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Camille Bourgneuf - One of the best experts on this subject based on the ideXlab platform.
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The Goto-Kakizaki Rat is a spontaneous prototypical rodent model of polycystic ovary syndrome.
Nature communications, 2021Co-Authors: Camille Bourgneuf, Danielle Bailbé, Antonin Lamazière, Charlotte Dupont, Marthe Moldes, Dominique Farabos, Natacha Roblot, Camille Gauthier, Emmanuelle Mathieu D'argent, Joelle Cohen-tannoudjiAbstract:Polycystic ovary syndrome (PCOS) is characterized by an oligo-anovulation, hyperandrogenism and polycystic ovarian morphology combined with major metabolic disturbances. However, despite the high prevalence and the human and economic consequences of this syndrome, its etiology remains unknown. In this study, we show that female Goto-Kakizaki (GK) Rats, a type 2 diabetes mellitus model, encapsulate naturally all the reproductive and metabolic hallmarks of lean women with PCOS at puberty and in adulthood. The analysis of their gestation and of their fetuses demonstRates that this PCOS-like phenotype is developmentally programmed. GK Rats also develop features of ovarian hyperstimulation syndrome. Lastly, a comparison between GK Rats and a cohort of women with PCOS reveals a similar reproductive signature. Thus, this spontaneous rodent model of PCOS represents an original tool for the identification of the mechanisms involved in its pathogenesis and for the development of novel stRategies for its treatment.
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the Goto Kakizaki Rat is a spontaneous prototypical rodent model of polycystic ovary syndrome
Nature Communications, 2021Co-Authors: Camille Bourgneuf, Danielle Bailbé, Antonin Lamazière, Charlotte Dupont, Marthe Moldes, Dominique Farabos, Natacha RoblotAbstract:Polycystic ovary syndrome (PCOS) is characterized by an oligo-anovulation, hyperandrogenism and polycystic ovarian morphology combined with major metabolic disturbances. However, despite the high prevalence and the human and economic consequences of this syndrome, its etiology remains unknown. In this study, we show that female Goto-Kakizaki (GK) Rats, a type 2 diabetes mellitus model, encapsulate naturally all the reproductive and metabolic hallmarks of lean women with PCOS at puberty and in adulthood. The analysis of their gestation and of their fetuses demonstRates that this PCOS-like phenotype is developmentally programmed. GK Rats also develop features of ovarian hyperstimulation syndrome. Lastly, a comparison between GK Rats and a cohort of women with PCOS reveals a similar reproductive signature. Thus, this spontaneous rodent model of PCOS represents an original tool for the identification of the mechanisms involved in its pathogenesis and for the development of novel stRategies for its treatment. Although polycystic ovary syndrome is the most common cause of female infertility, its etiology remains poorly understood. Here, the authors report a Rat model that spontaneously exhibits the clinical heterogeneity of this syndrome and demonstRate that the phenotype is developmentally programmed.
Jefferson C. Frisbee - One of the best experts on this subject based on the ideXlab platform.
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Endothelium-dependent impairments to cerebral vascular reactivity with type 2 diabetes mellitus in the Goto-Kakizaki Rat
American journal of physiology. Regulatory integrative and comparative physiology, 2019Co-Authors: Brayden Halvorson, Shawn N. Whitehead, John J. Mcguire, Robert W. Wiseman, Jefferson C. FrisbeeAbstract:Type 2 diabetes mellitus (T2DM) is a prevalent pathology associated with elevated cerebrovascular disease risk. We determined wall mechanics and vascular reactivity in ex vivo middle cerebral arteries (MCA) from male Goto-Kakizaki Rats (GK; ~17 wk old) versus control Wistar Kyoto Rats (WKY) to test the hypothesis that the diabetic environment in GK, in the absence of obesity and other comorbidities, leads to endothelial dysfunction and impaired vascular tone regulation. Dilation of MCA following challenge with acetylcholine and hypoxia was blunted in MCA from GK versus WKY, due to lower nitric oxide bioavailability and altered arachidonic acid metabolism, whereas myogenic activation and constrictor responses to serotonin were unchanged. MCA wall distensibility and cross-sectional area were not different between GK and WKY, suggesting that wall mechanics were unchanged at this age, supported by the determination that MCA dilation to sodium nitroprusside was also intact. With the use of ex vivo aortic rings as a bioassay, altered vascular reactivity determined in MCA was paralleled by relaxation responses in artery segments from GK, whereas measurements of vasoactive metabolite production indicated a loss of nitric oxide and prostacyclin bioavailability and an increased thromboxane A2 production with both methacholine challenge and hypoxia. These results suggest that endothelium-dependent dilator reactivity of MCA in GK is impaired with T2DM, and that this impairment is associated with the genesis of a prooxidant/pro-inflammatory condition with diabetes mellitus. The restriction of vascular impairments to endothelial function only, at this age and development, provide insight into the severity of multimorbid conditions of which T2DM is only one constituent.
