Persistent Improvement of Type 2 Diabetes in the Goto-Kakizaki Rat Model by Expansion of the β-Cell Mass During the Prediabetic Period With Glucagon-Like Peptide-1 or Exendin-4

Tourrel, Cécile; Bailbé, Danielle; Lacorne, Matthieu; Meile, Marie-Jo; Kergoat, Micheline; Portha, Bernard

doi:10.2337/diabetes.51.5.1443

Cited by 273 publications

(193 citation statements)

References 37 publications

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“…The stronger glucose-lowering effect of roflumilast-N-oxide following chronic treatment is consistent with its greater GLP-1-increasing effect following acute treatment. This observation and extensive published literature regarding the glucoselowering role of GLP-1 [9,[21][22][23][24][25][26][27] support the view that roflumilast-mediated GLP-1 elevation and the prevention of diabetes progression in our db/db mice are linked. In particular, treatment of db/db mice with GLP-1 mimetics shows parallels to our study results with respect to reduced food and water consumption and preservation of pancreatic islets [28].…”

Section: Discussionsupporting

confidence: 56%

The glucose-lowering effects of the PDE4 inhibitors roflumilast and roflumilast-N-oxide in db/db mice

Vollert

Kaessner²,

Heuser

et al. 2012

Diabetologia

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Aims/hypothesis The cAMP-degrading phosphodiesterase 4 (PDE4) enzyme has recently been implicated in the regulation of glucagon-like peptide-1 (GLP-1), an incretin hormone with glucose-lowering properties. We investigated whether the PDE4 inhibitor roflumilast elevates GLP-1 levels in diabetic db/db mice and whether this elevation is accompanied by glucose-lowering effects. Methods Plasma GLP-1 was determined in db/db mice after single oral administration of roflumilast or its active metabolite roflumilast-N-oxide. Diabetes-relevant variables including HbA 1c , blood glucose, serum insulin, body weight, food and water intake, and pancreas morphology were determined in db/db mice treated daily for 28 days with roflumilast or roflumilast-N-oxide. Pharmacokinetic/pharmacodynamic analysis clarified the contribution of roflumilast vs its metabolite. In addition, the effect of roflumilast-N-oxide on insulin release was investigated in primary mouse islets.Results Single treatment of db/db mice with 10 mg/kg roflumilast or roflumilast-N-oxide enhanced plasma GLP-1 2.5-and fourfold, respectively. Chronic treatment of db/db mice with roflumilast or roflumilast-N-oxide at 3 mg/kg showed prevention of disease progression. Roflumilast-N-oxide abolished the increase in blood glucose, reduced the increment in HbA 1c by 50% and doubled fasted serum insulin compared with vehicle, concomitant with preservation of pancreatic islet morphology. Furthermore, roflumilast-N-oxide amplified forskolininduced insulin release in primary islets. Roflumilast-N-oxide showed stronger glucose-lowering effects than its parent compound, consistent with its greater effect on GLP-1 secretion and explainable by pharmacokinetic/pharmacodynamic modelling. Conclusions/interpretation Our results suggest that roflumilast and roflumilast-N-oxide delay the progression of diabetes in db/db mice through protection of pancreatic islet physiology potentially involving GLP-1 and insulin activities.

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Section: Discussionsupporting

confidence: 56%

The glucose-lowering effects of the PDE4 inhibitors roflumilast and roflumilast-N-oxide in db/db mice

Vollert

Kaessner²,

Heuser

et al. 2012

Diabetologia

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“…This conclusion is consistent with our and others' previous reports that GLP-1 therapy increases b-cell mass. 6,19,47 In addition, the severity of and the acute onset of diabetes in db/db mice could contribute to the delay in reversal of hyperglycemia. Progressive degranulation and necrosis of islets has been observed in db/db mice in addition to reduced islet insulin content.…”

Section: Discussionmentioning

confidence: 99%

“…13 Also, GLP-1 improves peripheral insulin resistance [14][15][16] and in turn renders pancreatic b-cells glucose competent. 17 Importantly, GLP-1 enhances b-cell mass via inhibition of b-cell apoptosis and stimulation of b-cell proliferation in rodents 6,13,18,19 and in humans. 20 As a result of these important biological features, GLP-1 has been evaluated for use in the treatment of T2D.…”

