Improved glucose tolerance and insulin secretion by inhibition of dipeptidyl peptidase IV in mice

Åhrén, Bo; Holst, Jens J.; Mårtensson, Hans; Balkan, Börk

doi:10.1016/s0014-2999(00)00600-2

Cited by 190 publications

(105 citation statements)

References 29 publications

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“…Beneficial effects of DP4 deficiency in glucose metabolism (31,32) may also be reflected in lipid metabolism (1,13). Actually, our findings provide evidence that DP4 deficiency facilitates leptin signaling (33,34).…”

Section: Dp4 Deficiency Reduces Body Weight Protects From High-fat Dsupporting

confidence: 50%

Phenotyping of congenic dipeptidyl peptidase 4 (DP4) deficient Dark Agouti (DA) rats suggests involvement of DP4 in neuro-, endocrine, and immune functions

Frerker

Raber²,

Bode³

et al. 2009

Clinical Chemistry and Laboratory Medicine

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Section: Dp4 Deficiency Reduces Body Weight Protects From High-fat Dsupporting

confidence: 50%

Phenotyping of congenic dipeptidyl peptidase 4 (DP4) deficient Dark Agouti (DA) rats suggests involvement of DP4 in neuro-, endocrine, and immune functions

Frerker

Raber²,

Bode³

et al. 2009

Clinical Chemistry and Laboratory Medicine

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“…DPP-4 inhibition has thereby been demonstrated to be anti-diabetic both in animal models of diabetes (4)(5)(6)(7) and in patients with type 2 diabetes (8)(9)(10). The antidiabetic action of DPP-4 inhibition is explained by increased insulin secretion in association with inhibited glucagon secretion with a possible long-term action to increase β-cell mass (1)(2)(3).…”

Section: Introductionmentioning

confidence: 99%

DPP-4 inhibition improves glucose tolerance and increases insulin and GLP-1 responses to gastric glucose in association with normalized islet topography in mice with β-cell-specific overexpression of human islet amyloid polypeptide

Åhrén

Winzell

Wierup

et al. 2007

Regulatory Peptides

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Inhibition of dipeptidyl peptidase-4 (DPP-4) is currently explored as a novel therapy of type 2 diabetes. The strategy has been shown to improve glycemia in most, but not all, rodent forms of glucose intolerance. In this study, we explored the effects of DPP-4 inhibition in mice with β-cell overexpression of human islet amyloid polypeptide (IAPP). We therefore administered the orally active and highly selective DPP-4 inhibitor, vildagliptin (3µmol/mouse daily) to female mice with β-cell overexpression of human IAPP. Controls were given plain water, and a series of untreated wildtype mice was also included. After five weeks, an intravenous glucose tolerance test showed improved glucose disposal and a markedly enhanced insulin response in mice treated with vildagliptin. After eight weeks, a gastric tolerance test showed that vildagliptin improved glucose tolerance and markedly (approximately ten-fold) augmented the insulin response in association with augmented (approximately five-fold) levels of intact glucagon-like peptide-1 (GLP-1). Furthermore, after nine weeks, islets were isolated.Islets from vildagliptin-treated mice showed augmented glucose-stimulated insulin response and a normalization of the islet insulin content, which was reduced by approximately 50% in transgenic controls versus wildtype animals. Double immunostaining of pancreatic islets for insulin and glucagon revealed that transgenic islets displayed severely disturbed intra-islet topography with frequently observed centrally located α-cells. Treatment with vildagliptin restored the islet topography. We therefore conclude that DPP-4 inhibition improves islet function and islet topography in mice with specific ß cell transgenic overexpression of human IAPP.

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“…Thus, DPP IV inhibition proved to be remarkably efficient at preventing in vivo degradation of exogenously infused GLP-1, and this effect was associated with augmented insulin secretion in response to intravenous glucose in anaesthetised pigs . Subsequently, DPP IV inhibition has been shown to improve glucose tolerance in rodent models of insulin resistance (Pederson et al 1998, Balkan et al 1999, Ahrén et al 2000. This effect was attributed to the higher concentrations of intact biologically active GLP-1 arising as a consequence of inhibition of DPP IV activity, since specific analyses showed that the inhibitor abolished degradation of endogenous GLP-1 (Balkan et al 1999).…”

Section: Introductionmentioning

confidence: 99%

Preservation of active incretin hormones by inhibition of dipeptidyl peptidase IV suppresses meal-induced incretin secretion in dogs

Cf¹,

Wamberg²,

Bie³

et al. 2002

Journal of Endocrinology

141

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The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are degraded by dipeptidyl peptidase IV (DPP IV), thereby losing insulinotropic activity. DPP IV inhibition reduces exogenous GLP-1 degradation, but the extent of endogenous incretin protection has not been fully assessed, largely because suitable assays which distinguish between intact and degraded peptides have been unavailable. Using newly developed assays for intact GLP-1 and GIP, the effect of DPP IV inhibition on incretin hormone metabolism was examined.Conscious dogs were given NVP-DPP728, a specific DPP IV inhibitor, at a dose that inhibited over 90% of plasma DPP IV for the first 90 min following treatment. Total and intact incretin concentrations increased (P<0·0001) following a mixed meal, but on control days (vehicle infusion), intact peptide concentrations were lower (P<0·01) than total peptide concentrations (22·6 1·2% intact GIP; 10·1 0·4% intact GLP-1).Following inhibitor treatment, the proportion of intact peptide increased (92·5 4·3% intact GIP, P<0·0001; 99·0 22·6% intact GLP-1, P<0·02). Active (intact) incretins increased after NVP-DPP728 (from 4797 364 to 10 649 106 pM min for GIP, P<0·03; from 646 134 to 2822 528 pM min for GLP-1, P<0·05). In contrast, total incretins fell (from 21 632 654 to 12 084 1723 pM min for GIP, P<0·002; from 5145 677 to 3060 601 pM min for GLP-1, P<0·05). Plasma glucose, insulin and glucagon concentrations were unaltered by the inhibitor.We have concluded that DPP IV inhibition with NVP-DPP728 prevents N-terminal degradation of endogenous incretins in vivo, resulting in increased plasma concentrations of intact, biologically active GIP and GLP-1. Total incretin secretion was reduced by DPP IV inhibition, suggesting the possibility of a feedback mechanism.

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Improved glucose tolerance and insulin secretion by inhibition of dipeptidyl peptidase IV in mice

Cited by 190 publications

References 29 publications

Phenotyping of congenic dipeptidyl peptidase 4 (DP4) deficient Dark Agouti (DA) rats suggests involvement of DP4 in neuro-, endocrine, and immune functions

Phenotyping of congenic dipeptidyl peptidase 4 (DP4) deficient Dark Agouti (DA) rats suggests involvement of DP4 in neuro-, endocrine, and immune functions

DPP-4 inhibition improves glucose tolerance and increases insulin and GLP-1 responses to gastric glucose in association with normalized islet topography in mice with β-cell-specific overexpression of human islet amyloid polypeptide

Preservation of active incretin hormones by inhibition of dipeptidyl peptidase IV suppresses meal-induced incretin secretion in dogs

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