lay AC, Ni L, Barrington AF, Woodgett JR, Quaggin SE, Welsh GI, Coward RJ. Podocyte GSK3α is important for autophagy and its loss detrimental for glomerular function. FASEB Bioadv 2019; 1:498-510. [PMID: 31825015 PMCID: PMC6902909 DOI: 10.1096/fba.2019-00011] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Podocytes are key cells in maintaining the integrity of the glomerular filtration barrier and preventing albuminuria. Glycogen synthase kinase 3 (GSK3) is a multi-functional serine/threonine kinase existing as two distinct but related isoforms (α and β). In the podocyte it has previously been reported that inhibition of the β isoform is beneficial in attenuating a variety of glomerular disease models but loss of both isoforms is catastrophic. However, it is not known what the role of GSK3α is in these cells. We now show that GSK3α is present and dynamically modulated in podocytes. When GSK3α is transgenically knocked down specifically in the podocytes of mice it causes mild but significant albuminuria by 6-weeks of life. Its loss also does not protect in models of diabetic or Adriamycin-induced nephropathy. In vitro deletion of podocyte GSK3α causes cell death and impaired autophagic flux suggesting it is important for this key cellular process. Collectively this work shows that GSK3α is important for podocyte health and that augmenting its function may be beneficial in treating glomerular disease.
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Affiliation(s)
| | - A C Lay
- Bristol Renal, University of Bristol
| | - L Ni
- Bristol Renal, University of Bristol
| | | | - J R Woodgett
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System & University of Toronto, Canada
| | - S E Quaggin
- Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois, US
| | - G I Welsh
- Bristol Renal, University of Bristol
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McKimpson WM, Accili D. A fluorescent reporter assay of differential gene expression response to insulin in hepatocytes. Am J Physiol Cell Physiol 2019; 317:C143-C151. [PMID: 31091147 PMCID: PMC6689749 DOI: 10.1152/ajpcell.00504.2018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 04/22/2019] [Accepted: 05/07/2019] [Indexed: 01/06/2023]
Abstract
Insulin regulates multiple hepatic metabolic pathways in a seemingly heterogeneous manner. To understand this heterogeneity, we hypothesized that different subpopulations of hepatocytes have different sensitivity to insulin. To test this hypothesis, we developed a fluorescent reporter in which the insulin-responsive fatty acid synthase (FAS) promoter drove expression of a time-dependent fluorescent protein ("timer") and characterized timer expression in flow-sorted cell populations. In Hepa1c1c7 and AML12 hepatocytes, we found that different cell populations express distinct timer fluorescence following insulin treatment, consistent with cellular heterogeneity in the response to insulin. RNA measurements indicated an enrichment of forkhead box O transcription factors in cells with a greater response to insulin. Moreover, we found evidence of increased Akt activation. These data are consistent with a heterogeneous cellular response to insulin and raise the possibility that these different subpopulations underlie the peculiar pathophysiology of hepatic insulin resistance.
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Affiliation(s)
- Wendy M McKimpson
- Department of Medicine (Endocrinology), Columbia University , New York, New York
| | - Domenico Accili
- Department of Medicine (Endocrinology), Columbia University , New York, New York
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Chase KA, Feiner B, Ramaker MJ, Hu E, Rosen C, Sharma RP. Examining the effects of the histone methyltransferase inhibitor BIX-01294 on histone modifications and gene expression in both a clinical population and mouse models. PLoS One 2019; 14:e0216463. [PMID: 31185023 PMCID: PMC6559633 DOI: 10.1371/journal.pone.0216463] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Accepted: 04/08/2019] [Indexed: 01/03/2023] Open
Abstract
Schizophrenia has been consistently characterized by abnormal patterns of gene down-regulation, increased restrictive chromatin assemblies, and reduced transcriptional activity. Histone methyltransferase (HMT) mRNA and H3K9me2 levels are elevated in postmortem brain and peripheral blood cells of persons with schizophrenia. Moreover, this epigenomic state likely contributes to the disease, as HMT levels correlate with clinical symptomatology. This manuscript sought to establish the potential therapeutic value of the HMT inhibitor BIX-01294 (BIX). Human peripheral mononuclear cells (PBMC) from 24 individuals with schizophrenia and 24 healthy individuals were cultured in the presence of BIX (5uM or 10uM). Mice were given once daily intraperitoneal injections of BIX (0.5 or 1mg/kg) for one week. Cultured cells, mouse cortex, or striatum was harvested, RNA extracted and RT-PCR conducted for several schizophrenia candidate genes: IL-6, Gad1, Nanog, KLF4, Reln, and Bdnf9a. Total H3K9me2 levels were measured using western blot while H3K9me2 binding to selected genes of interest was conducted using chromatin immunoprecipitation (ChIP). Neuronal subtype-specific BDNF conditional knockdown was conducted using the cre/lox system of mutant animals. Treatment with BIX decreased H3K9me2 and increased selected mRNA levels in cultured PBMCs from both normal controls and participants with schizophrenia. In mice, peripheral administration of BIX decreased cortical H3K9me2 levels and increased schizophrenia candidate gene expression. In BDNF conditional knockdown animals, BIX administration was able to significantly rescue Bdnf9a mRNA levels in ChAT and D1 Bdnf conditional knockdown mice. The results presented in this manuscript demonstrate a potential for further research into the clinical effectiveness of histone modifying pharmacology in the treatment of schizophrenia.
