Xenin-25[Lys(13)PAL]: a novel long-acting acylated analogue of xenin-25 with promising antidiabetic potential

Victor Gault, CM Martin, Peter Flatt, Parthsarathy V, Nigel Irwin

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

AIMS: Xenin-25 is co-secreted with glucose-dependent insulinotropic polypeptide (GIP) from intestinal K-cells following a meal. Xenin-25 is believed to play a key role in glucose homoeostasis and potentiate the insulinotropic effect of GIP.METHODS: This study investigated the effects of sub-chronic administration of the stable and longer-acting xenin-25 analogue, xenin-25[Lys(13)PAL] (25 nmol/kg), in diabetic mice fed with a high-fat diet.RESULTS: Initial studies confirmed the significant persistent glucose-lowering (p <0.05) and insulin-releasing (p <0.05) actions of xenin-25[Lys(13)PAL] compared with native xenin-25. Interestingly, xenin-25 retained significant glucose-lowering activity in GIP receptor knockout mice. Twice-daily intraperitoneal (i.p.) injection of xenin-25[Lys(13)PAL] for 14 days had no significant effect on food intake or body weight in high-fat-fed mice. Non-fasting glucose and insulin levels were also unchanged, but overall glucose levels during an i.p. glucose tolerance and oral nutrient challenge were significantly (p <0.05) lowered by xenin-25[Lys(13)PAL] treatment. These changes were accompanied by significant improvements in i.p. (p <0.05) and oral (p <0.001) nutrient-stimulated insulin concentrations. No appreciable changes in insulin sensitivity were observed between xenin-25[Lys(13)PAL] and saline-treated high-fat mice. However, xenin-25[Lys(13)PAL] treatment restored notable sensitivity to the biological actions of exogenous GIP injection. Consumption of O2, production of CO2, respiratory exchange ratio and energy expenditure were not altered by 14-day twice-daily treatment with xenin-25[Lys(13)PAL]. In contrast, ambulatory activity was significantly (p <0.05 to p <0.001) increased during the dark phase in xenin-25[Lys(13)PAL] mice compared with high-fat controls.
LanguageEnglish
Pages461-471
JournalActa Diabetologica
Volume52
Issue number3
DOIs
Publication statusPublished - 1 Jun 2015

Fingerprint

Hypoglycemic Agents
Glucose
Fats
Insulin
xenin 25
Peptides
Food
High Fat Diet
Glucose Tolerance Test
Intraperitoneal Injections
Knockout Mice
Energy Metabolism
Meals
Insulin Resistance
Homeostasis
Therapeutics
Eating
Body Weight

Keywords

  • Xenin
  • GIP
  • Diabetes
  • Obesity
  • Glucose tolerance

Cite this

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title = "Xenin-25[Lys(13)PAL]: a novel long-acting acylated analogue of xenin-25 with promising antidiabetic potential",
abstract = "AIMS: Xenin-25 is co-secreted with glucose-dependent insulinotropic polypeptide (GIP) from intestinal K-cells following a meal. Xenin-25 is believed to play a key role in glucose homoeostasis and potentiate the insulinotropic effect of GIP.METHODS: This study investigated the effects of sub-chronic administration of the stable and longer-acting xenin-25 analogue, xenin-25[Lys(13)PAL] (25 nmol/kg), in diabetic mice fed with a high-fat diet.RESULTS: Initial studies confirmed the significant persistent glucose-lowering (p <0.05) and insulin-releasing (p <0.05) actions of xenin-25[Lys(13)PAL] compared with native xenin-25. Interestingly, xenin-25 retained significant glucose-lowering activity in GIP receptor knockout mice. Twice-daily intraperitoneal (i.p.) injection of xenin-25[Lys(13)PAL] for 14 days had no significant effect on food intake or body weight in high-fat-fed mice. Non-fasting glucose and insulin levels were also unchanged, but overall glucose levels during an i.p. glucose tolerance and oral nutrient challenge were significantly (p <0.05) lowered by xenin-25[Lys(13)PAL] treatment. These changes were accompanied by significant improvements in i.p. (p <0.05) and oral (p <0.001) nutrient-stimulated insulin concentrations. No appreciable changes in insulin sensitivity were observed between xenin-25[Lys(13)PAL] and saline-treated high-fat mice. However, xenin-25[Lys(13)PAL] treatment restored notable sensitivity to the biological actions of exogenous GIP injection. Consumption of O2, production of CO2, respiratory exchange ratio and energy expenditure were not altered by 14-day twice-daily treatment with xenin-25[Lys(13)PAL]. In contrast, ambulatory activity was significantly (p <0.05 to p <0.001) increased during the dark phase in xenin-25[Lys(13)PAL] mice compared with high-fat controls.",
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Xenin-25[Lys(13)PAL]: a novel long-acting acylated analogue of xenin-25 with promising antidiabetic potential. / Gault, Victor; Martin, CM; Flatt, Peter; V, Parthsarathy; Irwin, Nigel.