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endothelium dependent impairments to cerebral vascular reactivity with type 2 diabetes mellitus in the Goto Kakizaki Rat
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2019Co-Authors: Brayden Halvorson, Shawn N. Whitehead, John J. Mcguire, Robert W. Wiseman, Jefferson C. FrisbeeAbstract:Type 2 diabetes mellitus (T2DM) is a prevalent pathology associated with elevated cerebrovascular disease risk. We determined wall mechanics and vascular reactivity in ex vivo middle cerebral arter...
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Type 2 diabetes mellitus in the Goto-Kakizaki Rat impairs microvascular function and contributes to premature skeletal muscle fatigue
Journal of applied physiology (Bethesda Md. : 1985), 2018Co-Authors: Jefferson C. Frisbee, Matthew T. Lewis, Jonathan D. Kasper, Paul D. Chantler, Robert W. WisemanAbstract:The impact of type 2 diabetes mellitus on vascular structure/function remains an area lacking clarity. Using diabetic Goto-Kakizaki Rats before the development of other risk factors, we determined ...
Teruo Nishida - One of the best experts on this subject based on the ideXlab platform.
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Delayed Wound Closure and Phenotypic Changes in Corneal Epithelium of the Spontaneously Diabetic Goto-Kakizaki Rat
Investigative Ophthalmology & Visual Science, 2007Co-Authors: Makiko Wakuta, Naoyuki Morishige, Taiichiro Chikama, Keisuke Seki, Takashi Nagano, Teruo NishidaAbstract:PURPOSE. To characterize wound closure and phenotypic changes in the corneal epithelium of the Goto-Kakizaki (GK) Rat, a spontaneous model of type 2 diabetes. METHODS. Corneal wound healing was monitored by fluorescein staining after epithelial debridement. Tear secretion was measured with the Schirmer test, and corneal sensation was evaluated with an esthesiometer in 13- to 15-week-old GK and Wistar (control) Rats. The distributions of cytokeRatin 12 (K12), K14, and connexin43 in the corneal epithelium were examined by immunohistofluorescence analysis. The prolifeRation capacity of epithelial cells in the intact cornea and during wound healing was evaluated by immunostaining for Ki-67. RESULTS. Tear secretion, corneal sensation, and corneal epithelial wound closure Rate were all decreased in GK Rats compared with those in Wistar Rats. Whereas connexin43, K14, and Ki-67 were all restricted to the single layer of basal cells in the corneal epithelium of Wistar Rats, they were detected in the two layers of cells closest to the basement membrane in that of GK Rats. The frequency of Ki-67-positive cells in the intact corneal epithelium was greater in GK Rats than in Wistar Rats, and it was increased to a greater extent in the peripheral cornea of GK Rats than in that of Wistar Rats during wound healing. CONCLUSIONS. Spontaneously diabetic GK Rats manifest characteristics similar to those of diabetic keRatopathy in humans, including delayed wound closure, and they exhibit phenotypic changes in corneal epithelial cells.
