Beta-cell insensitivity to glucose in the GK rat, a spontaneous nonobese model for type II diabetes

Portha, Bernard; Serradas, Patricia; Bailbé, Danielle; Suzuki, K.; Goto, Y.; Giroix, Marie‐Hélène

doi:10.2337/diabetes.40.4.486

Cited by 108 publications

(91 citation statements)

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“…Although the diabetic state is moderate and remains stable as these animals age, glucose intolerance develops early and significant hyperglycaemia appears at around 4 weeks of age [5]. Proteinuria and decreases in nerve conducting velocity are observed, as well as pathological changes in the glomerulus and nerve tissue that are similar to those in human diabetic nephropathy and neuropathy.…”

mentioning

confidence: 68%

“…This suggests that a continuous exposure to a high-glucose environment is required for VEGF up-regulation. As hyperglycaemia appeared as early as 4 weeks of age in the GK rat [5], it is speculated that a hyperglycaemic environment also stimulates upregulation of VEGF in vivo. Although our previous work [4] showed that only 10 days were necessary for cultured retinal pigment epithelial cells to significantly up-regulate VEGF production, the reason why more than 18 weeks was required for the difference in ocular VEGF levels between GK and Wistar rats to become significant cannot be deduced from the present study.…”

Section: Discussionmentioning

confidence: 99%

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Ocular vascular endothelial growth factor levels in diabetic rats are elevated before observable retinal proliferative changes

et al. 1997

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mentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Ocular vascular endothelial growth factor levels in diabetic rats are elevated before observable retinal proliferative changes

et al. 1997

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“…It could be argued therefore, that GK tissues are a suitable source for the investigation of fundamental mechanisms of diabetes, in the absence of complicating factors such as obesity. Severe pathophysiological symptoms including defects in insulin secretion and peripheral insulin resistance usually occur by 4 weeks of age (Abdel-Halim et al, 1994;Portha et al, 1991). GK skeletal muscles appear to exhibit a reduced percentage of oxidative fibres (Yasuda et al, 2002) and also show fibre type-specific defects, with IRS1 and PI3K activity decreased primarily in oxidative muscles (Song et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Expression of the skeletal muscle dystrophin–dystroglycan complex and syntrophin-nitric oxide synthase complex is severely affected in the type 2 diabetic Goto–Kakizaki rat

Mulvey

Harno

Keenan

et al. 2005

European Journal of Cell Biology

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The inability of insulin to stimulate glucose metabolism in skeletal muscle fibres is a classic characteristic of type 2 diabetes. Using the non-obese Goto-Kakizaki rat as an established animal model of this type of diabetes, sucrose gradient centrifugation studies were performed and confirmed the abnormal subcellular location of the glucose transporter GLUT4. In addition, this analysis revealed an unexpected drastic reduction in the surface membrane marker b-dystroglycan, a dystrophin-associated glycoprotein. Based on this finding, a comprehensive immunoblotting survey was conducted which showed a dramatic decrease in the Dp427 isoform of dystrophin and the a/b-dystroglycan subcomplex, but not in laminin, sarcoglycans, dystrobrevin, and excitation-contraction-relaxation cycle elements. Thus, the backbone of the trans-sarcolemmal linkage between the extracellular matrix and the actin membrane cytoskeleton might be structurally impaired in diabetic fibres. Immunohistochemical studies revealed that the reduction in the dystrophin-dystroglycan complex does not induce obvious signs of muscle pathology, and is neither universal in all fibres, nor fibre-type specific. Most importantly, the expression of a-syntrophin and the syntrophinassociated neuronal isoform of nitric oxide synthase, nNOS, was demonstrated to be severely reduced in diabetic fibres. The loss of the dystrophin-dystroglycan complex and the syntrophin-nNOS complex in selected fibres suggests a weakening of the sarcolemma, abnormal signalling and probably a decreased cytoprotective mechanism in diabetes. Impaired anchoring of the cortical actin cytoskeleton via dystrophin might interfere with the proper recruitment of the glucose transporter to the surface membrane, following stimulation by insulin or muscle contraction. This may, at least partially, be responsible for the insulin resistance in diabetic skeletal muscles.

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“…Studies of the perfused pancreas from beta-cell-reduced rodents have indicated a dysfunction of the remaining beta cell population in hyperglycaemic animals [16,17], but not in normoglycaemic animals [16,18]. However, it is at present unclear how the changes observed in vitro relate to the defects in insulin secretion seen in individual beta-cell-reduced animals in vivo, and what their role in the development of diabetes might be.…”

Section: Introductionmentioning

confidence: 99%

Reduction of beta cell mass: partial insulin secretory compensation from the residual beta cell population in the nicotinamide?streptozotocin G�ttingen minipig after oral glucose in vivo and in the perfused pancreas

et al. 2004

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Aims/hypothesis. A progressive loss of beta cell function and mass are important contributory factors in the development and progression of type 2 diabetes. The aim of this study was to evaluate the effects of a primary reduction in beta cell mass on beta cell function in vivo and in the perfused pancreas and to relate these characteristics to beta cell mass. Methods. The beta cell mass of six Göttingen minipigs was reduced chemically (using 67 mg/kg nicotinamide and 125 mg/kg streptozotocin). Six untreated minipigs were kept as control animals. Insulin responses were evaluated in vivo using the mixed meal tolerance test (2 g/kg oral glucose) and in the isolated perfused pancreata from the same animals by stimulation with glucose, glucagon-like peptide-1 or arginine. Results. Beta cell mass was reduced in the beta-cellreduced animals compared with the control minipigs (182±76 vs 464±156 mg, p<0.01). AUC glucose was increased in the beta-cell-reduced animals (1383±385 vs 853±113 mmol·l −1 ·min in control minipigs, p<0.01), as was the insulin response to oral glucose per unit of beta cell mass (123±84 vs 56±24 pmol·l -1 ·min·mg -1 , p<0.05). Total in vitro insulin secretion was increased per unit of beta cell mass in nicotinamide + streptozotocin pancreata compared to controls (83.7±45.9 vs 34.6±14.4 nmol/mg beta cells, p<0.05) with responses to glucose and glucagon-like peptide-1 showing a partial compensation for reduced beta cell mass, whereas no compensation was seen in response to arginine. Conclusions/interpretation. A primary reduction in beta cell mass impairs glucose tolerance and leads to a compensatory increase in insulin secretion from the remaining beta cells after oral glucose in vivo, which is even more apparent in the perfused pancreas. It remains to be determined whether this compensation can be maintained in the long term.

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Beta-cell insensitivity to glucose in the GK rat, a spontaneous nonobese model for type II diabetes

Cited by 108 publications

References 0 publications

Ocular vascular endothelial growth factor levels in diabetic rats are elevated before observable retinal proliferative changes

Ocular vascular endothelial growth factor levels in diabetic rats are elevated before observable retinal proliferative changes

Expression of the skeletal muscle dystrophin–dystroglycan complex and syntrophin-nitric oxide synthase complex is severely affected in the type 2 diabetic Goto–Kakizaki rat

Reduction of beta cell mass: partial insulin secretory compensation from the residual beta cell population in the nicotinamide?streptozotocin G�ttingen minipig after oral glucose in vivo and in the perfused pancreas

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