GLUT2 expression and function in beta-cells of GK rats with NIDDM. Dissociation between reductions in glucose transport and glucose-stimulated insulin secretion

Ohneda, M.; Johnson, J. H.; Inman, L. R.; Chen, L.; Suzuki, K.; Goto, Y.; Alam, T.; Ravazzola, M.; Orci, L.; Unger, R. H.

doi:10.2337/diabetes.42.7.1065

Cited by 27 publications

(14 citation statements)

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“…However, in previous investigations involving 8-week-old Wistar, GK and hybrid rats from the Stockholm colony, a majority of the islets appeared histologically normal and only a few starfishshaped islets were found (Abdel-Halim et al 1994, Guenifi et al 1995. In other studies, no differences in islet -cell density or insulin content were seen between GK rats and Wistar rats at 12 weeks of age (Ohneda et al 1993, Höög et al 1996, Metz et al 1999. The animals studied in the present experiments were 14 weeks old, and were thus not expected to show significant aberrations in islet architecture or -cell mass.…”

Section: Discussionmentioning

confidence: 82%

Lack of compensatory increase in islet blood flow and islet mass in GK rats following 60% partial pancreatectomy

Svensson

Östenson²,

Bodin³

et al. 2005

Journal of Endocrinology

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The effects of a 60% partial pancreatectomy were studied in hyperglycemic GK (Goto-Kakizaki) rats. Partial pancreatectomy or a sham operation was performed on 12-weekold female Wistar rats, GK rats or hybrids between male GK rats and female Wistar rats. Measurements of pancreatic blood flow and islet blood flow were performed by a microsphere technique 2 weeks after surgery. Glucose tolerance was decreased in hybrid compared with Wistar rats, and in GK rats compared with both hybrid and Wistar rats before surgery. Partial pancreatectomy induced minor changes in glucose tolerance. Wistar rats had a decreased islet mass following partial pancreatectomy. Both hybrid and GK rats showed a significant decrease in relative islet volume, but only GK rats in total islet mass, compared with Wistar rats 2 weeks after surgery. Pancreatic blood flow and islet blood flow did not significantly differ between sham-operated Wistar, hybrid or GK rats. After partial pancreatectomy, islet blood flow in relation to islet mass increased 3-fold in Wistar rats and 2-fold in hybrid rats. In contrast, GK rats showed no increase in islet blood flow following partial pancreatectomy. It is concluded that compensatory mechanisms after partial pancreatectomy are operating less efficiently in hybrid and GK rats.

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Section: Discussionmentioning

confidence: 82%

Lack of compensatory increase in islet blood flow and islet mass in GK rats following 60% partial pancreatectomy

Svensson

Östenson²,

Bodin³

et al. 2005

Journal of Endocrinology

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“…27,41 Decreased expression of GLUT2 has been reported in several animal models of diabetes. 48,49 In addition, mice with GLUT2-deficient b-cells also have impaired insulin secretion, leading to diabetes development. 50 Therefore, defective glucose-sensing likely has a significant role in the impairment of b-cell function that is present in the VHL mutant mice.…”

Section: Discussionmentioning

confidence: 99%

Vhl is required for normal pancreatic β cell function and the maintenance of β cell mass with age in mice

