The GK rat beta-cell: A prototype for the diseased human beta-cell in type 2 diabetes?

Portha, Bernard; Lacraz, Grégory; Kergoat, Micheline; Homo‐Delarche, Françoise; Giroix, M.H.; Bailbé, Danièle; Gangnerau, Marie-Noëlle; Dolz, Manuel; Tourrel-Cuzin, Cécile; Movassat, Jamileh

doi:10.1016/j.mce.2008.06.013

Cited by 116 publications

(119 citation statements)

References 141 publications

(209 reference statements)

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“…Commonalities in b-cell dysfunction regarding human type 2 diabetes and GK rats include reduction in b-cell mass, alterations in islets microenvironment, and multiple functional deficits (Seiça et al 2004, Portha et al 2009). As expected, GK rats in this study showed impaired metabolic control in comparison with Wistar rats, with significantly worse HbA1c levels and higher blood glucose levels, 2 h after an OGTT, both at the beginning and at the end of the observation period.…”

Section: Discussionmentioning

confidence: 99%

“…However, little is known about the effect of surgery on glucagon metabolism and its influence on outcome regarding remission of diabetes. Goto-Kakizaki (GK) rats have been studied extensively as a model for type 2 diabetes in non-obese humans, and display similar features in comparison with the human pancreatic phenotype in patients with type 2 diabetes (Seiça et al 2003, Portha et al 2009). Thus, we studied the effect of common bariatric procedures such as sleeve gastrectomy and gastric bypass on glucose metabolism, insulin sensitivity, and pancreatic hormone secretion in this rodent model.…”

Section: Introductionmentioning

confidence: 99%

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Glucagon secretion after metabolic surgery in diabetic rodents

Eickhoff¹,

Louro²,

Matafome³

et al. 2014

Journal of Endocrinology

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Excessive or inadequate glucagon secretion promoting hepatic gluconeogenesis and glycogenolysis is believed to contribute to hyperglycemia in patients with type 2 diabetes. Currently, metabolic surgery is an accepted treatment for obese patients with type 2 diabetes and has been shown to improve glycemic control in Goto-Kakizaki (GK) rats, a lean animal model for type 2 diabetes. However, the effects of surgery on glucagon secretion are not yet well established. In this study, we randomly assigned forty 12-to 14-week-old GK rats to four groups: control group (GKC), sham surgery (GKSS), sleeve gastrectomy (GKSG), and gastric bypass (GKGB). Ten age-matched Wistar rats served as a non-diabetic control group (WIC). Glycemic control was assessed before and 4 weeks after surgery. Fasting-and mixed-meal-induced plasma levels of insulin and glucagon were measured. Overall glycemic control improved in GKSG and GKGB rats. Fasting insulin levels in WIC rats were similar to those for GKC or GKSS rats. Fasting glucagon levels were highest in GKGB rats. Whereas WIC, GKC, and GKSS rats showed similar glucagon levels, without any significant meal-induced variation, a significant rise occurred in GKSG and GKGB rats, 30 min after a mixed meal, which was maintained at 60 min. Both GKSG and GKGB rats showed an elevated glucagon:insulin ratio at 60 min in comparison with all other groups. Surprisingly, the augmented post-procedural glucagon secretion was accompanied by an improved overall glucose metabolism in GKSG and GKGB rats. Understanding the role of glucagon in the pathophysiology of type 2 diabetes requires further research.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Glucagon secretion after metabolic surgery in diabetic rodents

Eickhoff¹,

Louro²,

Matafome³

et al. 2014

Journal of Endocrinology

View full text Add to dashboard Cite

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“…We did, however, find a notable reduction in ir NUCB2 in islet homogenates obtained from the GK rats, which normalized with fasting (present results). The inbred non-obese GK rats recapitulate several of the salient features of b-cell pathology in T2DM, including impaired insulin secretion and glucose intolerance (Ö stenson & Efendic 2007, Portha et al 2009). (Of note, in the Stockholm GK colony used in this study, no reduction in b-cell mass is detected at three months, which is the maximum age for animals included in the present study; Guenifi et al 1995).…”

