Improvement of high fat-diet-induced insulin resistance in dipeptidyl peptidase IV-deficient Fischer rats

Yasuda, Nobuyuki; Nagakura, Tadashi; Yamazaki, Kazuto; Inoue, Takashi; Tanaka, Isao

doi:10.1016/s0024-3205(02)01637-5

Cited by 53 publications

(32 citation statements)

References 24 publications

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“…Furthermore, we have performed comparative histological studies on Ͼ40 organs from DP-IV Ϫ͞Ϫ and WT mice and have not observed any remarkable differences (data not shown), suggesting that the deficiency in DP-IV is well tolerated in mice. Consistent with this finding, Fischer rats that are genetically deficient in DP-IV are also normal phenotypically and exhibit improved HFD-induced insulin resistance (35).…”

Section: Discussionsupporting

confidence: 64%

Mice lacking dipeptidyl peptidase IV are protected against obesity and insulin resistance

Conarello

Ronan

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

328

223

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Dipeptidyl peptidase IV (DP-IV), a member of the prolyl oligopeptidase family of peptidases, is involved in the metabolic inactivation of a glucose-dependent insulinotropic hormone, glucagon-like peptide 1 (GLP-1), and other incretin hormones. Here, we investigated the impact of DP-IV deficiency on body weight control and insulin sensitivity in mice. Whereas WT mice displayed accelerated weight gain and hyperinsulinemia when fed a high-fat diet (HFD), mice lacking the gene encoding DP-IV (DP-IV ؊͞؊ ) are refractory to the development of obesity and hyperinsulinemia. Pair-feeding and indirect calorimetry studies indicate that reduced food intake and increased energy expenditure accounted for the resistance to HFD-induced obesity in the DP-IV ؊͞؊ mice. Ablation of DP-IV also is associated with elevated GLP-1 levels and improved metabolic control in these animals, resulting in improved insulin sensitivity, reduced pancreatic islet hypertrophy, and protection against streptozotocin-induced loss of ␤ cell mass and hyperglycemia. Together, these observations suggest that chronic deletion of DP-IV gene has significant impact on body weight control and energy homeostasis, providing validation of DP-IV inhibition as a viable therapeutic option for the treatment of metabolic disorders related to diabetes and obesity.

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Section: Discussionsupporting

confidence: 64%

Mice lacking dipeptidyl peptidase IV are protected against obesity and insulin resistance

Conarello

Ronan

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

328

223

View full text Add to dashboard Cite

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“…The elevation of GLP-1 in GCGR ASO-treated animals is consistent with the observed pancreatic effects in these animals, including an increase in islet insulin content and the preservation of β cell function as demonstrated by an improvement in glucose tolerance with preserved insulin secretion. GLP-1 levels achieved by GCGR ASO therapy are similar to or exceed those shown to be efficacious in humans by exogenous dosing (31) and in rodents via ablation of dipeptidyl peptidase-IV (DPP-IV) activity (32). In addition, because of recent evidence describing intraislet signaling (33), α cell produced GLP-1 may have local β cell effects within islets.…”

Section: Figurementioning

confidence: 71%

Hepatic and glucagon-like peptide-1–mediated reversal of diabetes by glucagon receptor antisense oligonucleotide inhibitors

Sloop¹,

Cao²,

Siesky³

et al. 2004

J. Clin. Invest.

128

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Uncontrolled hepatic glucose production contributes significantly to hyperglycemia in patients with type 2 diabetes. Hyperglucagonemia is implicated in the etiology of this condition; however, effective therapies to block glucagon signaling and thereby regulate glucose metabolism do not exist. To determine the extent to which blocking glucagon action would reverse hyperglycemia, we targeted the glucagon receptor (GCGR) in rodent models of type 2 diabetes using 2′-methoxyethyl-modified phosphorothioate-antisense oligonucleotide (ASO) inhibitors. Treatment with GCGR ASOs decreased GCGR expression, normalized blood glucose, improved glucose tolerance, and preserved insulin secretion. Importantly, in addition to decreasing expression of cAMP-regulated genes in liver and preventing glucagon-mediated hepatic glucose production, GCGR inhibition increased serum concentrations of active glucagon-like peptide-1 (GLP-1) and insulin levels in pancreatic islets. Together, these studies identify a novel mechanism whereby GCGR inhibitors reverse the diabetes phenotype by the dual action of decreasing hepatic glucose production and improving pancreatic β cell function.

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“…F344 rats exhibit improved glucose tolerance and increased levels of plasma GLP-1 and insulin following oral glucose challenge. Furthermore, high-fat feeding of F344 rats for 7 weeks was associated with reduced weight gain, increased levels of intact GLP-1, improved glucose tolerance, and enhanced insulin sensitivity as assessed by homeostatic model assessment (36). Hence, loss of DPP-4 activity in rats is associated with potentiation of endogenous GLP-1 action and improvement of glucose tolerance.…”

Section: Role Of Endogenous Dpp-4mentioning

confidence: 97%

Dipeptidyl Peptidase-4 Inhibition and the Treatment of Type 2 Diabetes

2007

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Improvement of high fat-diet-induced insulin resistance in dipeptidyl peptidase IV-deficient Fischer rats

Cited by 53 publications

References 24 publications

Mice lacking dipeptidyl peptidase IV are protected against obesity and insulin resistance

Mice lacking dipeptidyl peptidase IV are protected against obesity and insulin resistance

Hepatic and glucagon-like peptide-1–mediated reversal of diabetes by glucagon receptor antisense oligonucleotide inhibitors

Dipeptidyl Peptidase-4 Inhibition and the Treatment of Type 2 Diabetes

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