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Affiliation(s)
- Kayla A. Chase
- Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, United States of America
- Jesse Brown Veterans Affairs Medical Center, Chicago, IL, United States of America
| | - Benjamin Feiner
- Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, United States of America
| | - Marcia J. Ramaker
- Department of Psychiatry, University of California, La Jolla, CA, United States of America
| | - Edward Hu
- Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, United States of America
| | - Cherise Rosen
- Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, United States of America
| | - Rajiv P. Sharma
- Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, United States of America
- Jesse Brown Veterans Affairs Medical Center, Chicago, IL, United States of America
- * E-mail:
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Selig JI, Ouwens DM, Raschke S, Thoresen GH, Fischer JW, Lichtenberg A, Akhyari P, Barth M. Impact of hyperinsulinemia and hyperglycemia on valvular interstitial cells - A link between aortic heart valve degeneration and type 2 diabetes. Biochim Biophys Acta Mol Basis Dis 2019; 1865:2526-2537. [PMID: 31152868 DOI: 10.1016/j.bbadis.2019.05.019] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2019] [Revised: 04/27/2019] [Accepted: 05/28/2019] [Indexed: 12/11/2022]
Abstract
Type 2 diabetes is a known risk factor for cardiovascular diseases and is associated with an increased risk to develop aortic heart valve degeneration. Nevertheless, molecular mechanisms leading to the pathogenesis of valve degeneration in the context of diabetes are still not clear. Hence, we hypothesized that classical key factors of type 2 diabetes, hyperinsulinemia and hyperglycemia, may affect signaling, metabolism and degenerative processes of valvular interstitial cells (VIC), the main cell type of heart valves. Therefore, VIC were derived from sheep and were treated with hyperinsulinemia, hyperglycemia and the combination of both. The presence of insulin receptors was shown and insulin led to increased proliferation of the cells, whereas hyperglycemia alone showed no effect. Disturbed insulin response was shown by impaired insulin signaling, i.e. by decreased phosphorylation of Akt/GSK-3α/β pathway. Analysis of glucose transporter expression revealed absence of glucose transporter 4 with glucose transporter 1 being the predominantly expressed transporter. Glucose uptake was not impaired by disturbed insulin response, but was increased by hyperinsulinemia and was decreased by hyperglycemia. Analyses of glycolysis and mitochondrial respiration revealed that VIC react with increased activity to hyperinsulinemia or hyperglycemia, but not to the combination of both. VIC do not show morphological changes and do not acquire an osteogenic phenotype by hyperinsulinemia or hyperglycemia. However, the treatment leads to increased collagen type 1 and decreased α-smooth muscle actin expression. This work implicates a possible role of diabetes in early phases of the degeneration of aortic heart valves.
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Affiliation(s)
- Jessica I Selig
- Department of Cardiovascular Surgery, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany.
| | - D Margriet Ouwens
- Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Düsseldorf, Germany; German Center for Diabetes Research, München-Neuherberg, Germany; Department of Endocrinology, Ghent University Hospital, Ghent, Belgium.
| | - Silja Raschke
- Department of Cardiovascular Surgery, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany
| | - G Hege Thoresen
- Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway; Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
| | - Jens W Fischer
- Department of Pharmacology and Clinical Pharmacology, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany.
| | - Artur Lichtenberg
- Department of Cardiovascular Surgery, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany.
| | - Payam Akhyari
- Department of Cardiovascular Surgery, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany.
| | - Mareike Barth
- Department of Cardiovascular Surgery, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany.