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Delayed wound closure and phenotypic changes in corneal epithelium of the spontaneously diabetic Goto-Kakizaki Rat.
Investigative ophthalmology & visual science, 2007Co-Authors: Makiko Wakuta, Naoyuki Morishige, Taiichiro Chikama, Keisuke Seki, Takashi Nagano, Teruo NishidaAbstract:To characterize wound closure and phenotypic changes in the corneal epithelium of the Goto-Kakizaki (GK) Rat, a spontaneous model of type 2 diabetes. Corneal wound healing was monitored by fluorescein staining after epithelial debridement. Tear secretion was measured with the Schirmer test, and corneal sensation was evaluated with an esthesiometer in 13- to 15-week-old GK and Wistar (control) Rats. The distributions of cytokeRatin 12 (K12), K14, and connexin43 in the corneal epithelium were examined by immunohistofluorescence analysis. The prolifeRation capacity of epithelial cells in the intact cornea and during wound healing was evaluated by immunostaining for Ki-67. Tear secretion, corneal sensation, and corneal epithelial wound closure Rate were all decreased in GK Rats compared with those in Wistar Rats. Whereas connexin43, K14, and Ki-67 were all restricted to the single layer of basal cells in the corneal epithelium of Wistar Rats, they were detected in the two layers of cells closest to the basement membrane in that of GK Rats. The frequency of Ki-67-positive cells in the intact corneal epithelium was greater in GK Rats than in Wistar Rats, and it was increased to a greater extent in the peripheral cornea of GK Rats than in that of Wistar Rats during wound healing. Spontaneously diabetic GK Rats manifest characteristics similar to those of diabetic keRatopathy in humans, including delayed wound closure, and they exhibit phenotypic changes in corneal epithelial cells.
B Portha - One of the best experts on this subject based on the ideXlab platform.
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The novel oral drug Subetta exerts an antidiabetic effect in the diabetic Goto-Kakizaki Rat: comparison with rosiglitazone.
Journal of diabetes research, 2013Co-Authors: D. Bailbé, Erwann Philippe, Evgeniy A. Gorbunov, S. A. Tarasov, Oleg I. Epstein, B PorthaAbstract:The aim of the present study was to evaluate the potential antidiabetic effects of two-component drug Subetta and its components (release-active dilutions of antibodies to β -subunit insulin receptor (RAD of Abs to β -InsR) and to endothelial nitric oxide synthase (RAD of Abs to eNOS)) in Goto-Kakizaki (Paris colony) (GK/Par) diabetic Rats. Subetta was administered orally for 28 days once daily (5 mL/kg) and compared to its two components (2.5 mL/kg), Rosiglitazone (5 mg/kg), and vehicle (5 mL water/kg). At day 28, fasting plasma glucose levels were significantly decreased only in Subetta and Rosiglitazone groups as compared to vehicle (P < 0.01): 147 ± 4 mg/dL and 145 ± 4 mg/dL and 165 ± 4 mg/dL, respectively. The data of glucose tolerance test showed that Subetta and RAD of Abs to β -InsR (similar to Rosiglitazone) prevented significantly (P < 0.01) the age-related spontaneous deterioRation of glucose tolerance as seen in the control group. Subetta and RAD of Abs to β -InsR did not significantly modify the glucose-induced insulin secretion. Chronic administRation of Subetta and RAD of Abs to β -InsR improves glucose control, to an extent similar to that of Rosiglitazone. We hypothesize that Subetta and RAD of Abs to β -InsR mostly act via an insulin-sensitizing effect upon target tissues.
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The GK Rat: a prototype for the study of non-overweight type 2 diabetes.