Section: Introductionmentioning

confidence: 99%

Gene therapy of diabetes using a novel GLP-1/IgG1-Fc fusion construct normalizes glucose levels in db/db mice

et al. 2006

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Glucagon-like peptide (GLP-1), a major physiological incretin, plays numerous important roles in modulating blood glucose homeostasis and has been proposed for the treatment of type 2 diabetes. The major obstacles for using native GLP-1 as a therapeutic agent are that it must be delivered by a parenteral route and has a short half-life. In an attempt to develop a strategy to prolong the physiological t 1/2 and enhance the potency of GLP-1, a fusion protein consisting of active human GLP-1 and mouse IgG 1 heavy chain constant regions (GLP-1/Fc) was generated. A plasmid encoding an IgK leader peptide-driven secretable fusion protein of the active GLP-1 and IgG 1 -Fc was constructed for mammalian expression. This plasmid allows for expression of bivalent GLP-1 peptide ligands as a result of IgG-Fc homodimerization. In vitro studies employing purified GLP-1/ Fc indicate that the fusion protein is functional and elevates cAMP levels in insulin-secreting INS-1 cells. In addition, it stimulates insulin secretion in a glucose concentrationdependent manner. Intramuscular gene transfer of the plasmid in db/db mice demonstrated that expression of the GLP-1/Fc peptide normalizes glucose tolerance by enhancing insulin secretion and suppressing glucagon release. This strategy of using a bivalent GLP-1/Fc fusion protein as a therapeutic agent is a novel approach for the treatment of diabetes.

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“…We are, however, left with no clear picture about the nature and role of diabetes-predisposing genes, especially those involved in defective BCM, which is certainly the primary functional defect involved in the pathogenesis of diabetes in the GK rat. Previous investigations in the GK model using therapeutic agents such as glucagon-like peptide 1 receptor agonists [33] during early developmental stages of a given generation showed efficient amelioration of the adult phenotype (improved BCM and milder diabetes). Whether correction of pancreatic deficiencies in a given 'n' generation is likely to overcome the heritable BCM dysregulation in the 'n+1' generation remains an open question.…”

Section: Discussionmentioning

confidence: 99%

A euglycaemic/non-diabetic perinatal environment does not alleviate early beta cell maldevelopment and type 2 diabetes risk in the GK/Par rat model

Chavey¹,

Bailbé²,

Maulny³

et al. 2012

Diabetologia

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Aims/hypothesis We used the GK/Par rat, a spontaneous model of type 2 diabetes with early defective beta cell neogenesis, to determine whether the development of GK/Par offspring in a non-diabetic intrauterine/postnatal environment would prevent the alteration of fetal beta cell mass (BCM) and ultimately decrease the risk of diabetes later in adult life. Methods We used an embryo-transfer approach, with fertilised GK/Par ovocytes (oGK) being transferred into pregnant Wistar (W) or GK/Par females (pW and pGK). Offspring were phenotyped at fetal age E18.5 and at 10 weeks of age, for BCM, expression of genes of pancreatic progenitor cell regulators (Igf2, Igf1r, Sox9, Pdx1 and Ngn3), glucose tolerance and insulin secretion. Results (1) Alterations in neogenesis markers/regulators and BCM were as severe in the oGK/pW E18.5 fetuses as in the oGK/pGK group. (2) Adult offspring from oGK transfers into GK (oGK/pGK/sGK) had the expected diabetic phenotype compared with unmanipulated GK rats. (3) Adult offspring from oGK reared in pW mothers and milked by GK foster mothers had reduced BCM, basal hyperglycaemia, glucose intolerance and low insulin, to an extent similar to that of oGK/pGK/sGK offspring. (4) In adult offspring from oGK transferred into pW mothers and milked by their W mothers (oGK/pW/sW), the phenotype was similar to that in oGK/pGK/sGK or oGK/pW/sGK offspring. Conclusions/interpretation These data support the conclusion that early BCM alteration and subsequent diabetes risk in the GK/Par model are not removed despite normalisation of the prenatal and postnatal environments, either isolated or combined.

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Persistent Improvement of Type 2 Diabetes in the Goto-Kakizaki Rat Model by Expansion of the β-Cell Mass During the Prediabetic Period With Glucagon-Like Peptide-1 or Exendin-4

Cited by 273 publications

References 37 publications

The glucose-lowering effects of the PDE4 inhibitors roflumilast and roflumilast-N-oxide in db/db mice

The glucose-lowering effects of the PDE4 inhibitors roflumilast and roflumilast-N-oxide in db/db mice

Gene therapy of diabetes using a novel GLP-1/IgG1-Fc fusion construct normalizes glucose levels in db/db mice

A euglycaemic/non-diabetic perinatal environment does not alleviate early beta cell maldevelopment and type 2 diabetes risk in the GK/Par rat model

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