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Evaluating the Impact of Different Hypercaloric Diets on Weight Gain, Insulin Resistance, Glucose Intolerance, and its Comorbidities in Rats. Nutrients 2019; 11:nu11061197. [PMID: 31141900 PMCID: PMC6627141 DOI: 10.3390/nu11061197] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 05/08/2019] [Accepted: 05/22/2019] [Indexed: 12/12/2022] Open
Abstract
Animal experimentation has a long history in the study of metabolic syndrome-related disorders. However, no consensus exists on the best models to study these syndromes. Knowing that different diets can precipitate different metabolic disease phenotypes, herein we characterized several hypercaloric rat models of obesity and type 2 diabetes, comparing each with a genetic model, with the aim of identifying the most appropriate model of metabolic disease. The effect of hypercaloric diets (high fat (HF), high sucrose (HSu), high fat plus high sucrose (HFHSu) and high fat plus streptozotocin (HF+STZ) during different exposure times (HF 3 weeks, HF 19 weeks, HSu 4 weeks, HSu 16 weeks, HFHSu 25 weeks, HF3 weeks + STZ) were compared with the Zucker fatty rat. Each model was evaluated for weight gain, fat mass, fasting plasma glucose, insulin and C-peptide, insulin sensitivity, glucose tolerance, lipid profile and liver lipid deposition, blood pressure, and autonomic nervous system function. All animal models presented with insulin resistance and dyslipidemia except the HF+STZ and HSu 4 weeks, which argues against the use of these models as metabolic syndrome models. Of the remaining animal models, a higher weight gain was exhibited by the Zucker fatty rat and wild type rats submitted to a HF diet for 19 weeks. We conclude that the latter model presents a phenotype most consistent with that observed in humans with metabolic disease, exhibiting the majority of the phenotypic features and comorbidities associated with type 2 diabetes in humans.
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Benzler M, Benzler J, Stoehr S, Hempp C, Rizwan MZ, Heyward P, Tups A. "Insulin-like" effects of palmitate compromise insulin signalling in hypothalamic neurons. J Comp Physiol B 2019; 189:413-424. [PMID: 31123821 DOI: 10.1007/s00360-019-01220-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 04/16/2019] [Accepted: 05/05/2019] [Indexed: 12/22/2022]
Abstract
Saturated fatty acids are implicated in the development of metabolic diseases, including obesity and type 2 diabetes. There is evidence, however, that polyunsaturated fatty acids can counteract the pathogenic effects of saturated fatty acids. To gain insight into the early molecular mechanisms by which fatty acids influence hypothalamic inflammation and insulin signalling, we performed time-course experiments in a hypothalamic cell line, using different durations of treatment with the saturated fatty acid palmitate, and the omega-3 polyunsaturated fatty acid, docosahexaenoic acid (DHA). Western blot analysis revealed that palmitate elevated the protein levels of phospho(p)AKT in a time-dependent manner. This effect is involved in the pathogenicity of palmitate, as temporary inhibition of the PI3K/AKT pathway by selective PI3K inhibitors prevented the palmitate-induced attenuation of insulin signalling. Similar to palmitate, DHA also increased levels of pAKT, but to a weaker extent. Co-administration of DHA with palmitate decreased pAKT close to the basal level after 8 h, and prevented the palmitate-induced reduction of insulin signalling after 12 h. The monounsaturated fatty acid oleate had a similar effect on the palmitate-induced attenuation of insulin signalling, the polyunsaturated fatty acid linoleate had no effect. Measurement of the inflammatory markers pJNK and pNFκB-p65 revealed tonic elevation of both markers in the presence of palmitate alone. DHA alone transiently induced elevation of pJNK, returning to basal levels by 12 h treatment. Co-administration of DHA with palmitate prevented palmitate-induced inflammation after 12 h, but not at earlier timepoints.
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Affiliation(s)
- Martin Benzler
- Department of Animal Physiology, Faculty of Biology, Philipps University Marburg, Marburg, Germany
| | - Jonas Benzler
- Department of Animal Physiology, Faculty of Biology, Philipps University Marburg, Marburg, Germany
| | - Sigrid Stoehr
- Department of Animal Physiology, Faculty of Biology, Philipps University Marburg, Marburg, Germany
| | - Cindy Hempp
- Department of Animal Physiology, Faculty of Biology, Philipps University Marburg, Marburg, Germany
| | - Mohammed Z Rizwan
- Centre for Neuroendocrinology and Brain Health Research Centre, Department of Physiology, School of Medical Sciences, University of Otago, Dunedin, 9054, New Zealand
| | - Phil Heyward
- Brain Health Research Centre, Department of Physiology, School of Medical Sciences, University of Otago, Dunedin, 9054, New Zealand
| | - Alexander Tups
- Department of Animal Physiology, Faculty of Biology, Philipps University Marburg, Marburg, Germany. .,Centre for Neuroendocrinology and Brain Health Research Centre, Department of Physiology, School of Medical Sciences, University of Otago, Dunedin, 9054, New Zealand.