Choi

Cai

Schroer

et al. 2011

Laboratory Investigation

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Type 2 diabetes is hallmarked by insulin resistance and insufficient b-cell function. Islets of type 2 diabetes patients have been shown to have decreased hypoxia-inducible factor (HIF)-1a/b expression. Target genes of the HIF pathway are involved in angiogenesis, survival, proliferation, and energy metabolism, and von Hippel-Lindau protein (VHL) is a negative regulator of this pathway. We hypothesized that increased HIF-mediated gene transcription by VHL deletion in the b-cells would increase b-cell mass and function. We generated b-cell-specific VHL-knockout mice using the Cre-loxP recombination system driven by the rat insulin promoter to assess the role of VHL in glucose homeostasis and b-cell function. VHL deletion in the pancreatic b-cells led to impaired glucose tolerance due to defects in glucose-stimulated insulin secretion and b-cell mass with age. VHL-knockout islets had decreased GLUT2, but increased glucose transporter 1 and vascular endothelial growth factor expression. Furthermore, there were significant aberrations in islet morphology in the VHL-knockout mice, likely due to increased islet vasculature. Given that erythropoietin (EPO) is a target gene of the HIF pathway, which is not expressed in islets, we tested whether activating EPO signaling by systemic administration with recombinant human EPO (rHuEPO) can overcome the b-cell defects that occurred with VHL loss. We observed improved glucose tolerance and restoration of GLUT2 expression in VHL-deficient b-cells in response to rHuEPO. Contrary to our hypothesis, loss of VHL and increased transcription of HIF-target genes resulted in impaired b-cell function and mass, which can be overcome with exogenous EPO. Our results indicate a critical role for VHL in b-cell function and mass, and that EPO administration improved b-cell function making it a potential strategy for diabetes treatment. KEYWORDS: angiogenesis; b-cell; diabetes mellitus; GLUT2; hypoxia-inducible factor; insulin secretion; von Hippel-Lindau Type 2 diabetes is a disease that is now considered epidemic, as it affects over 200 million people globally, and its prevalence continues to rise despite advances in treatment. 1,2 The two hallmark characteristics of type 2 diabetes are insulin resistance and b-cell dysfunction. 3,4 Under insulin-resistant conditions, b-cells undergo a compensation process by expanding b-cell mass and enhancing b-cell function. When b-cell compensation can adequately meet the insulin demands of the body, normoglycemia is maintained. 5-7 However, in susceptible individuals perhaps with genetic defects and/or environmental insults, the b-cells cannot meet the metabolic demands, ultimately resulting in type 2 diabetes. [8][9][10][11] A previous study by Gunton et al 12 reported results of gene expression profiling analyses on islets of humans with type 2 diabetes, and found a significant decrease in aryl-hydrocarbon-receptor nuclear translocator (ARNT)/hypoxiainducible factor-1b (HIF-1b) expression in these islets. 12 Concomitant with the decrease in ARNT expre...

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“…Several critical defects in the activity of enzymes that control oxidative glycolysis have been identified in Goto-Kakizaki rats, namely, FAD-linked (flavin adenine dinucleotide-linked) mitochondrial glycerophosphate dehydrogenase (mGPD) activity and content (Fabregat et al, 1996;Malaisse, 1993), glucokinase activity (Matsuoka et al, 1995), and pyruvate dehydrogenase activity (Zhou et al, 1995). Changes in other β-cell functions have also been recorded, such as expression of CD38 (Matsuoka et al, 1995) and GLUT2 (Ohneda et al, 1993) were reduced in Goto-Kakizaki islets. However, reduced mGPD and pyruvate carboxylase were normalized when glucose is controlled by exogenous insulin, indicating that defects in these were secondary to diabetes rather than causative factors (MacDonald et al, 1996a).…”

Section: Goto Kakizaki Ratsmentioning

confidence: 99%

A Review of Islet of Langerhans Degeneration in Rodent Models of Type 2 Diabetes

2008

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Type 2 diabetes mellitus (TTDM) is characterized by progressive loss of glucose control through multifactorial mechanisms. The search for an understanding of TTDM has relied on animal models since the realization of the importance of the pancreas in controlling plasma glucose concentration. Rodent models of TTDM are developed to express hyperglycemia and not islet degeneration per se. Degeneration of the islets of Langerhans with β-cell loss is secondary to insulin resistance and is regarded as the more important lesion. Despite this, differences between models are seen in the development and progression of islet degeneration. Assessing the differences between the models is important to appreciate the various aspects of TTDM and understand their advantages as well as their deficiencies. Relevant animal models of TTDM provide opportunities to investigate important physiological and cell biological processes that may ultimately lead to development of targeted therapies. This article reviews the importance, advantages, and limitations of rodent models of TTDM in relation to the histopathological changes that characterize islet degeneration. Pathophysiological mechanisms that contribute to islet degeneration are also discussed and are placed into the context of changes in islet histological appearances.

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GLUT2 expression and function in beta-cells of GK rats with NIDDM. Dissociation between reductions in glucose transport and glucose-stimulated insulin secretion

Cited by 27 publications

References 0 publications

Lack of compensatory increase in islet blood flow and islet mass in GK rats following 60% partial pancreatectomy

Lack of compensatory increase in islet blood flow and islet mass in GK rats following 60% partial pancreatectomy

Vhl is required for normal pancreatic β cell function and the maintenance of β cell mass with age in mice

A Review of Islet of Langerhans Degeneration in Rodent Models of Type 2 Diabetes

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