Methods in molecular biology (Clifton N.J.), 2012Co-Authors: B Portha, M-h Giroix, C Tourrel-cuzin, Hervé Le-stunff, J MovassatAbstract:Type 2 diabetes mellitus (T2D) arises when the endocrine pancreas fails to secrete sufficient insulin to cope with the metabolic demand because of β-cell secretory dysfunction and/or decreased β-cell mass. Defining the nature of the pancreatic islet defects present in T2D has been difficult, in part because human islets are inaccessible for direct study. This review is aimed to illustRate to what extent the Goto Kakizaki Rat, one of the best characterized animal models of spontaneous T2D, has proved to be a valuable tool offering sufficient commonalities to study this aspect. A comprehensive compendium of the multiple functional GK abnormalities so far identified is proposed in this perspective, together with their time-course and interactions. A special focus is given toward the pathogenesis of defective β-cell number and function in the GK model. It is proposed that the development of T2D in the GK model results from the complex interaction of multiple events: (1) several susceptibility loci containing genes responsible for some diabetic traits; (2) gestational metabolic impairment inducing an epigenetic programming of the offspring pancreas and the major insulin target tissues; and (3) environmentally induced loss of β-cell differentiation due to chronic exposure to hyperglycemia/hyperlipidemia, inflammation, and oxidative stress.
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Early reduction of circulating homocysteine levels in Goto-Kakizaki Rat, a spontaneous nonobese model of type 2 diabetes.
Biochimica et biophysica acta, 2011Co-Authors: Christophe Noll, B Portha, G Lacraz, F Homo-delarche, D Bailbé, Jan A. Ehses, Josiane Coulaud, Jean-louis Paul, Nathalie JanelAbstract:Diabetes mellitus is associated with increased risk for cardiovascular disorders, which are major causes of mortality in this disease. Hyperhomocysteinemia, defined by high plasma homocysteine levels, is an independent risk factor for the development of cardiovascular diseases. Type 2 diabetic patients have higher circulating homocysteine levels than healthy subjects and these levels are even higher in plasma of obese than nonobese diabetic patients. Homocysteine metabolism that has been studied in 2 animal models of type 2 diabetes with obesity led to conflicting data. The aim of the present study was to analyze homocysteine metabolism in a spontaneous nonobese model of type 2 diabetes, the Goto-Kakizaki Rats at various successive and well characterized stages of the disease: during early postnatal normoglycemia, at the onset of hyperglycemia (around weaning), and during chronic mild hyperglycemia with progressive insulin resistance. Compared to age-matched Wistar controls, Goto-Kakizaki Rats showed lower plasma levels of homocysteine and a falling trend in its major byproduct antioxidant, glutathione, from the prediabetic stage onwards. Concomitantly, Goto-Kakizaki Rats exhibited increased liver activity of cystathionine beta synthase, which catalyzes the condensation of homocysteine with serine in the first step of the transsulfuRation pathway. These results emphasize a strong association between homocysteine metabolism and insulin via the first step of the hepatic transsulfuRation pathway in Goto-Kakizaki Rats.
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Islet Structure and Function in the GK Rat
Advances in experimental medicine and biology, 2010Co-Authors: B Portha, G Lacraz, F Homo-delarche, M-h Giroix, D Bailbé, C Tourrel-cuzin, Audrey Chavey, Florence Figeac, Magali Fradet, M-n GangnerauAbstract:Type 2 diabetes mellitus (T2D) arises when the endocrine pancreas fails to secrete sufficient insulin to cope with the metabolic demand because of β-cell secretory dysfunction and/or decreased β-cell mass. Defining the nature of the pancreatic islet defects present in T2D has been difficult, in part because human islets are inaccessible for direct study. This review is aimed to illustRate to what extent the Goto–Kakizaki Rat, one of the best characterized animal models of spontaneous T2D, has proved to be a valuable tool offering sufficient commonalities to study this aspect. A comprehensive compendium of the multiple functional GK islet abnormalities so far identified is proposed in this perspective. The pathogenesis of defective β-cell number and function in the GK model is also discussed. It is proposed that the development of T2D in the GK model results from the complex interaction of multiple events: (i) several susceptibility loci containing genes responsible for some diabetic traits (distinct loci encoding impairment of β-cell metabolism and insulin exocytosis, but no quantitative trait locus for decreased β-cell mass); (ii) gestational metabolic impairment inducing an epigenetic programming of the offspring pancreas (decreased β-cell neogenesis and prolifeRation) transmitted over geneRations; and (iii) loss of β-cell differentiation related to chronic exposure to hyperglycaemia/hyperlipidaemia, islet inflammation, islet oxidative stress, islet fibrosis and perturbed islet vasculature.