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Park JH, Mun S, Choi DP, Lee JY, Kim HC. Association between Changes in Anthropometric Indices and in Fasting Insulin Levels among Healthy Korean Adolescents: The JS High School Study. Diabetes Metab J 2019; 43:183-191. [PMID: 30688051 PMCID: PMC6470103 DOI: 10.4093/dmj.2018.0034] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Accepted: 11/08/2018] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND This study investigated the association between changes in anthropometric indices and fasting insulin levels among healthy adolescents and whether the association differed by baseline obesity status. METHODS This analysis was based on data collected for the JS High School study; 884 healthy adolescents aged 15 to 16 years followed up for 24 to 30 months were included. Changes in anthropometric indices and fasting insulin levels were computed as the difference between baseline and follow-up values. Multivariate linear regression models were used to determine the association between changes in anthropometric indices and fasting insulin levels. Based on body mass index (BMI)-for-age and waist circumference (WC)-for-age percentiles, participants were classified as normal weight (<85th percentile), overweight (85th percentile to <95th percentile), or obese (≥95th percentile). RESULTS Changes in BMI, WC, waist-hip ratio, and waist-height ratio were significantly associated with changes in fasting insulin levels in both sexes (P<0.05). In analyses stratified by baseline obesity status, the association between change in BMI and change in fasting insulin was significantly stronger in overweight (males: standardized β=1.136; females: standardized β=1.262) and obese (males: standardized β=1.817; females: standardized β=2.290) participants than in those with normal weight (males: standardized β=0.957; females: standardized β=0.976) at baseline. Results were similar for changes in WC. CONCLUSION Changes in anthropometric indices were positively associated with fasting insulin level increases. Moreover, those who were overweight or obese at baseline had a higher absolute increase in fasting insulin levels per one standard deviation unit increase in anthropometric indices than adolescents with normal weight.
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Affiliation(s)
- Ji Hye Park
- Department of Public Health, Yonsei University Graduate School, Seoul, Korea
- Cardiovascular and Metabolic Diseases Etiology Research Center, Yonsei University College of Medicine, Seoul, Korea
| | - Seyeon Mun
- Department of Public Health, Yonsei University Graduate School, Seoul, Korea
| | - Dong Phil Choi
- National Academy of Agricultural Science, Rural Development Administration, Wanju, Korea
| | - Joo Young Lee
- Department of Medical and Pharmaceutical Affairs, Mapo-gu Health Center, Seoul, Korea
| | - Hyeon Chang Kim
- Cardiovascular and Metabolic Diseases Etiology Research Center, Yonsei University College of Medicine, Seoul, Korea
- Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, Korea.
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Pappachan JM, Fernandez CJ, Chacko EC. Diabesity and antidiabetic drugs. Mol Aspects Med 2019; 66:3-12. [PMID: 30391234 DOI: 10.1016/j.mam.2018.10.004] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Revised: 10/10/2018] [Accepted: 10/30/2018] [Indexed: 02/06/2023]
Abstract
The prevalence of "diabesity" - diabetes related to obesity - has increased tremendously over the past few decades because of the global obesity epidemic. Although bariatric surgery is the best treatment option for patients with diabesity, a majority of patients are managed only with antidiabetic drugs for various reasons. Diabetes control with antidiabetic agents may affect diabesity outcomes positively or negatively because of their effects on body weight and other metabolic parameters. For this reason, rational use of anti-diabetic medications is imperative to optimise long-term management of diabesity. Understanding the molecular mechanisms of antidiabetic drugs and/or drug combinations on diabesity outcomes are therefore important not only for the basic scientists but also for clinicians. This review explores the molecular signalling cascades of antidiabetic medications in the management of diabesity.