In: Acta Diabetologica, Vol. 52, No. 3, 01.06.2015, p. 461-471.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Xenin-25[Lys(13)PAL]: a novel long-acting acylated analogue of xenin-25 with promising antidiabetic potential

AU - Gault, Victor

AU - Martin, CM

AU - Flatt, Peter

AU - V, Parthsarathy

AU - Irwin, Nigel

PY - 2015/6/1

Y1 - 2015/6/1

N2 - AIMS: Xenin-25 is co-secreted with glucose-dependent insulinotropic polypeptide (GIP) from intestinal K-cells following a meal. Xenin-25 is believed to play a key role in glucose homoeostasis and potentiate the insulinotropic effect of GIP.METHODS: This study investigated the effects of sub-chronic administration of the stable and longer-acting xenin-25 analogue, xenin-25[Lys(13)PAL] (25 nmol/kg), in diabetic mice fed with a high-fat diet.RESULTS: Initial studies confirmed the significant persistent glucose-lowering (p <0.05) and insulin-releasing (p <0.05) actions of xenin-25[Lys(13)PAL] compared with native xenin-25. Interestingly, xenin-25 retained significant glucose-lowering activity in GIP receptor knockout mice. Twice-daily intraperitoneal (i.p.) injection of xenin-25[Lys(13)PAL] for 14 days had no significant effect on food intake or body weight in high-fat-fed mice. Non-fasting glucose and insulin levels were also unchanged, but overall glucose levels during an i.p. glucose tolerance and oral nutrient challenge were significantly (p <0.05) lowered by xenin-25[Lys(13)PAL] treatment. These changes were accompanied by significant improvements in i.p. (p <0.05) and oral (p <0.001) nutrient-stimulated insulin concentrations. No appreciable changes in insulin sensitivity were observed between xenin-25[Lys(13)PAL] and saline-treated high-fat mice. However, xenin-25[Lys(13)PAL] treatment restored notable sensitivity to the biological actions of exogenous GIP injection. Consumption of O2, production of CO2, respiratory exchange ratio and energy expenditure were not altered by 14-day twice-daily treatment with xenin-25[Lys(13)PAL]. In contrast, ambulatory activity was significantly (p <0.05 to p <0.001) increased during the dark phase in xenin-25[Lys(13)PAL] mice compared with high-fat controls.

AB - AIMS: Xenin-25 is co-secreted with glucose-dependent insulinotropic polypeptide (GIP) from intestinal K-cells following a meal. Xenin-25 is believed to play a key role in glucose homoeostasis and potentiate the insulinotropic effect of GIP.METHODS: This study investigated the effects of sub-chronic administration of the stable and longer-acting xenin-25 analogue, xenin-25[Lys(13)PAL] (25 nmol/kg), in diabetic mice fed with a high-fat diet.RESULTS: Initial studies confirmed the significant persistent glucose-lowering (p <0.05) and insulin-releasing (p <0.05) actions of xenin-25[Lys(13)PAL] compared with native xenin-25. Interestingly, xenin-25 retained significant glucose-lowering activity in GIP receptor knockout mice. Twice-daily intraperitoneal (i.p.) injection of xenin-25[Lys(13)PAL] for 14 days had no significant effect on food intake or body weight in high-fat-fed mice. Non-fasting glucose and insulin levels were also unchanged, but overall glucose levels during an i.p. glucose tolerance and oral nutrient challenge were significantly (p <0.05) lowered by xenin-25[Lys(13)PAL] treatment. These changes were accompanied by significant improvements in i.p. (p <0.05) and oral (p <0.001) nutrient-stimulated insulin concentrations. No appreciable changes in insulin sensitivity were observed between xenin-25[Lys(13)PAL] and saline-treated high-fat mice. However, xenin-25[Lys(13)PAL] treatment restored notable sensitivity to the biological actions of exogenous GIP injection. Consumption of O2, production of CO2, respiratory exchange ratio and energy expenditure were not altered by 14-day twice-daily treatment with xenin-25[Lys(13)PAL]. In contrast, ambulatory activity was significantly (p <0.05 to p <0.001) increased during the dark phase in xenin-25[Lys(13)PAL] mice compared with high-fat controls.

KW - Xenin

KW - GIP

KW - Diabetes

KW - Obesity

KW - Glucose tolerance

U2 - 10.1007/s00592-014-0681-0

DO - 10.1007/s00592-014-0681-0

M3 - Article

VL - 52

SP - 461

EP - 471

JO - Acta Diabetologica

T2 - Acta Diabetologica

JF - Acta Diabetologica

SN - 0940-5429

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ER -