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The GK Rat beta-cell: a prototype for the diseased human beta-cell in type 2 diabetes?
Molecular and cellular endocrinology, 2008Co-Authors: B Portha, G Lacraz, M Kergoat, F Homo-delarche, M-h Giroix, D Bailbé, M-n Gangnerau, M Dolz, C Tourrel-cuzin, J MovassatAbstract:Increasing evidence indicates that decreased functional beta-cell mass is the hallmark of type 2 diabetes (T2D) mellitus. Nowadays, the debate focuses on the possible mechanisms responsible for abnormal islet microenvironment, decreased beta-cell number, impaired beta-cell function, and their multifactorial aetiologies. This review is aimed to illustRate to what extend the Goto-Kakizaki Rat, one of the best characterized animal models of spontaneous T2D, has proved be a valuable tool offering sufficient commonalities to study these aspects. We propose that the defective beta-cell mass and function in the GK model reflect the complex interactions of multiple pathogenic players: (i) several independent loci containing genes responsible for some diabetic traits (but not decreased beta-cell mass); (ii) gestational metabolic impairment inducing an epigenetic programming of the pancreas (decreased beta-cell neogenesis and/or prolifeRation) which is transmitted to the next geneRation; and (iii) loss of beta-cell differentiation due to chronic exposure to hyperglycemia/hyperlipidemia, inflammatory mediators, oxidative stress and to perturbed islet microarchitecture.
J Movassat - One of the best experts on this subject based on the ideXlab platform.
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Hypothesis and Theory: Circulating Alzheimer's-Related Biomarkers in Type 2 Diabetes. Insight From the Goto-Kakizaki Rat.
Frontiers in neurology, 2019Co-Authors: J Movassat, Etienne Delangre, Junjun Liu, Nathalie JanelAbstract:Epidemiological data suggest an increased risk of developing Alzheimer's disease (AD) in individuals with type 2 diabetes (T2D). AD is anatomically associated with an early progressive accumulation of Aβ leading to a gradual Tau hyperphosphorylation, which constitute the main characteristics of damaged brain in AD. Apart from these processes, mounting evidence suggests that specific features of diabetes, namely impaired glucose metabolism and insulin signaling in the brain, play a key role in AD. Moreover, several studies report a potential role of Aβ and Tau in peripheral tissues such as pancreatic β cells. Thus, it appears that several biological pathways associated with diabetes overlap with AD. The link between peripheral insulin resistance and brain insulin resistance with concomitant cognitive impairment may also potentially be mediated by a liver/pancreatic/brain axis, through the excessive trafficking of neurotoxic molecules across the blood-brain barrier. Insulin resistance incites inflammation and pro-inflammatory cytokine activation modulates the homocysteine cycle in T2D patients. Elevated plasma homocysteine level is a risk factor for AD pathology and is also closely associated with metabolic syndrome. We previously demonstRated a strong association between homocysteine metabolism and insulin via cystathionine beta synthase (CBS) activity, the enzyme implicated in the first step of the trans-sulfuRation pathway, in Goto-Kakizaki (GK) Rats, a spontaneous model of T2D, with close similarities with human T2D. CBS activity is also correlated with DYRK1A, a serine/threonine kinase regulating brain-derived neurotrophic factor (BDNF) levels, and Tau phosphorylation, which are implicated in a wide range of disease such as T2D and AD. We hypothesized that DYRK1A, BDNF, and Tau, could be among molecular factors linking T2D to AD. In this focused review, we briefly examine the main mechanisms linking AD to T2D and provide the first evidence that certain circulating AD biomarkers are found in diabetic GK Rats. We propose that the spontaneous model of T2D in GK Rat could be a suitable model to investigate molecular mechanisms linking T2D to AD.