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Affiliation(s)
- Joseph M Pappachan
- Department of Endocrinology, Diabetes& Metabolism, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, LE21 9QS, United Kingdom.
| | - Cornelius J Fernandez
- Department of Endocrinology, Diabetes& Metabolism, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, LE21 9QS, United Kingdom
| | - Elias C Chacko
- Department of Endocrinology & Diabetes, Jersey Hospital, Jersey, JE1 4SE, United Kingdom
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Singh S, Sharma R, Kumari M, Tiwari S. Insulin receptors in the kidneys in health and disease. World J Nephrol 2019; 8:11-22. [PMID: 30705868 PMCID: PMC6354081 DOI: 10.5527/wjn.v8.i1.11] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 11/15/2018] [Accepted: 12/10/2018] [Indexed: 02/06/2023] Open
Abstract
Insulin is an important hormone that affects various metabolic processes, including kidney function. Impairment in insulin’s action leads to insulin resistance in the target tissue. Besides defects in post-receptor insulin signaling, impairment at the receptor level could significantly affect insulin sensitivity of the target tissue. The kidney is a known target of insulin; however, whether the kidney develops “insulin resistance” is debatable. Regulation of the insulin receptor (IR) expression and its function is very well studied in major metabolic tissues like liver, skeletal muscles, and adipose tissue. The physiological relevance of IRs in the kidney has recently begun to be clarified. The credit goes to studies that showed a wide distribution of IR throughout the nephron segments and their reduced expression in the insulin resistance state. Moreover, altered renal and systemic metabolism observed in mice with targeted deletion of the IR from various epithelial cells of the kidney has strengthened this proposition. In this review, we recapitulate the crucial findings from literature that have expanded our knowledge regarding the significance of the renal IR in normal- and insulin-resistance states.
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Affiliation(s)
- Sarojini Singh
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Rajni Sharma
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Manju Kumari
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Swasti Tiwari
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
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Kumari M, Sharma R, Pandey G, Ecelbarger CM, Mishra P, Tiwari S. Deletion of insulin receptor in the proximal tubule and fasting augment albumin excretion. J Cell Biochem 2019; 120:10688-10696. [PMID: 30644120 DOI: 10.1002/jcb.28359] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2018] [Accepted: 11/29/2018] [Indexed: 12/29/2022]
Abstract
The contribution of proximal tubules (PT) to albumin uptake is now well recognized, however, its regulation is understudied area. There are reports suggesting that insulin resistance is associated with the development of albuminuria in nondiabetic individuals. We have previously reported reduced insulin receptor (IR) expression in renal-tubular-epithelial cells, including PT in various models of insulin resistance. However, the effect of a physiological fall in insulin levels and the role for IR in PT in tubular albumin uptake is not clear. To address these gaps in our understanding, we estimated urine excretion and renal uptake of albumin in fasted and fed C57Bl/6 mice injected with fluorescein isothiocyanate (FITC)-albumin (5 µg/mL/kg body weight, intraperitoneal, n = 6 per group). In addition, we compared spot urine analysis from 33 clinically healthy humans after overnight fasting (when insulin levels are lower than in the fed state) and then at 2 hours after 75 g oral glucose challenge (postprandial). Fasted mice had attenuated renal uptake of FITC-albumin and higher excretion in urine, relative to fed mice ( P = 0.04). Moreover, a significant drop in urine albumin-to-creatinine ratio (ACR) and urine albumin concentration (UAC) was observed in the postprandial state in these subjects ( P = 0.001 and P = 0.017, for ACR and UAC, respectively). The drop was negatively associated with postprandial blood glucose levels (ρ = -0.36, P = 0.03 for ΔUAC and ρ = -0.34, P = 0.05 for ΔACR). To test the role of IR in PT, we analyzed 24-hour urine albumin excretion in male mice with targeted deletion of IR from PT (insulin receptor knockout [IRKO]) and their wild-type (WT) littermates ( n = 7 per group). IRKO mice had significantly higher 24-hour urine albumin excretion relative to WT. Moreover, kidneys from KO mice revealed reduced expression of megalin and cubulin proteins in the PT relative to the WT. We also demonstrated insulin (100 nM) induced albumin internalization in human proximal tubule cells (hPT) and this effect of insulin was attenuated in hydroxy-2-naphthalenylmethylphosphonic acid (100 µM), a tyrosine kinase inhibitor, pretreated hPT. Our findings revealed albumin excretion was attenuated by glucose administration to fasting individuals implying a regulatory role for insulin in PT albumin reabsorption. Thus albuminuria associated with insulin resistance/diabetes may relate not only to glomerular dysfunction but also to impairment in insulin-mediated reabsorption.
