Chronic administration of the glucagon-like peptide-1 analog, liraglutide, delays the onset of diabetes and lowers triglycerides in UCD-T2DM rats

Bethany P Cummings, Kimber L Stanhope, James L Graham, Denis G Baskin, Steven C Griffen, Cecilia Nilsson, Anette Sams, Lotte B Knudsen, Kirsten Raun, Peter J Havel, Bethany P Cummings, Kimber L Stanhope, James L Graham, Denis G Baskin, Steven C Griffen, Cecilia Nilsson, Anette Sams, Lotte B Knudsen, Kirsten Raun, Peter J Havel

Abstract

Objective: The efficacy of liraglutide, a human glucagon-like peptide-1 (GLP-1) analog, to prevent or delay diabetes in UCD-T2DM rats, a model of polygenic obese type 2 diabetes, was investigated.

Research design and methods: At 2 months of age, male rats were divided into three groups: control, food-restricted, and liraglutide. Animals received liraglutide (0.2 mg/kg s.c.) or vehicle injections twice daily. Restricted rats were food restricted to equalize body weights to liraglutide-treated rats. Half of the animals were followed until diabetes onset, whereas the other half of the animals were killed at 6.5 months of age for tissue collection.

Results: Before diabetes onset energy intake, body weight, adiposity, and liver triglyceride content were higher in control animals compared with restricted and liraglutide-treated rats. Energy-restricted animals had lower food intake than liraglutide-treated animals to maintain the same body weights, suggesting that liraglutide increases energy expenditure. Liraglutide treatment delayed diabetes onset by 4.1 ± 0.8 months compared with control (P < 0.0001) and by 1.3 ± 0.8 months compared with restricted animals (P < 0.05). Up to 6 months of age, energy restriction and liraglutide treatment lowered fasting plasma glucose and A1C concentrations compared with control animals. In contrast, liraglutide-treated animals exhibited lower fasting plasma insulin, glucagon, and triglycerides compared with both control and restricted animals. Furthermore, energy-restricted and liraglutide-treated animals exhibited more normal islet morphology.

Conclusions: Liraglutide treatment delays the development of diabetes in UCD-T2DM rats by reducing energy intake and body weight, and by improving insulin sensitivity, improving lipid profiles, and maintaining islet morphology.

Figures

FIG. 1.
FIG. 1.
Kaplan-Meier analysis of diabetes incidence in control, restricted, and liraglutide-treated animals up to 6 months (n = 32 per group) (A) and 12 months (n = 16 per group) (B) of age. ***P < 0.0001, **P < 0.01 compared with control; *P < 0.05 compared with the food-restricted group by log-rank test. Nonfasting blood glucose in control, restricted, and liraglutide-treated animals (C). ***P < 0.0001 by two-factor (time and treatment) repeated-measures ANOVA, ***P < 0.001 compared with restricted and liraglutide-treated animals by Bonferroni post-test. Control: n = 27; restricted: n = 31; liraglutide-treated animals: n = 32.
FIG. 2.
FIG. 2.
Energy intake (A) and body weight (B) in control, restricted, and liraglutide-treated animals. ***P < 0.0001 by two-factor (time and treatment) repeated-measures ANOVA; ***P < 0.001 compared with restricted and liraglutide-treated animals; *P < 0.05 liraglutide-treated animals versus restricted by Bonferroni post-test. Control: n = 27; restricted: n = 31; liraglutide-treated animals: n = 32.
FIG. 3.
FIG. 3.
Fasting circulating glucose (A), A1C (B), and insulin (C) in control, restricted, and liraglutide-treated animals. ***P < 0.0001 by two-factor (time and treatment) repeated-measures ANOVA; ***P < 0.001, *P < 0.05 compared with restricted and liraglutide-treated animals; **P < 0.001 compared with restricted and control; ++P < 0.001 compared with restricted; +P < 0.05 compared with control by Bonferroni post-test. Control: n = 27; restricted: n = 31; liraglutide-treated animals: n = 32.
FIG. 4.
FIG. 4.
Fasting plasma TG (A), cholesterol (B), glucagon (C), and adiponectin (D) in control, food-restricted, and liraglutide-treated animals. ***P < 0.0001, *P < 0.05 by two-factor (time and treatment) repeated-measures ANOVA; ***P < 0.001 compared with food-restricted and control; **P < 0.001 compared with food-restricted; *P < 0.05 compared with control; +P < 0.05 compared with food-restricted; ++P < 0.05 compared with food-restricted and liraglutide-treated animals by Bonferroni post-test. Control: n = 27; restricted: n = 31; liraglutide-treated animals: n = 32.
FIG. 5.
FIG. 5.
Representative pancreas sections from control, food-restricted, and liraglutide-treated animals at 6 months of age. Hematoxylin and eosin staining for control (A), restricted (D), and liraglutide-treated animals (G) is shown. Anti-insulin immunostaining for control (B), restricted (E), and liraglutide-treated animals (H) is shown. Anti-glucagon immunostaining for control (C), restricted (F), and liraglutide-treated animals (I) is shown. (A high-quality digital representation of this figure is available in the online issue.)

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