Section: Discussionmentioning

confidence: 99%

“…We have also performed the first investigation of the relationship between pancreatic NUCB2 and metabolic state. Thus, we investigated the levels of NUCB2 in serum and pancreatic islets under different metabolic conditions, including food restriction, and in the Goto-Kakizaki (GK) rats, model of type 2 diabetes mellitus (T2DM; Goto et al 1975, Ö stenson & Efendic 2007, Portha et al 2009). …”

Section: Introductionmentioning

confidence: 99%

Nucleobindin-2/nesfatin in the endocrine pancreas: distribution and relationship to glycaemic state

Foo¹,

Brauner²,

Östenson³

et al. 2009

Journal of Endocrinology

129

114

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The protein nucleobindin-2 (NUCB2, also known as nesfatin) was recently implicated as a mediator of anorexia and catabolism in the central nervous system, and has been suggested to act as a cleaved and secreted messenger. Given the overlap of signalling molecules between the brain and pancreas, we have explored the presence of NUCB2 in the islets of Langerhans. We also performed an investigation of the dynamic regulation of pancreatic NUCB2 in different metabolic states. NUCB2-like immunoreactivity was detected by immunofluorescence in all human and rat islet b-cells (as detected by co-localization with insulin), but not in other islet cells or in the exocrine pancreas. Islet NUCB2 content, as measured by enzyme immunoassay, did not change significantly following an overnight fast, but was substantially lower in islets isolated from an animal model of type 2 diabetes, the Goto-Kakizaki (GK) rats (48% of non-diabetic Wistar rat control). Serum levels, however, were not different between Wistar and GK rats. The release of NUCB2 from isolated rat islets was significantly elevated following glucose challenge (123%), but this effect was substantially lower than that observed for insulin (816%). In contrast, serum levels of NUCB2 showed a reversible decrease in an i.p. glucose tolerance test. These data suggest a role for NUCB2 in b-cell function and a potential involvement in diabetic pathology. However, our findings, together with previous reports, appear more compatible with intracellular actions rather than with endocrine/paracrine communication, and suggest that NUCB2 in serum derives primarily from non-islet sources.

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“…We have found that ciliary/basal body defects lead to pre-diabetic phenotypes in vitro and in vivo, but to establish a link between primary cilia and diabetes, we tested for ciliary dysfunction in diabetic GotoKakizaki (GK) rats 50,51 . GK rats from the Stockholm colony manifest a marked glucose intolerance with hyperglycemia, mainly due to impaired glucose-stimulated insulin secretion.…”

Section: Disruption Of Basal Body Integrity Impairs Insulin Secretionmentioning

confidence: 99%

Ciliary dysfunction impairs beta-cell insulin secretion and promotes development of type 2 diabetes in rodents

Christou-Savina²,

et al. 2014

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Type 2 diabetes mellitus is affecting more than 382 million people worldwide. Although much progress has been made, a comprehensive understanding of the underlying disease mechanism is still lacking. Here we report a role for the b-cell primary cilium in type 2 diabetes susceptibility. We find impaired glucose handling in young Bbs4 À / À mice before the onset of obesity. Basal body/ciliary perturbation in murine pancreatic islets leads to impaired first phase insulin release ex and in vivo. Insulin receptor is recruited to the cilium of stimulated b-cells and ciliary/basal body integrity is required for activation of downstream targets of insulin signalling. We also observe a reduction in the number of ciliated b-cells along with misregulated ciliary/basal body gene expression in pancreatic islets in a diabetic rat model. We suggest that ciliary function is implicated in insulin secretion and insulin signalling in the b-cell and that ciliary dysfunction could contribute to type 2 diabetes susceptibility.

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The GK rat beta-cell: A prototype for the diseased human beta-cell in type 2 diabetes?

Cited by 116 publications

References 141 publications

Glucagon secretion after metabolic surgery in diabetic rodents

Glucagon secretion after metabolic surgery in diabetic rodents

Nucleobindin-2/nesfatin in the endocrine pancreas: distribution and relationship to glycaemic state

Ciliary dysfunction impairs beta-cell insulin secretion and promotes development of type 2 diabetes in rodents

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