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Affiliation(s)
- Manju Kumari
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Rajni Sharma
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Gaurav Pandey
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Carolyn M Ecelbarger
- Department of Medicine, Division of Endocrinology and Metabolism, Georgetown University, Washington, District of Columbia
| | - Prabhaker Mishra
- Department of Biostatistics and Health Informatics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Swasti Tiwari
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
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Al-Attar AM, Alsalmi FA. Effect of Olea europaea leaves extract on streptozotocin induced diabetes in male albino rats. Saudi J Biol Sci 2019; 26:118-128. [PMID: 30622415 PMCID: PMC6318816 DOI: 10.1016/j.sjbs.2017.03.002] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2017] [Revised: 02/24/2017] [Accepted: 03/05/2017] [Indexed: 12/16/2022] Open
Abstract
The present study was aimed to evaluate the effect of olive (Olea europaea) leaves extract on streptozotocin (STZ)-induced diabetic male rats. The experimental rats were divided into six groups. Rats of the first group were served as normal controls. Rats of the second group were diabetic control. The third and fourth groups were diabetic rats, treated with olive leaves extract at low and high doses respectively. The fifth and sixth groups were non diabetic rats, subjected to olive leaves extract at the same doses given to the third and fourth groups respectively. The minimum of body weigh gain was noted in diabetic rats of the second group. the levels of serum glucose, insulin, total protein, albumin, triglycerides, cholesterol, low density lipoprotein cholesterol (LDL-C), very low density lipoprotein cholesterol (VLDL-C), creatine kinase (CK), lactate dehydrogenase (LDH) and malondialdehyde (MDA) were significantly increased, while the levels of high density lipoprotein cholesterol (HDL-C), superoxide dismutase, (SOD) glutathione (GSH) and catalase (CAT) were statistically decreased in diabetic rats of the second group. The levels of liver insulin receptor substrate 1 (IRS1) and insulin receptor A (IRA) were significantly declined in diabetic rats of the second group. The diabetic pancreatic sections from diabetic rats of the second group showed several histopathological changes. Administration of low and high doses of olive leaves extract improved the observed physiological, molecular and histopathological alterations. Collectively, the obtained results confirmed that the protective effects of olive leaves extract are attributed to the antioxidant activities of olive leaves extract and its active constituents.
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Affiliation(s)
- Atef M. Al-Attar
- Department of Biological Sciences, Faculty of Sciences, King Abdulaziz University, P.O. Box 139109, Jeddah 21323, Saudi Arabia
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Tricò D, Natali A, Arslanian S, Mari A, Ferrannini E. Identification, pathophysiology, and clinical implications of primary insulin hypersecretion in nondiabetic adults and adolescents. JCI Insight 2018; 3:124912. [PMID: 30568042 DOI: 10.1172/jci.insight.124912] [Citation(s) in RCA: 91] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Accepted: 11/06/2018] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Excessive insulin secretion may lead to glucose dysregulation. Our aim was to identify primary (independent of insulin resistance) insulin hypersecretion in subjects with normal glucose tolerance and its role in the progression of dysglycemia. METHODS In 1,168 adults, insulin secretion rate (ISR) and β cell function were estimated by C-peptide modeling during an oral glucose tolerance test (OGTT) and an i.v. glucose tolerance test. Whole-body insulin sensitivity was measured by a hyperinsulinemic-euglycemic clamp. After regressing ISR on insulin sensitivity, subjects in the upper tertile of the distribution of residuals were defined as primary hypersecretors. This approach was applied to a biethnic cohort of 182 obese adolescents, who received an OGTT, a hyperglycemic, and a euglycemic clamp. RESULTS Adult hypersecretors showed older age, more familial diabetes, sedentary lifestyle, increased fat mass, and worse lipid profile compared with the rest of the cohort, despite virtually identical BMI and insulin sensitivity. Insulin secretion was increased by 53% due to enhanced (+23%) β cell glucose sensitivity. Despite the resulting hyperinsulinemia, glucose tolerance was worse in hypersecretors among both adults and adolescents, coupled with higher indices of liver insulin resistance and increased availability of gluconeogenic substrates. At the 3-year follow-up, adult hypersecretors had increased incidence of impaired glucose tolerance/type 2 diabetes. CONCLUSION Primary insulin hypersecretion, independent of insulin resistance, is associated with a worse clinical and metabolic phenotype in adults and adolescents and predicts deterioration of glucose control over time. FUNDING The relationship between insulin sensitivity and cardiovascular disease (RISC) Study was partly supported by EU grant QLG1-CT-2001-01252.