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The GK Rat: a prototype for the study of non-overweight type 2 diabetes.
Methods in molecular biology (Clifton N.J.), 2012Co-Authors: B Portha, M-h Giroix, C Tourrel-cuzin, Hervé Le-stunff, J MovassatAbstract:Type 2 diabetes mellitus (T2D) arises when the endocrine pancreas fails to secrete sufficient insulin to cope with the metabolic demand because of β-cell secretory dysfunction and/or decreased β-cell mass. Defining the nature of the pancreatic islet defects present in T2D has been difficult, in part because human islets are inaccessible for direct study. This review is aimed to illustRate to what extent the Goto Kakizaki Rat, one of the best characterized animal models of spontaneous T2D, has proved to be a valuable tool offering sufficient commonalities to study this aspect. A comprehensive compendium of the multiple functional GK abnormalities so far identified is proposed in this perspective, together with their time-course and interactions. A special focus is given toward the pathogenesis of defective β-cell number and function in the GK model. It is proposed that the development of T2D in the GK model results from the complex interaction of multiple events: (1) several susceptibility loci containing genes responsible for some diabetic traits; (2) gestational metabolic impairment inducing an epigenetic programming of the offspring pancreas and the major insulin target tissues; and (3) environmentally induced loss of β-cell differentiation due to chronic exposure to hyperglycemia/hyperlipidemia, inflammation, and oxidative stress.
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The GK Rat beta-cell: a prototype for the diseased human beta-cell in type 2 diabetes?
Molecular and cellular endocrinology, 2008Co-Authors: B Portha, G Lacraz, M Kergoat, F Homo-delarche, M-h Giroix, D Bailbé, M-n Gangnerau, M Dolz, C Tourrel-cuzin, J MovassatAbstract:Increasing evidence indicates that decreased functional beta-cell mass is the hallmark of type 2 diabetes (T2D) mellitus. Nowadays, the debate focuses on the possible mechanisms responsible for abnormal islet microenvironment, decreased beta-cell number, impaired beta-cell function, and their multifactorial aetiologies. This review is aimed to illustRate to what extend the Goto-Kakizaki Rat, one of the best characterized animal models of spontaneous T2D, has proved be a valuable tool offering sufficient commonalities to study these aspects. We propose that the defective beta-cell mass and function in the GK model reflect the complex interactions of multiple pathogenic players: (i) several independent loci containing genes responsible for some diabetic traits (but not decreased beta-cell mass); (ii) gestational metabolic impairment inducing an epigenetic programming of the pancreas (decreased beta-cell neogenesis and/or prolifeRation) which is transmitted to the next geneRation; and (iii) loss of beta-cell differentiation due to chronic exposure to hyperglycemia/hyperlipidemia, inflammatory mediators, oxidative stress and to perturbed islet microarchitecture.
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Defective functional β-cell mass and Type 2 diabetes in the Goto-Kakizaki Rat model.
Expert review of endocrinology & metabolism, 2007Co-Authors: B Portha, G Lacraz, F Homo-delarche, M-h Giroix, M Dolz, J MovassatAbstract:Increasing evidence indicates that decreased functional β-cell mass is the hallmark of Type 2 diabetes mellitus. Therefore, the debate focuses on the possible mechanisms responsible for abnormal islet microenvironment, decreased β-cell number, impaired β-cell function and their multifactorial etiologies. The information available on the Goto–Kakizaki/Par Rat line, one of the best characterized animal models of spontaneous Type 2 diabetes mellitus, are reviewed in such a perspective. We propose that the defective β-cell mass and function in the Goto–Kakizaki/Par model reflect the complex interactions of multiple pathogenic players, including several independent loci containing genes responsible for some diabetic traits (but not decreased β-cell mass), gestational metabolic impairment inducing an epigenetic programming of the pancreas (decreased β-cell neogenesis), which is transmitted to the next geneRation, and loss of β-cell differentiation due to chronic exposure to hyperglycemia, inflammatory mediators...