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Affiliation(s)
- Domenico Tricò
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.,Institute of Life Sciences, Sant'Anna School of Advanced Studies, Pisa, Italy
| | - Andrea Natali
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Silva Arslanian
- Center for Pediatric Research in Obesity and Metabolism, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.,Division of Pediatric Endocrinology, Diabetes and Metabolism, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Andrea Mari
- Institute of Neuroscience, National Research Council, Padua, Italy
| | - Ele Ferrannini
- Institute of Clinical Physiology, National Research Council, Pisa, Italy
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Vella V, Milluzzo A, Scalisi NM, Vigneri P, Sciacca L. Insulin Receptor Isoforms in Cancer. Int J Mol Sci 2018; 19:ijms19113615. [PMID: 30453495 PMCID: PMC6274710 DOI: 10.3390/ijms19113615] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Revised: 11/05/2018] [Accepted: 11/13/2018] [Indexed: 12/17/2022] Open
Abstract
The insulin receptor (IR) mediates both metabolic and mitogenic effects especially when overexpressed or in clinical conditions with compensatory hyperinsulinemia, due to the metabolic pathway resistance, as obesity diabetes. In many cancers, IR is overexpressed preferentially as IR-A isoform, derived by alternative splicing of exon 11. The IR-A overexpression, and the increased IR-A:IR-B ratio, are mechanisms that promote the mitogenic response of cancer cells to insulin and IGF-2, which is produced locally by both epithelial and stromal cancer cells. In cancer IR-A, isoform predominance may occur for dysregulation at both mRNA transcription and post-transcription levels, including splicing factors, non-coding RNAs and protein degradation. The mechanisms that regulate IR isoform expression are complex and not fully understood. The IR isoform overexpression may play a role in cancer cell stemness, in tumor progression and in resistance to target therapies. From a clinical point of view, the IR-A overexpression in cancer may be a determinant factor for the resistance to IGF-1R target therapies for this issue. IR isoform expression in cancers may have the meaning of a predictive biomarker and co-targeting IGF-1R and IR-A may represent a new more efficacious treatment strategy.
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Affiliation(s)
- Veronica Vella
- Department of Clinical and Experimental Medicine, Endocrinology Section, University of Catania Medical School, Garibaldi-Nesima Hospital, via Palermo 636, 95122 Catania, Italy.
- School of Human and Social Science, University "Kore" of Enna, 94100 Enna, Italy.
| | - Agostino Milluzzo
- Department of Clinical and Experimental Medicine, Endocrinology Section, University of Catania Medical School, Garibaldi-Nesima Hospital, via Palermo 636, 95122 Catania, Italy.
| | - Nunzio Massimo Scalisi
- Department of Clinical and Experimental Medicine, Endocrinology Section, University of Catania Medical School, Garibaldi-Nesima Hospital, via Palermo 636, 95122 Catania, Italy.
| | - Paolo Vigneri
- Department of Clinical and Experimental Medicine, University of Catania Medical School, Center of Experimental Oncology and Hematology, A.O.U. Policlinico Vittorio Emanuele, via Santa Sofia, 78, 95123 Catania, Italy.
| | - Laura Sciacca
- Department of Clinical and Experimental Medicine, Endocrinology Section, University of Catania Medical School, Garibaldi-Nesima Hospital, via Palermo 636, 95122 Catania, Italy.
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Abstract
Taste buds are the dedicated sensory end organs of taste, comprising a complex and evolving profile of signaling elements. The sensation and ultimate perception of taste depends on the expression of a diverse array of receptors and channels that sense their respective tastes. Receptor regulation is a recognized and well-studied phenomenon in many systems, observed in opioid addiction, insulin resistance and caffeine tolerance. Results from human sensory studies suggest that receptor sensitivity or expression level may decrease after chronic exposure to respective tastants through diet. We review data supporting the theory that taste receptors may become downregulated with exposure to a specific tastant, along with presenting data from a small pilot study, showing the impact of long-term tastant exposure on taste receptor expression in mice. Mice treated with monosodium salt monohydrate (MSG), saccharin and NaCl (typically appetitive tastes) all displayed a significant decrease in mRNA expression for respective umami, sweet and salty receptors/sensory channels. Reduced sensitivity to appetitive tastes may promote overconsumption of foods high in such stimuli.
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48
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Silva TE, Ronsoni MF, Schiavon LL. Challenges in diagnosing and monitoring diabetes in patients with chronic liver diseases. Diabetes Metab Syndr 2018; 12:431-440. [PMID: 29279271 DOI: 10.1016/j.dsx.2017.12.013] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Accepted: 12/19/2017] [Indexed: 02/07/2023]
Abstract
The prevalence and mortality of diabetes mellitus and liver disease have risen in recent years. The liver plays an important role in glucose homeostasis, and various chronic liver diseases have a negative effect on glucose metabolism with the consequent emergence of diabetes. Some aspects related to chronic liver disease can affect diagnostic tools and the monitoring of diabetes and other glucose metabolism disorders, and clinicians must be aware of these limitations in their daily practice. In cirrhotic patients, fasting glucose may be normal in up until 23% of diabetes cases, and glycated hemoglobin provides falsely low results, especially in advanced cirrhosis. Similarly, the performance of alternative glucose monitoring tests, such as fructosamine, glycated albumin and 1,5-anhydroglucitol, also appears to be suboptimal in chronic liver disease. This review will examine the association between changes in glucose metabolism and various liver diseases as well as the particularities associated with the diagnosis and monitoring of diabetes in liver disease patients. Alternatives to routinely recommended tests will be discussed.
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Affiliation(s)
- Telma E Silva
- Division of Gastroenterology, Federal University of Santa Catarina, Campus Universitário Reitor João David Ferreira Lima, Trindade Florianópolis, SC, 88040-970, Brazil.
| | - Marcelo F Ronsoni
- Division of Endocrinology, Federal University of Santa Catarina, Campus Universitário Reitor João David Ferreira Lima, Trindade, Florianópolis, SC, 88040-970, Brazil
| | - Leonardo L Schiavon
- Division of Gastroenterology, Federal University of Santa Catarina, Campus Universitário Reitor João David Ferreira Lima, Trindade Florianópolis, SC, 88040-970, Brazil
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49
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Wu J, Tao WW, Chong DY, Lai SS, Wang C, Liu Q, Zhang TY, Xue B, Li CJ. Early growth response-1 negative feedback regulates skeletal muscle postprandial insulin sensitivity via activating Ptp1b transcription. FASEB J 2018. [PMID: 29543533 DOI: 10.1096/fj.201701340r] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Postprandial insulin desensitization plays a critical role in maintaining whole-body glucose homeostasis by avoiding the excessive absorption of blood glucose; however, the detailed mechanisms that underlie how the major player, skeletal muscle, desensitizes insulin action remain to be elucidated. Herein, we report that early growth response gene-1 ( Egr-1) is activated by insulin in skeletal muscle and provides feedback inhibition that regulates insulin sensitivity after a meal. The inhibition of the transcriptional activity of Egr-1 enhanced the phosphorylation of the insulin receptor (InsR) and Akt, thus increasing glucose uptake in L6 myotubes after insulin stimulation, whereas overexpression of Egr-1 decreased insulin sensitivity. Furthermore, deletion of Egr-1 in the skeletal muscle improved systemic insulin sensitivity and glucose tolerance, which resulted in lower blood glucose levels after refeeding. Mechanistic analysis demonstrated that EGR-1 inhibited InsR phosphorylation and glucose uptake in skeletal muscle by binding to the proximal promoter region of protein tyrosine phosphatase-1B (PTP1B) and directly activating transcription. PTP1B knockdown largely restored insulin sensitivity and enhanced glucose uptake, even under conditions of EGR-1 overexpression. Our results indicate that EGR-1/PTP1B signaling negatively regulates postprandial insulin sensitivity and suggest a potential therapeutic target for the prevention and treatment of excessive glucose absorption.-Wu, J., Tao, W.-W., Chong, D.-Y., Lai, S.-S., Wang, C., Liu, Q., Zhang, T.-Y., Xue, B., Li, C.-J. Early growth response-1 negative feedback regulates skeletal muscle postprandial insulin sensitivity via activating Ptp1b transcription.
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Affiliation(s)
- Jing Wu
- Medicine School of Nanjing University, Nanjing, China
| | - Wei-Wei Tao
- Model Animal Research Center, Nanjing University, Nanjing, China
| | - Dan-Yang Chong
- Model Animal Research Center, Nanjing University, Nanjing, China
| | - Shan-Shan Lai
- Model Animal Research Center, Nanjing University, Nanjing, China
| | - Chuang Wang
- Medicine School of Nanjing University, Nanjing, China
| | - Qi Liu
- Medicine School of Nanjing University, Nanjing, China
| | - Tong-Yu Zhang
- Model Animal Research Center, Nanjing University, Nanjing, China
| | - Bin Xue
- Medicine School of Nanjing University, Nanjing, China
| | - Chao-Jun Li
- Medicine School of Nanjing University, Nanjing, China.,Model Animal Research Center, Nanjing University, Nanjing, China
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50
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Colmegna P, Sánchez-Peña R, Gondhalekar R. Linear parameter-varying model to design control laws for an artificial pancreas. Biomed Signal Process Control 2018. [DOI: 10.1016/j.bspc.2017.09.021] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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